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At least 19 recordsLinked to original sources
PubMed1992

Effect of simvastatin, ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia.

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day). The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 +/- 0.10 to 0.94 +/- 0.05, mean +/- S.E.; p less than 0.02), with ursodeoxycholic acid (from 1.51 +/- 0.10 to 0.86 +/- 0.03, mean +/- S.E.; p less than 0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 +/- 0.01 to 0.70 +/- 0.05, p less than 0.02). The cholesterol saturation index during combination therapy was significantly lower (p less than 0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 +/- 14 mumols/hr to 81 +/- 12 mumols/hr, p less than 0.01, and 70 +/- 9 mumols/hr, p less than 0.01) without affecting bile acid and phospholipid outputs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of simvastatin and probucol in hypercholesterolemia (Simvastatin Multicenter Study Group II).

This 12-week, randomized, double-blind, multicenter study compared the efficacy, tolerability and safety of simvastatin (a potent HMG-CoA reductase inhibitor) and probucol. Two doses of simvastatin, 20 or 40 mg once daily, were compared to probucol, 500 mg twice daily. Both simvastatin doses were significantly more effective than probucol in improving the plasma lipid profile. Mean reduction in low density lipoprotein (LDL) cholesterol was 34% with 20-mg simvastatin and 40% with the 40-mg dosage, compared to a mean reduction of 8% with probucol. Simvastatin significantly decreased total cholesterol, triglycerides and apolipo-protein B, and increased high density lipoprotein (HDL) cholesterol and apolipoprotein A-I. Probucol caused some reduction in LDL cholesterol but significantly decreased HDL cholesterol. Both simvastatin and probucol were well tolerated and no serious drug-related events occurred. Simvastatin appears to be a well-tolerated and effective new agent used once-a-day as an adjunct to diet in the management of patients with hypercholesterolemia.

Adult↗
PubMed1989

Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol. A multicenter study. The Simvastatin Study Group.

A 12-week, randomized, double-blind, multicenter study was undertaken to compare the efficacy, tolerability, and safety of simvastatin and gemfibrozil in 290 patients with primary hypercholesterolemia. Patients in stratum I (initial low-density lipoprotein cholesterol level less than 195 mg/dl) received simvastatin 5 to 10 mg once every afternoon; patients in stratum II (initial low-density lipoprotein cholesterol level at least 195 mg/dl) received 10 to 20 mg once every afternoon. Gemfibrozil was given in a constant dosage of 600 mg twice daily in both strata. Simvastatin reduced low-density lipoprotein cholesterol levels by 26 and 34 percent in strata I and II, respectively. The corresponding reductions brought about by gemfibrozil were 18 and 17 percent. High-density lipoprotein cholesterol was increased by 7 and 9 percent by simvastatin and by 17 and 16 percent by gemfibrozil in strata I and II, respectively. Ratios of low-density to high-density lipoprotein cholesterol were reduced by approximately 25 percent by simvastatin 5 to 10 mg once every afternoon and gemfibrozil 600 mg twice daily, but were reduced by 37 percent by simvastatin 10 to 20 mg once every afternoon. Both drugs reduced plasma triglyceride levels, but gemfibrozil was much more effective. The short-term tolerability and safety of both drugs appeared to be good during the 12-week study. The results suggest that both drugs have useful but distinctly different lipid-modifying properties.

Anticholesteremic Agents↗
PubMed1990

Safety, tolerability, and efficacy of simvastatin and fenofibrate--a multicenter study. Simvastatin-Fenofibrate Study Group.

Five centers participated in a double-blind, randomized, active-drug controlled study. The selected patients had a diagnosis of primary hypercholesterolemia (phenotype IIa or IIb, total cholesterol [TC] greater than 300 mg/dl, low-density lipoprotein [LDL] cholesterol greater than 195 mg/dl, triglycerides [TG] less than 350 mg/dl). Throughout the study the patients observed a lipid-lowering diet (American Heart Association). After a baseline placebo period (4 weeks), the patients were randomly assigned to simvastatin 20 mg q.p.m. or fenofibrate 200 mg b.i.d. If after 6 weeks of treatment the LDL cholesterol level remained over 140 mg/dl the dose of simvastatin was doubled. The total duration of treatment was 10 weeks. One hundred eighty-four patients completed the study; age ranged from 17 to 72 years (mean 46; 129 men, 55 women). Seventy-nine patients had ischemic heart diseases. Simvastatin significantly reduces TC, LDL, and apolipoprotein (apo) B (30%, 35%, and 27%, respectively). These effects are larger than those of fenofibrate (19%, 22%, and 14%, respectively). Fenofibrate decreased very-low-density lipoprotein and TG, and increased high-density lipoprotein and apo A1, to a larger extent than simvastatin. However, the difference reached statistical significance only for TG (29% versus 17%). Both drugs were well tolerated. Clinical adverse experiences occurred with a low frequency, and few of these were considered drug related (6 and 8% in the simvastatin and fenofibrate groups, respectively). Only two patients had serious laboratory adverse experiences considered drug related or possibly drug related (one in each treatment group with increased SGPT, gamma-GT, and/or creatine phosphokinase).

Adolescent↗
PubMedDate not supplied

Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. The Simvastatin and Lovastatin Multicenter Study Participants.

The efficacy, safety profile, and tolerability of the HMG-CoA reductase inhibitors simvastatin and lovastatin were compared in a multicenter, randomized, double-blind study in patients with moderate hypercholesterolemia. Commonly prescribed doses of these two drugs were used by 544 men and women, who followed an American Heart Association phase I diet during a 6-week baseline period and for the 24 weeks of active treatment. Simvastatin 10 mg and lovastatin 20 mg produced statistically significant reductions in total and low-density lipoprotein cholesterol (LDL-C). Patients receiving simvastatin 10 mg once daily and lovastatin 20 mg once daily experienced similar reductions in LDL-C and total cholesterol; however, simvastatin 20 mg was statistically superior to lovastatin 40 mg in decreasing these lipid fractions. For all treatment groups, increases in high-density lipoprotein cholesterol were inversely related to baseline levels. Moderate decreases in triglycerides occurred with all doses. Lipoprotein(a) levels, measured in a subset of patients, were similar before and after treatment. Both drugs were well tolerated.

Adult↗
PubMed1989

[Swiss simvastatin multicenter study: 1. Efficacy of 10 mg simvastatin daily in patients with primary hypercholesterolemia].

In a Swiss multicenter study with determination of lipid and lipoprotein parameters in a central laboratory, the efficacy of simvastatin, MSD, was evaluated in patients with primary hypercholesterolemia. Lipid and lipoprotein values were determined in 109 patients before and after 6 weeks' therapy with 10 mg simvastatin per day. A significant decrease in total cholesterol, LDL-cholesterol and apo B, of 21.1, 25.8 and 24.1% respectively, was observed. No influence of simvastatin on apo A-II was found, but HDL-cholesterol and apo A-I were slightly increased (+6.1 and 4.4% respectively). The data show that HMG-CoA reductase inhibitors constitute a new class of effective drugs for the treatment of hypercholesterolemia.

Adult↗
PubMed1992

[The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin].

Previous studies had determined the role played by L-carnitine and simvastatin in the treatment of altered lipidemia in dialyzed patients with chronic uremia. The authors carried out a study on the above substances either singly or together administered to the same patients with chronic uremia in hemodialysis. This study was aimed at demonstrating the possible synergic normolipidemic action of both substances in comparison with their single administration, because their different mechanism of action could be metabolically enhanced. The obtained results demonstrated that the therapeutic association proposed is preferable to the use of the single substances. Moreover, a higher and more rapid normolipidemic effect was obtained after using L-carnitina associated with simvastatin with respect to the separated substances.

Aged↗
PubMed1991

Lecithin: cholesterol acyltransferase activity in familial hypercholesterolemia treated with simvastatin and simvastatin plus low-dose colestipol.

In 19 patients with heterozygous familial hypercholesterolemia (FH), the effects of simvastatin (S) 20 mg/d, 40 mg/d, and 40 mg/d plus low-dose colestipol (10 g/d) on plasma lipids, plasma lipoproteins, and plasma lecithin: cholesterol acyltransferase (LCAT) activity were investigated after an original dose-range escalation/descalation design. The drug regimen was changed every 8 weeks. A significant reduction in total cholesterol and LDL-cholesterol was observed, reaching 39% and 54% for the drug combination (week 28), and total apoprotein B and LDL-apoprotein B were reduced by 39% and 50%, respectively. Triglycerides were significantly lowered by S alone (up to 29% with 40 mg/d). HDL-cholesterol increased during therapy but the cholesterol content in HDL2-HDL3 fractions (isolated by ultracentrifugation) did not change significantly during the different steps. The ratio LDL-C/HDL-C fell by 57% at week 28. Plasma LCAT activity expressed as FER was significantly enhanced by S alone (+33%), and a further increase on drug combination regimen (+58%) was observed. This effect could be considered as a consequence of the increased fractional clearance of LDL-C. It tended to be sustained during the descalation part of the study. Biochemical adverse effects were scarce and transient. In conclusion, the combination therapy increased the plasma LCAT/FER activity without a preferential enhancement in HDL2-C concentration. This original design allowed to define the most appropriate individual cholesterol-lowering drug dosage in FH patients.

Adolescent↗
PubMed1991

Bioconversion of the sodium salt of simvastatin (MK-733) to 6-desmethyl-6-alpha-hydroxymethyl simvastatin.

An actinomycete (MA 6474, ATCC 53828) isolated from a soil sample (Mutare, Zimbabwe) was found to biotransform the sodium salt of Simvastatin (MK-733) to 6-alpha-hydroxymethyl MK-733, 6-beta-hydroxymethyl MK-733, and 6-ring-hydroxy MK-733. The bioconversion efficiency to the desired compound, 6-alpha-hydroxymethyl MK-733, was enhanced by optimizing the physico-chemical parameters of the process. In shake flask cultures, addition of magnesium (0.125 mg/l Mg SO4.7H2O) to the medium resulted in a five-fold increase in the rate of bioconversion to the alpha diastereomer. The ratio of bioconversion products (6-alpha-hydroxymethyl,6-beta-hydroxymethyl, and 6-ring-hydroxy MK-733) was regulated by pH. Process improvements and scale up in 23-1 fermentors, which consisted of a controlled addition of substrate (MK-733), resulted in a 2-fold increase in alpha diastereomer production (42 vs. 79 U/ml) and a 23-fold rate increase in the formation of alpha-diastereomer. A high diastereomeric ratio (alpha: beta = 9:1) facilitated downstream processing.

Actinomycetales↗
PubMed1992

Effects of combined bezafibrate-simvastatin appraised in healthy subjects.

The occurrence of clinical and biochemical side effects of bezafibrate (400 mg daily) or simvastatin (20 mg daily) alone or combined was appraised in 13 healthy male normolipidemic subjects according to a single blind design. Each period of 2 weeks of treatment with bezafibrate or simvastatin or bezafibrate plus simvastatin was followed by a period of placebo (1 week). No subjects experienced myalgia or muscle weakness. Plasma creatine kinase (CK) elevations, particularly skeletal muscle CK (CK-MM), were observed in 6 subjects: 11 times during different placebo periods, 5 times on bezafibrate, 4 times on simvastatin, and 4 times on combined bezafibrate-simvastatin, but never reached 1,600 IU/L. Only a trend to an increase of CK mean values on combined bezafibrate-simvastatin was shown. The hepatic transaminase and gamma-glutamyltransferase activities remained unmodified throughout the trial, unlike alkaline phosphatase activity, which fell on bezafibrate and on bezafibrate plus simvastatin. The low-density lipoprotein cholesterol level was more reduced with simvastatin than with bezafibrate. The addition of bezafibrate to simvastatin did not decrease it further. Lecithin:cholesterol acyltransferase activity expressed as fractional esterification rate was enhanced only on simvastatin and bezafibrate-simvastatin.

Adult↗
PubMed1990

Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia.

Simvastatin (epistatin; synvinolin; MK 733), an HMG-CoA reductase inhibitor, acts by decreasing cholesterol synthesis and by increasing low density lipoprotein (LDL) catabolism via increased LDL receptor activity. In patients with heterozygous familial and nonfamilial hypercholesterolaemia, orally administered simvastatin 10 to 40mg once daily reduces plasma total and LDL-cholesterol concentrations by about 30 to 45%. It also produces a beneficial moderate decrease in plasma triglycerides and a small, although significant, increase in high density lipoprotein (HDL)-cholesterol. Like many other hypocholesterolaemic agents simvastatin does not appear useful in patients with homozygous familial hypercholesterolaemia who lack LDL receptors. The hypocholesterolaemic activity of simvastatin is greater than that of the bile acid sequestrants, probucol and the fibrates. Combined administration of simvastatin with bile acid sequestrants results in further reductions in plasma cholesterol levels beyond those seen with either drug alone. Simvastatin appears well tolerated in the short to medium term, but its long term tolerability needs to be confirmed. No comparisons of simvastatin and other HMG-CoA reductase inhibitors have been reported. As yet there have been few investigations to determine the impact of simvastatin or other HMG-CoA reductase inhibitors on cardiovascular events relative to their hypocholesterolaemic effects, but at least one such trial is ongoing. Simvastatin, like other HMG-CoA reductase inhibitors, has considerable potential advantages over other classes of hypocholesterolaemic agents, i.e. the magnitude of its cholesterol-lowering effect and convenience of administration. If further study confirms long term tolerability and an impact on cardiac mortality and morbidity, then simvastatin and others of its class should offer a significant new approach to the treatment of hypercholesterolaemia.

Animals↗
PubMed1989

Comparative effects of simvastatin and cholestyramine in treatment of patients with hypercholesterolaemia.

The efficacy and safety of 20 mg simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) and of 16 g cholestyramine daily in the treatment of 34 hypercholesterolaemic patients have been compared after dietary treatment and stratified randomization. The effect of combined treatment with the two drugs was studied in 5 patients with severe hypercholesterolaemia. After 6 weeks of treatment the simvastatin group showed a significantly greater (p less than 0.05) decrease in the mean total plasma cholesterol concentration from 7.88 to 5.48 mmol/l than in the cholestyramine group in whom there was a fall from 7.82 to 6.73 mmol/l. Simvastatin decreased the mean plasma LDL cholesterol concentration from 6.07 to 3.76 mml/l and cholestyramine decreased it from 6.16 to 4.46 mmol/l. Simvastatin also reduced the mean plasma total triglycerides by 24%, VLDL triglycerides by 20% and VLDL cholesterol by 36%, while cholestyramine led to increases in these parameters by 64%, 85% and 63%, respectively. Mean plasma HDL cholesterol concentration and the subfractions HDL2 and HDL3 cholesterol were significantly increased by simvastatin. Simvastatin and cholestyramine reduced the mean plasma apolipoprotein B concentration by 28% and 13%, respectively. The mean plasma apolipoprotein A-I concentration was significantly higher only on simvastatin treatment. Simvastatin did not cause any subjective or objective side effects, while cholestyramine caused gastrointestinal problems in 31% of patients. Small increases in serum alanine aminotransferase (S-ALT) activity were seen with both drugs. Cholestyramine significantly raised the serum alkaline phosphatase (S-ALP) although to a level still within the normal range. It is concluded that 20 mg simvastatin was more effective than 16 g cholestyramine in the treatment of hypercholesterolaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia.

Sixteen patients with primary hypercholesterolaemia received double-blind either fenofibrate (n = 8; 200 mg bid) or the HMG-CoA reductase inhibitor simvastatin (n = 8; 20 mg q.p.m. [corrected] or 40 mg q.p.m. [corrected] if LDL-cholesterol did not fall below 3.6 mmol.l-1 after 4 weeks of treatment). Simvastatin reduced total cholesterol from 9.7 to 7.0 mmol.l-1 after 10 weeks (-28%), and fenofibrate reduced it from 9.2 to 7.7 mmol.l-1 (-15%). The decrease was less during fenofibrate than during simvastatin treatment (time x drug: p = 0.02). Serum LDL-cholesterol fell from 8.3 to 5.3 mmol.l-1 (-36%) during simvastatin and from 7.2 to 6.0 mmol.l-1 (-16%) during fenofibrate administration. Again, the effect of simvastatin was more pronounced than that of fenofibrate (time x drug: p = 0.03). HDL-cholesterol increased significantly from 1.1 to 1.2 mmol.l-1 (+13%) during fenofibrate administration and it did not change significantly during simvastatin. Serum triglycerides fell from 1.3 to 1.1 mmol.l-1 (-16%) during simvastatin, and even more significantly from 2.2 to 1.1 mmol.l-1 (-51%) during fenofibrate (time x drug: p = 0.002). Apolipoprotein B fell on simvastatin from 1.9 to 1.4 g.l-1 (-24%) and from 1.8 to 1.4 g.l-1 (-22%) during fenofibrate. Both drugs were well tolerated and had no significant adverse effects. Simvastatin lowered total and LDL-cholesterol concentrations more than fenofibrate, while the latter had more effect on triglycerides, suggesting specific indications for the two drugs in the treatment of hyperlipoproteinaemias.

Adult↗
PubMed1991

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.d., if their total cholesterol and their LDL cholesterol remained above 7.60 mmol/l (300 mg/dl) and 4.95 mmol/l (195 mg/dl) after a 4-week placebo period. Simvastatin dosage was doubled at the end of 6 weeks of therapy if the LDL-cholesterol level remained above 3.55 mmol/l (140 mg/dl). Analyses were done after 6 and 10 weeks of therapy. Apolipoprotein AI was increased significantly only at week 10 with fenofibrate (+7.4%). Simvastatin had a more pronounced effect than fenofibrate on apolipoprotein B. There was a significant difference between drugs at weeks 6 and 10. No change was observed in the LpAII:AI level with simvastatin, whereas fenofibrate increased these particles quite significantly (+13.9 and +22.3%). The drugs had opposite effects on LpAI (+2.5 and +5.6% with simvastatin; -12.8 and -15.1% with fenofibrate). LP E:B (-33.0 and -40.8% with simvastatin; -53.8 and -52.2% with fenofibrate) and LpCIII:B (-23.8 and -31.8% with simvastatin; -35.1 and -43.5% with fenofibrate) were decreased by both drugs, but fenofibrate was significantly more effective in reducing these particles than simvastatin at week 6. This study suggests that both drugs led to different structural modifications of the lipoproteins, which would not be revealed by total apolipoprotein analysis. These differences are probably related to the mechanisms of action of these drugs.

Adolescent↗
PubMed1991

Effect of simvastatin on receptor mediated metabolism of low density lipoprotein in guinea pigs.

This study examined the effects of simvastatin, an inhibitor of HMG-CoA reductase, on the metabolism of labelled human low density lipoprotein (LDL) in animal models. Administration of 10 mg/kg per day simvastatin for 2 weeks reduced the levels of total cholesterol, LDL-cholesterol and triglycerides by 5.7 mg/dl (16%), 8.8 mg/dl (36%) and 4.9 mg/dl (13%), respectively in guinea pigs. High density lipoprotein-cholesterol levels rose 0.8 mg/dl (29%) by simvastatin treatment. Measurements of turnover of LDL were determined between simvastatin-treated guinea pigs and untreated guinea pigs using intravenous injection of 131I-labelled LDL and 125I-labelled galactose-treated LDL to quantify the LDL receptor pathway. Simvastatin significantly increased the fractional catabolic rate (FCR) of the LDL receptor-dependent pathway. In contrast, the FCR of the LDL receptor-independent pathway was not altered by simvastatin therapy. The FCR for LDL isolated from simvastatin-treated subjects compared to that from control subjects was very similar in both control and simvastatin-fed guinea pigs. These findings suggest that simvastatin mainly reduced serum cholesterol levels by accelerated FCR of LDL receptor mediated pathway.

Animals↗
PubMed1991

Treatment of primary hypercholesterolaemia with simvastatin. New Zealand multicentre evaluation.

OBJECTIVE: To assess the efficacy of simvastatin in a large patient cohort. DESIGN: In an open multicentre study, after a four week placebo phase, patients were treated with simvastatin for 24 weeks; a subgroup continued therapy for a further 24 weeks. Efficacy of simvastatin (a) with prolonged use over three years, and (b) in combination with bezafibrate was assessed in an open single site study. SETTING: Lipid or cardiology specialist hospital outpatient clinics. PATIENTS: For the open multicentre study, 228 patients with primary hypercholesterolaemia (total cholesterol level greater than 6.5 mmol/L) were recruited, of whom 224 met entry criteria and completed the study. Forty-seven of these patients continued therapy for one year. In the open single site study, 22 patients (with low density lipoprotein [LDL] cholesterol levels greater than 4.3 mmol/L) participated in studies of long term use (n = 9) or of combined therapy (n = 13). INTERVENTION: Therapy in the open multicentre study began with 10 mg of simvastatin per day, doubling to 20 mg after six weeks and then 40 mg after 12 weeks of therapy if total cholesterol levels persisted above 5.2 mmol/L. In the study of long term use, simvastatin (40 mg daily) was taken continuously over three years. In the study of combination therapy, bezafibrate (600 mg daily) was taken in addition to simvastatin (40 mg daily) for 10 months. MAIN OUTCOME MEASURES: Plasma lipid and lipoprotein concentrations. RESULTS: In the multicentre study, total plasma cholesterol levels were reduced by 32.8% from 9.11 +/- 1.84 (in mmol/L, mean +/- SD) to 6.12 +/- 1.25 (P less than 0.001), and LDL cholesterol levels by 41.4% from 6.90 +/- 1.92 to 4.04 +/- 0.31 (P less than 0.001). The effect of therapy was sustained in those patients continuing therapy to 48 weeks. The study of long term use found no significant attenuation of effect over three years of monotherapy. Combined simvastatin/bezafibrate therapy reduced the LDL cholesterol concentration by a further 19.9% (P less than 0.001) from levels achieved on simvastatin alone. CONCLUSIONS: Simvastatin is an effective, well tolerated lipid lowering drug, without significant attenuation of effect with prolonged use. Simvastatin plus bezafibrate appears to be a potentially useful drug combination.

Adult↗
PubMed1992

Regulation of HMG-CoA reductase, apoprotein-B and LDL receptor gene expression by the hypocholesterolemic drugs simvastatin and ciprofibrate in Hep G2, human and rat hepatocytes.

The comparative effects of simvastatin (a competitive inhibitor of HMG-CoA reductase) and ciprofibrate (another inhibitor of cholesterogenesis) on the incorporation of [14C]acetate and [3H]mevalonate into cholesterol HMG-CoA reductase activity, apo-B synthesis, LDL receptor, and their corresponding mRNAs, have been studied in the human hepatoma cell line Hep G2 and in human and rat hepatocytes in primary culture. Incubation of Hep G2 with simvastatin (0.01-1.5 microM) or ciprofibrate (25-100 microM) produced not only a marked inhibition of cholesterogenesis from [14C]acetate but also from [3H]mevalonate, an intermediate downstream of the HMG-CoA reductase reaction. However, in human and rat hepatocytes, cultured in similar conditions, simvastatin inhibited only the cholesterol synthesis from [14C]acetate, as expected. HMG-CoA reductase activity was greatly induced in Hep G2 and rat hepatocytes after incubation with simvastatin (up to 400% of controls), but not with ciprofibrate. Increased enzyme activity was accompanied by a higher cell content of reductase mRNA. Apo-B concentration in the medium of Hep G2 cells was 31% lower after 31 h incubation with simvastatin than in controls. However, neither simvastatin nor ciprofibrate modified the synthesis rate of apo-B or its mRNA level. Both LDL-receptor and its mRNA levels were raised by simvastatin at concentrations inhibiting cholesterol synthesis. Our data show that, in this human hepatoma cell line, HMG-CoA reductase competitive inhibition by simvastatin triggers a coordinate regulation of the expression of genes coding for reductase and LDL receptor but not for apo-B. Ciprofibrate, though efficient in inhibiting cholesterogenesis, did not induce the same regulatory reactions. The reason for this discrepancy is unknown.

Acetates↗
PubMed1989

Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors.

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.

Animals↗