Experimental model of escape phenomenon in hamsters and the effectiveness of YM-53601 in the model

British Journal of Pharmacology
Tohru UgawaHisataka Shikama

Abstract

1. 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. 2. Pravastatin inhibited cholesterol biosynthesis in hamster primary hepatocytes (IC(50), 14 nM). After pre-treatment with pravastatin, in contrast, almost no effect on cholesterol biosynthesis was seen. 3. 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. 4. This an...Continue Reading

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Citations

Aug 16, 2011·Journal of Lipid Research·Jose Castro-PerezDouglas G Johns
Jun 10, 2008·Expert Opinion on Emerging Drugs·Raghda K Elsayed, Jeffery D Evans
Jul 31, 2014·Memórias do Instituto Oswaldo Cruz·Eduardo Milton Ramos-SanchezMagnus Gidlund
Mar 7, 2017·World Journal of Experimental Medicine·Fotios BarkasEvangelos Liberopoulos

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