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M J Mol

Publications and source records attributed to M J Mol.

33 records · Page 2Linked to original sources
PubMed1990

Simvastatin in the effective reduction of plasma lipoprotein levels in familial dysbetalipoproteinemia (type III hyperlipoproteinemia).

PURPOSE: Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is characterized by an increase of serum lipids caused by an accumulation of remnant particles of triglyceride-rich lipoproteins. We studied the efficacy of simvastatin, an inhibitor of the biosynthesis of cholesterol, in this disorder. PATIENTS AND METHODS: Twelve patients participated in an open-label study. After a three-week placebo period, they were treated with increasing doses (10 mg twice a day, 20 mg twice a day, and 40 mg twice a day) of simvastatin in six-week periods. RESULTS: With the 80-mg dose, the mean serum cholesterol level decreased from 12.30 +/- 4.96 to 5.29 +/- 1.24 mmol/L (mean reduction, 54%) and the mean serum triglyceride level decreased from 8.77 +/- 7.16 to 3.61 +/- 1.33 mmol/L (-48%); this was due to a decrease in very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) lipids. There was a decrease in the ratio of VLDL cholesterol to serum triglycerides and in the apolipoproteins B and E, suggesting a reduction in the amount of circulating atherogenic remnant particles. Except for a slight increase in serum alanine aminotransferase levels in three patients, no side effects were observed. CONCLUSION: These data show that levels of serum lipids can be effectively reduced by simvastatin in familial dysbetalipoproteinemia.

Adult↗
PubMed1990

Homozygous familial hypercholesterolaemia: metabolic studies and treatment with LDL apheresis.

A 14-yr-old Turkish girl presented with serum cholesterol levels of 15-20 mmol/l, skin and tendon xanthomata, and anginal attacks. A coronary angiography demonstrated severe coronary atherosclerosis including a 70% stenosis at the origin of the left coronary artery. The clinical diagnosis, homozygous familial hypercholesterolaemia, was confirmed by: (1) investigation of the family revealing hypercholesterolaemia in both her parents and siblings; (2) fibroblast association studies, in which the specific association of low density lipoprotein (LDL) was 35% of normal; and (3) LDL turnover study, in which the fractional catabolic rate of LDL was decreased to 0.213 pools/day. Treatment with cholestyramine or simvastatin had little effect on serum cholesterol levels. After coronary artery bypass grafting, the patient was treated with selective LDL apheresis using columns containing dextran-sulphate bound to cellulose. These columns bind apolipoprotein B containing lipoproteins but not high density lipoproteins. After 2 yr of therapy, the level of serum cholesterol has declined by 56%. Skin xanthomata have disappeared and there is no recurrence of angina pectoris. On repeated coronary angiography, two of the three bypasses are patent and there is no progression of atherosclerotic lesions. We conclude that LDL apheresis is an efficient procedure to lower serum cholesterol in patients who do not respond to pharmacological treatment of hypercholesterolaemia.

Adolescent↗
PubMed1989

Efficacy and tolerability of simvastatin (MK-733).

The efficacy of simvastatin, a new inhibitor of cholesterol biosynthesis, was studied in patients with familial hypercholesterolemia. A mean reduction in low-density lipoprotein cholesterol of 38 percent was observed after eight weeks of treatment with 20 mg of simvastatin; a 42 percent reduction was seen after the next 16 weeks with 40 mg. There was no difference in response whether the drug was taken in one or two doses. In another study, simvastatin (40 mg per day) was compared with cholestyramine (8 to 16 g per day). After 12 weeks, low-density lipoprotein cholesterol was reduced 43 percent by simvastatin and 29 percent by cholestyramine. Combination therapy caused a reduction in low-density lipoprotein cholesterol of 54 percent. Simvastatin appeared also to be a potent hypolipidemic drug in 10 patients with familial dysbetalipoproteinemia. The drug was well tolerated. Adverse effects were primarily composed of increases in serum transaminases and creatine phosphokinase. No effects of simvastatin on the production of steroid hormones were observed.

Adrenal Cortex↗
PubMed1989

Low-density lipoprotein catabolism in WHHL rabbits after partial ileal bypass surgery.

The effect of partial ileal bypass surgery (PIB) on lipoprotein concentrations and compositions and on the catabolism of low-density lipoproteins (LDL) was studied in Watanabe heritable hyperlipidemic (WHHL) rabbits. After PIB, total serum cholesterol was 65% lower (6.22 +/- 1.58 vs. 17.24 +/- 3.22 mmol/l) and LDL cholesterol 81% lower (2.02 +/- 0.95 vs. 10.90 +/- 3.60 mmol/l) than in control WHHL rabbits; cholesteryl esters, expressed as percentage of mass, were 55% lower in the very-low and intermediate-density lipoprotein (VLDL + IDL) fractions, and 45% lower in LDL, whereas triacylglycerols were 89% higher in VLDL + IDL and 121% higher in LDL. The fractional catabolic rate (FCR) of LDL protein (apoLDL) from operated animals was 10% higher than that from controls in all animals (0.55 +/- 0.10 vs. 0.50 +/- 0.10 pools/day; P less than 0.01). The FCR of autologous apoLDL in PIB rabbits was 50% higher than that of autologous apoLDL in control rabbits (0.63 +/- 0.05 vs. 0.42 +/- 0.06 pools/day); this was not caused by induction of receptor-mediated clearance of LDL. The production rate of apoLDL after PIB in PIB rabbits was 50% lower compared to control apoLDL in controls (26.0 +/- 6.7 vs. 51.7 +/- 16.4 mg/kg per day). We conclude that PIB lowers LDL cholesterol in WHHL rabbits by a decreased production of LDL, by an increased non-specific clearance of LDL and by compositional changes, which lead to LDL particles containing less cholesterol.

Animals↗
PubMed1989

[Efficacy and safety of simvastatin, a new cholesterol-lowering drug].

The effects of simvastatin, an inhibitor of cholesterol synthesis, was studied in 50 patients with hypercholesterolaemia. In the first study, 24 patients with serum cholesterol levels of 10.74 +/- 1.59 mmol/l were treated with simvastatin 40 mg daily for 6 months. Serum cholesterol levels decreased within 4 to 8 weeks to stable values 30 to 36% below the basal value. Serum triglycerides decreased by 16 to 28% and high density lipoprotein (HDL) cholesterol increased by 6 to 11% on average. In the second study, 26 patients with serum cholesterol levels of 12.35 +/- 2.05 mmol/l were treated with simvastatin 40 mg daily as monotherapy or combined with a bile acid binding resin for 2 years. Cholesterol levels decreased to values which remained stable throughout the entire study period; after 2 years the decrease amounted to 43%. Compared with monotherapy, combination with a bile acid binding resin yielded a further 12% decrease of cholesterol. In the entire group, triglycerides decreased by 16% and HDL cholesterol increased by 9% on the average. Side effects were limited to slight increases in alanine aminotransferase and creatine phosphokinase occurring in some patients. Simvastatin appears to be an important asset in the treatment of hypercholesterolaemia.

Anticholesteremic Agents↗
PubMed1989

Effects of inhibition of cholesterol synthesis by simvastatin on the production of adrenocortical steroid hormones and ACTH.

Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single-blind, placebo-controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol +/- SD = 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short-term infusion of ACTH; the ACTH and cortisol response during insulin-induced hypoglycaemia. Total serum cholesterol decreased by 35.0 +/- 8.1% (P less than 0.001) and low-density lipoprotein (LDL) cholesterol by 39.8 +/- 9.8% (P less than 0.001); high-density lipoprotein (HDL) increased by 9.2 +/- 11.1% (P less than 0.001). Basal levels of ACTH were higher after simvastatin (2.9 +/- 1.9 pmol/l vs 4.1 +/- 2.9 pmol/l; P less than 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 +/- 0.23 mumol/l vs 0.78 +/- 0.10 mumol/l; P less than 0.05), but was unaltered during insulin-induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic-pituitary-adrenal axis.

Adrenal Cortex Hormones↗
PubMed1989

Pseudogout attacks after successful treatment of hyperparathyroidism.

Two patients developed pseudogout attacks during treatment for hyperparathyroidism, the first shortly after surgery and the second during medical treatment of her hypercalcaemia. From our observations in these patients and from data in the literature, we conclude that pseudogout attacks following parathyroidectomy in patients with chondrocalcinosis are caused by the decrease in the serum calcium levels and not by the major surgical procedure itself.

Aged↗
PubMed1988

Some metabolic characteristics of low-density lipoprotein subfractions, LDL-1 and LDL-2: in vitro and in vivo studies.

Two low-density lipoprotein subfractions, LDL-1 and LDL-2, with density ranges of respectively 1.023-1.034 and 1.036-1.041 g/ml, were isolated by aspiration after density gradient ultracentrifugation of human pooled serum. In vitro interactions of both LDL subfractions with the LDL receptor of human cultured fibroblasts, human hepatoma cell line Hep G2 and human hepatocytes were compared. No difference in association (binding and internalization) nor in degradation between LDL-1 and LDL-2 by these cells was found. However, kinetic studies in guinea pigs showed that LDL-2 disappeared faster from the circulation and accumulated to a greater extent in the liver, compared to LDL-1. Thus, we were unable to show a difference in the LDL receptor-mediated uptake of both LDL subfractions by various cells in vitro. The results obtained in vivo suggest that LDL-1 is more atherogenic than LDL-2, because its longer half-life renders the particle more susceptible to uptake by the scavenger LDL receptor on macrophages.

Animals↗
PubMed1988

Simvastatin (MK-733): a potent cholesterol synthesis inhibitor in heterozygous familial hypercholesterolaemia.

Simvastatin (MK-733), a new inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was administered to 38 patients with heterozygous familial hypercholesterolaemia for 24 weeks. A dose of 40 mg per day produced a mean reduction in low density lipoprotein cholesterol of 43-45% and in triglycerides of 21-31%. Mean high density lipoprotein cholesterol increased significantly by 10-13%. There were no major differences in response whether the drug was taken in one or two doses. MK-733 was tolerated well. Adverse effects were infrequent and limited to slight increases of alanine aminotransferase, creatine phosphokinase and bilirubin. This drug appears to be a potent inhibitor of cholesterol synthesis and has produced the largest therapeutic response as monotherapy in patients with familial hypercholesterolaemia.

Anticholesteremic Agents↗
PubMed1988

Clinical experience with simvastatin compared with cholestyramine.

Simvastatin (MK733), derived from lovastatin by substituting CH3 for H at the 2' position, is a potent hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Its cholesterol-lowering effect in 40 patients with heterozygous familial hypercholesterolaemia was more pronounced (an LDL-cholesterol reduction of 43%) than that of cholestyramine monotherapy in a matched group of 20 patients (30% reduction). The combination of the 2 drugs for 50 patients who tolerated cholestyramine was even more effective (a 54% reduction of LDL-cholesterol). The other changes were as follows: total cholesterol (simvastatin [S] -36%, cholestyramine [C] -23%, both drugs in combination [S + C] -45%); HDL-cholesterol (S +16%, C +9%, S + C +20%); triglyceride (S -21%, C +11%, S + C -17%); and the apolipoprotein B/apolipoprotein A ratio (S -51%, C -39%, S + C -67%). Cholestyramine caused more gastrointestinal adverse effects (12 of 20 patients), whereas a transaminase increase was seen both with cholestyramine (2 of 20 patients) and simvastatin (3 of 40 patients) and with the combination (6 of 50 patients). Treatment with simvastatin decreases the atherogenic potential of plasma more than cholestyramine monotherapy and causes fewer adverse effects. For those patients who tolerate cholestyramine, the combination of the drugs is even more potent.

Adult↗
PubMed1986

Effects of synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia.

The effects of synvinolin (MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were investigated in 43 patients with heterozygous familial hypercholesterolaemia in a double-blind, placebo-controlled, dose-finding study. Synvinolin was given in doses ranging from 2.5 mg to 80 mg per day for 4 weeks. 8 patients received placebo. Low-density-lipoprotein cholesterol fell on average by 18% on 2.5 mg/day and 42% on 80 mg/day. The drug was as effective whether it was given once or twice daily. Serum high-density-lipoprotein cholesterol tended to increase and serum triglycerides to decrease on the higher doses. The drug was tolerated well. Except for a slight rise in alanine aminotransferase in 3 patients no objective side-effects were observed.

Adult↗
PubMed1977

A gas chromatographic method for the estimation of phenprocoumon, 3-(1-phenyl-propyl)-4-hydroxycoumarin (Marcoumar, Liquamar), in human serum or plasma.

A rapid and reliable gas-chromatographic method is described for the estimation of phenprocoumon from human serum or plasma. No interference was found from other usual oral anticoagulant drugs. The method can be used for therapeutic and toxic levels. The appearance of two volatile derivatives of phenprocoumon (in constant ratio) is discussed.

4-Hydroxycoumarins↗