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Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008

Lu L., Yan H., Shyam-Sundar V., Janowitz T.

(Lu L.; Yan H.; Shyam-Sundar V.) School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom. , (Janowitz T., tj212@cam.ac.uk) Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.

T. Janowitz, Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.

Drug Design, Development and Therapy (2014) 8 (1539-1553). Date of Publication: 27 Sep 2014

1177-8881 (electronic),1177-8881

Dove Medical Press Ltd., PO Box 300-008, Albany, Auckland, New Zealand.

Results: The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination.Conclusion: The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure may be due to inadequate assessment of survival-related endpoints in Phase II trials. The clinical trial development of tumor vaccines should include mechanism-based translational endpoints, as well as the discovery of immune biomarkers with which to stratify, monitor, and prognosticate patients.Methods: We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database.Introduction: Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints.

algenpantucel L (clinical trial, drug therapy), belagenpumatucel L (clinical trial, drug therapy), cancer vaccine (clinical trial, drug therapy), falimarev (clinical trial, drug therapy), granulocyte macrophage colony stimulating factor vaccine (clinical trial, drug combination, drug therapy), human papillomavirus 16 18 L1 viruslike AS04 vaccine (clinical trial, drug therapy), human papillomavirus 16 18 L1 viruslike particle vaccine (clinical trial, drug therapy), human papillomavirus V503 vaccine (clinical trial, drug therapy), ima 901 (clinical trial, drug therapy), mitumprotimut T (clinical trial, drug therapy), nelipepimut S (clinical trial, drug combination, drug therapy), racotumomab (clinical trial, drug therapy), seviprotimut L (clinical trial, drug therapy), tecemotide (clinical trial, drug therapy), tertomotide (clinical trial, drug therapy), unclassified drug, vaccinia vaccine (clinical trial, drug therapy), Wart virus vaccine (clinical trial, drug therapy)

cancer immunization, cancer registry, factual database, US Clinical Trial Database

article, cancer prevention, cancer research, cross-sectional study, drug formulation, experimental design, human, longitudinal study, neoplasm (drug therapy), outcomes research, phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), quality control, treatment duration, treatment indication, validation process

falimarev (685563-14-8), mitumprotimut T (1211789-89-7), nelipepimut S (160212-35-1), racotumomab (946832-34-4), tecemotide (1225284-76-3, 221214-84-2), tertomotide (915019-08-8)

Cancer (16), Immunology, Serology and Transplantation (26), Drug Literature Index (37)

ClinicalTrials.gov (NCT00496626, NCT00637195, NCT00652938, NCT00676507, NCT00693342, NCT00779766, NCT00799825, NCT00811798, NCT00849381, NCT00877877, NCT00925548, NCT00929526, NCT00937950, NCT00943722, NCT00947115, NCT00964210, NCT00988884, NCT01015443, NCT01047345, NCT01072981, NCT01073293, NCT01190176, NCT01190189, NCT01245764, NCT01249365, NCT01254643, NCT01265901, NCT01277042, NCT01322490, NCT01375868, NCT01381575, NCT01418937, NCT01460472, NCT01461096, NCT01479244, NCT01546571, NCT01579188, NCT01627561, NCT01651949, NCT01735006)

http://dx.doi.org/10.2147/DDDT.S65963

Copyright 2014 Elsevier B.V., All rights reserved.

Safety and tolerability of linagliptin in patients with type 2 diabetes: A comprehensive pooled analysis of 22 placebo-controlled studies

Lehrke M., Marx N., Patel S., Seck T., Crowe S., Cheng K., Von Eynatten M., Johansen O.E.

(Lehrke M.; Marx N.) Department of Internal Medicine i, University Hospital Aachen, Aachen, Germany. , (Patel S.) Boehringer Ingelheim Ltd, Bracknell, United Kingdom. , (Seck T.; Crowe S.; Cheng K.) Boehringer Ingelheim GmbH and Co KG, Ingelheim, Germany. , (Von Eynatten M.) Boehringer Ingelheim Inc, Ridgefield, CT, United States. , (Johansen O.E., odd-erik.johansen@boehringer-ingelheim.com) Medical Department, Boehringer Ingelheim Norway KS, PO Box 405, 1373 Asker, Norway.

O.E. Johansen, Medical Department, Boehringer Ingelheim Norway KS, PO Box 405, 1373 Asker, Norway. Email: odd-erik.johansen@boehringer-ingelheim.com

Clinical Therapeutics (2014) 36:8 (1130-1146). Date of Publication: 1 Aug 2014

1879-114X (electronic),0149-2918

Excerpta Medica Inc.

Purpose Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. Methods Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of (less-than or equal to)102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs). Findings Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for 5 years; approximately 75% were receiving (greater-than or equal to)1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. Implications This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. (copyright) 2014 The Authors.

linagliptin (adverse drug reaction, clinical trial, drug combination, drug therapy)

amylase (endogenous compound), antilipemic agent, calcium antagonist, dipeptidyl carboxypeptidase inhibitor, diuretic agent, glimepiride (clinical trial, drug therapy), glucose (endogenous compound), hemoglobin A1c (endogenous compound), insulin (drug therapy), metformin (clinical trial, drug combination, drug therapy), pioglitazone (clinical trial, drug combination, drug therapy), placebo, sitagliptin (clinical trial, drug therapy), voglibose (clinical trial, drug therapy)

drug safety, drug tolerability, non insulin dependent diabetes mellitus (drug therapy, drug therapy)

acute coronary syndrome (side effect), acute heart failure (side effect), acute heart infarction (side effect), adult, aged, amylase blood level, angina pectoris (side effect), antihypertensive therapy, arteriosclerosis (side effect), arthralgia (side effect), article, backache (side effect), benign tumor (side effect), brain ischemia (side effect), breast disease (side effect), cardiogenic shock (side effect), cerebrovascular accident (side effect), chronic pancreatitis (side effect), congenital disorder (side effect), congestive heart failure (side effect), connective tissue disease (side effect), coronary artery disease, coughing (side effect), deep vein thrombosis (side effect), diabetic patient, diarrhea (side effect), dizziness (side effect), drug exposure, drug hypersensitivity (side effect), drug intoxication (side effect), endocrine disease (side effect), eye disease (side effect), female, gastrointestinal disease (side effect), genetic disorder (side effect), glucose blood level, headache (side effect), heart arrest (side effect), heart arrhythmia (side effect), heart failure (side effect), heart infarction (side effect), heart left ventricle failure (side effect), heart muscle ischemia (side effect), heart right ventricle failure (side effect), hemoglobin blood level, hepatobiliary disease (side effect), hospitalization, human, hyperglycemia (side effect), hypertension (side effect), hypoglycemia (side effect), infestation (side effect), influenza (side effect), injury (side effect), inner ear disease (side effect), insulin treatment, kidney disease (side effect), kidney function, lung edema (side effect), major clinical study, male, malignant neoplastic disease (side effect), mental disease (side effect), metabolic disorder (side effect), microangiopathy, musculoskeletal disease (side effect), neurologic disease (side effect), nutritional disorder (side effect), pancreas cancer (side effect), pancreatitis (side effect), peripheral occlusive artery disease (side effect), phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), post hoc analysis, pregnancy disorder (side effect), randomized controlled trial (topic), rhinopharyngitis (side effect), side effect (side effect), silent myocardial infarction (side effect), skin disease (side effect), tachycardia (side effect), transient ischemic attack (side effect), treatment duration, unstable angina pectoris (side effect), upper respiratory tract infection (side effect), urinary tract disease (side effect), urinary tract infection (side effect), vascular disease (side effect), vulnerable population

amylase (9000-90-2, 9000-92-4, 9001-19-8), glimepiride (93479-97-1), glucose (50-99-7, 84778-64-3), hemoglobin A1c (62572-11-6), insulin (9004-10-8), linagliptin (668270-12-0), metformin (1115-70-4, 657-24-9), pioglitazone (105355-27-9, 111025-46-8), sitagliptin (486460-32-6, 654671-78-0), voglibose (112653-29-9, 83480-29-9)

Drug Literature Index (37), Adverse Reactions Titles (38), Internal Medicine (6)

ISRCTN (ISRCTN01084005), ClinicalTrials.gov (NCT00309608, NCT00328172, NCT00601250, NCT00602472, NCT00621140, NCT00641043, NCT00654381, NCT00716092, NCT00740051, NCT00798161, NCT00800683, NCT00819091, NCT00954447, NCT00996658, NCT01012037, NCT01087502, NCT01194830, NCT01214239, NCT01215097)

http://dx.doi.org/10.1016/j.clinthera.2014.06.008

Copyright 2014 Elsevier B.V., All rights reserved.

Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: An indirect comparison of olodaterol and indacaterol

Roskell N.S., Anzueto A., Hamilton A., Disse B., Becker K.

(Roskell N.S., nroskell@bresmed.co.uk) Bresmed Health Solutions Ltd, Sheffield, United Kingdom. , (Anzueto A.) School of Medicine, University of Texas Health Science Center, San Antonio, TX, United States. , (Hamilton A.) Medical Department, Boehringer Ingelheim (Canada) Ltd, Burlington, ON, Canada. , (Disse B.) Medical Department, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany. , (Becker K.) Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany.

N. S. Roskell, BresMed Health Solutions Ltd, North Church House, 84 Queen Street, Sheffield S1 2DW, United Kingdom. Email: nroskell@bresmed.co.uk

International Journal of COPD (2014) 9 (813-824). Date of Publication: 31 Jul 2014

1178-2005 (electronic),1176-9106

Dove Medical Press Ltd., PO Box 300-008, Albany, Auckland, New Zealand.

Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV(1)), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV(1) (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV(1) favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network. Conclusion: When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD. (copyright) 2014 Roskell et al.

indacaterol (clinical trial, drug combination, drug comparison, drug therapy), olodaterol (clinical trial, drug combination, drug comparison, drug therapy)

bronchodilating agent (clinical trial, drug combination, drug therapy), formoterol (clinical trial, drug comparison, drug therapy), placebo, salmeterol (clinical trial, drug comparison, drug therapy), tiotropium bromide (clinical trial, drug combination, drug therapy)

chronic obstructive lung disease (drug therapy, drug therapy)

article, clinical assessment tool, combination chemotherapy, disease exacerbation, disease severity, dosage schedule comparison, drug efficacy, drug response, drug safety, drug sensitivity, forced expiratory volume, human, meta analysis, outcome assessment, randomized controlled trial (topic), scoring system, St. George Respiratory Questionnaire, systematic review, Transition Dyspnea Index

formoterol (73573-87-2), indacaterol (312753-06-3), olodaterol (868049-49-4, 869477-96-3), salmeterol (89365-50-4), tiotropium bromide (136310-93-5)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Drug Literature Index (37)

ClinicalTrials.gov (NCT00782210, NCT00782509, NCT00793624, NCT00796653, NCT00931385, NCT00932646, NCT01040689, NCT01040728)

http://dx.doi.org/10.2147/COPD.S59673

Copyright 2014 Elsevier B.V., All rights reserved.

Serum metabolomic response of myasthenia gravis patients to chronic prednisone treatment

Sengupta M., Cheema A., Kaminski H.J., Kusner L.L.

(Sengupta M.; Kaminski H.J.) Department of Neurology, George Washington University, Washington, DC, United States. , (Cheema A.) Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States. , (Kusner L.L., lkusner@gwu.edu) Department of Pharmacology and Physiology, George Washington University, Washington, DC, United States.

PLoS ONE (2014) 9:7 Article Number: e102635. Date of Publication: 17 Jul 2014

1932-6203 (electronic)

Public Library of Science, plos@plos.org

Prednisone is often used for the treatment of autoimmune and inflammatory diseases but they suffer from variable therapeutic responses and significant adverse effects. Serum biological markers that are modulated by chronic corticosteroid use have not been identified. Myasthenia gravis is an autoimmune neuromuscular disorder caused by antibodies directed against proteins present at the post-synaptic surface of neuromuscular junction resulting in weakness. The patients with myasthenia gravis are primarily treated with prednisone. We analyzed the metabolomic profile of serum collected from patients prior to and after 12 weeks of prednisone treatment during a clinical trial. Our aim was to identify metabolites that may be treatment responsive and be evaluated in future studies as potential biomarkers of efficacy or adverse effects. Ultra-performance liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry was used to obtain comparative metabolomic and lipidomic profile. Untargeted metabolic profiling of serum showed a clear distinction between pre- and post- treatment groups. Chronic prednisone treatment caused upregulation of membrane associated glycerophospholipids: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 1, 2-diacyl-sn glycerol 3 phosphate and 1-Acyl-sn-glycero-3-phosphocholine. Arachidonic acid (AA) and AA derived proinflammatory eicosanoids such as 18-carboxy dinor leukotriene B4 and 15 hydroxyeicosatetraenoic acids were reduced. Perturbations in amino acid, carbohydrate, vitamin and lipid metabolism were observed. Chronic prednisone treatment caused increase in membrane associated glycerophospholipids, which may be associated with certain adverse effects. Decrease of AA and AA derived pro-inflammatory eicosanoids demonstrate that immunosuppression by corticosteroid is via suppression of pro-inflammatory pathways. The study identified metabolomic fingerprints that can now be validated as prednisone responsive biomarkers for the improvement in diagnostic accuracy and prediction of therapeutic outcome. (copyright) 2014 Sengupta et al.

prednisone (drug therapy, pharmacology)

1 acyl sn glycero 3 phosphocholine (endogenous compound), 1,2 diacyl sn glycerol 3 phosphate (endogenous compound), 15 hydroxyicosatetraenoic acid (endogenous compound), 18 carboxy dinor leukotriene B4 (endogenous compound), amino acid (endogenous compound), arachidonic acid (endogenous compound), carbohydrate (endogenous compound), glycerophosphate (endogenous compound), phosphatidylcholine (endogenous compound), phosphatidylethanolamine (endogenous compound), phosphatidylserine (endogenous compound), unclassified drug

drug response, metabolomics, myasthenia gravis (drug therapy, drug therapy), serum

amino acid metabolism, article, carbohydrate metabolism, drug efficacy, drug mechanism, human, lipid metabolism, lipidomics, metabolite, time of flight mass spectrometry, ultra performance liquid chromatography, upregulation, vitamin metabolism

15 hydroxyicosatetraenoic acid (73180-00-4), amino acid (65072-01-7), arachidonic acid (506-32-1, 6610-25-9, 7771-44-0), glycerophosphate (12040-65-2, 1555-56-2, 17603-42-8, 27082-31-1, 39951-36-5, 57-03-4, 89923-83-1, 91846-83-2, 1334-74-3, 55073-41-1), phosphatidylcholine (55128-59-1, 8002-43-5), phosphatidylethanolamine (1405-71-6), prednisone (53-03-2)

Clinical and Experimental Biochemistry (29), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00683969)

http://dx.doi.org/10.1371/journal.pone.0102635

Copyright 2014 Elsevier B.V., All rights reserved.

Exploring the association of hemoglobin level and adverse events in children with cancer presenting with fever in neutropenia

Ammann R.A., Niggli F.K., Leibundgut K., Teuffel O., Bodmer N.

(Ammann R.A., roland.ammann@insel.ch; Leibundgut K.; Teuffel O.) Department of Pediatrics, University of Bern, Bern, Switzerland. , (Niggli F.K.; Bodmer N.) Division of Oncology, Department of Pediatrics, University of Zurich, Zurich, Switzerland. , (Teuffel O.) Division of Oncology, Medical Services of the Statutory Health Insurance Baden-Wurttemberg, Tubingen, Germany.

PLoS ONE (2014) 9:7 Article Number: e101696. Date of Publication: 14 Jul 2014

1932-6203 (electronic)

Public Library of Science, plos@plos.org

Background: In children and adolescents with fever in neutropenia (FN) during chemotherapy for cancer, hemoglobin (greater-than or equal to) 90 g/L at presentation with FN had been associated with adverse events (AE). This analysis explored three hypothetical pathophysiological mechanisms potentially explaining this counterintuitive finding, and further analyzed the statistical association between hemoglobin and AE. Methods: Two of 8 centers, reporting on 311 of 421 FN episodes in 138 of 215 patients participated in this retrospective analysis based on prospectively collected data from three databases (SPOG 2003 FN, transfusion and hematology laboratories). Associations with AE were analyzed using mixed logistic regression. Results: Hemoglobin was (greater-than or equal to)90 g/L in 141 (45%) of 311 FN episodes, specifically in 59/103 (57%) episodes with AE, and in 82/208 (39%) without (OR, 2.3; 99%CI, 1.1-4.9; P = 0.004). In FN with AE, hemoglobin was bimodally distributed with a dip around 85 g/L. There were no significant interactions for center, age and sex. In multivariate mixed logistic regression, AE was significantly and independently associated with leukopenia (leukocytes <0.3 G/L; OR, 3.3; 99%CI, 1.1-99; P = 0.004), dehydration (hemoglobin(Presentation)/hemoglobin(8-72 hours) (greater-than or equal to)1.10 in untransfused patients; OR, 3.5; 99%CI, 1.1-11.4; P = 0.006) and non-moderate anemia (difference from 85 g/L; 1.6 per 10 g/L; 1.0-2.6; P = 0.005), but not with recent transfusion of packed red blood cells (pRBC), very recent transfusion of pRBC or platelets, or with hemoglobin (greater-than or equal to)90 g/L as such. Conclusions: Non-moderate anemia and dehydration were significantly and relevantly associated with the risk of AE in children with cancer and FN. These results need validation in prospective cohorts before clinical implementation. (copyright) 2014 Ammann et al.

hemoglobin (endogenous compound)

childhood cancer, febrile neutropenia, hemoglobin blood level, prognosis, risk assessment

adolescent, age, anemia, article, cancer chemotherapy, child, dehydration, disease association, erythrocyte concentrate, erythrocyte transfusion, female, gender, human, leukopenia, major clinical study, male, retrospective study, thrombocyte transfusion

hemoglobin (9008-02-0)

Cancer (16), Hematology (25), Clinical and Experimental Biochemistry (29), Pediatrics and Pediatric Surgery (7)

ClinicalTrials.gov (NCT00107081)

http://dx.doi.org/10.1371/journal.pone.0101696

Copyright 2014 Elsevier B.V., All rights reserved.

Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat(registered trademark) versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: Results from two replicate 48-week studies

Koch A., Pizzichini E., Hamilton A., Hart L., Korducki L., De Salvo M.C., Paggiaro P.

(Koch A., andrea.koch@bergmannsheil.de) Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bochum-Bergmannsheil, Bochum, Germany. , (Pizzichini E.) NUPAIVA (Asthma Research Center), Universidade Federal de Santa Catarina, Santa Catarina, Brazil. , (Hamilton A.; Hart L.) Boehringer Ingelheim, Burlington, ON, Canada. , (Korducki L.) Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, United States. , (De Salvo M.C.) Centro Medico Dra. De Salvo, Fundacion Respirar, Buenos Aires, Argentina. , (Paggiaro P.) Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy.

A. Koch, Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bochum-Bergmannsheil, Burkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. Email: andrea.koch@bergmannsheil.de

International Journal of COPD (2014) 9 (697-714). Date of Publication: 5 Jul 2014

1178-2005 (electronic),1176-9106

Dove Medical Press Ltd., PO Box 300-008, Albany, Auckland, New Zealand.

Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat(registered trademark) versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 (mu)g, twice-daily formoterol 12 (mu)g, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0-3 hours response, FEV(1) trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George's Respiratory Questionnaire. Overall, 904 (Study 1222.13) and 934 (Study 1222.14) patients received treatment. Olodaterol significantly improved FEV(1) area under the curve from 0-3 hours versus placebo in both studies (with olodaterol 5 (mu)g, 0.151 L and 0.129 L; with olodaterol 10 (mu)g, 0.165 L and 0.154 L; for all comparisons P,0.0001) and FEV(1) trough responses versus placebo (0.053-0.085 L; P,0.01), as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for discontinuations) demonstrated statistical significance for olodaterol versus placebo. St George's Respiratory Questionnaire total score was significantly improved with olodaterol, but not formoterol, versus placebo. No safety signals were identified from adverse-event or other safety data. Once-daily olodaterol 5 (mu)g and 10 (mu)g is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy, with a satisfactory safety profile. (copyright) 2014 Koch et al.

formoterol (adverse drug reaction, drug comparison, drug therapy), olodaterol (adverse drug reaction, drug comparison, drug therapy)

chronic obstructive lung disease (drug therapy, drug therapy), forced expiratory volume, inhaler

adult, article, backache (side effect), bronchitis (side effect), coughing (side effect), diarrhea (side effect), disease severity, dizziness (side effect), drug efficacy, drug fatality (side effect), drug response, drug safety, drug withdrawal, dyspnea (side effect), female, fever (side effect), gastroenteritis (side effect), headache (side effect), human, influenza (side effect), maintenance therapy, major clinical study, male, multicenter study (topic), myalgia (side effect), phase 3 clinical trial (topic), pneumonia (side effect), randomized controlled trial (topic), rhinopharyngitis (side effect), sex ratio, spirometry, thorax pain (side effect), treatment duration, treatment outcome, upper respiratory tract infection (side effect), urinary tract infection (side effect), vital capacity

Respimat (Boehringer Ingelheim, Germany)

Boehringer Ingelheim (Germany)

formoterol (73573-87-2), olodaterol (868049-49-4, 869477-96-3)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Biophysics, Bioengineering and Medical Instrumentation (27), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00793624, NCT00796653)

http://dx.doi.org/10.2147/COPD.S62502

Copyright 2014 Elsevier B.V., All rights reserved.

Efficacy and safety of olodaterol once daily delivered via Respimat(registered trademark) in patients with GOLD 2-4 COPD: Results from two replicate 48-week studies

Ferguson G.T., Feldman G.J., Hofbauer P., Hamilto A., Allen L., Korducki L., Sachs P.

(Ferguson G.T., garytferguson@msn.com) Pulmonary Research Institute of Southeast Michigan, Livonia, MI, United States. , (Feldman G.J.) S Carolina Pharmaceutical Research, Spartanburg, SC, United States. , (Hofbauer P.) Pneumologie, Weinheim, Germany. , (Hamilto A.) Boehringer Ingelheim, Burlington, ON, Canada. , (Allen L.; Korducki L.) Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States. , (Sachs P.) Pulmonary Associates of Stamford, Stamford, CT, United States.

G. T. Ferguson, Pulmonary Research Institute of Southeast Michigan, 28815 Eight Mile Road, Livonia, MI 48152, United States. Email: garytferguson@msn.com

International Journal of COPD (2014) 9 (629-645). Date of Publication: 16 Jun 2014

1178-2005 (electronic),1176-9106

Dove Medical Press Ltd., PO Box 300-008, Albany, Auckland, New Zealand.

Background: Olodaterol is a long-acting (beta)(2)-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy. Methods: Patients received olodaterol 5 (mu)g or 10 (mu)g or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0 to 3 hours (AUC(0-3)) response (change from baseline), and trough FEV(1) response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV(1) AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. Results: Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 (mu)g and 10 (mu)g significantly improved the FEV(1) AUC(0-3) response (P<0.0001) and trough FEV(1) (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol. Conclusion: These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 (mu)g and 10 (mu)g in patients with moderate to very severe COPD continuing with usual-care maintenance therapy. (copyright) 2014 Ferguson et al.

olodaterol (adverse drug reaction, clinical trial, drug combination, drug concentration, drug dose, drug interaction, drug therapy, inhalational drug administration, oral drug administration)

creatine kinase (endogenous compound), placebo, tiotropium bromide (drug combination, drug interaction, drug therapy, inhalational drug administration)

chronic obstructive lung disease (drug therapy, drug therapy), drug delivery system

adult, aged, area under the curve, arthralgia (side effect), article, backache (side effect), bronchitis (side effect), cause of death, clinical practice, constipation (side effect), controlled study, coughing (side effect), creatine kinase blood level, diarrhea (side effect), disease exacerbation (side effect), disease severity, dizziness (side effect), double blind procedure, drug blood level, drug dose reduction, drug efficacy, drug fatality (side effect), drug safety, drug withdrawal, dyspnea (side effect), female, forced expiratory volume, headache (side effect), heart ventricle extrasystole (side effect), human, hypertension (side effect), incidence, inhaler, long term care, lung function test, major clinical study, male, multicenter study, nausea (side effect), patient risk, phase 2 clinical trial, phase 3 clinical trial, pneumonia (side effect), randomized controlled trial, rhinopharyngitis (side effect), sinusitis (side effect), treatment outcome, upper respiratory tract infection (side effect), urinary tract infection (side effect)

respimat (Boehringer Ingelheim, Germany)

Boehringer Ingelheim (Germany)

creatine kinase (9001-15-4), olodaterol (868049-49-4, 869477-96-3), tiotropium bromide (136310-93-5)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Biophysics, Bioengineering and Medical Instrumentation (27), Clinical and Experimental Biochemistry (29), Drug Literature Index (37), Adverse Reactions Titles (38), Pharmacy (39)

ClinicalTrials.gov (NCT00782210, NCT00782509, NCT01431274, NCT01431287, NCT01525615, NCT01533922, NCT01533935, NCT01536262, NCT01559116, NCT01694771, NCT01696058)

http://dx.doi.org/10.2147/COPD.S61717

Copyright 2014 Elsevier B.V., All rights reserved.

Tobramycin inhalation powder in cystic fibrosis patients: Response by age group

Geller D.E., Nasr S.Z., Piggott S., He E., Angyalosi G., Higgins M.

(Geller D.E., degeller2@earthlink.net) College of Medicine, Orlando Regional Campus, Florida State University, Orlando, FL, United States. , (Nasr S.Z.) Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, United States. , (Piggott S.; He E.; Angyalosi G.; Higgins M.) Novartis Pharmaceuticals, Basel, Switzerland.

D. E. Geller, College of Medicine, Orlando Regional Campus, Florida State University, Orlando, FL, United States. Email: degeller2@earthlink.net

Respiratory Care (2014) 59:3 (388-398). Date of Publication: 1 Mar 2014

0020-1324,1943-3654 (electronic)

American Association for Respiratory Care, 9425 N. MacArthur Blvd. Suite 100, Irving, United States.

Background: Tobramycin powder for inhalation (TIP) is a drug-device combination designed to reduce treatment time and improve ease of use compared with tobramycin inhalation solution (TIS) in cystic fibrosis (CF) patients. However, the ability of patients to use dry powder inhalers, and the efficacy of the treatments, may vary by age. Methods: The "Establish a New Gold Standard for Efficacy and Safety With Tobramycin in Cystic Fibrosis" (EAGER) trial was a randomized, 24-week, multicenter, open-label, parallel-group study designed to evaluate the safety of TIP versus TIS in 553 subjects, ages (greater-than or equal to) 6 years, with CF and P. aeruginosa infection. The main efficacy end point was percent-of-predicted FEV(1) at week 20 (end of third cycle of treatment). A post hoc analysis was undertaken in 517 subjects who took (greater-than or equal to) 1 dose of study medication, to evaluate the relative efficacy and safety of TIP and TIS by age group: (greater-than or equal to) 6 to < 13 y (children, n = 46); (greater-than or equal to) 13 to < 20 y (adolescents, n = 114); and (greater-than or equal to) 20 y (adults, n = 357). Results: Improvements in percent-of-predicted FEV(1) from baseline to end of cycle 3 were greatest in the children for both TIP and TIS. The treatment differences (TIP - TIS) were 4.7% (85% CI -1.2 to 10.6), 3.7% (85% CI -0.1 to 7.5), and -0.8% (85% CI -3.1 to 1.5) in children, adolescents, and adults, respectively. Sputum P. aeruginosa density decreased from baseline with both treatments, with comparable treatment differences across the age groups after 3 cycles: children -0.93 (85% CI -2.4 to 0.5), adolescents -0.17 (85% CI -1.2 to 0.8), and adults -0.89 (85% CI -1.3 to -0.4). Overall, subject satisfaction scores were greater in all subjects with TIP, irrespective of age group. With the exception of cough and dysphonia, the safety profile of TIP was comparable to TIS, irrespective of age. Conclusions: TIP is comparable to TIS in efficacy outcomes and safety profile but had greater patient satisfaction in all the age groups. (copyright) 2014 Daedalus Enterprises.

tobramycin (adverse drug reaction, drug therapy, inhalational drug administration)

cystic fibrosis (drug therapy, drug therapy)

adolescent, adult, age, article, child, clinical assessment, clinical evaluation, coughing (side effect), drug efficacy, drug safety, dry powder inhaler, dysgeusia (side effect), dysphonia (side effect), female, forced expiratory volume, hemoptysis (side effect), hospitalization, human, lung function, major clinical study, male, oropharynx pain (side effect), patient satisfaction, pneumonia (side effect), post hoc analysis, Pseudomonas infection (drug therapy), randomized controlled trial, rhinorrhea (side effect), school child, sinusitis (side effect), spirometry, structured questionnaire, upper respiratory tract infection (side effect), young adult

tobramycin (32986-56-4)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00388505)

http://dx.doi.org/10.4187/respcare.02264

Copyright 2014 Elsevier B.V., All rights reserved.

Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: Pooled analysis of 20 clinical trials

Iqbal N., Parker A., Frederich R., Donovan M., Hirshberg B.

(Iqbal N., nayyar.iqbal@bms.com; Frederich R., bob.frederich@bms.com; Donovan M., mark.donovan@bms.com) Bristol-Myers Squibb, Route 206 and Providence Line Rd, Princeton, NJ 08543, United States. , (Parker A., artist.parker@astrazeneca.com; Hirshberg B., boaz.hirshberg@astrazeneca.com) AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850, United States.

N. Iqbal, Bristol-Myers Squibb, Route 206 and Providence Line Rd, Princeton, NJ 08543, United States. Email: nayyar.iqbal@bms.com

Cardiovascular Diabetology (2014) 13:1 Article Number: 33. Date of Publication: 4 Feb 2014

1475-2840 (electronic)

BioMed Central Ltd., Floor 6, 236 Gray's Inn Road, London, United Kingdom.

Background: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs.Methods: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method).Results: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12).Conclusions: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk. (copyright) 2014 Iqbal et al.; licensee BioMed Central Ltd.

saxagliptin (adverse drug reaction, clinical trial, drug combination)

metformin (drug combination), placebo

drug safety, non insulin dependent diabetes mellitus

add on therapy, adult, aged, article, cardiovascular risk, cerebrovascular accident (side effect), comparative study, controlled study, female, hazard ratio, heart failure, heart infarction (side effect), human, incidence, major clinical study, male, Mantel Haenszel test, monotherapy, phase 2 clinical trial (topic), phase 3 clinical trial (topic), post hoc analysis, randomized controlled trial (topic), sudden cardiac death (side effect)

metformin (1115-70-4, 657-24-9), saxagliptin (361442-04-8, 945667-22-1)

Endocrinology (3), Cardiovascular Diseases and Cardiovascular Surgery (18), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00121641, NCT00121667, NCT00295633, NCT00313313, NCT00316082, NCT00327015, NCT00575588, NCT00614939, NCT00661362, NCT00666458, NCT00683657, NCT00698932, NCT00757588, NCT00885378, NCT00918138, NCT00918879, NCT00950599, NCT00960076, NCT01006590)

http://dx.doi.org/10.1186/1475-2840-13-33

Copyright 2014 Elsevier B.V., All rights reserved.

Efficacy and safety of initial combination of DPP-IV inhibitors and metformin versus metformin monotherapy in type 2 diabetes: A systematic review of randomized controlled trials

Gao W., Dong J., Liu J., Li Y., Liu F., Yang L., Zhou X., Liao L.

(Gao W.) Department of Cadres Health Care, Qilu Hospital of Shandong University, Jinan, China. , (Dong J.) Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China. , (Liu J.) Laboratory of Medicrovascular Medicine and Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. , (Li Y.) Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. , (Liu F.) Department of Endocrinology, Tengzhou Central People's Hospital, Shandong, China. , (Yang L.) Department of Medical Ultrasonics, Qilu Hospital of Shandong University, Jinan, China. , (Zhou X.) College of Medicine, Shandong University, Jinan, China. , (Liao L., liaolin@medmail.com.cn) Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.

L. Liao, Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China. Email: liaolin@medmail.com.cn

Diabetes, Obesity and Metabolism (2014) 16:2 (179-185). Date of Publication: February 2014

1462-8902,1463-1326 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Aims: We reviewed randomized controlled trials (RCTs) to compare the efficacy and safety of initial dipeptidyl peptidase-IV (DPP-IV) inhibitors and metformin combination therapy with equal-dosage metformin monotherapy in type 2 diabetes. Methods: We conducted a systematic review of English articles using MEDLINE and EMBASE. Search terms included randomized controlled trial, controlled clinical trial, random allocation, sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, duotogliptin and dipeptidyl peptidase IV inhibitor. Double-blinded RCTs comparing DPP-IV inhibitors initially combined with metformin and metformin monotherapy in non-pregnant drug-naive adults with type 2 diabetes were included for this study. Extraction of articles was performed by two authors using predefined data fields. Meta-analysis was used when studies were homogeneous enough, and data were shown and not combined if no formal meta-analysis was performed. Results: Five RCTs met the inclusion criteria. By analysis of different outcomes, patients receiving initial combination of DPP-IV inhibitors and metformin showed a greater reduction in haemoglobinA1c (HbA1c) from baseline [weighted mean difference (WMD), -0.55%; 95% confidence interval (CI), -0.63 to -0.46%], a higher rate of achieving target of HbA1c<7% [risk ratio (RR), 1.55; 95% CI, 1.43-1.67], a significantly lower fasting plasma glucose (FPG) (WMD, -0.97mmol/l; 95% CI, -1.26 to -0.68mmol/l),while the initial combination therapy and monotherapy did not show a significant difference in incidence of total adverse events (AEs, 51.8 vs. 53.7%, respectively; RR, 0.96; 95% CI, 0.91-1.02), gastrointestinal AEs (18.2 vs. 19.4%, respectively; RR, 0.94; 95% CI, 0.82-1.07), drug-related AEs (RR, 0.88; 95% CI, 0.74-1.03) and discontinuation due to AEs (RR, 0.85; 95% CI, 0.61-1.20). The following outcomes were not included for meta-analysis: change from baseline in postprandial glycaemia, (beta)-cell function, insulin sensitivity and body weight as well as incidence of hypoglycaemia. The analyses of these trials revealed that the change from baseline of the postprandial glycaemia and index of (beta)-cell function were greater while the RRs for incidence of hypoglycaemia and body weight increase had no statistical significance. Conclusions: Compared with equal-dosage metformin monotherapy, the initial combination of metformin and DPP-IV inhibitors were more effective in glycaemic control without additional risk of AEs, therefore it can be considered as a beneficial therapeutic regimen for drug-naive type 2 diabetes patients. (copyright) 2013 John Wiley & Sons Ltd.

dipeptidyl peptidase IV inhibitor (drug combination, drug comparison, drug therapy), metformin (drug combination, drug comparison, drug therapy)

alogliptin, dutogliptin, hemoglobin A1c, linagliptin, saxagliptin, sitagliptin, vildagliptin

non insulin dependent diabetes mellitus (drug therapy, drug therapy)

article, cell function, drug effect, drug safety, follow up, glucose blood level, human, hypoglycemia, insulin resistance, insulin sensitivity, intention to treat analysis, meta analysis, outcome assessment, publishing, randomized controlled trial (topic), systematic review, weight gain

alogliptin (850649-61-5, 850649-62-6), dutogliptin (852329-66-9, 890402-81-0), hemoglobin A1c (62572-11-6), linagliptin (668270-12-0), metformin (1115-70-4, 657-24-9), saxagliptin (361442-04-8, 945667-22-1), sitagliptin (486460-32-6, 654671-78-0), vildagliptin (274901-16-5)

Internal Medicine (6), Drug Literature Index (37)

ClinicalTrials.gov (NCT00103857, NCT00327015, NCT00382096, NCT00482729, NCT00798161)

http://dx.doi.org/10.1111/dom.12193

Copyright 2014 Elsevier B.V., All rights reserved.

When should FDG-PET be used in the modern management of lymphoma?

Barrington S.F., Mikhaeel N.G.

(Barrington S.F., sally.barrington@kcl.ac.uk) Division of Imaging and Biomechanical Engineering, PET Imaging Centre at St Thomas' Hospital, King's College, London, United Kingdom. , (Mikhaeel N.G.) Department of Clinical Oncology, Guy's and St Thomas' Foundation Trust, London, United Kingdom.

S.F. Barrington, PET Imaging Centre, Westminster Bridge Road, London SE1 7EH, United Kingdom. Email: sally.barrington@kcl.ac.uk

British Journal of Haematology (2014) 164:3 (315-328). Date of Publication: February 2014

0007-1048,1365-2141 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Positron Emission Tomography (PET) is a functional imaging technique that, combined with computerized tomography (PET-CT), is increasingly used in lymphoma. Most subtypes accumulate fluorodeoxyglucose (FDG) and the increased sensitivity of PET-CT, especially for extranodal disease, compared to CT, makes PET-CT an attractive staging tool. The availability of a staging PET-CT scan also improves the accuracy of subsequent response assessment. 'Interim' PET-CT can be used to assess early response and end-of-treatment PET-CT assesses remission. Clinical trials are currently seeking to establish whether the predictive value of PET-CT can be successfully used to guide individual treatment to reduce toxicity and/or to improve outcomes. Standardized methods for performing and reporting PET have been developed in the context of trials. The role of PET in transplantation selection is currently evolving, as it appears to be more accurate and prognostic than CT. The role of FDG PET-CT throughout the management course in patients with lymphoma is explored in this review, with areas discussed that may limit the use of PET-CT imaging which clinicians should be familiar with to inform practice. (copyright) 2013 John Wiley & Sons Ltd.

fluorodeoxyglucose f 18

bleomycin (drug combination, drug therapy), cyclophosphamide (drug combination, drug therapy), dacarbazine (drug combination, drug therapy), doxorubicin (drug combination, drug therapy), etoposide (drug combination, drug therapy), prednisolone (drug combination, drug therapy), prednisone (drug combination, drug therapy), procarbazine (drug combination, drug therapy), rituximab (drug therapy), vinblastine (drug combination, drug therapy), vincristine (drug combination, drug therapy), vindesine (drug combination, drug therapy)

computer assisted emission tomography, lymphoma

article, autologous stem cell transplantation, Burkitt lymphoma (drug therapy), cancer combination chemotherapy, cancer radiotherapy, contrast enhancement, diagnostic value, disease classification, disease surveillance, event free survival, follicular lymphoma, Hodgkin disease (drug therapy, radiotherapy), human, large cell lymphoma (drug therapy), lymphocytoma, mantle cell lymphoma, marginal zone lymphoma, nonhodgkin lymphoma, overall survival, predictive value, priority journal, progression free survival, radiation dose, relapse, remission, skin lymphoma, survival rate, T cell lymphoma

bleomycin (11056-06-7, 9041-93-4), cyclophosphamide (50-18-0), dacarbazine (4342-03-4), doxorubicin (23214-92-8, 25316-40-9), etoposide (33419-42-0), fluorodeoxyglucose f 18 (63503-12-8), prednisolone (50-24-8), prednisone (53-03-2), procarbazine (366-70-1, 671-16-9), rituximab (174722-31-7), vinblastine (865-21-4), vincristine (57-22-7), vindesine (53643-48-4)

Radiology (14), Cancer (16), Hematology (25), Drug Literature Index (37)

ClinicalTrials.gov (NCT00392314, NCT00515554, NCT00678327, NCT00736320, NCT00784537, NCT00795613, NCT00822120, NCT01356680, NCT01358747, NCT01599559, NCT01719835)

http://dx.doi.org/10.1111/bjh.12601

Copyright 2014 Elsevier B.V., All rights reserved.

Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: Meta-analysis of randomized clinical trials with 55,141 participants

Wu S., Hopper I., Skiba M., Krum H.

(Wu S.; Hopper I., ingrid.hopper@monash.edu; Skiba M.; Krum H.) Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic, Australia. , (Hopper I., ingrid.hopper@monash.edu; Skiba M.; Krum H.) Department of Clinical Pharmacology, The Alfred Hospital, Melbourne, Vic, Australia.

I. Hopper, Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University/ The Alfred Centre, Melbourne, Vic 3004, Australia. Email: ingrid.hopper@monash.edu

Cardiovascular Therapeutics (2014) 32:4 (147-158). Date of Publication: August 2014

1755-5922 (electronic),1755-5914

Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com

Aims: The association between glucose lowering in diabetes mellitus and major cardiovascular (CV) outcomes is weak; indeed, some oral hypoglycemic agents are associated with increased CV events. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are a new class of oral hypoglycemic agent that may have beneficial CV effects. We undertook a systematic review and meta-analysis to appraise the CV safety and efficacy of DPP-4 inhibitors. Methods: Comprehensive search for prospective trials involving DPP-4 inhibitors. Trials included reported at least one of the outcomes examined, recruited minimum 100 patients and minimum follow-up 24 weeks. The risk ratio (RR) was calculated using the Mantel-Haenszel random-effects model for mortality and major cardiovascular (CV) outcomes. Results: Fifty trials enrolling 55,141 participants were included. Mean follow-up 45.3 weeks. DPP-4 inhibitors compared with all comparators (placebo and active) showed no difference in all-cause mortality (n = 50,982, RR = 1.01, 95% CI 0.91-1.13, P = 0.83), CV mortality (n = 48,151, RR = 0.97, 95% CI 0.85-1.11, P = 0.70), acute coronary syndrome (ACS) (n = 53,034 RR = 0.97, 95% CI 0.87-1.08, P = 0.59), or stroke (n = 42,737, RR = 0.98, 95% CI 0.81-1.18, P = 0.80), and a statistically significant increase in heart failure outcomes (n = 39,953, RR = 1.16, 95% CI 1.01-1.33, P = 0.04). Discussion: Treatment with DPP-4 inhibitors compared with placebo shows no increase in risk with regards to all-cause mortality, CV mortality, ACS, or stroke, but a statistically significant trend toward increased risk of HF outcomes. Conclusion: These findings suggest no cardiovascular harm (or benefit) with DPP-4 inhibitors; further large-scale CV outcome studies will resolve the issue of excess HF risk. (copyright) 2014 John Wiley & Sons Ltd.

dipeptidyl peptidase IV inhibitor

2,4 thiazolidinedione derivative, linagliptin, metformin, saxagliptin, sitagliptin, sulfonylurea derivative, vildagliptin

cardiovascular disease

acute coronary syndrome, article, cardiovascular mortality, cerebrovascular accident, drug efficacy, drug safety, follow up, heart failure, hospitalization, human, meta analysis, outcome assessment, priority journal, prospective study, quality control, randomized controlled trial (topic), sensitivity analysis

linagliptin (668270-12-0), metformin (1115-70-4, 657-24-9), saxagliptin (361442-04-8, 945667-22-1), sitagliptin (486460-32-6, 654671-78-0), vildagliptin (274901-16-5)

Public Health, Social Medicine and Epidemiology (17), Cardiovascular Diseases and Cardiovascular Surgery (18), Drug Literature Index (37)

ClinicalTrials.gov (NCT00086515, NCT00094770, NCT00099866, NCT00099892, NCT00099931, NCT00103857, NCT00106340, NCT00106704, NCT00121641, NCT00121667, NCT00138567, NCT00237237, NCT00286429, NCT00286442, NCT00286455, NCT00286468, NCT00286494, NCT00295633, NCT00300287, NCT00313313, NCT00316082, NCT00327015, NCT00337610, NCT00383578, NCT00395343, NCT00432276, NCT00449930, NCT00468039, NCT00509262, NCT00541450, NCT00575588, NCT00601250, NCT00602472, NCT00614939, NCT00622284, NCT00637273, NCT00641043, NCT00654381, NCT00698932, NCT00701090, NCT00722371, NCT00740051, NCT00757588, NCT00798161, NCT00894868, NCT00968708, NCT01006590, NCT01028391, NCT01107886)

http://dx.doi.org/10.1111/1755-5922.12075

Copyright 2014 Elsevier B.V., All rights reserved.

Vortioxetine: First global approval

Gibb A., Deeks E.D.

(Gibb A., dru@adis.com) Adis R and D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand. , (Deeks E.D.) Adis, Auckland, New Zealand.

A. Gibb, Adis R and D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand. Email: dru@adis.com

Drugs (2014) 74:1 (135-145). Date of Publication: January 2014

0012-6667,1179-1950 (electronic)

Springer International Publishing AG, Gewerbestrasse 11, Cham (ZG), Switzerland.

Vortioxetine is an orally administered small molecule developed by Lundbeck A/S for the once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Vortioxetine received its first global approval for MDD in the USA in September 2013 and regulatory approval for its use in this indication in the EU (where it has received a positive opinion) and Canada is awaited. The drug is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation. In vitro studies indicate that vortioxetine is an inhibitor of the 5-HT transporter and is a 5-HT(1D), 5-HT(3) and 5-HT(7) receptor antagonist, a 5-HT(1A) receptor agonist and a 5-HT(1B) receptor partial agonist. Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating (gamma)-aminobutyric acid and glutamate neurotransmission. Phase III trials of vortioxetine in both MDD and GAD have been conducted worldwide. This article summarizes the milestones in the development of vortioxetine leading to this first approval for MDD. (copyright) 2013 Springer International Publishing Switzerland.

vortioxetine (drug therapy, pharmacoeconomics, pharmacokinetics, pharmacology)

4 aminobutyric acid (endogenous compound), acetylcholine (endogenous compound), dopamine (endogenous compound), glutamic acid (endogenous compound), histamine (endogenous compound), noradrenalin (endogenous compound), placebo, serotonin (endogenous compound)

drug approval

antidepressant activity, article, Canada, drug bioavailability, drug blood level, drug elimination, drug excretion, drug half life, drug interaction, drug metabolism, drug receptor binding, generalized anxiety disorder (disease management, drug therapy), human, major depression (disease management, drug therapy), maximum plasma concentration, neurotransmission, nonhuman, pharmacodynamics, phase 2 clinical trial (topic), phase 3 clinical trial (topic), randomized controlled trial (topic), tranquilizing activity, United States

4 aminobutyric acid (28805-76-7, 56-12-2), acetylcholine (51-84-3, 60-31-1, 66-23-9), dopamine (51-61-6, 62-31-7), glutamic acid (11070-68-1, 138-15-8, 56-86-0, 6899-05-4), histamine (51-45-6, 56-92-8, 93443-21-1), noradrenalin (1407-84-7, 51-41-2), serotonin (50-67-9), vortioxetine (508233-74-7, 960203-27-4)

Clinical and Experimental Pharmacology (30), Psychiatry (32), Health Policy, Economics and Management (36), Drug Literature Index (37)

ClinicalTrials.gov (NCT00596817, NCT00635219, NCT00672620, NCT00672958, NCT00694304, NCT00707980, NCT00730691, NCT00731120, NCT00734071, NCT00735709, NCT00744627, NCT00761306, NCT00788034, NCT00811252, NCT00839423, NCT01140906, NCT01152996, NCT01153009, NCT01163266, NCT01179516, NCT01255787, NCT01323478, NCT01355081, NCT01364649, NCT01395147, NCT01422213, NCT01488071, NCT01491035, NCT01564862, NCT01571453), EudraCT (2006-001515-29, 2007-001870-95, 2007-001871-13, 2007-004992-21, 2008-001580-11, 2008-001581-91, 2008-002901-38, 2009-017523-26, 2011-001572-19, 2011-002362-21, 2011-005298-22)

http://dx.doi.org/10.1007/s40265-013-0161-9

Copyright 2014 Elsevier B.V., All rights reserved.

Minimal clinically important difference in parkinson's disease as assessed in pivotal trials of pramipexole extended release

Hauser R.A., Gordon M.F., Mizuno Y., Poewe W., Barone P., Schapira A.H., Rascol O., Debieuvre C., Frassdorf M.

(Hauser R.A., rhauser@health.usf.edu) University of South Florida, Byrd Institute, National Parkinson Foundation Center of Excellence, Tampa, FL 33613, United States. , (Gordon M.F., mark.gordon@boehringer-ingelheim.com) Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States. , (Mizuno Y., y_mizuno@juntendo.ac.jp) Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. , (Poewe W., werner.poewe@i-med.ac.at) Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. , (Barone P., pbarone@unisa.it) Center for Neurodegenerative Diseases, Department of Medicine and Surgery, University of Salerno, Salerno, Italy. , (Schapira A.H., a.schapira@medsch.ucl.ac.uk) Department of Clinical Neurosciences, University College London Institute of Neurology, London, United Kingdom. , (Rascol O., rascol@cict.fr) Clinical Investigation Center, Departments of Clinical Pharmacology and Neurosciences, Toulouse University Hospital, Toulouse, France. , (Debieuvre C., catherine.debieuvre@boehringer-ingelheim.com) Boehringer Ingelheim France S.A.S., Reims, France. , (Frassdorf M., mandy.fraessdorf@boehringer-ingelheim.com) Boehringer Ingelheim Pharmaceuticals, GmbH and Co. KG, Ingelheim, Germany.

R.A. Hauser, University of South Florida, Byrd Institute, National Parkinson Foundation Center of Excellence, Tampa, FL 33613, United States. Email: rhauser@health.usf.edu

Parkinson's Disease (2014) 2014 Article Number: 467131. Date of Publication: 2014

2042-0080 (electronic)

Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New York, United States.

Background. The minimal clinically important difference (MCID) is the smallest change in an outcome measure that is meaningful for patients. Objectives. To calculate the MCID for Unified Parkinson's Disease Rating Scale (UPDRS) scores in early Parkinson's disease (EPD) and for UPDRS scores and "OFF" time in advanced Parkinson's disease (APD). Methods. We analyzed data from two pivotal, double-blind, parallel-group trials of pramipexole ER that included pramipexole immediate release (IR) as an active comparator. We calculated MCID as the mean change in subjects who received active treatment and rated themselves "a little better" on patient global impression of improvement (PGI-I) minus the mean change in subjects who received placebo and rated themselves unchanged. Results. MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were -1.8 and -2.0, for UPDRS III -6.2 and -6.1, and for UPDRS II + III -8.0 and -8.1. MCIDs in APD for UPDRS II were -1.8 and -2.3, for UPDRS III -5.2 and -6.5, and for UPDRS II + III -7.1 and -8.8. MCID for "OFF" time (pramipexole ER, pramipexole IR) was -1.0 and -1.3 hours. Conclusions. A range of MCIDs is emerging in the PD literature that provides the basis for power calculations and interpretation of clinical trials. (copyright) 2014 Robert A. Hauser et al.

pramipexole (clinical trial, drug therapy, pharmaceutics)

minimal clinically important difference, Parkinson disease (drug therapy, drug therapy), statistical model

advanced parkinson disease (drug therapy), advanced parkinson disease (drug therapy), article, chronotherapy, Clinical Global Impression scale, controlled study, dose response, drug dose titration, drug release, early parkinson disease (drug therapy), early parkinson disease (drug therapy), human, major clinical study, named inventories, questionnaires and rating scales, outcome assessment, parallel design, Patient rated Global Impression of Improvement, randomized controlled trial (topic), treatment response, Unified Parkinson Disease Rating Scale

pramipexole (104632-26-0, 104632-25-9)

Drug Literature Index (37), Pharmacy (39), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00466167, NCT00479401)

http://dx.doi.org/10.1155/2014/467131

Copyright 2014 Elsevier B.V., All rights reserved.

Pharmacokinetics of recombinant human antithrombin in delivery and surgery patients with hereditary antithrombin deficiency

Dejongh J., Frieling J., Lowry S., Drenth H.-J.

(Dejongh J.; Drenth H.-J.) LAP and P Consultants BV, Leiden, Netherlands. , (Frieling J., johan.frieling@revobiologics.com; Lowry S.) REVO Biologics, Inc., 175 Crossing Blvd, Framingham, MA 01702, United States.

J. Frieling, REVO Biologics, Inc., 175 Crossing Blvd, Framingham, MA 01702, United States. Email: johan.frieling@revobiologics.com

Clinical and Applied Thrombosis/Hemostasis (2014) 20:4 (355-364). Date of Publication: May 2014

1938-2723 (electronic),1076-0296

SAGE Publications Inc., claims@sagepub.com

Population pharmacokinetic (PK) analyses were conducted to refine dosing recommendations for recombinant human anti-thrombin therapy in surgery and delivery patients with hereditary antithrombin deficiency (HD). Single-dose PK data from patients with HD and nonlinear mixed-effects modeling were used to devise a dosing regimen to target antithrombin (AT) activity levels between 80% and 120% of normal. External validation with data from a phase 3 trial confirmed the correctness of a covariate-free model for surgery patients, but dosing adjustment was necessary for delivery patients. After different covariates were tested, the model was updated to incorporate the influential covariate, delivery. Simulations were used to develop a therapeutic drug-monitoring scenario that results in steady state AT activity levels within the target range as quickly as practically feasible. Data from a second clinical trial provided additional external validation and confirmed the accuracy of the dosing model for both groups of patients. (copyright) The Author(s) 2013.

recombinant human antithrombin (drug dose, drug therapy, intravenous drug administration, pharmacokinetics), recombinant protein (drug dose, drug therapy, intravenous drug administration, pharmacokinetics), thrombin inhibitor (drug dose, drug therapy, intravenous drug administration, pharmacokinetics)

unclassified drug

anticoagulant therapy, antithrombin deficiency (drug therapy, drug therapy), genetic disorder (drug therapy, drug therapy), hereditary antithrombin deficiency (drug therapy, drug therapy)

area under the curve, article, chronotherapy, clinical article, continuous infusion, controlled study, disease simulation, dose calculation, drug clearance, drug dose increase, drug dose reduction, drug dose regimen, drug half life, drug monitoring, feasibility study, female, human, loading drug dose, maintenance drug dose, male, maximum plasma concentration, open study, phase 3 clinical trial (topic), priority journal, protein function, single drug dose, steady state, time to maximum plasma concentration, validation study

Human Genetics (22), Hematology (25), Clinical and Experimental Pharmacology (30), Drug Literature Index (37)

ClinicalTrials.gov (NCT00056550, NCT00110513)

http://dx.doi.org/10.1177/1076029613516188

Copyright 2014 Elsevier B.V., All rights reserved.

Genetic markers of bevacizumab-induced hypertension

Lambrechts D., Moisse M., Delmar P., Miles D.W., Leighl N., Escudier B., Van Cutsem E., Bansal A.T., Carmeliet P., Scherer S.J., De Haas S., Pallaud C.

(Lambrechts D., Diether.Lambrechts@vib-kuleuven.be; Moisse M.; Carmeliet P.) Vesalius Research Center, VIB, Campus Gasthuisberg, Herestraat 49, Box 912, 3000 Leuven, Belgium. , (Lambrechts D., Diether.Lambrechts@vib-kuleuven.be; Moisse M.) Laboratory of Translational Genetics, Department of Oncology, University of Leuven (KU Leuven), Leuven, Belgium. , (Delmar P.; De Haas S.; Pallaud C.) F. Hoffmann-La Roche, Basel, Switzerland. , (Miles D.W.) Mount Vernon Cancer Centre, Northwood, United Kingdom. , (Leighl N.) Department of Medicine, Princess Margaret Hospital, Toronto, ON, Canada. , (Escudier B.) Institut Gustave Roussy, Villejuif, France. , (Van Cutsem E.) Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. , (Bansal A.T.) Acclarogen Ltd, St John's Innovation Centre, Cambridge, United Kingdom. , (Scherer S.J.) Genentech Inc, South San Francisco, CA, United States.

D. Lambrechts, Vesalius Research Center, VIB, Campus Gasthuisberg, Herestraat 49, Box 912, 3000 Leuven, Belgium. Email: Diether.Lambrechts@vib-kuleuven.be

Angiogenesis (2014) 17:3 (685-694). Date of Publication: July 2014

1573-7209 (electronic),0969-6970

Kluwer Academic Publishers

Purpose: There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. Experimental design: Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. Results: Ten SNPs were associated with bevacizumab-induced hypertension (P (less-than or equal to) 0.05), but none surpassed the threshold adjusted for multiple testing (P < 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). Conclusions: The genes described in this large genetic analysis using pooled datasets warrant further functional investigation regarding their role in mediating bevacizumab-induced hypertension. (copyright) 2014 Springer Science+Business Media Dordrecht.

bevacizumab (adverse drug reaction, drug therapy)

epidermal growth factor (endogenous compound), protein kinase WNK1 (endogenous compound), vasculotropin A (endogenous compound), vasculotropin receptor (endogenous compound), vasculotropin receptor 2 (endogenous compound)

genetic marker, hypertension (side effect, side effect)

adult, article, drug efficacy, drug safety, EGF gene, EGLN3 gene, female, FLT1 gene, gene function, genetic analysis, genetic association, genetic variability, human, kdr gene, major clinical study, male, outcome assessment, phase 3 clinical trial (topic), priority journal, signal transduction, single nucleotide polymorphism, solid tumor (drug therapy), tumor gene, VEGF A gene, WNK1 gene

bevacizumab (216974-75-3), epidermal growth factor (62229-50-9), vasculotropin A (489395-96-2), vasculotropin receptor (301253-48-5)

Cancer (16), Cardiovascular Diseases and Cardiovascular Surgery (18), Human Genetics (22), Drug Literature Index (37), Adverse Reactions Titles (38), Internal Medicine (6)

ClinicalTrials.gov (NCT00069095, NCT00333775, NCT00548548, NCT00738530, NCT00806923, NCT01214720)

http://dx.doi.org/10.1007/s10456-014-9424-7

Copyright 2014 Elsevier B.V., All rights reserved.

Management of Gaucher disease: Enzyme replacement therapy

Zimran A., Elstein D.

(Zimran A., azimran@gmail.com; Elstein D.) Gaucher Clinic, Hadassah-Hebrew University, School of Medicine, Jerusalem, Israel.

A. Zimran, Gaucher Clinic, Hadassah-Hebrew University, School of Medicine, Jerusalem, Israel.

Pediatric Endocrinology Reviews (2014) 12 Supplement 1 (82-87). Date of Publication: 1 Sep 2014

1565-4753

YS Medical Media Ltd., per@medmedia.co.il

Starting in 1994, 3 years after the first approval of the placental-derived enzyme replacement therapy (ERT) with alglucerase, the recombinant form imiglucerase was the introduced and became the standard of care for the visceral symptoms of Gaucher disease. For patients with non-neuronopathic (type 1) Gaucher disease, ERT is safe, with few adverse/side events, and effective in reducing hepatosplenomegaly, improving hematological parameters such as anemia and thrombocytopenia, and to a lesser degree, ameliorating lung-and bone-referred disease. Dosage differences are appreciated mainly as differences in the initial slope in achieving improvements before plateauing. Because ERT does not pass the blood-brain barrier, for patients with the acute neuronopathic form (type 2), there is no substantial change in the life-threatening neurological parameters and hence ERT is not seen as efficacious; but for patients with sub-acute neuronopathic forms (type 3), ERT for the often devastating visceral symptoms, improved quality of life, and longevity make ERT part of the standard care.Due to a world-wide reduction in imiglucerase availability mid-2009 that was not resolved quickly, patients were ERT-stopped or dose-reduced, re-invigorated the movement to provide additional therapeutic options. Early access programs of two new ERTs, then at the pre-license stage, were initiated at regulatory authorities' request for patients requiring ERT. At that point, velaglucerase alfa which has the native-enzyme sequence produced in a (proprietary) human cell line, and taliglucerase alfa, which is plant-cell-derived and produced in an inexpensive platform, were completing Phase 3 clinical trials. Velaglucerase alfa was FDA-approved in February 2010 while taliglucerase alfa was approved in May 2012. Marketing of these ERTs has also targeted the extraordinarily high cost of imiglucerase. However, with > 20 years' experience with infusible ERTs, many patients are eager to consider oral options including substrate reduction and/or pharmacological chaperone treatments taken as pills or possibly oral formulations of an ERT.

alglucerase (drug therapy), hemoglobin (endogenous compound), imiglucerase (drug therapy), taliglucerase alfa (adverse drug reaction, clinical trial, drug dose, drug therapy), velaglucerase alfa (adverse drug reaction, clinical trial, drug dose, drug therapy)

enzyme replacement, Gaucher disease (drug therapy, drug therapy)

anemia, article, bone density, bone necrosis, bone radiography, cortical bone, drug cost, drug dose comparison, drug dose reduction, drug effect, drug formulation, drug hypersensitivity (side effect), drug marketing, drug safety, health care quality, hemoglobin blood level, hepatosplenomegaly, human, liver weight, longevity, multicenter study (topic), nuclear magnetic resonance imaging, phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), quality of life, randomized controlled trial (topic), spleen weight, splenectomy, thrombocyte count, thrombocytopenia, viral contamination

hemoglobin (9008-02-0), imiglucerase (154248-97-2), velaglucerase alfa (884604-91-5)

Human Genetics (22), Clinical and Experimental Biochemistry (29), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00376168, NCT00391625, NCT00478647, NCT00553631, NCT00635427, NCT01411228)

Copyright 2014 Elsevier B.V., All rights reserved.

Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion

Kuppermann B.D., Haller J.A., Bandello F., Loewenstein A., Jiao J., Li X.-Y., Whitcup S.M.

(Kuppermann B.D., bdkupper@uci.edu) Gavin Herbert Eye Institute, University of California, 850 Health Sciences Road, Irvine, CA 92697-4375, United States. , (Haller J.A.) Wills Eye Institute, Philadelphia, Pennsylvania, United States. , (Bandello F.) University of Udine, Udine, Italy. , (Loewenstein A.) Department of Ophthalmology, Tel Aviv Medical Center, Sackler Facility of Medicine, Tel Aviv, Israel. , (Jiao J.; Li X.-Y.; Whitcup S.M.) Allergan, Inc, Irvine, CA, United States.

B.D. Kuppermann, Gavin Herbert Eye Institute, University of California, 850 Health Sciences Road, Irvine, CA 92697-4375, United States. Email: bdkupper@uci.edu

Retina (2014) 34:9 (1743-1749). Date of Publication: September 2014

1539-2864 (electronic),0275-004X

Lippincott Williams and Wilkins, LRorders@phl.lrpub.com

PURPOSE:: To evaluate the onset and duration of improvement in best-corrected visual acuity (BCVA) in eyes treated with dexamethasone intravitreal implant 0.7 mg (DEX implant) for macular edema after branch or central retinal vein occlusion. METHODS:: Post hoc analysis of data from 2 previously reported multicenter, 6-month, randomized sham-controlled clinical trials. Patients received a single DEX implant (n = 427) or sham procedure (n = 426) in the study eye. The primary endpoint was the percentage of eyes with 15-letter improvement in BCVA from baseline at postimplant Day 7. RESULTS:: The baseline mean BCVA was 20/80. At Day 7, 10.3% of DEX implant-treated eyes versus 4.0% of sham-treated eyes (P < 0.001) had 15-letter improvement in the BCVA, and 27.2% of DEX implant-treated eyes versus 10.6% of sham-treated eyes had 10-letter improvement (P < 0.001). The mean improvement at Day 7 was 5.3 letters (branch retinal vein occlusion, 5.1; and central retinal vein occlusion, 5.8) with DEX implant and 1.6 letters (branch retinal vein occlusion, 2.3; and central retinal vein occlusion, 0.1) with sham (P < 0.001). The mean time from initial observation of 15-letter BCVA gain to the last observation of 15-letter BCVA gain was 70 days. CONCLUSION:: Dexamethasone intravitreal implant treatment led to improvement in BCVA compared with sham procedure as early as postimplant Day 7. The duration of 3-line improvement was typically 2 to 3 months. Copyright (copyright) by Ophthalmic Communications Society, Inc.

dexamethasone (clinical trial, drug therapy, intravitreal drug administration)

branch retinal vein occlusion, central retina vein occlusion, macular edema (drug therapy, drug therapy), visual acuity

adult, aged, article, controlled study, drug implant, female, human, major clinical study, male, multicenter study, randomized controlled trial, treatment outcome

dexamethasone (50-02-2)

Ophthalmology (12), Drug Literature Index (37)

ClinicalTrials.gov (NCT00168298, NCT00168324)

http://dx.doi.org/10.1097/IAE.0000000000000167

Copyright 2014 Elsevier B.V., All rights reserved.

Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: A meta-analysis of randomized clinical trials

Monami M., Dicembrini I., Mannucci E.

(Monami M.) Section of Geriatric Cardiology and Medicine, Careggi Teaching Hospital, Florence, Italy. , (Dicembrini I.) Obesity Agency, Careggi Teaching Hospital, Florence, Italy. , (Dicembrini I.; Mannucci E., edoardo.mannucci@unifi.it) Diabetes Agency, Careggi Teaching Hospital, Florence, Italy.

E. Mannucci, Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy. Email: edoardo.mannucci@unifi.it

Diabetes, Obesity and Metabolism (2014) 16:1 (48-56). Date of Publication: January 2014

1462-8902,1463-1326 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Aim: Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase-4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim of the present meta-analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i. Methods: Data Sources: an extensive Medline, Embase and Cochrane Database search for 'vildagliptin', 'sitagliptin', 'saxagliptin', 'alogliptin', 'linagliptin' and 'dutogliptin' was performed up to 1 March 2013. Study Selection: studies were included if they satisfied the following criteria: (i) randomized trials, (ii) duration (greater-than or equal to)12weeks, (iii) on type 2 diabetes and (iv) comparison of DPP4i with placebo or active drugs. The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis. Results: A total of 134 eligible trials were identified. The overall risk of pancreatitis and pancreatic cancer was not different between DPP4i and comparators (MH-OR: 0.93[0.51-1.69]; p=0.82). Conclusions: It should be recognized that the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. However, the present meta-analysis do not suggest any increase in the risk of pancreatitis with DPP4i. (copyright) 2013 John Wiley & Sons Ltd.

dipeptidyl peptidase IV inhibitor (adverse drug reaction)

alogliptin (adverse drug reaction), dutogliptin (adverse drug reaction), linagliptin (adverse drug reaction), saxagliptin (adverse drug reaction), sitagliptin (adverse drug reaction), vildagliptin (adverse drug reaction)

pancreatitis (side effect, side effect), risk

article, disease association, drug safety, human, incidence, meta analysis, non insulin dependent diabetes mellitus, pancreas cancer, randomized controlled trial (topic)

alogliptin (850649-61-5, 850649-62-6), dutogliptin (852329-66-9, 890402-81-0), linagliptin (668270-12-0), saxagliptin (361442-04-8, 945667-22-1), sitagliptin (486460-32-6, 654671-78-0), vildagliptin (274901-16-5)

Internal Medicine (6), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00121641, NCT00121667, NCT00127192, NCT00286429, NCT00286442, NCT00286455, NCT00286468, NCT00286494, NCT00295633, NCT00309608, NCT00313313, NCT00316082, NCT00327015, NCT00328172, NCT00328627, NCT00395512, NCT00411554, NCT00432276, NCT00449930, NCT00482950, NCT00575588, NCT00601250, NCT00602472, NCT00614939, NCT00621140, NCT00622284, NCT00641043, NCT00642278, NCT00654381, NCT00655863, NCT00661362, NCT00698932, NCT00700817, NCT00707993, NCT00740051, NCT00751114, NCT00755846, NCT00757588, NCT00798161, NCT00800683, NCT00819091, NCT00856284, NCT00870194, NCT00915772, NCT00918879, NCT00954447, NCT00960076, NCT00968708, NCT00996658, NCT01006590, NCT01012037, NCT01023581, NCT01046110, NCT01084005, NCT01092663, NCT01194830, NCT01204294, NCT01263470, NCT01263483, NCT01289119, NCT01318070, NCT01318083, NCT01318109, NCT01602003)

http://dx.doi.org/10.1111/dom.12176

Copyright 2014 Elsevier B.V., All rights reserved.

Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials

Monami M., Dicembrini I., Mannucci E.

(Monami M.) Section of Geriatric and Medicine, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy. , (Dicembrini I.) Obesity Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy. , (Dicembrini I.; Mannucci E., edoardo.mannucci@unifi.it) Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy.

E. Mannucci, Diabetes Agency, Careggi Teaching Hospital, Via delle Oblate 4, 50141 Florence, Italy. Email: edoardo.mannucci@unifi.it

Nutrition, Metabolism and Cardiovascular Diseases (2014) 24:7 (689-697). Date of Publication: July 2014

1590-3729 (electronic),0939-4753

Background & aims: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus - Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. Methods & results: Data sources: An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration (greater-than or equal to)24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; p=0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. Conclusion: Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients. (copyright) 2014 Elsevier B.V.

dipeptidyl peptidase IV inhibitor (adverse drug reaction)

alogliptin (adverse drug reaction), linagliptin (adverse drug reaction), saxagliptin (adverse drug reaction), sitagliptin (adverse drug reaction), vildagliptin (adverse drug reaction)

heart failure (side effect, side effect)

age, article, body mass, cardiovascular risk, disease duration, drug safety, human, meta analysis, non insulin dependent diabetes mellitus, priority journal, quality control, randomized controlled trial (topic), treatment outcome

alogliptin (850649-61-5, 850649-62-6), linagliptin (668270-12-0), saxagliptin (361442-04-8, 945667-22-1), sitagliptin (486460-32-6, 654671-78-0), vildagliptin (274901-16-5)

Cardiovascular Diseases and Cardiovascular Surgery (18), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00086502, NCT00086515, NCT00087516, NCT00094757, NCT00106704, NCT00121641, NCT00121667, NCT00286442, NCT00286455, NCT00286468, NCT00286494, NCT00295633, NCT00305604, NCT00313313, NCT00316082, NCT00327015, NCT00337610, NCT00395343, NCT00395512, NCT00397631, NCT00420511, NCT00449930, NCT00482729, NCT00532935, NCT00541450, NCT00575588, NCT00601250, NCT00602472, NCT00614939, NCT00621140, NCT00622284, NCT00637273, NCT00641043, NCT00654381, NCT00661362, NCT00698932, NCT00701090, NCT00707993, NCT00740051, NCT00798161, NCT00800683, NCT00813995, NCT00875394, NCT00885352, NCT00918879, NCT00954447, NCT00968708, NCT00996658, NCT01006590, NCT01023581, NCT01028391, NCT01081834, NCT01106690, NCT01107886, NCT01137812, NCT01177384, NCT01189890, NCT01194830, NCT01204294, NCT01289990, NCT01356381, NCT01462266, NCT01545388, NCT01582230)

http://dx.doi.org/10.1016/j.numecd.2014.01.017

Copyright 2014 Elsevier B.V., All rights reserved.

Comparison of Fondaparinux with Low-Molecular-Weight Heparin for Venous Thromboembolism Prevention in Patients Requiring Rigid or Semi-Rigid Immobilization for Isolated Non-Surgical Below-Knee Injury

Etude comparant le fondaparinux a une heparine de bas poids moleculaire dans la prevention de la maladie thromboembolique veineuse en cas d'immobilisation rigide ou semi-rigide apres traumatisme isole non chirurgical du membre inferieur au-dessous du genou

Samama C.M., Lecoules N., Kierzek G., Claessens Y.E., Riou B., Rosencher N., Mismetti P., Sautet A., Barrellier M.-T., Apartsin K., Jonas M., Caeiro J.R., Van der veen A.H., Roy P.-M.

(Samama C.M., marc.samama@cch.aphp.fr; Rosencher N.) Service d'anesthesie-reanimation, centre hospitalier universitaire Cochin-Hotel-Dieu, Assistance publique-Hopitaux de Paris (AP-HP), universite Paris-Descartes, 27, rue du Faubourg-Saint-Jacques, F-75014 Paris, France. , (Lecoules N.) Pole medecine d'urgences, CHU Purpan, F-31000 Toulouse, France. , (Kierzek G.) Service des urgences medicales et medicojudiciaires, CHU Cochin-Hotel-Dieu, AP-HP, Universite Paris-Descartes, F-75004 Paris, France. , (Claessens Y.E.) Service des urgences medicales, hopital Princesse-Grace, principaute de Monaco, France. , (Riou B.) Service des urgences, CHU Pitie-Salpetriere, Universite Pierre-et-Marie-Curie, Paris-VI, AP-HP, Paris, France. , (Mismetti P.) Unite de recherche EA3065, universite Jean-Monnet, Saint-Etienne, France. , (Mismetti P.) Unite de pharmacologie clinique, Departement de medecine et therapeutique, CHU de Saint-Etienne, F-42000 Saint-Etienne, France. , (Sautet A.) Departement de chirurgie orthopedique et traumatologique, CHU Saint-Antoine, Universite Pierre-et-Marie-Curie, Paris-VI, AP-HP, F-75012 Paris, France. , (Barrellier M.-T.) Unite d'explorations vasculaires, CHU Cote-de-Nacre, F-14000 Caen, France. , (Apartsin K.) Scientific Center for Reconstructive and Restorative Surgery of the Siberian Branch, Russian Academy of Medical Sciences, Irkutsk, Russian Federation. , (Jonas M.) Sankt-Josef Hospital, Moers, Germany. , (Caeiro J.R.) Department of Orthopedic Surgery, Santiago de Compostela University Hospital, Santiago, Spain. , (Van der veen A.H.) Department of Surgery, Catharina Hospital, Eindhoven, Netherlands. , (Roy P.-M.) Service des urgences medicales, CHU d'Angers, universite d'Angers, F-49000 Angers, France.

C. M. Samama, Service d'anesthesie-reanimation, centre hospitalier universitaire Cochin-Hotel-Dieu, Assistance publique-Hopitaux de Paris (AP-HP), universite Paris-Descartes, 27, rue du Faubourg-Saint-Jacques, F-75014 Paris, France. Email: marc.samama@cch.aphp.fr

Annales Francaises de Medecine d'Urgence (2014) 4:3 (153-166). Date of Publication: May 2014

2108-6591 (electronic),2108-6524

Springer-Verlag France, york@springer-paris.fr

Background: In several small studies, anticoagulant therapy reduced the incidence of venous thromboembolism (VTE) in patients with isolated lower-limb injuries. Objective: To compare the efficacy and safety of fondaparinux 2.5 mg (1.5 mg in patients with a creatinine clearance between 30 and 50 ml/min) over nadroparin 2,850 antifactor Xa IU. Patients/methods: In this international, multicenter, randomized, open-label study, patients with an isolated nonsurgical unilateral below-knee injury, having at least one additional major risk factor for VTE and requiring (in the investigator's opinion) rigid or semi-rigid immobilization for 21-45 days with thromboprophylaxis up to complete mobilization, received subcutaneously once-daily either fondaparinux or nadroparin. The primary efficacy outcome was the composite of VTE (symptomatic or ultrasonographically detected asymptomatic deep-vein thrombosis of the lowerlimb or symptomatic pulmonary embolism) and death up to complete mobilization. The main safety outcome was major bleeding. Results: One thousand three hundred and forty-nine patients (mean age: 46 years) were randomized, 88.7% had a bone fracture, and 83.8% had a plaster cast fitted (mean duration of immobilization: 34 days). The primary efficacy outcome occurred in 15/584 patients (2.6%) in the fondaparinux group and 48/586 patients (8.2%) in the nadroparin group (odds ratio: 0.30; 95% CI: [0.15-0.54]; P < 0.001). A single major bleed was experienced by fondaparinux-treated patients and none by nadroparin-treated patients. These results were maintained up to the end of follow-up. Conclusions: Fondaparinux 2.5 mg/day may be a valuable therapeutic option over nadroparin 2,850 anti-factor Xa IU/day for preventing VTE after below-knee injury requiring prolonged immobilization in patients with additional risk factors. ClinicalTrials.gov number NCT00843492. (copyright) 2014 Societe francaise de medecine d'urgence and Springer-Verlag France.

fondaparinux, low molecular weight heparin, nadroparin

knee injury, venous thromboembolism (diagnosis)

adult, article, creatinine clearance, deep vein thrombosis, follow up, human, limb injury, lung embolism, major clinical study, multicenter study, open study, randomized controlled trial, treatment outcome

fondaparinux (104993-28-4, 114870-03-0), nadroparin (104521-37-1)

Hematology (25), Drug Literature Index (37), Internal Medicine (6)

ClinicalTrials.gov (NCT00843492)

English, French

English, French

http://dx.doi.org/10.1007/s13341-014-0405-z

Copyright 2014 Elsevier B.V., All rights reserved.

A report on the long-term use of fentanyl pectin nasal spray in patients with recurrent breakthrough pain

Taylor D., Radbruch L., Revnic J., Torres L.M., Ellershaw J.E., Perelman M.

(Taylor D., dtaylor@cpcnopain.com) Georgia Center for Cancer Pain Management and Palliative Medicine, Marietta, GA, United States. , (Radbruch L.) Klinik fur Palliativmedizin, Universitatsklinikum Bonn, Bonn, Germany. , (Revnic J.) Hopital Jean Jaures, Paris, France. , (Torres L.M.) Hospital Universitario Puerta Del Mar, Cadiz, Spain. , (Ellershaw J.E.) Marie Curie Palliative Care Institute, Liverpool, United Kingdom. , (Perelman M.) Archimedes Development Ltd., Nottingham, United Kingdom.

D. Taylor, Comprehensive Pain Care, PC, Taylor Research, LLC, 840 Church Street NE, Marietta, GA 30060, United States. Email: dtaylor@cpcnopain.com

Journal of Pain and Symptom Management (2014) 47:6 (1001-1007). Date of Publication: June 2014

1873-6513 (electronic),0885-3924

Elsevier Inc., usjcs@elsevier.com

Context As patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use. Objectives To investigate the long-term use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients receiving regular opioid therapy. Methods Adult patients (N = 401) taking at least 60 mg/day oral morphine or equivalent, experiencing one to four episodes of BTPc a day, entered an open-label long-term study (NCT00458510). Patients had either completed an FPNS randomized controlled trial or were newly identified. Of these, 171 patients continued into an extension study. Up to four episodes of BTPc a day were treated with FPNS at 100-800 (mu)g titrated doses. During the extension study, patients visited the clinic every four weeks for assessment and reporting of adverse events (AEs). Results There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for (greater-than or equal to)360 days; the maximum duration was 44 months. Seventy percent of patients did not change their FPNS dose; 2% of patients withdrew from the study because of the lack of efficacy. The most common AEs, aside from disease progression, were insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of FPNS-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced nasal AEs, most of which were mild or moderate. Conclusion FPNS appeared to provide sustained benefit and was well tolerated during long-term treatment of BTPc. (copyright) 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

fentanyl (adverse drug reaction, clinical trial, drug therapy, intranasal drug administration)

morphine (drug therapy, oral drug administration), pectin

breakthrough pain (drug therapy, drug therapy), cancer pain (drug therapy, drug therapy), recurrent disease (drug therapy, drug therapy)

adult, anemia (side effect), anorexia (side effect), article, asthenia (side effect), backache (side effect), breast cancer (side effect), constipation (side effect), controlled study, coughing (side effect), depression (side effect), diarrhea (side effect), dizziness (side effect), drug dose titration, drug efficacy, drug safety, drug withdrawal, dysgeusia (side effect), epistaxis (side effect), female, human, insomnia (side effect), long term care, major clinical study, male, nausea (side effect), nose obstruction (side effect), pain (side effect), peripheral edema (side effect), pneumonia (side effect), randomized controlled trial, rhinopharyngitis (side effect), side effect (side effect), sinusitis (side effect), sleep disordered breathing (side effect), thorax pain (side effect), urinary tract infection (side effect), vomiting (side effect), weight reduction

fentanyl (437-38-7), morphine (52-26-6, 57-27-2), pectin (9000-69-5)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Internal Medicine (6)

ClinicalTrials.gov (NCT00458510, NCT00459277, NCT00589823)

http://dx.doi.org/10.1016/j.jpainsymman.2013.07.012

Copyright 2014 Elsevier B.V., All rights reserved.

Efficacy and safety of aciclovir mucoadhesive buccal tablet in immunocompetent patients with labial herpes (LIP trial): A double-blind, placebo-controlled, self-initiated trial

Bieber T., Chosidow O., Bodsworth N., Tyring S., Hercogova J., Bloch M., Davis M., Lewis M., Boutolleau D., Attali P., Bisshop F.R., Bloch M.T., Bodworth N.J., Aster V., Asterova J., Hercogova J., Klimesova R., Krajsova I., Ben Slama L., Cambazard F., Chosidow O., Dubertret L., Granel F., Humbert P., Ortonne J.P., Rostain G., Ruer-Mulard M., Vaillant L., Beiber T., Degen A.J., Dorzapf O., Von Hake G., Miller A., Naudts I., Steinert M., Stockfleth E., Weihe J., Wunderlich U., Jasieniak-Pinis G., Kazina M., Pawlaczyk-Strugala E., Placek W., Petryka R., Romanowski L., Dixon C.J., Lewis M., Sharma R., Archuleta M., Baker D.A., Cady R.K., Conant M.A., Crump W.L., Davis M.G., Dunlap F.E., Lee P.C., McCarthy F.T., Tyring S.K.

(Bieber T.) Department of Dermatology and Allergy, University of Bonn, Bonn, Germany. , (Chosidow O.) Department of Dermatology, Hospital Henri Mondor, Creteil, France. , (Bodsworth N.) Taylor Square Private Clinic, Darlinghurst, NSW, Australia. , (Tyring S.) Department of Dermatology, University of Texas Health Science Center, Houston, TX, United States. , (Hercogova J.) Dermatovenereology Department, Bulovka Hospital, Prague, Czech Republic. , (Bloch M.) Holdsworth House Medical Practice, Darlinghurst, NSW, Australia. , (Davis M.) Rochester Clinical Research, Rochester, NY, United States. , (Lewis M.) School of Dentistry, College of Biomedical and Life Sciences, Cardiff, United Kingdom. , (Boutolleau D.) Virology Department, Hospital Pitie-Salpetriere, Paris, France. , (Attali P., pierre.attali@bioalliancepharma.com) BioAlliance Pharma, Paris, France. , (Bisshop F.R.; Bloch M.T.; Bodworth N.J.) , (Aster V.; Asterova J.; Hercogova J.; Klimesova R.; Krajsova I.) , (Ben Slama L.; Cambazard F.; Chosidow O.; Dubertret L.; Granel F.; Humbert P.; Ortonne J.P.; Rostain G.; Ruer-Mulard M.; Vaillant L.) , (Beiber T.; Degen A.J.; Dorzapf O.; Von Hake G.; Miller A.; Naudts I.; Steinert M.; Stockfleth E.; Weihe J.; Wunderlich U.) , (Jasieniak-Pinis G.; Kazina M.; Pawlaczyk-Strugala E.; Placek W.; Petryka R.; Romanowski L.) , (Dixon C.J.; Lewis M.; Sharma R.) , (Archuleta M.; Baker D.A.; Cady R.K.; Conant M.A.; Crump W.L.; Davis M.G.; Dunlap F.E.; Lee P.C.; McCarthy F.T.; Tyring S.K.)

P. Attali, BioAlliance Pharma, Paris, France. Email: pierre.attali@bioalliancepharma.com

Journal of Drugs in Dermatology (2014) 13:7 (791-798). Date of Publication: July 2014

1545-9616

Journal of Drugs in Dermatology, staff@jddonline.com

Background: Single-day, high-dose systemic antiviral drugs are effective in the treatment of labial herpes (herpes labialis [HL]). Aciclovir Lauriad mucoadhesive buccal tablet (ABT) is an innovative drug delivery system providing high and prolonged exposure to aciclovir in the oral cavity, supporting its evaluation as a single low dose in HL. Methods: In this multicenter double-blind placebo-controlled patient-initiated trial, 775 patients with recurrent HL were randomly assigned to either a single application of ABT 50 mg or a matching placebo as soon as prodromal symptoms occurred. The primary endpoint was the time to healing (TTH) of primary vesicular lesion (modified intention-to-treat population). Other endpoints included incidence of blocked episodes, duration of herpes episodes, and incidence and time to next recurrence evaluated during a 9-month follow-up period (intention-to-treat population). Results: With ABT 50 mg, median TTH of primary vesicular lesion was reduced (7 days vs 7.3 days, P=.015), the incidence of blocked herpes episodes was increased by 24.2% (34.9% vs 28.1%; P=.042), and the median duration of herpes episodes was reduced (5.6 days vs 6.4 days, P=.003). During the 9-month follow-up period, recurrence of herpes lesions was less frequent (64.2% vs 73.6%; P=.027) and delayed (205 days vs 165 days, P=.041) in the ABT 50 mg. Both treatments were safe. Conclusion: A single application of ABT improves all endpoints of HL and might modify its clinical course in decreasing the incidence and delaying the onset of the next recurrence. Copyright (copyright) 2014 Journal of Drugs in Dermatology.

aciclovir (adverse drug reaction, buccal drug administration, clinical trial, drug administration, drug therapy)

aciclovir lauriad, placebo, unclassified drug

herpes labialis (drug therapy, drug therapy), immunocompromised patient

adolescent, aphthous stomatitis (side effect), application site irritation (side effect), application site pain (side effect), article, controlled study, coughing (side effect), dizziness (side effect), double blind procedure, drug efficacy, drug eruption (side effect), drug safety, erythema (side effect), fatigue (side effect), female, follow up, gingiva pain (side effect), headache (side effect), human, incidence, influenza (side effect), lethargy (side effect), major clinical study, male, multicenter study, nausea (side effect), outcome assessment, pharyngitis (side effect), prodromal symptom, randomized controlled trial, recurrent infection, rhinopharyngitis (side effect), sore throat (side effect), stomach discomfort (side effect), vesicular rash, virus infection (side effect)

aciclovir lauriad

aciclovir (59277-89-3)

Otorhinolaryngology (11), Immunology, Serology and Transplantation (26), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00769314)

Copyright 2014 Elsevier B.V., All rights reserved.

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery

Carpenter R., Doughty J.C., Cordiner C., Moss N., Gandhi A., Wilson C., Andrews C., Ellis G., Gui G., Skene A.I.

(Carpenter R., robert.carpenter@uclh.nhs.uk) Breast Unit, University College London Hospitals NHS Trust, 250 Euston Road, London NW1 2PQ, United Kingdom. , (Doughty J.C.; Wilson C.) University Department of Surgery, Western Infirmary Glasgow, Glasgow, United Kingdom. , (Cordiner C.; Moss N.) West of Scotland Breast Screening Centre, Glasgow, United Kingdom. , (Gandhi A.) University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom. , (Andrews C.) Novartis Pharmaceuticals UK Ltd, Camberley, United Kingdom. , (Ellis G.) CR Projects Ltd, Guildford, United Kingdom. , (Gui G.) Royal Marsden Hospital, London, United Kingdom. , (Skene A.I.) Royal Bournemouth Hospital, Bournemouth, United Kingdom.

R. Carpenter, Breast Unit, University College London Hospitals NHS Trust, 250 Euston Road, London NW1 2PQ, United Kingdom. Email: robert.carpenter@uclh.nhs.uk

Breast Cancer Research and Treatment (2014) 144:3 (569-576). Date of Publication: April 2014

1573-7217 (electronic),0167-6806

Springer New York LLC, journals@springer-sbm.com

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors ((greater-than or equal to)T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69% of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95% CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS. (copyright) Springer Science+Business Media 2014.

letrozole (adverse drug reaction, clinical trial, drug therapy, oral drug administration)

estrogen receptor (endogenous compound), progesterone receptor (endogenous compound)

adjuvant chemotherapy, breast cancer (drug therapy, diagnosis, drug therapy, surgery), early cancer (drug therapy, diagnosis, drug therapy, surgery), partial mastectomy, treatment duration

adult, arthralgia (side effect), article, cancer growth, cancer recurrence, cancer staging, carpal tunnel syndrome (side effect), cerebrovascular accident (side effect), disease course, dizziness (side effect), drug efficacy, drug tolerability, drug withdrawal, fatigue (side effect), female, headache (side effect), hot flush (side effect), human, human tissue, longitudinal study, maculopapular rash (side effect), major clinical study, medical decision making, multicenter study, musculoskeletal pain (side effect), open study, osteoporosis (side effect), patient compliance, phase 4 clinical trial, priority journal, prospective study, treatment indication, tumor invasion, tumor volume

femara (Novartis, United States)

Novartis (United States)

letrozole (112809-51-5)

Cancer (16), Public Health, Social Medicine and Epidemiology (17), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00330317)

http://dx.doi.org/10.1007/s10549-014-2835-8

Copyright 2014 Elsevier B.V., All rights reserved.

A randomized, investigator-masked, double-blind, placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis

Droitcourt C., Rybojad M., Porcher R., Juillard C., Cosnes A., Joly P., Lacour J.-P., D'Incan M., Dupin N., Sassolas B., Misery L., Chevrant-Breton J., Lebrun-Vignes B., Desseaux K., Valeyre D., Revuz J., Tazi A., Chosidow O., Dupuy A.

(Droitcourt C.; Dupuy A.) Department of Dermatology, CHU Rennes, Pontchaillou Hospital, 2 rue Henri le Guilloux, 35000 Rennes, France. , (Droitcourt C.; Dupuy A.) Inserm CIC 1414, Universite de Rennes 1, Rennes, France. , (Droitcourt C.; Dupuy A.) Inserm CIC 1414, Pharmacoepidemiology Unit, Rennes, France. , (Rybojad M.; Juillard C.) Department of Dermatology, Hopital Saint-Louis, AP-HP, Paris, France. , (Porcher R.; Desseaux K.) Department of Biostatistics and Medical Informatics, Hopital Saint-Louis, AP-HP, Paris, France. , (Tazi A.) Department of Pneumology, Hopital Saint-Louis, AP-HP, Paris, France. , (Porcher R.; Desseaux K.; Tazi A.) Universite de Paris Diderot-Sorbonne Paris Cite, Paris, France. , (Porcher R.; Desseaux K.) Inserm U717, Paris, France. , (Dupin N.) Department of Dermatology, Hopital Cochin, AP-HP, Paris, France. , (Dupin N.) Universite Rene Descartes, Paris, France. , (Lebrun-Vignes B.) Pharmacovigilance Center, Groupe Hospitalier Pitie-Salpetriere - Charles Foix, AP-HP, Paris, France. , (Chevrant-Breton J.; Valeyre D.) Department of Pneumology, Hopital Avicenne, AP-HP, Bobigny, France. , (Valeyre D.) Universite Paris-Nord, Bobigny, France. , (Revuz J.) 11 chaussee de la Muette, Paris, France. , (Joly P.) Clinique Dermatologique, CHU Rouen, Rouen, France. , (Joly P.) Institute for Research and Innovation in Biomedicine (IRIB), Universite de Rouen, Inserm U905, Rouen, France. , (Lacour J.-P.) Department of Dermatology, Hopital Archet-2, CHU Nice, Nice, France. , (Lacour J.-P.) Sophia Antipolis, Universite de Nice, Nice, France. , (D'Incan M.) Department of Dermatology, CHU Estaing, Universite D'Auvergne, Clermont-Ferrand, France. , (Sassolas B.; Misery L.) Department of Dermatology, CHRU Brest, Brest, France. , (Misery L.) UFR Medicine, Universite de Brest, Brest, France. , (Cosnes A.; Chosidow O.) Department of Dermatology, Hopital Henri-Mondor, AP-HP, Creteil, France. , (Chosidow O.) UPEC Universite de Paris Est-Creteil Val-de-Marne, Creteil, France. , (Chosidow O.) French Satellite of Cochrane Skin Group, Centre D'Investigation Clinique 006-Inserm, Creteil, France.

A. Dupuy, Department of Dermatology, CHU Rennes, Pontchaillou Hospital, 2 rue Henri le Guilloux, 35000 Rennes, France.

Chest (2014) 146:4 (1046-1054). Date of Publication: 1 Oct 2014

1931-3543 (electronic),0012-3692

American College of Chest Physicians

BACKGROUND: Th alidomide use in cutaneous sarcoidosis is based on data from small case series or case reports. The objective of this study was to evaluate the efficacy and safety of thalidomide in severe cutaneous sarcoidosis.METHODS: This study consisted of a randomized, double-bind, parallel, placebo-controlled, investigator-masked, multicenter trial lasting 3 months and an open-label study from month 3 to month 6. Adults with a clinical and histologic diagnosis of cutaneous sarcoidosis were included in nine hospital centers in France. Patients were randomized 1:1 to oral thalidomide (100 mg once daily ) or to a matching oral placebo for 3 months. In the course of an open-label follow-up from month 3 to month 6, all patients received thalidomide, 100 mg to 200 mg daily. The proportions of patients with a partial or complete cutaneous response at month 3, based on at least a 50% improvement in three target lesions scored for area and infiltration, were compared across randomization groups.RESULTS: The intent-to-treat population included 39 patients. None of them had a complete cutaneous response. Four out of 20 patients in the thalidomide group (20%) vs four out of 19 patients in the placebo group (21%) had a partial cutaneous response at month 3 (difference in proportion of 2 1% [95% CI, 2 26% to 1 24%] for thalidomide vs placebo, P 5 1.0). Eight patients with side effects were recorded in the thalidomide group vs three in the placebo group. We observed a large number of adverse event-related discontinuations in patients taking thalidomide in the first 3 months (four patients with thalidomide, zero with placebo) and in the 3 following months (five patients).CONCLUSIONS: At a dose of 100 mg daily for 3 months, our results do not encourage thalidomide use in cutaneous sarcoidosis.TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT0030552; URL: Www.clinicaltrials.gov.

thalidomide (adverse drug reaction, clinical trial, drug comparison - placebo, drug dose, drug therapy, oral drug administration)

sarcoidosis (drug therapy, drug therapy)

abdominal pain (side effect), adult, article, bone pain (side effect), brain hemorrhage (side effect), cell infiltration, clinical article, controlled study, depression (side effect), diarrhea (side effect), disease severity, dizziness (side effect), double blind procedure, drowsiness (side effect), drug dose increase, drug efficacy, drug safety, drug withdrawal, dyspnea (side effect), elbow disease (side effect), facial nerve paralysis (side effect), female, follow up, headache (side effect), human, hypothyroidism (side effect), intention to treat analysis, male, multicenter study, open study, outcome assessment, parallel design, peripheral neuropathy (side effect), randomized controlled trial, skin defect, thorax pain (side effect), treatment duration, treatment response

thalidomide (50-35-1)

Dermatology and Venereology (13), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00305552)

http://dx.doi.org/10.1378/chest.14-0015

Copyright 2014 Elsevier B.V., All rights reserved.

Once-daily prandial lixisenatide versus once-daily rapid-acting insulin in patients with type 2 diabetes mellitus insufficiently controlled with basal insulin: Analysis of data from five randomized, controlled trials

Raccah D., Lin J., Wang E., Germe M., Perfetti R., Bonadonna R.C., De Pablos-Velasco P., Roussel R., Rosenstock J.

(Raccah D., denis.raccah@ap-hm.fr) Service de Nutrition Endocrinologie, Maladies Metaboliques, Hopital Sainte Marguerite, 270 Boulevard de Sainte Marguerite, 13009 Marseille, France. , (Lin J.) Outcomes Research, Novosys Health, Flemington, NJ, United States. , (Wang E.) Diabetes-Metabolism Franchise, Sanofi-Aventis US, Bridgewater, NJ, United States. , (Germe M.; Perfetti R.) Diabetes-Metabolism Franchise, Sanofi, Paris, France. , (Bonadonna R.C.) University of Verona Medical School, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. , (De Pablos-Velasco P.) Dr Negrin Hospital, Las Palmas University, Las Palmas, Spain. , (Roussel R.) Department of Diabetology, Endocrinology and Nutrition, Assistance Publique Hopitaux de Paris, Paris, France. , (Roussel R.) INSERM, Research Unit 872, Paris, France. , (Roussel R.) University Paris Diderot, Sorbonne Paris Cite, UFR de Medecine, Paris, France. , (Rosenstock J.) Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, United States.

D. Raccah, Service de Nutrition Endocrinologie, Maladies Metaboliques, Hopital Sainte Marguerite, 270 Boulevard de Sainte Marguerite, 13009 Marseille, France. Email: denis.raccah@ap-hm.fr

Journal of Diabetes and its Complications (2014) 28:1 (40-44). Date of Publication: January-February 2014

1056-8727,1873-460X (electronic)

Elsevier Inc., 360 Park Avenue South, New York, United States.

Aims To compare the efficacy and safety of lixisenatide (LIXI), a once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist, as add-on to basal insulin (Basal + LIXI) versus once-daily rapid-acting insulin (Basal + RAI) in patients with type 2 diabetes mellitus (T2DM). Methods Data were extracted from five randomized controlled trials assessing the efficacy and safety of basal insulin + insulin glulisine (n = 3) or basal insulin + LIXI (n = 2). Patients in the Basal + LIXI cohort were matched to patients in the Basal + RAI cohort using propensity score matching. Results In the matched population, Basal + LIXI was twice as likely to reach composite outcomes of glycated haemoglobin (HbA(1c)) < 7% and no symptomatic hypoglycaemia compared with the Basal + RAI group (odds ratio [OR]: 1.90; 95% confidence interval [CI]: 1.01, 3.55; P = 0.0455), as well as HbA(1c) < 7% and no severe hypoglycaemia (OR: 1.97; 95 CI: 1.06, 3.66; P = 0.0311). Furthermore, Basal + LIXI was more than twice as likely to reach HbA(1c) < 7%, no weight gain and no symptomatic hypoglycaemia (OR: 2.58; 95% CI: 1.23, 5.40; P = 0.0119). Conclusions Both basal + LIXI and Basal + RAI improved glycaemic control in patients with T2DM with inadequate glycaemic control on basal insulin. Basal + LIXI offers an effective therapeutic option to advance basal insulin therapy, improving glucose control without weight gain and with less risk of hypoglycaemia than prandial insulin. (copyright) 2014 Elsevier Inc.

basal insulin (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), insulin (clinical trial, drug therapy), lixisenatide (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), short acting insulin (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy)

glucose (endogenous compound), hemoglobin A1c (endogenous compound), insulin glargine (drug combination, drug therapy), insulin glulisine (drug combination, drug therapy), unclassified drug

insulin treatment, non insulin dependent diabetes mellitus (drug therapy, drug therapy)

absence of side effects (side effect), article, cohort analysis, controlled study, drug efficacy, drug safety, female, glucose blood level, glycemic control, human, major clinical study, male, priority journal, randomized controlled trial (topic), single drug dose, treatment outcome

apidra, lantus

glucose (50-99-7, 84778-64-3), hemoglobin A1c (62572-11-6), insulin (9004-10-8), insulin glargine (160337-95-1), insulin glulisine (207748-29-6), lixisenatide (320367-13-3)

Endocrinology (3), Internal Medicine (6), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00135083, NCT00272012, NCT00272064, NCT00715624, NCT00975286, NCT01768559)

http://dx.doi.org/10.1016/j.jdiacomp.2013.10.003

Copyright 2014 Elsevier B.V., All rights reserved.

An individual patient-based meta-analysis of the effects of dronedarone in patients with atrial fibrillation

Hohnloser S.H., Connolly S.J., John Camm A., Halperin J.L., Radzik D.

(Hohnloser S.H., hohnloser@em.uni-frankfurt.de) Division of Clinical Electrophysiology, J. W. Goethe University, Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany. , (Connolly S.J.) McMaster University, Hamilton, ON, Canada. , (John Camm A.) Department of Clinical Sciences, St George's University of London, London, United Kingdom. , (Halperin J.L.) Cardiovascular Institute, Mount Sinai Medical Center, New York, NY, United States. , (Radzik D.) Sanofi Recherche, Paris, France.

S.H. Hohnloser, Division of Clinical Electrophysiology, J. W. Goethe University, Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany. Email: hohnloser@em.uni-frankfurt.de

Europace (2014) 16:8 (1117-1124). Date of Publication: August 2014

1532-2092 (electronic),1099-5129

Oxford University Press, jnl.info@oup.co.uk

Aims Dronedarone is a non-iodinated benzofuran derivative with antiarrhythmic properties. In placebo-controlled atrial fibrillation (AF) trials, the drug was found to have divergent effects on endpoints such as cardiovascular death or hospitalization. The objective of this meta-analysis of all placebo-controlled studies was to provide insights on possible reasons for these divergent effects. Methods and results Individual data on 9664 patients were used from all AF placebo-controlled studies. The primary outcome measure was cardiovascular death. Cardiovascular hospitalization and hospitalization for heart failure were secondary endpoints. Predefined procedures were used to reduce inter-study heterogeneity adjusting for important baseline variables using a Cox model. Despite adjustments, a significant inter-trial heterogeneity of the outcome of cardiovascular mortality persisted (P-value of 0.005 for the treatment effect null study interaction). Further analyses were conducted in subgroups based on baseline clinical criteria: digoxin co-prescription, advanced heart failure, coronary artery disease, or the presence of permanent AF. These analyses allowed the calculation of a global treatment effect in two important patient subgroups, those with permanent AF in whom there was harm with respect to cardiovascular mortality [hazard ratio (HR) = 2.32; 95% confidence interval (CI) 1.13-4.75] and hospitalization for heart failure (HR = 1.674; 95% CI 1.05-2.67); and those with non-permanent AF in whom there was benefit in terms of cardiovascular hospitalization [HR = 0.751 95% CI (0.68-0.83)]. Conclusion This meta-analysis demonstrates significant heterogeneity of dronedarone treatment effects across the placebo-controlled randomized trials. The most important predictor of a harmful effect of dronedarone on cardiovascular death and heart failure hospitalization was the presence of permanent AF. (copyright) 2014 Published on behalf of the European Society of Cardiology. All rights reserved. (copyright) The Author 2014.

dronedarone (adverse drug reaction, clinical trial, drug therapy, pharmacology)

digoxin, placebo

heart atrium fibrillation (drug therapy, drug therapy)

article, cardiovascular mortality, coronary artery disease, drug effect, drug efficacy, drug safety, heart failure, hospitalization, human, meta analysis, outcome assessment, phase 2 clinical trial (topic), phase 3 clinical trial (topic), prescription, priority journal, randomized controlled trial (topic), unspecified side effect (side effect)

digoxin (20830-75-5, 57285-89-9), dronedarone (141626-36-0)

Cardiovascular Diseases and Cardiovascular Surgery (18), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00174785, NCT00259376, NCT00259428, NCT00543699, NCT00697086, NCT01151137)

http://dx.doi.org/10.1093/europace/euu065

Copyright 2014 Elsevier B.V., All rights reserved.

Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor- related pain

Kress H.G., Koch E.D., Kosturski H., Steup A., Karcher K., Lange B., Dogan C., Etropolski M., Eerdekens M.

(Kress H.G., anaesthesie-schmerz@meduniwien.ac.at) Department of Special Anesthesia and Pain Therapy, Medical University of Vienna/ AKH, Vienna, Austria. , (Koch E.D.; Kosturski H.; Steup A.; Lange B.; Dogan C.; Eerdekens M.) Grunenthal GmbH, Aachen, Germany. , (Karcher K.; Etropolski M.) Janssen Research and Development, LLC, Raritan, NJ, United States.

H. G. Kress, Department of Special Anesthesia and Pain Therapy, Medical University of Vienna/ AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Email: anaesthesie-schmerz@meduniwien.ac.at

Pain Physician (2014) 17:4 (329-343). Date of Publication: July/August 2014

1533-3159

American Society of Interventional Pain Physicians, editor@painphysicianjournal.com

Background: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain. Objectives: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain. Study Design: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303). Setting: Primary, secondary, and tertiary care settings in 16 countries. Methods: Eligible patients (pain intensity (greater-than or equal to) 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100 - 250 mg bid) or morphine sulfate CR (40 - 100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use (less-than or equal to) 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: 1) completed the maintenance period, 2) a mean pain intensity < 5 during maintenance, and 3) used an average of (less-than or equal to) 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration. Results: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively. Limitations: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration. Conclusions: Results obtained during maintenance indicate that tapentadol PR (100 - 250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40 - 100 mg bid), but is associated with better gastrointestinal tolerability.

tapentadol (adverse drug reaction, clinical trial, drug comparison, drug therapy)

morphine sulfate (adverse drug reaction, clinical trial, drug comparison, drug therapy), placebo

cancer pain (drug therapy, drug therapy), drug release

adult, aged, article, constipation (side effect), controlled drug release, decreased appetite (side effect), dizziness (side effect), double blind procedure, drug dose titration, drug efficacy, drug safety, drug tolerability, drug withdrawal, evaluation study, fatigue (side effect), female, gastrointestinal disease (side effect), human, hyperhidrosis (side effect), maintenance therapy, major clinical study, male, multicenter study, nausea and vomiting (side effect), neurologic disease (side effect), phase 3 clinical trial, randomized controlled trial, somnolence (side effect), treatment outcome, xerostomia (side effect)

morphine sulfate (23095-84-3, 35764-55-7, 64-31-3), tapentadol (175591-09-0, 175591-23-8)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Internal Medicine (6)

ClinicalTrials.gov (NCT00472303, NCT00505414)

Copyright 2014 Elsevier B.V., All rights reserved.

Bioequivalence and dose proportionality of inhaled fluticasone furoate

Allen A., Bal J., Moore A., Stone S., Tombs L.

(Allen A., ann.allen@gsk.com) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline R and D, Stevenage, United Kingdom. , (Bal J.; Moore A.; Stone S.) GlaxoSmithKline R and D, Stockley Park, United Kingdom. , (Tombs L.) Synergy, Slough, Berkshire, United Kingdom.

A. Allen, Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, SG1 2NY, United Kingdom. Email: ann.allen@gsk.com

Journal of Bioequivalence and Bioavailability (2014) 6:1 (24-32). Date of Publication: 2014

0975-0851 (electronic)

OMICS Publishing Group, 1058 Reed Terrace, Ste 1, Sunnyvale, United States.

Fluticasone furoate (FF), a new inhaled corticosteroid delivered via the ELLIPTA dry powder inhaler, is being developed as a once-daily inhaled treatment for asthma. Study 1 was a part-randomised, open-label, four-way crossover, single and repeat-dose study in healthy subjects (n=36) to assess whether the systemic exposure of FF increased proportionately across different strengths of FF (50 (mu)g, 100 (mu)g and 200 (mu)g) and to determine the absolute bioavailability of FF inhalation powder. Study 2 was a randomised, open-label, replicate, six-way crossover, single-dose study in healthy subjects (n=30) to determine the bioequivalence of FF inhalation powder (single-strip configuration) compared with FF inhalation powder (two-strip configuration) and with fluticasone furoate/vilanterol (FF/VI) inhalation powder. A population pharmacokinetic analysis was also conducted on sparse samples collected from asthma patients in five Phase III studies conducted with FF/ VI or FF. Overall, FF systemic exposure, as measured by single-dose AUC((0-(infinity))), was dose proportional whilst C(max) showed a less than proportional increase. Inhaled absolute bioavailability of FF was 14%. Bioequivalence was not demonstrated for FF single-strip compared with either FF two-strip or FF/VI since the estimated 90% confidence interval for the ratio of adjusted geometric means for AUC and C(max) did not fall completely between 0.8000-1.2500. However, this difference was in line with the higher respirable mass delivered by the batch of single-strip product used in this study. Although the formal bioequivalence study showed higher exposure with FF single-strip ELLIPTA compared with FF two-strip or FF/VI, the results of the population PK analysis of data in asthmatics show that there is no notable difference in systemic exposure between the FF configurations (single-strip, two-strip or FF/VI). In healthy subjects all treatments were generally safe and no new safety issues were apparent at these supra-therapeutic inhaled doses of FF (up to 1200 (mu)g) and high intravenous FF dose (250 (mu)g). (copyright) 2014 Allen A, et al.

fluticasone furoate (adverse drug reaction, drug combination, drug concentration, inhalational drug administration, intravenous drug administration, pharmacokinetics, pharmacology)

codeine (drug therapy), doxycycline (drug therapy), fluticasone propionate, lactose, magnesium stearate, paracetamol (drug therapy), umeclidinium, unclassified drug, vilanterol (adverse drug reaction, drug combination, drug concentration, inhalational drug administration, pharmacokinetics)

bioequivalence, dose calculation

adult, aged, area under the curve, article, body mass, controlled study, crossover procedure, drug bioavailability, dysphonia (side effect), electrocardiography, female, headache (drug therapy, side effect), high performance liquid chromatography, human, human experiment, ligament sprain (side effect), ligament sprain (side effect), major clinical study, male, multicenter study, normal human, phase 3 clinical trial, randomized controlled trial, rash (side effect), repeated drug dose, rhinopharyngitis (side effect), single drug dose, sore throat (drug therapy), sprain (side effect), tandem mass spectrometry, upper respiratory tract infection (drug therapy, side effect)

cci 18781, ellipta, gw 685698

codeine (76-57-3), doxycycline (10592-13-9, 17086-28-1, 564-25-0, 94088-85-4), fluticasone furoate (397864-44-7), fluticasone propionate (80474-14-2), lactose (10039-26-6, 16984-38-6, 63-42-3, 64044-51-5), magnesium stearate (557-04-0), paracetamol (103-90-2), vilanterol (503068-34-6)

Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT01018186, NCT01086410, NCT01134042, NCT01431950, NCT01485445, NCT01669070)

http://dx.doi.org/10.4172/jbb.1000176

Copyright 2014 Elsevier B.V., All rights reserved.

Cognitive effects of statin medications

Kelley B.J., Glasser S.

(Kelley B.J., brendan.kelley@osumc.edu) Department of Neurology, Ohio State University, Columbus, OH 43210, United States. , (Glasser S., sglasser@uabmc.edu) Division of Preventive Medicine, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, United States.

S. Glasser, Division of Preventive Medicine, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, United States. Email: sglasser@uabmc.edu

CNS Drugs (2014) 28:5 (411-419). Date of Publication: May 2014

1179-1934 (electronic),1172-7047

Adis International Ltd

The demonstrated benefits of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for cardiovascular and cerebrovascular disease are well established in the medical literature, and this class of medications is among those most commonly prescribed in the USA. In 2012, the US Food and Drug Administration issued updated recommendations regarding statin medications, and the panel's comments regarding memory impairment fostered clinical confusion (in part because of the lay media's amplification). Cognitive data from several large epidemiological studies have not reliably demonstrated a robust association between incident cognitive impairment and statin use, with some studies reporting a protective effect, some reporting an increased risk and others finding no association. Although several interventional studies have evaluated statins as a possible adjunctive treatment for Alzheimer's disease, none have clearly demonstrated a benefit. A small number of case series have reported infrequent memory difficulties associated with statin use. In these series, the patients' cognitive symptoms resolved after statin discontinuation. The existing medical literature does not suggest that cognitive considerations should play a major role in medical decision making to prescribe statins for the large majority of patients. As with any medication prescribed for older adults, careful clinical monitoring for side effects should be exercised. If a patient is suspected of having idiosyncratic memory impairment associated with use of a statin medication, the drug can be discontinued. The patient should then be followed with careful clinical observation for 1-3 months for resolution of the cognitive symptoms. (copyright) 2014 Springer International Publishing Switzerland.

hydroxymethylglutaryl coenzyme A reductase inhibitor

atorvastatin, mevinolin, pitavastatin, pravastatin, simvastatin

cognition, cognitive defect

Alzheimer disease, amnesia, article, blood pressure, dementia, disorders of mitochondrial functions, drug monitoring, human, medical decision making, mild cognitive impairment, nonhuman, patient assessment, prevalence, priority journal, short term memory, word list recall

atorvastatin (134523-00-5, 134523-03-8), mevinolin (75330-75-5), pitavastatin (147526-32-7), pravastatin (81093-37-0, 81131-70-6), simvastatin (79902-63-9)

Drug Literature Index (37), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00024531, NCT00046358, NCT00053599, NCT00151502, NCT00303277, NCT00486044, NCT00548145, NCT00751907, NCT00842920, NCT00939822, NCT01142336, NCT01439555)

http://dx.doi.org/10.1007/s40263-014-0147-5

Copyright 2014 Elsevier B.V., All rights reserved.

FAP neuropathy and emerging treatments

Adams D., Theaudin M., Cauquil C., Algalarrondo V., Slama M.

(Adams D., david.adams@bct.aphp.fr; Theaudin M.; Cauquil C.; Algalarrondo V.; Slama M.) APHP, HUPS, Univ. Paris Sud, Le Kremlin Bicetre Cedex, France. , (Adams D., david.adams@bct.aphp.fr; Theaudin M.; Cauquil C.) Department of Neurology, CHU Bicetre, 78 rue du general leclerc, 94275 Le Kremlin Bicetre Cedex, France. , (Algalarrondo V.) Department of Cardiology (NNERf), CHU Antoine Beclere, Clamart, France. , (Adams D., david.adams@bct.aphp.fr; Theaudin M.; Algalarrondo V.; Slama M.) Inserm U788, French Referral Center for Familial Amyloid Polyneuropathy (NNERf), Paris, France.

D. Adams, Department of Neurology, CHU Bicetre, 78 rue du general leclerc, 94275 Le Kremlin Bicetre Cedex, France. Email: david.adams@bct.aphp.fr

Current Neurology and Neuroscience Reports (2014) 14:3. Date of Publication: March 2014

1534-6293 (electronic),1528-4042

Current Medicine Group LLC, info@currentmedicinegroup.com

Transthyretin familial amyloid polyneuropathy (TTR-FAP) classically presents as a length dependent small fiber polyneuropathy in endemic countries like Portugal. In nonendemic countries, it may mimic a variety of chronic polyneuropathies, with several phenotypes: ataxic, upper limb onset neuropathy, or motor. In these cases, there is usually a late onset and no positive family history. TTR gene sequencing appears the most pertinent first-line test for diagnosis. Cardiac involvement of various severities is common in FAP. Liver transplantation remains the standard antiamyloid therapy with better results in Val30Met TTR-FAP of early onset. Antiamyloid medication has been developed. (1) TTR stabilizers: Tafamidis was the first drug approved in Europe in stage 1 (walking unaided) TTR-FAP to slow progression of the disease; diflunisal has been assessed in a phase 3 clinical trial; (2) TTR gene silencing is a new strategy to inhibit production of both mutant and nonmutant TTR with antisense oligonucleotides or SiRNA (2 ongoing phase 3 clinical trials). (copyright) Springer Science+Business Media 2014.

antisense oligonucleotide (clinical trial, drug therapy, pharmaceutics, pharmacology), beta 2 microglobulin (endogenous compound), diflunisal (clinical trial, drug therapy), methionine (endogenous compound), placebo, prealbumin (endogenous compound), serum amyloid P (clinical trial, drug therapy), small interfering RNA (clinical trial, drug therapy, pharmaceutics, pharmacology), tafamidis (adverse drug reaction, clinical trial, drug therapy), valine (endogenous compound)

familial amyloid polyneuropathy (drug therapy, diagnosis, drug therapy, etiology, surgery)

article, diarrhea (side effect), disease course, drug binding site, drug delivery system, feces incontinence (side effect), gene mutation, gene sequence, gene silencing, genetic counseling, genetic heterogeneity, heart disease, human, liver transplantation, multicenter study (topic), neurologic disease (side effect), nonhuman, orthostatic hypotension (side effect), phase 3 clinical trial (topic), phenotype, protein synthesis inhibition, randomized controlled trial (topic), urinary tract infection (side effect), walking difficulty (side effect)

beta 2 microglobulin (9066-69-7), diflunisal (22494-42-4), methionine (59-51-8, 63-68-3, 7005-18-7), tafamidis (594839-88-0), valine (7004-03-7, 72-18-4)

Human Genetics (22), Clinical and Experimental Biochemistry (29), Drug Literature Index (37), Adverse Reactions Titles (38), General Pathology and Pathological Anatomy (5), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00294671, NCT00409175, NCT01737398, NCT01960348)

http://dx.doi.org/10.1007/s11910-013-0435-3

Copyright 2014 Elsevier B.V., All rights reserved.

Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: A randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder

Boulenger J.-P., Loft H., Olsen C.K.

(Boulenger J.-P., jp-boulenger@chu-montpellier.fr) University Department of Adult Psychiatry, Hopital la Colombiere, CHRU de Montpellier, 39 Avenue Charles Flahault, F-34295 Montpellier Cedex 5, France. , (Loft H.; Olsen C.K.) H. Lundbeck A/S, Copenhagen, Denmark.

J.-P. Boulenger, University Department of Adult Psychiatry, Hopital la Colombiere, CHRU de Montpellier, 39 Avenue Charles Flahault, F-34295 Montpellier Cedex 5, France. Email: jp-boulenger@chu-montpellier.fr

International Clinical Psychopharmacology (2014) 29:3 (138-149). Date of Publication: May 2014

1473-5857 (electronic),0268-1315

Lippincott Williams and Wilkins, agents@lww.com

This study assessed the efficacy, tolerability and safety of vortioxetine versus placebo in adults with recurrent major depressive disorder. This double-blind, randomized, placebo-controlled study included 608 patients [Montgomery-Asberg Depression Rating Scale (MADRS) total score(greater-than or equal to)26 and Clinical Global Impression-Severity score(greater-than or equal to)4]. Patients were randomly assigned (1 : 1 : 1 : 1) to vortioxetine 15 mg/day, vortioxetine 20 mg/day, duloxetine 60 mg/day or placebo. The primary efficacy endpoint was change from baseline in MADRS total score at week 8 (mixed model for repeated measurements). Key secondary endpoints were: MADRS responders; Clinical Global Impression- Improvement scale score; MADRS total score in patients with baseline Hamilton Anxiety Rating Scale (greater-than or equal to)20; remission (MADRS(less-than or equal to)10); and Sheehan Disability Scale total score at week 8. On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n=158) of-5.5 (vortioxetine 15 mg, P<0.0001, n=149) and-7.1 MADRS points (vortioxetine 20 mg, P<0.0001, n=151). Duloxetine (n=146) separated from placebo, thus validating the study. In all key secondary analyses, both vortioxetine doses were statistically significantly superior to placebo. Vortioxetine treatment was well tolerated; common adverse events (incidence(greater-than or equal to)5%) were nausea, headache, diarrhea, dry mouth and dizziness. No clinically relevant changes were seen in clinical safety laboratory values, weight, ECG or vital signs parameters. Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder. (copyright) 2014 Wolters Kluwer Health.

vortioxetine (adverse drug reaction, clinical trial, drug dose, drug therapy, oral drug administration)

duloxetine (adverse drug reaction, drug therapy), lormetazepam, lu aa 21004, placebo, unclassified drug, zolpidem

major depression (drug therapy, disease management, drug therapy)

adult, aged, agitation, anorgasmia (side effect), anxiety disorder (side effect), article, automutilation (side effect), Clinical Global Impression scale, controlled study, crying, diarrhea (side effect), disease severity, dizziness (side effect), dose response, double blind procedure, dreaming, drug dose reduction, drug efficacy, drug induced headache (side effect), drug overdose, drug safety, drug tolerability, drug withdrawal, ejaculation disorder (side effect), electrocardiogram, erectile dysfunction (side effect), family life, fatigue (side effect), female, Hamilton Anxiety Scale, human, hyperhidrosis (side effect), insomnia (side effect), irritability, libido disorder (side effect), major clinical study, male, Montgomery Asberg Depression Rating Scale, mood disorder (side effect), multicenter study, nausea (side effect), nervousness, nightmare (side effect), orgasm disorder (side effect), patient satisfaction, priority journal, quality of life, quality of life enjoyment and satisfaction questionnaire, questionnaire, randomized controlled trial, recurrent disease, remission, sexual dysfunction (side effect), sexual function, Sheehan Disability Scale, side effect (side effect), social life, suicidal behavior (side effect), suicidal ideation (side effect), treatment withdrawal, vertigo (side effect), vital sign, work, xerostomia (side effect)

lu aa 21004

duloxetine (116539-59-4, 136434-34-9), lormetazepam (848-75-9), vortioxetine (508233-74-7, 960203-27-4), zolpidem (82626-48-0)

Psychiatry (32), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00788034)

http://dx.doi.org/10.1097/YIC.0000000000000018

Copyright 2014 Elsevier B.V., All rights reserved.

Quantifying Gp96/Grp94 complexes preparations for vaccines: A key step often inaccurate

Seignez A., Kohli E., Garrido C., Seigneuric R.

(Seignez A.; Kohli E.; Garrido C., cgarrido@u-bourgogne.fr; Seigneuric R.) Inserm U866: Lipids, Nutr., Cancer,Equipe Labellisee Par la Ligue Nationale Contre le Cancer, 21000 Dijon, France. , (Seignez A.; Kohli E.; Garrido C., cgarrido@u-bourgogne.fr; Seigneuric R.) Universite de Bourgogne, 21000 Dijon, France. , (Seignez A.) Service de Medecine Interne et Immunologie Clinique, CHU de Dijon, 21000 Dijon, France. , (Garrido C., cgarrido@u-bourgogne.fr) Centre Georges-Francois Leclerc, 21000 Dijon, France.

C. Garrido, INSERM U866, Faculty of Medicine and Pharmacy, 7 boulevard Jeanne D'Arc, 21079 Dijon, France. Email: cgarrido@u-bourgogne.fr

Current Medicinal Chemistry (2014) 21:2 (153-163). Date of Publication: January 2014

0929-8673,1875-533X (electronic)

Bentham Science Publishers B.V., P.O. Box 294, Bussum, Netherlands.

Glycoprotein 96 (Gp96)-peptide complexes are highly investigated for vaccines preparation, particularly in cancer therapy. Gp96, formerly called tumor rejection antigen (TRA)-1, is able to elicit an immune response that can protect mice against tumors, when the mice share the same haplotype than those bearing the tumors from which Gp96 was purified. Secreted Gp96-peptide complexes act as danger signals thereby stimulating the innate immunity regardless of the chaperoned peptides. In contrast, the tumor rejection antigen role of Gp96-peptide complexes is held by the chaperoned peptides in a dose-dependent manner. The purification step is crucial both for insuring the quality and the quantity of Gp96-peptide complexes. To this aim, different methods have been described but they are often suboptimal for the quantification of these complexes. In this review, we discuss a hot topic: the use of the chaperone Gp96 for vaccination purposes in cancer, and also detail the current methods for quantifying Gp96-peptide preparations. (copyright) 2014 Bentham Science Publishers.

cancer vaccine (drug development, pharmaceutics), glucose regulated protein 94, glycoprotein gp 96 (drug dose, drug therapy), heat shock protein 90, heat shock protein 90B1, vitespen (clinical trial, drug development, drug therapy, pharmaceutics)

amino acid, bovine serum albumin, chaperone, cystine, immunoglobulin, ovotransferrin, phenylalanine, protein precursor, recombinant protein, signal peptide, smallpox vaccine (drug therapy), tryptophan, tyrosine, unclassified drug, vaccine

cancer immunotherapy, immunomodulation, vaccine production

article, assay, bicinchoninic acid assay, Bradford Assay, brain tumor (drug therapy), cancer cell, complex formation, drug megadose, glioblastoma (drug therapy), glioma (drug therapy), glycosylation, graft rejection (complication, drug therapy, prevention), human, immunoenzymatic assay, immunogenicity, kidney carcinoma (drug therapy), lowry assay, lymphoma (drug therapy), melanoma (drug therapy), multicenter study (topic), non small cell lung cancer (drug therapy), nonhuman, pancreas cancer (drug therapy), phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), protein purification, protein secretion, protein structure, protein synthesis, quality control, quantitative analysis, sarcoma (drug therapy), smallpox (drug therapy), ultraviolet spectrophotometry, vaccination

oncophage (Antigenics)

Antigenics

amino acid (65072-01-7), cystine (24645-67-8, 56-89-3, 6020-39-9), immunoglobulin (9007-83-4), ovotransferrin (1391-06-6), phenylalanine (3617-44-5, 63-91-2), tryptophan (6912-86-3, 73-22-3), tyrosine (16870-43-2, 55520-40-6, 60-18-4), vitespen (492448-75-6)

Cancer (16), Immunology, Serology and Transplantation (26), Clinical and Experimental Biochemistry (29), Drug Literature Index (37), Pharmacy (39)

ClinicalTrials.gov (NCT00003025, NCT00005628, NCT00033904, NCT00039000, NCT00081809, NCT00082459, NCT00098085, NCT00126178, NCT00293423, NCT00503568, NCT00905060, NCT01147536, NCT01799161, NCT01814813)

http://dx.doi.org/10.2174/09298673113206660304

Copyright 2014 Elsevier B.V., All rights reserved.

Adenosine A(2A) receptor antagonists in Parkinson's disease: Progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued

(Pinna A., apinna@unica.it) National Research Council of Italy (CNR), Neuroscience Institute-Cagliari, Via Ospedale, 72, 09124 Cagliari, Italy. , (Pinna A., apinna@unica.it) National Institute of Neuroscience, Cagliari, Italy.

A. Pinna, National Research Council of Italy (CNR), Neuroscience Institute-Cagliari, Via Ospedale, 72, 09124 Cagliari, Italy. Email: apinna@unica.it

CNS Drugs (2014) 28:5 (455-474). Date of Publication: May 2014

1179-1934 (electronic),1172-7047

Adis International Ltd

Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A(2A) antagonists have emerged as promising candidates. The development of new highly selective adenosine A(2A) receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clinical research regarding A (2A) antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivatives in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compounds have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A(2A) antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with l-DOPA. In addition, early findings suggest that A(2A) antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacological and clinical data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant. (copyright) 2014 Springer International Publishing Switzerland.

adenosine A2 receptor (endogenous compound), adenosine A2 receptor antagonist (clinical trial, drug therapy), istradefylline (adverse drug reaction, clinical trial, drug therapy)

amantadine (drug therapy), entacapone (drug therapy), levodopa (clinical trial, drug therapy), mk 3814, pbf 509 (clinical trial, drug therapy), pbs 509 (drug therapy), placebo, preladenant (adverse drug reaction, drug therapy), rasagiline (drug therapy), st 1535, st 4206 (drug therapy), sti 535 (drug therapy), tozadenant (clinical trial, drug therapy), unclassified drug, v 81444 (clinical trial, drug therapy), vipadenant (adverse drug reaction, clinical trial, drug therapy)

drug approval, Parkinson disease (drug therapy, drug therapy, therapy)

article, binding affinity, brain depth stimulation, clinical research, cognitive defect, constipation (side effect), diastolic blood pressure, disease exacerbation (side effect), dizziness (side effect), dose response, double blind procedure, drug efficacy, drug half life, drug induced headache (side effect), drug safety, drug tolerability, drug withdrawal, dyskinesia (side effect), elevated blood pressure (side effect), functional magnetic resonance imaging, functional neuroimaging, hallucination (side effect), heart hemodynamics, human, insomnia (side effect), Japan, locomotion, long term care, meta analysis (topic), monotherapy, muscle rigidity (side effect), nausea (side effect), nonhuman, parkinsonism (side effect), phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), priority journal, protein expression, receptor occupancy, somnolence (side effect), statistical significance, substantia nigra pars reticulata, systolic blood pressure, treatment response, Unified Parkinson Disease Rating Scale, unspecified side effect (side effect), vomiting (side effect)

biib 014 (Vernalis), kw 6002 (Kyowa Hakko Kirin), mk 3814 (Merck and Co), pbf 509, pbs 509 (palobiofarma), sch 420814 (Merck and Co), st 1535 (Sigma Tau), st 4206 (Sigma Tau), syn 115 (Biotie), syn 115 (UCB), v 2006 (Vernalis), v 81444 (Vernalis)

Biotie, Kyowa Hakko Kirin, Merck and Co, palobiofarma, Sigma Tau, UCB, Vernalis

amantadine (665-66-7, 768-94-5), entacapone (116314-67-1), istradefylline (155270-99-8), levodopa (59-92-7), preladenant (377727-87-2), rasagiline (136236-51-6, 161735-79-1, 1875-50-9), tozadenant (870070-55-6), vipadenant (442908-10-3)

Drug Literature Index (37), Adverse Reactions Titles (38), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00199394, NCT00199407, NCT00199420, NCT00199433, NCT00406029, NCT00438607, NCT00442780, NCT00455507, NCT00456586, NCT00456794, NCT00531193, NCT00537017, NCT00605553, NCT00845000, NCT00955045, NCT00955526, NCT01017666, NCT01155466, NCT01155479, NCT01215227, NCT01227265, NCT01283594, NCT01294800, NCT01634568, NCT01691924, NCT01968031)

http://dx.doi.org/10.1007/s40263-014-0161-7

Copyright 2014 Elsevier B.V., All rights reserved.

Adjuvant therapy for renal cell carcinoma: Past, present, and future

Pal S.K., Haas N.B.

(Pal S.K.) Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, United States. , (Haas N.B., naomi.haas@uphs.upenn.edu) Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.

N. B. Haas, Division of Hematology-Oncology, Perelman School of Medicine, Philadelphia, PA 19104, United States. Email: naomi.haas@uphs.upenn.edu

Oncologist (2014) 19:8 (851-859). Date of Publication: 2014

1549-490X (electronic),1083-7159

AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.

At the present time, the standard of care for patients who have received nephrectomy for localized renal cell carcinoma (RCC) is radiographic surveillance. With a number of novel targeted agents showing activity in the setting of metastatic RCC, there has been great interest in exploring the potential of the same agents in the adjuvant setting. Herein, we discuss the evolution of adjuvant trials in RCC, spanning from the immunotherapy era to the targeted therapy era. Pitfalls of current studies are addressed to provide a context for interpreting forthcoming results. Finally, we outline avenues to incorporate promising investigational agents, such as PD-1 (programmed death-1) inhibitors and MNNG transforming gene inhibitors, in future adjuvant trials. (copyright) AlphaMed Press.

ags 003, alpha interferon (drug therapy), antineoplastic agent (drug therapy), aromatase inhibitor (drug therapy), axitinib (drug therapy), bevacizumab (drug therapy), dendritic cell vaccine (drug therapy), dendritic cell vaccine ags 003 (drug therapy), everolimus (drug therapy), fluorouracil (drug therapy), girentuximab (drug therapy), interleukin 2 (drug therapy), mammalian target of rapamycin (endogenous compound), mpdl 3280a (drug therapy), multipeptide vaccine ima901 (drug therapy), nivolumab (drug therapy), pazopanib (drug therapy), placebo, programmed death 1 receptor (endogenous compound), sorafenib (drug therapy), sunitinib (drug therapy), tamoxifen (drug therapy), temsirolimus (drug therapy), trastuzumab (drug therapy), tumor cell vaccine (drug therapy), unclassified drug, vasculotropin (endogenous compound)

cancer adjuvant therapy, kidney carcinoma (drug therapy, drug therapy)

adjuvant therapy, article, cancer immunotherapy, disease free survival, human, kidney metastasis, meta analysis (topic), nonhuman, overall survival, phase 3 clinical trial (topic), priority journal, randomized controlled trial (topic)

ags 003, bms 936558, mdx 1106, mpdl3280a

axitinib (319460-85-0), bevacizumab (216974-75-3), everolimus (159351-69-6), fluorouracil (51-21-8), girentuximab (916138-87-9, 858130-47-9), interleukin 2 (85898-30-2), nivolumab (946414-94-4), pazopanib (444731-52-6, 635702-64-6), sorafenib (284461-73-0), sunitinib (341031-54-7, 557795-19-4), tamoxifen (10540-29-1), temsirolimus (162635-04-3, 343261-52-9), trastuzumab (180288-69-1), vasculotropin (127464-60-2)

Cancer (16), Urology and Nephrology (28), Drug Literature Index (37)

ClinicalTrials.gov (NCT00053807, NCT01265901, NCT01582672, NCT01668784)

http://dx.doi.org/10.1634/theoncologist.2014-0105

Copyright 2014 Elsevier B.V., All rights reserved.

Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy

Bryzinski B., Allen E., Cook W., Hirshberg B.

(Bryzinski B., brian.bryzinski@astrazeneca.com; Cook W.; Hirshberg B.) AstraZeneca, 1800 Concord Pike, Wilmington, United States. , (Allen E.) Novo Nordisk, New York, United States.

B. Bryzinski, AstraZeneca, 1800 Concord Pike, Wilmington, United States.

Journal of Diabetes and its Complications (2014) 28:6 (887-893). Date of Publication: 1 Nov 2014

1873-460X (electronic),1056-8727

Elsevier Inc., usjcs@elsevier.com

Aims: To examine whether concomitant statin therapy affects glycemic control with saxagliptin 2.5 and 5 mg/d in patients with type 2 diabetes mellitus (T2DM).Methods: Efficacy and safety were analyzed post hoc for pooled data from 9 saxagliptin randomized, placebo-controlled trials with a primary 24-week treatment period (4 monotherapy, 2 add-on to metformin, 1 each add-on to a sulfonylurea, thiazolidinedione, or insulin (plus or minus) metformin). Safety was also assessed in an 11-study, 24-week pool and an extended 20-study pool, which included 9 additional 4- to 52-week randomized studies. Comparisons were performed for patient groups defined by baseline statin use.Results: Saxagliptin produced greater mean reductions in glycated hemoglobin than placebo, with no interaction between treatment and baseline statin use (P = 0.47). In patients receiving saxagliptin 2.5 and 5 mg and placebo, the proportion of patients with (greater-than or equal to) 1 adverse event (AE) was 78.1%, 64.0%, and 63.2%, respectively, in patients with any statin use and 70.6%, 57.9%, and 55.0% in patients with no statin use. Serious AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose (less-than or equal to) 50 mg/dL) were few and similar, irrespective of baseline statin use.Conclusions: Saxagliptin improves glycemic control and is generally well tolerated in patients with T2DM, irrespective of concomitant statin therapy.Inc.

hydroxymethylglutaryl coenzyme A reductase inhibitor (adverse drug reaction, clinical trial, drug combination), saxagliptin (adverse drug reaction, clinical trial, drug combination, drug comparison - placebo, drug dose, drug therapy)

2,4 thiazolidinedione derivative (drug combination, drug therapy), atorvastatin (adverse drug reaction, clinical trial, drug combination), fluindostatin (adverse drug reaction, clinical trial, drug combination), glucose (endogenous compound), hemoglobin A1c (endogenous compound), insulin (drug combination, drug therapy), metformin (drug combination, drug therapy), mevinolin (adverse drug reaction, clinical trial, drug combination), pitavastatin (adverse drug reaction, clinical trial, drug combination), placebo, pravastatin (adverse drug reaction, clinical trial, drug combination), rosuvastatin (adverse drug reaction, clinical trial, drug combination), saxagliptin (adverse drug reaction, clinical trial, drug combination, drug comparison - placebo, drug dose, drug therapy), simvastatin (adverse drug reaction, clinical trial, drug combination), sulfonylurea (drug combination, drug therapy)

drug efficacy, drug safety, non insulin dependent diabetes mellitus (drug therapy, drug therapy)

add on therapy, adjuvant therapy, adult, article, body mass, controlled study, death, diabetic patient, diarrhea (side effect), disease duration, drug dose comparison, drug induced headache (side effect), drug tolerability, drug withdrawal, female, glycemic control, human, hypersensitivity (side effect), hypoglycemia (side effect), major clinical study, male, monotherapy, myopathy (side effect), outcome assessment, pancreatitis (side effect), randomized controlled trial (topic), rhinopharyngitis (side effect), treatment duration, upper respiratory tract infection (side effect), urinary tract infection (side effect)

atorvastatin (134523-00-5, 134523-03-8), fluindostatin (93957-54-1), glucose (50-99-7, 84778-64-3), hemoglobin A1c (62572-11-6), insulin (9004-10-8), metformin (1115-70-4, 657-24-9), mevinolin (75330-75-5), pitavastatin (147526-32-7), pravastatin (81093-37-0, 81131-70-6), rosuvastatin (147098-18-8, 147098-20-2), saxagliptin (361442-04-8, 945667-22-1), simvastatin (79902-63-9)

Cardiovascular Diseases and Cardiovascular Surgery (18), Drug Literature Index (37), Adverse Reactions Titles (38), Internal Medicine (6)

ClinicalTrials.gov (NCT00121641, NCT00121667, NCT00295633, NCT00316082, NCT00327015, NCT00374907, NCT00575588, NCT00614939, NCT00666458, NCT00698932, NCT00757588, NCT00885378, NCT00918138, NCT00918879, NCT00950599, NCT00960076, NCT01006590)

http://dx.doi.org/10.1016/j.jdiacomp.2014.07.006

Copyright 2014 Elsevier B.V., All rights reserved.

Current treatment approaches in patients with advanced-stage Hodgkin lymphoma

Soucasne pohledy na lecbu nemocnych v pokrocilem stadiu Hodgkinova lymfomu

Mocikova H.

(Mocikova H., heidi.mocikova@seznam.cz) Interni hematologicka klinika, FN Kralovske Vinohrady, Praha, 3. lekarska fakulta Univerzity Karlovy v Praze, Czech Republic.

H. Mocikova, Interni hematologicka klinika, FN Kralovske Vinohrady, 3. LF UK v Praze, Srobarova 50, 100 34 Praha 10, Czech Republic. Email: heidi.mocikova@seznam.cz

Onkologie (Czech Republic) (2014) 8:3 (117-120). Date of Publication: 2014

1803-5345 (electronic),1802-4475

SOLEN s.r.o., Lazecka 297/51, Olomouc, Czech Republic.

More than 80 % of patients with Hodgkin lymphoma (HL) younger than 60 years are likely to be cured with modern treatment strategies. The goal of current treatment approaches is to maintain the high treatment efficacy and to reduce the toxicity. BEACOPP escalated has a 10 % overall survival advantage over ABVD in patients with advanced-stage HL, therefore 6 cycles of BEACOPP escalated has become the standard of care for patients younger than 60 years. Six cycles of ABVD remain the standard of care for patients over 60 years. Radiotherapy could be omitted in patients with a negative positrone emission tomography (PET) finding after chemotherapy. Mature trial results of the treatment stratification based on PET and trial results of brentuximab vedotin combined with chemotherapy in the first-line treatment are awaited.

antineoplastic agent (clinical trial, drug combination, drug therapy), bleomycin (drug combination, drug therapy), brentuximab vedotin (clinical trial, drug combination, drug therapy), cyclophosphamide (drug combination, drug therapy), dacarbazine (drug combination, drug therapy), doxorubicin (drug combination, drug therapy), etoposide (drug combination, drug therapy), prednisone (drug combination, drug therapy), procarbazine (drug combination, drug therapy), vinblastine (drug combination, drug therapy), vincristine (drug combination, drug therapy)

advanced cancer (drug therapy, drug therapy), Hodgkin disease (drug therapy, drug therapy)

article, cancer combination chemotherapy, cancer radiotherapy, human, multiple cycle treatment, overall survival, positron emission tomography

bleomycin (11056-06-7, 9041-93-4), brentuximab vedotin (914088-09-8), cyclophosphamide (50-18-0), dacarbazine (4342-03-4), doxorubicin (23214-92-8, 25316-40-9), etoposide (33419-42-0), prednisone (53-03-2), procarbazine (366-70-1, 671-16-9), vinblastine (865-21-4), vincristine (57-22-7)

Cancer (16), Hematology (25), Drug Literature Index (37)

ClinicalTrials.gov (NCT00305149, NCT00515554, NCT00678327, NCT00784537, NCT00795613, NCT00822120, NCT01356680, NCT01358747, NCT01652261, NCT01712490)

English, Czech

Copyright 2014 Elsevier B.V., All rights reserved.

Comparison of idrabiotaparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: The Borealis-Atrial Fibrillation Study

Buller H.R., Halperin J., Hankey G.J., Pillion G., Prins M.H., Raskob G.E.

(Buller H.R., h.r.buller@amc.uva.nl) Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. , (Halperin J.) The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY, United States. , (Hankey G.J.) School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia. , (Hankey G.J.) Department of Neurology, Sir Charles Gairdner Hospital, Perth, WA, Australia. , (Pillion G.) Sanofi-Aventis Recherche et Developpement, Chilly Mazarin, France. , (Prins M.H.) Department of Epidemiology, Maasticht University Medical Centre, Maastricht, Netherlands. , (Raskob G.E.) The University of Oklahoma Health Sciences Center, Oklahoma city, OK, United States.

H.R. Buller, Academic Medical Center, Amsterdam, Netherlands. Email: h.r.buller@amc.uva.nl

Journal of Thrombosis and Haemostasis (2014) 12:6 (824-830). Date of Publication: June 2014

1538-7836 (electronic),1538-7933

Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com

Summary: Background: Idrabiotaparinux, a long-acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism. Objective: To assess non-inferiority for the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed. Methods: This randomized, double-blind trial enrolled patients with electrocardiogram-documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30-50 mL min(-1) or aged (greater-than or equal to) 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non-fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non-major bleeding). Results: The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49-1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46-0.81). Conclusion: If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose-adjusted warfarin, with a lower bleeding risk. (copyright) 2014 International Society on Thrombosis and Haemostasis.

idrabiotaparinux (adverse drug reaction, clinical trial, drug comparison, drug therapy, subcutaneous drug administration), warfarin (adverse drug reaction, drug comparison, drug therapy)

anticoagulant therapy, heart atrium fibrillation, thromboembolism (drug therapy, drug therapy, prevention)

aged, article, bleeding (side effect), brain hemorrhage, brain ischemia, cerebrovascular accident, CHADS2 score, controlled study, creatinine clearance, double blind procedure, drug efficacy, drug indication, drug safety, female, heart failure, heart left ventricle function, human, hypertension, international normalized ratio, lung embolism (drug therapy, prevention), major clinical study, male, multicenter study, outcome assessment, priority journal, randomized controlled trial, treatment duration, vein thrombosis (drug therapy, prevention)

idrabiotaparinux (405159-59-3), warfarin (129-06-6, 2610-86-8, 3324-63-8, 5543-58-8, 81-81-2)

Cardiovascular Diseases and Cardiovascular Surgery (18), Hematology (25), Drug Literature Index (37), Adverse Reactions Titles (38), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00580216)

http://dx.doi.org/10.1111/jth.12546

Copyright 2014 Elsevier B.V., All rights reserved.

Long-term remission in schizophrenia and schizoaffective disorder: Results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE)

Smeraldi E., Cavallaro R., Folnegovic-Smalc V., Bidzan L., Ceylan M.E., Schreiner A.

(Smeraldi E., enrico.smeraldi@hsr.it) Department of Clinical Neuroscience, San Raffaele University Scientific Institute, Vita-Salute University School of Medicine, Via Stamira D'Ancona 20, 20127 Milan, Italy. , (Cavallaro R.) Department of Clinical Neuroscience, I.R.C.C.S. Ospedale San Raffaele, Milan, Italy. , (Folnegovic-Smalc V.) University Department of Psychiatry, Psychiatric Hospital Vrapce, Zagreb, Croatia. , (Bidzan L.) Department of Developmental, Psychotic, and Geriatric Psychiatry, Medical University of Gdask, Gdansk, Poland. , (Ceylan M.E.) Molecular Biology and Genetics Department, Uskudar University, Istanbul, Turkey. , (Schreiner A.) Medical Affairs EMEA, Janssen-Cilag GmbH, Neuss, Germany.

E. Smeraldi, Department of Clinical Neuroscience, San Raffaele University Scientific Institute, Vita-Salute University School of Medicine, Via Stamira D'Ancona 20, 20127 Milan, Italy. Email: enrico.smeraldi@hsr.it

Therapeutic Advances in Psychopharmacology (2013) 3:4 (191-199). Date of Publication: 2013

2045-1253,2045-1261 (electronic)

SAGE Publications Ltd, 55 City Road, London, United Kingdom.

Objective: The objective of this study was to report the long-term remission results from the ConstaTRE relapse prevention trial, in which clinically stable adults with schizophrenia or schizoaffective disorder treated with oral risperidone, olanzapine, or oral conventional antipsychotics were randomized to risperidone long-acting injectable (RLAI) or oral quetiapine, dosed according to package-insert recommendations. Methods: In the ConstaTRE trial, efficacy and tolerability were recorded for up to 24 months. This post hoc analysis presents remission data, defined, according to the Schizophrenia Working Group criteria, as achieving and maintaining eight core symptoms of schizophrenia that are mild or less over 6 months. Additional secondary outcome measures are also presented. Results: A total of 710 patients were randomized to RLAI (n = 355) or quetiapine (n = 355). Mean mode (plus or minus) standard deviation (SD) drug doses were RLAI 33 (plus or minus) 10 mg every 2 weeks and quetiapine 413 (plus or minus) 159 mg daily. Full remission was achieved by 51.1% of patients with RLAI and 39.3% with quetiapine (p = 0.003). Mean (plus or minus) SD of full remission durations were not significantly different with RLAI (540 (plus or minus) 181 days) and quetiapine (508 (plus or minus) 188 days). Overall tolerability was similar between treatment groups. Conclusions: Among stable patients with schizophrenia or schizoaffective disorder, remission was more likely after switching to RLAI than quetiapine. (copyright) The Author(s), 2013.

quetiapine (adverse drug reaction, clinical trial, drug comparison, drug therapy, oral drug administration), risperidone (adverse drug reaction, clinical trial, drug comparison, drug therapy, oral drug administration)

remission, schizoaffective psychosis (drug therapy, drug therapy)

article, deep vein thrombosis (side effect), drug efficacy, drug safety, drug tolerability, heart infarction (side effect), human, mental disease (side effect), neurologic disease (side effect), post hoc analysis, priority journal, randomized controlled trial (topic), relapse, somnolence (side effect), suicide (side effect), ulcer perforation (side effect)

quetiapine (111974-72-2), risperidone (106266-06-2)

Psychiatry (32), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00216476)

http://dx.doi.org/10.1177/2045125313479127

Copyright 2013 Elsevier B.V., All rights reserved.

Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy

Finkel R.S., Flanigan K.M., Wong B., Bonnemann C., Sampson J., Sweeney H.L., Reha A., Northcutt V.J., Elfring G., Barth J., Peltz S.W.

(Finkel R.S., info@ptcbio.com; Bonnemann C.) Children's Hospital of Philadelphia, Philadelphia, PA, United States. , (Finkel R.S., info@ptcbio.com) Nemours Children's Hospital, Orlando, FL, United States. , (Flanigan K.M.; Sampson J.) University of Utah School of Medicine, Salt Lake City, UT, United States. , (Wong B.) Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. , (Sweeney H.L.) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. , (Reha A.; Northcutt V.J.; Elfring G.; Barth J.; Peltz S.W.) PTC Therapeutics, Inc., South Plainfield, NJ, United States. , (Flanigan K.M.) Nationwide Children's Hospital, Columbus, OH, United States. , (Sampson J.) Columbia University, New York, NY, United States. , (Bonnemann C.) National Institute of Neurological Disorders and Stroke, NIH Porter Neuroscience Research Center, Bethesda, MD, United States.

Children's Hospital of Philadelphia, Philadelphia, PA, United States.

PLoS ONE (2013) 8:12 Article Number: e81302. Date of Publication: 11 Dec 2013

1932-6203 (electronic)

Public Library of Science, 185 Berry Street, Suite 1300, San Francisco, United States.

Background: Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins. Methods: This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and posttreatment muscle biopsy specimens, was the primary endpoint. Findings: Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated. Interpretation: Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD. Trial Registration: ClinicalTrials.gov NCT00264888.

ataluren (adverse drug reaction, clinical trial, drug combination, drug concentration, drug dose, drug therapy, oral drug administration, pharmacokinetics, pharmacology), dystrophin (endogenous compound)

deflazacort (drug combination), prednisolone (drug combination), prednisone (drug combination), spectrin (endogenous compound)

Duchenne muscular dystrophy (drug therapy, drug therapy), nonsense mutation

abdominal discomfort (side effect), abdominal pain (side effect), adolescent, area under the curve, article, child, clinical article, cohort analysis, diarrhea (side effect), drug absorption, drug activity, drug blood level, drug dose escalation, drug safety, drug tolerability, evening dosage, exon, flatulence (side effect), gastrointestinal symptom (side effect), human, immunohistochemistry, male, morning dosage, muscle biopsy, nausea (side effect), open study, phase 2 clinical trial, protein expression, protein synthesis, quantitative analysis, time to maximum plasma concentration, treatment duration, vomiting (side effect), X chromosome linked muscular dystrophic mouse

ataluren (775304-57-9, 775304-59-1), deflazacort (14484-47-0), dystrophin (116978-02-0), prednisolone (50-24-8), prednisone (53-03-2), spectrin (12634-43-4)

Pediatrics and Pediatric Surgery (7), Neurology and Neurosurgery (8), Human Genetics (22), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00264888, NCT00592553, NCT01826487)

http://dx.doi.org/10.1371/journal.pone.0081302

Copyright 2014 Elsevier B.V., All rights reserved.

Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: Results from a randomised, controlled, double-blind trial

Richardus J.H.

(Richardus J.H., jh.richardus@rotterdam.nl) Department of Infectious Disease Control, Municipal Public Health Service (GGD) Rotterdam-Rijnmond, Rotterdam, The Netherlands P. O. Box 70032, 3000 LP Rotterdam, Netherlands.

J.H. Richardus, Department of Infectious Disease Control, Municipal Public Health Service (GGD) Rotterdam-Rijnmond, Rotterdam, The Netherlands P. O. Box 70032, 3000 LP Rotterdam, Netherlands. Email: jh.richardus@rotterdam.nl

Vaccine (2013) 31:51 (6136-6143). Date of Publication: 9 Dec 2013

0264-410X,1873-2518 (electronic)

Elsevier Ltd, Langford Lane, Kidlington, Oxford, United Kingdom.

Objective: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed. Methods: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix(trademark); HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus. Results: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants. Conclusion: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus. (copyright) 2013.

glycoprotein D (adverse drug reaction, clinical trial, drug therapy), herpes simplex vaccine (adverse drug reaction, clinical trial, drug therapy)

3 o deacylated monophosphoryl lipid A, aluminum hydroxide, hepatitis A vaccine (adverse drug reaction, clinical trial, drug therapy), immunological adjuvant, sodium chloride (adverse drug reaction, clinical trial, drug therapy), unclassified drug

drug safety, genital herpes (drug therapy, drug therapy, prevention), immunogenicity

acne (side effect), adolescent, antibody blood level, antibody response, arthralgia (side effect), article, asthma (side effect), child, controlled study, double blind procedure, drug withdrawal, female, fever (side effect), headache (side effect), Herpes simplex virus 1, Herpes simplex virus 2, human, human experiment, injection site erythema (side effect), injection site pain (side effect), lip disease (side effect), lip swelling (side effect), lip swelling (side effect), malaise (side effect), mental disease (side effect), migraine (side effect), nephrotic syndrome (side effect), normal human, outcome assessment, pain (side effect), phase 3 clinical trial, post hoc analysis, priority journal, randomized controlled trial, randomized controlled trial (topic), rash (side effect), school child, spontaneous abortion (side effect), suicidal ideation (side effect), tachycardia (side effect), urticaria (side effect), virus infection (side effect)

havrix (Glaxo SmithKline)

Glaxo SmithKline

aluminum hydroxide (1330-44-5, 20257-20-9, 21645-51-2, 80206-84-4), sodium chloride (7647-14-5)

Obstetrics and Gynecology (10), Immunology, Serology and Transplantation (26), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00224484)

http://dx.doi.org/10.1016/j.vaccine.2013.06.081

Copyright 2013 Elsevier B.V., All rights reserved.

Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture a double-blind randomized controlled phase-ii/iii trial

Lyon T., Scheele W., Bhandari M., Koval K.J., Sanchez E.G., Christensen J., Valentin A., Huard F.

(Lyon T., TLyon@lmcmc.com) Department of Trauma Services, Lutheran Medical Center, 150 55th Street, Brooklyn, NY 11220, United States. , (Scheele W.; Christensen J.) Pfizer Research, 35 Cambridge Park Drive, Cambridge,MA 02140, United States. , (Bhandari M.) Department of Surgery and Department of Clinical Epidemiology,and Biostatistics, McMaster University, 293 Wellington,Street North, Toronto, ON, Canada. , (Koval K.J.) Department of Orthopaedics, Orlando Regional Medical Center, 1414 Kuhl Avenue, Orlando,FL 32806, United States. , (Sanchez E.G.) Antiguo Hospital Civil de Guadalajara, Servicio de Ortopedia Guadalajara, Guadalajara CP44280, Mexico. , (Valentin A.) 72 Rutledge Road, Belmont, MA 02478, United States. , (Huard F.) Pfizer Global Research and Development, Coeur Defense, La Defense 4, 92931 Paris La Defense CEDEX, France.

Department of Trauma Services, Lutheran Medical Center, 150 55th Street, Brooklyn, NY 11220, United States.

Journal of Bone and Joint Surgery - Series A (2013) 95:23 (2088-2096). Date of Publication: 4 Dec 2013

0021-9355,1535-1386 (electronic)

Journal of Bone and Joint Surgery Inc., 20 Pickering Street, Needham, United States.

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. Methods: Patients were randomized (1:2:2:1) to receive standard of care which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. Results: Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks) 1.0-mg/mL rhBMP-2/CPM(13.0 weeks) 2.0-mg/mL rhBMP-2/CPM (15.9 weeks) or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks) 1.0-mg/mL rhBMP-2/CPM (13.4 weeks) 2.0-mg/mL rhBMP-2/CPM (14.3 weeks) and buffer/CPM (16.4 weeks) treatment groups. Conclusions: In patients with closed tibial fractures treated with reamed intramedullary nailing the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. COPYRIGHT (copyright) 2013 BY THE JOURNAL OF BONE AND JOINT SURGERY.

calcium phosphate (adverse drug reaction, clinical trial, drug therapy), calcium phosphate matrix (adverse drug reaction, clinical trial, drug therapy), recombinant bone morphogenetic protein 2 (adverse drug reaction, clinical trial, drug therapy)

unclassified drug

closed tibial diaphyseal fracture (drug therapy, drug therapy, surgery), tibia fracture (drug therapy, drug therapy, surgery)

adjuvant therapy, adult, arthralgia (side effect), article, calcification (side effect), compartment syndrome (side effect), controlled study, deep vein thrombosis (side effect), diaphysis, double blind procedure, drug activity, drug efficacy, drug safety, erythema (side effect), female, fracture fixation, fracture healing, fracture nonunion (side effect), fracture reduction, heterotopic ossification (side effect), human, infection (side effect), intramedullary nail, intramedullary nailing, lung embolism (side effect), major clinical study, male, medical device breakage (complication), medical device complication (complication), medical device failure (complication), medical device malfunction (complication), multicenter study, pain (side effect), peripheral edema (side effect), phase 2 clinical trial, phase 3 clinical trial, priority journal, pseudarthrosis, randomized controlled trial, swelling (side effect), treatment outcome, vascular disease (side effect), weight bearing

calcium phosphate (10103-46-5, 13767-12-9, 14358-97-5, 7758-87-4), recombinant bone morphogenetic protein 2 (246539-15-1)

Internal Medicine (6), Biophysics, Bioengineering and Medical Instrumentation (27), Orthopedic Surgery (33), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00387686)

http://dx.doi.org/10.2106/JBJS.L.01545

Copyright 2014 Elsevier B.V., All rights reserved.

An ELCWP phase III trial comparing ifosfamide and cisplatin regimens in advanced NSCLC

Berghmans T., Lafitte J.-J., Scherpereel A., Paesmans M., Lecomte J., Marco V.G., Meert A.-P., Leclercq N., Sculier J.-P.

(Berghmans T., thierry.berghmans@bordet.be; Meert A.-P.; Leclercq N.; Sculier J.-P.) Department of Intensive Care and Thoracic Oncology, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Brussels, Belgium. , (Lafitte J.-J.; Scherpereel A.) Department of Pneumology, CHU Lille, Lille, France. , (Paesmans M.) Data Centre, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Brussels, Belgium. , (Lecomte J.) Department of Pneumology, CHU Charleroi, Charleroi, Belgium. , (Marco V.G.) Department of Medical Oncology, Hospital de Sagunto, Valencia, Spain.

T. Berghmans, Department of Intensive Care and Thoracic Oncology, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Brussels, Belgium. Email: thierry.berghmans@bordet.be

Anticancer Research (2013) 33:12 (5477-5482). Date of Publication: December 2013

0250-7005

International Institute of Anticancer Research, 1st km Kapandritiou - Kalamou Rd., P.O. Box 22, Kapandriti, Attica, Greece.

Aim: While meta-analyses and clinical trials show improved survival in advanced NSCLC treated with platinum-containing chemotherapy, there are few data concerning front-line platinum-free ifosfamide-based regimens. We aimed to compare cisplatin-based chemotherapy to ifosfamide-gemcitabine (IG) with pre-defined second-line docetaxel. Patients and Methods: 693 Untreated advanced inoperable NSCLC cases were randomised to either GIP (gemcitabine, ifosfamide, cisplatin), DP (docetaxel, cisplatin) or IG. Primary outcome was overall survival. Results: Median age of the patients was 58 years with a predominance of males (75%), adenocarcinoma (56%), Karnofsky PS 80-100 (77%) and stage-IV disease (81%). Median survival times were 8.7, 8.8 and 8.3 months for IG, GIP and DP (p=0.79). GIP presented with (p<0.05) greater neutropenia, thrombopenia, vomiting, while greater cardiotoxicity, diarrhea, peripheral neuropathy were observed for DP and encephalopathy for IG. Conclusion: In advanced NSCLC, cisplatin-based CT is not superior to a platinum-free regimen (ifosfamide-gemcitabine) with a favourable toxicity profile.

cisplatin (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), ifosfamide (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy)

docetaxel (adverse drug reaction, clinical trial, drug combination, drug therapy), gemcitabine (adverse drug reaction, clinical trial, drug combination, drug therapy)

advanced cancer (drug therapy, drug therapy), non small cell lung cancer (drug therapy, drug therapy)

adult, aged, alopecia (side effect), article, bleeding (side effect), cancer combination chemotherapy, cancer staging, cancer survival, cardiotoxicity (side effect), comparative study, constipation (side effect), diarrhea (side effect), febrile neutropenia (side effect), female, follow up, hearing impairment (side effect), human, induction chemotherapy, infection (side effect), irradiation, Karnofsky Performance Status, kidney disease (side effect), leukopenia (side effect), local therapy, male, middle aged, nausea (side effect), outcome assessment, overall survival, peripheral neuropathy (side effect), phase 3 clinical trial, priority journal, respiratory tract disease (side effect), salvage therapy, sex difference, skin manifestation (side effect), stomatitis (side effect), sudden death, survival rate, survival time, thrombocytopenia (side effect), treatment response, urogenital tract disease (side effect), very elderly, vomiting (side effect)

cisplatin (15663-27-1, 26035-31-4, 96081-74-2), docetaxel (114977-28-5), gemcitabine (103882-84-4), ifosfamide (3778-73-2)

Radiology (14), Chest Diseases, Thoracic Surgery and Tuberculosis (15), Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00622349)

Copyright 2014 Elsevier B.V., All rights reserved.

A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. the METHEP trial

Ychou M., Rivoire M., Thezenas S., Quenet F., Delpero J.-R., Rebischung C., Letoublon C., Guimbaud R., Francois E., Ducreux M., Desseigne F., Fabre J.-M., Assenat E.

(Ychou M., marc.ychou@icm.unicancer.fr; Thezenas S.; Quenet F.) Institut du Cancer de Montpellier-Val D'Aurelle, Montpellier Cedex 05, France. , (Rivoire M.; Desseigne F.) CRLC Leon Berard, Lyon, France. , (Delpero J.-R.) Institut Paoli Calmettes Marseille, Marseille, France. , (Rebischung C.; Letoublon C.) CHU la Tronche Grenoble, Grenoble, France. , (Guimbaud R.) CHU Rangueil Purpan Toulouse, Toulouse, France. , (Francois E.) CRLC Antoine Lacassagne, Nice, France. , (Ducreux M.) Institut Gustave Roussy Villejuif, Villejuif, France. , (Fabre J.-M.; Assenat E.) CHU Montpellier, Montpellier, France.

Institut du Cancer de Montpellier-Val D'Aurelle, Montpellier Cedex 05, France.

Annals of Surgical Oncology (2013) 20:13 (4289-4297). Date of Publication: 2013

1068-9265,1534-4681 (electronic)

Springer New York, 233 Spring Street, New York, United States.

Purpose. This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC). Methods. Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25-30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI- HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS). Results. A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI ? FOLFOX4)/FOLFIRI-HD/ FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI ? FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively. Conclusions. FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens. (copyright) Society of Surgical Oncology 2013.

fluorouracil (adverse drug reaction, clinical trial, drug therapy), folinic acid (adverse drug reaction, clinical trial, drug therapy), irinotecan (adverse drug reaction, clinical trial, drug therapy, intravenous drug administration), oxaliplatin (adverse drug reaction, clinical trial, drug therapy, intravenous drug administration)

granulocyte colony stimulating factor (drug therapy), recombinant granulocyte colony stimulating factor

cancer adjuvant therapy, cancer combination chemotherapy, colorectal liver metastasis (drug therapy, drug therapy, surgery), inoperable cancer (drug therapy, drug therapy, surgery)

adult, aged, article, asthenia (side effect), cancer patient, cancer surgery, cancer survival, chemotherapy induced emesis (side effect), controlled study, cryosurgery, diarrhea (side effect), disease free survival, drug dose reduction, drug response, drug safety, drug withdrawal, febrile neutropenia (drug therapy, side effect), female, human, liver resection, major clinical study, male, metastasis resection, middle aged, mucosa inflammation (side effect), multicenter study, multiple cycle treatment, neurotoxicity (side effect), neutropenia (drug therapy, side effect), overall survival, peripheral neuropathy (side effect), phase 2 clinical trial, progression free survival, radiofrequency ablation, randomized controlled trial, surgical risk, thrombocytopenia (side effect), very elderly, wedge resection

fluorouracil (51-21-8), folinic acid (58-05-9), irinotecan (100286-90-6), oxaliplatin (61825-94-3), recombinant granulocyte colony stimulating factor (1117844-87-7, 1192706-53-8, 121181-53-1)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00208260)

http://dx.doi.org/10.1245/s10434-013-3217-x

Copyright 2014 Elsevier B.V., All rights reserved.

Long-term quality-of-life and functioning comparison of atomoxetine versus other standard treatment in pediatric attention-deficit/hyperactivity disorder

Fuentes J., Danckaerts M., Cardo E., Puvanendran K., Berquin P., De Bruyckere K., Montoya A., Quail D., Escobar R.

(Fuentes J.) Fundacion Dr Carlos Elosegui de Policlinica Guipuzcoa, San-Sebastian, Spain. , (Danckaerts M.) Child Psychiatry, Katholieke Universiteit Leuven, Leuven, Belgium. , (Cardo E.) Neuropediatric Hospital Son Llatzer, Department of Psychology, University of the Balearic Islands (UIB), Palma de Mallorca, Spain. , (Puvanendran K.) Child Development Centre, Basildon Hospital, United Kingdom. , (Berquin P.) Service de Neuropediatrie, CHU Amiens, France. , (De Bruyckere K.) Eli Lilly and Company, Brussels, Belgium. , (Montoya A.; Escobar R., Escobar_rodrigo@lilly.com) Psychiatry and Pain Disorders, Lilly BioMedicines, Eli Lilly and Company, Indianapolis, IN 46285, United States. , (Quail D.) Eli Lilly and Company, Erl Wood, United Kingdom.

R. Escobar, Psychiatry and Pain Disorders, Lilly BioMedicines, Eli Lilly and Company, Indianapolis, IN 46285, United States. Email: Escobar_rodrigo@lilly.com

Journal of Clinical Psychopharmacology (2013) 33:6 (766-774). Date of Publication: December 2013

0271-0749,1533-712X (electronic)

Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, Philadelphia, United States.

Psychopharmacological agents were shown to be important for improving the quality of life (QoL) of patients with attention-deficit/hyperactivity disorder (ADHD). A short-term, 10-week study found atomoxetine (ATX) to be effective in improving QoL of ADHD patients. We compared, for the first time, long-term treatment outcomes of ATX and other early standard therapy (OEST, any pharmacological ADHD treatment except ATX) in QoL and functional impairment in pharmacologically naive children/adolescents in a randomized, controlled, open-label study at 6 and 12 months. Patients received ATX (0.5-1.8 mg/kg per day) or OEST (mainly methylphenidate). Quality of life and functioning were assessed by the Child Health and Illness Profile-Child Edition, Parent Rating Form and the Weiss Functional Impairment Rating Scale-Parent Report. Three hundred ninety-eight patients (79.4% male; mean age, 9.3 years) received study treatment. The Child Health and Illness Profile-Child Edition, Parent Rating Form achievement domain t scores significantly improved from baseline to 6 months from means of 28.0 to 37.1 for ATX and from 28.3 to 40.7 for OEST. Mean t scores at 12 months were 40.0 for ATX and 41.0 for OEST. The Weiss Functional Impairment Rating Scale-Parent Report total score improved from baseline to 6 months in both groups (ATX: mean 1.02 to 0.63; OEST: 0.96 to 0.59). Both treatments were safe with no statistically significant difference in the overall rate of adverse events. Overall, the improvements in QoL and functional impairment observed over time for ATX and OEST were meaningful and stable over the study period of 12 months. Between-group differences were small but sometimes statistically significant, providing the first-time long-term comparative symptomatic and QoL analysis between ATX and OEST. (copyright) 2013 by Lippincott Williams & Wilkins.

atomoxetine (adverse drug reaction, drug therapy)

methylphenidate (drug therapy)

attention deficit disorder (drug therapy, drug therapy), long term care, quality of life

abdominal pain (side effect), anorexia (side effect), article, child, Child Health and Illness Profile Child Edition, clinical assessment tool, controlled study, coughing (side effect), daily life activity, decreased appetite (side effect), drug induced headache (side effect), drug safety, ear infection (side effect), fatigue (side effect), female, fever (side effect), follow up, functional disease, gastroenteritis (side effect), health status, human, influenza (side effect), insomnia (side effect), major clinical study, male, maximum permissible dose, nausea (side effect), open study, outcome assessment, pharyngitis (side effect), priority journal, quality of life index, randomized controlled trial, rhinopharyngitis (side effect), school child, standard, treatment outcome, vomiting (side effect), Weiss functional impairment rating sacle parent report

atomoxetine (82248-59-7, 82857-39-4, 82857-40-7, 83015-26-3), methylphenidate (113-45-1, 298-59-9)

Pediatrics and Pediatric Surgery (7), Public Health, Social Medicine and Epidemiology (17), Psychiatry (32), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00447278)

http://dx.doi.org/10.1097/JCP.0b013e31829c762b

Copyright 2013 Elsevier B.V., All rights reserved.

Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis

Chakraborty A., Van L.M., Skerjanec A., Floch D., Klein U.R., Krammer G., Sunkara G., Howard D.

(Chakraborty A., abhijit.chakraborty@novartis.com; Howard D.) Clinical Pharmacology, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, United States. , (Van L.M.) Advanced Quantitative Sciences, Novartis Institute for Biomedical Research, Cambridge, MA, United States. , (Skerjanec A.; Floch D.; Klein U.R.) Biologics and Safety Disposition, Novartis Institute for Biomedical Research, Basel, Switzerland. , (Krammer G.) Clinical Development Unit, Department of Integrated Hospital Care Franchise, Novartis Pharma AG, Basel, Switzerland. , (Sunkara G.) Clinical PK/PD, Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, NJ, United States.

A. Chakraborty, Clinical Pharmacology, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, United States. Email: abhijit.chakraborty@novartis.com

Journal of Clinical Pharmacology (2013) 53:12 (1240-1251). Date of Publication: December 2013

0091-2700,1552-4604 (electronic)

Wiley-Blackwell Publishing Ltd, 9600 Garsington Rd, Chiswell Green Ln, Oxford, United Kingdom.

Pharmacokinetics and pharmacodynamics of the anti ]interleukin (IL)]1b monoclonal antibody, canakinumab, in gouty arthritis patients from three studies are reported. Canakinumab has low serum clearance (0.214 L/day), low steady]state volume of distribution (7.44 L), a 25.8]day half]life, and approximately 60% subcutaneous absolute bioavailability in a typical 93]kg patient. Creatinine clearance had a small positive impact on serum canakinumab clearance that is not likely to be clinically relevant. Binding to circulating IL]1b was demonstrated by increases in total serum IL]1b following canakinumab dosing. Total IL]1b kinetics and canakinumab pharmacokinetics were characterized by a population]based pharmacokinetic]binding model, where the estimated apparent in vivo dissociation constant (signifying binding affinity of canakinumab to circulating IL]1b) was 0.99 nmol/L in gouty arthritis patients. Canakinumab treatment provided rapid, sustained decreases in C]reactive protein and serum amyloid A, provided superior pain relief to triamcinolone acetonide, and increased time to first recurrent attack (P0.01 favoring all canakinumab doses vs. triamcinolone acetonide). (copyright) 2013, The American College of Clinical Pharmacology.

canakinumab (clinical trial, drug comparison, drug dose, drug therapy, pharmacokinetics, pharmacology, subcutaneous drug administration)

C reactive protein (endogenous compound), interleukin 1beta (endogenous compound), serum amyloid A (endogenous compound), triamcinolone acetonide (clinical trial, drug comparison, drug therapy, subcutaneous drug administration)

gout (drug therapy, drug therapy)

analgesia, area under the curve, article, binding affinity, comorbidity, creatinine clearance, dissociation constant, dose response, drug bioavailability, drug blood level, drug clearance, drug efficacy, drug half life, drug safety, drug tolerability, human, immunogenicity, in vivo study, kidney failure, maximum plasma concentration, phase 2 clinical trial (topic), phase 3 clinical trial (topic), randomized controlled trial (topic), single drug dose, steady state, time to maximum plasma concentration

C reactive protein (9007-41-4), canakinumab (402710-25-2, 402710-27-4), triamcinolone acetonide (76-25-5)

Clinical and Experimental Pharmacology (30), Arthritis and Rheumatism (31), Drug Literature Index (37)

ClinicalTrials.gov (NCT00798369, NCT01029652, NCT01071213, NCT01080131, NCT01137344)

http://dx.doi.org/10.1002/jcph.162

Copyright 2014 Elsevier B.V., All rights reserved.

Initial combination of linagliptin and metformin in patients with type 2 diabetes: Efficacy and safety in a randomised, double-blind 1-year extension study

Haak T., Meinicke T., Jones R., Weber S., Von Eynatten M., Woerle H.-J.

(Haak T., haak@diabetes-zentrum.de) Diabetes Center Mergentheim, Bad Mergentheim, Germany. , (Meinicke T.) Boehringer Ingelheim, Pharma GmbH and Co. KG, Biberach, Germany. , (Jones R.) Boehringer Ingelheim Ltd., Bracknell, United Kingdom. , (Weber S.; Von Eynatten M.; Woerle H.-J.) Boehringer Ingelheim, Pharma GmbH and Co. KG, Ingelheim, Germany.

T. Haak, Diabetes Klinik Bad Mergentheim GmbH and Co. KG, Theodor-Klotzbucher-Strasse 12, Bad Mergentheim, Germany. Email: haak@diabetes-zentrum.de

International Journal of Clinical Practice (2013) 67:12 (1283-1293). Date of Publication: December 2013

1368-5031,1742-1241 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Objective: To determine the efficacy and safety of linagliptin in initial combination with metformin in patients with type 2 diabetes. Methods: This 1-year randomised, double-blind study was an extension of a 6-month randomised controlled trial, in which adults with type 2 diabetes received one of six treatment regimens (linagliptin 2.5 mg plus metformin 500 mg bid, linagliptin 2.5 mg plus metformin mg 1000 bid, metformin 1000 mg bid, metformin 500 mg bid, linagliptin 5 mg qd or placebo). In the extension, patients in the first three treatment groups continued their regimen (non-switched group, n = 333) while the metformin 500 mg bid, linagliptin 5 mg qd and placebo groups were re-randomised to one of the three continuing regimens (switched group, n = 233). Results: All three non-switched groups maintained reductions in glycosylated haemoglobin (HbA1c; mean (plus or minus) standard deviation reductions across the 1.5-year period: linagliptin 2.5 plus metformin 1000 bid, -1.63 (plus or minus) 1.05%; linagliptin 2.5 plus metformin 500 bid, -1.32 (plus or minus) 1.06%; metformin 1000 bid, -1.25 (plus or minus) 0.91%) while the switched groups showed additional HbA1c reductions. During the extension, there were no clinically meaningful changes in body weight in any group. Adverse event rates were similar between groups, with most events being mild or moderate, and the incidence of investigator-defined hypoglycaemia was low, with no severe events. Discussion: Initial combination of linagliptin and metformin was well tolerated over the 1-year extension period, with low risk of hypoglycaemia, and improved glycaemic control vs. metformin alone. Conclusion: The initial combination of linagliptin and metformin appears to provide a useful treatment option in patients whose blood glucose levels are increased to an extent that metformin monotherapy may not achieve treatment targets. (copyright) 2013 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.

linagliptin (adverse drug reaction, clinical trial, drug combination), metformin (adverse drug reaction, clinical trial, drug combination)

hemoglobin A1c (endogenous compound), placebo

non insulin dependent diabetes mellitus (side effect, side effect)

acute heart infarction (side effect), add on therapy, adult, aged, alcohol liver disease (side effect), amylase blood level, anemia (side effect), article, cardiogenic shock (side effect), cerebrovascular accident (side effect), combination chemotherapy, controlled study, double blind procedure, drug dose increase, drug dose titration, drug efficacy, drug safety, drug tolerability, drug withdrawal, fatigue (side effect), female, follow up, glomerulus filtration rate, glycemic control, human, hyperglycemia (side effect), hypoglycemia (side effect), major clinical study, male, monotherapy, multicenter study, parallel design, patient compliance, priority journal, randomized controlled trial, randomized controlled trial (topic), side effect (side effect), supraventricular tachycardia (side effect), weight change

hemoglobin A1c (62572-11-6), linagliptin (668270-12-0), metformin (1115-70-4, 657-24-9)

Endocrinology (3), Internal Medicine (6), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00798161)

http://dx.doi.org/10.1111/ijcp.12308

Copyright 2013 Elsevier B.V., All rights reserved.

Olodaterol: First global approval

Gibb A., Yang L.P.H.

(Gibb A., dru@adis.com) Adis R and D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North-Shore-0754-Auckland, New Zealand. , (Yang L.P.H.) Adis, Auckland, New Zealand.

A. Gibb, Adis R and D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North-Shore-0754-Auckland, New Zealand. Email: dru@adis.com

Drugs (2013) 73:16 (1841-1846). Date of Publication: November 2013

0012-6667,1179-1950 (electronic)

Springer International Publishing AG, Gewerbestrasse 11, Cham (ZG), Switzerland.

Olodaterol (Striverdi((registered trademark)) Respimat((registered trademark))) is a novel, long-acting, (beta)(2)-adrenergic receptor agonist developed by Boehringer Ingelheim for the treatment of chronic obstructive pulmonary disease (COPD). The drug is delivered via the Respimat((registered trademark)) Soft Mist(trademark) inhaler. Olodaterol received its first global approval for the once-daily maintenance treatment of COPD in Canada and Russia, and submissions for regulatory approval have also been made in the USA, the EU and elsewhere. Phase II trials have been conducted in patients with asthma. The company is also developing a fixed-dose combination of olodaterol with tiotropium bromide, a long-acting anti-muscarinic agent, for the treatment of COPD. This article summarizes the milestones in the development of olodaterol leading to this first approval for COPD. (copyright) 2013 Springer International Publishing Switzerland.

olodaterol (adverse drug reaction, clinical trial, drug combination, drug comparison, drug concentration, drug interaction, drug therapy, inhalational drug administration, pharmacoeconomics, pharmacokinetics, pharmacology)

ciclesonide (drug combination, drug interaction), diuretic agent (adverse drug reaction, drug combination, drug interaction), formoterol (adverse drug reaction, drug comparison, drug therapy), ketoconazole (drug combination, drug interaction), monoamine oxidase inhibitor (adverse drug reaction, drug combination, drug interaction), placebo, soft mist inhaler, steroid (adverse drug reaction, drug combination, drug interaction), striverdi, tiotropium bromide (drug combination, drug interaction), tricyclic antidepressant agent (adverse drug reaction, drug combination, drug interaction), unclassified drug, xanthine derivative (adverse drug reaction, drug combination, drug interaction)

chronic obstructive lung disease (drug therapy, side effect, drug therapy, side effect), drug approval

area under the curve, article, asthma (drug therapy), dosage schedule comparison, drug blood level, drug potentiation, drug receptor binding, forced expiratory volume, heart ventricle arrhythmia (side effect), human, hypokalemia (side effect), lung cancer (side effect), maximum plasma concentration, nonhuman, pneumonia (side effect), rhinopharyngitis (side effect), single drug dose, small cell lung cancer (side effect), sudden cardiac death (side effect), upper respiratory tract infection (side effect)

respimat (Boehringer Ingelheim), striverdi (Boehringer Ingelheim)

Boehringer Ingelheim

ciclesonide (126544-47-6), formoterol (73573-87-2), ketoconazole (65277-42-1), olodaterol (868049-49-4, 869477-96-3), tiotropium bromide (136310-93-5)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Clinical and Experimental Pharmacology (30), Health Policy, Economics and Management (36), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00452400, NCT00467740, NCT00696020, NCT00720499, NCT00782210, NCT00782509, NCT00793624, NCT00796653, NCT00824382, NCT00846768, NCT00928668, NCT00931385, NCT00932646, NCT01013753, NCT01040403, NCT01040689, NCT01040728, NCT01311661, NCT01431274, NCT01431287, NCT01525615, NCT01533922, NCT01533935, NCT01536262, NCT01559116, NCT01694771, NCT01696058, NCT01809262), EudraCT (2006-004829-29, 2007-005087-26, 2008-000562-23, 2008-001933-84, 2008-001934-28, 2008-003704-67, 2008-006334-10, 2008-006625-14, 2009-010668-40, 2009-010669-22, 2009-013395-48, 2009-014395-21, 2009-014416-35, 2009-014417-27, 2009-014418-86, 2009-014880-38, 2011-004253-11, 2011-004659-37, 2011-004660-30, 2011-004710-42)

http://dx.doi.org/10.1007/s40265-013-0137-9

Copyright 2013 Elsevier B.V., All rights reserved.

Motor complications in Parkinson's disease: A comprehensive review of emergent management strategies

De Sousa S.M., Massano J.

(De Sousa S.M.; Massano J., jmassano@med.up.pt) Department of Clinical Neurosciences and Mental Health, University of Porto, Porto, Portugal. , (Massano J., jmassano@med.up.pt) Movement Disorders and Functional Surgery Unit, Department of Neurology, Centro Hospitalar Sao Joao, Porto, Portugal.

J. Massano, Movement Disorders and Functional Surgery Unit, Department of Neurology, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-139 Porto, Portugal. Email: jmassano@med.up.pt

CNS and Neurological Disorders - Drug Targets (2013) 12:7 (1017-1049). Date of Publication: November 2013

1871-5273,1996-3181 (electronic)

Bentham Science Publishers B.V., P.O. Box 294, Bussum, Netherlands.

Motor complications (dyskinesias and motor fluctuations) are a common and disabling problem of dopaminergic therapy in Parkinson's disease, which are often difficult to treat with the current therapeutic strategies. It has been proposed that continuous dopaminergic delivery could reduce the emergence of motor complications, which has been tried with levodopa intestinal infusion or subcutaneous apomorphine infusion. In selected refractory cases, surgical approaches such as deep brain stimulation should be considered. Ongoing clinical and preclinical research tried to lead the field into the discovery of other therapeutic targets and strategies that might prevent or reduce motor complications. These include drugs targeting non-dopaminergic systems (e.g. glutamatergic, serotonergic, noradrenergic, adenosinergic and cholinergic systems), gene therapy for delivering neurotrophic factors or critical enzymes for dopamine synthesis, and cell therapy. These studies found variable results, some of them promising, with the possibility of new therapeutic armamentarium in the management of Parkinson's disease in the near future. (copyright) 2013 Bentham Science Publishers.

ads 5102 (clinical trial, drug therapy), adx 48621, antiparkinson agent (clinical trial, drug therapy), apomorphine (adverse drug reaction, clinical trial, drug therapy, inhalational drug administration, pharmacokinetics, subcutaneous drug administration), aqw 051, avp 923 (clinical trial, drug therapy), bia 3202, carbidopa (drug combination, drug comparison, drug therapy, oral drug administration), carbidopa plus entacapone plus levodopa, carbidopa plus levodopa (adverse drug reaction, clinical trial, drug therapy, oral drug administration, pharmacokinetics, subcutaneous drug administration), cp 101, cp 106, cvt 301, dopamine (endogenous compound), eliprodil (clinical trial, drug therapy), entacapone (clinical trial, drug comparison, drug therapy), fipamezole, ipx 054, istradefylline, levodopa (adverse drug reaction, clinical trial, drug therapy, inhalational drug administration, oral drug administration, subcutaneous drug administration), levodopa methyl ester (clinical trial, drug combination, drug comparison, drug therapy, oral drug administration), lisuride (clinical trial, drug therapy), mavoglurant, methylphenidate (clinical trial, drug therapy), mk 0657 (clinical trial, drug therapy), nd 0611, nd 0612, nebicapone (adverse drug reaction, clinical trial, drug comparison, drug therapy), neu 120 (clinical trial, drug therapy), np 002, opicapone (clinical trial, drug comparison, drug therapy), ordopidine (clinical trial, drug therapy), pardoprunox (adverse drug reaction, clinical trial, drug therapy), perampanel (clinical trial, drug comparison, drug therapy), pimavanserin, piribedil (clinical trial, drug therapy), placebo, pramipexole (adverse drug reaction, drug therapy, transdermal drug administration), preladenant, prosavin, pym 50028, riluzole (clinical trial, drug therapy), ropinirole (clinical trial, drug therapy), rotigotine (clinical trial, drug therapy, intranasal drug administration, transdermal drug administration), s 90049, safinamide (clinical trial, drug therapy), sirio, spm 952, talampanel, tesofensine (adverse drug reaction, clinical trial, drug therapy), tozadenant, traxoprodil (clinical trial, drug therapy), unclassified drug, unindexed drug, vipadenant, vr 040, xp 21279

motor dysfunction (therapy), Parkinson disease (drug therapy, drug therapy, surgery, therapy)

abscess (side effect), application site erythema (side effect), application site pruritus (side effect), article, brain depth stimulation, cholinergic system, cognitive defect (side effect), continuous infusion, dizziness (side effect), dopaminergic nerve cell, drug dose escalation, drug megadose, drug withdrawal, dyskinesia (drug therapy, side effect), gastrointestinal symptom (side effect), gene delivery system, gene therapy, human, hypertransaminasemia (side effect), infusion pump, low drug dose, mental disease (side effect), motor fluctuation, multicenter study (topic), nausea (side effect), neural stem cell transplantation, neurosurgery, nonhuman, noradrenergic system, phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), phase 4 clinical trial (topic), pruritus (side effect), randomized controlled trial (topic), serotoninergic system, somnolence (side effect), stomach disease (side effect), torsion (side effect), ulcer (side effect), visual hallucination (side effect), vomiting (side effect)

acp 103, ads 5102, adx 48621, afq 056, aqw 051, bia 3202, bia 91067, biib 014, cp 101, cp 106, cvt 301, duodopa, e 2007, ipx 054, ipx 066, jp 1730, kw 6002, ly 300164, mk 0657, nd 0611, nd 0612, neu 120, np 002, ns 2330, prosavin, pym 50028, s 90049, sch 420814, sirio, slv 308, spm 952, stalevo, syn 115, vr 040, xp 21279

apomorphine (314-19-2, 58-00-4), carbidopa (28860-95-9), carbidopa plus levodopa (57308-51-7), dopamine (51-61-6, 62-31-7), eliprodil (119431-25-3, 127293-58-7, 136634-88-3), entacapone (116314-67-1), fipamezole (150586-58-6, 150586-72-4), istradefylline (155270-99-8), levodopa (59-92-7), levodopa methyl ester (7101-51-1), lisuride (18016-80-3), mavoglurant (543906-09-8), methylphenidate (113-45-1, 298-59-9), nebicapone (274925-86-9), opicapone (923287-50-7), ordopidine (871351-60-9), pardoprunox (269718-83-4, 269718-84-5), perampanel (380917-97-5), pimavanserin (706779-91-1, 706782-28-7, 868855-07-6), piribedil (3605-01-4), pramipexole (104632-25-9, 104632-26-0), preladenant (377727-87-2), riluzole (1744-22-5), ropinirole (91374-21-9), rotigotine (92206-54-7), safinamide (133865-89-1, 174756-44-6, 202825-46-5), talampanel (161832-65-1, 161832-67-3), tesofensine (402856-42-2), tozadenant (870070-55-6), traxoprodil (134234-12-1), vipadenant (442908-10-3)

Neurology and Neurosurgery (8), Psychiatry (32), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00001929, NCT00004576, NCT00006077, NCT00036296, NCT00086294, NCT00089622, NCT00108667, NCT00163085, NCT00296192, NCT00296959, NCT00307450, NCT00335153, NCT00357994, NCT00360568, NCT00407095, NCT00408915, NCT00427011, NCT00438607, NCT00477802, NCT00522379, NCT00582673, NCT00607451, NCT00623363, NCT00627640, NCT00660387, NCT00758368, NCT00873392, NCT00888004, NCT00909883, NCT00957918, NCT00986414, NCT01023282, NCT01092065, NCT01113320, NCT01155466, NCT01190735, NCT01227265, NCT01227655, NCT01229332, NCT01283594, NCT01291537, NCT01336088, NCT01385592, NCT01397422, NCT01474421, NCT01479127, NCT01491529, NCT01491932, NCT01536015, NCT01568034, NCT01568047, NCT01568073, NCT01617135, NCT01628926, NCT01631825, NCT01646255, NCT01693081, NCT01723904, NCT01725802, NCT01738178, NCT01747655, NCT01754129, NCT01767129, NCT01777555)

Copyright 2013 Elsevier B.V., All rights reserved.

Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease

Kramann R., Dirocco D.P., Humphreys B.D.

(Kramann R.; Dirocco D.P.; Humphreys B.D., bhumphreys@partners.org) Brigham and Women's Hospital, Boston, MA, United States. , (Kramann R.; Dirocco D.P.; Humphreys B.D., bhumphreys@partners.org) Harvard Medical School, Boston, MA, United States. , (Kramann R.) RWTH Aachen University, Division of Nephrology, Aachen, Germany. , (Humphreys B.D., bhumphreys@partners.org) Harvard Stem Cell Institute, Cambridge, MA, United States.

B.D. Humphreys, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, United States. Email: bhumphreys@partners.org

Journal of Pathology (2013) 231:3 (273-289). Date of Publication: November 2013

0022-3417,1096-9896 (electronic)

John Wiley and Sons Ltd, Southern Gate, Chichester, West Sussex, United Kingdom.

Fibrosis and scar formation results from chronic progressive injury in virtually every tissue and affects a growing number of people around the world. Myofibroblasts drive fibrosis, and recent work has demonstrated that mesenchymal cells, including pericytes and perivascular fibroblasts, are their main progenitors. Understanding the cellular mechanisms of pericyte/fibroblast-to- myofibroblast transition, myofibroblast proliferation and the key signalling pathways that regulate these processes is essential to develop novel targeted therapeutics for the growing patient population suffering from solid organ fibrosis. In this review, we summarize the current knowledge about different progenitor cells of myofibroblasts, discuss major pathways that regulate their transdifferentiation and discuss the current status of novel targeted anti-fibrotic therapeutics in development. Copyright (copyright) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

alpha interferon (clinical trial, drug therapy), alpha smooth muscle actin (endogenous compound), ambrisentan (clinical trial, drug therapy), belimumab (clinical trial, drug therapy), bosentan (clinical trial, drug therapy), carlumab (clinical trial, drug therapy), connective tissue growth factor (endogenous compound), epidermal growth factor receptor (endogenous compound), etanercept (clinical trial, drug therapy), fg 3019 (clinical trial, drug therapy), fresolimumab (clinical trial, drug therapy), gamma1b interferon (clinical trial, drug therapy), ly 2382770 (clinical trial, drug therapy), macitentan (clinical trial, drug therapy), metelimumab (adverse drug reaction, clinical trial, drug therapy), monoclonal antibody (clinical trial, drug therapy), Notch receptor (endogenous compound), pf 06473871 (clinical trial, drug therapy), pf 06473871], pirfenidone (clinical trial, drug therapy), platelet derived growth factor beta receptor (endogenous compound), pomalidomide (clinical trial, drug therapy), qax 576 (clinical trial, drug therapy), re 021 (clinical trial, drug therapy), rilonacept (clinical trial, drug therapy), rxi 109 (clinical trial, drug therapy), sonic hedgehog protein (endogenous compound), stx 100 (clinical trial, drug therapy), tralokinumab (clinical trial, drug therapy), transforming growth factor beta (endogenous compound), unclassified drug, Wnt protein (endogenous compound)

fibrosis, myofibroblast

article, cell differentiation, cell proliferation, cytokine production, diabetic nephropathy (drug therapy), drug targeting, epithelial mesenchymal transition, extracellular matrix, fibrosing alveolitis (drug therapy), focal glomerulosclerosis (drug therapy), human, kidney fibrosis, liver fibrosis, lung fibrosis, nonhuman, pericyte, priority journal, scar (drug therapy), signal transduction, skin hypertrophy (drug therapy), systemic sclerosis (drug therapy), tissue injury, unspecified side effect (side effect)

fg 3019 (FibroGen), pf 06473871] (Pfizer), re 021 (retrophin), stx 100 (Biogen)

Actelion, Amarillo Biosciences, Biogen, Celgene, FibroGen, Gilead, Glaxo SmithKline, Intermune, Labaz, Lilly, Pfizer, Regeneron, retrophin, rxi

ambrisentan (177036-94-1), belimumab (356547-88-1), bosentan (147536-97-8, 157212-55-0), carlumab (915404-94-3), epidermal growth factor receptor (79079-06-4), etanercept (185243-69-0, 200013-86-1), fresolimumab (948564-73-6), gamma1b interferon (98059-61-1), macitentan (441798-33-0), metelimumab (272780-74-2), pirfenidone (53179-13-8), pomalidomide (19171-19-8, 443912-23-0, 443919-33-3), rilonacept (501081-76-1), tralokinumab (1044515-88-9)

General Pathology and Pathological Anatomy (5), Clinical and Experimental Biochemistry (29), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00077584, NCT00125385, NCT00631475, NCT00903331, NCT01113801, NCT01284322, NCT01366209, NCT01371305, NCT01665391)

http://dx.doi.org/10.1002/path.4253

Copyright 2014 Elsevier B.V., All rights reserved.

Molecular pathways: Targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer

Li B., Simon M.C.

(Li B.; Simon M.C., celeste2@mail.med.upenn.edu) Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 456 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, United States. , (Simon M.C., celeste2@mail.med.upenn.edu) Howard Hughes Medical Institute, Philadelphia, PA, United States.

M.C. Simon, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 456 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, United States. Email: celeste2@mail.med.upenn.edu

Clinical Cancer Research (2013) 19:21 (5835-5841). Date of Publication: 1 Nov 2013

1078-0432,1557-3265 (electronic)

American Association for Cancer Research Inc., 615 Chestnut Street, 17th Floor, Philadelphia, United States.

MYC is a multifunctional transcription factor that is deregulated in many human cancers. MYC impacts a collaborative genetic program that orchestrates cell proliferation, metabolism, and stress responses. Although the progression of MYC-amplified tumors shows robust dependence on MYC activity, directly targeting MYC as a therapeutic method has proven to be technically difficult. Therefore, alternative approaches are currently under development with a focus on interference with MYC-mediated downstream effects. To fuel rapid cell growth, MYC reprograms cancer cell metabolism in a way that is substantially different from normal cells. TheMYC-induced metabolic signature is characterized by enhanced glucose and glutamine uptake, increased lactate production, and altered amino acid metabolism. Targeting MYCreprogrammed cancer cell metabolism is considered to be promising based on multiple preclinical studies. In addition, the increased biosynthetic demand of MYC-driven tumors coupled with limited nutrient access within tumor microenvironments create multiple levels of oncogenic stress, which can also be used as tumor-specific targets for pharmacologic intervention. Presumably, the best therapeutic strategy for treating MYC-amplified tumors is combined targeting of multiple MYC-mediated pathways, especially those involved in regulating cell proliferation, metabolism, and oncogenic stress. (copyright) 2013 American Association for Cancer Research.

Myc protein (endogenous compound)

6 (4 chlorophenyl) n ethyl 8 methoxy 1 methyl 4h [1,2,4]triazolo[4,3 a][1,4]benzodiazepine 4 acetamide (clinical trial), 6 diazo 5 oxonorleucine, aminooxyacetic acid (adverse drug reaction, drug therapy), antineoplastic agent (drug therapy), at 7519m (clinical trial), azd 3965 (drug therapy), deoxyglucose (clinical trial), dichloroacetic acid (clinical trial, drug therapy), eflornithine (clinical trial), epigallocatechin gallate (clinical trial, drug therapy), everolimus (clinical trial, drug therapy), fenretinide (clinical trial, drug therapy), glutamine (endogenous compound), glycine (endogenous compound), gsk 2656157 (drug therapy), lactic acid (endogenous compound), lonidamine (clinical trial), proline (endogenous compound), roscovitine (clinical trial), serine (endogenous compound), unclassified drug

cancer cell, cell metabolism

amino acid metabolism, apoptosis, article, B cell lymphoma (drug therapy), brain tumor (drug therapy), cancer inhibition, colorectal cancer (drug therapy), drug targeting, glucose transport, glycolysis, head and neck carcinoma (drug therapy), human, large cell lymphoma (drug therapy), lymphoma (drug therapy), metabolic stress, multiple myeloma (drug therapy), neuroblastoma (drug therapy), nonhuman, oncogene myc, ovary cancer (drug therapy), pancreas cancer (drug therapy), priority journal, prostate cancer (drug therapy), solid tumor (drug therapy), stomach cancer (drug therapy), tumor growth, tumor microenvironment, unfolded protein response, unspecified side effect (side effect)

azd 3965, gsk 2656157, gsk 525762

6 diazo 5 oxonorleucine (157-03-9, 764-17-0), aminooxyacetic acid (2921-14-4, 645-88-5), deoxyglucose (154-17-6), dichloroacetic acid (13425-80-4, 2156-56-1, 79-43-6), eflornithine (67037-37-0, 70052-12-9), epigallocatechin gallate (989-51-5), everolimus (159351-69-6), fenretinide (65646-68-6, 75686-07-6), glutamine (56-85-9, 6899-04-3), glycine (56-40-6, 6000-43-7, 6000-44-8), lactic acid (113-21-3, 50-21-5), lonidamine (50264-69-2), proline (147-85-3, 7005-20-1), roscovitine (186692-46-6), serine (56-45-1, 6898-95-9)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00288067, NCT00435448, NCT00566410, NCT00633087, NCT00646230, NCT00942422, NCT00983580, NCT00999401, NCT01059071, NCT01111097, NCT01183949, NCT01360320, NCT01386632, NCT01535157, NCT01586260, NCT01587703, NCT01627054, NCT01652144, NCT01791595)

http://dx.doi.org/10.1158/1078-0432.CCR-12-3629

Copyright 2013 Elsevier B.V., All rights reserved.

Development of the Performance of the Upper Limb module for Duchenne muscular dystrophy

Mayhew A., Mazzone E.S., Eagle M., Duong T., Ash M., Decostre V., Vandenhauwe M., Klingels K., Florence J., Main M., Bianco F., Henrikson E., Servais L., Campion G., Vroom E., Ricotti V., Goemans N., Mcdonald C., Mercuri E.

(Mayhew A.; Eagle M.) Institute of Genetic Medicine, Newcastle Upon Tyne, United Kingdom. , (Mazzone E.S.; Bianco F.; Mercuri E., mercuri@rm.unicatt.it) Department of Paediatric Neurology, Catholic University, Rome, Italy. , (Duong T.) Children's National Medical Center, Washington, DC, United States. , (Ash M.; Main M.; Ricotti V.) Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, United Kingdom. , (Decostre V.; Servais L.) Institut de Myologie, GH Pitie Salpetriere, Paris, France. , (Vandenhauwe M.; Goemans N.) Child Neurology, University Hospitals Leuven, Leuven, Belgium. , (Klingels K.) Department of Rehabilitation Sciences, University of Leuven, Leuven, Belgium. , (Florence J.) Department of Neurology, Washington University School of Medicine, St Louis, MO, United States. , (Henrikson E.; Mcdonald C.) Department of Physical Medicine and Rehabilitation, University of California, Davis, CA, United States. , (Campion G.) Prosensa, Holdings, Leiden, Netherlands. , (Vroom E.) Duchenne Parent Project, Veenendaal, Netherlands.

E. Mercuri, Department of Child Neurology, Policlinico Gemelli, Largo Gemelli 00168, Roma, Italy. Email: mercuri@rm.unicatt.it

Developmental Medicine and Child Neurology (2013) 55:11 (1038-1045). Date of Publication: November 2013

0012-1622,1469-8749 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Aim: An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper limb. We report the steps leading to the development of the Performance of the Upper Limb (PUL), a tool specifically designed for assessing upper limb function in ambulant and non-ambulant patients with Duchenne muscular dystrophy (DMD). Method: The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma. Results: The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician-reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living. Interpretation: The module was developed using innovative approaches and will be useful for designing clinical trials. (copyright) 2013 Mac Keith Press.

Duchenne muscular dystrophy, named inventories, questionnaires and rating scales, performance of the upper limb module

adolescent, adult, article, child, daily life activity, human, male, outcome assessment, preschool child, priority journal, Rasch analysis, school child, systematic review

Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00592553, NCT01207908, NCT01396239, NCT01462292)

http://dx.doi.org/10.1111/dmcn.12213

Copyright 2014 Elsevier B.V., All rights reserved.

Orphan drug development in muscular dystrophy: Update on two large clinical trials of dystrophin rescue therapies

Hoffman E.P., Connor E.M.

(Hoffman E.P.) Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, United States. , (Hoffman E.P.) Department of Integrative Systems Biology, George Washington University School of Medicine, Washington, DC, United States. , (Connor E.M.) Office of Innovation Development, Children's National Medical Center, Washington, DC, United States. , (Connor E.M.) George Washington University School of Medicine, Washington, DC, United States.

E.P. Hoffman, Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, United States.

Discovery Medicine (2013) 16:89 (233-239). Date of Publication: November 2013

1539-6509,1944-7930 (electronic)

Solariz, Inc., 10 Gerard Ave, Ste 201,, Timonium, United States.

Duchenne muscular dystrophy is a relatively common 'rare disorder,' with an incidence of about 1/5,000 males worldwide. The responsible gene and deficient protein (dystrophin) were identified in 1987, an early success of human molecular genetics and emerging genome projects. A rational approach to therapeutics is to replace dystrophin in patient muscle, thus addressing the primary biochemical defect. Fast forward 25 years, and two phase 2b/3 trials have been carried out with agents designed to induce de novo dystrophin production in DMD patient's muscle; ataluren (stop codon read through) with 174 patients, and drisapersen (exon skipping) with 186 patients. Both used a six minute walk test as the primary outcome measure. Neither drisapersen nor high dose ataluren showed any significant improvement in this outcome, whereas low dose ataluren is reported to show some possible improvement. Experience with ataluren and drisapersen has been disappointing and this is a good time to ask: What can we learn from these programs and how can this inform further drug development in DMD? At the times these two trials were started, there was a lack of existing data and infrastructure regarding both clinical and biochemical outcome measures. The recent publications of more extensive natural history data in multiple DMD cohorts, and ongoing efforts to define reliable and sensitive dystrophin assays are important. If the drisapersen and ataluren programs were instead begun today, new progress in biochemical and clinical endpoints may have triggered a re-design, with better de-risking in phase 2 studies prior to resource-intensive phase 3 trials. (copyright) Discovery Medicine.

ataluren (clinical trial), drisapersen (clinical trial, drug development), dystrophin (endogenous compound)

drug manufacture, Duchenne muscular dystrophy

article, cystic fibrosis, disease course, drug efficacy, exon skipping, gene mutation, human, immunoblotting, immunohistochemistry, incidence, muscle biopsy, nonhuman, outcome assessment, phase 2 clinical trial (topic), phase 3 clinical trial (topic), protein expression

ataluren (775304-57-9, 775304-59-1), drisapersen (1181666-20-5, 1251830-50-8), dystrophin (116978-02-0)

Drug Literature Index (37), Internal Medicine (6), Neurology and Neurosurgery (8)

ClinicalTrials.gov (NCT00592553, NCT01826487)

Copyright 2014 Elsevier B.V., All rights reserved.

Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): Important lessons for future trials

Schweizer M.T., Huang P., Kattan M.W., Kibel A.S., De Wit R., Sternberg C.N., Epstein J.I., Eisenberger M.A.

(Schweizer M.T.; Huang P.; Epstein J.I.; Eisenberger M.A., eisenma@jhmi.edu) Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, United States. , (Kattan M.W.) Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States. , (Kibel A.S.) Division of Urologic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. , (De Wit R.) Daniel Den Hoed Cancer Center, Erasmus University Medical Center, Rotterdam, Netherlands. , (Sternberg C.N.) Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy. , (Epstein J.I.) Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, United States. , (Epstein J.I.; Eisenberger M.A., eisenma@jhmi.edu) Brady Urological Institute, Johns Hopkins University, Baltimore, MD, United States.

M.A. Eisenberger, Bunting Blaustein Cancer Research Building, 1650 Orleans St, CRB1-1M51, Baltimore, MD 21231, United States. Email: eisenma@jhmi.edu

Cancer (2013) 119:20 (3610-3618). Date of Publication: 15 Oct 2013

0008-543X,1097-0142 (electronic)

John Wiley and Sons Inc., P.O.Box 18667, Newark, United States.

BACKGROUND The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting. METHODS TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n = 228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of (less-than or equal to) 60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value. RESULTS Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3-3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457-546 days). The nomogram's predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P <.00001). CONCLUSIONS TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible. Cancer 2013;119:3610-3618. (copyright) 2013 American Cancer Society.

docetaxel (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, intravenous drug administration), leuprorelin (adverse drug reaction, clinical trial, drug combination, drug therapy, subcutaneous drug administration)

prostate specific antigen (endogenous compound), testosterone (endogenous compound)

cancer adjuvant therapy, prostate cancer (drug therapy, drug therapy, surgery), prostatectomy

adjuvant therapy, adult, article, cancer growth, cancer hormone therapy, cancer mortality, cancer recurrence, consensus, controlled study, diagnostic accuracy, febrile neutropenia (side effect), follow up, high risk patient, human, major clinical study, male, metastasis, multicenter study, multiple cycle treatment, nomogram, patient selection, phase 3 clinical trial, postoperative care, prediction, priority journal, progression free survival, randomized controlled trial, testosterone blood level, unspecified side effect (side effect)

docetaxel (114977-28-5), leuprorelin (53714-56-0, 74381-53-6), testosterone (58-22-0)

Cancer (16), Urology and Nephrology (28), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00283062)

http://dx.doi.org/10.1002/cncr.28270

Copyright 2014 Elsevier B.V., All rights reserved.

Efficacy and safety of bevacizumab in metastatic colorectal cancer: Pooled analysis from seven randomized controlled trials

Hurwitz H.I., Tebbutt N.C., Kabbinavar F., Giantonio B.J., Guan Z.-Z., Mitchell L., Waterkamp D., Tabernero J.

(Hurwitz H.I., herbert.hurwitz@duke.edu) Duke University Medical Center, Division of Hematology and Oncology, Durham, NC, United States. , (Tebbutt N.C.) Department of Medical Oncology, Austin Health, Heidelberg, Australia. , (Kabbinavar F.) Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. , (Giantonio B.J.) Abramson Cancer Center, Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, PA, United States. , (Guan Z.-Z.) State Key Laboratory of Oncology in South China, People's Republic of China, Sun Yatsen University Cancer Center, Guangzhou, Guangdong, China. , (Mitchell L.; Waterkamp D.) F. Hoffmann-La Roche Ltd., Basel, Switzerland. , (Tabernero J.) Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.

H. I. Hurwitz, Duke University Medical Center, Division of Hematology and Oncology, GI Oncology Unit, 10 Bryan Searle Dr., Durham, NC 27710, United States. Email: herbert.hurwitz@duke.edu

Oncologist (2013) 18:9 (1004-1012). Date of Publication: 2013

1083-7159,1549-490X (electronic)

AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.

Purpose. This analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). Patients and Methods. Patient data were pooled from the first-line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second-line E3200 RCT. All analyses were based on the intent-to-treat population. To assess differences in time-to-event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random-effects (overall) and fixed-effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results. The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71-0.90) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.46-0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin-based, irinotecanbased), extent of disease (liver metastases only, extensive disease), age (<65, (greater-than or equal to)65 years), Eastern Cooperative Oncology Group performance status (0, (greater-than or equal to)1), and KRAS status (wild-type, mutant) were consistent with the overall analysis. Incidence rates of grade (greater-than or equal to)3 hypertension, proteinuria, bleeding, wound-healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment. Conclusion. The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials. (copyright) AlphaMed Press 2013.

bevacizumab (adverse drug reaction, clinical trial, drug combination, drug therapy)

capecitabine (adverse drug reaction, clinical trial, drug combination, drug therapy), fluorouracil (adverse drug reaction, clinical trial, drug combination, drug therapy), folinic acid (adverse drug reaction, clinical trial, drug combination, drug therapy), irinotecan (adverse drug reaction, clinical trial, drug combination, drug therapy), K ras protein (endogenous compound), mitomycin (adverse drug reaction, clinical trial, drug combination, drug therapy), oxaliplatin (adverse drug reaction, clinical trial, drug combination, drug therapy), placebo

metastatic colorectal cancer (drug therapy, drug therapy)

arterial thromboembolism (side effect), article, asthenia (side effect), bleeding (side effect), cancer chemotherapy, diarrhea (side effect), digestive system perforation (side effect), disease course, drug efficacy, drug response, drug safety, fatigue (side effect), gene mutation, human, hypertension (side effect), incidence, liver metastasis, monotherapy, nausea and vomiting (side effect), neuropathy (side effect), neutropenia (side effect), overall survival, phase 2 clinical trial (topic), phase 3 clinical trial (topic), priority journal, progression free survival, proteinuria (side effect), randomized controlled trial (topic), stomatitis (side effect), venous thromboembolism (side effect), wound healing impairment (side effect)

avastin (Genentech, United States)

Genentech (United States)

bevacizumab (216974-75-3), capecitabine (154361-50-9), fluorouracil (51-21-8), folinic acid (58-05-9), irinotecan (100286-90-6), mitomycin (1404-00-8, 50-07-7, 74349-48-7), oxaliplatin (61825-94-3)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00025337, NCT00069095, NCT00109070, NCT00109226, NCT00294359, NCT00642577)

http://dx.doi.org/10.1634/theoncologist.2013-0107

Copyright 2013 Elsevier B.V., All rights reserved.

A systematic review of pharmacological pain management in multiple sclerosis

Jawahar R., Oh U., Yang S., Lapane K.L.

(Jawahar R.; Yang S.) Department of Epidemiology and Community Health, Virginia Commonwealth University, Richmond VA, United States. , (Oh U.) Department of Neurology, Virginia Commonwealth University, Richmond VA, United States. , (Lapane K.L., kate.lapane@umassmed.edu) Department of Quantitative Health Sciences, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester MA 01655, United States.

K.L. Lapane, Department of Quantitative Health Sciences, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester MA 01655, United States. Email: kate.lapane@umassmed.edu

Drugs (2013) 73:15 (1711-1722). Date of Publication: October 2013

0012-6667,1179-1950 (electronic)

Springer International Publishing AG, Gewerbestrasse 11, Cham (ZG), Switzerland.

Background: Both chronic and acute pain have been cited as the most common symptoms amongst patients with multiple sclerosis (MS), with recent prevalence estimates as high as 83 %. The evidence for spasticity and trigeminal neuralgia pharmacological treatments in MS has been systematically reviewed, but no equivalent reviews have been published concerning MS pain unrelated to these two conditions. Objective: Our objective was to systematically review pain management strategies for the reduction of non-spastic and non-trigeminal neuralgic pain in MS patients. Data Sources: Experimental studies published after 1965 were chosen for review by searching electronic databases (e.g. PubMed, Cumulative Index to Nursing and Allied Health Literature, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and clinicaltrials.gov) and bibliographies/citations of previously published reviews. Study Selection: Studies were included if all participants were adults clinically diagnosed with MS, study sample was not restricted to participants with spasticity or trigeminal neuralgia, and participant-reported pain was a primary or secondary outcome measured with a validated tool. Study Appraisal and Synthesis Methods: Records were screened and methodological qualities of included studies were assessed independently by two reviewers under the supervision of another reviewer using the principles recommended in the Cochrane Handbook for Systematic Review of Interventions and the levels of evidence espoused by the American Academy of Neurology. Results: Fifteen studies met the inclusion and exclusion criteria for review; interventions included antidepressants, anticonvulsants, dextromethorphan/quinidine, cannabinoids, and opioids/opioid antagonists. The pooled effect size for anticonvulsants (4 studies, 78 participants) was -1.88 (95 % CI: -3.13 to -0.64). The pooled effect size for cannabinoids (3 studies, 565 participants) was 0.08 (95 % CI: -0.74 to 0.89). Overall, only four trials reported Class 1 evidence. For these trials, dizziness was the most commonly reported adverse event, followed by nausea and somnolence. Limitations: The relatively small number of trials in MS patients with chronic pain precludes specific recommendations for treatment strategies. The review did not reveal any studies of drug combinations. Conclusions: More trials with rigorous design and reporting are needed to determine effective treatments for specific pain types presenting in people living with MS. (copyright) 2013 Springer International Publishing Switzerland.

anticonvulsive agent (adverse drug reaction, clinical trial, drug therapy), antidepressant agent (adverse drug reaction, clinical trial, drug therapy), cannabinoid (adverse drug reaction, clinical trial, drug therapy), dextromethorphan plus quinidine (adverse drug reaction, clinical trial, drug therapy), dronabinol (drug therapy), duloxetine (adverse drug reaction, drug comparison, drug therapy), etiracetam (drug therapy), gabapentin (adverse drug reaction, drug therapy), lamotrigine (adverse drug reaction, drug therapy), morphine (adverse drug reaction, drug therapy, intravenous drug administration), nabiximols (drug therapy, topical drug administration), naltrexone (adverse drug reaction, drug therapy), nortriptyline (adverse drug reaction, drug comparison, drug therapy), opiate (drug therapy), opiate antagonist (adverse drug reaction, clinical trial, drug therapy), oxcarbazepine (drug therapy), placebo, pregabalin (adverse drug reaction, drug therapy)

analgesia, multiple sclerosis, neuralgia (drug therapy, complication, drug therapy, therapy)

article, diarrhea (side effect), disease duration, dizziness (side effect), drug dose titration, drug efficacy, electronic medical record, Expanded Disability Status Scale, headache (side effect), human, mental disease (side effect), nausea (side effect), outcome assessment, pain assessment, sedation, side effect (side effect), somnolence (side effect), spasticity, systematic review, transcutaneous nerve stimulation, trigeminus neuralgia, visual analog scale, vivid dream (side effect)

dronabinol (7663-50-5), duloxetine (116539-59-4, 136434-34-9), etiracetam (102767-28-2, 33996-58-6), gabapentin (60142-96-3), lamotrigine (84057-84-1), morphine (52-26-6, 57-27-2), nabiximols (56575-23-6), naltrexone (16590-41-3, 16676-29-2), nortriptyline (72-69-5, 894-71-3), opiate (53663-61-9, 8002-76-4, 8008-60-4), oxcarbazepine (28721-07-5), pregabalin (148553-50-8)

Neurology and Neurosurgery (8), Anesthesiology (24), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00391079, NCT00423527, NCT00501696, NCT00755807, NCT01604265, NCT01610700)

http://dx.doi.org/10.1007/s40265-013-0125-0

Copyright 2013 Elsevier B.V., All rights reserved.

Ruboxistaurin for the treatment of diabetic peripheral neuropathy: A systematic review of randomized clinical trials

Bansal D., Badhan Y., Gudala K., Schifano F.

(Bansal D., dipikabansal079@gmail.com; Badhan Y.; Gudala K.) Clinical Research Unit, Department of Pharmacy Practice, National Institute of Pharmaceutical and Education Research, Mohali, India. , (Schifano F.) Clinical Pharmacology and Therapeutics, University of Hertfordshire, Hertfordshire, United Kingdom.

D. Bansal, Clinical Research Unit, Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Mohali 160062, India. Email: dipikabansal079@gmail.com

Diabetes and Metabolism Journal (2013) 37:5 (375-384). Date of Publication: October 2013

2233-6079,2233-6087 (electronic)

Korean Diabetes Association, Room 1010, Renalssance Tower Bldg 456, Gongdeok-dong,, Mapo-gu, Seoul,, South Korea.

Background: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. Protein kinase C (PKC) inhibitor's has been thought to be a potential disease modifying drug's in DPN as it slows or reverse neuropathy's progression. To assesses the efficacy and safety of ruboxistaurin on the progression of symptoms, signs, or functional disability in DPN. Methods: A systematic review of the literature databases like PubMed, ProQuest, EBSCO, EMBASE, and Cochrane Central was performed up to August 2012. We included randomized controlled trials (RCTs) comparing PKC inhibitor ruboxistaurin (RBX) with control and lasting at least 6 months. Our primary outcome measure was change in neurological examination, measured by neurological total symptom score (NTSS) and vibration detection threshold (VDT). Secondary outcome measures were total quality of life (QoL), skin microvascular blood flow and others. Results: Six RCTs were included in review. Change in neurological function assessed by NTSS was reported in six studies, out of which significant difference between the RBX and placebo group seen in four studies favouring treatment group while remaining two studies reported no significant difference. VDT was assessed in only one study in which no significant difference seen between RBX and placebo group. Two studies reported significant improvement in QoL data. Safety data was reported in only two studies in which none of side effect was related to RBX. Conclusion: RBX had effects on DPN in some studies, but the evidence is not enough for meta-analysis and firm conclusion.

ruboxistaurin (adverse drug reaction, clinical trial, drug therapy)

diabetic neuropathy (drug therapy, diagnosis, drug therapy)

article, disease course, drug efficacy, drug safety, drug tolerability, functional assessment, human, neurologic examination, neurological total symptom score, outcome assessment, QT prolongation (side effect), quality of life, randomized controlled trial (topic), scoring system, side effect (side effect), skin blood flow, systematic review, vibration detection threshold

ruboxistaurin (169939-93-9, 169939-94-0)

Endocrinology (3), Internal Medicine (6), Neurology and Neurosurgery (8), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00044395, NCT00044408)

http://dx.doi.org/10.4093/dmj.2013.37.5.375

Copyright 2013 Elsevier B.V., All rights reserved.

Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: Randomised, double-blind, placebo-controlled study

Allen A., Schenkenberger I., Trivedi R., Cole J., Hicks W., Gul N., Jacques L.

(Allen A., ann.allen@gsk.com) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, United Kingdom. , (Schenkenberger I.) Medizinische Leitung, Klinische Forschung, Berlin, Germany. , (Trivedi R.) Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, NC, United States. , (Cole J.) IPS Research Company, Oklahoma City, OK, United States. , (Hicks W.; Gul N.; Jacques L.) Respiratory Medicines Development Centre, GlaxoSmithKline, Uxbridge, United Kingdom.

A. Allen, Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stevenage, SG1 2NY, United Kingdom. Email: ann.allen@gsk.com

Clinical Respiratory Journal (2013) 7:4 (397-406). Date of Publication: October 2013

1752-6981,1752-699X (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Introduction: Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24-h activity. FF is in development as a once-daily treatment for asthma as monotherapy and in combination with vilanterol (VI), a long-acting (beta)(2) agonist. Corticosteroids can have systemic effects on hypothalamic-pituitary-adrenal (HPA) axis function, potentially resulting in cortisol suppression. Objectives: To assess the effect of FF/VI compared with placebo on the HPA axis by evaluating 24-h weighted mean serum cortisol levels in adolescent and adult patients with persistent asthma. Methods: One hundred eighty-five patients with >12 weeks history of asthma were randomised in a 4:4:4:1 ratio to one of two once-daily FF/VI treatments (100/25(mu)g or 200/25(mu)g), placebo or an active control group that received inhaled placebo plus one prednisolone 10mg capsule daily for the last 7 days of the study. Twenty-four-hour serum and urinary cortisol was measured at baseline and on day 42. Results: Non-inferiority in 24-h weighted mean serum cortisol after 6 weeks of treatment with once-daily FF/VI at either strength was shown. Treatment ratios [95% confidence interval (CI)] to placebo for FF/VI 100/25(mu)g [0.99 (0.87-1.12)] or FF/VI 200/25(mu)g [0.97 (0.86-1.10)] indicated non-inferiority of both FF/VI doses to placebo as the lower limit of the 95% CI was greater than the predefined 0.8. Prednisolone substantially reduced 24-h weighted mean serum cortisol [treatment ratio to placebo 0.34 (0.28-0.41)]. FF/VI was well-tolerated, and no safety concerns were identified. Conclusions: FF/VI was found to be non-inferior to placebo on HPA axis function, with no indication of significant cortisol suppression after 42 days. (copyright) 2013 John Wiley & Sons Ltd.

fluticasone furoate plus vilanterol (adverse drug reaction, clinical trial, drug comparison, drug dose, drug therapy, inhalational drug administration, pharmacokinetics)

corticosteroid (adverse drug reaction, drug therapy), hydrocortisone (endogenous compound), placebo, prednisolone (drug comparison, drug therapy), salbutamol (drug therapy, inhalational drug administration)

adolescent disease (drug therapy, drug therapy), adult disease (drug therapy, drug therapy), asthma (drug therapy, drug therapy), hypothalamus hypophysis adrenal system

adolescent, adult, aged, area under the curve, article, cardiovascular effect, child, controlled study, deterioration, disease exacerbation, double blind procedure, drug blood level, drug excretion, drug induced headache (side effect), drug safety, drug tolerability, dysphonia (side effect), facial nerve paralysis (side effect), female, forced expiratory volume, heart palpitation (side effect), human, hydrocortisone blood level, hydrocortisone urine level, limit of quantitation, liquid chromatography, lung function, major clinical study, male, maximum plasma concentration, medication compliance, multicenter study, outcome assessment, parallel design, patient compliance, phase 3 clinical trial, priority journal, provocation test, randomized controlled trial, risk assessment, school child, sinusitis (side effect), solid phase extraction, tandem mass spectrometry, throat irritation (side effect), thrush (side effect), time to maximum plasma concentration, varicosis (side effect)

hydrocortisone (50-23-7), prednisolone (50-24-8), salbutamol (18559-94-9, 35763-26-9)

Pediatrics and Pediatric Surgery (7), Chest Diseases, Thoracic Surgery and Tuberculosis (15), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT01086410)

http://dx.doi.org/10.1111/crj.12026

Copyright 2013 Elsevier B.V., All rights reserved.

Impact of age, diagnosis, and history of glaucoma surgery on outcomes in pediatric patients treated with latanoprost

Maeda-Chubachi T., Chi-Burris K., Simons B., Bremond-Gignac D., Freedman S., Khaw P.T., Wirostko B., Yan E.

(Maeda-Chubachi T., tomokomaeda@hotmail.com; Yan E.) Pfizer Inc., New London, CT, United States. , (Chi-Burris K.) Pfizer Inc., San Diego, CA, United States. , (Simons B.) Private Practice, Jupiter, FL, United States. , (Bremond-Gignac D.) Pediatric Ophthalmology Department, University Hospital of Amiens, INSERM UMRS 968, France. , (Freedman S.) 8Duke Eye Center, Durham, NC, United States. , (Khaw P.T.) NIHR Biomedical Research Centre, Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, United Kingdom. , (Wirostko B.) Moran Eye Center, University of Utah, Salt Lake City, UT, United States.

T. Maeda-Chubachi, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States. Email: tomokomaeda@hotmail.com

Journal of Glaucoma (2013) 22:8 (614-619). Date of Publication: October-November 2013

1057-0829,1536-481X (electronic)

Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, Philadelphia, United States.

PURPOSE:: To evaluate the impact of age, glaucoma-specific diagnosis, and history of prior glaucoma surgery on outcomes in pediatric patients treated with latanoprost monotherapy. PATIENTS AND METHODS:: Prospective, randomized, double-masked 12-week, multicenter study included individuals 18 years or younger with glaucoma. Subjects stratified by age (0 to <3, 3 to <12, 12 to 18 y), diagnosis [primary congenital glaucoma (PCG) vs. non-PCG], and baseline intraocular pressure (IOP; 22 to <27, 27 to 31, >31 mm Hg), and randomized (1:1) to latanoprost vehicle (8 AM) and latanoprost 0.005% (8 PM) or timolol 0.5% (or 0.25% for those less than 3 y old; 8 AM/8 PM). IOP and safety assessments performed and adverse events recorded at baseline, weeks 1, 4, 12. Post hoc analyses in age-specific and diagnosis-specific groups of latanoprost-treated subjects were conducted (intent-to-treat population). RESULTS:: Sixty-eight subjects were treated with latanoprost (0 to <3, n=17; 3 to <12, n=26; 12 to 18, n=25); 82%, 42%, and 24%, respectively, had a primary diagnosis of PCG. Among Non-PCG subjects, 0% (0/3), 47% (7/15), and 63% (12/19) had a primary diagnosis of juvenile open-angle glaucoma in the 0 to <3, 3 to <12, and 12 to 18 year cohorts, respectively. Mean percent IOP reductions from baseline at week 12 were 22%, 24%, and 30% in the youngest through oldest age groups, respectively (P=0.3600). At week 12, a higher responder rate ((greater-than or equal to)15% IOP reduction) was observed in the non-PCG than in the PCG group (70% vs. 45%, respectively; P=0.0361). Latanoprost was well tolerated. CONCLUSION:: All age and diagnosis subgroups showed clinically relevant (>20%) mean IOP reduction at week 12 with latanoprost monotherapy. (copyright) 2013 Lippincott Williams & Wilkins.

latanoprost (adverse drug reaction, clinical trial, drug comparison, drug therapy, topical drug administration)

timolol (clinical trial, drug comparison, drug therapy)

childhood disease (drug therapy, drug therapy, surgery), glaucoma (drug therapy, drug therapy, surgery), groups by age

adolescent, adult, aphakia, article, bronchopneumonia (side effect), child, congenital glaucoma (congenital disorder, drug therapy, surgery), conjunctival hyperemia (side effect), controlled study, cornea perforation (side effect), drug efficacy, drug safety, drug withdrawal, female, glaucoma surgery, headache (side effect), human, infant, influenza (side effect), intraocular pressure, major clinical study, male, open angle glaucoma (drug therapy, surgery), outcome assessment, post hoc analysis, preschool child, priority journal, prospective study, pseudophakia, rhinitis (side effect), rhinopharyngitis (side effect), school child, treatment response

latanoprost (130209-82-4), timolol (26839-75-8)

Pediatrics and Pediatric Surgery (7), Ophthalmology (12), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00716859), EudraCT (2007-004543-30)

http://dx.doi.org/10.1097/IJG.0b013e31824d4fb9

Copyright 2013 Elsevier B.V., All rights reserved.

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for chinese patients with squamous cell carcinoma of lung harboring EGFR mutation

Fang W., Zhang J., Liang W., Huang Y., Yan Y., Wu X., Hu Z., Ma Y., Zhao H., Zhao Y., Yang Y., Xue C., Zhang J., Zhang L.

(Fang W.; Zhang J.; Liang W.; Huang Y.; Yan Y.; Wu X.; Hu Z.; Ma Y.; Zhao H.; Zhao Y.; Yang Y.; Xue C.; Zhang J.; Zhang L., zhangli@sysucc.org.cn) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. , (Zhang J.) Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510610, China.

L. Zhang, Department of Medical Oncology, State key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, 651 East Dong-Feng Road, Guangzhou 510060, China. Email: zhangli@sysucc.org.cn

Journal of Thoracic Disease (2013) 5:5 (585-592). Date of Publication: October 2013

2072-1439,2077-6624 (electronic)

Pioneer Bioscience Publishing Company, 8/F,Cnt Comm Bldg,, 302 Queen's Rd Central, Hong Kong.

Objective: Epidermal growth factor receptor (EGFR) mutation mostly occurred in lung adenocarcinoma, rarely in squamous cell carcinoma (SQCC). EGFR mutation rate in SQCC varied in previous reports, and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in SQCC harboring EGFR mutation has not yet been fully evaluated. The aim of this study was to investigate the efficacy EGFR-TKIs for Chinese patients with SQCC of lung harboring EGFR mutation. Patients and methods: Two cohorts of patients were analyzed. The first cohort included 146 consecutive post-operation SQCC patients from January 2008 to October 2012. The second cohort included 63 patients with advanced SQCC receiving EGFR-TKIs treatment. EGFR mutation analysis was performed with Real-time PCR method. The pathologic diagnosis was validated with immunohistochemistry (IHC) for patients harboring activated EGFR mutation. And the efficacy of EGFR-TKIs in squamous cell carcinoma of lung (SQCC) was evaluated in patients with activated EGFR mutations. Results: In the first cohort, 146 resected patients, EGFR mutations were detected in 3 patients, with the mutation rate of 2.0%. In cohort two, 63 patients treated with EGFR-TKIs, 15 patients possessed activated EGFR mutations. The response rate and disease control rate in these patients was 26.7% and 66.7% respectively. 5 patients had disease control over 6 months. The progression free survival (PFS) in EGFR-mutated patients was 3.9 months. Conclusions: In Chinese SQCC patients, EGFR mutation rate was extremely low. EGFR-TKIs seemed to be less effective in EGFR-mutated SQCC patients, but some patients could still obtain benefit from EGFR-TKIs. To identify this part of patients, further study was warranted in the future. (copyright) Pioneer Bioscience Publishing Company.

epidermal growth factor receptor kinase inhibitor (drug therapy)

epidermal growth factor receptor (endogenous compound), erlotinib (drug therapy), gefitinib (drug therapy)

EGFR gene, lung squamous cell carcinoma (drug therapy, drug therapy), mutator gene

adult, advanced cancer (drug therapy), aged, article, cancer chemotherapy, cancer control, cancer survival, Chinese, clinical evaluation, drug efficacy, female, gene activation, human, human tissue, immunohistochemistry, major clinical study, male, mutation rate, mutational analysis, patient assessment, progression free survival, real time polymerase chain reaction

epidermal growth factor receptor (79079-06-4), erlotinib (183319-69-9, 183321-74-6), gefitinib (184475-35-2, 184475-55-6, 184475-56-7)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Cancer (16), Human Genetics (22), Drug Literature Index (37)

ClinicalTrials.gov (NCT00036647, NCT00637910, NCT00949910)

http://dx.doi.org/10.3978/j.issn.2072-1439.2013.09.15

Copyright 2013 Elsevier B.V., All rights reserved.

Multidisciplinary management of locally advanced rectal cancer: Neoadjuvant approaches

Murugappan S., Harris W.P., Willett C.G., Lin E.

(Murugappan S.; Harris W.P.; Lin E., elin88@u.washington.edu) Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Division of Gastrointestinal Oncology, 825 Eastlake Avenue North, Seattle, WA 98109, United States. , (Murugappan S.; Harris W.P.; Lin E., elin88@u.washington.edu) University of Washington, Seattle, WA, United States. , (Willett C.G.) Department of Radiation Oncology, Duke University Medical Center, Durham, NC, United States.

E. Lin, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Division of Gastrointestinal Oncology, 825 Eastlake Avenue North, Seattle, WA 98109, United States. Email: elin88@u.washington.edu

JNCCN Journal of the National Comprehensive Cancer Network (2013) 11:5 (548-557). Date of Publication: 2013

1540-1405,1540-1413 (electronic)

Harborside Press, 37 main Street, Cold Spring Harbor, United States.

Although tumor biology and genomics of colon and rectal cancer are no different, patients with locally advanced rectal cancer (LARC) require neoadjuvant fluoropyrimidine-based chemoradiation and total mesorectal excision. In addition to known clinical risk factors, improved algorithms integrating molecular tools are needed to stratify patients with LARC to improve treatment outcomes and reduce acute and long-term toxicities. Simply combining newer systemic or targeted agents with standard treatment in all patients yielded little success but added toxicities. This article reviews the historical data, current standards of care, and ongoing research efforts regarding biomarkers, molecular imaging, and personalized genomic information. Copyright (copyright) 2013 by the National Comprehensive Cancer Network. All rights reserved.

bevacizumab (drug therapy), capecitabine (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy, oral drug administration), cetuximab (drug combination, drug therapy), fluoropyrimidine (clinical trial, drug combination, drug therapy), fluorouracil (clinical trial, drug comparison, drug therapy), irinotecan (drug combination, drug therapy), oxaliplatin (adverse drug reaction, clinical trial, drug combination, drug therapy), panitumumab (drug therapy)

locally advanced rectum cancer (drug therapy, drug therapy, radiotherapy, surgery), rectum cancer (drug therapy, drug therapy, radiotherapy, surgery)

add on therapy, article, cancer adjuvant therapy, cancer prognosis, cancer radiotherapy, cancer recurrence, cancer stem cell, cancer survival, chemoradiotherapy, chromosomal instability, continuous infusion, distant metastasis, DNA methylation, DNA repair, gastrointestinal toxicity (side effect), human, induction chemotherapy, intensity modulated radiation therapy, lymph node dissection, metastatic colorectal cancer (drug therapy), microsatellite instability, multimodality cancer therapy, overall survival, phase 2 clinical trial (topic), phase 3 clinical trial (topic), randomized controlled trial (topic), rectum carcinoma, recurrence risk, treatment response

bevacizumab (216974-75-3), capecitabine (154361-50-9), cetuximab (205923-56-4), fluoropyrimidine (675-21-8), fluorouracil (51-21-8), irinotecan (100286-90-6), oxaliplatin (61825-94-3), panitumumab (339177-26-3)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00766155)

Copyright 2014 Elsevier B.V., All rights reserved.

Early combination therapy with telmisartan plus amlodipine for rapid achievement of blood pressure goals

Neldam S., Dahlof B., Oigman W., Schumacher H.

(Neldam S., neldam@dadlnet.dk) Rodovre Centrum 294, 2610 Rodovre, Denmark. , (Dahlof B.) Sahlgrenska University Hospital, Ostra Hospital, Gothenburg, Sweden. , (Oigman W.) UERJ - Universidade Do Estado Do Rio de Janeiro, Rio de Janeiro, Brazil. , (Schumacher H.) Boehringer Ingelheim Pharma GmbH and Co. KG, Ingelheim am Rhein, Germany.

S. Neldam, Rodovre Centrum 294, 2610 Rodovre, Denmark. Email: neldam@dadlnet.dk

International Journal of Clinical Practice (2013) 67:9 (843-852). Date of Publication: September 2013

1368-5031,1742-1241 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Background Rapid and sustained blood pressure (BP) goal attainment is important to reduce cardiovascular risk. Initial use of combination therapy may improve BP goal attainment. Methods The Boehringer Ingelheim trial database was searched for randomised, double-blind studies comparing telmisartan/amlodipine combination therapy with monotherapy. Eight studies were identified. Eight separate analyses were used to compare combination therapy with respective monotherapies at the earliest available time points (weeks 1, 2 and/or 4). Results In patients initiated on combination therapy, greater systolic BP (SBP)/diastolic BP (DBP) reductions were seen with combination therapy (p < 0.0001); BP (< 140/90 mmHg), SBP (< 140 mmHg) and DBP (< 90 mmHg) goal attainment rates were significantly higher with combination therapy at all time points. In patients uncontrolled by monotherapy, greater SBP/DBP reductions were seen with combination therapy (p < 0.05 in all but one measure), and all goal attainment rates were significantly higher with combination therapy, except in one measure. Conclusion Many people can achieve their BP targets when taking a combination of telmisartan and amlodipine after failing to do so with monotherapy. Furthermore, BP targets can be achieved more rapidly using a combination of telmisartan and amlodipine as initial therapy than with either monotherapy. (copyright) 2013 John Wiley & Sons Ltd.

amlodipine (clinical trial, drug combination, drug therapy), telmisartan (clinical trial, drug combination, drug therapy)

amlodipine plus telmisartan (clinical trial, drug therapy), placebo

blood pressure regulation, combination chemotherapy, hypertension (drug therapy, drug therapy)

aged, article, cardiovascular risk, comparative effectiveness, controlled study, diastolic blood pressure, drug megadose, drug response, early intervention, female, goal attainment, human, low drug dose, major clinical study, male, monotherapy, morning dosage, priority journal, randomized controlled trial (topic), risk reduction, systolic blood pressure, treatment duration, treatment outcome

amlodipine (103129-82-4, 736178-83-9, 88150-42-9), telmisartan (144701-48-4)

Cardiovascular Diseases and Cardiovascular Surgery (18), Drug Literature Index (37)

ClinicalTrials.gov (NCT00281580, NCT00550953, NCT00553267, NCT00860262, NCT00877929, NCT01103960, NCT01222520, NCT05584280)

http://dx.doi.org/10.1111/ijcp.12180

Copyright 2014 Elsevier B.V., All rights reserved.

ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis

Wiestler B., Capper D., Holland-Letz T., Korshunov A., Von Deimling A., Pfister S.M., Platten M., Weller M., Wick W.

(Wiestler B.; Platten M.; Wick W., wolfgang.wick@med.uni-heidelberg.de) Department of Neurooncology, National Center for Tumor Disease, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. , (Capper D.; Korshunov A.; Von Deimling A.) Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg, Germany. , (Pfister S.M.) Department of Pediatric Hematology and Oncology, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, Germany. , (Wiestler B.; Wick W., wolfgang.wick@med.uni-heidelberg.de) Clinical Cooperation Unit Neurooncology, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany. , (Capper D.; Korshunov A.; Von Deimling A.) Clinical Cooperation Unit Neuropathology, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany. , (Pfister S.M.) Division of Pediatric Neurooncology, German Cancer Research Center, INF 580, 69120 Heidelberg, Germany. , (Holland-Letz T.) Division of Biostatistics, German Cancer Research Center, INF 280, 69120 Heidelberg, Germany. , (Weller M.) Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland.

W. Wick, Department of Neurooncology, National Center for Tumor Disease, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Email: wolfgang.wick@med.uni-heidelberg.de

Acta Neuropathologica (2013) 126:3 (443-451). Date of Publication: September 2013

0001-6322,1432-0533 (electronic)

Springer Verlag, Tiergartenstrasse 17, Heidelberg, Germany.

Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients (n = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis. (copyright) 2013 Springer-Verlag Berlin Heidelberg.

isocitrate dehydrogenase (endogenous compound), methylated DNA protein cysteine methyltransferase (endogenous compound)

astrocytoma (radiotherapy), ATRX gene, glioblastoma (radiotherapy), glioma (radiotherapy), oligodendroglioma (radiotherapy), oncogene

adult, aged, article, cancer prognosis, cancer radiotherapy, cancer survival, gene deletion, gene expression, gene function, gene loss, gene mutation, human, IDH gene, immunohistochemistry, major clinical study, priority journal, progression free survival, treatment failure

isocitrate dehydrogenase (9001-58-5)

Neurology and Neurosurgery (8), Cancer (16)

ClinicalTrials.gov (NCT00717210)

http://dx.doi.org/10.1007/s00401-013-1156-z

Copyright 2013 Elsevier B.V., All rights reserved.

Changes in tumour vessel density upon treatment with anti-angiogenic agents: Relationship with response and resistance to therapy

Vasudev N.S., Goh V., Juttla J.K., Thompson V.L., Larkin J.M.G., Gore M., Nathan P.D., Reynolds A.R.

(Vasudev N.S.; Thompson V.L.; Reynolds A.R., andrew.reynolds@icr.ac.uk) Tumour Biology Team, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom. , (Vasudev N.S.; Goh V.; Juttla J.K.) Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood HA6 2RN, United Kingdom. , (Vasudev N.S.; Larkin J.M.G.; Gore M.) Royal Marsden Hospital, London SW3 6JJ, United Kingdom. , (Nathan P.D.) Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, HA6 2RN, United Kingdom. , (Vasudev N.S.) Cancer Research UK Centre, Leeds Institute of Cancer Studies and Pathology, St James's University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom.

A.R. Reynolds, Tumour Biology Team, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom. Email: andrew.reynolds@icr.ac.uk

British Journal of Cancer (2013) 109:5 (1230-1242). Date of Publication: September 2013

0007-0920,1532-1827 (electronic)

Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.

Background:We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy.Methods:In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions.Results:No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size (r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy (P=0.008).Interpretation:Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent. (copyright) 2013 Cancer Research UK. All rights reserved.

cediranib (clinical trial, drug therapy, oral drug administration), pazopanib (clinical trial, drug therapy, oral drug administration), regorafenib (clinical trial, drug therapy, oral drug administration), sunitinib (clinical trial, drug therapy, oral drug administration)

barium sulfate (oral drug administration), ioversol (intravenous drug administration)

antiangiogenic therapy, cancer chemotherapy, cancer resistance, tumor vascularization, tumour vessel density

adrenal metastasis, adult, aged, article, blood vessel reactivity, cancer growth, cancer patient, clinical article, computed tomography scanner, contrast enhancement, disease marker, female, human, kidney metastasis (drug resistance, drug therapy), liver metastasis, lung metastasis, lymph node metastasis, male, multidetector computed tomography, pancreas metastasis, pleura metastasis, priority journal, rebound, treatment response, tumor growth stimulation, tumor volume

ezem (bicester, United Kingdom), optiray (Covidien, United States)

Astra Zeneca, Bayer, bicester (United Kingdom), Covidien (United States), Glaxo SmithKline, Pfizer

Sensation 16 (Siemens, Germany), Somatom Definition (Siemens, Germany)

Siemens (Germany)

barium sulfate (13462-86-7, 7727-43-7, 8057-67-8), cediranib (288383-20-0, 857036-77-2), ioversol (87771-40-2), pazopanib (444731-52-6, 635702-64-6), regorafenib (1019206-88-2, 755037-03-7), sunitinib (341031-54-7, 557795-19-4)

Radiology (14), Cancer (16), Biophysics, Bioengineering and Medical Instrumentation (27), Urology and Nephrology (28), Drug Literature Index (37)

ClinicalTrials.gov (NCT00397345, NCT00423332, NCT00664326, NCT00720941)

http://dx.doi.org/10.1038/bjc.2013.429

Copyright 2013 Elsevier B.V., All rights reserved.

A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee

Spierings E.L.H., Fidelholtz J., Wolfram G., Smith M.D., Brown M.T., West C.R.

(Spierings E.L.H., Spierings@MedVadis.com) Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. , (Fidelholtz J.) Hilltop Physicians Inc., Cincinnati, OH, United States. , (Wolfram G.; Smith M.D.; Brown M.T.; West C.R.) Pfizer Inc., Groton, CT, United States.

E.L.H. Spierings, 72 Mount Auburn Street, Watertown, MA 02472-3930, United States. Email: Spierings@MedVadis.com

Pain (2013) 154:9 (1603-1612). Date of Publication: September 2013

0304-3959,1872-6623 (electronic)

Elsevier, P.O. Box 211, Amsterdam, Netherlands.

Tanezumab is a humanized monoclonal antinerve growth factor antibody in development for treatment of chronic pain. In a phase III, placebo- and active-controlled study, we investigated the efficacy and safety of tanezumab for osteoarthritis (OA) hip or knee pain. Patients (N = 610) received up to 2 doses of intravenous tanezumab (5 or 10 mg in 8-week intervals), controlled-release oral oxycodone (10 to 40 mg every 12 hours), or placebo. The primary endpoint was mean change from baseline to week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score for tanezumab versus placebo and oxycodone. Secondary endpoints included change from baseline in WOMAC Physical Function and Stiffness scores, Patient's Global Assessment (PGA) of OA, and patient response, defined as (greater-than or equal to)30%, (greater-than or equal to)50%, (greater-than or equal to)70%, and (greater-than or equal to)90% improvement from baseline in WOMAC Pain score. Tolerability and safety also were assessed. Both tanezumab groups demonstrated significant improvements in WOMAC Pain score versus placebo (P <.001) and oxycodone (P (less-than or equal to).018). Tanezumab also provided significant improvements versus placebo and oxycodone for WOMAC Physical Function and Stiffness scores and PGA of OA (P (less-than or equal to).002 for all) at week 8. For all analyses, oxycodone did not differ from placebo. Adverse event frequency was higher with oxycodone (63.3%) than tanezumab (40.7% to 44.7%) or placebo (35.5%); serious adverse event frequency was similar among treatments. The adverse event profile for tanezumab was similar to previous tanezumab studies. Results indicate that tanezumab is efficacious in the treatment of OA pain; no new safety signals were identified. (copyright) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

oxycodone (adverse drug reaction, drug comparison, drug therapy, oral drug administration, pharmacokinetics), tanezumab (adverse drug reaction, drug comparison, drug therapy, intravenous drug administration, pharmacokinetics)

hip osteoarthritis (drug therapy, drug therapy), hip pain (drug therapy, drug therapy), knee osteoarthritis (drug therapy, drug therapy), knee pain (drug therapy, drug therapy)

adult, aged, allodynia (side effect), arthralgia (side effect), article, bone necrosis (side effect), burning sensation (side effect), constipation (side effect), controlled drug release, controlled study, cubital tunnel syndrome (side effect), diabetic neuropathy (side effect), dizziness (side effect), double blind procedure, drug efficacy, drug induced headache (side effect), drug safety, drug tolerability, drug withdrawal, dysesthesia (side effect), fatigue (side effect), female, formication (side effect), human, hyperalgesia (side effect), hyperesthesia (side effect), hypertension (side effect), hypesthesia (side effect), major clinical study, male, nausea (side effect), neuralgia (side effect), neuritis (side effect), paresthesia (side effect), peripheral neuropathy (side effect), phase 3 clinical trial, polyneuropathy (side effect), priority journal, pruritus (side effect), radiculopathy (side effect), randomized controlled trial, rhinopharyngitis (side effect), sensory neuropathy (side effect), somnolence (side effect), vomiting (side effect), Western Ontario and McMaster Universities Osteoarthritis Index

oxycodone (124-90-3, 76-42-6), tanezumab (880266-57-9)

Arthritis and Rheumatism (31), Orthopedic Surgery (33), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00985621)

http://dx.doi.org/10.1016/j.pain.2013.04.035

Copyright 2014 Elsevier B.V., All rights reserved.

A randomized trial of intensified vs. standard dosing for enteric-coated mycophenolate sodium in de novo kidney transplant recipients: Results at 1 year

Arns W., Sommerer C., Glander P., Ariatabar T., Porstner M., May C., Paulus E.-M., Shipkova M., Fischer W., Liefeldt L., Hackenberg R., Schemmer P., Domhan S., Zeier M., Budde K.

(Arns W., wolfgang.arns@uni-koeln.de; Ariatabar T.; Hackenberg R.) Department of Nephrology, Medical Clinic Koln-Merheim, Cologne, Germany. , (Sommerer C.; Domhan S.; Zeier M.) Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany. , (Glander P.; Liefeldt L.; Budde K.) Department of Nephrology, Charite University Hospital Berlin, Berlin, Germany. , (Porstner M.; May C.; Paulus E.-M.; Fischer W.) Novartis Pharma GmbH, Nuremberg, Germany. , (Shipkova M.) Department of Clinical Chemistry and Laboratory Medicine, Stuttgart, Germany. , (Schemmer P.) Department of General, Visceral and Transplant Surgery, University of Heidelberg, Germany.

W. Arns, Department of Nephrology, Medical Clinic Koln-Merheim, Ostmerheimer Str. 200, 51109 Cologne, Germany. Email: wolfgang.arns@uni-koeln.de

Clinical Nephrology (2013) 79:6 (421-431). Date of Publication: 2013

0301-0430

Dustri-Verlag Dr. Karl Feistle, Bajuwarenring 4, Oberhaching, Germany.

In a 6-month prospective, openlabel, multicenter study, 128 de novo kidney transplant patients receiving cyclosporine (CsA) and steroids were randomized to an intensified regimen of enteric-coated mycophenolate sodium (EC-MPS) or to a standard EC-MPS regimen to Week 6 posttransplant, after which the regimen was identical. In a follow-up study to Month 12 post-transplant (49 intensified regimen, 52 standard regimen), the reduced rate of BPAR observed at Month 6 (intensified regimen 3.2%, standard regimen 16.9%, p = 0.016) was maintained at Month 12 (4.8% vs. 18.5%, p = 0.026). Estimated GFR (Cockcroft-Gault) at Month 12 was comparable in the intensified group (mean (SD) 54.8 (22.9) ml/min) vs. the standard group (mean (SD) 57.5 (23.6) ml/min, p = 0.83). The incidence of adverse events and serious adverse events at Month 12 was similar in both treatment groups, although adverse events with a suspected relation to study drug were reported in 69.8% and 50.8% of patients in the intensified and standard regimen groups, respectively (p = 0.032). Infections and hematological parameters were similar between groups. In conclusion, an early regimen of intensified EC-MPS with CsA and steroids achieves a low rate of BPAR over the first year after kidney transplantation with similar renal function to a standard regimen, and without a clinically relevant impact on safety. (copyright) 2013 Dustri-Verlag Dr. K. Feistle ISSN 0301-0430.

mycophenolic acid (adverse drug reaction, clinical trial, drug dose)

cyclosporin, steroid

abdominal pain (side effect), adult, aged, anemia (side effect), article, bk virus infection (side effect), constipation (side effect), controlled study, cytomegalovirus infection (side effect), diarrhea (side effect), drug dose comparison, dyspepsia (side effect), enteric coated tablet, female, flatulence (side effect), follow up, graft recipient, human, immunosuppressive treatment, kidney disease (side effect), kidney function, kidney graft, leukopenia (side effect), major clinical study, male, multicenter study, nausea (side effect), pneumonia (side effect), randomized controlled trial, thrombocytopenia (side effect), upper respiratory tract infection (side effect), urinary tract infection (side effect), vomiting (side effect)

cyclosporin (79217-60-0), mycophenolic acid (23047-11-2, 24280-93-1)

Urology and Nephrology (28), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00369278)

http://dx.doi.org/10.5414/CN107908

Copyright 2013 Elsevier B.V., All rights reserved.

New and developing drugs for the treatment of neuropathic pain in diabetes

Freeman R.

(Freeman R., rfreeman@bidmc.harvard.edu) Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215, United States.

R. Freeman, Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215, United States. Email: rfreeman@bidmc.harvard.edu

Current Diabetes Reports (2013) 13:4 (500-508). Date of Publication: August 2013

1534-4827,1539-0829 (electronic)

Current Medicine Group LLC, 400 Market St,, Ste 700 Philadelphia, United States.

A number of agents from diverse pharmacological classes are used to treat neuropathic pain associated with diabetic peripheral neuropathy. Only three of these have regulatory approval for this indication in the U.S. In this focused article, I will discuss selected drugs, newly approved or in development, to treat neuropathic pain in patients with diabetic neuropathy. These will include agonists and antagonists of the transient receptor potential channels, a family of receptor proteins that play a role in the transduction of physical stress; sodium channel isoform specific antagonists; a recently approved dual-action opioid receptor agonist-norepinephrine reuptake inhibitor; gene therapy for neuropathic pain; and anti-nerve growth factor molecules. Mechanisms of action, preclinical supporting data, clinical trial evidence, and adverse effects will be reviewed. (copyright) 2013 Springer Science+Business Media New York.

analgesic agent (clinical trial, drug analysis, drug development, drug therapy, intrathecal drug administration, intravenous drug administration, oral drug administration, topical drug administration)

adenovirus vector, atipamazole (drug therapy, pharmacology), capsaicin (clinical trial, drug dose, drug therapy, pharmacology, topical drug administration), lentivirus vector, morphine (drug therapy), mu opiate receptor agonist (clinical trial), nerve growth factor (endogenous compound), nerve growth factor antibody (drug therapy), neurotrophin 3 (endogenous compound), noradrenalin uptake inhibitor (drug therapy), opiate agonist (drug therapy), oxycodone (clinical trial, drug therapy), parvovirus vector, placebo, plasmid DNA (endogenous compound), retrovirus vector, sodium channel blocking agent (drug therapy), sodium channel Nav1.7 (endogenous compound), tapentadol (adverse drug reaction, clinical trial, drug dose, drug therapy, pharmaceutics, pharmacology), transient receptor potential channel (endogenous compound), transient receptor potential channel A1 (endogenous compound), transient receptor potential channel affecting agent (clinical trial, drug therapy), unclassified drug, unindexed drug, vanilloid receptor 1 (endogenous compound), vasculotropin (endogenous compound), virus vector, voltage gated sodium channel (endogenous compound), voltage gated sodium channel blocking agent (clinical trial, drug therapy), yohimbine (drug therapy, pharmacology)

diabetic neuropathy (drug therapy, complication, drug therapy, therapy), neuropathic pain (drug therapy, complication, drug therapy, therapy)

analgesia, analgesic activity, article, calcium transport, clinical trial (topic), disease association, drug approval, drug control, drug efficacy, drug formulation, drug mechanism, drug safety, erythromelalgia (drug therapy), gain of function mutation, gastrointestinal symptom (side effect), gene, gene expression, Herpes simplex virus, human, hyperthermia, low drug dose, molecularly targeted therapy, musculoskeletal pain (drug therapy), neurotransmission, nociception, nonhuman, optimal drug dose, phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), physical stress, postherpetic neuralgia (drug therapy), protein expression, protein function, radiculopathy (drug therapy), randomized controlled trial (topic), SCN9A gene, single drug dose, treatment indication, treatment outcome, trigeminus neuralgia (drug therapy), United States, visual analog scale

capsaicin (404-86-4), morphine (52-26-6, 57-27-2), nerve growth factor (9061-61-4), oxycodone (124-90-3, 76-42-6), tapentadol (175591-09-0, 175591-23-8), vanilloid receptor 1 (363242-41-5), vasculotropin (127464-60-2), yohimbine (146-48-5, 65-19-0)

Endocrinology (3), Neurology and Neurosurgery (8), Human Genetics (22), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT01019824, NCT01087203, NCT01195636, NCT01475786, NCT01478607, NCT01533428, NCT01540630, NCT01561027, NCT01726413, NCT01769274)

http://dx.doi.org/10.1007/s11892-013-0396-6

Copyright 2014 Elsevier B.V., All rights reserved.

Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril

Bonner G., Bakris G.L., Sica D., Weber M.A., White W.B., Perez A., Cao C., Handley A., Kupfer S.

(Bonner G., g.boenner@park-klinikum.de) Park-Klinikum Bad Krozingen, Herbert-Hellmann-Allee 44, Bad Krozingen, Baden-Wurttemberg 79189, Germany. , (Bakris G.L.) ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL, United States. , (Sica D.) Division of Nephrology, Virginia Commonwealth University Health System, Richmond, VA, United States. , (Weber M.A.) Division of Cardiovascular Medicine, SUNY Downstate College of Medicine, Brooklyn, NY, United States. , (White W.B.) Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT, United States. , (Perez A.) Department of Clinical Science, Takeda Global Research and Development, Deerfield, IL, United States. , (Cao C.) Department of Statistics, Takeda Global Research and Development, Deerfield, IL, United States. , (Handley A.; Kupfer S.) Department of Pharmaceutical Development Division, Takeda Pharmaceuticals International, Deerfield, IL, United States.

G. Bonner, Park-Klinikum Bad Krozingen, Herbert-Hellmann-Allee 44, Bad Krozingen, Baden-Wurttemberg 79189, Germany. Email: g.boenner@park-klinikum.de

Journal of Human Hypertension (2013) 27:8 (479-486). Date of Publication: August 2013

0950-9240,1476-5527 (electronic)

Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.

Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150-180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57(plus or minus)11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1(plus or minus)7.9/94.9(plus or minus)9.0 mm Hg. Clinic SBP decreased by 20.6(plus or minus)0.95 and 21.2(plus or minus)0.95 mm Hg with AZL-M 40 and 80 mg vs12.2(plus or minus)0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1-2 hypertension with AZL-M was more effective than RAM and better tolerated. (copyright) 2013 Macmillan Publishers Limited All rights reserved.

azilsartan medoxomil (adverse drug reaction, drug comparison, drug therapy), ramipril (adverse drug reaction, drug comparison, drug therapy)

antihypertensive agent

hypertension (drug therapy, drug therapy)

adult, aged, article, backache (side effect), blood pressure monitoring, body mass, controlled study, contusion (side effect), coughing (side effect), creatine kinase blood level, diastolic blood pressure, dizziness (side effect), double blind procedure, drug dose titration, drug efficacy, drug safety, drug tolerability, female, follow up, gamma glutamyl transferase blood level, headache (side effect), human, hypotension (side effect), major clinical study, male, multicenter study, phase 3 clinical trial, potassium blood level, randomized controlled trial, rhinopharyngitis (side effect), side effect (side effect), sodium blood level, systolic blood pressure, uric acid blood level

azilsartan medoxomil (863031-21-4, 863031-24-7), ramipril (87333-19-5)

Internal Medicine (6), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00760214)

http://dx.doi.org/10.1038/jhh.2013.6

Copyright 2013 Elsevier B.V., All rights reserved.

Bendamustine in indolent non-hodgkin's lymphoma: A practice guide for patient management

Brugger W., Ghielmini M.

(Brugger W., wolfram.brugger@sbk-vs.de) Department of Hematology, Oncology, and Palliative Care, Schwarzwald-Baar Clinic, Academic Teaching Hospital, University of Freiburg, Villingen-Schwenningen, Germany. , (Ghielmini M.) Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland.

W. Brugger, Department of Hematology, Oncology, Immunology, and Palliative Care, Schwarzwald-Baar Clinic, Academic Teaching Hospital, University of Freiburg, Klinikstrasse 11, 78050 Villingen-Schwenningen, Germany. Email: wolfram.brugger@sbk-vs.de

Oncologist (2013) 18:8 (954-964). Date of Publication: August 2013

1083-7159,1549-490X (electronic)

AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.

For patients with advanced indolent non-Hodgkin's lymphoma (NHL) or elderly patients with mantle cell lymphoma (MCL), the recently reported results of the German StiL NHL-1 2003 and the international BRIGHT phase III trials showed that, as first-line treatment, the combination of bendamustine and rituximab is at least as effective as rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone or rituximab/cyclophosphamide/vincristine/prednisone, possibly with a better therapeutic index. Bendamustine is therefore increasingly used in clinical practice. Because bendamustine has been used for many years in Germany and in Switzerland, our institutions have had extensive experience with bendamustine, both as a single agent and in combination with rituximab. In this comprehensive review, we summarize the most important clinical data from phase II/III trials with bendamustine in patients with indolent NHL and MCL, both in the relapsed/refractory setting and in the first-line setting. In addition, this review provides practical advice on how to optimally manage bendamustine therapy in patients with NHL. (copyright) AlphaMed Press 2013.

bendamustine (adverse drug reaction, clinical trial, drug combination, drug comparison, drug interaction, drug therapy)

aciclovir (drug interaction), allopurinol (adverse drug reaction, drug combination), antihistaminic agent (drug therapy), aprepitant (drug therapy), bortezomib (clinical trial, drug combination, drug therapy), chlorambucil (clinical trial, drug comparison, drug therapy), cimetidine (drug interaction), ciprofloxacin (drug interaction), corticosteroid (drug therapy), cyclophosphamide (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), cyclosporin (drug combination), cytarabine (adverse drug reaction, clinical trial, drug combination, drug therapy), dexamethasone (drug combination, drug therapy, intravenous drug administration), doxorubicin (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), fludarabine (clinical trial, drug combination, drug comparison, drug therapy), fluvoxamine (drug interaction), ibrutinib (clinical trial, drug combination, drug therapy), idelalisib (clinical trial, drug combination, drug therapy), inotuzumab ozogamicin (clinical trial, drug combination, drug therapy), lenalidomide (clinical trial, drug combination, drug comparison, drug therapy), obinutuzumab (clinical trial, drug combination, drug comparison, drug therapy), ofatumumab (clinical trial, drug combination, drug comparison, drug therapy), prednisone (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), rituximab (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy, intravenous drug administration, subcutaneous drug administration), serotonin 3 antagonist (drug combination, drug therapy), steroid (drug therapy), tacrolimus (drug combination), temsirolimus (clinical trial, drug combination), vincristine (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy)

nonhodgkin lymphoma (drug therapy, drug therapy)

alopecia (side effect), anaphylaxis (side effect), article, autoimmune hemolytic anemia, CD4+ T lymphocyte, chill (side effect), chronic lymphatic leukemia (drug therapy), drug dose reduction, drug efficacy, drug hypersensitivity (side effect), drug megadose, drug response, drug safety, drug tolerability, drug withdrawal, febrile neutropenia (side effect), fever (side effect), follicular lymphoma (drug therapy), follow up, hematologic disease (side effect), human, infection (side effect), infusion related reaction (drug therapy), kidney failure, leukopenia (side effect), liver dysfunction, low drug dose, lymphocytopenia (side effect), maintenance therapy, mantle cell lymphoma (drug therapy), monotherapy, mucosa inflammation (side effect), multiple cycle treatment, nausea and vomiting (drug therapy, side effect), neutropenia (side effect), overall survival, paresthesia (side effect), peripheral neuropathy (side effect), phase 1 clinical trial (topic), phase 2 clinical trial (topic), phase 3 clinical trial (topic), phlebitis (side effect), priority journal, progression free survival, pruritus (side effect), quality of life, randomized controlled trial (topic), rash (side effect), recommended drug dose, relapse, retreatment, single drug dose, skin toxicity (side effect), Stevens Johnson syndrome (side effect), stomatitis (side effect), thrombocytopenia (side effect), toxic epidermal necrolysis (side effect)

ga 101, mabthera, rituxan, ro 5072759, treanda

aciclovir (59277-89-3), allopurinol (315-30-0), aprepitant (170729-80-3, 221350-96-5), bendamustine (16506-27-7, 3543-75-7), bortezomib (179324-69-7, 197730-97-5), chlorambucil (305-03-3), cimetidine (51481-61-9, 70059-30-2), ciprofloxacin (85721-33-1), cyclophosphamide (50-18-0), cyclosporin (79217-60-0), cytarabine (147-94-4, 69-74-9), dexamethasone (50-02-2), doxorubicin (23214-92-8, 25316-40-9), fludarabine (21679-14-1), fluvoxamine (54739-18-3), ibrutinib (936563-96-1), idelalisib (1146702-54-6, 870281-82-6), inotuzumab ozogamicin (635715-01-4), lenalidomide (191732-72-6), obinutuzumab (949142-50-1), ofatumumab (679818-59-8), prednisone (53-03-2), rituximab (174722-31-7), tacrolimus (104987-11-3), temsirolimus (162635-04-3, 343261-52-9), vincristine (57-22-7)

Cancer (16), Hematology (25), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00139841, NCT00877006, NCT00877214, NCT01059630, NCT01073163, NCT01077518, NCT01232556, NCT01289223, NCT01332968, NCT01456351, NCT01500083, NCT01570049, NCT01596621, NCT01650701, NCT01724021, NCT01732926)

http://dx.doi.org/10.1634/theoncologist.2013-0079

Copyright 2013 Elsevier B.V., All rights reserved.

Driving performance in adults with ADHD: Results from a randomized, waiting list controlled trial with atomoxetine

Sobanski E., Sabljic D., Alm B., Dittmann R.W., Wehmeier P.M., Skopp G., Strohbeck-Kuhner P.

(Sobanski E., esther.sobanski@zi-mannheim.de; Sabljic D.; Alm B.) Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159 Mannheim, Germany. , (Sabljic D.; Skopp G.; Strohbeck-Kuhner P.) Ruprecht-Karls-University Heidelberg, Department of Legal and Traffic Medicine, Vossstr. 2, 69115 Heidelberg, Germany. , (Dittmann R.W.) Central Institute of Mental Health Mannheim, Eli Lilly Endowed Chair for Paediatric Psychopharmacology Dept.of Child and Adolescent Psychiatry, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159 Mannheim, Germany. , (Wehmeier P.M.) Central Institute of Mental Health, Department of Child and Adolescent Psychiatry, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159 Mannheim, Germany. , (Wehmeier P.M.) Vitos Hospital for Psychiatry and Psychotherapy, Weilstr. 10, 35789 Weilmuenster, Germany.

E. Sobanski, Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159 Mannheim, Germany. Email: esther.sobanski@zi-mannheim.de

European Psychiatry (2013) 28:6 (379-385). Date of Publication: August 2013

0924-9338,1778-3585 (electronic)

Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, France.

Purpose: To investigate effects of a 12-week treatment with atomoxetine (ATX) on driving performance in real traffic, driving-related neuropsychological performance tests and self-evaluation of driving in adult patients with ADHD compared to an untreated control group with ADHD. Methods: Parallel group design with an ATX and a waiting list group. At baseline and endpoint patients were evaluated with a standardized on-road driving test (SDBO), a driving-related neuropsychological test battery (Act and React Test System [ART2020]), and subjective measures of driving performance (one-week driving diary, Driver Coping Questionnaire). Results: Forty-three of the 64 included patients completed the study (n= 22 ATX, n= 21 controls). Mean intervention period was 11.9. (plus or minus). 3.0 weeks, mean daily ATX dosage was 71.6. (plus or minus). 14.9. mg. At endpoint, 60.1% of patients treated with ATX and 0% of waiting list group had reduced ADHD symptoms by greater or equal to 30%. In SDBO, ATX group reduced driving errors in three of four driving performance categories (attention, P<. 0.05; risk-related self-control, P<. 0.005; driver skills, P<. 0.001), number of driving errors remained stable in control group. At endpoint, 47.6% of control group and 18.2% of ATX group (P< 0.05) did not fulfil the driving fitness criteria according to German Guidelines (percentile rank less or equal to 16 in one or more subtests in ART2020). Total number of self-reported critical traffic situations decreased from 12.0 to 6.8 per week in ATX group (P< 0.05) and remained stable in controls by 9.3 and 9.9 at baseline and endpoint (ns). Coping strategies with stressful traffic situations did not change within both groups. Conclusion: Our study provides first evidence that treatment with ATX improves driving performance in real traffic in adults with ADHD. (copyright) 2012 Elsevier Masson SAS.

atomoxetine (adverse drug reaction)

attention deficit disorder, driving ability

act and react test system, adult, appetite, article, clinical article, clinical assessment, controlled study, coping behavior, driver coping questionnaire, drug dose titration, drug efficacy, drug safety, fatigue (side effect), female, Germany, hospital admission, human, irritability, male, nausea (side effect), neuropsychological test, practice guideline, priority journal, questionnaire, risk assessment, self control, self evaluation, side effect (side effect), traffic, treatment duration, treatment response

atomoxetine (82248-59-7, 82857-39-4, 82857-40-7, 83015-26-3)

Neurology and Neurosurgery (8), Psychiatry (32), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00619840)

http://dx.doi.org/10.1016/j.eurpsy.2012.08.001

Copyright 2014 Elsevier B.V., All rights reserved.

HPV16 L1 and L2 DNA methylation predicts high-grade cervical intraepithelial neoplasia in women with mildly abnormal cervical cytology

Lorincz A.T., Brentnall A.R., Vasiljevic N., Scibior-Bentkowska D., Castanon A., Fiander A., Powell N., Tristram A., Cuzick J., Sasieni P.

(Lorincz A.T., a.lorincz@qmul.ac.uk; Brentnall A.R.; Vasiljevic N.; Scibior-Bentkowska D.; Castanon A.; Cuzick J.; Sasieni P.) Centre for Cancer Prevention, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. , (Fiander A.; Powell N.; Tristram A.) Obstetrics and Gynaecology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.

A.T. Lorincz, Centre for Cancer Prevention, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. Email: a.lorincz@qmul.ac.uk

International Journal of Cancer (2013) 133:3 (637-644). Date of Publication: 1 Aug 2013

0020-7136,1097-0215 (electronic)

Wiley-Liss Inc., 111 River Street, Hoboken, United States.

DNA methylation changes in human papillomavirus type 16 (HPV16) DNA are common and might be important for identifying women at increased risk of cervical cancer. Using recently published data from Costa Rica we developed a classification score to differentiate women with cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) from those with no evident high-grade lesions. Here, we aim to investigate the performance of the score using data from the UK. Exfoliated cervical cells at baseline and 6-months follow-up were analyzed in 84 women selected from a randomized clinical trial of women undergoing surveillance for low-grade cytology. Selection of women for the methylation study was based on detectable HPV16 in the baseline sample. Purified DNA was bisulfite converted, amplified and pyrosequenced at selected CpG sites in the viral genome (URR, E6, L1 and L2), with blinding of laboratory personnel to the clinical data. The primary measure was a predefined score combining the mean methylation in L1 and any methylation in L2. At the second follow-up visit, 73/84 (87%) women were HPV16 positive and of these 25 had a histopathological diagnosis of CIN2/3. The score was significantly associated with CIN2/3 (area under curve = 0.74, p = 0.002). For a cutoff with 92% sensitivity, colposcopy could have been avoided in 40% (95% CI 27-54%) of HPV16 positive women without CIN2/3; positive predictive value was 44% (32-58%) and negative predictive value was 90% (71-97%). We conclude that quantitative DNA methylation assays could help to improve triage among HPV16 positive women. What's new? The human papillomavirus (HPV) genome is subject to changes in DNA methylation. Here, the quantification of DNA methylation in HPV16 from exfoliated cervical cells of women with detectable virus was found to be significantly associated with cervical intraepithelial neoplasia grade 2 or 3. The methlyation score was based on the combined mean of methylation specifically in the HPV16 late regions (L1 and L2). The approach could be used to aid decisions concerning triage to colposcopy and has the potential to be expanded to other carcinogenic HPVs. Copyright (copyright) 2013 UICC.

DNA methylation, Human papillomavirus type 16, uterine cervix carcinoma in situ (diagnosis), uterine cervix cytology

article, classifier, colposcopy, female, follow up, histopathology, human, major clinical study, open reading frame, predictive value, priority journal, pyrosequencing, randomized controlled trial (topic), receiver operating characteristic, scoring system, sensitivity and specificity, virus genome

Obstetrics and Gynecology (10), Cancer (16)

ISRCTN (ISRCTN47437431), ClinicalTrials.gov (NCT00462813)

http://dx.doi.org/10.1002/ijc.28050

Copyright 2013 Elsevier B.V., All rights reserved.

Teduglutide enhances structural adaptation of the small intestinal mucosa in patients with short bowel syndrome

Tappenden K.A., Edelman J., Joelsson B.

(Tappenden K.A., tappende@uiuc.ed) Department of Nutrition and Gastrointestinal Physiology, University of Illinois at Urbana-Champaign, 443 Bevier Hall, 905 South Goodwin Avenue, Champaign, IL 61820, United States. , (Edelman J.) Department of Pathology, Christian Hospital, St Louis, MO, United States. , (Joelsson B.) Department of Research and Development, NPS Pharmaceuticals, Inc., Bedminster, NJ., United States.

K.A. Tappenden, Department of Nutrition and Gastrointestinal Physiology, University of Illinois at Urbana-Champaign, 443 Bevier Hall, 905 South Goodwin Avenue, Champaign, IL 61820, United States. Email: tappende@uiuc.ed

Journal of Clinical Gastroenterology (2013) 47:7 (602-607). Date of Publication: August 2013

0192-0790,1539-2031 (electronic)

Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, Philadelphia, United States.

BACKGROUND:: Intestinotrophic therapies, such as glucagon-like peptide-2 (GLP-2) analogs, may enhance intestinal adaptation and reduce dependence on parenteral nutrition (PN) in patients with intestinal failure associated with short bowel syndrome (SBS-IF). However, because GLP-2 enhances cellular growth, there is concern that GLP-2 analogs may also encourage growth of malignant cells. AIMS:: To histologically examine the effects of teduglutide, a recombinant human GLP-2 analog, on the mucosa of the small and large intestine for indications of dysplastic transformation. METHODS:: In a multicenter, prospective, randomized, placebo-controlled study, 83 PN-dependent patients with SBS-IF were monitored for several weeks to ensure optimal and stable PN. Patients were then randomized to receive 24 weeks of placebo (n=16), teduglutide (0.5 mg/kg/d; n=35), or teduglutide (0.10 mg/kg/d; n=32). RESULTS:: Biopsies were obtained from 77 patients to yield 390 individual histologic interpretations. After 6 months of treatment, no features of dysplasia were found in any biopsy from the large or small intestine of patients receiving placebo or either dose of teduglutide. New secondary diagnoses, such as eosinophilic colitis or Crohn's disease, were found at a low frequency overall: teduglutide (0.05 mg/kg/d; range, 3.1% to 6.3%); teduglutide (0.10 mg/kg/d, 3.3%); placebo (range, 6.7% to 13.3%). CONCLUSIONS:: Although this histologic substudy of biopsy samples was not powered to detect differences in occurrence of dysplasia between teduglutide-treated patients and those randomized to placebo, it demonstrated that no dysplasia or other pathologic processes were evident within the intestinal mucosa in the placebo group or the 2 teduglutide groups after 6 months of treatment. Copyright (copyright) 2013 by Lippincott Williams & Wilkins.

teduglutide (clinical trial, drug therapy, pharmacology)

short bowel syndrome (drug therapy, drug therapy, therapy), small intestine mucosa

article, colitis (diagnosis), collagenous colitis (diagnosis), controlled study, Crohn disease (diagnosis), dysplasia, eosinophilic colitis (diagnosis), human, human tissue, intestinal failure (therapy), intestine biopsy, large intestine, lymphocytic colitis (diagnosis), major clinical study, multicenter study, parenteral nutrition, phase 3 clinical trial, priority journal, prospective study, randomized controlled trial, sarcoidosis (diagnosis), small intestine, ulcerative colitis (diagnosis)

teduglutide (197922-42-2, 287714-30-1)

Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Gastroenterology (48)

ClinicalTrials.gov (NCT00081458)

http://dx.doi.org/10.1097/MCG.0b013e3182828f57

Copyright 2013 Elsevier B.V., All rights reserved.

Mitochondrial alterations during carcinogenesis. A review of metabolic transformation and targets for anticancer treatments

Wang X., Peralta S., Moraes C.T.

(Wang X.; Moraes C.T., cmoraes@med.miami.edu) Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, United States. , (Peralta S.; Moraes C.T., cmoraes@med.miami.edu) Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States. , (Moraes C.T., cmoraes@med.miami.edu) Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, United States.

C.T. Moraes, Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, United States. Email: cmoraes@med.miami.edu

Advances in Cancer Research (2013) 119 (127-160). Date of Publication: 2013

0065-230X

Academic Press Inc., 1250 Sixth Avenue, San Diego, California, United States.

Mitochondria play important roles in multiple cellular processes including energy metabolism, cell death, and aging. Regulated energy production and utilization are critical in maintaining energy homeostasis in normal cells and functional organs. However, mitochondria go through a series of morphological and functional alterations during carcinogenesis. The metabolic profile in transformed cells is altered to accommodate their fast proliferation, confer resistance to cell death, or facilitate metastasis. These transformations also provide targets for anticancer treatment at different levels. In this review, we discuss the major modifications in cell metabolism during carcinogenesis, including energy metabolism, apoptotic and autophagic cell death, adaptation of tumor microenvironment, and metastasis. We also summarize some of the main metabolic targets for treatments. (copyright) 2013 Elsevier Inc.

antineoplastic agent (pharmacology)

bezafibrate (pharmacology), caveolin 1 (endogenous compound), dichloroacetic acid (pharmacology), hypoxia inducible factor (endogenous compound), hypoxia inducible factor 1 (endogenous compound), hypoxia inducible factor 1alpha (endogenous compound), lonidamine, Myc protein (endogenous compound), protein p53 (endogenous compound), Ras protein (endogenous compound), succinate dehydrogenase (endogenous compound), von Hippel Lindau protein (endogenous compound)

carcinogenesis, mitochondrial respiration, molecularly targeted therapy

apoptosis, article, cancer cell, cell energy, cell metabolism, cell survival, energy metabolism, human, malignant transformation, metastasis, mitophagy, nonhuman, oncogene, priority journal, tumor microenvironment

bezafibrate (41859-67-0), dichloroacetic acid (13425-80-4, 2156-56-1, 79-43-6), lonidamine (50264-69-2), succinate dehydrogenase (9002-02-2, 9028-10-8)

Cancer (16), Clinical and Experimental Biochemistry (29), Drug Literature Index (37)

ClinicalTrials.gov (NCT00237536, NCT00435448, NCT01029925, NCT01111097)

http://dx.doi.org/10.1016/B978-0-12-407190-2.00004-6

Copyright 2014 Elsevier B.V., All rights reserved.

New-onset diabetes after transplantation (NODAT): An evaluation of definitions in clinical trials

First M.R., Dhadda S., Croy R., Holman J., Fitzsimmons W.E.

(First M.R., roy.first@astellas.com; Dhadda S.; Croy R.; Holman J.; Fitzsimmons W.E.) Astellas Pharma Global Development, 1 Astellas Way, N6-291, Northbrook, IL 60062, United States.

M.R. First, Astellas Pharma Global Development, 1 Astellas Way, N6-291, Northbrook, IL 60062, United States. Email: roy.first@astellas.com

Transplantation (2013) 96:1 (58-64). Date of Publication: 15 Jul 2013

0041-1337

Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, Philadelphia, United States.

BACKGROUND: New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT. METHODS: Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels (greater-than or equal to)126 mg/dL ((greater-than or equal to)7.0 mmol/L) (greater-than or equal to)30 days apart, (ii) oral hypoglycemic agent use for (greater-than or equal to)30 consecutive days, (iii) insulin therapy for (greater-than or equal to)30 consecutive days, and (iv) hemoglobin A1c (greater-than or equal to)6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT. RESULTS: The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations. CONCLUSIONS: Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes. Copyright (copyright) 2013 by Lippincott Williams & Wilkins.

cyclosporin A (clinical trial, drug comparison), glucose (endogenous compound), hemoglobin A1c (endogenous compound), oral antidiabetic agent (oral drug administration), tacrolimus (clinical trial, drug comparison)

diabetes mellitus (complication), new onset diabetes after transplantation (complication)

adult, article, clinical evaluation, disease association, drug effect, drug use, ethnicity, female, glucose blood level, graft recipient, hemoglobin blood level, human, kidney transplantation, liver transplantation, major clinical study, male, multicenter study (topic), outcome assessment, phase 3 clinical trial (topic), priority journal, randomized controlled trial (topic), risk assessment, treatment duration

advagraf (Astellas), neoral (Novartis, United States), prograf (Astellas, United States)

Astellas (United States), Novartis (United States)

cyclosporin A (59865-13-3, 63798-73-2), glucose (50-99-7, 84778-64-3), hemoglobin A1c (62572-11-6), tacrolimus (104987-11-3)

Endocrinology (3), Public Health, Social Medicine and Epidemiology (17), Drug Literature Index (37)

ClinicalTrials.gov (NCT00064701, NCT00189826, NCT00189839)

http://dx.doi.org/10.1097/TP.0b013e318293fcf8

Copyright 2014 Elsevier B.V., All rights reserved.

Development of lacosamide for the treatment of partial-onset seizures

Doty P., Hebert D., Mathy F.-X., Byrnes W., Zackheim J., Simontacchi K.

(Doty P., pamela.doty@ucb.com; Hebert D.; Byrnes W.) UCB Pharma, Raleigh, NC, United States. , (Mathy F.-X.) UCB Pharma, Brussels, Belgium. , (Zackheim J.; Simontacchi K.) UCB Pharma, Smyrna, Georgia.

P. Doty, UCB Pharma, 8010 Arco Corporate Drive, Raleigh, NC 27617, United States. Email: pamela.doty@ucb.com

Annals of the New York Academy of Sciences (2013) 1291:1 (56-68). Date of Publication: July 2013

0077-8923,1749-6632 (electronic)

Blackwell Publishing Inc., 350 Main Street, Malden, United States.

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug-drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy. (copyright) 2013 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals Inc. on behalf of The New York Academy of Sciences.

harkoseride (adverse drug reaction, clinical trial, drug therapy, intravenous drug administration, oral drug administration, pharmacokinetics, pharmacology)

cytochrome P450 (endogenous compound), placebo, sodium channel (endogenous compound)

focal epilepsy (drug therapy, drug therapy), partial onset seizure (drug therapy, drug therapy)

anticonvulsant activity, article, ataxia (side effect), balance disorder (side effect), bioequivalence, blurred vision (side effect), coordination, diplopia (side effect), dizziness (side effect), drug absorption, drug efficacy, drug mechanism, drug protein binding, drug safety, drug tolerability, fatigue (side effect), headache (side effect), human, maintenance therapy, monotherapy, nausea (side effect), nerve cell membrane, nonhuman, nystagmus (side effect), rhinopharyngitis (side effect), side effect (side effect), somnolence (side effect), tremor (side effect), vertigo (side effect), vision, vomiting (side effect)

cytochrome P450 (9035-51-2), harkoseride (175481-36-4)

Neurology and Neurosurgery (8), Clinical and Experimental Pharmacology (30), Drug Literature Index (37), Adverse Reactions Titles (38), Epilepsy Abstracts (50)

ClinicalTrials.gov (NCT00136019, NCT00151879, NCT00220415, NCT00515619, NCT00520741, NCT00522275, NCT00530855, NCT00552305, NCT00655486, NCT00655551, NCT00800215, NCT00938431, NCT00938912, NCT01243177, NCT01465997, NCT01710657)

http://dx.doi.org/10.1111/nyas.12213

Copyright 2013 Elsevier B.V., All rights reserved.

Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion

Sadda S., Danis R.P., Pappuru R.R., Keane P.A., Jiao J., Li X.-Y., Whitcup S.M.

(Sadda S., SSadda@doheny.org) Doheny Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Los Angeles, CA 90033, United States. , (Danis R.P.) Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI, United States. , (Pappuru R.R.) Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, L. V. Prasad Eye Institute, Hyderabad, India. , (Keane P.A.) NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom. , (Jiao J.) Biostatistics Allergan Inc., Irvine, CA, United States. , (Li X.-Y.) Clinical Development - Ophthalmology Allergan Inc., Irvine, CA, United States. , (Whitcup S.M.) Research and Development Allergan Inc., Irvine, CA, United States.

S. Sadda, Doheny Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Los Angeles, CA 90033, United States. Email: SSadda@doheny.org

Ophthalmology (2013) 120:7 (1423-1431). Date of Publication: July 2013

0161-6420,1549-4713 (electronic)

Elsevier Inc., 360 Park Avenue South, New York, United States.

Objective: To evaluate the angiographic findings in eyes from 2 clinical trials of the dexamethasone intravitreal implant (DEX implant) 0.7 mg in the treatment of macular edema (ME) after branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Design: Post hoc analysis of pooled data from 2 identical phase 3 clinical trials. Participants: Patients with vision loss as a result of ME ((greater-than or equal to)6 weeks' duration) after BRVO or CRVO for whom angiographic data were available (n = 329 eyes). Methods: Fluorescein angiography (FA) results assessed by masked, certified graders using standardized grading protocols. Main Outcome Measures: The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]). Results: At baseline, 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable assessments because of hemorrhage. At day 180, significantly fewer DEX implant-treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage (P = 0.029). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady from baseline to day 180. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed relatively constant in the DEX implant group (P = 0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups (no statistically significant between-group difference). There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r = 0.22; 95% confidence interval, 0.03-0.40; P = 0.023) and the sham group (r = 0.29; 95% confidence interval, 0.10-0.46; P = 0.003). Conclusions: This study demonstrated that the clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters and suggests that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. (copyright) 2013 American Academy of Ophthalmology.

dexamethasone (clinical trial, drug therapy, intravitreal drug administration)

branch retinal vein occlusion (drug therapy, drug therapy), central retina vein occlusion (drug therapy, drug therapy), intravitreal implant, macular edema (drug therapy, drug therapy)

article, capillary leak syndrome, central retinal thickness, clinical evaluation, correlation analysis, fluorescence angiography, human, incidence, major clinical study, multicenter study (topic), neovascularization (pathology), optical coherence tomography, outcome assessment, phase 3 clinical trial (topic), post hoc analysis, priority journal, prospective study, randomized controlled trial (topic), retina angiography, retina hemorrhage, statistical significance, visual acuity, visual impairment

ozurdex (Allergan, United States)

Allergan (United States)

Ozurdex (Allergan, United States)

Allergan (United States)

dexamethasone (50-02-2)

Ophthalmology (12), Biophysics, Bioengineering and Medical Instrumentation (27), Drug Literature Index (37)

ClinicalTrials.gov (NCT00168298, NCT00168324)

http://dx.doi.org/10.1016/j.ophtha.2012.12.021

Copyright 2013 Elsevier B.V., All rights reserved.

Interim (18)F-FDG PET in hodgkin lymphoma: Would PET-adapted clinical trials lead to a paradigm shift?

Kostakoglu L., Gallamini A.

(Kostakoglu L., lale.kostakoglu@mssm.edu) Department of Radiology, Division of Nuclear Medicine, Mount Sinai Medical Center, Box 1141, New York, NY 10029, United States. , (Gallamini A.) Onco-Haematology Department, Centre Antoine Lacassgne, Nice University, Nice, France.

L. Kostakoglu, Department of Radiology, Division of Nuclear Medicine, Mount Sinai Medical Center, Box 1141, New York, NY 10029, United States. Email: lale.kostakoglu@mssm.edu

Journal of Nuclear Medicine (2013) 54:7 (1082-1093). Date of Publication: 1 Jul 2013

0161-5505

Society of Nuclear Medicine Inc., 1850 Samuel Morse Drive, Reston, United States.

Hodgkin lymphoma (HL) is a curable disease with currently available chemotherapy regimens. Major late morbidities can potentially be avoided in most limited-stage HL patients if the treatment can be adapted to the patient's early response profile. The therapy efficacy can also be increased early during therapy in nonresponding HL patients with the addition of involved-field radiation therapy or a switch to an escalated therapy protocol, particularly in advancedstage or unfavorable-risk patients. (18)F-FDG PET is a well-established surrogate for tumor chemosensitivity early during therapy. The ongoing PET-adaptive clinical trials are testing the hypothesis that a decision can reliably be made on escalating or deescalating therapy based on interim PET results. Discussed in this review is the integral role of interim (18)F-FDG PET in HL, challenges, critical issues to improve its accuracy, and the observations from completed interim PET studies and ongoing PET-adaptive clinical trials. (copyright) 2013 by the Society of Nuclear Medicine.

fluorodeoxyglucose f 18

bleomycin (adverse drug reaction, clinical trial, drug combination, drug therapy), cyclophosphamide (adverse drug reaction, clinical trial, drug combination, drug therapy), dacarbazine (adverse drug reaction, clinical trial, drug combination, drug therapy), doxorubicin (adverse drug reaction, clinical trial, drug combination, drug therapy), etoposide (adverse drug reaction, clinical trial, drug combination, drug therapy), gemcitabine (adverse drug reaction, clinical trial, drug combination, drug therapy), prednisone (adverse drug reaction, clinical trial, drug combination, drug therapy), procarbazine (adverse drug reaction, clinical trial, drug combination, drug therapy), rituximab (clinical trial, drug combination, drug therapy), vinblastine (adverse drug reaction, clinical trial, drug combination, drug therapy), vincristine (adverse drug reaction, clinical trial, drug combination, drug therapy)

Hodgkin disease (drug therapy, drug therapy, radiotherapy), positron emission tomography

article, cancer chemotherapy, cancer radiotherapy, cancer regression, cancer staging, cancer survival, chemosensitivity, clinical trial (topic), drug efficacy, human, minimal residual disease, multiple cycle treatment, observational study, priority journal, prognosis, sensitivity and specificity, unspecified side effect (side effect)

bleomycin (11056-06-7, 9041-93-4), cyclophosphamide (50-18-0), dacarbazine (4342-03-4), doxorubicin (23214-92-8, 25316-40-9), etoposide (33419-42-0), fluorodeoxyglucose f 18 (63503-12-8), gemcitabine (103882-84-4), prednisone (53-03-2), procarbazine (366-70-1, 671-16-9), rituximab (174722-31-7), vinblastine (865-21-4), vincristine (57-22-7)

Cancer (16), Nuclear Medicine (23), Hematology (25), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00392314, NCT00433433, NCT00515554, NCT00678327, NCT00736320, NCT00784537, NCT00795613, NCT00822120, NCT00943423, NCT01118026, NCT01132807, NCT01356680, NCT01358747)

http://dx.doi.org/10.2967/jnumed.113.120451

Copyright 2013 Elsevier B.V., All rights reserved.

Lack of transparency of clinical trials on endometriosis

Guo S.-W., Evers J.L.H.

(Guo S.-W., hoxa10@gmail.com) Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011, China. , (Evers J.L.H.) The Division of Reproductive Medicine and Biology, School for Oncology and Developmental Biology GROW, Maastricht University Medical Center, Maastricht, the Netherlands

S.-W. Guo, Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011, China. Email: hoxa10@gmail.com

Obstetrics and Gynecology (2013) 121:6 (1281-1290). Date of Publication: June 2013

0029-7844,1873-233X (electronic)

Lippincott Williams and Wilkins, 250 Waterloo Road, London, United Kingdom.

OBJECTIVE: To estimate patterns of publication of clinical trials of endometriosis registered in ClinicalTrials.gov and their associated characteristics. METHODS: Information on interventional clinical trials on endometriosis that were registered at ClinicalTrials. gov and updated as having been completed by October 25, 2012, was retrieved and the publication status and time to publication in Medline-indexed journals were ascertained by searching PubMed and by sending e-mail inquiries to the principal investigators listed by the registry. RESULTS: Seventy-one interventional trials of endometriosis, testing various drugs and biologicals, were identified. Among them, 49.3% (35/71) were completed by October 25, 2012, 21.1% were either stopped or inactive in the past 2 years, and the remaining 29.6% were ongoing. Among the 35 completed trials, 25 (71.4%) were sponsored by industry and results were published for only 11 (31.4%; five industry-sponsored, and six non-industry-sponsored). Trials sponsored by industry were nearly four times less likely to publish their results than nonindustry-sponsored trials, even though these trials typically had larger sample sizes and were completed faster. Compared with the publication rate of 20% found 4 years ago, the current rate has increased only marginally but still lies significantly below the reported 66.3% surveyed recently among 546 completed nonendometriosis trials registered at ClinicalTrials.gov (P<.001). CONCLUSION: Despite mounting pressure on more transparency of clinical trials, the current state of transparency or lack thereof of clinical trials on endometriosis is worrisome and does not benefit the trial sponsor or the public. Thus, we again call for more transparency for endometriosis trials. (copyright) 2013 by The American College of Obstetricians and Gynecologists.

abt 620, anastrozole (clinical trial, drug therapy), aromatase inhibitor (clinical trial, drug therapy), asoprisnil (clinical trial, drug therapy), bgs 649 (clinical trial, drug therapy), danazol (clinical trial, drug therapy), degarelix (clinical trial, drug therapy), desogestrel (clinical trial, drug therapy), dienogest (clinical trial, drug therapy), elagolix (clinical trial, drug therapy), gonadorelin antagonist (clinical trial, drug therapy), goserelin (clinical trial, drug therapy), klh 2109 (clinical trial, drug therapy), letrozole (clinical trial, drug therapy), leuprorelin (clinical trial, drug therapy), nafarelin (clinical trial, drug therapy), npc 01 (clinical trial, drug therapy), oral contraceptive agent (clinical trial, drug therapy), peroxisome proliferator activated receptor gamma (clinical trial, drug therapy), pf 02413873 (clinical trial, drug therapy), pioglitazone (clinical trial, drug therapy), prinaberel (clinical trial, drug therapy), raloxifene (clinical trial, drug therapy), rosiglitazone (clinical trial, drug therapy), selective estrogen receptor modulator (clinical trial, drug therapy), tak 385 (clinical trial, drug therapy), telapristone acetate (clinical trial, drug therapy), tranexamic acid (clinical trial, drug therapy), triptorelin (clinical trial, drug therapy), ulipristal (clinical trial, drug therapy), unclassified drug, unindexed drug

clinical trial (topic), endometriosis (drug therapy, drug therapy)

adenomyosis, article, drug efficacy, drug industry, drug safety, female infertility, fertilization in vitro, human, medical literature, Medline, priority journal

abt 620, bgs 649, cdb 2914, cdb 4124, erb 041, j 867, klh 2109, nbi 56418, npc 01, pf 02413873, proellex, tak 385

anastrozole (120511-73-1), asoprisnil (163883-84-9), danazol (17230-88-5), degarelix (214766-78-6), desogestrel (54024-22-5), dienogest (65928-58-7), elagolix (832720-36-2, 834153-87-6), goserelin (65807-02-5), letrozole (112809-51-5), leuprorelin (53714-56-0, 74381-53-6), nafarelin (76932-56-4), pioglitazone (105355-27-9, 111025-46-8), prinaberel (524684-52-4), raloxifene (82640-04-8, 84449-90-1), rosiglitazone (122320-73-4, 155141-29-0), telapristone acetate (198414-31-2), tranexamic acid (1197-18-8, 701-54-2), triptorelin (57773-63-4), ulipristal (126784-99-4, 159811-51-5)

Obstetrics and Gynecology (10), Drug Literature Index (37)

ClinicalTrials.gov (NCT00212342, NCT00225186, NCT00225199, NCT01620528)

http://dx.doi.org/10.1097/AOG.0b013e318291f299

Copyright 2013 Elsevier B.V., All rights reserved.

Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: A meta-analysis

Zhang D., Ye J., Xu T., Xiong B.

(Zhang D.; Xu T.; Xiong B., binxiong88@yahoo.com) Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China. , (Ye J.) Department of Radio-chemotherapy, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.

B. Xiong, Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei 430071, China. Email: binxiong88@yahoo.com

Journal of Chemotherapy (2013) 25:3 (170-175). Date of Publication: June 2013

1120-009X,1973-9478 (electronic)

Maney Publishing, Suite 1C, Joseph's Well, Hanover Walk, Leeds, United Kingdom.

Purpose: Cetuximab has been approved by FDA for the treatment of advanced/metastatic colorectal cancer. Whether cetuximab treatment is associated with an increase of severe adverse events in colorectal cancer (CRC) patients remains a question. The purpose is to assess the risk of severe adverse events of cetuximab treatment in advanced/metastatic CRC patients. Patients and methods: Search of EMBASE, PubMed, and ScienceDirect between 1 January, 2000 and 1 July 2012 for relevant randomized control trials (RCTs). Previous meta-analyses related with cetuximab treatment were also identified for eligible RCTs. Eligible studies were RCTs of advanced/metastatic CRC patients assigned to cetuximab or control group. Data were extracted by two authors for severe and fatal adverse events. Results: Nine RCTs, involving 8520 patients with CRC were included. Using a fixed-effects model, the proportion of patients with severe adverse events was higher in the cetuximab group than in control group with Mantel-Haenszel methods (OR, 2.19; 95% CI, 1.99-2.41; incidence, 70.0% versus 51.2%; P<0.001). The most common severe adverse events were neutropenia, diarrhea, and rash. However, cetuximab was not associated with increased risk of fatal adverse events (OR, 1.41; 95% CI, 0.99-2.03; incidence, 1.8% versus. 1.3%). Conclusion: In this meta-analysis of RCTs, cetuximab was associated with an increased risk of severe adverse events. There is no evidence of an increased risk of fatal adverse events with cetuximab. (copyright) 2013 Edizioni Scientifiche per l'Informazione su Farmaci e Terapia.

cetuximab (adverse drug reaction, clinical trial, drug combination, drug therapy, intravenous drug administration)

capecitabine (clinical trial, drug combination, drug therapy), fluoropyrimidine (clinical trial, drug combination, drug therapy), fluorouracil (clinical trial, drug combination, drug therapy), folinic acid (clinical trial, drug combination, drug therapy), irinotecan (clinical trial, drug combination, drug therapy), oxaliplatin (clinical trial, drug combination, drug therapy)

colorectal cancer (drug therapy, drug therapy)

anemia (side effect), anorexia (side effect), article, diarrhea (side effect), drug fatality, dyspnea (side effect), fatigue (side effect), hand foot syndrome (side effect), human, hypomagnesemia (side effect), infection (side effect), infusion related reaction (side effect), meta analysis, metastatic colorectal cancer (drug therapy), mucosa inflammation (side effect), nausea and vomiting (side effect), neutropenia (side effect), peripheral neuropathy (side effect), randomized controlled trial (topic), rash (side effect), stomatitis (side effect), thromboembolism (side effect)

capecitabine (154361-50-9), cetuximab (205923-56-4), fluoropyrimidine (675-21-8), fluorouracil (51-21-8), folinic acid (58-05-9), irinotecan (100286-90-6), oxaliplatin (61825-94-3)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00182715)

http://dx.doi.org/10.1179/1973947813Y.0000000070

Copyright 2013 Elsevier B.V., All rights reserved.

Istradefylline: First global approval

Dungo R., Deeks E.D.

(Dungo R., dru@adis.com) Adis RandD Insight, 41 Centorian Drive, Mairangi Bay, North Shore, 0754 Auckland, New Zealand. , (Deeks E.D.) Adis, Auckland, New Zealand.

R. Dungo, Adis RandD Insight, 41 Centorian Drive, Mairangi Bay, North Shore, 0754 Auckland, New Zealand. Email: dru@adis.com

Drugs (2013) 73:8 (875-882). Date of Publication: June 2013

0012-6667,1179-1950 (electronic)

Springer International Publishing AG, Gewerbestrasse 11, Cham (ZG), Switzerland.

Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A(2A) receptor antagonist, for the once-daily oral treatment of Parkinson's disease (PD). Adenosine A(2A) receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control. Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008. This article summarizes the milestones in the development of istradefylline leading to its first approval for the treatment of patients with PD. (copyright) 2013 Springer International Publishing Switzerland.

istradefylline (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, oral drug administration, pharmacoeconomics, pharmacokinetics, pharmacology)

4 aminobutyric acid (endogenous compound), adenosine A2a receptor (endogenous compound), carbidopa plus levodopa (drug combination, drug therapy), cytochrome P450 3A4 (endogenous compound), glutamic acid (endogenous compound), levodopa (drug combination, drug therapy), nouriast, oxidopamine (endogenous compound), placebo, unclassified drug

drug approval

add on therapy, area under the curve, article, asthma (side effect), cardiovascular risk, cerebellum, constipation (side effect), dizziness (side effect), dopamine metabolism, dose response, drug absorption, drug half life, drug megadose, drug protein binding, drug safety, drug tolerability, drug tolerance, drug withdrawal, dyskinesia (side effect), food and drug administration, globus pallidus, hallucination (side effect), heart failure (side effect), heart infarction (side effect), human, infection (side effect), insomnia (side effect), intention to treat analysis, low drug dose, maximum plasma concentration, monotherapy, motor performance, multicenter study (topic), nausea (side effect), neuroprotection, neurotransmitter release, nonhuman, nucleus accumbens, optimal drug dose, Parkinson disease (drug therapy), parkinsonism (side effect), phase 2 clinical trial (topic), phase 3 clinical trial (topic), plasma concentration-time curve, positional dizziness (side effect), randomized controlled trial (topic), restless legs syndrome (drug therapy), smoking, steady state, substantia nigra pars reticulata, thalamus, treatment duration, urosepsis (side effect)

kw 6002, nouriast

4 aminobutyric acid (28805-76-7, 56-12-2), carbidopa plus levodopa (57308-51-7), cytochrome P450 3A4 (329736-03-0), glutamic acid (11070-68-1, 138-15-8, 56-86-0, 6899-05-4), istradefylline (155270-99-8), levodopa (59-92-7), oxidopamine (1199-18-4, 28094-15-7, 636-00-0)

Neurology and Neurosurgery (8), Health Policy, Economics and Management (36), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00006337, NCT00199355, NCT00199368, NCT00199381, NCT00199394, NCT00199407, NCT00199420, NCT00199433, NCT00199446, NCT00203957, NCT00250393, NCT00455507, NCT00456586, NCT00456794, NCT00955045, NCT00955526, NCT00957203)

http://dx.doi.org/10.1007/s40265-013-0066-7

Copyright 2014 Elsevier B.V., All rights reserved.

Multimodality therapy for patients with high-risk prostate cancer: Current status and future directions

Zaorsky N.G., Trabulsi E.J., Lin J., Den R.B.

(Zaorsky N.G.; Den R.B., robert.den@jeffersonhospital.org) Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Hospital, 111 S 11th St, Philadelphia, PA 19107, United States. , (Trabulsi E.J.) Department of Urology, Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, United States. , (Lin J.) Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, United States.

R.B. Den, Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Hospital, 111 S 11th St, Philadelphia, PA 19107, United States. Email: robert.den@jeffersonhospital.org

Seminars in Oncology (2013) 40:3 (308-321). Date of Publication: June 2013

0093-7754

W.B. Saunders, Independence Square West, Philadelphia, United States.

Prostate cancer is the most commonly diagnosed cancer and second most common cause of cancer death in American men. Although high-risk disease accounts for less than 15% of diagnoses, high-risk prostate cancer patients have a cancer-specific mortality rate of 15% at 10 years. There is currently no consensus on the optimal management of high-risk disease because (1) there are different primary modalities available (ie, surgery, radiation), for which there are no randomized trials comparing efficacy; and (2) unstandardized timing of different therapies (ie, neoadjuvant v concurrent v adjuvant), which makes comparisons of efficacy problematic. Increased understanding into the mechanisms leading to the formation of advanced metastatic disease has spurred the development of agents to target these pathways. However, new questions regarding optimal management of disease arise with regard to the role of these therapies in combination with "conventional" primary modalities for earlier stage, high-risk prostate cancer patients. In this article, we review the transforming world of multimodality therapy in high-risk prostate cancer. (copyright) 2013 Elsevier Inc.

4 diallylaminomethylene 1,3,4,7,10,11,12,13,14,15,16,17 dodecahydro 6 hydroxy 1 methoxymethyl 10,13 dimethyl 3,7,17 trioxo 2 oxacyclopenta[a]phenanthren 11 yl acetate (drug therapy), 6 [4 (4 ethyl 1 piperazinylmethyl)phenyl] 4 (alpha methylbenzylamino) 7h pyrrolo[2,3 d]pyrimidine (drug therapy), abiraterone (drug therapy), abiraterone acetate, aragon, asp 9521, azd 509, bevacizumab (drug therapy), buparlisib (drug therapy), cabazitaxel (drug combination, drug therapy), cabozantinib (drug therapy), calcitriol (drug therapy), cixutumumab (drug therapy), custirsen, denosumab (drug combination, drug therapy), docetaxel (drug comparison, drug therapy), enzalutamide (drug therapy), epi 001, estramustine (drug comparison, drug therapy), everolimus (drug therapy), ezn 4176, galeterone (drug therapy), ipilimumab (drug therapy), mitoxantrone (drug combination, drug therapy), odm 201, orteronel (drug therapy), pazopanib (drug therapy), placebo, prednisone (drug combination, drug comparison, drug therapy), radium chloride ra 223 (drug therapy), rapamycin (drug therapy), sipuleucel T (drug therapy), sorafenib (drug therapy), temsirolimus (drug therapy), trilostane (drug therapy), unclassified drug, unindexed drug, valaciclovir (drug therapy), zoledronic acid (drug combination, drug therapy)

multimodality cancer therapy, prostate cancer (drug therapy, drug therapy, radiotherapy, surgery)

androgen deprivation therapy, article, cancer adjuvant therapy, cancer chemotherapy, cancer immunotherapy, cancer mortality, cancer survival, consensus, disease free interval, disease free survival, external beam radiotherapy, health care quality, high risk population, human, lymph node metastasis, orchiectomy, overall survival, phase 3 clinical trial (topic), priority journal, prostatectomy, randomized controlled trial (topic), salvage therapy, systemic therapy

aragon, asp 9521, azd 509, cci 779, epi 001, ezn 4176, mdv 3100, modrenal, odm 201, ogx 011, orteronel, tok 001, zytiga

abiraterone (154229-19-3), abiraterone acetate (154229-18-2), bevacizumab (216974-75-3), buparlisib (1202777-78-3, 944396-07-0), cabazitaxel (183133-96-2), cabozantinib (1140909-48-3, 849217-68-1, 942407-59-2), calcitriol (32222-06-3, 32511-63-0, 66772-14-3), cixutumumab (947687-12-9), custirsen (685922-56-9, 809298-11-1, 903916-27-8), denosumab (615258-40-7), docetaxel (114977-28-5), enzalutamide (915087-33-1), estramustine (2998-57-4, 62899-40-5), everolimus (159351-69-6), galeterone (851983-85-2), ipilimumab (477202-00-9), mitoxantrone (65271-80-9, 70476-82-3), orteronel (566939-85-3), pazopanib (444731-52-6, 635702-64-6), prednisone (53-03-2), rapamycin (53123-88-9), sipuleucel T (917381-47-6), sorafenib (284461-73-0), temsirolimus (162635-04-3, 343261-52-9), trilostane (13647-35-3), valaciclovir (124832-26-4), zoledronic acid (118072-93-8, 131654-46-1, 165800-06-6, 165800-07-7)

Surgery (9), Radiology (14), Cancer (16), Urology and Nephrology (28), Drug Literature Index (37)

ClinicalTrials.gov (NCT00004054, NCT00030654, NCT00055731, NCT00116142, NCT00283062, NCT00430183, NCT00541047, NCT00653848, NCT00860652, NCT00949962, NCT01436968, NCT01546987)

http://dx.doi.org/10.1053/j.seminoncol.2013.04.006

Copyright 2013 Elsevier B.V., All rights reserved.

The use of interim (18)F-fluorodeoxyglucose PET to guide therapy in lymphoma

Araf S., Montoto S.

(Araf S., s.araf@qmul.ac.uk; Montoto S.) Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

S. Araf, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Email: s.araf@qmul.ac.uk

Future Oncology (2013) 9:6 (807-815). Date of Publication: June 2013

1479-6694,1744-8301 (electronic)

Future Medicine Ltd., 2nd Albert Place, Finchley Central, London, United Kingdom.

Over the past decade (18)F-fluorodeoxyglucose (FDG)-PET combined with computed tomography has gained a central role in the management of patients with lymphoma. The use of FDG-PET for staging and assessing treatment response in Hodgkin's and 'aggressive' non-Hodgkin's lymphoma is now well established, and the prognostic impact of the response to treatment assessed by FDG-PET is being increasingly recognized. Despite the widespread utilization of FDG-PET in clinical practice, key questions remain on its optimal use in certain contexts. One such area that is generating intense interest is the role of interim FDG-PET (typically performed after two to four cycles of chemotherapy) to guide treatment strategies. The author's will review the current available evidence in this area, highlighting questions in need of further study. (copyright) 2013 Future Medicine Ltd.

fluorodeoxyglucose f 18

bleomycin, carboplatin, cyclophosphamide, doxorubicin, etoposide, ifosfamide, prednisolone, prednisone, procarbazine, rituximab, vincristine

lymphoma, positron emission tomography

article, cancer chemotherapy, event free survival, follicular lymphoma, Hodgkin disease, human, large cell lymphoma, overall survival, PET scanner, predictive value, priority journal, progression free survival, treatment response

bleomycin (11056-06-7, 9041-93-4), carboplatin (41575-94-4), cyclophosphamide (50-18-0), doxorubicin (23214-92-8, 25316-40-9), etoposide (33419-42-0), fluorodeoxyglucose f 18 (63503-12-8), ifosfamide (3778-73-2), prednisolone (50-24-8), prednisone (53-03-2), procarbazine (366-70-1, 671-16-9), rituximab (174722-31-7), vincristine (57-22-7)

Radiology (14), Cancer (16), Drug Literature Index (37)

ClinicalTrials.gov (NCT00324467, NCT00392314, NCT00433433, NCT00498043, NCT00515554, NCT00530179, NCT00554164, NCT00678327, NCT00736320, NCT00784537, NCT00795613, NCT00822120, NCT00943423, NCT01118026, NCT01132807, NCT01358747, NCT01390584, NCT01652261)

http://dx.doi.org/10.2217/fon.13.55

Copyright 2013 Elsevier B.V., All rights reserved.

An integrated analysis of the efficacy of fluticasone furoate nasal spray versus placebo on the nasal symptoms of perennial allergic rhinitis

Wu W., Walters R.D., Nadeau G.A., Botnick W., Broughton N.

(Wu W.) Quantitative Sciences Division, Medicines Discovery and Development, Research and Development, GlaxoSmithKline, Research Triangle Park, NC, United States. , (Walters R.D.; Nadeau G.A., gilbert.a.nadeau@gsk.com; Broughton N.) Respiratory Centre of Excellence, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, UB11 1BT, United Kingdom. , (Botnick W.) Clinical Development, GlaxoSmithKline, Research Triangle Park, NC, United States.

G.A. Nadeau, Respiratory Centre of Excellence, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, UB11 1BT, United Kingdom. Email: gilbert.a.nadeau@gsk.com

Allergy and Asthma Proceedings (2013) 34:3 (283-291). Date of Publication: May-June 2013

1088-5412,1539-6304 (electronic)

OceanSide Publications Inc., 95 Pitman Street, Providence, United States.

Intranasal corticosteroids are widely prescribed for the treatment of perennial allergic rhinitis (PAR). The aim of this analysis was to determine whether the beneficial effects of once-daily (q.d.) fluticasone furoate nasal spray (FFNS) effectively improved individual nasal symptoms of PAR. An integrated analysis was performed on data from three randomized, double-blind, placebo-controlled, parallel-group trials designed to evaluate the efficacy and safety of FFNS at 110 micrograms, q.d. in subjects with PAR. The analysis included 460 subjects who received FFNS and 459 who received placebo for 4 weeks. All subjects evaluated the severity of individual nasal symptoms of nasal congestion, nasal itching, rhinorrhea, and sneezing on a four-point categorical scale. The main efficacy measures included change from baseline in daily reflective total nasal symptom score (rTNSS), reflective daily scores for each individual symptom, and predose instantaneous TNSS (iTNSS). Over 4 weeks of treatment, FFNS significantly improved rTNSS, iTNSS, and the reflective scores for each individual symptom compared with placebo. The least squares (LS) mean treatment difference over weeks 1-4 between FFNS and placebo for rTNSS was -0.93, ranging from -0.20 to -0.28 for the individual nasal symptoms (p < 0.001 for all versus placebo). For the iTNSS, the LS mean treatment difference between FFNS and placebo over weeks 1-4 was -0.95 (95% CI,-1.24, -0.66; p < 0.001). FFNS at 110 micrograms q.d. effectively relieved all nasal symptoms of PAR including nasal congestion over a 24-hour period. Copyright (copyright) 2013, OceanSide Publications, Inc., U.S.A.

fluticasone furoate (clinical trial, drug therapy, intranasal drug administration)

perennial rhinitis (drug therapy, drug therapy)

adolescent, adult, aged, article, child, controlled study, disease severity, drug efficacy, drug safety, female, human, major clinical study, male, nasal pruritus, nose obstruction, randomized controlled trial (topic), rhinorrhea, school child, sneezing, treatment response

fluticasone furoate (397864-44-7)

Chest Diseases, Thoracic Surgery and Tuberculosis (15), Immunology, Serology and Transplantation (26), Drug Literature Index (37)

ClinicalTrials.gov (NCT00103454, NCT00289198, NCT00609674)

http://dx.doi.org/10.2500/aap.2013.34.3662

Copyright 2013 Elsevier B.V., All rights reserved.

Efficacy and tolerability of propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity

Stohrer M., Murtz G., Kramer G., Warnack W., Primus G., Jinga V., Manu-Marin A., Calomfirescu N., Strugala G.

(Stohrer M., manfred@stoehrer.com) Department of Urology and Paediatric Urology, Universitat Essen, Hufelandstr. 55, Essen 45122, Germany. , (Murtz G.; Strugala G.) APOGEPHA Arzneimittel GmbH, Dresden, Germany. , (Kramer G.) , (Warnack W.) Urological Practice, Hagenow, Germany. , (Primus G.) Department of Urology, Medical University Graz, Austria. , (Jinga V.) Prof. Dr. Th. Burghele Clinical Hospital, Bucharest, Romania. , (Manu-Marin A.) Department of Urology, Geroia Hospital, Bucharest, Romania. , (Calomfirescu N.) Uro-Andro-Med, Bucharest, Romania.

M. Stohrer, Department of Urology and Paediatric Urology, Universitat Essen, Hufelandstr. 55, Essen 45122, Germany. Email: manfred@stoehrer.com

Spinal Cord (2013) 51:5 (419-423). Date of Publication: May 2013

1362-4393,1476-5624 (electronic)

Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.

Study design:Double-blind, randomised, multicentre study.Objectives: Efficacy and tolerability of propiverine extended-release (ER) compared with immediate-release (IR) were evaluated in patients with proven neurogenic detrusor overactivity (NDO).Setting:Six Spinal Cord Injury Units located in Austria, Germany and Romania.Methods:Propiverine ER 45 mg s.i.d. or IR 15 mg t.i.d. were administered in patients with proven NDO. Outcomes were assessed at baseline (V1), and after 21 days of treatment (V2): Reflex volume served as primary, leak point volume and maximum detrusor pressure as secondary efficacy outcomes, treatment-related adverse events as tolerability outcomes.Results: Sixty-six patients with proven NDO were enrolled. Reflex volume (ml) increased significantly in the IR (V1: 100.9, V2: 202.9) and in the ER (V1: 89.8, V2: 180.3) group, no significant intergroup difference. Leak point volume increased, and maximum detrusor pressure decreased significantly in both groups, no significant intergroup differences. The percentage of patients presenting with incontinence was reduced by 14% in the IR and by 39% in the ER group, the difference is significant. Treatment-related adverse events manifested in 42 and 36% following propiverine IR and ER, respectively.Conclusion:The urodynamic efficacy outcomes demonstrated both galenic formulations to be equieffective. However, following propiverine ER 45 mg s.i.d. higher continence rates compared with propiverine IR 15 mg t.i.d. were achieved, possibly indicative of more balanced plasma-levels. A slight tendency for superior tolerability outcomes of propiverine ER compared with IR was demonstrated.Sponsorship:The study was sponsored by an unrestricted educational grant of APOGEPHA Arzneimittel GmbH, Dresden, Germany. (copyright) 2013 International Spinal Cord Society. All rights reserved.

propiverine (adverse drug reaction, drug therapy, pharmaceutics)

neurogenic bladder (drug therapy, drug therapy), neurogenic detrusor overactivity (drug therapy, drug therapy), overactive bladder (drug therapy, drug therapy)

abdominal pain (side effect), accommodation disorder (side effect), adult, aged, article, Austria, bladder capacity, bladder pressure, blurred vision (side effect), controlled study, dizziness (side effect), double blind procedure, drug efficacy, drug fever (side effect), drug induced headache (side effect), drug safety, drug tolerability, dysuria (side effect), female, gastrointestinal motility disorder (side effect), Germany, human, major clinical study, male, multicenter study, nausea (side effect), outcome assessment, phase 3 clinical trial, priority journal, randomized controlled trial, Romania, xerostomia (side effect)

propiverine (60569-19-9)

Urology and Nephrology (28), Drug Literature Index (37), Adverse Reactions Titles (38), Pharmacy (39)

ClinicalTrials.gov (NCT01530620)

http://dx.doi.org/10.1038/sc.2012.174

Copyright 2014 Elsevier B.V., All rights reserved.

Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile neutropenia: A randomized, double-blind, placebo-controlled, multicenter study

Maschmeyer G., Heinz W.J., Hertenstein B., Horst H.-A., Requadt C., Wagner T., Cornely O.A., Loffler J., Ruhnke M.

(Maschmeyer G., gmaschmeyer@klinikumevb.de) Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467 Potsdam, Germany. , (Heinz W.J.; Loffler J.) Universitatsklinikum Wurzburg, Wurzburg, Germany. , (Hertenstein B.) Klinikum Bremen Mitte, Bremen, Germany. , (Horst H.-A.) Universitat Kiel, Kiel, Germany. , (Requadt C.) Universitat Erlangen-Nurnberg, Erlangen, Germany. , (Wagner T.) Universitatsklinikum Schleswig-Holstein, Campus Lubeck, Lubeck, Germany. , (Cornely O.A.) 1st Department of Internal Medicine; ZKS Koln, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. , (Ruhnke M.) Charite Universitatsmedizin (Campus Mitte), Berlin, Germany.

G. Maschmeyer, Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467 Potsdam, Germany. Email: gmaschmeyer@klinikumevb.de

European Journal of Clinical Microbiology and Infectious Diseases (2013) 32:5 (679-689). Date of Publication: May 2013

0934-9723,1435-4373 (electronic)

Springer Verlag, Tiergartenstrasse 17, Heidelberg, Germany.

Empirical antifungal therapy is widely used in high-risk neutropenic hematology patients with fever persisting for more than 4 days. This clinical trial assessed whether immediate empirical therapy with voriconazole could lower the rates of invasive fungal infections (IFIs) compared with this approach. In a double-blind, placebo-controlled, multicenter study, patients with acute leukemia undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) recipients were randomized to broad-spectrum antibacterial therapy plus voriconazole (immediate) or placebo (deferred) after the onset of neutropenic fever. If fever persisted for 96 h, patients were switched to open-label intravenous voriconazole; oral treatment was permitted after 96 h. The primary endpoint was the rate of proven/probable IFIs between Days 2 and 28 after fever onset in the modified intent-to-treat (mITT) complete-case population. One hundred and forty-seven patients were randomized to immediate (n = 81) or deferred (n = 66) voriconazole. In the mITT population, six patients in the immediate group and nine in the deferred group developed proven/probable IFI between Days 2 and 28 (p = 0.258). The safety profiles were similar in both groups. While immediate empirical therapy with voriconazole appears to be safe in febrile neutropenic high-risk patients, it was not associated with a significant reduction in IFIs compared with therapy deferred for 96 h after fever onset. (copyright) 2012 Springer-Verlag Berlin Heidelberg.

voriconazole (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, intravenous drug administration, oral drug administration)

fluconazole (drug combination, drug therapy), placebo

febrile neutropenia (drug therapy, drug therapy)

acute leukemia (therapy), adult, adverse outcome, aged, allogeneic hematopoietic stem cell transplantation, antimicrobial therapy, article, clinical assessment, clinical evaluation, controlled study, coughing (side effect), diarrhea (side effect), dose response, double blind procedure, drug efficacy, drug eruption (side effect), drug induced headache (side effect), drug safety, female, hallucination (side effect), high risk patient, human, hypokalemia (side effect), infection risk, loading drug dose, major clinical study, male, multicenter study, nausea (side effect), outcome assessment, polymerase chain reaction, priority journal, randomized controlled trial, risk assessment, risk factor, risk reduction, systemic mycosis (side effect), visual impairment (side effect), vomiting (side effect)

fluconazole (86386-73-4), voriconazole (137234-62-9)

Microbiology: Bacteriology, Mycology, Parasitology and Virology (4), Hematology (25), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00150345)

http://dx.doi.org/10.1007/s10096-012-1794-4

Copyright 2014 Elsevier B.V., All rights reserved.

Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation

Kobashigawa J., Ross H., Bara C., Delgado J.F., Dengler T., Lehmkuhl H.B., Wang S.-S., Dong G., Witte S., Junge G., Potena L.

(Kobashigawa J.) Cedars-Sinai Heart Institute, Los Angeles, CA, United States. , (Ross H.) University Health Network, Toronto, Canada. , (Bara C.) Hannover Medical School, Hannover, Germany. , (Delgado J.F.) Hospital Universitario 12 de Octubre, Madrid, Spain. , (Dengler T.) Klinikum Bad Friedrichshall, Bad Friedrichshall, Germany. , (Lehmkuhl H.B.) Deutsches Herzzentrum Berlin, Berlin, Germany. , (Wang S.-S.) National Taiwan University Hospital, Taipei, Taiwan. , (Dong G.) Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States. , (Witte S.; Junge G.) Novartis Pharma AG, Basel, Switzerland. , (Potena L., luciano.potena2@unibo.it) Dipartimento Cardiovascolare, Bologna, Italy.

L. Potena, Dipartimento Cardiovascolare, Pad. 21, Policlinico S. Orsola-Malpighi, via Massarenti 9, Bologna 40138, Italy. Email: luciano.potena2@unibo.it

Transplant Infectious Disease (2013) 15:2 (150-162). Date of Publication: April 2013

1398-2273,1399-3062 (electronic)

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.

Background: Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens. Methods: CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176). Results: In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus-treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naive recipients and is independent of anti-CMV prophylaxis or preemptive approaches. Conclusions: Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes. (copyright) 2012 John Wiley & Sons A/S.

everolimus (drug combination, drug comparison, drug therapy, oral drug administration)

azathioprine (drug combination, drug comparison, drug therapy, oral drug administration), cyclosporin (drug combination, drug therapy), ganciclovir (drug therapy), mycophenolic acid 2 morpholinoethyl ester (drug combination, drug comparison, drug therapy, oral drug administration), prednisone (drug therapy, oral drug administration), valaciclovir (drug therapy), valganciclovir (drug therapy)

cytomegalovirus infection (drug therapy, drug therapy, prevention), heart transplantation, immunosuppressive treatment

acute graft rejection (drug therapy), adult, aged, article, comparative study, controlled study, disease association, drug dose reduction, female, graft recipient, human, incidence, major clinical study, male, priority journal, randomized controlled trial

azathioprine (446-86-6), cyclosporin (79217-60-0), everolimus (159351-69-6), ganciclovir (82410-32-0), mycophenolic acid 2 morpholinoethyl ester (116680-01-4, 128794-94-5), prednisone (53-03-2), valaciclovir (124832-26-4), valganciclovir (175865-59-5, 175865-60-8, 175865-61-9, 175865-62-0, 175865-64-2, 175865-67-5)

Microbiology: Bacteriology, Mycology, Parasitology and Virology (4), Cardiovascular Diseases and Cardiovascular Surgery (18), Immunology, Serology and Transplantation (26), Drug Literature Index (37)

ClinicalTrials.gov (NCT00098007)

http://dx.doi.org/10.1111/tid.12007

Copyright 2013 Elsevier B.V., All rights reserved.

Four-week parenteral nutrition using a third generation lipid emulsion (SMOFlipid) - A double-blind, randomised, multicentre study in adults

Klek S., Chambrier C., Singer P., Rubin M., Bowling T., Staun M., Joly F., Rasmussen H., Strauss B.J., Wanten G., Smith R., Abraham A., Szczepanek K., Shaffer J.

(Klek S.; Szczepanek K.) Jagiellonian University Medical College, Krakow, Poland. , (Chambrier C.) Hopital de la Croix Rousse, Lyon, France. , (Singer P.; Rubin M.) Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel. , (Bowling T.) University Hospital, Nottingham, United Kingdom. , (Staun M.) Rigshospitalet, Copenhagen, Denmark. , (Joly F.) Hopital Beaujon, Clichy la Garenne, France. , (Rasmussen H.) Aalborg University Hospital, Aalborg, Denmark. , (Strauss B.J.) Monash Medical Centre, Monash University, Melbourne, Australia. , (Wanten G.) University Medical Center, Nijmegen, Netherlands. , (Smith R.) North Shore Private Hospital, Saint Leonards, Australia. , (Abraham A.; Shaffer J., jon.shaffer@srft.nhs.uk) Salford Royal NHS Foundation Trust, Intestinal Failure Unit, Salford M68HD, United Kingdom.

J. Shaffer, Salford Royal NHS Foundation Trust, Intestinal Failure Unit, Salford M68HD, United Kingdom. Email: jon.shaffer@srft.nhs.uk

Clinical Nutrition (2013) 32:2 (224-231). Date of Publication: April 2013

0261-5614,1532-1983 (electronic)

Churchill Livingstone, 1-3 Baxter's Place, Leith Walk, Edinburgh, United Kingdom.

Precis: The aim of this study was to evaluate the safety and tolerance of a soybean/MCT/olive/fish oil emulsion in intestinal failure patients on long-term parenteral nutrition. 73 patients took part in a randomized, double-blind, multi-centre study. The study demonstrates that the lipid emulsion containing four different types of oils is safe and well tolerated in long-term PN. Background & aim: Long-term safety and efficacy of a lipid emulsion containing soybean oil, medium-chain triglycerides (MCT), olive oil and fish oil and enriched in vitamin E have not yet been evaluated in adult patients requiring long-term parenteral nutrition (PN). Methods: Randomised, controlled, double-blind, multicentre study in 73 patients with stable intestinal failure, requiring PN with either soybean/MCT/olive/fish emulsion (SMOFlipid, n = 34) or soybean emulsion (Intralipid, control n = 39) for 4 weeks. Safety and tolerance were monitored with standard clinical laboratory parameters, adverse events (AEs, according to the Common Terminology Criteria for Adverse Events (CTCAE) classification v 3.0) and vital signs. Fatty acid pattern in red blood cell phospholipids and plasma lipoproteins, serum Vitamin E, Interleukin (IL)-6, and soluble tumour necrosis (s-TNF)-receptor(R)II were also evaluated. Results: Mean concentrations of alanine transaminase (ALT), aspartate transaminase (AST) and total bilirubin, whilst remaining within the reference range, were significantly lower with soybean/MCT/olive/fish (SMOF) oil emulsion after the treatment period compared to control. Eicosapentaenoic acid, docosahexaenoic acid and n-3/. n-6 fatty acid ratio increased in the SMOF group, while they remained unchanged in the control in plasma and RBC. Serum (alpha)-tocopherol concentrations significantly increased in the study group compared to control (p = 0.0004). IL-6 and sTNF-RII levels did not change during the study period. Grade 4 (serious) adverse events occurred in 2 SMOF patients and in 8 control patients (p = 0.03). Conclusions: Soybean/MCT/olive/fish emulsion was safe and well tolerated over 4 weeks and leads to positive change in fatty acids profile. (copyright) 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

fish oil (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), medium chain triacylglycerol (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy), olive oil (adverse drug reaction, clinical trial, drug combination, drug therapy), soybean oil (adverse drug reaction, clinical trial, drug combination, drug comparison, drug therapy)

alanine aminotransferase (endogenous compound), alpha tocopherol (endogenous compound), aspartate aminotransferase (endogenous compound), bilirubin (endogenous compound), docosahexaenoic acid (endogenous compound), fatty acid (endogenous compound), glycerol (endogenous compound), icosapentaenoic acid (endogenous compound), interleukin 6 (endogenous compound), intralipid (adverse drug reaction, drug comparison, drug therapy), lipid emulsion, lipoprotein (endogenous compound), omega 3 fatty acid (endogenous compound), omega 6 fatty acid (endogenous compound), phospholipid (endogenous compound), tumor necrosis factor receptor 2 (endogenous compound)

intestinal failure (drug therapy, diagnosis, drug therapy, therapy), parenteral nutrition

abdominal pain (side effect), adult, alanine aminotransferase blood level, arthralgia (side effect), article, aspartate aminotransferase blood level, bilirubin blood level, catheter infection (side effect), controlled study, dehydration (side effect), diarrhea (side effect), double blind procedure, drug induced headache (side effect), drug safety, drug tolerability, drug withdrawal, erythrocyte, female, human, hypomagnesemia (side effect), laboratory test, lipoprotein blood level, major clinical study, male, multicenter study, myalgia (side effect), nausea (side effect), randomized controlled trial, reference value, side effect (side effect), skin disease (side effect), soft tissue disease (side effect), urinary tract infection (side effect), vital sign, vitamin blood level, vomiting (side effect)

Fresenius Kabi (Germany)

alanine aminotransferase (9000-86-6, 9014-30-6), alpha tocopherol (1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9), aspartate aminotransferase (9000-97-9), bilirubin (18422-02-1, 635-65-4), docosahexaenoic acid (25167-62-8, 32839-18-2), fish oil (8016-13-5), glycerol (56-81-5), icosapentaenoic acid (25378-27-2, 32839-30-8), intralipid (68890-65-3), olive oil (8001-25-0), soybean oil (8001-22-7)

Public Health, Social Medicine and Epidemiology (17), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00451646)

http://dx.doi.org/10.1016/j.clnu.2012.06.011

Copyright 2013 Elsevier B.V., All rights reserved.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial

Squires R.H., Dhawan A., Alonso E., Narkewicz M.R., Shneider B.L., Rodriguez-Baez N., Olio D.D., Karpen S., Bucuvalas J., Lobritto S., Rand E., Rosenthal P., Horslen S., Ng V., Subbarao G., Kerkar N., Rudnick D., Lopez M.J., Schwarz K., Romero R., Elisofon S., Doo E., Robuck P.R., Lawlor S., Belle S.H.

(Squires R.H., squiresr@upmc.edu; Shneider B.L.) Children's Hospital of Pittsburgh, UPMC, Pittsburgh, PA, United States. , (Dhawan A.) Kings College, London, United Kingdom. , (Alonso E.) Northwestern University, Evanston, IL, United States. , (Narkewicz M.R.) University of Colorado SOM, Children's Hospital Colorado, Boulder, CO, United States. , (Rodriguez-Baez N.) University of Texas Southwestern Medical Center, Dallas, TX, United States. , (Olio D.D.) Birmingham Children's Hospital, Birmingham, United Kingdom. , (Karpen S., skarpen@emory.edu) Baylor College of Medicine, Houston, TX, United States. , (Bucuvalas J.) Cincinnati Children's Hospital, Cincinnati, OH, United States. , (Lobritto S.) Columbia University, New York, NY, United States. , (Rand E.) Children's Hospital of Philadelphia, Philadelphia, PA, United States. , (Rosenthal P.) University of California-San Francisco, San Francisco, CA, United States. , (Horslen S.) University of Washington, Seattle, WA, United States. , (Ng V.) Hospital for Sick Children, Toronto, Canada. , (Subbarao G.) Indiana University, Indianapolis, IN, United States. , (Kerkar N.) Mt. Sinai Medical Center, New York, NY, United States. , (Rudnick D.) Washington University, St. Louis, MO, United States. , (Lopez M.J.) University of Michigan, Ann Arbor, MI, United States. , (Schwarz K.) Johns Hopkins University, Baltimore, MD, United States. , (Romero R.) Emory University, Atlanta, GA, United States. , (Elisofon S.) Children's Hospital of Boston, Boston, MA, United States. , (Doo E.; Robuck P.R.) National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, United States. , (Lawlor S.; Belle S.H.) Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States. , (Karpen S., skarpen@emory.edu) Emory-Children's Center, 2015 Uppergate Dr. NE, Atlanta, GA 30322-1015, United States.

R.H. Squires, University of Pittsburgh, Children's Hospital of Pittsburgh, UPMC, 4401 Penn Ave., Pittsburgh, PA 15224, United States. Email: squiresr@upmc.edu

Hepatology (2013) 57:4 (1542-1549). Date of Publication: April 2013

0270-9139,1527-3350 (electronic)

John Wiley and Sons Inc., P.O.Box 18667, Newark, United States.

N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion: NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults. (copyright) 2012 American Association for the Study of Liver Diseases.

acetylcysteine (adverse drug reaction, clinical trial, drug therapy, intravenous drug administration)

glucose, placebo

acute liver failure (drug therapy, drug therapy), childhood disease (drug therapy, drug therapy)

aplastic anemia (side effect), article, bacteremia (side effect), bradycardia (side effect), bronchospasm (side effect), child, chill (side effect), continuous infusion, controlled study, disease severity, double blind procedure, drug fever (side effect), Epstein Barr virus infection (side effect), event free survival, female, heart arrhythmia (side effect), hepatic encephalopathy, human, hypertension (side effect), hypoglycemia (side effect), infection (side effect), intensive care unit, length of stay, liver transplantation, major clinical study, male, multiple organ failure, outcome assessment, pleura effusion (side effect), posttransplant lymphoproliferative disease (side effect), preschool child, priority journal, randomized controlled trial, respiratory distress (side effect), school child, scoring system, sinusitis (side effect), Staphylococcus infection (side effect), survival rate, survival time, treatment duration

acetylcysteine (616-91-1), glucose (50-99-7, 84778-64-3)

Pediatrics and Pediatric Surgery (7), Drug Literature Index (37), Adverse Reactions Titles (38), Gastroenterology (48)

ClinicalTrials.gov (NCT00248625)

http://dx.doi.org/10.1002/hep.26001

Copyright 2013 Elsevier B.V., All rights reserved.

Epratuzumab for systemic lupus erythematosus

Wallace D.J., Goldenberg D.M.

(Wallace D.J., dwallace@ucla.edu) Cedars-Sinai/David Geffen School of Medicine, UCLA, Los Angeles, CA, United States. , (Goldenberg D.M.) Center for Molecular Medicine and Immunology, Morris Plains, NJ, United States. , (Goldenberg D.M.) Immunomedics, Inc., Morris Plains, NJ, United States.

D.J. Wallace, 8737 Beverly Blvd #302, West Hollywood, CA 90048, United States. Email: dwallace@ucla.edu

Lupus (2013) 22:4 (400-405). Date of Publication: April 2013

0961-2033,1477-0962 (electronic)

SAGE Publications Ltd, 55 City Road, London, United Kingdom.

Epratuzumab (EMab, UCB, Immunomedics) is a humanized monoclonal antibody targeting CD22 that is being studied in clinical trials for patients with a variety of rheumatic and hematologic conditions, including systemic lupus erythematosus (SLE). An overview of its mechanism of action is followed by a summary of completed lupus studies, and a preview of studies in progress. The agent clearly has anti-inflammatory activity and is a potentially useful agent in the management of autoimmune disorders. (copyright) The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav.

epratuzumab (clinical trial, drug therapy, pharmacology)

CD22 antigen (endogenous compound), emab, methylprednisolone, prednisone, unclassified drug

systemic lupus erythematosus (drug therapy, drug therapy)

antiinflammatory activity, article, autoimmune disease, B lymphocyte, drug dose increase, human, priority journal

emab (UCB)

epratuzumab (205923-57-5), methylprednisolone (6923-42-8, 83-43-2), prednisone (53-03-2)

Immunology, Serology and Transplantation (26), Drug Literature Index (37)

ClinicalTrials.gov (NCT00111306)

http://dx.doi.org/10.1177/0961203312469692

Copyright 2013 Elsevier B.V., All rights reserved.

Adenosine receptors as drug targets-what are the challenges?

Chen J.-F., Eltzschig H.K., Fredholm B.B.

(Chen J.-F.) Department of Neurology and Pharmacology, Boston University School of Medicine, Boston, MA 02118, United States. , (Eltzschig H.K.) Department of Anesthesiology, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO 80045, United States. , (Fredholm B.B., Bertil.Fredholm@ki.se) Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.

B.B. Fredholm, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. Email: Bertil.Fredholm@ki.se

Nature Reviews Drug Discovery (2013) 12:4 (265-286). Date of Publication: April 2013

1474-1776,1474-1784 (electronic)

Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors-either directly or indirectly-have now entered the clinic. However, only one adenosine receptor-specific agent-the adenosine A 2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)-has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.

adenosine receptor (endogenous compound)

6 n (3 iodobenzyl)adenosine 5' n methylcarboxamide (clinical trial, drug analysis, drug therapy, oral drug administration), adenosine (clinical trial, drug analysis, drug comparison, endogenous compound, intradermal drug administration), adenosine A1 receptor (endogenous compound), adenosine A1 receptor agonist (clinical trial, drug therapy), adenosine A2a receptor (endogenous compound), adenosine A2b receptor (endogenous compound), adenosine A3 receptor (endogenous compound), adenosine A3 receptor agonist (clinical trial, drug analysis, drug therapy, oral drug administration), apadenoson (clinical trial, drug analysis, drug comparison), caffeine (clinical trial, drug analysis, drug therapy), cf 102 (clinical trial, drug analysis, drug therapy), dipyridamole (clinical trial, drug analysis, drug combination, drug therapy), gw 493838 (clinical trial, drug analysis, drug therapy), ino 8875 (clinical trial, drug therapy), istradefylline (clinical trial, drug analysis, drug therapy), levodopa (clinical trial, drug combination, drug therapy), placebo, prednisolone (clinical trial, drug combination, drug therapy), preladenant (clinical trial, drug analysis, drug therapy), regadenoson (clinical trial, drug analysis, drug comparison, drug therapy), rolofylline (clinical trial, drug analysis, drug therapy), tonapofylline (clinical trial, drug analysis, drug therapy, intravenous drug administration), tozadenant (clinical trial, drug analysis, drug combination, drug therapy), unclassified drug

acute heart failure (drug therapy), allosterism, article, autoimmune disease, brain ischemia, cocaine dependence, coronary artery bypass surgery, coronary artery disease, daytime somnolence (drug therapy), dimerization, disease course, drug structure, drug targeting, dry eye (drug therapy), functional magnetic resonance imaging, glaucoma (drug therapy), heart failure, hepatitis (drug therapy), human, inflammatory disease, intraocular hypertension (drug therapy), kidney failure (drug therapy), liver cancer (drug therapy), liver cell carcinoma (drug therapy), melanoma (drug therapy), motor dysfunction (drug therapy), myocardial perfusion imaging, neuropathic pain (drug therapy), newborn apnea (drug therapy), nonhuman, Parkinson disease (drug therapy), pathophysiology, peripheral nerve injury (drug therapy), postherpetic neuralgia (drug therapy), priority journal, protein expression, psoriasis (drug therapy), psoriasis vulgaris (drug therapy), rheumatoid arthritis (drug therapy), sickle cell anemia (drug therapy), signal transduction, single photon emission computer tomography, tissue distribution, tissue specificity

bg 9928, cf 101, cf 102, gw 493838, ino 8875, kw 3902, kw 6002, lexiscan (Astellas), sch 420814, syn 115

adenosine (58-61-7), apadenoson (250386-15-3), caffeine (58-08-2), dipyridamole (58-32-2), istradefylline (155270-99-8), levodopa (59-92-7), prednisolone (50-24-8), preladenant (377727-87-2), regadenoson (313348-27-5), rolofylline (136199-02-5), tonapofylline (340021-17-2), tozadenant (870070-55-6)

Clinical and Experimental Biochemistry (29), Drug Literature Index (37)

ClinicalTrials.gov (NCT00208312, NCT00284323, NCT00328692, NCT00354458, NCT00376454, NCT00428974, NCT00459420, NCT00556894, NCT00580905, NCT00612521, NCT00709865, NCT00760708, NCT00783276, NCT00790218, NCT00809055, NCT00881218, NCT00955526, NCT00957203, NCT01019486, NCT01085201, NCT01123785, NCT01155466, NCT01155479, NCT01190735, NCT01215227, NCT01227265, NCT01283594, NCT01295567, NCT01369745, NCT01408173, NCT01566890)

http://dx.doi.org/10.1038/nrd3955

Copyright 2013 Elsevier B.V., All rights reserved.

Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: Population pharmacokinetic analysis from a randomised Phase III study

Reif S., Snelder N., Blode H.

(Reif S., stefanie.reif@bayer.com; Blode H.) Global Drug Discovery - Clinical Sciences, Bayer HealthCare Pharmaceuticals, Sellerstrasse 31, Berlin 13342, Germany. , (Snelder N.) LAP and P Department BV, Leiden, Netherlands.

S. Reif, Global Drug Discovery - Clinical Sciences, Bayer HealthCare Pharmaceuticals, Sellerstrasse 31, Berlin 13342, Germany. Email: stefanie.reif@bayer.com

Journal of Family Planning and Reproductive Health Care (2013) 39:2 (e1). Date of Publication: April 2013

1471-1893

Royal College of Obstetricians and Gynaecologists, 27 Sussex Place, Regent's Park, London, United Kingdom.

Objectives: The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) of ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated the contraceptive efficacy and safety of three different regimens of EE 20 (mu)g/DRSP 3 mg. Methods: Non-linear mixed-effects modelling was used to develop population PK models for EE and DRSP. EE and DRSP serum concentrations were determined in blood samples obtained from approximately 1100 healthy young women on two occasions during the first cycle (Week 3) and after 6 months (Week 27) of EE 20 (mu)g/DRSP 3 mg use. EE 20 (mu)g/DRSP 3 mg was administered as a flexible extended regimen [24-120 days' active hormonal intake followed by 4 days with no tablet intake (tablet-free interval)], a conventional 28-day cyclic regimen (24 days' active hormonal intake followed by 4 days of placebo tablets) or a fixed extended regimen (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) over 1 year. Results: The population PK of EE and DRSP in this population were successfully described using the developed population models. All three regimens led to similar steady-state drug exposure during long-term treatment. Only minor changes ((less-than or equal to)8%) in the steady-state PK of EE and DRSP were observed between Week 3 and Week 27 of an extended regimen. Body weight (BW) and age had a small, statistically significant impact on the PK of EE and DRSP (BW only) in a covariate analysis, however, these changes were not considered to be clinically relevant. Conclusions Extending the established 24/4-day regimen of EE 20 (mu)g/DRSP 3 mg does not change the known steady-state PK of EE and DRSP, suggesting that the clinical efficacy is also similar. This is in line with the published clinical results from this study.

drospirenone (clinical trial, drug analysis, drug concentration, pharmacokinetics), ethinylestradiol (clinical trial, drug analysis, drug concentration, pharmacokinetics)

contraception

adult, alcohol consumption, area under the curve, article, blood sampling, body mass, drug bioavailability, drug blood level, drug clearance, drug determination, drug distribution, drug efficacy, drug exposure, drug safety, female, human, human tissue, limit of quantitation, major clinical study, phase 3 clinical trial (topic), randomized controlled trial (topic), smoking, treatment duration

drospirenone (67392-87-4), ethinylestradiol (57-63-6)

Obstetrics and Gynecology (10), Clinical and Experimental Pharmacology (30), Drug Literature Index (37)

ClinicalTrials.gov (NCT00266032)

http://dx.doi.org/10.1136/jfprhc-2012-100397

Copyright 2013 Elsevier B.V., All rights reserved.

Meta-analysis of pregnancy outcomes in pooled randomized trials on a prophylactic adjuvanted glycoprotein D subunit herpes simplex virus vaccine

Tavares F., Cheuvart B., Heineman T., Arellano F., Dubin G.

(Tavares F., fernanda.tavares@gsk.com; Cheuvart B.; Arellano F.) GlaxoSmithKline Vaccines, Wavre, Belgium. , (Heineman T.; Dubin G.) GlaxoSmithKline Vaccines, King of Prussia, PA, United States.

F. Tavares, GlaxoSmithKline Vaccines, Avenue Fleming 20, B-1300 Wavre, Belgium. Email: fernanda.tavares@gsk.com

Vaccine (2013) 31:13 (1759-1764). Date of Publication: 25 Mar 2013

0264-410X,1873-2518 (electronic)

Elsevier Ltd, Langford Lane, Kidlington, Oxford, United Kingdom.

The primary objective of this investigation was to assess whether the AS04-adjuvanted herpes simplex virus (HSV) glycoprotein D candidate prophylactic vaccine against genital herpes disease increases the risk of spontaneous abortion associated with pregnancy conceived within the vaccination exposure window (vaccine dose received within the period starting 60 days before and ending 20 weeks post-conception day). We performed a meta-analysis of studies designed as part of the clinical development program for this vaccine, to examine the relative risk of abortion (spontaneous or elective) associated with unintended vaccination exposure during pregnancy. Nineteen studies, completed before September 2010, were eligible; 5 matched the inclusion criteria for this analysis (presence of a control arm and at least one adverse pregnancy outcome reported). All vaccinated women (N=19,727) were included, of whom 660 reported a pregnancy during the study period. Overall, 13.3% of pregnancies in the HSV vaccine group and 11.0% in the control group resulted in spontaneous abortion; 24.2% and 20.0% resulted in elective abortion. Among 180 women with a first pregnancy conceived in the vaccination exposure window, 16.7% (HSV vaccine) and 9.5% (control) had a spontaneous abortion and 38.5% and 33.3%, elective abortion. The relative risk for spontaneous abortion associated with vaccine exposure during the risk period for abortion in the course of pregnancy was 1.7 (95% CI: 0.7-4.6). For all women receiving HSV vaccine, this relative risk was 1.3 (95% CI: 0.8-2.1). The corresponding relative risks for elective abortion were 1.2 (95% CI: 0.7-2.0) and 1.3 (95% CI: 0.9-1.8). There was no apparent relationship to dosing and no difference between groups in gestational age at the time of spontaneous or elective abortion. In conclusion there is no statistical evidence that the investigational HSV vaccine increased the risk of spontaneous or elective abortion. (copyright) 2013 Elsevier Ltd.

glycoprotein D (clinical trial, drug therapy), herpes simplex glycoprotein D vaccine (clinical trial, drug therapy), herpes simplex vaccine (clinical trial, drug therapy)

adjuvant, unclassified drug

genital herpes (drug therapy, drug therapy, prevention), pregnancy outcome, vaccination

article, clinical evaluation, confidence interval, controlled study, Herpes simplex virus, human, induced abortion, meta analysis, priority journal, prophylaxis, randomized controlled trial, risk assessment, risk factor, spontaneous abortion

Glaxo SmithKline

Microbiology: Bacteriology, Mycology, Parasitology and Virology (4), Obstetrics and Gynecology (10), Immunology, Serology and Transplantation (26), Drug Literature Index (37)

ClinicalTrials.gov (NCT00057330, NCT00224471, NCT00224484, NCT00697567, NCT00698490, NCT00698568, NCT00698893, NCT00699764)

http://dx.doi.org/10.1016/j.vaccine.2013.01.002

Copyright 2013 Elsevier B.V., All rights reserved.

Inhibition/activation in bipolar disorder: Validation of the Multidimensional Assessment of Thymic States scale (MAThyS)

Henry C., Luquiens A., Lancon C., Sapin H., Zins-Ritter M., Gerard S., Perrin E., Falissard B., Lukasiewicz M.

(Henry C., chantal.henry@inserm.fr) INSERM, U995, IMRB, Department of Genetics, AP-HP, Henri Mondor-Albert Chenevier Group, Psychiatry, Faculty of Medicine, Univ Paris 12, IFR10, Creteil, France. , (Luquiens A., amandineluquiens@yahoo.fr; Falissard B., falissard_b@wanadoo.fr; Lukasiewicz M., michael.lukasiewicz@gmail.com) AP-HP, Paul-Brousse Hospital, Department of Psychiatry and Addictology, Villejuif, France. , (Lancon C., christophe.lancon@mail.ap-hm.fr) Self-Perceived Health Assessment Research Unit, School of Medicine, La Timone University, Marseille 13005, France. , (Lancon C., christophe.lancon@mail.ap-hm.fr) Department of Psychiatry, Sainte-Marguerite University Hospital, Marseille, France. , (Sapin H., sapin_helene@lilly.com; Gerard S., gerardst@lilly.com; Perrin E., perrin_elena@lilly.com) Eli Lilly and Company, 24 Boulevard Vital Bouhot, 92200 Neuilly-Sur-Seine, France. , (Zins-Ritter M., psywords@wanadoo.fr) Private practice, Orvault, France. , (Falissard B., falissard_b@wanadoo.fr; Lukasiewicz M., michael.lukasiewicz@gmail.com) INSERM, U669, Univ Paris-Sud and Univ Paris Descartes, UMR-S0669, Paris, France.

S. Gerard, Eli Lilly and Company, 24 Boulevard Vital Bouhot, 92200, Neuilly-Sur-Seine, France. Email: gerardst@lilly.com

BMC Psychiatry (2013) 13 Article Number: 79. Date of Publication: 13 Mar 2013

1471-244X (electronic)

BioMed Central Ltd., Floor 6, 236 Gray's Inn Road, London, United Kingdom.

Background: One of the major issues in clinical practice is the accurate differential diagnosis between mixed states and depression, often leading to inappropriate prescriptions of antidepressants in mixed states, and as a consequence, increasing the risk of manic switch and suicide. In order to better define the spectrum of mixed states, it may be useful to develop a dimensional approach. In this context, the MAThyS (Multidimensional Assessment of Thymic States) scale was built to assess activation/inhibition levels in all bipolar mood episodes, and to determine whether a clinical description in terms of activation/inhibition can help better define bipolar states with which both manic and depressive symptoms are associated. The aim of this paper is the validation of the MAThyS scale in 141 bipolar patients in acute states (manic, hypomanic, mixed, or depressive). Methods: The validation of the MAThyS scale was the primary outcome of this 24-week, phase III, open-label, olanzapine single-arm clinical trial. Principal component, factorial analysis, and Cronbach's coefficient calculation (internal consistency) were performed. Concurrent validity (correlations with 17-item Hamilton Depression Rating Scale [HAMD-17], Hamilton Anxiety Rating Scale [HAMA], and Young Mania Rating Scale [YMRS]) and responsiveness to the clinical intervention were assessed (change in MAThyS scale and effect size) at 6 and 24 weeks. Results: Scree plot of eigenvalues identified a 2-dimension structure (" activation/inhibition level" and " emotional component" ). Psychometric properties were good: Cronbach's coefficient was >0.9. Concurrent validity was good with low correlation (-0.19) with the HAMA scale and a higher correlation at baseline with the YMRS (0.72) and HAMD-17(-0.43). As expected, the activation state was predominant in manic, hypomanic, and mixed states while inhibition was predominant in depressive states. MAThyS score improvement was observed (effect size: -0.3 at 6 and 24 weeks). Conclusions: The MAThyS demonstrated good psychometric properties. The MAThyS scale may help clinicians to better discriminate and follow bipolar episodes, especially the broad spectrum of mixed episodes.Trial registration: ClinicalTrials.gov registration identification number: NCT#002592722. (copyright) 2013 Henry et al; licensee BioMed Central Ltd.

fluoxetine plus olanzapine (clinical trial, drug therapy), lithium (clinical trial, drug combination, drug therapy), olanzapine (clinical trial, drug combination, drug therapy, oral drug administration), valproic acid (clinical trial, drug combination, drug therapy)

bipolar disorder (drug therapy, diagnosis, drug therapy), Multidimensional Assessment of Thymic States scale, psychologic assessment

adult, article, depression (drug therapy), effect size, factorial analysis, female, Hamilton Anxiety Scale, Hamilton scale, human, hypomania, major clinical study, male, mania, outcome assessment, phase 3 clinical trial, principal component analysis, psychometry, rating scale, validation process, Young Mania Rating Scale

lithium (7439-93-2), olanzapine (132539-06-1), valproic acid (1069-66-5, 99-66-1)

Psychiatry (32), Drug Literature Index (37)

ClinicalTrials.gov (NCT00259272)

http://dx.doi.org/10.1186/1471-244X-13-79

Copyright 2013 Elsevier B.V., All rights reserved.

Impact of genetic targets on cancer therapy in acute myelogenous leukemia

Shah M.V., Barochia A., Loughran T.P.

(Shah M.V., mshah@hmc.psu.edu) Department of Internal Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States. , (Barochia A., ABAROCHIA@hmc.psu.edu; Loughran T.P., tpl2@psu.edu) Division of Hematology and Oncology, Penn State Hershey Cancer Institute, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, United States.

T.P. Loughran, Division of Hematology and Oncology, Penn State Hershey Cancer Institute, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033, United States. Email: tpl2@psu.edu

El-Deiry W.S.

Advances in Experimental Medicine and Biology (2013) 779 (405-437). Date of Publication: 2013

0065-2598

9781461461753 (volume)

Springer New York, 233 Spring Street, New York, United States.

Acute myelogenous leukemia (AML) is characterized by uncontrolled proliferation of the cells of myeloid origin. It can present at all ages, but is more common in adults. It is one of the most common leukemias in adults and continues to pose significant challenge in diagnosis and long-term management. AML is a disease at the forefront of genetic and genomic approaches to medicine. It is a disease that has witnessed rapid advances in terms of diagnosis, classification, prognosis and ultimately individualized therapy. Newly diagnosed AML patients are now routinely stratified according to cytogenetics and molecular markers which guides long-term prognosis and treatment. On the other hand, with few exceptions, the initial treatment (also known as induction treatment) of AML has been 'one-size-fits-all'. It remains a great challenge for patients and physicians to consolidate and translate these advances into eventual success in clinic [1, 2]. (copyright) Springer Science+Business Media New York 2013.

alemtuzumab (clinical trial, drug therapy, pharmacology), antineoplastic agent (clinical trial, drug therapy, pharmacology), arsenic trioxide (drug comparison, drug therapy, pharmacology), bortezomib (clinical trial, drug therapy, pharmacology), cediranib (clinical trial, drug therapy, pharmacology), cytarabine (drug combination, drug comparison, drug dose, drug therapy, pharmacology), diphtheria toxin interleukin 3 fusion protein (clinical trial, drug therapy, pharmacology), etoposide (drug therapy, pharmacology), Flt3 ligand (clinical trial, drug therapy, pharmacology), gemtuzumab ozogamicin (clinical trial, drug comparison, drug therapy, pharmacology), gti 2040 (clinical trial, drug combination, drug therapy, pharmacology), idarubicin (drug therapy, pharmacology), lintuzumab (clinical trial, drug combination, drug comparison, drug therapy, pharmacology), lonafarnib (clinical trial, drug therapy, pharmacology), midostaurin (clinical trial, drug therapy, pharmacology), pazopanib (clinical trial, drug therapy, pharmacology), peptide vaccine (clinical trial, drug therapy), pixantrone (clinical trial, drug therapy, pharmacology), placebo, retinoic acid (drug comparison, drug therapy, pharmacology), semaxanib (clinical trial, drug therapy, pharmacology), tasisulam (clinical trial, drug therapy, pharmacology), tipifarnib (clinical trial, drug therapy, pharmacology), topotecan (drug therapy, pharmacology), unclassified drug, unindexed drug, valspodar (clinical trial, drug therapy, pharmacology), vasculotropin inhibitor (clinical trial, drug therapy, pharmacology), vorinostat (clinical trial, drug therapy, pharmacology), WT1 protein (clinical trial, drug therapy, pharmacology), zosuquidar (clinical trial, drug therapy, pharmacology)

acute granulocytic leukemia (drug therapy, diagnosis, drug therapy, etiology, therapy)

age distribution, anemia, article, bone marrow depression, cancer chemotherapy, cancer prognosis, cancer stem cell, cancer survival, clinical feature, consolidation chemotherapy, cytogenetics, drug dose comparison, drug megadose, drug targeting, drug tolerability, event free survival, gene expression, gene mutation, gene sequence, gene targeting, genetic marker, genetic risk, hematopoietic stem cell transplantation, human, induction chemotherapy, leukemogenesis, maintenance chemotherapy, myelodysplastic syndrome (diagnosis, etiology), neutropenia, nonhuman, overall survival, pharmacogenomics, priority journal, promyelocytic leukemia (etiology), recurrence free survival, thrombocytopenia

azd 2171, bbr 2778, gti 2040, ly 573636, psc 833, sgn 33

Flt3 ligand (171404-15-2), alemtuzumab (216503-57-0), arsenic trioxide (1303-24-8, 1327-53-3, 13464-58-9, 15502-74-6), bortezomib (179324-69-7, 197730-97-5), cediranib (288383-20-0, 857036-77-2), cytarabine (147-94-4, 69-74-9), etoposide (33419-42-0), idarubicin (57852-57-0, 58957-92-9), lintuzumab (166089-32-3), lonafarnib (193275-84-2), midostaurin (120685-11-2), pazopanib (444731-52-6, 635702-64-6), pixantrone (144510-96-3, 144675-97-8), retinoic acid (302-79-4), semaxanib (186610-95-7), tasisulam (519055-62-0), tipifarnib (192185-68-5, 192185-72-1), topotecan (119413-54-6, 123948-87-8), valspodar (121584-18-7), vorinostat (149647-78-9), zosuquidar (167354-41-8, 167465-36-3, 312905-17-2, 474276-97-6)

Cancer (16), Human Genetics (22), Hematology (25), Immunology, Serology and Transplantation (26), Clinical and Experimental Pharmacology (30), Drug Literature Index (37)

ClinicalTrials.gov (NCT00002800, NCT00003190, NCT00006045, NCT00006084, NCT00006223, NCT00006363, NCT00017982, NCT00038805, NCT00046930, NCT00085124, NCT00091234, NCT00093470, NCT00093990, NCT00096122, NCT00106600, NCT00109538, NCT00121303, NCT00179982, NCT00226512, NCT00283114, NCT00357032, NCT00397579, NCT00479232, NCT00486265, NCT00488592, NCT00509249, NCT00510133, NCT00528333, NCT00565058, NCT00601991, NCT00651261, NCT00656617, NCT00665126, NCT00672165, NCT00718159, NCT00860639, NCT00927498, NCT00997243, NCT01096602, NCT01266083, NCT01361334, NCT01371981, NCT01397799, NCT01486784, NCT01513109)

http://dx.doi.org/10.1007/978-1-4614-6176-0-19

Copyright 2013 Elsevier B.V., All rights reserved.

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase

Zimran A., Pastores G.M., Tylki-Szymanska A., Hughes D.A., Elstein D., Mardach R., Eng C., Smith L., Heisel-Kurth M., Charrow J., Harmatz P., Fernhoff P., Rhead W., Longo N., Giraldo P., Ruiz J.A., Zahrieh D., Crombez E., Grabowski G.A.

(Zimran A.; Elstein D.) Shaare Zedek Medical Center and Hebrew University-Hadassah Medical School, Jerusalem, Israel. , (Pastores G.M.) New York University School of Medicine, New York, NY, United States. , (Tylki-Szymanska A.) Children's Memorial Health Institute, Warsaw, Poland. , (Hughes D.A.) Royal Free Hospital, University College London School of Medicine, London, United Kingdom. , (Mardach R.) Kaiser Permanente, Los Angeles, CA, United States. , (Eng C.) Baylor College of Medicine, Houston, TX, United States. , (Smith L.) Children's Mercy Hospital, Kansas City, MO, United States. , (Heisel-Kurth M.) Children's Hospitals of Minnesota, Minneapolis, MN, United States. , (Charrow J.) Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States. , (Harmatz P.) Children's Hospital Oakland, Oakland, CA, United States. , (Fernhoff P.) Emory University, Decatur, GA, United States. , (Rhead W.) Children's Hospital of Wisconsin, Milwaukee, WI, United States. , (Longo N.) University of Utah, Salt Lake City, UT, United States. , (Giraldo P.) Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Hospital Universitario Miguel Servet, Zaragoza, Spain. , (Ruiz J.A.; Zahrieh D.; Crombez E.) Shire Human Genetic Therapies, Lexington, MA, United States. , (Grabowski G.A., greg.grabowski@cchmc.org) Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.

G.A. Grabowski, Division and Program in Human Genetics Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, United States. Email: greg.grabowski@cchmc.org

American Journal of Hematology (2013) 88:3 (172-178). Date of Publication: March 2013

0361-8609,1096-8652 (electronic)

Wiley-Liss Inc., 111 River Street, Hoboken, United States.

Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, (greater-than or equal to)2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a Grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa Phase 3 clinical trial program. (copyright) 2012 Wiley Periodicals, Inc.

imiglucerase (drug therapy), velaglucerase alfa (adverse drug reaction, clinical trial, drug therapy, intravenous drug administration)

diphenhydramine (drug combination, drug therapy), hemoglobin (endogenous compound), hydrocortisone (drug combination, drug therapy)

enzyme therapy, Gaucher disease (drug therapy, drug therapy, surgery)

adolescent, adult, aged, anaphylaxis (drug therapy, side effect), arthralgia (side effect), article, child, clinical article, disease severity, drug efficacy, drug hypersensitivity (drug therapy, side effect), drug induced headache (side effect), drug safety, drug tolerability, drug withdrawal, face edema (side effect), female, hemoglobin blood level, hospitalized child, human, immunogenicity, liver weight, male, multicenter study, open study, phase 2 clinical trial, phase 3 clinical trial, priority journal, rhinopharyngitis (side effect), school child, spleen weight, splenectomy, thrombocyte count, treatment duration, treatment outcome, urticaria (side effect)

vpriv (Shire, United States)

Shire (United States)

diphenhydramine (147-24-0, 58-73-1), hemoglobin (9008-02-0), hydrocortisone (50-23-7), imiglucerase (154248-97-2), velaglucerase alfa (884604-91-5)

Internal Medicine (6), Hematology (25), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00391625, NCT00460625, NCT00478647, NCT00553631)

http://dx.doi.org/10.1002/ajh.23383

Copyright 2013 Elsevier B.V., All rights reserved.

Side effects of standard adjuvant and neoadjuvant chemotherapy regimens according to age groups in primary breast cancer

Reinisch M., Von Minckwitz G., Harbeck N., Janni W., Kummel S., Kaufmann M., Elling D., Nekljudova V., Loibl S.

(Reinisch M.; Von Minckwitz G.; Nekljudova V.; Loibl S., Sibylle.Loibl@germanbreastgroup.de) German Breast Group, Martin-Behaim Strasse 12, 63263 Neu-Isenburg, Germany. , (Harbeck N.) Frauenklinik, Universitatsklinikum Munchen, Essen, Germany. , (Janni W.) Frauenklinik, Universitatsklinikum Ulm, Essen, Germany. , (Kummel S.) Frauenklinik, Klinikum Essen Mitte, Essen, Germany. , (Kaufmann M.) Frauenklinik, Universitatsklinikum Frankfurt/M., Klinikum Offenbach, Germany. , (Elling D.) Arbeitsgemeinschaft Gynakologische Onkologie, Frauenklinik Sana Klinikum Berlin-Lichtenberg, Klinikum Offenbach, Germany. , (Loibl S., Sibylle.Loibl@germanbreastgroup.de) Brustzentrum, Klinikum Offenbach, Germany.

S. Loibl, German Breast Group, Martin-Behaim Strasse 12, 63263 Neu-Isenburg, Germany. Email: Sibylle.Loibl@germanbreastgroup.de

Breast Care (2013) 8:1 (60-66). Date of Publication: March 2013

1661-3791,1661-3805 (electronic)

S. Karger AG, Allschwilerstrasse 10, P.O. Box, Basel, Switzerland.

Background: Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination. Patients and Methods: In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age. Results: Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60-64 years and 10.6% were > 64 years. The patients' compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/ cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin- cyclophosphamide (FE(120)C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE (120)C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE(120)C- than in TAC- and dd-doxorubicin/docetaxel-treated groups. Conclusion: The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE(120)C-treated patients. FE(120)C without G-CSFs is not an option in patients older than 64 years. (copyright) 2013 S. Karger AG, Basel.

cyclophosphamide (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, intravenous drug administration, oral drug administration), docetaxel (adverse drug reaction, clinical trial, drug combination, drug therapy, intravenous drug administration), doxorubicin (adverse drug reaction, clinical trial, drug combination, drug therapy, intravenous drug administration), epirubicin (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, intravenous drug administration), fluorouracil (adverse drug reaction, clinical trial, drug combination, drug dose, drug therapy, intravenous drug administration)

capecitabine (clinical trial, drug combination, drug therapy), ciprofloxacin (drug combination), paclitaxel (clinical trial, drug therapy), recombinant granulocyte colony stimulating factor (clinical trial, drug combination, drug therapy), vinorelbine ditartrate (clinical trial, drug combination, drug therapy)

adjuvant chemotherapy, breast cancer (drug therapy, drug therapy), cancer combination chemotherapy, primary tumor (drug therapy, drug therapy)

antibiotic therapy, article, clinical trial, diarrhea (side effect), drug dose reduction, feasibility study, febrile neutropenia (side effect), groups by age, human, kidney function, liver function, multiple cycle treatment, nausea (side effect), neuropathy (side effect), patient compliance, priority journal, side effect (side effect), stomatitis (side effect), vomiting (side effect)

capecitabine (154361-50-9), ciprofloxacin (85721-33-1), cyclophosphamide (50-18-0), docetaxel (114977-28-5), doxorubicin (23214-92-8, 25316-40-9), epirubicin (56390-09-1, 56420-45-2), fluorouracil (51-21-8), paclitaxel (33069-62-4), recombinant granulocyte colony stimulating factor (1117844-87-7, 1192706-53-8, 121181-53-1), vinorelbine ditartrate (125317-39-7)

Cancer (16), Drug Literature Index (37), Adverse Reactions Titles (38)

ClinicalTrials.gov (NCT00047099, NCT00643829, NCT00668616)

English, German

http://dx.doi.org/10.1159/000346834

Copyright 2013 Elsevier B.V., All rights reserved.