One year experience in the treatment of familial hypercholesterolaemia with simvastatin.

Lewis B.

Department of Endocrinology and Chemical Pathology, United Medical School, Guy's Hospital, London, UK.

Patients with heterozygous familial hypercholesterolaemia (FH) have a substantially increased risk of atherosclerosis due to very high plasma levels of cholesterol. Recent evidence has shown that coronary heart disease in these patients may regress with lipid-lowering therapy. In this study the efficacy and safety of simvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A, was investigated in 30 patients with FH over a period of one year. Substantial reductions in the plasma concentrations of total cholesterol (-28%), low-density lipoprotein (LDL) cholesterol (-32%), intermediate-density lipoprotein (IDL) cholesterol and apolipoprotein (apo) B (-33%) were achieved with 20 mg/day of simvastatin; there were no significant changes in triglycerides high-density lipoprotein cholesterol or apo A. In contrast to previous studies, 40 mg/day of simvastatin did not result in a further statistically significant fall in LDL cholesterol, IDL cholesterol or apo B in the group as a whole. The drug was well tolerated and no adverse clinical or laboratory events were recorded. In particular, no ophthalmological, hepatic or renal disorders were observed and there were no sleep disturbances. We conclude that simvastatin is an efficacious and safe drug to treat patients with heterozygous FH and that rarely will the dose need to be increased above 20 mg/day.

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Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats.

Griffioen M, et al.

Department of Nephrology, Medical Faculty, University of Utrecht, The Netherlands.

Recent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in different rat models of hyperlipidaemia. However, this effect is not seen after oral administration of HMG-CoA reductase inhibitors in rats. We found that oral administration of the HMG-CoA reductase inhibitor Simvastatin also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene glycol) was infused continuously for 28 days into the subcutis of control Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses which were effective in reducing cholesterol in the NAR (reductions up to approximately 60%), reduced apolipoprotein AI but not apolipoprotein B and caused a severe inflammatory reaction in the dermis. Similar toxicity was observed in the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not cause this reaction and did not affect plasma lipids. Administration of Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. Incorporation of Simvastatin into liposomes did not diminish the toxic effect. On the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor dissolved in isotonic saline) caused no changes in the dermis and had no effect on plasma lipids in NAR or SDR. Liver microsomes prepared from the Pravastatin-treated rats demonstrated a 3- to 4-fold increase in HMG-CoA reductase activity as compared to untreated rats, confirming uptake of the drug. We conclude that continuous subcutaneous administration of the HMG-CoA reductase inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce plasma cholesterol in rats by a mechanism which is related to inhibition of HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides with, and may be related to inflammatory changes caused by administering these compounds into the dermis.

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Simvastatin: a review.

Tobert JA.

Centre for Preventive Medicine, Ulleval University Hospital, Oslo, Norway. t.r.pedersen ioks.uio.no

Simvastatin is a long-established hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, first introduced in 1988. At the maximal recommended dose of 80 mg/day, it produces an average reduction in low-density lipoprotein cholesterol (LDL-C) of 47%, accompanied by reductions in very LDL-C, triglycerides and apolipoprotein B, and a modest increase in high-density lipoprotein cholesterol. The only important, although rare, adverse effect of simvastatin is myopathy, an effect shared by all members of the class; when severe, this can take the form of rhabdomyolysis, which may lead to acute renal failure. The mechanism of the myopathy is not understood. The risk is increased by certain concomitant drugs, including gemfibrozil and potent inhibitors of cytochrome P450 3A4. Simvastatin has been studied in two large outcome trials, the Scandinavian Simvastatin Survival Study (4S), and the Heart Protection Study (HPS), both of which demonstrated strikingly beneficial effects on a variety of cardiovascular outcomes, with minimal adverse effects. 4S was the first study with a cholesterol-lowering agent to demonstrate an unequivocal reduction in all-cause mortality (30%; p = 0.0003). HPS showed that the beneficial effects of simvastatin were obtainable in a broad array of patients with, or at high risk of, coronary heart disease (CHD) in categories previously little studied, including women, the elderly, patients with diabetes without known CHD, and, perhaps most importantly, patients with LDL-C well below the UK population average. Simvastatin has recently become available in many countries as a combination product with the cholesterol absorption inhibitor, ezetimibe. Because of its long record of safety and demonstrated ability to reduce cardiovascular risk, simvastatin has recently become available without a prescription in the UK at the 10 mg dosage level.

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[Mid-term clinical study of the effectiveness of and tolerability to simvastatin ++ in dyslipidemic patients]

[Article in Italian]

Dragonetti C.

Universita degli Studi di Napoli Federico II, Cattedra di Cardiologia.

The HGM-CoA reductase inhibitors, blaking up intracellular synthesis of cholesterol, support the receptorial captation of cholesterol with a reduction in plasma levels. The simvastatin efficacy was evaluated in 12 patients, mean age 59 +/- 10 years with a primary hypercholesterolemia. All the patients were on a pharmacologic wash out for at least 6 weeks and dietetic treatment (according to their weight and daily needs) for a week. Total cholesterol, HDL-cholesterol and triglycerides plasma levels were taken at time 0. Then a treatment with simvastatin 10 mg/die was begin for 4 weeks and than increased to 20 mg in patients with plasma cholesterol > 200 mg/100 ml at the end of fourth week. In some patients the dose was increased up to 40 mg for the elevated levels of plasma cholesterol at the end of the second month. All the parameters above were controlled monthly for three months. A control was performed at the end of sixth month of treatment. After 4 weeks treatment, simvastatin induced reduction in cholesterol plasma levels (p < 0.005), that continued during the whole time treatment (228 mg/dl at 24 week, p < 0.005 vs basal). The mean dosage of the simvastatin at fourth month was of 25 mg/die. During the treatment an increase of HDL plasma levels was noted, but this increment wasn't statistical significant (40 +/- 7 vs 45 +/- 9 mg/100 ml). No significant impairment of principal metabolic and laboratory parameters were observed during the treatment. These data indicate that simvastatin in small dose induce a reduction in cholesterol plasma levels with a significant increase in HDL without side effects.

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[Dyslipidemia in the uremic patient: the therapeutic role played by simvastatin]

[Article in Italian]

Savica V.

Istituto Polidisciplinare di Clinica Medica e Terapia Medica, Universita degli Studi di Messina.

Simvastatin is a pharmacological molecule belonging to the family of HMG-CoA reductase inhibitors, recently included in plasma cholesterol lowering therapy. The authors carried out a study on the possible triglyceride lowering activity of simvastatin in dialyzed patients with chronic uremia considering its particular mechanism of action. The subjects selected for the study were suffering from uremia either complied with dosage prescribed or not. The obtained data showed the substance's triglyceride lowering effect, but no simvastatin-related side effect in the dialysed patients with uremia. For these reasons and for the substance's well-known cholesterol-lowering effect, simvastatin seems to deserve the definition of choice drug in the treatment of altered lipidemia in patients with uremia.

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Efficacy and cost-effectiveness of simvastatin and gemfibrozil in the treatment of hyperlipidaemia.

Foo WM.

Cardiac Department, National University Hospital, Singapore.

The aim of this study is to compare the efficacy and cost-effectiveness of simvastatin with gemfibrozil in regulating the serum lipid profiles in the local population. In this study, we reviewed the effect of medication on 75 patients with hypercholesterolaemia with or without hypertriglyceridaemia; 26 patients were on simvastatin 10 mg nightly, 24 patients were on gemfibrozil 300 mg twice daily and 25 patients were on gemfibrozil 600 mg twice daily. The average follow-up period was 10.8 weeks, 19.0 weeks and 16.2 weeks for simvastatin 10 mg, gemfibrozil 300 mg and gemfibrozil 600 mg groups respectively. Prior to drug therapy, patients were put on dietary control. The pre-treatment and post-treatment serum lipid profiles were monitored. The mean changes in the lipid profiles of the patients on gemfibrozil 600 mg twice daily were a 21.6% reduction in total cholesterol, a 21.8% reduction in low-density lipoprotein cholesterol (LDL-C), a 46.3% reduction in serum triglyceride and an 11.2% increase in high density lipoprotein cholesterol (HDL-C). The patients in all three groups had raised HDL-C and lowered triglyceride levels post-treatment but patients on gemfibrozil had a greater increase in HDL-C and a greater decrease in triglycerides as compared to the simvastatin group. In comparison to gemfibrozil, simvastatin was more efficacious in the reduction of LDL-C. The mean reduction in the LDL-C was 21.8% for gemfibrozil 600 mg twice daily group as compared to 28.0% for simvastatin 10 mg nightly group.(ABSTRACT TRUNCATED AT 250 WORDS)

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