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Barchuk W.T.,Immunology Translational Medicine Development | Salapatek A.M.,McMaster University | Ge T.,Immunology Translational Medicine Development | D'Angelo P.,Cetero Research | Liu X.,Immunology Translational Medicine Development
Journal of Allergy and Clinical Immunology | Year: 2013

Background: H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion. Objective: This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model. Methods: In this single-dose, patient-blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period. Results: Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, -0.126; P =.06) and pseudoephedrine (least square mean difference, -0.195; P =.004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P =.0003) and pseudoephedrine (P =.04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P ≤.05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment. Conclusion: Prophylactic treatment with the H 3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures. © 2013 American Academy of Allergy, Asthma and Immunology.

Lehman P.A.,PRACS Institute | Franz T.J.,PRACS Institute | Franz T.J.,Cetero Research
Skin Pharmacology and Physiology | Year: 2012

Purpose: To develop a simple pharmacodynamic (PD) assay for the evaluation of the bioequivalence of topically applied retinoid products. Methods: Daily applications of products containing tretinoin or adapalene were made to the forearms of human subjects for up to 21 days. Percutaneous absorption was enhanced through the use of polyethylene film occlusion (5 h). Pharmacologic activity was assessed through the daily measurement of three cutaneous responses intimately linked to retinoid-induced changes in epidermal differentiation: (1) erythema; (2) exfoliation (scaling/peeling), and (3) increased transepidermal water loss. Results: The PD model exhibited the sensitivity and specificity required to function as a bioequivalence surrogate. It was possible to differentiate between: (1) three concentrations of tretinoin in a commercial cream product line; (2) two concentrations of tretinoin in a commercial gel product line; (3) different vehicles (gel vs. cream) containing the same concentration of tretinoin, and (4) tretinoin and adapalene at the same concentration. The applicability of this model for bioequivalence testing was established by showing that it had sufficient power to determine that three test tretinoin cream products and two approved generic tretinoin gel products were equivalent to their corresponding reference products. Conclusions: A surrogate PD model to assess retinoid bioequivalence has been developed. Copyright © 2012 S. Karger AG, Basel.

Patel D.,Cetero Research | Couroux P.,Cetero Research | Hickey P.,Adiga Life science | Salapatek A.M.,Cetero Research | And 3 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Allergic rhinoconjunctivitis is an increasingly common source of morbidity, with sensitivity to cats accounting for 10% to 15% of disease burden. Allergy to cats is also a major risk factor for the development of asthma. Objectives: We sought to probe the persistence of the treatment effect of a novel Fel d 1-derived peptide antigen desensitization (Cat-PAD) 1 year after the start of treatment in subjects with cat allergy-induced rhinoconjunctivitis after standardized allergen challenge. Methods: In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, subjects attended an environmental exposure chamber in which they were exposed to cat allergen before and after treatment with 2 different regimens of Cat-PAD over a 3-month period. Clinical efficacy was assessed as a change in total rhinoconjunctivitis symptom scores 18 to 22 weeks and 50 to 54 weeks after the start of treatment. Results: Treatment with Cat-PAD showed greater efficacy with 4 administrations of a 6-nmol dose 4 weeks apart than with 8 administrations of a 3-nmol dose 2 weeks apart. The treatment effect of 6 nmol persisted 1 year after the start of treatment and was significantly different from that of 3 nmol (P =.0342) and placebo (P =.0104). The treatment effect was apparent on both nasal and ocular symptoms at 1 year. Conclusions: A short course of Cat-PAD improves the ocular and nasal components of rhinoconjunctivitis symptoms in subjects with cat allergy, with the treatment effect persisting 1 year after the start of treatment. © 2012 American Academy of Allergy, Asthma & Immunology.

Wald A.,Fred Hutchinson Cancer Research Center | Corey L.,Fred Hutchinson Cancer Research Center | Timmler B.,Aicuris Inc. | Magaret A.,Fred Hutchinson Cancer Research Center | And 12 more authors.
New England Journal of Medicine | Year: 2014

Background: Pritelivir, an inhibitor of the viral helicase-primase complex, exhibits antiviral activity in vitro and in animal models of herpes simplex virus (HSV) infection. We tested the efficacy and safety of pritelivir in otherwise healthy persons with genital HSV-2 infection. Methods: We randomly assigned 156 HSV-2-positive persons with a history of genital herpes to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) or placebo for 28 days. Participants obtained daily swabs from the genital area for HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Participants also maintained a diary of genital signs and symptoms. The primary end point was the rate of genital HSV shedding. Results: HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups. Conclusions: Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dosedependent manner in otherwise healthy men and women with genital herpes. Copyright © 2014 Massachusetts Medical Society.

Berg J.K.,Cetero Research | Shenouda S.K.,Lilly United States LLC | Heilmann C.R.,Lilly United States LLC | Gray A.L.,Lilly United States LLC | Holcombe J.H.,Lilly United States LLC
Diabetes, Obesity and Metabolism | Year: 2011

Aim: To compare exenatide and sitagliptin glucose and glucoregulatory measures in subjects with type 2 diabetes. Methods: An 8-week, double-blind, randomized, crossover, single-centre study. Eighty-six subjects (58% female, body mass index 35 ± 5 kg/m2, haemoglobin A1c 8.3 ± 1.0%) received either exenatide 10 μg (subcutaneous) twice daily or sitagliptin 100 mg (oral) daily for 4 weeks and crossed to the other therapy for an additional 4 weeks. Main outcome was time-averaged glucose during the 24-h inpatient visits. Results: Both treatments decreased average 24-h glucose, but exenatide had a greater effect [between-group difference: -0.67 mmol/l, 95% confidence interval (CI): -0.9 to -0.4 mmol/l]. Both treatments decreased 2-h postprandial glucose (PPG), area under the curve of glucose above 7.8 mmol/l (140 mg/dl) and 11 mmol/l (200 mg/dl) and increased the time spent with glucose between 3.9 and 7.8 mmol/l (70 and 140 mg/dl) during 24 h, but exenatide had a significantly greater effect (p < 0.05). Both treatments decreased postprandial serum glucagon, with exenatide having a greater effect (p < 0.005). Both treatments decreased fasting blood glucose to a similar degree (p = 0.766). Sitagliptin increased, while exenatide decreased, postprandial intact glucagon-like peptide-1. Both drugs improved homeostasis model assessment of β-cell function (HOMA-B), with exenatide having a significantly greater effect (p = 0.005). Both exenatide and sitagliptin decreased 24-h caloric intake, with exenatide having a greater effect (p < 0.001). There was no episode of major hypoglycaemia. Adverse events were mild to moderate and mostly gastrointestinal in nature with exenatide. No study withdrawals were due to an adverse event. Conclusion: Compared to sitagliptin, exenatide showed significantly lower average 24-h glucose, 2-h PPG, glucagon, caloric intake and improved HOMA-B. © 2011 Blackwell Publishing Ltd.

Subbarayan S.,Cleveland Clinic | Kipnes M.,Cetero Research
Expert Opinion on Pharmacotherapy | Year: 2011

Introduction: The ever-increasing burden of type 2 diabetes mellitus (T2DM) and inadequate control in the majority of patients has led to a quest for newer therapeutic options. There have been recent exciting advances in the treatment of T2DM, targeting the enteroinsular axis with incretin-based therapies that include the dipeptidyl peptidase IV (DPP-IV) inhibitors. Areas covered: The background, pharmacodynamic and pharmacokinetic profile of sitagliptin and important clinical trials with this drug are discussed in this paper. This review is intended to provide a comprehensive overview of the DPP-IV inhibitor sitagliptin, its clinical use and an expert opinion about its place in the treatment algorithm of diabetes management. Expert opinion: Sitagliptin is a well-tolerated, moderately efficacious, weight-neutral oral antidiabetic agent, with a low incidence of hypoglycemia. It may have a particular role in the management of diabetic patients with kidney or liver dysfunction. Animal studies indicate a protective effect on the pancreatic beta cell, thus limiting the progression of the disease, but this remains to be proven in humans. © Informa UK, Ltd.

Sloan-Lancaster J.,Eli Lilly and Company | Abu-Raddad E.,Eli Lilly and Company | Polzer J.,Eli Lilly and Company | Miller J.W.,Eli Lilly and Company | And 4 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1b antibody, in T2DM patients. RESEARCH DESIGN AND METHODS-Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications. RESULTS-LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: 20.27, 20.38 and 20.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated. CONCLUSIONS-Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM. © 2013 by the American Diabetes Association.

Lehman P.A.,Cetero Research
International journal of pharmaceutical compounding | Year: 2012

An in vitro human percutaneous absorption study was conducted to assess the delivery of ketoprofen and testosterone from two base formulations, a Pluronic lecithin organogel and Pentravan Cream. Each formulation was applied to ex vivo human trunk skin (from three skin donors) on triplicate sections mounted onto Franz Diffusion Cells. Following a 5-mcL/cm2 applied dose, serial dermal receptor solutions were collected over 48 hours. For both compounds, a greater rate and extent of absorption was found from the Pentravan formulation than from the Pluronic lecithin organogel formulation: 3.8-fold greater for ketoprofen, 1.7-fold greater for testosterone, for amount absorbed.

Background: Achievement of glycemic control in elderly patients with type 2 diabetes mellitus (DM) is complicated by many factors. Objective: The aim of this article was to systematically review evidence on the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors (ie, lowering of glycosylated hemoglobin [HbA 1c]), the risk of hypoglycemia associated with these agents, and the effects of these agents on body weight in elderly patients with type 2 DM. Methods: The PubMed and Biosis databases were searched for reports of clinical trials and meeting presentations (eg, abstracts, posters) published in English between January 1, 2000, and October 25, 2009, that included elderly patients with type 2 DM who were treated with sitagliptin, saxagliptin, vildagliptin, alogliptin, BI-1356, DSP-7238, or PF-734200. Pharmacokinetic and pharmacodynamic studies were excluded from the review, as were studies that did not specifically provide quantitative clinical data on glycemic parameters or specifically list patients aged <65 years. Results: Eighty-five articles and 5 presentations were identified in the search; of those, 18 articles and 3 presentations were included in the review. These publications described studies of DPP-4 inhibitors administered as monotherapy or in combination with metformin, a thiazolidinedione, glimepiride, glibenclamide, or insulin. Quantitative data indicated that, in these elderly patients (generally defined as <65 years of age) with type 2 DM, DPP-4 inhibitors were associated with significant HbA 1c reductions that ranged from 0.7% (baseline HbA 1c = 7.8%; P < 0.001) to 1.2% (baseline HbA 1c = 8.3%; P < 0.05). Additional studies that did not quantify the number of elderly patients (as would a subanalysis), but did specify that elderly patients were included and that patient age did not influence the results, were incorporated in this review to support the quantitative results. No significant differences were noted in the HbA 1c-lowering effects of these agents between elderly and younger patients. Less information about the incidence of hypoglycemia or weight gain in elderly patients was reported, but the available results suggested that the risk of hypoglycemia with DPP-4 inhibitors was not significantly different from that with placebo (sitagliptin 50 or 100 mg/d [0%] vs placebo [0%]; saxagliptin 5 mg/d [6.3%] vs placebo [8.0%]; vildagliptin 100 mg/d [2.32 events per patient-year] vs placebo [2.64 events per patient-year]; alogliptin 12.5 mg/d [8.0%] vs placebo [10.5%]) and that these agents were weight neutral (change, ≤0.9 kg). Conclusions: For elderly patients with type 2 DM, reductions in HbA 1c after treatment with a DPP-4 inhibitor were not significantly different from those in younger patients. Use of DPP-4 inhibitors in these studies was associated with a low risk of hypoglycemia, and these agents were weight neutral. © 2010 Elsevier HS Journals, Inc.

Lehman P.A.,Cetero Research | Raney S.G.,Cetero Research | Franz T.J.,Cetero Research
Skin Pharmacology and Physiology | Year: 2011

Aims: To examine the existing literature to determine the degree to which percutaneous absorption data obtained using the excised human skin model match those obtained from living man. Methods: The scientific literature was reviewed to collect data on compounds whose percutaneous absorption through human skin had been measured under both in vitro and in vivo conditions. The in vitro-in vivo (IVIV) correlation was evaluated by computing the in vitro/in vivo ratio using total absorption (percent of applied dose) as the metric for comparison. Results: A total of 92 data sets were collected from 30 published studies. The average IVIV ratio across all values was 1.6, though for any single data set there could be a nearly 20-fold difference between the in vitro and in vivo values. In 85% of the cases, however, the difference was less than 3-fold. The correlation was significantly improved when data were excluded from studies in which the protocols for both studies were not fully harmonized. For harmonized data sets the average IVIV ratio was 0.96 and there was a less than 2-fold difference between the in vitro and in vivo results for any one compound, with IVIV ratios ranging from 0.58 to 1.28. The dominant factors leading to exclusion of data were the use of skin from different anatomical sites and vehicles of differing composition. Conclusions: Percutaneous absorption data obtained from the excised human skin model closely approximate those obtained from living man when the two study protocols are appropriately matched. Copyright © 2011 S. Karger AG, Basel.

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