1 To better understand how it decreases plasma cholesterol and triglyceride levels, we evaluated the effect of (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole monohydrochloride (YM-53601) on lipogenic biosynthesis in the liver and lipid secretion from the liver in rats and hamsters. 2 Single administration of YM-53601 in cholestyramine-treated rats inhibited triglyceride and free fatty acid (FFA) biosynthesis at a similar dose range to that at which it inhibited cholesterol biosynthesis. YM-53601 inhibited both triglyceride and FFA biosynthesis in hamsters treated with cholestyramine. 3 YM-53601 by single oral administration decreased the enhanced plasma triglyceride levels in hamsters induced by an injection of protamine sulfate, which inhibits lipoprotein lipase (LPL) and consequently increases plasma very low-density lipoprotein (VLDL) triglyceride levels. YM-53601 also decreased the enhanced plasma triglyceride and cholesterol levels in hamsters treated with Triton WR1339, which also inhibits the degradation of VLDL. Plasma cholesterol was significantly decreased as soon as 1 h after single administration of YM-53601 in hamsters fed a normal diet. 4 This is the first report that a squalene synthase inhibitor suppresses lipogenic biosynthesis in the liver and cholesterol and triglyceride secretion from the liver in vivo. We therefore suggest that the mechanism by which YM-53601 decreases plasma triglyceride might include these effects. The finding that YM-53601 rapidly decreased plasma cholesterol suggests that this compound may be effective in decreasing plasma cholesterol levels early in the course of treatment of hypercholesterolemia in humans.
The aim of this study was to establish an experimental model of the escape phenomenon, in which plasma cholesterol, initially reduced by a 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase inhibitor such as pravastatin, increases again on long‐term administration. We also evaluated the efficacy of YM‐53601 ((E)‐2‐[2‐fluoro‐2‐ (quinuclidin‐3‐ylidene) ethoxy]‐9H‐carbazole monohydrochloride), a squalene synthase inhibitor, in this model.
Pravastatin inhibited cholesterol biosynthesis in hamster primary hepatocytes (IC50, 14 nM). After pre‐treatment with pravastatin, in contrast, almost no effect on cholesterol biosynthesis was seen.
In hamsters fed a high fat diet, 3 mg kg−1 pravastatin for 9 days decreased plasma non‐HDL cholesterol (total cholesterol – high density lipoprotein cholesterol) (P<0.01), but this effect was lost between 17 and 27 days of treatment, accompanied by an increase in HMG‐CoA reductase activity. No such increase in plasma non‐HDL cholesterol was seen with YM‐53601 at 30 mg kg−1 after 9 (P<0.001), 17 (P<0.01) or 27 (P<0.001) days of treatment. Replacement of pravastatin with YM‐53601 caused a decrease in plasma non‐HDL cholesterol by 53% (P<0.001) and in HMG‐CoA reductase activity.
This animal model thus satisfactorily replicates the escape phenomenon observed in humans and may therefore be useful in evaluation of lipid‐lowering agents, specifically comparison of HMG‐CoA reductase inhibitors. Further, YM‐53601 may be useful in the treatment of hypercholesterolemia without induction of the escape phenomenon.
British Journal of Pharmacology (2002) 135, 1572–1578; doi:
The methanolic extract of one of the common Vitaceaeous plants, Vitis coignetiae, showed marked prevention against injuries of primary cultured rat liver cells induced by carbon tetrachloride and D-galactosamine. Activity-guided fractionation of the extract resulted in the isolation of not only an antihepatotoxic stilbene derivative, e-viniferin, but also novel oligostilbenes, vitisin A and its stereoisomer cis-vitisin A as a mixture. The structures of the oligostilbenes have been determined on the basis of spectroscopic evidence, especially by 2D NMR methods such as HMBC spectra of degradative products. The mixture of vitisin A and cis-vitisin A was found to cause marked liver lesions in mice.
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