Evaluation of rosiglitazone administration on cardiovascular function in severe obesity.

BACKGROUND: Obese patients have myocardial structural and functional alterations related to insulin resistance. HYPOTHESIS: The purpose of the study was to analyze the effects of rosiglitazone, an insulin sensitizer agent, on cardiac morphometry and functioning. METHODS: In 2 groups of sex- and age-matched, nondiabetic, obese patients (5 men and 7 women, age 19-51 y; group A: body mass index [BMI] 40.6 +/- 3.4 kg/m(2); group B: BMI 42.6 +/- 2.7 kg/m(2)), we evaluated the basal insulin sensitivity index (HOMA[IS]), body composition by bioelectrical impedance analysis and 24-h blood pressure monitoring. Furthermore, all patients underwent conventional 2-Dimensional and color Doppler echocardiography, and pulsed-wave tissue Doppler imaging (TDI). After the baseline evaluation, all patients were put on a hypocaloric diet (70% basal metabolic rate) plus placebo if they were in group A, or plus rosiglitazone (4 mg twice daily; Avandia [GlaxoSmithKline plc., Brentford, Middlesex, United Kingdom]) if they were in group B, for 6 mo. RESULTS: Significant decreases in body weight, total fat mass, BMI, and systolic blood pressure were registered in both groups. Rosiglitazone administration appeared more efficient in improving HOMA(IS) (mean difference: 0.30 +/- 0.19 versus 0.11 +/- 0.21, p < 0.05). Left ventricular (LV) diastolic diameter (49.4 +/- 7.7 versus 52.3 +/- 5.4 mm, p < 0.05) and E wave (0.89 +/- 0.18 versus 0.99 +/- 0.20 m/sec, p < 0.05) increased in the rosiglitazone group due to a rise in preload and water content without peripheral edema. The increase in systolic (Sa) wave velocity in both groups was probably a result of the general improvement in insulin metabolism and the decrease in blood pressure. CONCLUSIONS: We confirmed the positive effect of rosiglitazone on glucose metabolism in obese, nondiabetic patients, but changes in insulin sensitivity did not explain the cardiac effects produced by further mechanisms.

Solid lipid nanoparticles incorporating melatonin as new model for sustained oral and transdermal delivery systems.

melatonin (MT) is a hormone produced by the pineal gland at night, involved in the regulation of circadian rhythms. For clinical purposes, exogenous MT administration should mimic the typical nocturnal endogenous MT levels, but its pharmacokinetics is not favourable due to short half-life of elimination. Aim of this study is to examine pharmacokinetics of MT incorporated in solid lipid nanoparticles (SLN), administered by oral and transdermal route. SLN peculiarity consists in the possibility of acting as a reservoir, permitting a constant and prolonged release of the drugs included. In 7 healthy subjects SLN incorporating MT 3 mg (MT-SLN-O) were orally administered at 8.30 a.m. MT 3 mg in standard formulation (MT-S) was then administered to the same subjects after one week at 8.30 a.m. as controls. In 10 healthy subjects SLN incorporating MT were administered transdermally (MT-SLN-TD) by the application of a patch at 8.30 a.m. for 24 hours. Compared to MT-S, Tmax after MT-SLN-O administration resulted delayed of about 20 minutes, while mean AUC and mean half life of elimination was significantly higher (respectively 169944.7 +/- 64954.4 pg/ml x hour vs. 85148.4 +/- 50642.6 pg/ml x hour, p = 0.018 and 93.1 +/- 37.1 min vs. 48.2 +/- 8.9 min, p = 0.009). MT absorption and elimination after MT-SLN-TD demonstrated to be slow (mean half life of absorption: 5.3 +/- 1.3 hours; mean half life of elimination: 24.6 +/- 12.0 hours), so MT plasma levels above 50 pg/ml were maintained for at least 24 hours. This study demonstrates a significant absorption of MT incorporated in SLN, with detectable plasma level achieved for several hours in particular after transdermal administration. As dosages and concentrations of drugs included in SLN can be varied, different plasma level profile could be obtained, so disclosing new possibilities for sustained delivery systems.