Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HMG CoA reductase inhibitors are the most effective drugs for treating hypercholesterolaemia currently available. They inhibit cholesterol synthesis and thus stimulate receptor-mediated uptake and degradation of low-density lipoprotein cholesterol by the liver. In 30 patients with severe hypercholesterolaemia administration of lovastatin alone or in combination with other lipid-lowering manoeuvres maintained reductions of 25 to 31 per cent in serum cholesterol over five years. The drug was easy to take and well tolerated, the only significant side effect being a reversible myopathy. Two similar compounds, simvastatin and pravastatin, exert comparable effects on serum lipids, including modest reductions in triglycerides and increases in high-density lipoprotein cholesterol. The use of these drugs seems likely to exert a beneficial effect on atherosclerosis.
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PMID:HMG CoA reductase inhibitors as lipid-lowering agents: five years experience with lovastatin and an appraisal of simvastatin and pravastatin. 211 17

Hyperlipidemia is usually present in patients with the nephrotic syndrome. The most common lipid abnormality is hypercholesterolemia, although as the disorder progresses, hypertriglyceridemia may develop. Elevated plasma lipids have two potential vascular consequences, namely, atherosclerosis and progression of renal failure. Neither of these complications has been proven with certainty, but there is growing evidence to indicate that both may be long-term consequences of the nephrotic syndrome. Therefore, effective therapy of hyperlipidemia, particularly elevated cholesterol levels, is needed as a protection against these complications. Since nephrotic hypercholesterolemia frequently is severe, dietary therapy, although a valuable adjunct, will not normalize cholesterol levels in most nephrotic patients. Thus, if effective serum cholesterol lowering is to be achieved, drug therapy will be required. Bile acid-binding resins have been shown to lower cholesterol levels in nephrotic patients, but the decline in cholesterol concentrations is usually insufficient to produce a marked reduction in coronary risk. Nicotinic acid theoretically should be useful for treatment of nephrotic hyperlipidemia, but it has not been adequately tested. The new drugs that inhibit cholesterol synthesis, e.g., lovastatin, appear to be highly promising for treating elevations of both serum cholesterol and triglycerides in the nephrotic syndrome. However, testing of these drugs in this condition has been limited, and the possibility of significant side effects in an appreciable portion of patients has not been ruled out. Of particular concern is the development of severe myopathy that can produce myoglobinuria and acute renal failure. This side effect is relatively rare in patients without the nephrotic syndrome, but its prevalence in the latter condition has not been determined. The fibric acids will lower triglyceride levels in nephrotic patients, but they are not effective in lowering cholesterol levels; consequently, they probably have little role in the treatment of nephrotic hypercholesterolemia. Finally, the drug probucol will lower cholesterol levels in nephrotic patients, although not to desirable levels; still, probucol could prove useful in combination with other cholesterol-lowering drugs.
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PMID:Rationale and management of hyperlipidemia of the nephrotic syndrome. 248 42

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.
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PMID:Pharmacokinetics of the combination of fluvastatin and gemfibrozil. 760 6

Glucocorticoids mainly act through binding to cytosolic receptors that translocate to the nucleus after ligand binding, and dimerize to affect gene transcription in multiple fashions. The liganded receptors may interact with DNA at specific glucocorticoid responsive-elements, may physically hinder the ability of other transcription-regulating proteins to interact with their own DNA response-elements, and may form intranuclear complexes with the transcription factor c-jun, thus changing the number of c-jun/c-fos heterodimers that bind at AP-1 sites. By these, and perhaps other, mechanisms, physiologic concentrations of glucocorticoids regulate normal tissue metabolism, and supraphysiologic concentrations cause Cushing's syndrome. Cushing's syndrome leaves virtually no body tissue untouched. Left untreated, it results in progressive adiposity, myopathy, dermopathy (atrophy, stria, purpura, and hirsutism), psychopathy, glucose intolerance, hypercholesterolemia, hypertension, atherosclerosis, immunosuppression, and, ultimately, death. The physiology underlying each of these effects of hypercortisolism has been reviewed. The differences in the presentation of Cushing's syndrome in children and adults have also been discussed. The goal of the clinician must be to identify individuals with Cushing's syndrome as early in the course of the disease as possible so as to avoid the devastating complications that result from prolonged hypercortisolism. In patients for whom screening tests are equivocal, or only intermittently elevated, it may be necessary to re-evaluate the patient over time to establish that the patient has hypercortisolism. Some clinical guidelines for which patients to screen for hypercortisolism have been presented. Once hypercortisolism is established, patients with mild hypercortisolism (urine free cortisol less than four-fold above the upper limit of normal) should undergo tests to differentiate true Cushing's syndrome from a pseudo-Cushing state.
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PMID:Glucocorticoid action and the clinical features of Cushing's syndrome. 780 50

Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.
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PMID:The development of mitochondrial medicine. 809 Jul 15

Cholesterol-lowering drugs include three major pharmacological classes: a) fibrates, b) statines, HMG-CoA reductase inhibitors and c) cholestyramine. The late eighties were characterized by the introduction of HMG-CoA reductase inhibitors in therapeutics. For 12 months (1st January-31 December 1991), a prospective intensive program of pharmacovigilance investigated the occurrence of side effects among the three pharmacological classes of cholesterol-lowering drugs in a specialized unit for prevention of atherosclerosis and dyslipidemia. Among 3,506 out patients who received cholesterol-lowering drugs, 36 side effects were reported (i.e. 1 side effect for 98 out-patients). Most of the side effects were observed with statines (61%). The most frequently observed side effects were gastralgia (19.5%) observed with the three classes of drugs and hepatitis with HMG-CoA reductase inhibitors (8.5%) or fibrates (3%) whereas myopathy (12%) only occurred with statines. The other side effects were cutaneous (14%: eczema, skin rashes) or neuropsychiatric (11%: insomnia...) ones. This study emphasizes the low frequency of severe side effects (myopathy: 1 per 1,000 prescriptions, hepatitis: 1 per 1,000 prescriptions) with cholesterol-lowering drugs in current practice.
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PMID:[A one-year prospective and intensive pharmacovigilance of antilipemic drugs in an hospital consultation for prevention of risk factors]. 814 47

Single cardiovascular risk factor intervention is probably not sufficient to prevent atherosclerosis progression. There is a lack of data on concomitant use of hypocholesterolemic agents and antihypertensive drugs with respect to possible interactions and adverse experiences. We studied 293 patients (below 65 years of age) under treatment with either lisinopril (n = 144) or nifedipine (n = 149) for mild to moderate hypertension for 10 weeks, and with serum cholesterol above 6.5 mmol/L, who were randomized to either lovastatin 20 mg every day or placebo in a double-blind, double-dummy design for 6 weeks. Lovastatin effectively lowered cholesterol by 16% and 15% in the lisinopril and nifedipine group respectively (P < .01 compared to placebo for both groups) without any negative impact on the antihypertensive efficacy of either lisinopril or nifedipine. The drugs in combination were well tolerated and did not affect the well-being of the patients, and did not cause any more adverse effects than the antihypertensive agents alone. Liver enzymes increased slightly during lovastatin therapy, while no case of myopathy was reported. Combined therapy with lovastatin and antihypertensive therapy can be safely undertaken.
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PMID:Effect and tolerability of combining lovastatin with nifedipine or lisinopril. 821 32

Occlusive atherosclerosis is a major cause of morbidity and mortality in renal transplant recipients. Hyperlipidemia associated with the transplanted state may be at least partially responsible for this complication and is therefore an important target of therapy. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are powerful cholesterol-lowering drugs, but their broad use in transplant recipients has been hindered by concerns about interactions with cyclosporine. Cyclosporine interferes with the elimination of these agents, increasing their plasma and tissue levels and predisposing the patient to rhabdomyolysis. Fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor, possesses a distinct pharmacologic profile, including a shorter half-life and virtually no active circulating metabolites. Therefore, it may interact differently with cyclosporine. The pharmacokinetics and safety of fluvastatin, 20 mg/day, were evaluated in 20 hypercholesterolemic renal transplant recipients also receiving cyclosporine, usually in combination with azathioprine and methylprednisolone, during the 14-week study. Fluvastatin area under the curve, maximum plasma concentration, and time to maximum plasma concentration were minimally increased in these patients, unlike findings reported for lovastatin, pravastatin, and simvastatin. This suggests that metabolism of fluvastatin may be less affected by cyclosporine than that of other reductase inhibitors. Fluvastatin was well tolerated, with no evidence of myopathy, rhabdomyolysis, or ophthalmologic abnormalities. These findings and the significant reductions in total cholesterol and low-density lipoprotein cholesterol levels and the ratio of low-density to high-density lipoproteins achieved in these patients support the broader use of fluvastatin to treat hypercholesterolemia in renal transplant recipients.
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PMID:Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine. 897 Jun 7

Pravastatin is an HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting de novo cholesterol synthesis. Pravastatin produces consistent dose-dependent reductions in both total and low density lipoprotein (LDL)-cholesterol levels in patients with primary hypercholesterolaemia. Favourable changes in other parameters such as total triglyceride and high density lipoprotein (HDL)-cholesterol levels are generally modest. Combination therapy with other antihyperlipidaemic agents such as cholestyramine further enhances the efficacy of pravastatin in patients with severe dyslipidaemias. Available data suggest that pravastatin is effective in elderly patients and in patients with hypercholesterolaemia secondary to diabetes mellitus or renal disease. The benefit of cholesterol-lowering in terms of patient outcomes is currently an area of considerable interest. Recently completed regression studies (PLAC I, PLAC II, KAPS and REGRESS) show that pravastatin slows progression of atherosclerosis and lowers the incidence of coronary events in patients with mild to moderately severe hypercholesterolaemia and known coronary heart disease. Large scale primary (WOSCOPS) and secondary (CARE) prevention studies, moreover, demonstrate that pravastatin has beneficial effects on coronary morbidity and mortality. In WOSCOPS, all-cause mortality was reduced by 22%. Pravastatin is generally well tolerated by most patients (including the elderly), as evidenced by data from studies of up to 5 years in duration. As with other HMG-CoA reductase inhibitors, myopathy occurs rarely (< 0.1% of patients treated with pravastatin): approximately 1 to 2% of patients may present with raised serum levels of hepatic transaminases. Thus, with its favourable effects on cardiovascular morbidity/mortality and total mortality, pravastatin should be considered a first-line agent in patients with elevated cholesterol levels, multiple risk factors or coronary heart disease who are at high risk of cardiovascular morbidity.
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PMID:Pravastatin. A reappraisal of its pharmacological properties and clinical effectiveness in the management of coronary heart disease. 902 47

The focus of lipid-lowering therapy with drugs is prevention of complications of atherosclerosis. Landmark clinical trials have demonstrated that lowering low density lipoprotein cholesterol (LDL-C) may not only reduce coronary artery disease (CAD) risk but also may slow the progression and even induce regression of atherosclerosis in the coronary arteries. In addition, much attention has been given in recent years to the importance of triglyceride-rich lipoprotein (TRL) as a CAD risk factor, and the benefit of reducing plasma triglyceride levels and raising high density lipoprotein cholesterol (HDL-C) levels to prevent the recurrence of coronary events. Lipid-lowering drugs should be used within the framework of a systematic approach to treatment. Consideration must be given to the lipoprotein abnormality, the severity of disease, the role of combination therapy, and the spectrum of action of the drug and its pleiotropic effects (ie, effects beyond the expected action on lipoproteins). Five major agents have been used for the treatment of dyslipidemias. Three (resins, probucol and statins) target LDL-C, and two (fibrates and niacin) target primarily TRL and HDL-C. Fibrates and statins are the drugs of choice. Fibrates correct many abnormalities of lipoprotein metabolism in addition to having beneficial pleiotropic effects such as reducing fibrinogen and plasma viscosity. They inhibit the transcription of apolipoprotein (apo) CIII and enhance that of apoAI and lipoprotein lipase. Statins are safe and potent drugs for reducing LDL-C levels, and their efficacy in primary and secondary prevention of CAD has been amply demonstrated. They share a modes effect of raising HDL-C levels. Their pleiotropic effects, which include improvement of endothelial dysfunction, are numerous and may contribute to their spectacular beneficial effect of reducing CAD risk. They have effects that are complementary to those of fibrates, but the two drugs should be combined with caution because of the danger of myopathy. Atorvastatin is a major addition to this class of drugs because of its high efficacy and large spectrum of action. It lowers LDL-C levels effectively, not only in patients with severe forms of hypercholesterolemia but also in those with homozygous familial hypercholesterolemia. The effect of atorvastatin on LDL-C may be further enhanced by combining it with a resin. The ability of atorvastatin to lower triglyceride levels as well as LDL-C levels indicates that combined hyperlipidemia, a condition that, in the past, was best controlled with combination therapy, can now be treated with a single drug. It is also effective in patients with isolated hypertriglyceridemia and, although less potent than fenofibrate at reducing TRL and increasing HDL-C, it has a greater impact on the atherogenic risk ratios such as LDL-C:HDL-C. The profile of its pleiotropic effects is promising.
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PMID:Advances in drug treatment of dyslipidemia: focus on atorvastatin. 962 39


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