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Drugs

, Volume 36, Issue 4, pp 429–454 | Cite as

Lovastatin

A Preliminary Review of its Pharmacodynamic Properties and Therapeutic Use in Hyperlipidaemia
  • Julian M. Henwood
  • Rennie C. Heel
Drug Evaluation

Summary

Synopsis

Lovastatin is the first of a new class of cholesterol lowering drugs that competitively inhibit HMG-CoA reductase. This new drug decreases cholesterol synthesis and apolipoprotein B concentrations, and increases LDL receptor activity without adverse effects on other products in the cholesterol pathway. In patients with heterozygous familial or polygenic (non-familial) hypercholesterolaemia, oral lovastatin 20 to 40mg twice daily reduces plasma total cholesterol and LDL-cholesterol concentrations by 25 to 40% over a period of several weeks. Lovastatin also produces decreases in plasma triglyceride and VLDL-cholesterol concentrations, although to a lesser extent. In addition, small though significant increases in HDL-cholesterol concentrations have been observed. Combined administration of lovastatin with other lipid-lowering drugs results in further reductions in plasma total and LDL-cholesterol concentrations beyond those seen with either drug alone. From findings in short term studies, lovastatin appears to be well tolerated with a low incidence of side effects. However, liver function tests and eye examinations for possible lens opacities are advised, and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established.

As would be expected at this relatively early stage of its clinical ‘life’, lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration. Nevertheless, if the substantial improvements to patients’ lipid and lipoprotein profiles observed in short term studies are maintained during long term administration, then lovastatin will have an important role in the pharmacological management of hyperlipidaemia.

Pharmacodynamic Studies

Lovastatin is a reversible competitive inhibitor of HMG-CoA reductase in hepatocytes, an early and rate-limiting enzyme in the biosynthesis of cholesterol. Lovastatin effectively reduces cholesterol synthesis in vivo and in vitro, without depleting vital stores of cholesterol in vivo. It markedly lowers plasma cholesterol and LDL-cholesterol in animals, other than rodents, which are normolipidaemic or hypercholesterolaemic. In rodents, lovastatin is ineffective in reducing plasma cholesterol; in this model the inhibition of HMG-CoA reductase is accompanied by an increase in its synthesis and a decrease in its degradation.

Double-blind studies with placebo in healthy volunteers have shown lovastatin in doses from 12.5 to 100mg daily to significantly lower serum total cholesterol concentrations without significant alteration to HDL-cholesterol, VLDL-cholesterol and serum triglyceride concentrations. Administration of lovastatin decreases apolipoprotein B concentrations by 25 to 34% in healthy volunteers receiving 6.25 to 50mg twice daily, and by 23 to 33% in hyperlipidaemic patients receiving 20 to 40mg twice daily. Small elevations of approximately 10% were also observed for apolipoprotein A I and A II concentrations following similar doses of lovastatin in patients with heterozygous familial or non-familial (polygenic) hypercholesterolaemia. Lovastatin increases the number of hepatic LDL receptors and increases the fractional catabolic rate of LDL. The reduction in apolipoprotein B concentrations appears to be a result of an increase in LDL degradation, and thus the plasma cholesterol concentration is lowered.

Adrenocortical function, as assessed by response to ACTH, is not impaired to any significant degree following short term administration of lovastatin to healthy volunteers and hypercholesterolaemic patients.

Pharmacokinetic Properties

Lovastatin is converted to a number of active metabolites, with peak plasma concentrations occurring within 2 to 4 hours following oral administration, and steady-state concentrations are achieved within 2 to 3 days. Lovastatin undergoes extensive first-pass hepatic extraction with less than 5% of an oral dose reaching the general circulation as active HMG-CoA reductase inhibitors. Major metabolites are the β-hydroxyacid of lovastatin, its 6′-hydroxyderivative and two other unidentified metabolites. Parent drug and the metabolites are predominantly excreted in bile.

Therapeutic Trials

The majority of clinical studies have been conducted in patients with heterozygous familial hypercholesterolaemia or other less well defined causes of primary hypercholesterolaemia (non-familial), and have been mainly short term (1 to 2 months). Administration of lovastatin 20 to 40mg twice daily decreases plasma total cholesterol by 23 to 40% and LDL-cholesterol concentrations by 24 to 39% in patients heterozygous for familial hypercholesterolaemia, with similar reductions in patients with non-familial hypercholesterolaemia. Maximal hypocholesterolaemic effects are usually evident within 4 to 6 weeks. In 2 double-blind placebo-controlled multicentre trials, lovastatin decreased total triglyceride concentrations by 14 to 16% and by 23 to 27% in patients with familial or non-familial hypercholesterolaemia, respectively, following administration of 20 to 40mg twice daily for 6 weeks. Significant elevations in HDL-cholesterol concentrations of approximately 10% have frequently been observed in patients with primary hypercholesterolaemia during short term administration of lovastatin 20 to 40mg twice daily. At this dosage, ‘target’ therapeutic objectives of lowering concentrations of plasma total and LDL-cholesterol to 2.4 and 1.6 g/L or below, respectively, and lowering the LDL-C: HDL-C ratio to 3 or less, have been achieved in patients with non-familial hypercholesterolaemia, but not in patients heterozygous for familial hypercholesterolaemia. Lovastatin had minimal effect in reducing plasma cholesterol concentrations in the few homozygous patients studied.

Combined administration of lovastatin and other lipid-lowering drugs, such as the bile acid resins, has proved more effective than monotherapy in reducing elevated plasma cholesterol concentrations in patients with primary hypercholesterolaemia. Further reductions of 31 and 35% in the plasma total cholesterol concentration, and of approximately 50% in the LDL-C: HDL-C ratio, have been observed following addition of lovastatin 20mg 2 or 3 times daily for over 6 and 12 months, respectively, to the treatment of heterozygous patients maintained on cholestyramine or colestipol and nicotinic acid (niacin).

In 2 large comparative studies, lovastatin 40mg twice daily for 12 to 14 weeks reduced LDL-cholesterol concentrations to a significantly greater extent than cholestyramine 4 to 12g twice daily or probucol lg daily in patients with familial or non-familial hypercholesterolaemia.

Although in the few patients followed for long periods of continued treatment (up to 4 years) lovastatin maintained its hypocholesterolaemic effect, further long term studies in larger groups of patients are needed to confirm the continued effectiveness of this drug during treatment periods of several years, and to establish the effect of such treatment on cardiovascular morbidity and mortality.

Side Effects

Gastrointestinal disturbances, such as flatulence, irregular bowel movements and nausea, account for the majority of clinical symptoms reported during lovastatin therapy. Headaches, rashes, insomnia and myalgia occur in a small proportion of patients. Although lovastatin is generally well tolerated, the intensity and duration of unwanted events have been severe enough to warrant discontinuation of treatment in approximately 2% of patients. Increases in lens opacities have been observed after short term treatment with lovastatin, although the overall prevalence did not increase. However, further studies are required to clarify the clinical significance (if any) of this finding.

Myopathy, associated with increases in creatine phosphokinase and often characterised by myalgia or muscle weakness, has occurred in 0.5% of patients receiving lovastatin; this condition has also been noted in patients receiving concurrent cyclosporin, gemfibrozil, nicotinic acid or combinations of these drugs. Elevations in serum transaminases have occurred in 5% of patients, resulting in occasional withdrawal from lovastatin treatment. Enzyme elevations evident during lovastatin treatment are usually mild and transient, and dosage reductions or withdrawal of therapy have resulted in a return of these increases to within normal limits.

Since most studies reported to date have been relatively short term, and since lovastatin will be administered continuously over long periods in clinical practice, further long term studies are needed to confirm its side effect profile.

Dosage and Administration

Lovastatin is indicated as adjunct therapy in patients with elevated plasma cholesterol concentrations secondary to elevations of LDL-cholesterol when dietary measures alone, including weight reduction and limitation of alcohol intake, do not achieve adequate results. The standard starting dose is 20mg once daily with the evening meal for less severe forms of hypercholesterolaemia. These starting doses may be increased to a maximum of 80mg in single or divided doses, depending on the patient’s response. Dosage adjustments should be undertaken at intervals of 4 weeks or more. Dietary measures should be continued during lovastatin therapy. Eye examinations using a slit lamp, and laboratory measures of liver function, should be regularly undertaken during lovastatin administration.

Keywords

Lovastatin Probucol Familial Hypercholesterolaemia Preliminary Review Colestipol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Albers-Schönberg G, Joshua H, Lopez MB, Hensens OD, Springer JP, et al. Dihydromevinolin, a potent hypocholesterolemic metabolite produced by aspergillus terreus. Journal of Antibiotics 34: 507–512, 1981PubMedCrossRefGoogle Scholar
  2. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase and a cholesterol-lowering agent. Proceedings of the National Academy of Sciences of the United States of America 77: 3957–3961, 1980PubMedCrossRefGoogle Scholar
  3. Arad Y, Ramakrishnan R, Ginsberg HN. Effects of mevinolin therapy on apolipoprotein B metabolism in subjects with combined hyperlipidemia. Abstract. Clinical Research 35: 496A, 1987Google Scholar
  4. Bergstrom JD, Wong GA, Edwards PA, Edmond J. The regulation of acetoacetyl-CoA synthetase activity by modulators of cholesterol synthesis in vivo and the utilization of acetoacetate for cholesterogenesis. Journal of Biological Chemistry 259: 14548–14553, 1984PubMedGoogle Scholar
  5. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolaemia heterozygotes. Proceedings of the National Academy of Sciences of the United States of America 80: 4124–4128, 1983PubMedCrossRefGoogle Scholar
  6. Brown MS, Goldstein JL. Multivalent feedback regulation of HMG-CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. Journal of Lipid Research 21: 505–517, 1980PubMedGoogle Scholar
  7. Brown MS, Goldstein JL. Lipoprotein receptors in the liver control signals for plasma cholesterol traffic. Journal of Clinical Investigation 72: 743–749, 1983PubMedCrossRefGoogle Scholar
  8. Brown MS, Goldstein JL. The hyperlipoproteinemias and other disorders of lipid metabolism. In Braunwald et al. (Eds) Harrison’s principles of internal medicine. 11th ed., pp. 1650–1661, McGraw-Hill Book Company, New York, 1987Google Scholar
  9. Brown WV, Goldberg IJ, Ginsberg HN. Treatment of common lipoprotein disorders. Progress in Cardiovascular Diseases 27: 1–20, 1984PubMedCrossRefGoogle Scholar
  10. Chao Y-S, Kroon PA, Yamin T-T, Thompson GM, Alberts AW. Regulation of hepatic receptor-dependent degradation of LDL by mevinolin in rabbits with hypercholesterolaemia induced by a wheat starch-casein diet. Biochimica et Biophysica Acta 754: 134–141, 1983PubMedCrossRefGoogle Scholar
  11. Davis RA, Highsmith WE, Malone-McNeal M, Archambault-Schexnayder J, Kuan J-CW. Bile acid synthesis by cultured hepatocytes: inhibition by mevinolin, but not by bile acids. Journal of Biological Chemistry 258: 4079–4082, 1983PubMedGoogle Scholar
  12. Davis RA, Hyde PM, Kuan J-CW, Malone-McNeal M, Archambault-Schexnayder J. Bile acid secretion by cultured rat hepatocytes: regulation by cholesterol availability. Journal of Biological Chemistry 258: 3661–3667, 1983PubMedGoogle Scholar
  13. East C, Grundy SM, Bilheimer DW. Normal cholesterol levels with lovastatin (mevinolin) therapy in a child with homozygous familial hypercholesterolemia following liver transplantation. Journal of the American Medical Association 256: 2843–2848, 1986PubMedCrossRefGoogle Scholar
  14. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. New England Journal of Medicine 318: 47–48, 1988PubMedCrossRefGoogle Scholar
  15. Edwards PA, Lan S-F, Fogelman AM. Alterations in the rates of synthesis and degradation of rat liver 3-hydroxy-3-methylglutaryl Coenzyme A reductase produced by cholestyramine and mevinolin. Journal of Biological Chemistry 258: 10219–10222, 1983PubMedGoogle Scholar
  16. Endo A. Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. Journal of Medicinal Chemistry 28: 401–405, 1985PubMedCrossRefGoogle Scholar
  17. Endo A. Monacolin K, a new hypocholesterolemic agent produced by a Monascus species. Journal of Antibiotics 32: 852–854, 1979PubMedCrossRefGoogle Scholar
  18. Endo A, Kuroda M, Tsijita Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrium. Journal of Antibiotics 29: 1346–1348, 1976PubMedCrossRefGoogle Scholar
  19. Endo A, Tsujita Y, Kuroda M, Tanzawa K. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochimica et Biophysica Acta 575: 266–276, 1979PubMedCrossRefGoogle Scholar
  20. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. New England Journal of Medicine 276: 34–44, 94–103, 148–156, 215–225, 273–281, 1967PubMedCrossRefGoogle Scholar
  21. Garg A, Grundy SM. Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. New England Journal of Medicine 318: 81–86, 1988PubMedCrossRefGoogle Scholar
  22. Goldstein JL, Brown MS. The low density lipoprotein pathway and its regulation to atherosclerosis. Annual Review of Biochemistry 46: 897–930, 1977PubMedCrossRefGoogle Scholar
  23. Grundy SM, Bilheimer DW. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects on cholesterol balance. Proceedings of the National Academy of Sciences of the United States of America 81: 2538–2542, 1984PubMedCrossRefGoogle Scholar
  24. Grundy SM, Vega GL. Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia. Journal of Lipid Research 26: 1464–1475, 1985PubMedGoogle Scholar
  25. Grundy SM, Vega GL, Bilheimer DW. Influence of combined therapy with mevinolin and interrruption of bile-acid reabsorption on low density lipoproteins in heterozygous familial hypercholesterolaemia. Annals of Internal Medicine 103: 339–343, 1985PubMedGoogle Scholar
  26. Hagemenas FC, Lindsay S, Illingworth DR. The influence of mevinolin on cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia. Abstract. Circulation 74 (Suppl. II): 797, 1986Google Scholar
  27. Halpin RA, Vyas KP, Kari P, Arison BH, Ulm EH, et al. In vivo metabolism of lovastatin. Abstract no. 84. Pharmacologist 29: 150, 1987Google Scholar
  28. Havel RJ, Hunninghake DB, Illingworth DR, Lees RS, Stein EA, et al. Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolaemia. Annals of Internal Medicine 107: 609–615, 1987PubMedGoogle Scholar
  29. Hoeg JM, Maher MB, Bailey KR, Brewer Jr HB. The effects of mevinolin and neomycin alone and in combination on plasma lipid and lipoprotein concentrations in type II hyperlipoproteinemia. Atherosclerosis 60: 209–214, 1986PubMedCrossRefGoogle Scholar
  30. Hoeg JM, Maher MB, Zech LA, Bailey KR, Gregg RE, et al. Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia. American Journal of Cardiology 57: 933–939, 1986PubMedCrossRefGoogle Scholar
  31. Huff MW, Telford DE, Woodcroft K, Strong WLP. Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs. Journal of Lipid Research 26: 1175–1186, 1985PubMedGoogle Scholar
  32. Hunninghake DB, Miller VT, Goldberg I, Schonfeld G, Stein EA, et al. Lovastatin: follow-up ophthalmologic data. Journal of the American Medical Association 259: 354–355, 1988PubMedCrossRefGoogle Scholar
  33. Illingworth DR. Mevinolin plus colestipol in therapy for severe heterozygous familial hypercholesterolaemia. Annals of Internal Medicine 101: 598–604, 1984PubMedGoogle Scholar
  34. Illingworth DR. Comparative efficacy of once versus twice daily mevinolin in the therapy of familial hypercholesterolemia. Clinical Pharmacology and Therapeutics 40: 338–343, 1986PubMedCrossRefGoogle Scholar
  35. Illingworth DR. Long term administration of lovastatin in the treatment of hypercholesterolaemia. European Heart Journal 8 (Supplement E): 103–111, 1987PubMedCrossRefGoogle Scholar
  36. Illingworth DR, Corbin D. The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia. Proceedings of the National Academy of Sciences of the United States of America 82: 6291–6294, 1985PubMedCrossRefGoogle Scholar
  37. Illingworth DR, Sexton GJ. Hypocholesterolemic effects of mevinolin in patients with heterozygous familial hypercholesterolaemia. Journal of Clinical Investigation 74: 1972–1978, 1984PubMedCrossRefGoogle Scholar
  38. Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase. Journal of Clinical Investigation 66: 1094–1100, 1980PubMedCrossRefGoogle Scholar
  39. Kovanen PT, Bilheimer DW, Goldstein JL, Jaramillo JJ, Brown MS. Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog. Proceedings of the National Academy of Sciences of the United States of America 78: 1194–1198, 1981PubMedCrossRefGoogle Scholar
  40. Kritchevsky D, Tepper SA, Klurfield DM. Influence of mevinolin on experimental atherosclerosis in rabbits. Pharmacological Research Communications 13: 921–926, 1981PubMedCrossRefGoogle Scholar
  41. Kroon PA, Hand KM, Huff JW. Alberts AW. The effects of mevinolin on serum cholesterol levels of rabbits with endogenous hypercholesterolaemia. Atherosclerosis 44: 41–48, 1982PubMedCrossRefGoogle Scholar
  42. LaRosa JC. The mechanism of action of lipid-lowcring drugs. Angiology 33: 562–576, 1982PubMedCrossRefGoogle Scholar
  43. Laue L, Hoeg JM, Barnes K, Loriaux LD, Chrousos GP. The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway. Journal of Clinical Endocrinology and Metabolism 64: 531–535. 1987PubMedCrossRefGoogle Scholar
  44. Liscum L, Luskey KL, Chin DJ, Ho YK, Goldstein JL, et al. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and its MRNA in rat liver as studied with a monoclonal antibody and a cDNA probe. Journal of Biological Chemistry 258: 8450–8455, 1983PubMedGoogle Scholar
  45. Lovastatin Study Group II. Therapeutic response to lovastatin (mevinolin) in nonfamilial hypercholesterolaemia. Journal of the American Medical Association 256: 2829–2834, 1986CrossRefGoogle Scholar
  46. Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine in the therapy of severe primary hypercholesterolaemia. Journal of the American Medical Association 260: 359–366, 1988CrossRefGoogle Scholar
  47. Malloy MJ, Kane JP, Kunitake ST, Tun P. Complementarity of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolaemia. Annals of Internal Medicine 107: 616–623, 1987PubMedGoogle Scholar
  48. Maltese WA, Aprille JR. Induction of differentiation in neuroblastoma cells by mevinolin: relationship to cholesterol and ubiquinone synthesis and mitochondrial electron transport. Abstract. Journal of Cell Biology 99: A154. 1984Google Scholar
  49. National Cholesterol Education Program. Report of the national cholesterol education program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Archives of Internal Medicine 148: 36–39. 1988CrossRefGoogle Scholar
  50. Norman DJ, Illingworth DR, Munson J. Hosenpud J. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. New England Journal of Medicine 318: 46–47, 1988PubMedCrossRefGoogle Scholar
  51. Pappu AS, Bacon SP, Illingworth DR. The influence of lovastatin (mevinolin) on 24 hour urinary mevalonatc in familial hypercholesterolemia. Abstract. Clinical Research 35: 625A, 1987Google Scholar
  52. Parker TS, McNamara J, Brown CD, Kolb R, Ahrens Jr EH, et al. Plasma mevalonate as a measure of cholesterol synthesis in man. Journal of Clinical Investigation 74: 795–804, 1984PubMedCrossRefGoogle Scholar
  53. Singer II, Kawka DW, Kazazis DM, Alberts AW, Chen JS. et al. Hydroxymethylglutaryl coenzyme A reductase-containing hcpatocytes are distributed periportally in normal and mevinolin-treated rat livers. Proceedings of the National Academy of Sciences of the United States of America 81: 5556–5560, 1984PubMedCrossRefGoogle Scholar
  54. Sniderman A, Shapiro S, Marpole D, Skinner B, Tcng B, et al. Association of coronary atherosclerosis with hyperapobctalipoproteinemia [increased protein but normal cholesterol levels in human plasma low-density (B) lipoproteins]. Proceedings of the National Academy of Sciences of the United States of America 77: 604–608, 1980PubMedCrossRefGoogle Scholar
  55. Tanaka RD, Edwards PA, Lan S-F, Knöppel EM, Fogelman AM. The effect of cholestyramine and mevinolin on the diurnal cycle of rat hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase. Journal of Lipid Research 23: 1026–1031, 1982PubMedGoogle Scholar
  56. Thompson GR, Ford J, Jenkinson M, Traynor I. Efficacy of mevinolin as adjuvant therapy for refractory familial hypercholesterolaemia. Quarterly Journal of Medicine 232: 803–811, 1986Google Scholar
  57. Tobert JA. Lovastatin long-term safety study: interim study. Abstract, 8th International Symposium on Atherosclerosis, Rome, 1988Google Scholar
  58. Tobert JA. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. NEJM 318: 48, 1988CrossRefGoogle Scholar
  59. Tobert JA, Bell GD. Birtwell J, James I, Kukovetz WR, et al. Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzymc A reductase. in healthy volunteers. Journal of Clinical Investigation 69: 913–919. 1982PubMedCrossRefGoogle Scholar
  60. Tobert JA, Hitzcnberger G, Kukovetz WR, Holmes IB, Jones KH. Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymcthylglutaryl-coenzyme A reductase. Atherosclerosis 41: 61–65, 1982PubMedCrossRefGoogle Scholar
  61. Traber MG, Kayden HJ. Inhibition of cholesterol synthesis by mevinolin stimulates low density lipoprotein receptor activity in human monocyte-derived macrophages. Atherosclerosis 52: 1–11, 1984PubMedCrossRefGoogle Scholar
  62. Vega GL, Grundy SM. Treatment of primary moderate hypercholesterolemia with lovastatin (mevinolin) and colestipol. Journal of the American Medical Association 257: 33–38, 1987PubMedCrossRefGoogle Scholar
  63. Vyas KP, Kari PH, Pitzcnbcrger SM, Ranjit HG, Schwartz M, et al. Metabolism of lovastatin, a new cholesterol lowering drug, by rat and mouse liver microsomes. Abstract no. 85. Pharmacologist 29: 150, 1987Google Scholar
  64. Walker JF, Tobert JA. The clinical efficacy and safety of lovastatin and MK-733: an overview. European Heart Journal 8 (Suppl. E): 93–96, 1987PubMedCrossRefGoogle Scholar
  65. Warren G. Sorting signals and cellular membranes. British Medical Journal 295: 1259–1261. 1987PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1988

Authors and Affiliations

  • Julian M. Henwood
    • 1
    • 2
  • Rennie C. Heel
    • 1
    • 2
  1. 1.ADIS Drug Information ServicesAucklandNew Zealand
  2. 2.ADIS Press International Limited. Suite 15c, Manchester International Office CentreManchesterEngland

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