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Simvastatin Simvastatin Simvastatin is a lactone prodrug which is metabolized after oral ingestion to the dihydroxy open acid form which inhibits 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme which catalyses an early rate-limiting step in the biosynthesis of cholesterol. Chemistry Simvastatin (synvinolin, MK-733, Zocor) (1S,3R,7S,8S,8aR)1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-(2-[(2R,4R)-tetrahydro-4hydroxy-6-oxo-2H-pyran-2-yl]ethyl)-1-naphthyl-2,2dimethylbutanoate C25 H3805 Molecular weight :pKa Solubility in alcohol in water Octanol/water partition coefficient 418.6 - freely soluble almost insoluble high Simvastatin is a white crystalline powder. It is prepared by replacing the 2-methy-butyryl side chain of lovastatin with a 2,2-dimethybutyryl group. It is not present in any combination preparations. Pharmacology Simvastatin is a -lactone obtained by chemical modification of lovastatin. Hydrolysis of the lacton by esterases results in the dyhidroxy open acid originally desigrated by the manufacturer as L654,969, now known as Simvastatin add or SVA, which is the active form of the compound. This active metabolite is a competitive inhibitor of HMG-CoA reductase, a key rate-limiting enzyme in the cholesterol biosynthetic pathway. The Ki of inhibition of the solubil-ized HMG-CoA reductase preparation obtained from rat liver microsomes is approximately 1 x 10-10 M. The enzyme HMG-CoA reductase catalyses the conversion of HMG-CoA to mevalonate. The main mechanism of reduction of low density lipoprotein (LDL) cholesterol is that, following inhibition of HMG-CoA reductase activity, the LDL receptor density on the liver cells is increased (up regulation) and t h i s leads to an ircreased removal of LDL cholesterol from the plasma and increased catabolism of LDL cholesterol. In addition there is a reduction in the very low density lipoprotein (VLDL) cholesterol and reduced formation of LDL from VLDL. Inhibition of HMG-CoA reductase does not lead to a build up of intermediary metabolites since this enzyme step is involved early in the synthetic pathway for cholesterol. The precursor HMGCoA is readily metabolized back to acetyl CoA which participates in many biosynthetic processes throughout the tissues of the body. Two systems have been utilized to demonstrate that Simvastatin is an inhibitor of cholesterol synthesis; mammalian cells grown in culture and in vivo studies in various species. In cultured mammalian cells simvastatin inhibited the incorporation of radiolabelled acetate into sterols with IC50 values of 20 nM or less. In Hep-G2 cells Simvastatin inhibits cholesterol formation from acetate in a dose-dependent fashion without inhibiting its formation from mevalonate. HMG-CoA reductase activity was increased and the specific binding of LDL to the cells was increased, suggesting increased expression of the LDL receptor.1 In the rat the drug blocked cholesterol synthesis after a single oral dose with ID50 values of less than 0.2 mg.kg-1. Studies have been carried out in the dog to assess the effects of Simvastatin on serum total lipoprotein cholesterol. The drug effectively lowers circulating cholesterol in this species, both in the presence and absence of cholestyramine, whereas in rats it has no sustained effect on cholesterol levels. In rodents in vivo other products of the cholesterol synthetic pathway (e.g. oxysterols) inhibit cholesterol synthesis by feed back regulation and during simvastatin therapy this feed back is diminished or removed. The net result in the rat is that HMG-CoA reductase activity is increased so greatly that no fall in serum cholesterol takes place. In dogs treated with 12 g daily of cholestyramine, cholesterol is decreased by an average of 35%. Treatment of these animals with 1 and 2 mg.kg-1 daily of simvastatin resulted in an additional 29.1% and 37.6% decrease respectively from the cholestyramine baseline. These effects of simvastatin are primarily on LDL cholesterol in spite of the fact that approximately 70-80% of circulating cholesterol in the dog is in the form of high density lipoprotein (HDL). In the cholestyramineprimed dogs, LDL cholesterol decreased by 57-72% with a 19-38% increase in HDL. In cholesterol fed (0.25% of diet) rabbits 2 there was a dose dependent inhibition of the increase in serum cholesterol over the range 0.7 mg.kg -1 to 6 mg.kg-1. Ancillary pharmacology studies to assess effects on organ systems and biological parameters were conducted with L654,969. No major changes were seen. Minor effects were noted on acid secretion and respiratory parameters in dogs. s Toxicology The oral LD50 of simvastatin in mice is approximately 3.8 g.kg-1 and in rats approximately 5 g.kg-1 Hepatic changes have been detected in several species used in toxicity tests. In the rat these changes appeared to be due to proliferation of the smooth endoplasmic reticulum consequent upon induction of HMGCo-A reductase. They were reversible by mevalonate. In the rabbit a dose of 50 mg kg-1 caused a 50% mortality and a high incidence of centrilobular necrosis in the liver and tubular necrosis in the kidney. These changes were prevented by mevalonate feeding. In the dogs there were elevations of transaminases without histological changes and there were no hepatic changes in the monkey.3 Acanthosis and hyperkeratosis in the rat forestomach and testicular degeneration in the dog appear to be species specific changes. At very high doses simvastatin causes cataracts in dogs. 4 The amounts of drug in the lenses of animals developing cataracts (< 500 mg.l-1) were low and there was no change in cholesterol content or sterol composition in these lenses. While there is no clear correlation between the magnitude of serum lipid-lowering and the development of cataracts, a consistent relationship has been observed between high serum levels of drug and cataract development with simvastatin and related HMG-CoA reductase inhibitors. A suggested mechanism is that high concentrations of the drug in the aqueous humor inhibit cholesterol synthesis in the outer cortical region of the lens. There appears to be a wide margin of safety for the human lens, based on either dose or on plasma concentration. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no fetal malformations and had no effects on fertility, reproductive function or neonatal development. Other related inhibitors of HMG-CoA, however, including the open acid form of simvastatin (L-654,969) have produced treatment- related skeletal malformations in the fetus. This is thought to be a result of a decrease in the availability of mevalonic acid to the developing fetus. In vitro and in vivo genetic toxicity tests provided no evidence of an interaction of simvastatin or L-654,969 with genetic material. In mouse carcinogenicity studies conducted with simvastatin at S25 Simvastatin Simvastatin doses from 1 mg.kg -1 daily to 25 mg.kg -1 daily, there was no evidence of a treatment-related incidence of tumour types in any tissue. In similar studies in rats a statistically significant increased incidence of thyroid follicular cell adenomas was observed in females receiving 25 mg.kg -1 day-1 (31 times the maximum human dose). No other statistically significant increased incidence of tumour types was found in any tissues. Clinical pharmacology Simvastatin lowers both total and LDL cholesterol in patients with heterozygous familial, familial combined, familial dysbetalipoproteinemia and non-familial (non-FH) forms of hypercholesterolaemia 9 Simvastatin has been shown to reduce both normal and elevated LDL cholesterol concentrations by 25-40% in a dose-dependent manner with doses in the range 10-40 mg daily. Simvastatin also causes a modest reduction (10-15%) of VLDL cholesterol and a rise in HDL cholesterol of similar magnitude. There is a small reduction in concentration of triglycerides in plasma. Apolipoprotein B also falls substantially during treatment with simvastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that simvastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. As a result of these changes the ratio of total to HDL cholesterol and LDL to HDL cholesterol are reduced. However, Lp(a) levels are not reduced by treatment with this drug or other inhibitors of HMGCoA reductase 10 Female FH patients with the apoE3E3 phenotype appear to respond better to simvastatin than male patients with the same phenotype.11 In a study in 7 normolipidaemic volunteers given simvastatin 20 mg daily for a month, 125-I-labelled LDL and 131-I-labelled cyclohexanedione-treated LDL were used to quantify the receptor pathway. Simvastatin did not modify the synthetic rate of LDL-apo B but increased the catabolic rate of the receptor-dependent pathway and the contribution of this pathway to overall catabolism. It appeared that the fall in LDL could be entirely explained by enhanced fractional removal by the receptor route. 12 Simvastatin is a specific competitive inhibitor of HMG-CoA reductase. At therapeutic doses, however, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Steroidogenesis is unaffected although a small rise in ACTH levels has been noted 13 Platelet hyperreactivity in untreated FH patients is decreased by treatment with simvastatin. 14 Pharmacokinetics S26 Most pharmacokinetic studies with the drug have been carried out using radioactive tracer doses supplemented by HPLC with UV detection or FAB mass spectrometry. 15 Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding hydroxy acid, L-654,969 a potent inhibitor of HMG-CoA reductase. In some species conversion of the lactone to the open acid occurs in plasma but this 'lactonase' activity is not present in human plasma and the conversion takes place, mainly in the liver. Inhibition of HMG-CoA reductase is the basis for an assay used in pharmacokinetic studies for the -hydroxy acid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin. When the availability of L-654,969 to the systemic circulation following an oral dose of simvastatin was estimated using an intravenous reference dose of L-654,969, the value was found to be less than 5% of the dose. By analogy with the dog, simvastatin appears to be well absorbed, and undergoes extensive first- pass extraction in the liver, its primary site of action, with subsequent excretion of metabolites in the bile. Availability of active drug to the general circulation is low. Maximum plasma concentrations of inhibitors occur 1.3-2.4 hours post-dose. In dose-proportionality studies using doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg there was no substantial deviation from linearity of area under the curve (AUC) of inhibitors in the general circulation with increasing dose. The plasma profile of inhibitors is not affected when simvastatin is administered immediately before a test meal rather than in the fasting state. Pharmacokinetic studies of single and multiple doses of simvastatin showed that no accumulation of drug occurs during multiple dosing Both simvastatin and L-654,969 are highly bound to plasma proteins (98%). In a disposition study with 14C-labelled simvastatin, 100 mg (20 uCi) of drug was administered as capsules (5 x 20 mg), and blood, urine and faeces collected. 13% of the radioactivity was recovered in the urine and 60% in the faeces. Most of the urinary and faecal radioactivity was from metabolites, not simvastatin or the open acid. This suggests that the drug is well absorbed but subject to extensive biliary excretion as the drug is unlikely to be metabolised by gut flora. Less than 0.5% of the dose was recovered in the urine as HMG-CoA reductase inhibitors In plasma, inhibitors account for 14% and 28% (active and total inhibitors) of the AUC of total radioactivity, indicating that the majority of metabolites are inactive or weak inhibitors. Tissue distribution studies 4 h after a 1 mg.kg-1 intravenous dose in the rat showed high concentrations in intestinal contents and moderate amounts in the liver and kidneys. In dogs given a 60 mg.kg-1 radiolabelled dose by mouth the highest concentration 4h after the dose was in bile (2389 mg equiv.1 -1) with substantial amounts in the liver (15.6ug equiv.g -1) and kidney ( 8 . 2ug equiv.g-1). Amounts in the lens (0.08 ug equiv.g-1) aqueous humor and CSF were very low. Although it is not known whether simvastatin crosses the placenta or is excreted in breast milk, it seems likely that this will occur, given the lipid solubility of the parent compound No information is available on transfer of the active metabolites Little simvastatin or its inhibitory metabolites is excreted in the urine. Oral absorption Presystemic metabolism Plasma half life Volume of distribution Plasma protein binding extensive extensive 98% The effects of liver disease on the kinetics of simvastatin are no: known. Concentration-effect relationship There is insufficient data in man to establish concentration-effect relationships. Metabolism Simvastatin (SV) is extensively netabolized in the liver which is also the main site of action of the drug. 16 The paths of metabolism are shown in Figure 1. Metabolite 1, 6'-OH-SV, is formed by microsomal oxidation in liver. It is a major metabolite in microsomal prepara-tions. Metabolite II is an allylic rearrangement product of 1 with the with the 6'-OH group moving to the 3' position and double bond rearrangement. Metabolite IIIis a second oxidation product but with the hydroxyl group in the 3 position of the acyl side chain. It is-formed by rat microsomes. Metabolite IV is the triene, 6'- exomethy-lene-SV. It is a microsomal poduct and it may be formed by a double hydrogen abstraction catalysed by cytochrome P-450. Microsomal metabolism of these compounds is stereoselective. 17 Formation of simvastatin acid (SVA) ocurs as a result of the activity of microsomal and plasma esterases. The major metabolites pesent in human bile are the hydroxy acid form of 3'-OH-SV, and two products of 6'-exomethylene-SV (M-IV). 6'-COOH-SV (M-VI) and 6'-beta-CH2OH-SV (M-V). The acid form of M-II was inactive but M-V and M-VI were active with about 90% and 40% of the activity of SVA respectively. The main product in plasma is simvastatin acid but the main biliary metabolites have also been identified in plasma. Pharmaceutics Simvastatin is available only in tablet form. 1. Zocor (MSD, UK) tablets containing 10 mg simvastatin are peach coloured, oval film-coated and marked 'ZOCOR 10' on one side. Tablets containing 20 mg simvastatin are tan-coloured oval, film-coated and are marked 'ZOCOR 20' on one side. Simvastatin Simvastatin Simvastatin is currently marketed in Europe, Australia and South Africa. 2. Acute liver disease or unexplained persistent elevations of serum transaminases 3. Pregnancy and breast feeding 4. Women of child-bearing potential unless adequately protected by barrier contraceptive methods 5. In patients with the homozygous form of familial hypercholesterolaemia, in whom there is a complete absence of LDL receptors, therapy with simvastatin is unlikely to result in clinical benefit 6. As simvastatin has only a moderate triglyceride-lowering effect it is not indicated where hypertriglyeridaemia is the abnormality of most concern (i.e. hyperlipidaemia types I, IV and V). Therapeutic use Indications 1. Primary hypercholesterolaemia in patients who have a cholesterol ovel in excess of 7.8 mmol.l-1. Contraindications 1. Hypersensitivity to any component of the preparation Fig. 1 The metabolism of simvastatin Simvastatin acid II 3'Hydroxysimvastatin 6'-Hydroxymethylsimvastatin VI Simvastatin 6'carboxylic acid Simvastatin Simvastatin Mode of use markedly elevated CPK levels occur or if myopathy is diagnosed. Minor asymptomatic transient rises in serum transaminases may occur soon after initiation of treatment. These do not require the drug to be discontinued. There is no evidence of hypersensitivity. It is recommended that liver function tests be performed before treatment begins, every 4-6 weeks during the first 12 months of therapy and periodically thereafter in all patients. Special attention should be paid to patients who develop elevated serum transaminase levels and in such patients measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, the drug should be discontinued. Liver biopsy should be considered if elevations persist after the drug has been stopped. Simvastatin should be used with caution in patients who consume substantial quantities of alcohol. Simvastatin is generally well tolerated and adverse effects have usually been mild and transient in nature. Less than 2% of patients were withdrawn from controlled clinical studies because of effects attributable to simvastatin. Taking all clinical studies, both controlled and uncontrolled, adverse effects occurring with a frequency of 1% or more and considered by the investigator as possible, probably or definitely drug-related, were constipation, flatulence and headache. Other adverse effects occurring in 0.5-0.9% of patients were: nausea, dyspepsia, gastrointestinal cramps and other abdominal pains, diarrhoea and fatigue. 25 Before initiating therapy with simvastatin, secondary causes for elevated cholesterol values, such as obesity, poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, obstructive liver disease, or drug therapy, should be excluded. It is important to determine whether increased levels of total cholesterol are due to increased LDL cholesterol before initiating treatment. In primary hyperalphalipoproteinaemia (elevated HDL cholesterol), serum levels of total cholesterol may be elevated. Treatment with cholesterollowering agents in this instance is not indicated. When total cholesterol is elevated along with marked hypertriglyceridaemia (> 5.0 mmol.l -1), the intermediate density lipoprotein (IDL) fraction may be increased. The efficacy of simvastatin has not been evaluated in such patients. Prior to starting treatment with the drug, patients should be placed on a cholesterol-lowering diet and maintained on it during treatment. Fasting lipids should be measured and, as part of safety assessment procedures, liver function test, plasma creatine phosphokinase and urine microscopy should be performed. Simvastatin is administered initially as a 10 mg dose once daily at bed time. The maximum effect of a given dose is evident within 4 weeks. Measurement of the lipid profile and biochemical safety tests should be repeated and, if necessary, the dose can be increased to 20 mg. The maximum recommended dose is 40 mg daily although 80 mg has been used in clinical trials. In some studies the dose has been divided between morning and evening doses 8 and in others it has been given once a day but there is little to be gained by twice daily dosing or increasing the dose above 40 mg daily. Once the desired reduction of cholesterol has been achieved the patients can be seen at 2-3 month intervals. Drug therapy should be discontinued if there is a persistent increase greater than 3 times the upper limit of normal in serum transaminases or marked elevated CPK (MM fraction) of greater than ten times normal (although this test is very sensitive to heavy physical activity). Administration of simvastatin 10-40 mg daily is associated with a 23-38% decrease in LDL cholesterol which is similar regardless of the patients age, sex, pretreatment LDL-cholesterol level or diagnostic classification (familial hypercholesterolaemia, familial combined hyperlipidaemia, polygenic hyperlipidaemia). On average a 40 mg daily dose will bring about a 25-35% reduction in total cholesterol, a 15% increase in HDL-cholesterol and a 15-25% reduction in triglyceride levels.18-22 Combination therapy should be considered in patients who, despite maximal doses (40 mg) of simvastatin fail to achieve target cholesterol levels as recommended by the European Atherosclerosis Study Group 23 or National Cholesterol Education Program Expert Panel. 24 Simvastatin is effective alone or in combination with bile acid sequestrants. Combination of simvastatin 40 mg daily with cholestyramine resulted in an additional 12% reduction in cholesterol, a 9% increase in HDL and a 16% decrease in triglycerides. 19 Adverse reactions Potentially life-threatening effects None has been reported. Acute overdosage There are no data available on overdosage. No antidote is available. General measures should be adopted, and liver function should be monitored. Severe of Irreversible adverse effects Therapy with the closely associated compound, lovastatin, has been associated with myopathy, including rare instances of severe rhabdomyolysis with secondary acute renal failure. All patients recovered upon discontinuation of lovastatin therapy with appropriate supportive medical intervention. Myolysis has also been reported with simvastatin (see Clinical Trials, Emmerich et al). Symptomatic adverse effects Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness and/or marked elevations of creatine phosphokinase. Transient increases associated with heavy or unaccustomed physical activity are not a reason for cessation of treatment but patients should be asked to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin should be discontinued if Interference with clinical pathology tests No information is available. High risk groups Neonates Studies to show safety and effectiveness in neonates have not been carried out. Breast milk. It is not known whether simvastatin or its metabolites are excreted in human milk. Simvastatin should be avoided during lactation. Children Studies to show safety and effectiveness in children have not been carried out. Pregnant women The active metabolite, simvastatin acid was shown to produce fetal malformations in the offspring of pregnant rats. There are no data available for the use of simvastatin in pregnant women. Therefore, the drug is contraindicated for use in pregnancy. An interval of one month should elapse between the end of simvastatin therapy and planned conception. The elderly Although experience in elderly patients is relatively limited, efficacy using standard doses appears similar to that seen in the population as a whole. There is no apparent increase in the frequency of clinical or laboratory adverse findings. Concurrent disease Renal insufficiency. Because simvastatin does not undergo signiticant renal excretion, modifications of dosage should not be necessary in patients with renal insufficiency. Liver disease. The drug is contraindicated in patients with liver disease. Drug interactions Potentially hazardous interactions Coumarin derivatives. The administration of simvastatin appeared to slightly enhance the anticoagulant effect of warfarin mean changes in prothrombin time less than two seconds) in normal volunteers maintained in a state of low therapeutic anticoagulation The clinical importance of these findings for fully anticoagulated patients receiving concomitant chronic therapy with simvastatin is unknown. In patients taking anticoagulants, prothrombin time should be determined prior to starting therapy with simvastatin and then monitored at the intervals usually recommended for patients on coumarin anticoagulants. Simvastatin Simvastatin In clinical studies, simvastatin was used concomitantly with -_ blockers, calcium channel blockers, diuretics and non-steroidal antiinflammtory drugs (NSAIDs) without evidence of clinically significant adverse interactions. Other significant interactions Walker J F 1989 Simvastatin: the clinical profile. American Journal of Medicine 87: 44S-46S Todd PA, Goa K L 1990 Simvastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 40: 583-607 Potentially useful interactions No information yet available. References Clinical trials No outcome trial results are available. Many short term studies on hypercholesterolaemic patients have been undertaken. 1. Jones PH 1990 Lovastatin and simvastatin prevention studies. American Journal of Cardiology 66: 39B-43B An outline of the design of two proposed outcome trials. 2 Emmerich J, Aubert I, Bauduceau B et al 1990 Efficacy and safety of simvastatin (alone or in association with cholestyramine). A 1-year study in 66 patients with type II hyperlipoproteinaemia. European Heart Journal 11: 149-155 The effects and safety of simvastatin were investigated alone or in combination with cholestyramine in 66 patients with hypercholesteralaemia, in a 1-year open study. In type IIa hypercholesterolaemia (n = 41), the association was more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb hypercholesterolaemia (n = 23), combined treatment did not appear more effective than simvastatin used alone. The most serious sideas myolysis in two patients. 3. Stein E, Kreisberg R, Miller V, Mantell G, Washington L, Shapiro D R 1990 Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Multicenter Group I. Archives of Internal Medicine 150: 341-345 Simvastatin was compared with cholestyramine in a randomized open 12-week multi centre study of 251 patients with familial or confamilial hypercholesterolemia. Simvastatin, 20 mg and 40 mg daily, produced mean reductions in total cholesterol of 26% and 33%, respectively, and reductions in low-density lipoprotein choles-trol level of 32% and 40%. Cholestyramine resin, 4 to 12 g twice daily, reduced total cholesterol and low-density lipoprotein choles-erol levels 15% and 21%, respectively. High-density lipoprotein cholesterol levels were increased 8% to 10% by all treatments. Plasma triglyceride levels were moderately decreased by simvastatin treatment, while triglyceride levels increased with cholestyramine treatment. Simvastatin was better tolerated than cholestyramine, which caused many gastrointestinal tract side effects. No patient had serious drug-related adverse event. Tikkanen M J, Bocanegra T S, Walker J F, Cook T 1989 Comparison of low-dose simvastatin and gemfibrozil in the patient of elevated plasma cholesterol. A multicenter safety. The Simvastatin Study Group. American Journal of Medicine 87(4A): 47S-53S his was a 12-week, randomized, double-blind, multicentre study to compare the efficacy and safety of simvastatin and gemfibrozil in 290 patients with primary hypercholesterolemia. Patients were stratified to those with initial LDL cholesterol level less than 195 mg daily and stratum II with initial LDL at least 195 mg daily. Simvastatin as given as a dose of 5 to 20 mg once daily, gemfibrozil in a constant dosage of 600 mg twice daily. Simvastatin reduced LDL cholesterol levels by 26 and 34 percent in strata I and II, respectively. The corresponding reductions brought about by gemfibrozil were 18 and percent. Both were well tolerated. General review articles Father V M. Thompson G R 1990 HMG CoA reductase inhibitors as lipid-lowering agents: five years experience with lovastatin and an appraisal of simvastatin and pravastatin. Quarterly Journal of Medicine 74: 165-75 alker J F, Shapiro D R 1990 Hydroxymethylglutaryl coenzyme A reductase inhibitors as monotherapy in the treatment of hypercholesterolemia. American Journal of Cardiology 65: 19F-22F 1. Nagata Y, Hidaka Y, Ishida F, Kamei T 1990 Effect of simvastatin (MK-733) on the regulation of cholesterol synthesis in Hep G2 cells. Biochemical Pharmacology 40: 843-850 2. Ishida F, Watanabe K, Sato A et al 1990 Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochimica Biophysica Acta 1042: 365-373 3. Gerson R J, MacDonald J S, Alberts A W et al 1989 Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. American Journal of Medicine 87: 28S-38S 4. Gerson R J, MacDonald J S, Alberts A W et al 1990 On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. Experimental Eye Research 50: 65-78 5. Mol M J T M, Erkelens D W, Gevers-Leuven J A, Schouten J A, Stalenhoef A 1986 Effects of synvinolin (MK 733) on plasma lipids in familial hypercholesterolaemia. Lancet 2: 936-939 6. Hagemenas F C, Pappu A S, lllingworth D R 1990 The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia. European Journal of Clinical Investigation 20: 150-157 7. Molgaard J, Von Schencer H, Olsson A G 1988 Effects of simvastatin on plasma lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia. European Heart Journal 9: 541-555 8. Stuyt P M, Mol M J, Stalenhoef A F, Demacker P N, Van 't Laar A 1990 Simvastatin in the effective reduction of plasma lipoprotein levels in familial dysbetalipoproteinemia (type III hyperlipoproteinemia). American Journal of Medicine 88: 42N-45N 9. Bard J M, Luc G, Douste Blazy P et al 1989 Effect of simvastatin on plasma lipids, apolipoproteins and lipoprotein particles in patients with primary hypercholesterolaemia. European Journal of Clinical Pharmacology 37: 545-550 10. Kostner G M, Gavish D, Leopold B, Bolzano K, Weintraub M S, Breslow J L 1989 HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 80: 1313-1319 11. De Knijff P, Stalenhoef A F, Mol M J 1990 Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia. Atherosclerosis 83: 89-97 12. Malmendier C L, Lontie J F, Deleroix C, Magot T 1989 Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers. Atherosclerosis 80: 101-109 13. Mol M J, Stalenhoef A F, Stuyt P M, Hermus A R, Demacker P N, Van 'T Laar A 1989 Effects of inhibition of cholesterol synthesis by simvastatin on the production of adrenocortical steroid hormones and ACTH. Clinical Endocrinology Oxford 31: 679-689 14. Schror K, Lobel P, Steinhagen Thiessen E 1989 Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia. Eicosanoids 1989, 2: 39-45 15. Vickers S, Duncan C A, Chen I W, Rosegay A, Duggan D E 1990 Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metabolism and Disposition 18: 138-145 16. Vickers S, Duncan C A, Vyas K P et al 1990 In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metabolism and Disposition 18: 476-483 17. Vyas K P, Kari P H, Pitzenberger S M 1990 Regioselectivity and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors. Biochemical Biophysical Results and Communication 166: 1155-1162 18. Simons L A, Nestel P J, Calvert G D, Jennings G L 1987 Effects of MK-733 on plasma lipid and lipoprotein levels in subjects with hypercholesterolaemia. Medical Journal of Australia 147 (2): 65-68 19. Mol M J, Stuyt P M, Demacker P N, Stalenhoef A F 1990 The effects of simvastatin on serum lipoproteins in severe hypercholesterolaemia. Netherlands Journal of Medicine 36: 182-190 20. Antonicelli R, Onorato G, Pagelli P, Pierazzoli L, Paciaroni E 1990 Simvastatin in the treatment of hypercholesterolemia in elderly patients. Clinical Therapeutics 12: 165-171 21. Bach LA, Cooper M E, O'Brien R C, Jerums G 1990 The use of simvastatin, an HMG CoA reductase inhibitor, in older patients with hypercholesterolemia and atherosclerosis. Journal of the American Geriatric Society:38: 10-14 22. Schulzeck P, Bojanovski M, Jochim A, Canzler H, Bojanovski D:1988 Comparison between simvastatin and bezafibrate in effect on plasma lipoproteins and apolipoproteins in primary hypercholesterolaemia. Lancet 1: 611-613 23. European Atherosclerosis Society Study Group 1988 The recognition and management of hyperlipidaemia in adults: A policy statement of the European Atherosclerosis Society. European Heart Journal 9: 571-600 24. The Expert Panel. 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: 36-69 25. Stalenhoef A F, Mol M J, Stuyt PM 1989 Efficacy and tolerability of simvastatin (MK-733). American Journal of Medicine 87: 39S-43S S29