Lovastatin: An HMG-CoA Reductase Inhibitor for Lowering Cholesterol

Frishman, William H.; Rapier, Roderick

doi:10.1016/s0025-7125(16)30681-2

Cited by 19 publications

(13 citation statements)

References 46 publications

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“…The main effects of this drug were a consistent diminution of plasma LDL-cholesterol by about 40% and an increase in plasma HDL-cholesterol levels by about 11% as compared to baseline values. The magnitude of lipid lowering by simvastatin observed in this study was similar to that reported for both lovastatin and simvastatin in clinical trials [24,36,18,44,25]. The efficacy of simvastatin in lowering plasma LDL-cholesterol levels was independent of apolipoprotein E isoforms.…”

Section: Discussionmentioning

confidence: 99%

Effects of long-term treatment with simvastatin on plasma lipids and lipoproteins in patients with primary hypercholesterolemia

Thiery

Creutzfeldt²,

Creutzfeldt³

et al. 1990

Klin Wochenschr

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We investigated long-term hypolipidemic effects and clinical safety of simvastatin, a new competitive inhibitor of 3-hydroxy-methylglutaryl coenzyme A reductase in 24 patients with familial and non-familial hypercholesterolemia. Patients received up to 40 mg simvastatin for a period of 30 months. Significant decreases were noted in plasma cholesterol (30%), plasma triglycerides (25%), very low density lipoprotein-cholesterol (26%), and low density lipoprotein-cholesterol (40%), whereas an increase in plasma high density lipoprotein-cholesterol (11%) was observed. Furthermore, the percentage decrease in plasma low density lipoprotein cholesterol was independent of individual baseline concentrations. Simvastatin did not alter the composition of low density lipoproteins or high density lipoproteins. The percentage decrease in total plasma and low density lipoprotein-cholesterol was independent of apoprotein E isoforms and low density lipoprotein-receptor activity as assayed in cultured fibroblasts. The drug therapy was well tolerated and clinical examinations revealed no adverse effects. Clinical chemistry indices and hematological, as well as endocrinological parameters remained within normal limits and ranges.

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Section: Discussionmentioning

confidence: 99%

Effects of long-term treatment with simvastatin on plasma lipids and lipoproteins in patients with primary hypercholesterolemia

Thiery

Creutzfeldt²,

Creutzfeldt³

et al. 1990

Klin Wochenschr

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“…The oral absorption of lovastatin has been estimated at approximately 30%, based on studies in four animal species. About 5% of a lovastatin dose appears in the systemic circulation as lovastatin acid Frishman & Rapier, 1989). The pharmacokinetics of lovastatin have been assessed by measuring serum concentrations of active inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic interaction between propranolol and the HMG‐CoA reductase inhibitors pravastatin and lovastatin.

Pan

Triscari

et al. 1991

Brit J Clinical Pharma

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1 Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2 Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3 Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4 Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5 These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6 The clinical significance of these changes is likely to be small.

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“…To reduce the levels of cholesterol in hyperlipidaemic patients, and therefore the risk of atherosclerosis, many inhibitors of this enzyme are being tested for clinical use. These inhibitors are known to decrease the concentration of total plasma cholesterol, low-density lipoproteins (LDL) and, in some cases, very-low-density lipoproteins (VLDL) [ 51.They are also known to increase total high-density lipoproteins (HDL) in some patients [6], but their effect on the subfractions of HDL remains unknown. Specific subfractions of HDL are involved in reverse cholesterol transport and have a protective role against atherosclerosis.…”

mentioning

confidence: 99%

“…They are also known to increase total high-density lipoproteins (HDL) in some patients [6], but their effect on the subfractions of HDL remains unknown. Specific subfractions of HDL are involved in reverse cholesterol transport and have a protective role against atherosclerosis.…”

mentioning

confidence: 99%

“…HDL contains two major subclasses, HDL, and H D h , which can be further resolved Recent studies have suggested that it is the H D b subclass, and in particular the apolipoprotein E (apo E) -rich HDL,, subfraction, which offers coronary protection [5]. Since one stage in the system of particle conversion involves the exchange of cholesteryl ester and triacylglycerol (TG) molecules, and since hypertriglyceridaemic patients are known t o be at increased coronary risk [6], it is apparent that they could provide useful subjects for study. Blood samples (30 ml) were taken into EDTA (1 mg/ml) from 32 apparently healthy male subjects aged between 40 and 65 years who were attending a 'well man's clinic'.…”

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confidence: 99%

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The effect of 3-hydroxy 3-methylglutaryl-CoA reductase inhibitor on the subfractions of high-density lipoprotein of the rabbit

1990

Biochemical Society Transactions

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To study the development of atherosclerosis and its relation to lipoproteins and cholesterol, a variety of animal models have been used. Rabbits have been fed fats and animal proteins to induce atherosclerosis which resembles the disease process as it occurs in man [ l ] . The response is obtained in short periods of time and lipid-rich lesions are easily identified in aorta and coronary arteries of rabbits. The rabbit is also very sensitive to 3-hydroxy 3-methylglutaryl-CoA reductase (HMG-CoA reductase) inhibitors 121, the drug used in the present study.HMG-CoA reductase is an enzyme required for the synthesis of cholesterol from acetyl-CoA [3]. Approximately two-thirds of plasma cholesterol derives from this synthesis 141. To reduce the levels of cholesterol in hyperlipidaemic patients, and therefore the risk of atherosclerosis, many inhibitors of this enzyme are being tested for clinical use. These inhibitors are known to decrease the concentration of total plasma cholesterol, low-density lipoproteins (LDL) and, in some cases, very-low-density lipoproteins (VLDL) [ 51.They are also known to increase total high-density lipoproteins (HDL) in some patients [6], but their effect on the subfractions of HDL remains unknown. Specific subfractions of HDL are involved in reverse cholesterol transport and have a protective role against atherosclerosis.In the present study, we have therefore analysed the subfractions of HDL of the normolipidaemic rabbit submitted to treatment with Simvastatin, a potent HMG-CoA reductase inhibitor.Six female New Zealand White rabbits were fed a standard laboratory rabbit chow ad libitum. The normal lipoprotein profile and plasma cholesterol and triacylglycerol concentrations were determined over a 6 week period before administration of Simvastatin (10 mg/day per kg), dissolved in ether and sprinkled over the food, for a further 8 week period.Blood samples (20 ml) were drawn from marginal ear veins and collected in EDTA vials after 2 and 5 weeks from the start of the study and after 1, 3, 5 and 8 weeks of introducing Simvastatin to the diet.VLDL, LDL and HDL were isolated by ultracentrifugation at densities of 1.02 g/ml, 1.055 g/ml and 1.25 g/ml, respectively. An aliquot of each HDL sample obtained was submitted to gradient polyacrylamide-gel electrophoresis on Pharmacia PAA 4/30 gels and the resulting subfractions scanned and quantified using the BioRad 620 video densitometer.Abbreviations used: HMG-CoA reductase, 3-hydroxy 3-methylglutaryl-CoA reductase; LDL, low-density lipoproteins; VLDL. very-low-density lipoproteins; HDL, high-density lipoproteins.A further portion of each HDL sample was exhaustively dialysed for removal of NaBr and applied to Heparin-Sepharose affinity chromatography column, for the separation of apo-E-poor and apo-E-rich HDL [7,8].All the animals survived the study, but one rabbit was withdrawn at the eighth week of drug treatment owing to anorexia. [The following results are expressed as mean value k S.D. ( n = 6, except for week 8, when n = S)]. The mean concent...

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Lovastatin: An HMG-CoA Reductase Inhibitor for Lowering Cholesterol

Cited by 19 publications

References 46 publications

Effects of long-term treatment with simvastatin on plasma lipids and lipoproteins in patients with primary hypercholesterolemia

Effects of long-term treatment with simvastatin on plasma lipids and lipoproteins in patients with primary hypercholesterolemia

Pharmacokinetic interaction between propranolol and the HMG‐CoA reductase inhibitors pravastatin and lovastatin.

The effect of 3-hydroxy 3-methylglutaryl-CoA reductase inhibitor on the subfractions of high-density lipoprotein of the rabbit

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