piperidines and tripalmitin

The goal of this study was to determine whether administration of the CB₁ cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d₃₁-tripalmitin) and intravenously (¹³C₄-palmitate, ¹³C₁-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg⁻¹·h⁻¹, P = 0.03). These data support the potential for a strong effect of CB₁ receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.

Topics: Acetic Acid; Animals; Biotransformation; Body Composition; Carbon Isotopes; Deuterium; Fatty Acids; Insulin Resistance; Kinetics; Lipolysis; Liver; Male; Palmitic Acid; Papio; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Subcutaneous Fat, Abdominal; Triglycerides; Waist Circumference

The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance.. A 3(2) full factorial design was employed to study the effect of lipid type and drug-to-lipid ratio on the yield, encapsulation efficiency, mean diameter and the time required for 50% drug release (t(50%) ). The pharmacokinetic behaviour of the lipospheres in rabbits was studied using tandem mass spectrometry.. The yields of preparations were in the range of 66.22-90.90%, with high encapsulation efficiencies (89.68-97.55%) and mean particle size of 20.68-35.94 µm. Both lipid type and drug-to-lipid ratio significantly affected t(50%) (P<0.0001), where the lipids can be arranged: glyceryl tripalmitate>compritol>cetyl alcohol, and the drug-to-lipid ratios can be arranged: 1:40>1:20>1:10. The flow time of lipospheres through 19-gauge syringe needle was less than 6s indicating good syringeability. The mean residence time of the subcutaneous and intramuscular lipospheres was significantly higher than the solution (almost 20 fold increase), with values of 11.04, 11.34 and 0.53 days, respectively (P<0.01).. Subcutaneous and intramuscular delivery of donepezil glyceryl tripalmitate lipospheres achieves depot release, allowing less frequent dosing.

Topics: Animals; Chromatography, Liquid; Delayed-Action Preparations; Donepezil; Drug Delivery Systems; Indans; Injections, Intramuscular; Injections, Subcutaneous; Lipids; Male; Microspheres; Nootropic Agents; Particle Size; Piperidines; Rabbits; Tandem Mass Spectrometry; Time Factors; Triglycerides