10-mg Group Research Articles

The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease

We investigated the effects of the fatty acid-bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD). We performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function. No serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis. Three months' administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.

1034 Measures of Obesity and Risk of Gastric and Duodenal Ulcers

G A A b st ra ct s the recurrence of LDA-related peptic ulcers has not been reported. We conducted a randomized, double-blind, double-dummy, active-controlled trial to assess the efficacy, doseresponse relationship and safety of rabeprazole for peptic ulcer recurrence in Japanese patients in long-term LDA therapy. Methods: Patients were eligible for the trial if they had an endoscopically confirmed gastric or duodenal ulcer scars and were receiving long-term LDA (81 mg/day or 100 mg/day) therapy for cardiovascular and cerebrovascular protection. Patients on long-term LDA therapy were also eligible if they had a previous history of endoscopically confirmed active peptic ulcers, but did not present them at baseline endoscopy. Patients were randomly segregated into three groups receiving rabeprazole 10 mg once daily (standard dose in Japan), rabeprazole 5 mg once daily or teprenone (mucosal protective agent commercially available in Japan) 50 mg three times per day as an active control. The primary endpoint was recurrence of gastric and duodenal ulcers over 24 weeks. Secondary endpoints included an occurrence of bleeding ulcers with stigmata of recent hemorrhage or drop in hemoglobin level of more than 2 g/dl, changes from baseline in the modified Lanza score (endoscopic scoring system for gastroduodenal damage) or upper gastrointestinal symptom score, and newly-developed erosive esophagitis. Results: Among 472 randomized patients, 452 patients (rabeprazole 10 mg, n=151; rabeprazole 5 mg, n= 150; teprenone 150 mg, n=151) constituted the full analysis set. The cumulative recurrence rates of gastric and duodenal ulcers over 24 weeks in the 5and 10-mg rabeprazole groups were 2.8% and 1.4%, respectively, and both were significantly lower than that in the teprenone group (21.7%). The cumulative occurrence rate of bleeding ulcers over 24 weeks in the teprenone group was 6.1%, while bleeding ulcers were not observed in the 5or 10-mg rabeprazole groups. The rates of worsening in the modified Lanza and upper gastrointestinal symptom scores in the 5and 10-mg rabeprazole groups were significantly lower than those in the teprenone group. Significantly fewer patients developed erosive esophagitis in the 5 mg rabeprazole group (2%) and 10 mg rabeprazole group (0%), compared with the teprenone group (8.6%). Rabeprazole was well-tolerated at both doses. Conclusions: Rabeprazole prevents the recurrence of gastroduodenal ulcers with no evidence of a major dose response effect in patients taking LDA, and is well-tolerated.

1033 Underestimation of Small Bowel Bleeding in Users of Nonselective Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Low-Dose Aspirin (ASA): A Prospective Study

G A A b st ra ct s the recurrence of LDA-related peptic ulcers has not been reported. We conducted a randomized, double-blind, double-dummy, active-controlled trial to assess the efficacy, doseresponse relationship and safety of rabeprazole for peptic ulcer recurrence in Japanese patients in long-term LDA therapy. Methods: Patients were eligible for the trial if they had an endoscopically confirmed gastric or duodenal ulcer scars and were receiving long-term LDA (81 mg/day or 100 mg/day) therapy for cardiovascular and cerebrovascular protection. Patients on long-term LDA therapy were also eligible if they had a previous history of endoscopically confirmed active peptic ulcers, but did not present them at baseline endoscopy. Patients were randomly segregated into three groups receiving rabeprazole 10 mg once daily (standard dose in Japan), rabeprazole 5 mg once daily or teprenone (mucosal protective agent commercially available in Japan) 50 mg three times per day as an active control. The primary endpoint was recurrence of gastric and duodenal ulcers over 24 weeks. Secondary endpoints included an occurrence of bleeding ulcers with stigmata of recent hemorrhage or drop in hemoglobin level of more than 2 g/dl, changes from baseline in the modified Lanza score (endoscopic scoring system for gastroduodenal damage) or upper gastrointestinal symptom score, and newly-developed erosive esophagitis. Results: Among 472 randomized patients, 452 patients (rabeprazole 10 mg, n=151; rabeprazole 5 mg, n= 150; teprenone 150 mg, n=151) constituted the full analysis set. The cumulative recurrence rates of gastric and duodenal ulcers over 24 weeks in the 5and 10-mg rabeprazole groups were 2.8% and 1.4%, respectively, and both were significantly lower than that in the teprenone group (21.7%). The cumulative occurrence rate of bleeding ulcers over 24 weeks in the teprenone group was 6.1%, while bleeding ulcers were not observed in the 5or 10-mg rabeprazole groups. The rates of worsening in the modified Lanza and upper gastrointestinal symptom scores in the 5and 10-mg rabeprazole groups were significantly lower than those in the teprenone group. Significantly fewer patients developed erosive esophagitis in the 5 mg rabeprazole group (2%) and 10 mg rabeprazole group (0%), compared with the teprenone group (8.6%). Rabeprazole was well-tolerated at both doses. Conclusions: Rabeprazole prevents the recurrence of gastroduodenal ulcers with no evidence of a major dose response effect in patients taking LDA, and is well-tolerated.

Testosterone Dose-Response Relationships With Cardiovascular Risk Markers in Androgen-Deficient Women: A Randomized, Placebo-Controlled Trial

To determine dose-dependent effects of T administration on cardiovascular risk markers in women with low T levels. Seventy-one hysterectomized women with or without oophorectomy with total T < 31 ng/dL and/or free T < 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly im injections of placebo or 3-, 6.25-, 12.5-, or 25-mg T enanthate for 24 weeks. Total and free T levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. Insulin resistance and inflammatory markers were measured at baseline and 24 weeks. In a subset of women, magnetic resonance imaging of the abdomen was performed to quantify abdominal fat volume. Fifty-nine women who completed the 24-week intervention were included in the final analysis. The five groups were similar at baseline. Mean on-treatment nadir total T concentrations were 14, 79, 105, 130, and 232 ng/dL in the placebo group and the 3-, 6.25-, 12.5-, and 25-mg groups, respectively. No significant changes in fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, adiponectin, blood pressure, and heart rate were observed at any T dose when compared to placebo. Similarly, no dose- or concentration-dependent changes were observed in abdominal fat on magnetic resonance imaging. Short-term T administration over a wide range of doses for 24 weeks in women with low T levels was not associated with worsening of cardiovascular risk markers.

Efficacy, Safety, Tolerability, and Pharmacokinetic Profile of Evacetrapib Administered as Monotherapy or in Combination With Atorvastatin in Japanese Patients With Dyslipidemia

The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.

Maintenance of Efficacy and Safety of Rabeprazole in Children With Endoscopically Proven GERD

The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing ≥ 15 kg (high-weight cohort) received 10 or 20 mg. Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment-emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.

Effect of Change in Body Weight on Incident Diabetes Mellitus in Patients With Stable Coronary Artery Disease Treated With Atorvastatin (from the Treating to New Targets Study)

Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p <0.01 in both men and women) over 1 year after randomization. The increase in body weight was greater in patients with NODM than those without NODM (1.6 vs 0.9 kg, p <0.001). The association of change in body weight with NODM risk remained significant after adjusting for confounding factors (hazard ratios 1.33, 1.42, and 1.88 for quartiles 2, 3, and 4 compared with quartile 1, respectively). Similar results were obtained in patients with normal fasting glucose level. In conclusion, 1-year change in body weight is predictive of NODM in patients who underwent statin therapy from the TNT trial. Our study highlights the importance of weight control as a lifestyle measure to prevent statin-related NODM.

Effect of Darapladib Treatment on Endarterectomy Carotid Plaque Lipoprotein-Associated Phospholipase A2 Activity: A Randomized, Controlled Trial

BackgroundThe aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.MethodsPatients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.ResultsDarapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.ConclusionsShort-term treatment (14±4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.Trial Registration InformationName of Registry 1: ClinicalTrials.govRegistry Number 1: NCT01916720Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720 Name of Registry 2: GSK Clinical Study RegisterRegistry Number 2∶480848/010Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F

Long-term safety and efficacy of tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open-label, randomized controlled trials

Objective: To evaluate long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents, we conducted 52-week, open-label, randomized controlled trials.Research design and methods: The single-agent trial included patients with inadequate glycemic control on diet and exercise, whereas the add-on trial included those uncontrolled with any of the oral antidiabetic agents. In both trials, patients were randomly assigned to receive tofogliflozin 20 or 40 mg once daily orally for 52 weeks.Main outcome measures: Safety assessments.Results: A total of 194 patients (65, 20-mg group; 129, 40-mg group) were enrolled into the single-agent trial, whereas 602 (178 and 424, respectively) were enrolled into the add-on trial. Tofogliflozin was well tolerated for 52 weeks in both trials with < 6% of treatment discontinuation because of adverse events in each treatment group. It also reduced hemoglobin A1c. In the single-agent trial, mean reductions at 52 weeks were 0.67 and 0.66% in the 20- and 40-mg groups, respectively. In the add-on trial, mean reductions ranged from 0.71 to 0.93% across the subgroups by dose and background therapy.Conclusion: Tofogliflozin was well tolerated and showed sustained efficacy in both trials.

Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers.

The treatment of obesity is an increasing global health priority, yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. The aim of this study was to examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. Using a between-subjects, double-blind, placebo-controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15- or 30-mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate, and the participants completed the P1vital® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. mCPP reduced appetite and, in women, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs.

Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials.

Background/AimsThe aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA).MethodsA systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches.ResultsFive RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies.ConclusionsTofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.

Methylprednisolone Injections for the Carpal Tunnel Syndrome

LettersDecember 17, 2013Methylprednisolone Injections for the Carpal Tunnel SyndromeJosé Luis Andreu, MD, PhD and Domingo Ly-Pen, MD, PhDJosé Luis Andreu, MD, PhDFrom Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.Search for more papers by this author and Domingo Ly-Pen, MD, PhDFrom Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-159-12-201312170-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read Atroshi and colleagues’ article (1) with great interest. This placebo-controlled trial shows that injections in CTS are useful and safe, at least in the short term. Symptoms of CTS in patients who received corticosteroid injections improved significantly more than those in patients who received placebo, and corticosteroid recipients had no relevant adverse effects.We were surprised at how frequently surgery was required at 1-year follow-up, with 73% of the 80-mg methylprednisolone group versus 92% of the placebo group needing wrist surgery. In our study comparing corticosteroid injections with surgery (2), only 15% of participants who ...

A randomised, double-blind, placebo-controlled, duloxetine-referenced study of the efficacy and tolerability of vortioxetine in the acute treatment of adults with generalised anxiety disorder

This study aims to evaluate the efficacy and tolerability of vortioxetine 2.5-, 5- and 10-mg once-daily doses vs. placebo in the treatment of generalised anxiety disorder (GAD). In this 8-week, multicentre, double-blind, placebo-controlled, parallel-group, phase 3 study, patients with a primary GAD diagnosis were randomised to receive placebo (n = 157), vortioxetine 2.5 mg, vortioxetine 5 mg, vortioxetine 10 mg or duloxetine 60 mg once daily (n = 156 each). The primary end-point, mean change from baseline in Hamilton Anxiety Scale (HAM-A) total score and key secondary end-points for the 5- and 10-mg vortioxetine doses were analysed in a prespecified sequential testing procedure (all at week 8). Sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale. Differences from placebo in the primary efficacy end-point were not statistically significant for the vortioxetine groups. The mean difference from placebo was significant in the duloxetine arm. For all secondary efficacy end-points, results were similar among the vortioxetine groups and did not reach statistical significance. The vortioxetine 10-mg group showed separation from placebo on the Hospital Anxiety and Depression anxiety subscore (nominal p = 0.036). Duloxetine 60 mg significantly improved the primary end-point (p < 0.05 vs. placebo), validating the study. Nausea, dry mouth, diarrhoea, nasopharyngitis, headache, dizziness, somnolence, vomiting, dyspepsia, constipation and fatigue were reported in ≥ 5% of patients receiving vortioxetine. Rates of treatment-emergent sexual dysfunction (TESD) in the vortioxetine dosing groups were similar to placebo. In this study, vortioxetine 2.5-, 5- and 10-mg once-daily doses showed no significant improvement in HAM-A total scores vs. placebo. Vortioxetine was well tolerated at all doses and was not associated with TESD.

An improved dosage regimen of sertraline hydrochloride in the treatment for premature ejaculation: an 8-week, single-blind, randomized controlled study followed by a 4-week, open-label extension study

This study aimed at evaluating the safety and efficacy of an improved dosage regimen of sertraline in patients with premature ejaculation (PE) and to examine whether the premature ejaculation diagnostic tool (PEDT) can be used as a measure of treatment response in these patients. A total of 218 PE patients were randomized into control (n=61) and treatment (n=157) groups to receive mycelium of cordyceps sinensis C4 and sertraline 50mg daily for 8weeks, respectively. Following this blinded stage, sixty-three patients chose to take sertraline 100mg daily for an additional 4-week period, and 80 other patients continued treatment with sertraline 50mg. Main outcome measures include intravaginal ejaculatory latency time (IELT), PEDT score and Clinical Global Impression of Change (CGIC) score. At weeks 4 and 8, mean IELT of patients who subsequently chose to take 100mg of sertraline was significantly lower than that of patients who continued taking 50mg of sertraline, although the IELT value was comparable between the two groups of patients at baseline. However, with an additional 4-week treatment, the mean IELT increased significantly more in the 100-mg group than in the 50-mg continuation group. Similar results were also obtained in the analyses of the PEDT and CGIC scores. Both regimens were well tolerated, and relapse rate did not differ significantly between the two groups. These findings suggest that PE patients not responding to an 8-week treatment with sertraline 50mg can benefit from an additional 4-week treatment with sertraline 100mg and that the PEDT may be a valid measure of treatment response in PE patients.

Macitentan: Endothelin receptor antagonist

Macitentan: Endothelin receptor antagonist

Pharmacokinetic and Safety Profile of Ivabradine in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Increasing Single- and Multiple-Dose Study

BackgroundIvabradine is a pure heart rate–lowering agent that acts by inhibiting I(f), an important ionic current involved in pacemaker activity in the cells of the sinoatrial node. In the 2012 European Society of Cardiology Guidelines on Heart Failure, it was recommended that patients with a persistently high heart rate, despite treatment with an evidence-based dose of a β-blocker, should be considered for treatment with ivabradine. ObjectiveThe aim of this study was to explore the pharmacokinetic/pharmacodynamic properties and safety profile of ivabradine in healthy Chinese men. MethodsThis Phase I, randomized, open-label, parallel-arm, single- and multiple-dose study was conducted at the Clinical Pharmacology Center of the Cardiovascular Institute and Fu Wai Hospital at the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People’s Republic of China. Healthy, nonsmoking volunteers were randomly assigned to 1 of 3 treatment groups based on treatment with 5, 10 or 20 mg of ivabradine. After a single dose, the subjects assigned to the 3 dose groups received repeated oral doses of ivabradine BID for 6 days. The plasma concentrations of ivabradine were determined by using a HPLC-MS/MS method. Systolic and diastolic blood pressure and heart rate measurements were taken, and ECG and Holter monitoring was performed. Tolerability was assessed throughout the study by physical and ophthalmologic examinations, vital signs measurement, laboratory analyses, and monitoring of adverse effects. ResultsA total of 36 healthy Chinese men were enrolled in the study. After the single dose, plasma ivabradine Cmax and AUC increased approximately linearly with dosage, no statistically significant differences were found in t½ or Tmax between the dose groups. After multiple doses, there was no significant change in Tmax compared with the results after a single dose. After repeated doses, t½, Cmax, and AUC increased significantly (P < 0.001). After a single dose, a significant reduction in heart rate at 2 hours’ postdose was observed in the highest dose group, whereas after repeated doses, a significant reduction in heart rate was observed from 2 to 4 hours’ postdose for all 3 groups. The mean (SD) heart rate after repeated doses decreased 12.5 (4.8), 12.4 (6.9), and 20.5 (5.8) beats/min for the 5-, 10-, and 20-mg dose groups, respectively. No clear trend in the changes in QTc, systolic and diastolic blood pressures, or respiration rate was observed. Ivabradine was well tolerated in these healthy Chinese men. ConclusionsThe results of the study in a small population of healthy Chinese men suggest that the PK properties of ivabradine are linear with respect to dosing. After single and repeated oral administration of ivabradine, a significant decrease in heart rate was observed. Ivabradine appeared well tolerated in the population studied. Trial identifier: ACTRN1261300027741.

The efficacy and safety of bazedoxifene in postmenopausal women by baseline kidney function status

Introduction Two global, double-blind, placebo- and active-controlled, phase-3 studies (2-year prevention (n = 1583) and 3-year treatment (n = 7492)) have shown that bazedoxifene (BZA) is safe and effective for prevention and treatment of postmenopausal osteoporosis.Objective To evaluate the efficacy/safety of BZA according to baseline kidney function.Methods Data for the BZA 20- and 40-mg and placebo groups from both studies were integrated for assessment of bone turnover markers (BTMs), bone mineral density (BMD), and fracture incidence (treatment study only). Safety was assessed using integrated data for the BZA, placebo, and raloxifene 60-mg groups from both studies. Baseline glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease Study equation; among subjects with baseline GFR, renal function categories were defined by GFR (ml/min per 1.73 m2): normal (GFR ≥ 90; n = 1982), mild impairment (60 ≤ GFR < 90; n = 6032), or moderate/severe impairment (GFR < 60; n = 723).Results Demographics were similar across treatment groups and within GFR subgroups. Across GFR subgroups, BZA 20 and 40 mg reduced BTM levels and improved lumbar spine and total hip BMD versus placebo. At month 24, there were significant treatment-by-GFR (p = 0.003) and treatment-by-serum creatinine (p = 0.034) interactions for the increase in lumbar spine BMD versus placebo. Fracture incidence was lower with BZA than placebo across all GFR categories, with no treatment-by-GFR interaction. There were no significant differences among treatment groups in incidences of overall, serious, or renal-related adverse events across GFR subgroups.Conclusions Mild to moderate kidney impairment did not affect the efficacy and safety of BZA in postmenopausal women.

Methylprednisolone Injections for the Carpal Tunnel Syndrome

Steroid injections are used in idiopathic carpal tunnel syndrome (CTS), but evidence of efficacy beyond 1 month is lacking. To assess the efficacy of local methylprednisolone injections in CTS. Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT00806871). Regional referral orthopedic department in Sweden. Patients aged 18 to 70 years with CTS but no previous steroid injections. Three groups (37 patients each) received 80 mg of methylprednisolone, 40 mg of methylprednisolone, or placebo. The patients and treating surgeons were blinded. Primary end points were the change in CTS symptom severity scores at 10 weeks (range, 1 to 5) and rate of surgery at 1 year. Three patients had missing 10-week data. All patients had 1-year data. Improvement in CTS symptom severity scores at 10 weeks was greater in patients who received 80 mg of methylprednisolone and 40 mg of methylprednisolone than in those who received placebo (difference in change from baseline, -0.64 [95% CI, -1.06 to -0.21; P = 0.003] and -0.88 [CI, -1.30 to -0.46; P < 0.001], respectively), but there were no significant differences at 1 year. The 1-year rates of surgery were 73%, 81%, and 92% in the 80-mg methylprednisolone, 40-mg methylprednisolone, and placebo groups, respectively. Compared with patients who received placebo, those who received 80 mg of methylprednisolone were less likely to have surgery (odds ratio, 0.24 [CI, 0.06 to 0.95]; P = 0.042). With time to surgery incorporated, both the 80- and 40-mg methylprednisolone groups had lower likelihood of surgery (hazard ratio, 0.46 [CI, 0.27 to 0.77; P = 0.003] and 0.57 [CI, 0.35 to 0.94; P = 0.026], respectively). The study was conducted at 1 center, and wrist splinting had previously failed for all patients. Methylprednisolone injections for CTS have significant benefits in relieving symptoms at 10 weeks and reducing the rate of surgery 1 year after treatment, but 3 out of 4 patients had surgery within 1 year. Region of Scania Research and Development Foundation and Hässleholm Hospital Organization.

Study Finds Anti-NGF Factor Effective for Hip Arthritis

Treatment with the anti–nerve growth factor (NGF) tanezumab was associated with significant improvements over placebo in pain, physical function, and Patient's Global Assessment of osteoarthritis (OA) results, after 16 weeks in a phase III study of patients with OA of the hip. In the randomized, double-blind, placebo-controlled study of 621 patients with painful hip OA, treatment with tanezumab (an “anti-NGF”) was also well tolerated, according to Dr. Mark Brown and his associates. The study was funded by Pfizer, the manufacturer of tanezumab, and Dr. Brown and three of the five other authors are full-time employees of the company. Tanezumab “may eventually be useful in OA patients who are intolerant of or nonresponsive to nonopioid treatment,” the authors concluded. The study was published in Arthritis & Rheumatism (Arthritis Rheum. 2013;65[7];1795-1803). Anti-NGFs are monoclonal antibodies directed against nerve growth factor, which is associated with injury, inflammation, and chronic pain, according to the authors. Tanezumab is one of several anti-NGFs being studied for OA and other chronic pain conditions and is the furthest along in development. In 2010, the Food and Drug Administration (FDA) placed a partial hold on anti-NGF clinical trials after cases of osteonecrosis and avascular necrosis were reported in patients treated with tanezumab and in those treated with another anti-NGF. After an FDA advisory panel said that the anti-NGFs showed promise as analgesics, the clinical hold on tanezumab trials was lifted in August 2012, Dr. Brown's team noted. The development of the anti-NGFs “is an exciting potential addition to our present inadequate control of pain,” and research is resuming with a careful review of the risk of bone and joint changes, Dr. Roy Altman said in an interview. In his view, “the known risks would be acceptable to many people with poorly controlled pain.” Dr. Altman, professor of medicine, rheumatology, at the University of California, Los Angeles, was not an investigator in the study. The Pfizer study compared three tanezumab doses (2.5 mg, 5 mg, and 10 mg) administered intravenously at baseline, 8 weeks, and 16 weeks, with placebo, in 621 people with OA of the hip (mean age, 62-63 years) who could not or did not want to take nonopiate pain medications, did not get enough relief from these medications, or were candidates for hip surgery or other invasive treatments. Almost half were candidates for invasive treatment. At 16 weeks, tanezumab, at all three doses, “produced greater, clinically meaningful, and statistically significant improvements,” compared with placebo, in pain, physical function, and patient assessment of OA. Differences between placebo and treatment were greatest for the two higher doses. About two-thirds of the patients on treatment remained in the study through week 24 (considered the end of the study because of tanezumab's long half-life), compared with 38% of those on placebo. Overall, more patients on tanezumab reported adverse effects (55%-58% vs. 44% on placebo). Serious adverse events occurred in 3%-4.5% of patients in the treatment groups. The rate of total hip replacement was similar in the treatment and placebo groups, with a total of eight patients who had the operation (three in the placebo group, two each in the 2.5-mg and 5-mg groups, and one in the 10-mg group). These included two patients on tanezumab who had osteonecrosis thought to be related to tanezumab. The authors pointed out that an outside adjudication committee, however, did not confirm osteonecrosis in either of these patients and concluded that the reasons for joint replacements in the eight patients were inflammatory arthropathy, end-stage OA, rapidly progressive OA, or worsening OA. Dr. Altman said that he has consulted with Abbott and its now discontinued program on anti-NGF drugs.

Pharmacokinetics and Safety of Golimumab in Healthy Chinese Subjects Following a Single Subcutaneous Administration in a Randomized Phase I Trial

Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C(max)), time to reach C(max) (t(max)), area under the serum concentration-time curve from time zero to infinity (AUC∞), and terminal half-life (t(½))] of golimumab were derived using a noncompartmental analysis. Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C(max) (3.6 ± 1.6 and 7.5 ± 1.4 μg/mL, respectively) and AUC∞ (59.8 ± 19.8 and 132.8 ± 27.0 μg·day/mL, respectively) increased in a dose-proportional manner. The median t(max) was in the range of 4.5-5.0 days, and the mean t(½) was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects.