Effect of an oral [alpha]2-adrenergic blocker (MK-912) on pancreatic islet function in non-insulin-dependent diabetes mellitus

We used MK-912, a potent new selective [alpha]2-adrenergic receptor antagonist that is active orally, to study the effect of short-term, selective [alpha]2-blockade on fasting plasma glucose (FPG) and pancreatic islet function in non-insulin-dependent diabetes (NIDDM). Ten asymptomatic patients with NIDDM received either a single oral dose of MK-912 (2 mg) or placebo in a double-blind, cross-over study. B-cell function was measured by the acute insulin response (AIR) to glucose (1.66 mmol/kg intravenously [IV]) and by the AIR to arginine (5 g IV) during a hyperglycemic glucose clamp at a mean glucose level of 32.1 mmol/L to provide an estimation of maximal B-cell secretory capacity. A-cell function was estimated by the acute glucagon response (AGR) to arginine during the glucose clamp. Effective [alpha]2-adrenergic blockade was apparently achieved, as there were substantial increases of plasma norepinephrine (NE) (P P P P P P P P = .06) and the C-peptide response (P = .07) to glucose compared with placebo. There was a small, but significant, overall treatment effect for both the AIR and AGR to arginine with MK-912 (both P 2-adrenergic blockade; (2) a small decrease of FPG and a small increase of fasting plasma insulin; (3) a small improvement of B-cell function due to an increase in maximal B-cell secretory capacity; and (4) a small increase in basal and stimulated glucagon. These findings suggest that endogenous [alpha]2-adrenergic tone may contribute, although to a small extent, to the impaired B-cell function in NIDDM. If an [alpha]2-blocker becomes available that does not increase BP, studies would be warranted to evaluate its potential impact on glucose regulation in patients with NIDDM.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29070/1/0000105.pd

A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]

BACKGROUND: Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). METHODS: Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. RESULTS: 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. CONCLUSIONS: In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients

Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability

Aims The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra-arterial substance P infusion in the forearm of healthy man

152 Development of Deutetrabenazine as a Potential New Non-Antipsychotic Treatment for Tourette Syndrome in Children and Adolescents

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the hyperkinetic movements of motor and phonic tics manifested in young age. Currently approved treatments in the United States are antipsychotics: haloperidol, pimozide, and aripiprazole, which are associated with serious side effects, including tardive dyskinesia (TD). Deutetrabenazine, a vesicular monoamine transporter type 2 (VMAT2) inhibitor, was approved in 2017 by the US FDA for the treatment of chorea associated with Huntington's disease and TD. Three ongoing studies (Alternatives for Reducing Tics in TS [ARTISTS]) are evaluating the efficacy, safety, and tolerability of deutetrabenazine in reducing tics in TS in children and adolescents (age 6-16 years). ARTISTS 1, a phase 2/3, response-driven, dose-titration, placebo-controlled study, randomizes patients (N=116) 1:1 to deutetrabenazine or placebo for 12 weeks. ARTISTS 2, a phase 3, fixed-dose study, randomizes patients (N=150) 1:1:1 to deutetrabenazine high or low dose, or placebo for 8 weeks. The primary efficacy outcome in these pivotal studies is change from baseline to end of treatment in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Additional efficacy endpoints and safety/tolerability are also evaluated. ARTISTS is a 56-week, open-label, single-arm, long-term safety/tolerability study in patients who have successfully completed either ARTISTS 1 or ARTISTS 2. Not available yet. TS can have potentially long-term life impact, and there remains unmet medical need for effective and well-tolerated treatments. Three ARTISTS studies will evaluate the efficacy, safety, and tolerability of deutetrabenazine in patients with tics in TS. The studies are sponsored by Teva Pharmaceuticals and operationalized by Teva's development partner, Nuvelution TS Pharma INC

2001-1062.august

ABSTRACT. Objective. To evaluate the efficacy and tolerability of the highly selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib for the treatment of rheumatoid arthritis (RA). Methods. A double blind, randomized, placebo and active comparator controlled, 12 week study conducted at 88 US sites. Eligible patients were chronic nonsteroidal antiinflammatory drug (NSAID) users with clinical worsening of RA upon withdrawal of prestudy NSAID. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures: patient and investigator global assessments of disease activity and direct assessment of arthritis by counts of tender and swollen joints. Key secondary measures: patient global assessment of pain, the Stanford Health Assessment Questionnaire, and the percentage of patients both completing the study and meeting the ACR20 criteria. Tolerability was assessed by tabulation of adverse events and routine laboratory evaluations. Results. In all, 816 patients were randomized (placebo = 323, etoricoxib = 323, naproxen = 170), and 448 completed 12 weeks of treatment (placebo = 122, etoricoxib = 230, naproxen = 96). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p &lt; 0.01). Compared with patients receiving naproxen, patients receiving etoricoxib demonstrated significant improvements (p &lt; 0.05) on all primary endpoints and most other endpoints including ACR20 criteria. The percentage of patients who achieved an ACR20 response and who completed the study was 21%, 53%, and 39% in the placebo, etoricoxib and naproxen groups, respectively. Etoricoxib and naproxen were both generally well tolerated. Conclusion. In this study, etoricoxib 90 mg once daily was more effective than either placebo or naproxen 500 mg twice daily for treating patients with RA over 12 weeks