Publisher Summary This chapter discusses the role of recently appeared inhibitors in the treatmen... more Publisher Summary This chapter discusses the role of recently appeared inhibitors in the treatment of hypercholesterolemia (HC). The general subject of cholesterol biosynthesis inhibition has been recently reviewed. The indan-1,3-dione causes a 50% inhibition of cytoplasmic S-acetyl coenzyme A synthetase, the enzyme responsible for acetate activation in the first biosynthetic step. Compactin and lovastatin, the first fungal metabolite inhibitors of HMGR, have been the subject of many reviews. Lovastatin has been shown to be the most effective treatment for lowering both TC and LDL-C in patients with primary hypercholesterolemia. A third fungal metabolite under clinical development is pravastatin. Some steroids, bearing a second oxygen function, are known to inhibit HMGR in vitro , possibly by a feedback mechanism. Plant sterols are commonly present in the human diet in edible vegetable oils and fats. The hypocholesterolemic effect of plant sterols, most commonly β-sitosterol, has been well documented in animals and man. Several enzymes have been postulated to be responsible for cholesterol esterification. These are lecithin cholesterol acyl transferase (LCAT), cholesterol esterase (CEH), and acyl cholesterol acyltransferase (ACAT). Pancreatic cholesterol esterase has also been implicated in the esterification of exogenous C. Treatment of HC with bile acid sequestrants remains the first line and most cost effective method of drug therapy. The efficacy of bile-acid sequestrants and HMGR inhibitors, in treating HC in man, is now well documented. Recent research into C absorption inhibitors has uncovered a number of interesting drug types. In the future, increased knowledge of the underlying causes of HC might allow drug therapy to be targeted for specific defects in lipid metabolism.
Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded ili... more Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.
This was produced from a copy of a document sent to us for microfilming. While the most advanced ... more This was produced from a copy of a document sent to us for microfilming. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help you understand markings or notations which may appear on this reproduction.
Biochemical and Biophysical Research Communications, Jul 31, 1990
CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly li... more CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.
Publisher Summary This chapter discusses the role of recently appeared inhibitors in the treatmen... more Publisher Summary This chapter discusses the role of recently appeared inhibitors in the treatment of hypercholesterolemia (HC). The general subject of cholesterol biosynthesis inhibition has been recently reviewed. The indan-1,3-dione causes a 50% inhibition of cytoplasmic S-acetyl coenzyme A synthetase, the enzyme responsible for acetate activation in the first biosynthetic step. Compactin and lovastatin, the first fungal metabolite inhibitors of HMGR, have been the subject of many reviews. Lovastatin has been shown to be the most effective treatment for lowering both TC and LDL-C in patients with primary hypercholesterolemia. A third fungal metabolite under clinical development is pravastatin. Some steroids, bearing a second oxygen function, are known to inhibit HMGR in vitro , possibly by a feedback mechanism. Plant sterols are commonly present in the human diet in edible vegetable oils and fats. The hypocholesterolemic effect of plant sterols, most commonly β-sitosterol, has been well documented in animals and man. Several enzymes have been postulated to be responsible for cholesterol esterification. These are lecithin cholesterol acyl transferase (LCAT), cholesterol esterase (CEH), and acyl cholesterol acyltransferase (ACAT). Pancreatic cholesterol esterase has also been implicated in the esterification of exogenous C. Treatment of HC with bile acid sequestrants remains the first line and most cost effective method of drug therapy. The efficacy of bile-acid sequestrants and HMGR inhibitors, in treating HC in man, is now well documented. Recent research into C absorption inhibitors has uncovered a number of interesting drug types. In the future, increased knowledge of the underlying causes of HC might allow drug therapy to be targeted for specific defects in lipid metabolism.
Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded ili... more Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.
This was produced from a copy of a document sent to us for microfilming. While the most advanced ... more This was produced from a copy of a document sent to us for microfilming. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help you understand markings or notations which may appear on this reproduction.
Biochemical and Biophysical Research Communications, Jul 31, 1990
CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly li... more CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.
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