Preliminary Evaluation On The Pharmacodynamics And Toxicity Of4,5,6,7-tetrahydropravastatin Sodium

Sodium pravastatin, as a kind of high selectivity competitive inhibitor of3-hydroxy-3-methyl glutaryl coenzyme A reductase, is highly effective in the therapeutictreatment for lowering serum cholesterol levels in patients with atherosclerosis andhypercholesteremia and little side effects. It is one of the most widely prescribed medicationsin clinic in recent years. In our previous study of pravastatin,4,5,6,7-tetrahydropravastatinhas been isolated and purified from the fermentation of pravastatin as related substance. In theresearch on the inhibitory acitivity of4,5,6,7-tetrahydropravastatin and its sodium salt onthe3-hydroxy-3-methylglutary coenzyme A reductase,4,5,6,7-tetrahydropravastatin and itssodium salt exhibit similar inhibitory effect on HMG-CoA reductase to pravastatin whichwould be worth studying further. In this dissertation, two models, the high fat diet rabbitmodel of hyperlipidemia and fatty liver, and the high fat diet rat model of fat metabolicdisorder, were used to investigate the hypolipidemic activity of4,5,6,7-tetrahydropravastatinsodium. In addition, acute oral toxicity studies of4,5,6,7-tetrahydropravastatin sodium inmice were tested using limit dose test of Up-and-Down model as well.Compared with the rabbit model group investigated on high-fat diets, levels of totalcholesterol, triglyceride, low density lipoprotein and the content of malondialdehyde in serumand liver tissue from the animals of4,5,6,7-tetrahydropravastatin sodium5,10mg/kg dosegroup have been significantly reduced, while levels of high-density lipoprotein and thevitality of superoxide dismutase have significantly risen. According to the pathology study oneach dose rabbit groups of4,5,6,7-tetrahydropravastatin sodium, there are no apparentchanges in morphological appearance and histology discovered in the main organs. Inaddition, the test data shows that long-period dose of4,5,6,7-tetrahydropravastatin sodiumstudy conducted in rabbits has not led the increasing of creatine kinase to abnormal state.Compared with the rat model group investigated on high-fat diets, levels of totalcholesterol, triglyceride, low density lipoprotein and the content of malondialdehyde in serumand liver tissue from the animals of4,5,6,7-tetrahydropravastatin sodium20,40mg/kg dosegroup have been significantly reduced, while levels of high density lipoprotein and the vitalityof superoxide dismutase have significantly risen. Two experiments were also done to observe the little slid effects of4,5,6,7-tetrahydropravastatin sodium. According to the pathologystudy on each dose rat groups of4,5,6,7-tetrahydropravastatin sodium, there are no apparentchanges in morphological appearance and histology discovered in the main organs. Inaddition, the test data shows that long-period dose of4,5,6,7-tetrahydropravastatin sodiumstudy conducted in rats has not led the increasing of creatine kinase to abnormal state.Results of the acute oral toxicity for4,5,6,7-tetrahydropravastatin sodium alsoindicates that2000mg/kg of body weight of4,5,6,7-tetrahydropravastatin sodium has notbeen associated with death, while the mice’ weights have been reduced in3days after thetreatment before restored automatically and gradually. No other obvious abnormal symptomshave been found, too. Results suggest LD50>2000mg/kg.In summary, these studies reveal that4,5,6,7-tetrahydropravastatin sodium has obvioushypolipidemic activity as well as low oral toxicity on the treatment of hyperlipidemia andfatty liver caused by high-fat diets.