Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Illingworth, D. Roger; Sexton, Gary

doi:10.1172/jci111618

Cited by 176 publications

(39 citation statements)

References 33 publications

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“…Clinicians at lipid clinics were, however, eager to get mevinolin for compassionate use for patients with severe hypercholesterolemia and obtained this from 1982. 57 Mevinolin turned out to be effective with few adverse effects, and in 1983, formal clinical trials were started again. Because of the patent conflict with Sankyo who maintained the patent for mevinolin in 30 countries, Merck developed synvinolin, later to become simvastatin and mevinolin changed name to lovastatin.…”

Section: Statinsmentioning

confidence: 99%

The Success Story of LDL Cholesterol Lowering

Pedersen

2016

Circulation Research

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Abstract:We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence. (Circ Res. 2016;118:721-731.

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Section: Statinsmentioning

confidence: 99%

The Success Story of LDL Cholesterol Lowering

Pedersen

2016

Circulation Research

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“…The formation of mevalonate, which is catalyzed by 3-hydroxy-3-meth-ylglutaryl coenzyme A (HMG-CoA)' reductase, has long been regarded as the major regulatory step for de novo cholesterol biosynthesis (9-1 1). For this reason, competitive inhibitors of HMG-CoA reductase, such as compactin (ML 236B) (12) and mevinolin (MK803) (13), have received much attention as potential new therapeutic agents for treatment of hypercholesterolemia (14)(15)(16)(17)(18)(19)(20)(21). In addition to their cholesterol-lowering activity in vivo, these inhibitors ofmevalonate synthesis exhibit cytostatic activity when added to proliferating cells in tissue culture (22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Maltese¹,

Defendini²,

Green³

et al. 1985

J. Clin. Invest.

115

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3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, an essential precursor for isoprenoid compounds in mammalian cells. Recent studies have shown that mevinolin, a competitive inhibitor of the reductase, inhibits cell proliferation and induces differentiation in cultured C1300 (Neuro-2A) murine neuroblastoma cells. We now report that mevinolin can inhibit neuroblastoma growth in vivo. The specific activity of HMG-CoA reductase in subcutaneous neuroblastomas increased more than 20-fold between the fifth and eighth days after tumor inoculation, and remained elevated for the remainder of the tumor lifetime in mice. The increase in reductase activity was correlated with a marked increase in tumor DNA content and exponential increase in tumor weight. Using an in vitro assay to monitor the ability of mouse serum to suppress sterol synthesis, we determined that mevinolin was inactivated or cleared from the circulation within 3-6 h after a single subcutaneous injection. However, by using subcutaneous osmotic pumps to deliver a constant infusion of mevinolin, we were able to maintain adequate blood levels of the drug for 7 d. Mevinolin (5 mg/kg per h) suppressed tumor growth (wet weight) significantly when treatment was carried out between day 1 and day 8 or between day 5 and day 12 after tumor inoculation. Histopathological examination of tumors from mevinolin-treated mice revealed few or no mitotic figures and marked cellular degeneration. Measurements of incorporation of (3H)acetate into neuroblastoma sterols and ubiquinones 24 h after implantation of osmotic pumps showed that mevinolin produced a marked inhibition of isoprenoid synthesis in the tumors in vivo. The data suggest that, in addition to their demonstrated utility as cholesterol-lowering drugs, competitive inhibitors of HMG-CoA reductase may have considerable potential as novel antineoplastic agents.

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“…Lovastatin, formerly called mevinolin, is a powerful serum cholesterol-lowering agent in humans and other species (1)(2)(3)(4)(5)(6). It is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMG-CoA reductase; (S)-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], the rate-limiting enzyme of cholesterol synthesis (1).…”

mentioning

confidence: 99%

Lovastatin, an inhibitor of cholesterol synthesis, induces hydroxymethylglutaryl-coenzyme A reductase directly on membranes of expanded smooth endoplasmic reticulum in rat hepatocytes.

Singer

Scott

Kazazis

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Lovastatin is a potent competitive inhibitor of the rate-limiting enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (NADPH) [HMG-CoA reductase; (S)-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]. We determined the subcellular distribution of HMG-CoA reductase at high resolution by means of immunoelectron microscopy on ultrathin frozen liver sections of rats treated with lovastatin and cholestyramine. High concentrations of reductase were located on the outer (cytoplasmic) surfaces of smooth endoplasmic reticulum (SER) membranes induced in hepatocytes by acute drug administration. The enzyme was specifically localized over the whorled SER membranes and was absent from nonwhorled SER, rough endoplasmic reticulum, and peroxisomes. Intense HMG-CoA reductase labeling was only observed in hepatocytes containing high levels of HMG-CoA reductase activity; no staining was detected in untreated livers. These observations show that HMG-CoA reductase is induced as an integral component of the SER membranes that form in rat hepatocytes subsequent to lovastatin treatment and suggest that the formation of SER whorls in rat hepatocytes is due to mechanism-based effects of lovastatin.

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Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolemia.

Abstract: bstract. We have evaluated the hypolipidemic effects of mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis in 13 patients with heterozygous familial hypercholesterolemia (FH

Cited by 176 publications

References 33 publications

The Success Story of LDL Cholesterol Lowering

The Success Story of LDL Cholesterol Lowering

Suppression of murine neuroblastoma growth in vivo by mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Lovastatin, an inhibitor of cholesterol synthesis, induces hydroxymethylglutaryl-coenzyme A reductase directly on membranes of expanded smooth endoplasmic reticulum in rat hepatocytes.

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