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Girman C.J.,Merck And Co. | Kou T.D.,Merck And Co. | Cai B.,Merck And Co. | Alexander C.M.,Global Medical Affairs | And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2010

Aim: The aetiology of acute pancreatitis (AP) is complex, and many risk factors for AP are shared by patients with type 2 diabetes mellitus (T2DM). However, few have assessed risk factors for AP specifically in T2DM patients.Methods: Patients in the General Practice Research Database (2 984 755, 5.0% with T2DM) were used to estimate incidence of AP for T2DM relative to non-diabetes, adjusting for prior pancreatitis, gallbladder disease, obesity, smoking and alcohol use. Multivariate Cox regression analysis adjusting for risk factors and Charlson comorbidity index (CCI) was used to estimate hazard ratios (HR) with 95% confidence intervals (CI).Results: Between 2003 and 2007, 301 of 148 903 patients with T2DM and 2434 of almost 3 million patients without diabetes developed AP. Patients with T2DM had higher risk for AP compared with patients without diabetes (crude HR: 2.89, 95% CI: 2.56-3.27). Patients with T2DM had significantly higher rates of prior alcohol and tobacco exposure (44.2 and 61.9% vs. 34.1 and 35.9%, p < 0.001) and of comorbid conditions (14.7% with CCI ≥1 vs. 4.3%, p < 0.001). Histories of obesity, pancreatitis, gallbladder disease, smoking or alcohol use were significant predictors of AP. After adjusting for these factors, age, gender and comorbidities, the risk of developing AP remained elevated in patients with T2DM (adjusted HR: 1.49, 95% CI: 1.31-1.70).Conclusion: After adjusting for risk factors, patients with T2DM had an elevated risk of AP compared with patients without diabetes. Physicians should be aware of the increased risk in patients with T2DM, particularly in those with prior pancreatitis. © 2010 Blackwell Publishing Ltd.

Vandenbossche J.,Johnson and Johnson Pharmaceutical Research and Development | Richarz U.,Global Medical Affairs | Richards H.M.,Johnson and Johnson Pharmaceutical Research and Development
Journal of Pain Research | Year: 2012

Objective: To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications. Methods: This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3-14 days and stabilized between 8-48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration-time curve from 0-24 hours (AUC0-24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax - Cmin) ÷ Cavg]) were calculated based on data from 14 patients. Results: Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0-24, 41.1 ng {dot operator} h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2-21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred. Conclusion: These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications. © 2012 Vandenbossche et al, publisher and licensee Dove Medical Press Ltd.

Sugino H.,Otsuka Pharmaceutical Development and Commercialization Inc. | Watanabe A.,Otsuka Pharmaceutical Co. | Amada N.,Otsuka Pharmaceutical Co. | Yamamoto M.,Otsuka Pharmaceutical Co. | And 3 more authors.
Clinical Therapeutics | Year: 2015

Purpose Alzheimer disease (AD) is a growing global health and economic issue as elderly populations increase dramatically across the world. Despite the many clinical trials conducted, currently no approved disease-modifying treatment exists. In this commentary, the present status of AD drug development and the grounds for collaborations between government, academia, and industry to accelerate the development of disease-modifying AD therapies are discussed. Methods Official government documents, literature, and news releases were surveyed by MEDLINE and website research. Findings Currently approved anti-AD drugs provide only short-lived symptomatic improvements, which have no effect on the underlying pathogenic mechanisms or progression of the disease. The failure to approve a disease-modifying drug for AD may be because the progression of AD in the patient populations enrolled in clinical studies was too advanced for drugs to demonstrate cognitive and functional improvements. The US Food and Drug Administration and the European Medicines Agency recently published draft guidance for industry which discusses approaches for conducting clinical studies with patients in early AD stages. For successful clinical trials in early-stage AD, however, it will be necessary to identify biomarkers highly correlated with the clinical onset and the longitudinal progress of AD. In addition, because of the high cost and length of clinical AD studies, support in the form of global initiatives and collaborations between government, industry, and academia is needed. Implications In response to this situation, national guidance and international collaborations have been established. Global initiatives are focusing on 2025 as a goal to provide new treatment options, and early signs of success in biomarker and drug development are already emerging. © 2015 Elsevier HS Journals, Inc. All rights reserved.

Goldfarb D.S.,New York University | MacDonald P.A.,Global Medical Affairs | Gunawardhana L.,Clinical science | Chefo S.,Takeda Global Research and Development Center Inc. | McLean L.,Takeda California
Clinical Journal of the American Society of Nephrology | Year: 2013

Background and objectives Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. Design, setting, participants, & measurements In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. Results Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. Conclusions Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period. © 2013 by the American Society of Nephrology.

Chrystyn H.,Inhalation Consultancy Ltd | Safioti G.,Medical Affairs | Keegstra J.R.,Global Respiratory R and D | Gopalan G.,Global Medical Affairs
International Journal of Pharmaceutics | Year: 2015

Abstract Successful delivery of inhalation medication to the lungs can be affected by the inhalation manoeuvre used. Conventional in-vitro testing of the emitted dose from a dry powder inhaler (DPI) uses a vacuum pump to simulate an inhalation. We have adapted this method by replacing the pump with patient inhalation profiles and an anatomical throat. Three anatomical throat sizes and three inhalation profiles were used. The profiles represented the 10th, 50th and 90th percentiles of peak inhalation flow and acceleration of flow from a population of 50 COPD patients inhaling through empty Spiromax and Turbuhaler devices. Combining the dose emission results for the three throat sizes, the mean (SD) budesonide fine-particle dose (FPD) from budesonide-formoterol Spiromax 320/9 μg was 78.91 (20.18), 79.91 (15.36) and 75.10 (19.91) μg and the total emitted dose (TED) of budesonide was 263.69 (40.74), 261.20 (21.65) and 261.61 (45.65) μg. Similarly, the FPD from 320/9 μg Turbuhaler was 22.45 (3.24), 52.20 (12.57) and 69.11 (75.10) μg with a TED of 143.80 (14.90), 149.50 (26.61) and 158.61 (43.04) μg. Spiromax showed greater consistency than Turbuhaler over a range of inspiratory flow profiles. The results demonstrate the value of this new method to assess the doses that patients receive during real-life use of their DPI. © 2015 Z. Published by Elsevier B.V.

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