AbstractObjective:Mood disorders are often associated with poor glycemic control, and antidepressant treatments for mood and pain disorders can alter plasma glucose levels in patients with diabetes. A previous meta-analysis from three studies showed that duloxetine modestly increased fasting plasma glucose (FPG) and HbA1c levels in patients with diabetic peripheral neuropathic pain (DPNP). This meta-analysis examined whether there were any short- and long-term effects of duloxetine (20–120 mg/day) on glycemic control in patients with diagnoses other than DPNP.Research design and methods:Short-term data (9–27 weeks): seven studies of duloxetine in general anxiety disorder, fibromyalgia, and chronic lower back pain (CLBP). Long-term data: 41-week, uncontrolled extension of the short-term CLBP study and 52-week study in patients with recurrence of major depressive disorder.Main outcome measures:Baseline-to-endpoint changes in FPG and HbA1c levels.Results:In short-term studies, patients were randomly assigned to placebo (n = 1098) or duloxetine (n = 1563). Mean baseline-to-endpoint changes in FPG and HbA1c did not significantly differ in duloxetine-treated patients compared with placebo-treated patients. In the 41-week study (n = 181), duloxetine-treated patients experienced a small but significant within-group baseline-to-endpoint increase in HbA1c (mean change = 0.1%; p < 0.001). This result was in contrast to absence of effect on mean baseline-to-endpoint within-group changes in FPG (p = 0.326) in that study, and to absence of between-treatment changes in FPG (p = 0.744) and HbA1c (p = 0.180) in the 52-week placebo-controlled study.Conclusion:Duloxetine treatment did not significantly alter FPG and HbA1c levels compared with placebo treatment in the short-term studies. A small but statistically significant within-group increase in HbA1c was found in the 41-week study, but not in between-treatment group differences in the 52-week study. Neither of the long-term studies showed significant changes in the FPG levels. The small, non-reproducible HbA1c increase in one study of patients without DPNP may have resulted from patients with unrecognized diabetes in these trials.Key words: DiabetesDiabetic peripheral neuropathic painDuloxetineFasting plasma glucoseHbA1cSNRI TransparencyDeclaration of fundingFunding was provided by Eli Lilly and Company and Boehringer Ingelheim GmbH.Declaration of financial/other relationshipsAll authors except A.C, C.Y., and S.B. are employees of Eli Lilly and Company and are stock holders of the company. A.C. and C.Y. were employees of Eli Lilly when the manuscript was being written. S.B. is an employee of Boehringer Ingelheim GmbH, Germany. The peer reviewers may receive honoraria from CMRO for their review work. Peer reviewer 1 has disclosed that he/she is a recipient of sponsorship funding and research/grant funding from and is a consultant/advisor to Amgen, Alcon, Wyeth, Merck & Co. Inc., Ipsen, Pneuma Partners, Kinex, Endo, Sanofi-Pasteur, Nycomed, and Encysive.
Objective: The aim of this study was to assess the safety of subchronic fluoxetine treatment for major depressive disorder (MDD) in children and adolescents. Methods: Patients received up to 19 weeks of treatment with fluoxetine, 10 mg–60 mg daily. Safety was evaluated through the reporting of concomitant medications, vital signs, routine laboratory testing, electrocardiograms (ECGs), and adverse event data. Results: Ninety-six patients, aged 9–17 years, completed 19 weeks of treatment with fluoxetine (n = 49) or placebo (n = 47). There were statistically significant differences between the fluoxetine and placebo groups in mean change from baseline for alkaline phosphatase and total cholesterol levels (p < 0.001, and p < 0.014, respectively), but there were no statistically significant differences between the incidence of abnormal laboratory values for these 2 analytes. Fluoxetine-treated patients gained statistically significantly less height (fluoxetine: 1.0 cm ± 2.4; placebo: 2.1 cm ± 2.6; p = 0.004) and weight (fluoxetine: 1.2 kg ± 2.7; placebo: 2.3 kg ± 2.6; p = 0.008) than placebo-treated patients during the 19 weeks of treatment. There was no difference in the rate of reported suicide-related events between fluoxetine and placebo. Conclusion: Fluoxetine was found to be safe and well tolerated in this study of children and adolescents with MDD. Clarification and determination of the clinical significance of the growth-rate reduction seen during fluoxetine treatment requires further investigation. During treatment with fluoxetine, the growth of child and adolescent patients should be monitored.
In 2009, the Safety Planning, Evaluation, and Reporting Team (SPERT) (a team formed in 2006 by the Pharmaceutical Research and Manufacturers of America to recommend a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting) recommended that sponsors create a program safety analysis plan (PSAP) early in product development (Crowe et al., 2009). The PSAP is described as a living document (updated periodically and amended as needed in response to the emerging safety pro-le) that eventually forms the basis for the statistical analysis plan (SAP) for the Summary of Clinical Safety (SCS). The PSAP generally has two main sections: a standard data collection plan and an analytical section. It can be a stand-alone document or can be embedded in a different document.
Opioid treatment is associated with a wide range of gastrointestinal adverse effect collectively known as opioid-induced bowel dysfunction (OIBD). The most studied and prevalent symptom is constipation, occurring in up to 81% of patients. These adverse effects complicate effective pain management and furthermore, the current clinical gold standard for objective evaluation of constipation by abdominal x-ray exhibits poor inter-observer reliability and offers no quantifiable measure. The aims of the present study were 1) to develop a model for OIBD in healthy volunteers and 2) to establish whether a novel semi-automatic segmentation method to assess colon volume using Magnetic Resonance Imaging (MRI) was sensitive to changes in colonic volume brought on by treatment with oxycodone.
Method
25 healthy male subjects (mean age: 28 ± 9 years) were treated for five days with placebo or oxycodone 20 mg/day in a double-blind, cross-over design. Abdominal MRI scans were acquired at baseline and after 5 days of treatment in both treatment arms. Colonic volumes were determined for four separate colon segments (ascending, transverse, descending, and sigmoid+rectum). For each segment, volumes were compared using a two-way repeated measures ANOVA with factors treatment (oxycodone vs. placebo) and day (day 1 vs. day 5).
Results
Placebo treatment did not significantly alter volumes for any colon segments. Oxycodone treatment significantly increased the volume of the ascending colon (P < 0.01; day 1: 177 ± 72 mL vs. day 5: 250 ± 95 mL), the transverse colon (P < 0.05; day 1: 192 ± 80 mL vs. day 5: 221 ± 82 mL), and the total colon volume (P < 0.05; day 1: 760 ± 232 mL vs. day 5: 872 ± 220 mL).
Conclusion
An experimental model to assess OIBD in healthy volunteers has successfully been developed and may be used in future clinical and pharmacological studies to unravel the underlying pathophysiological mechanisms of OIBD or to assess efficacy of novel treatment strategies such as peripherally acting μ-opioid receptor antagonists (PAMORAs). Additionally, the present MRI-based method for objective assessment of colon volume is sensitive to changes in colon volumes brought on by treatment with oxycodone. Hence, it may be applied in other diseases or syndromes where information on colonic volume, content and morphology is valuable including conditions such as multiple sclerosis and irritable bowel syndrome.
Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi-automatic magnetic resonance imaging-based technique, the aims of this study were to describe: (i) inter-individual and intra-individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation.The inter-individual and intra-individual variability of four colorectal volumes (cecum/ascending colon, transverse, descending, and rectosigmoid colon) between two observations (separated by 52 ± 10) days was assessed in 25 healthy males and the effect of defecation on segmental colorectal volumes was studied in another seven healthy males.No significant differences between the two observations were detected for any segments (All p > 0.05). Inter-individual variability varied across segments from low correlation in cecum/ascending colon (intra-class correlation coefficient [ICC] = 0.44) to moderate correlation in the descending colon (ICC = 0.61) and high correlation in the transverse (ICC = 0.78), rectosigmoid (ICC = 0.82), and total volume (ICC = 0.85). Overall intra-individual variability was low (coefficient of variance = 9%). After defecation the volume of the rectosigmoid decreased by 44% (p = 0.003). The change in rectosigmoid volume was associated with the true fecal volume (p = 0.02).Imaging of segmental colorectal volume, morphology, and fecal accumulation is advantageous to conventional methods in its low variability, high spatial resolution, and its absence of contrast-enhancing agents and irradiation. Hence, the method is suitable for future clinical and interventional studies and for characterization of defecation physiology.
The PhUSE Computational Science Symposium (CSS) Development of Standard Scripts for Analysis and Reporting Working Group is providing recommendations for analyses, tables, and figures for data that is common across therapeutic areas (laboratory measurements, vital signs, electrocardiograms, adverse events, demographics, medications, disposition, hepatotoxicity, pharmacokinetics). This paper provides an update of this effort, and instructions for how to participate in the development and review process.
