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PubMed1999

[Antioxidative effects of fluvastatin, and its major metabolites].

Fluvastatin (FV) is a highly potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Recently, its antioxidant effect caused by inhibiting the formation of low density lipoproteins (LDL) in vitro has been reported. In this study, we reported the antioxidant effects of FV and its major metabolites in human (M-2, M-3, M-4, M-5, and M-7) on lipid peroxidation using rat liver microsomes. The extent of NADPH-induced microsomal (Ms) lipid peroxidation was determined by the thiobarbituric acid (TBA) assay. The antioxidant effect of each compound was shown as the percentage of inhibition on the formation of TBA reactive substances (TBARS) against the vehicle control. Probucol (PR), a potent antioxidant drug, was used as a reference control. The concentration of each compound in this experiment was set at 0.1 mM (final conc.). FV inhibited the formation of TBARS by 30 to 60% without depending on the used Ms concentrations (0.025-0.2 mg protein/ml). The antioxidant effects of M-2, M-3, and M-5 were comparable to that of FV at low Ms concentrations. At the highest Ms concentration, however, the antioxidant effects of these metabolites were considerably higher than that of FV. Inhibition of the formation of TBARS by M-4 or M-7 was approximately 30% of the control and independent of the used Ms concentrations. The antioxidant effect of PR was comparable to those of M-2, M-3, and M-5 in this study. Pravastatin (PV), a potent inhibitor of HMG-CoA reductase, reduced the formation of TBARS around 20% at 0.25 or 0.5 mg protein/ml of Ms concentrations. But the value of percentage of inhibition was around 5% at 0.1 or 0.2 mg protein/ml of Ms concentrations. In conclusion, the antioxidant effects of FV, M-2, M-3, and M-5 were found to be comparable to that of PR.

Animals↗
PubMed2002

Effects of pravastatin on exercise electrocardiography test performance and cardiovascular mortality and morbidity in patients with hypercholesterolemia: Lipid Intervention Study in Kyoto.

The long-term effects of the 3-hydoxy-3-methyl-glutaryl coenzyme A reductase inhibitor, pravastatin, on exercise electrocardiography (ECG) test performance and cardiovascular mortality and morbidity were compared with those of conventional lipid-lowering drugs in hypercholesterolemic patients with no history of myocardial infarction or stroke. One thousand two hundred and seventeen patients were randomly assigned with mean serum cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels of 6.98 +/- 0.91mmol/L, 2.08 +/- 1.87mmol/L, 1.38 +/- 0.44mmol/L, and 5.07 +/- 1.14 mmol/L, respectively, and received either pravastatin at a dose of 10-20mg/day (group P) or one of the conventional lipid-lowering drugs such as fibrates, nicotinic acid, and probucol (group C). The numbers of patients available for analysis in groups P and C were 305 and 278 at year 1, 261 and 216 at year 2, 206 and 184 at year 3, 159 and 122 at year 4, and 103 and 81 at year 5. Over the 3.2 year mean follow-up period, the reduction in serum LDL cholesterol levels was significantly greater (p<0.01) in group P (-24.3%) than in group C (-16.0%). Serum HDL cholesterol levels increased in group P (+11.6%), but decreased in group C (-0.3%) (p<0.01). There were no significant differences in the rate of patients who exhibited ischemic changes to exercise ECG test (ischemic responders) between the 2 groups. Coronary heart diseases (CHD) occurred in 6 patients in group P and 13 in group C; pravastatin significantly reduced CHD risk (reduction rate 0.369; 95% confidence interval 0.140-0.970; p<0.05). No significant differences existed between the treatment groups in terms of the number of strokes (group P, 6; group C, 7) or deaths unrelated to CHD (group P, 3; group C, 2). Although pravastatin did not improve the proportion of ischemic responders on exercise testing, it reduced CHD risk and serum LDL cholesterol levels more significantly than conventional lipid-lowering drugs without adversely affecting the risk of stroke and non-CHD death in hypercholesterolemic patients.

Adult↗
PubMed2001

[Lipid-lowering drugs].

Accumulating evidences in recent major clinical studies have shown the importance of anti-hyperlipidemic treatment in preventing atherosclerotic cardiovascular diseases. Lipid-lowering drugs can be divided into HMG-CoA reductase inhibitors (statins), bile-acid sequestrants (resins), nicotinic acid, fibrates and probucol. Among them, statins had revolutionary impact on the treatment of hyperlipidemia since pravastatin, which was developed in Japan, was launched in 1989. Several lipid-lowering drugs are now under development in Japan, including pitavastatin, rosuvastatin, F-1394 (ACAT inhibitor), CS-505 (ACAT inhibitor) and NO-1886 (LPL activator). In this review, characteristics of these new lipid-lowering drugs will be discussed.

Benzamides↗
PubMed2002

Japanese familial hypercholesterolaemia with a 327insC mutation in the LDL receptor gene.

Mutations in the LDL receptor (LDLR) cause familial hypercholesterolaemia (FH) in an autosomal dominant manner. The condition frequently progresses to coronary atherosclerosis. We describe a patient with FH, but without ischaemic heart disease, who had a novel frameshift mutation (327insC) in exon 4 of the LDLR gene. This mutation introduced a premature termination codon (TGA, codon 158). The patient was a 59-year-old man who had presented with hypercholesterolaemia and a plasma total cholesterol (TC) concentration of 12.2 mmol/L at age 44 years. The mutation 327insC in this patient was heterozygous and hypercholesterolaemia was common within his family. Despite taking lipid-lowering medications (probucol and pravastatin) for more than 20 years, his TC concentration hardly fell below 7.8 mmol/L. However, neither the patient nor anyone else in his family developed characteristic symptoms of ischaemic heart disease or xanthoma. This patient was discovered by an intensive mutation survey among 22 unrelated Japanese with FH mainly in the Kanto area of Japan, suggesting a low incidence of the mutation in the area.

Electrophoresis, Polyacrylamide Gel↗
PubMed1998

Mode of action and adverse effects of lipid lowering drugs.

Serum lipids, cholesterol and triglycerides are incorporated into hydrophilic lipoproteins, which include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). An elevated level of these lipoproteins, except for HDL, is the basis of all hyperlipidemias. However, only some of the lipoprotein fractions, particularly LDL and remnant particles, are potential risk factors for atherogenesis and subsequent cardiovascular disease. Several classes of pharmacological agents are currently available to increase the breakdown and reduce the synthesis of LDL and remnant factors. These include nicotinic acid and its analogs, fibric acid derivatives (e.g., clofibrate, gemfibrozil, bezafibrate), bile acid resins (e.g., cholestyramine), HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin) and probucol. Lipid lowering drugs of different classes have a synergistic effect on lipid metabolism and combination therapy is often used. Lipid lowering drugs are prescribed as long-term preventive therapy in apparently asymptomatic people. Several studies indicate that secondary prevention with lipid lowering drugs is cost-effective, particularly in patients with symptomatic coronary artery disease.

Journal Article↗
PubMed1999

Depending on their concentration oxidized low density lipoproteins stimulate extracellular matrix synthesis or induce apoptosis in human coronary artery smooth muscle cells.

Various lines of evidence indicate that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of atherosclerosis and coronary heart disease. We have investigated the effect of modified (oxidized) low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis in cultured human coronary artery smooth muscle cells (HCA-SMC). As shown by immunofluorescence microscopy and time-resolved fluorescence immunoassay, oxLDL dose-dependently stimulated collagen type I and fibronectin synthesis in cultured HCA-SMC. The effect on matrix synthesis was biphasic, with a maximum effect at concentrations between 1 and 10 microg/ml oxLDL. Higher oxLDL concentrations (>25 microg/ml) were cytotoxic. Beside oxLDL, malondialdehyde-modified LDL also stimulated extracellular matrix synthesis. In the presence of 100 microg/ml ascorbic acid, 25, 50 and 100 microg/ml oxLDL induced apoptosis within 6-8 hours (demonstrated by TUNEL-reaction, annexin-V binding and APO-2.7-expression). Apoptosis was not induced by normal (unmodified) LDL and malondialdehyde-modified LDL. The radical scavengers and antioxidants TROLOX and probucol and the hydrogen peroxide eliminator catalase significantly reduced oxLDL-induced apoptosis. Our results demonstrate that low concentrations of oxLDL are profibrogenic by stimulating extracellular matrix synthesis, whereas higher oxLDL concentrations induce oxidative stress and apoptosis in coronary artery smooth muscle cells. The profibrogenic effect might be relevant in the formation of atherosclerotic plaques, and the proapoptotic effect might contribute to an increased plaque vulnerability.

Apoptosis↗
PubMed2005

Ten-year follow-up of familial hypercholesterolemia patients after intensive cholesterol-lowering therapy.

To prevent coronary artery disease, it is necessary for patients with familial hyper-cholesterolemia (FH) to maintain a low cholesterol level. Recently a combination therapy of low-density lipoprotein (LDL) apheresis and statins has been used for FH patients, but their long-term prognosis over 10 years is unknown. In this single center prospective report, 18 FH patients with severe coronary stenosis received LDL apheresis every 2 or 4 weeks and statin therapy for 9.8 +/- 3.0 years. Probucol was given to 17 of the 18 patients. We observed their clinical events as well as coronary stenosis findings and ejection fractions for 10.7 +/- 2.6 years. Total and LDL cholesterol levels before therapy were 345 +/- 46 and 277 +/- 48 mg/dL, respectively. Immediately following LDL-apheresis, these levels decreased to 104 +/- 7.5 and 66 +/- 16 mg/dL, respectively. There were no cardiac deaths and 4 patients were free from any coronary events. There was one noncardiac death. Nonfatal myocardial in-farction occurred in 2 patients and coronary bypass surgery was required in one patient. Twelve patients received additional coronary angioplasty. There was little change in coronary stenosis and ejection fraction following 10 years of the combination therapy. Univariate Cox regression analysis revealed that the calculated mean LDL cholesterol level was the predictive value of treatment efficacy (mean LDL cholesterol < 140 mg/dL, hazard ratio 0.23, P = 0.028). The combination therapy of LDL-apheresis and antilipid drugs delayed the progression of coronary atherosclerosis and prevented a major cardiac event, although complete inhibition was limited to a small group. Additional coronary angioplasty is likely to be required for a favorable clinical outcome in FH patients.

Adult↗
PubMed2006

Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of drug-induced torsades de pointes in humans.

BACKGROUND: The issue of drug-induced QT interval prolongation and torsades de pointes represents a major concern for pharmaceutical development. In this investigation, we examined the value of the isolated rabbit Purkinje fibre as an in vitro action potential (AP) assay to predict the potential of drugs to induce these undesirable adverse effects. METHODS: First, we categorised the proarrhythmic risk of 26 medicinal products based on proportional reporting ratios for these two adverse events recorded in a US FDA database (Spontaneous Reporting System/Adverse Event Reporting System). Second, we measured drug effects on AP in rabbit Purkinje fibres. Finally, the results of the two analyses were compared to evaluate the predictive value of the in vitro assay. RESULTS: Analysis of the clinical data classified the drugs into 14 positive, 7 negative and 5 questionable for proarrhythmic risk. Based on in vitro electrophysiological profiles, the drugs were grouped into four categories: (i) profile 1 drugs prolong repolarisation without slowing depolarisation; (ii) profile 2 drugs prolong repolarisation and also slow depolarisation; (iii) profile 3 drugs shorten repolarisation; and (iv) profile 4 drugs are without effects. All 14 clinical-positive drugs fell into profiles 1 or 2 (prolongers) with low safety margins (except probucol, which showed no effect, probably because of its low solubility). Clinical-negative drugs belonged mostly to profiles 3 or 4 (non-prolongers) [except clemastine and amlodipine, which were prolongers but had large safety margins]. Clinical-questionable drugs either did not prolong or prolonged slightly but produced additional electrophysiological effects opposing prolongation. CONCLUSION: The rabbit Purkinje fibre is a valuable assay for evaluating the proarrhythmic liability of pharmaceuticals as it can reveal complex electrophysiological profiles that modulate repolarisation delay.

Action Potentials↗
PubMed2000

Drug interactions with cisapride: clinical implications.

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.

Animals↗
PubMed1987

Bezafibrate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidaemia.

Bezafibrate is a lipid-lowering drug, chemically related to clofibrate. At its recommended dosage of 200 mg 3 times daily, or alternatively 400 mg once daily as a sustained-release preparation, it produces substantial reductions in plasma triglyceride and cholesterol concentrations in patients with hypertriglyceridaemia and hypercholesterolaemia, respectively. Preliminary investigations indicate that a single daily dose of 400 mg in a sustained-release preparation is as effective as 200 mg 3 times daily. In patients with any type of hyperlipoproteinaemia bezafibrate also increases the plasma HDL-cholesterol concentration. These effects are equivalent in patients with primary hyperlipoproteinaemia or hyperlipoproteinaemia secondary to diabetes or renal disease, although dosage adjustment is important in the latter group. During long term therapy (2 to 4 years) the influence of bezafibrate on the lipid profile is sustained. The lipid-lowering effects of bezafibrate are at least equivalent to those of clofibrate, fenofibrate, colestipol, probucol or sustained release etofibrate. In addition, the increase in HDL-cholesterol tends to be at least as great as with all alternative treatments studied. Bezafibrate is rapidly eliminated, and thus does not accumulate during prolonged administration in patients with normal renal function. Experimental studies have shown bezafibrate to have a complex range of effects on lipoproteins and on the enzymes and receptors involved in lipid metabolism. However, its exact mechanism of lipid-lowering action is unclear. Bezafibrate enhances anticoagulation in hyperlipoproteinaemic patients requiring anticoagulant therapy, and preliminary investigations indicate that it reduces the plasma fibrinogen concentration, especially in patients with hyperfibrinogenaemia. These properties of bezafibrate could contribute to an antiatherogenic effect of the drug, but further investigation is required to establish the drug's potential as chronic therapy in patients with hyperfibrinogenaemic atherosclerosis. Adverse reactions to bezafibrate have largely been restricted to gastrointestinal disturbances, with some cutaneous reactions and central nervous system effects. The incidence of side effects has been no greater than with comparative lipid-lowering drugs. In patients with renal disease, a few cases of marked elevation of serum creatine phosphokinase and myoglobin, and associated muscle cramps, have been reported (diagnosed as rhabdomyolysis). Hepatic enzyme induction by bezafibrate in rats results in hepatomegaly, but there has been no case of significant hepatotoxicity in man.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Pharmacological intervention for altering lipid metabolism.

Pharmacological intervention for altering plasma levels of lipoproteins is usually aimed at reducing atherogenesis and preventing coronary heart disease (CHD). Drug therapy should be attempted only after other nonpharmacological methods (such as elimination of smoking, weight reduction and exercise) have been tried. An overview of the metabolism of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles is the basis of this paper. Various sites suitable for pharmacological intervention are identified. LDL metabolism can be altered at 2 potential sites, with a consequent reduction in the plasma level of this atherogenic lipoprotein. Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (such as lovastatin) and cation-exchange resins (e.g. cholestyramine) reduce LDL levels by stimulating the hepatic synthesis of apolipoprotein (apo) B,E receptors. Very low density lipoprotein (VLDL) secretion is inhibited by nicotinic acid (niacin) and gemfibrozil, leading to a secondary decrease in LDL production from VLDL. Probucol also reduces the LDL concentration and inhibits the oxidative modification of LDL. Gemfibrozil and other fibrates stimulate lipoprotein lipase activity, thereby decreasing VLDL concentration. Reduction of the LDL concentration is effective in reducing CHD incidence, whether this is achieved by stimulation of catabolism or inhibition of production of the lipoprotein. In contrast, the mechanism of raising plasma HDL-cholesterol levels is probably relevant to the potential clinical benefits associated with drug therapy. Gemfibrozil and cholestyramine stimulate synthesis of apoprotein A1, the major protein constituent of HDL particles. Both drugs have been shown to reduce the incidence of CHD in clinical trials, via mechanisms that are related in part to their HDL-raising activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1991

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

Pravastatin is an HMG-CoA reductase inhibitor which reduces plasma cholesterol levels by inhibiting de novo cholesterol synthesis and increasing the receptor-mediated catabolism of low density lipoprotein (LDL). Several large multicentre placebo-controlled trials have shown that pravastatin reduces total and LDL-cholesterol levels in a dose-proportional manner in patients with familial or nonfamilial hypercholesterolaemia. Reductions in LDL-cholesterol levels reported in the largest study were 18% (10 mg/day), 23% (20 mg/day) and 31% (40 mg/day) after 12 weeks. Once-daily administration appears to be as effective as two daily doses. Pravastatin consistently increases HDL-cholesterol levels and decreases levels of total triglycerides but these changes are not dose dependent. At the study dosages used, the antihypercholesterolaemic effects of pravastatin were superior to those of bezafibrate and clinofibrate, and were similar to those of simvastatin, lovastatin, gemfibrozil and cholestyramine although in some studies a trend towards a superior effect with pravastatin was seen. Pravastatin did not reduce HDL-cholesterol like probucol, or increase triglyceride levels like cholestyramine. Combined treatment with pravastatin and cholestyramine or colestipol enhances the cholesterol-lowering effects of either drug administered alone and offsets the increase in total triglyceride levels seen with cholestyramine or colestipol therapy. Pravastatin is well tolerated during treatment of up to 24 months but longer term tolerability has not yet been established. The effect of provastatin on cardiovascular events related to elevated plasma cholesterol levels is under investation in several large scale regression and primary and secondary prevention trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Simvastatin. A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia.

Simvastatin is an HMG-CoA reductase inhibitor used in the treatment of patients with hypercholesterolaemia. Since the time simvastatin was previously reviewed in Drugs, a number of large clinical trials have confirmed its clinical efficacy. Thus, reductions from baseline were approximately 20 to 40% for serum levels of total cholesterol, 35 to 45% for low density lipoprotein (LDL)-cholesterol and 10 to 20% for triglycerides in patients with primary hypercholesterolaemia receiving simvastatin 10 to 40 mg/day. High density lipoprotein (HDL)-cholesterol levels were increased modestly by about 5 to 15%. Recent data from long term studies indicate that little or no attenuation of these changes in serum lipid and lipoprotein levels occurred with administration of simvastatin for 3 to 5.4 years. Comparative studies with other HMG-CoA reductase inhibitors (lovastatin, pravastatin and fluvastatin), which were lacking at the time of the previous review of simvastatin, demonstrated greater reductions in serum levels of total cholesterol and LDL-cholesterol with simvastatin than equal dosages of lovastatin or pravastatin. Reductions in serum levels of total cholesterol and LDL-cholesterol were similar between agents only when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. In general, simvastatin 10 to 40 mg/day was also more effective than standard dosages of bile acid sequestrants, fibrates or probucol in lowering serum levels of total cholesterol and LDL-cholesterol; however, fibrates usually produced greater reductions in serum triglycerides and greater elevations in HDL-cholesterol levels. The Scandinavian Simvastatin Survival Study (4S), a large secondary prevention study in patients with coronary heart disease and concomitant hypercholesterolaemia, demonstrated that simvastatin 20 to 40 mg/day for a median of 5.4 years significantly reduced overall mortality (the primary end-point of the study) by 30% compared with placebo, which was attributed to a 42% relative reduction in coronary mortality. Coronary morbidity was also significantly reduced by simvastatin in the 4S trial. The tolerability profile of simvastatin appears to be comparable to that of other HMG-CoA reductase inhibitors. The most frequently reported adverse events are gastrointestinal disturbances, which are generally mild and tend to occur less frequently than with cholestyramine. In conclusion, simvastatin is among the most effective agents available for treating patients with hypercholesterolaemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1992

Minimally modified lipoproteins in diabetes.

Studies from several laboratories suggest that oxidized LDL may play an important role in atherogenesis. Our group previously showed that treatment of aortic endothelial cells with low levels of MM-LDL caused increased expression of MCP-1, M-CSF, tissue factor, and a monocyte-binding protein. In these studies MM-LDL was produced by storage of native LDL. We now show that cocultures of endothelial and smooth muscle cells can also produce MM-LDL from native LDL. This production of MM-LDL by cells is prevented by preincubating the LDL with probucol or vitamin E. However, addition of antioxidants to MM-LDL did not block its action. In past studies we also showed that endothelial cells exhibit differential sensitivity to the effects of MM-LDL. We report herein that in resistant cells there is no elevation of catalase, glutathione peroxidase, or copper-zinc-dependent SOD. However, manganese-dependent SOD is elevated in resistant cells. Ways in which MM-LDL production may be elevated in poorly controlled diabetics subjects are discussed.

Diabetes Mellitus↗
PubMed1994

Normalization of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels.

Hyperglycemia and diabetes have been shown to increase diacylglycerol (DAG) level and activate protein kinase C (PKC) activity in the vascular tissues, possibly altering vascular function. We have characterized the effects of D-alpha-tocopherol (vitamin E) on PKC activities and DAG levels in rat aortic smooth muscle cells (ASMCs) cultured with elevated glucose levels as well as in the vascular tissues obtained from control and diabetic rats. In ASMCs, the specific PKC activity from the membraneous fraction and total DAG level were increased by 31 +/- 4% (P < 0.05) and 50 +/- 7% (P < 0.05), respectively, when the glucose levels were changed from 5.5 to 22 mmol/l. The addition of D-alpha-tocopherol and another lipophilic antioxidant, probucol, prevented the glucose-stimulated increases in DAG level and PKC activity. By immunoblotting studies, D-alpha-tocopherol treatment was able to reduce the enhancement of PKC beta II isoform in the membraneous fraction isolated from ASMCs. Comparing streptozotocin-induced diabetic rats with their nondiabetic controls, both membraneous-specific PKC activities and total cellular DAG levels were increased in aorta by 162% (P < 0.05) and 60% (P < 0.05), respectively. Intraperitoneal injection of D-alpha-tocopherol (40 mg/kg) every other day prevented the increases in membraneous-specific PKC activities and total DAG levels in parallel with a significant increase of D-alpha-tocopherol contents in the aorta and plasma. These findings have demonstrated that D-alpha-tocopherol can prevent the activation of PKC activities in the vascular cells and tissues induced by hyperglycemia by lowering DAG levels, possibly via its antioxidant effect.

Animals↗
PubMed1994

Management of dyslipidemia in IDDM patients.

Patients with insulin-dependent diabetes mellitus (IDDM) are at an increased risk for coronary heart disease. Factors that may enhance the risk include dyslipidemia, hypertension, and hyperglycemia. Until recently, the importance of dyslipidemia in IDDM was ignored because the prevalence of high cholesterol levels was similar to that in the nondiabetic population. However, unique abnormalities in the composition and metabolism of lipoproteins may occur in IDDM patients. Management of IDDM patients, therefore, should include control of dyslipidemia as well as control of hyperglycemia and hypertension. The therapeutic goals for serum cholesterol reduction in IDDM patients should be lower than that for nondiabetic patients, and the goals for children should be even lower than those for adults. Both very-low-density lipoprotein and low-density lipoprotein (LDL) levels should be the targets for therapeutic interventions and not just the LDL alone. Because of the unique features of dyslipidemia in IDDM patients, the therapeutic options may not be the same as that for nondiabetic patients. Hyperglycemia should be controlled by matching daily energy intake and activity with appropriately timed doses of insulin. The diets should be low in saturated fats and cholesterol. If dyslipidemia persists despite diet and hyperglycemia management, drug therapy may be initiated. For IDDM children > or = 10 years of age with elevated LDL-cholesterol levels, the first-line therapy should be bile acid sequestrants. For adults with IDDM, bile acid sequestrants also may be the drugs of choice, particularly for normotriglyceridemic patients. Nicotinic acid therapy should be avoided. Among other drugs, hydroxymethyl-glutaryl coenzyme A reductase inhibitors may be preferable for patients with elevated LDL cholesterol and borderline hypertriglyceridemia. Fibric acid derivatives should be used for markedly hypertriglyceridemic patients. The role of probucol for dyslipidemia in IDDM patients is not clear.

Blood Glucose↗
PubMed1998

The ability of non-invasive physiological tests to detect arterial occlusions in the lower extremity. An ROC study with particular regard to recruitment of patients for clinical trials.

In the prerandomization phase of a clinical trial it is essential to be able to exclude, in a non-invasive way, patients who cannot be randomized into the trial. The ability of routine non-invasive physiological examinations to detect arterial occlusion in the lower extremities was investigated in 182 patients with hypercholesterolaemia. Ankle blood pressure measurement, pulse oscillometry, digital pulse plethysmography and treadmill and cycle exercise tests were performed as part of the prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). The PQRST was designed to compare the antiatherosclerotic effect of two different lipid-lowering regimens. Before randomization the patients also underwent aorto-femoral arteriography, which was used as 'gold standard'. The results were analysed with ROC methodology. Ankle blood pressure measurement (ABP) and inclination time (IT), measured with digital pulse plethysmography, without significant mutual difference, were the variables, best able to detect occlusions. For ABP, the AZ-values were 0.85, 0.82 and 0.94 in detection of right-sided, left-sided and bilateral occlusion, respectively. The corresponding figures for IT were AZ = 0.86, 0.91 and 0.93. If a bilateral occlusion was predicted in a patient with an ABP value of < = or 0.98, a specificity of 0.90 and a sensitivity of 0.87 were obtained, using arteriography as reference method. For IT, with a critical value of 320 ms, sensitivity and specificity were 0.83 and 0.90, respectively.

Adult↗