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[Research and development of pravastatin]
Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan
|September 1, 1991
Summary
Pravastatin, a potent HMG-CoA reductase inhibitor, selectively reduces cholesterol synthesis in liver cells. This cholesterol-lowering drug effectively treats hyperlipidemia and prevents atherosclerosis in preclinical models and humans.
Area of Science:
- Biochemistry
- Pharmacology
- Microbiology
Background:
- Research for HMG-CoA reductase inhibitors began in 1971 to target cholesterol biosynthesis.
- ML-236B (compactin) was the first potent inhibitor discovered, leading to the development of pravastatin.
- Pravastatin's potency and tissue selectivity made it a key focus for development.
Purpose of the Study:
- To detail the development and evaluation of pravastatin as a cholesterol-lowering agent.
- To investigate the microbial production and selective inhibition of sterol synthesis by pravastatin.
Main Methods:
- Microbial hydroxylation using Streptomyces carbophilus for pravastatin production.
- In vitro studies on rat hepatocytes and ex vivo/in vivo experiments in rodents.
- Animal studies in dogs, monkeys, rabbits, and WHHL rabbits; clinical trials in humans.
Main Results:
- Pravastatin selectively inhibited sterol synthesis in hepatocytes compared to non-hepatic cells.
- Marked reduction in serum cholesterol observed in various animal models, including hyperlipidemic rabbits.
- Clinical trials confirmed significant reductions in total and LDL cholesterol, with an increase in HDL cholesterol.
Conclusions:
- Pravastatin demonstrates potent and selective inhibition of cholesterol synthesis.
- It effectively lowers serum cholesterol and prevents atherosclerosis in preclinical models.
- Clinical efficacy in reducing LDL and improving HDL cholesterol levels was established.