Synthesis of a novel siliconized analog of clofibrate [silafibrate] and comparison of their anti-inflammatory activities

Fibrates, as hypolipidemic drugs known as agonists of peroxisome proliferator-activated receptors, diminish inflammatory responses. Studies have shown that incorporation of a silicon atom into a drug structure improves its pharmacological potency, modifies its selectivity toward a given target, or changes its metabolic rate, in addition to increasing the lipophilicity of the compounds. A siliconized analog of clofibrate, ethyl-2-methyl-2-[4-[trimethylsilyl]phenoxy]propionate was synthesized, whereby the chlorine atom in the phenoxy ring was replaced by a trimethylsilyl group. The anti-inflammatory effects of the siliconized analog [silafibrate] were evaluated in an air-pouch model of inflammation and compared with those of clofibrate. Oral administration of both drugs produced a significant anti-inflammatory action by reducing carrageenan induced pouch leukocyte recruitment, exudates production, and granulated tissue weight. The silicon isostere of clofibrate has improved anti-inflammatory properties

Ambivalent effects of atorvastatin on angiogenesis, epidermal cell proliferation and tumorgenesis in animal models

A growing body of preclinical data indicates that statins may possess antineoplastic properties; however, some studies have raised the possibility that statins may also have carcinogenic potential. An air pouch model was used for angiogenesis. Single or multiple applications of croton oil on the back of Swiss albino mice with or without initiation by dimethylbenz[a]antheracene [DMBA] were used to evaluate the skin tumorgenesis, ultrastructural and histological alterations. Atorvastatin [orally, 10 mg/kg/day] produced a significant [P<0.05] reduction in angiogenesis. Concurrent administration of mevalonate reversed the antiangiogenic effect of atorvastatin. However, local injection of atorvastatin [200 micro g] into the pouches induced a significant [P<0.5] increase in angiogenesis that was not reversed by co-administration of mevalonate. The disturbance of cell polarity, inflammatory response, thickness of epidermal layer, and mitotic index induced by croton oil were inhibited markedly and dose-dependently [P<0.001] by pre-treatment with atorvastatin. In spite of the strong anti-inflammatory and anti-proliferative effects of atorvastatin on epidermal cell proliferation, it was identified that the same doses of atorvastatin in DMBA-initiated and croton oil-promoted skin tumorgenesis in mice increased the incidence of tumors and their conversion into malignant carcinoma. The reasons for these discrepancies remain unclear, and could be related to ambivalent effects of atorvastatin on angiogenesis or to specific differences in the experimental conditions. It is suggested that the pro-angiogenic effect of the drug, which could be responsible for promotion of skin tumors, is independent of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition that can be mediated directly by atorvastatin

Vascular dysfunction in short-term hypercholesterolemia despite the absence of atherosclerotic lesions

The atherosclerotic effect of hypercholesterolemia on the vascular function is well-known. However, limited studies were done on the effect of hypercholesterolemia without atherosclerotic lesion on thq vascular compliance. The aim of this study was to investigate the effects of hyperlipidemia induced by cholesterol rich diet on vessel function in isolated rat aorta in the absence of atherosclerotic lesion. Male wistar rats were randomly divided into 3 groups of 6 animals in each. The rats in normal control group were fed a standard laboratory diet and two other groups were fed a high fat diet for 36 days. A group of high fat fed rats was treated orally with Lovastatin started at day of 16 and continued for last 20 days of the experimental period. At the end of the experiment, inferior vena cava blood was collected to measure the lipid levels and the thoracic aorta was excised and used for isolated vessel preparation and histological study. Results: The results of this study indicated that high-cholesterol diet significantly increased total cholesterol and LDL levels in serum [p<0.001]. The increase in the serum levels of cholesterol was associated with a profound reduction of endothelium dependent vasodilatation of the thoracic aorta. However, in histopathological study no atherosclerotic lesion was observed. Short-term treatment by Lovastatin [10 mg/kg/day] produced a significant reduction[p<0.05] in the level of total cholesterol and LDL. The endothelium-dependent vasodilatation was improved significantly [P<0.01] by Lovastatin as an anti-hyperlipidemic drug. Hypercholesterolemia is associated with endothelial dysfunction in aorta, despite the absence of atherosclerotic lesions

Biphasic effects of atorvastatin on inflammation

Statins have been shown to exert "pleiotropic effects" independent of their cholesterol lowering actions that include anti-inflammatory properties. We show in this study that atorvastatin dependent on the way of administration may exert anti- or pro- inflammation effects. Carrageenan-induced rat paw edema and mouse air-pouch as inflammatory models were used in this study. Animals were received statins orally prior to induction of inflammation by injection of carrageenan into rat paw or the pouch. The local effect of atorvastatin was determined by injection of the drug into the pouch. Oral administration of statins reduced both the maximal edema response and neutrophils infiltration in the inflammation zone. Lovastatin had the lowest and atorvastatin had the greatest effects. Also, in the mouse air-pouch model oral treatment by atorvastatin produced a very significant [p < 0.0001] reduction in carrageenan-induced pouch leukocyte recruitment and exudates production. Concurrent administration of mevalonate revers ed the anti-inflammatory effect of atorvastatin. However, local injection of atorvastatin into the pouch induced a dose depend and significant increase in leukocyte recruitment into the pouch that was not reversed by co-administration of mevalonate. This study shows that atorvastatin dependent on the way of administration has both pro- and anti- inflammatory properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of HMG CoA reductase inhibition and can be mediated directly by atorvastatin