eflucimibe and Disease-Models--Animal

The anti-atherosclerotic properties of F 12511, a novel acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, were studied in rabbits that were fed a cholesterol-free casein-rich diet and developed endogenous hypercholesterolemia and fibrofatty preatheroma lesions. After 6 weeks of casein feeding, an endothelial abrasion was performed in the abdominal aorta; at week 8, a control group was maintained on this diet while F 12511 (8 mg/kg/d) was administered as a diet admixture for the subsequent 24 weeks. Total plasma cholesterol level rose to 250-300 mg/dl in both groups before starting the treatment; F 12511 time-dependently reduced total plasma cholesterol by 50%, and also decreased by 50% the incidence of lesions and macrophage accumulation in uninjured aorta (thoracic arch, celiac bifurcation). Residual lesions in the treated group were characterized by few macrophages, essentially under the endothelium, and by a larger content of smooth muscle cells. Quantitative image analysis of serial sections of mechanically injured abdominal aorta revealed a 20% surface covered by preatheroma lesions in the placebo group; F 12511 significantly reduced this surface. These data suggest that the combination of endogenous hypercholesterolemia with endothelial injury in the rabbit may offer a useful model to study atherosclerosis; lipid lowering by F 12511 reduces the incidence of vascular lesions and macrophage infiltration and may reinforce the fibrous skeleton of the atheroma.

Topics: Anilides; Animals; Anticholesteremic Agents; Aorta, Abdominal; Aorta, Thoracic; Arteriosclerosis; Caseins; Catheterization; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Hypercholesterolemia; Hyperplasia; Immunohistochemistry; Male; Rabbits; Sterol O-Acyltransferase; Triglycerides; Tunica Intima

The pharmacological profile of F 12511 (S)-2',3', 5'-trimethyl-4'-hydroxy-alpha-dodecylthio-phenylacetanilide, a new inhibitor of acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26; ACAT), was evaluated by using different in vitro and in vivo models. In vitro, F 12511 was shown to be a highly potent inhibitor of ACAT activity in microsomal preparations from various animal species as well as of cholesterol esterification in relevant human cell lines in culture. The concentrations of F 12511 required to produce 50% inhibition of ACAT activity (IC(50) values) in microsomal preparations ranged from 41nM for hypercholesterolemic rabbit intestine to 223 nM for normocholesterolemic hamster liver. In whole cell assays using hepatic (Hep G2), intestinal (CaCo-2) and macrophagic (THP-1) cell lines, F 12511 inhibited ACAT activity with IC(50) values of 3, 7, and 71 nM, respectively. In vivo, orally administered F 12511 displayed high potency and efficacy as an antihypercholesterolemic compound in different cholesterol-fed animals (rat, guinea-pig, rabbit). For instance, in guinea-pigs the dose required to reduce plasma cholesterol levels by 30% (ED(30) value) was 0.008 mg.kg(-1.) In rabbits, an animal species prone to atherosclerosis, the hypocholesterolemic effect was accompanied by a dose-related reduction in the incidence of aortic fatty streaks that reached asymptote at 2.5 mg.kg(-1) and by an improvement of the impaired endothelial function. When given orally to chow-fed hamsters, F 12511 elicited a dose-related decrease in plasma cholesterol from 9% at 0.63 mg.kg(-1) up to 31% at 40 mg.kg(-1) associated with a preferential reduction in atherogenic lipoproteins, very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Moreover, in the same dose range, F 12511 decreased hepatic cholesteryl ester concentrations and reduced liver ex vivo ACAT activity. By using a bioassay, ACAT inhibitory activity was present in plasma of treated hamsters 1 hr after oral administration of F 12511. Hence, the results in chow-fed hamsters are consistent with systemic and direct hepatic effects of F 12511. In guinea-pigs, an adreno-sensitive species, F 12511 did not impair the adrenal function (adrenocorticotrophic hormone challenge) at doses up to 2.5 mg.kg(-1,) far higher than those eliciting hypocholesterolemic effects in the same species. In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appropriate tool to det

Topics: Adrenal Glands; Anilides; Animals; Anticholesteremic Agents; Arteriosclerosis; Cells, Cultured; Cholesterol; Diet; Dietary Supplements; Disease Models, Animal; Enzyme Inhibitors; Guinea Pigs; Hypolipidemic Agents; Male; Rabbits; Rats; Sterol O-Acyltransferase