Early Response to Sibutramine in Patients Not Meeting Current Label Criteria: Preliminary Analysis of SCOUT Lead‐in Period

The Sibutramine Cardiovascular Outcomes (SCOUT) trial protocol defines a patient population predominantly outside current European Union label criteria. This article explores responses to sibutramine during the 6‐week, single‐blind, lead‐in period between patients who conformed to the label requirements (“conformers”) and those who did not (“nonconformers”). SCOUT is an ongoing, randomized, double‐blind, placebo‐controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. In total, 10,742 patients received sibutramine and weight management during the lead‐in period. Initial responses were assessed post hoc in label conformers and nonconformers. Of that 8.1% patients met label criteria; 91.9%, the majority with cardiovascular disease and/or blood pressure >145/90 mm Hg, were nonconformers. Conformers and nonconformers had similar reductions in body weight (median change ?2.2 kg) and waist circumference (women: ?2.0 cm for both groups; men: ?1.5 cm vs. ?2.0 cm for conformers and nonconformers, respectively) over the 6‐week period. Greater blood pressure falls were evident in nonconformers (median change ?3.5/?1.0 vs. ?1.0/0.0 mm Hg). Both groups had small pulse rate increases; median 1.5 bpm (nonconformers) vs. 3.0 bpm (conformers). There was a low incidence of serious adverse events (conformers: 1.0%; nonconformers: 2.8%) and ～93% of patients in both groups completed the 6‐week period. The SCOUT lead‐in period evaluating weight management with sibutramine confirms its good tolerability and efficacy in patients who meet current label criteria. Preliminary data from high‐risk patients for whom sibutramine is currently contraindicated suggest a low discontinuation rate and few serious adverse events but confirmation from the SCOUT outcome data is needed.     

Effects of CL 115,347, (±)-15-deoxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation

The effect of CL 115,347, a topically active antihypertensive PGE₂ analog, and PGE₂ on changes in blood pressure (BP), heart rate (HR) response and plasma epinephrine (E) and norepinephrine (NE) levels induced by stimulation of the sympathetic spinal cord outflow were studied in pithed stroke-prone spontaneously hypertensive rats (SHRSP). Surgical pithing significantly reduced plasma E but not NE levels suggesting that the sympathoadrenal medullary system differentially affects E and NE release. Sympathetic stimulation of the spinal cord of pithed SHRSP increased HR, BP, plasma E and NE levels. Topically applied CL 115,347 (0.001–0.1 mg/kg) dose-dependently decreased BP, while intravenously infused PGE₂ (30 μg/kg/min) did not alter BP except for a brief initial drop. Topical application of CL 115,347 (0.1 mg/kg) also inhibited BP responses to sympathetic stimulation without effects on HR or plasma E or NE levels. Intravenous infusion of PGE₂ (30 μg/kg/min) inhibited both BP and HR responses to spinal cord stimulation but did not alter plasma catecholamine levels. These studies in SHRSP suggest that CL 115,347 and PGE₂ modulate cardiovascular responses mainly via postjunctional effects, but act differently on the cardiovascular elements, CL 115,347 acts primarily on blood vessels while PGE₂ acts on blood vessels and heart.