Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reasons for the current emphasis on cholesterol as coronary risk factor are multiple. On one hand current studies have shown that primary as well as secondary prevention of ischemic heart disease is a realistic possibility with lipid lowering measures. On the other hand new drugs are actually available which permit a potent and adapted therapy of hyperlipidemias. According to new guidelines of the Swiss "lipid task force" screening for hypercholesterolemia is recommended. A cholesterol value greater than 6.5 mmol/l should be investigated and treated. Because a great proportion of adult Swiss fall into this category (approximately 1/3) it is essential that all those are efficiently treated that have markedly abnormal cholesterol values or present with other risk factors such as smoking and hypertension or have a personal or familiar history of ischemic heart disease. Because progression is likely in patients with or after manifest ischemic heart disease even when hypercholesterolemia is mild (over 5.2 mmol/l) all patients presenting with an infarct should be investigated for dyslipidemia. Cholesterol, triglycerides and HDL should be determined. Dietary measures are the basis of every attempt to reduce hyperlipidemia. Most importantly intake of saturated fats prevailing in animal products should be restricted. The next important step is reduction of dietary cholesterol and in obese patients also caloric restriction. Lipid lowering agents are recommended in patients at risk who do not respond to or comply with dietary regimens. According to type of dyslipidemia bile-acid-binding resins, fibrates, nicotinic acid or HMG-CoA reductase inhibitors are available.
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PMID:[Lipid-lowering therapy in the prevention of coronary heart disease]. 221 47

Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.
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PMID:Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment. 291 50

In the recently reported Scandinavian Simvastatin Survival Study (4S), 4,444 men and women between 35 and 70 years of age who had coronary heart disease and plasma total cholesterol concentrations of 212 to 310 mg per deciliter (5.5 to 8.0 mmol/l) received simvastatin or placebo for 5.4 years; in the treatment group, mortality from coronary heart disease was 42 percent lower and mortality from all causes was 30 percent lower. Further analysis of the relation between the risk of major coronary events and baseline cholesterol levels in patients randomised to placebo or simvastatin therapy in the study showed that simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, high-density-lipoprotein, and low-density-lipoprotein cholesterol, by a similar amount in each quartile. Clearly, cholesterol-modifying interventions can substantially improve the outlook for patients with coronary heart disease and should be considered in identification and treatment of patients with established coronary heart disease. The available data from secondary intervention trials indicates that all patients with documented ischemic heart disease should be offered a reliable assessment of plasma total cholesterol. However, since the impact of simvastatin on CHD seems to begin after about one year of therapy it would be reasonable to exclude very old persons and patients with serious disease with a limited life-expectancy. As a consequence of the 4S data it should be recommended that all the patients in question, who after lifestyle modifications and non-pharmacological risk factor modification still have total cholesterol levels above 200 mg per deciliter (5.2 mmol) should be offered treatment with a HMG-CoA reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The Scandinavian Simvastatin Survival Study: the clinical consequences]. 749 39

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are potent cholesterol reducing agents that have been successfully used for the treatment of heterozygous familial hypercholesterolaemia (FH). A recent investigation revealed that several constitutional and genetic factors significantly determined the response of plasma lipids and lipoproteins to the HMG CoA reductase inhibitor fluvastatin. Gender has been identified through multivariate analysis as a major determinant of the plasma high density lipoprotein (HDL) cholesterol response. The current analysis was undertaken to determine possible gender-related fluvastatin dose-response differences. The analysis revealed that for HDL cholesterol, gender-related differences reach statistical significance only at the highest fluvastatin dose of 40 mg/day (females 22.9%, males 12.9%, p < 0.01). In parallel, the change in low density lipoprotein (LDL) cholesterol: HDL cholesterol ratio, an indicator of ischaemic heart disease risk, was also found to be affected by gender (females -38.4%, males -32.2%, p < 0.01). For LDL cholesterol, no consistent gender-related differences were found. In conclusion, the response of plasma lipid levels to fluvastatin in heterozygote FH patients is significantly affected by gender, with females achieving a more marked overall response, as indicated by higher HDL cholesterol levels and a lower LDL cholesterol: HDL cholesterol ratio.
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PMID:Gender-related response to fluvastatin in patients with heterozygous familial hypercholesterolaemia. 751 34

Platelets are involved in the initiation of atheromas and arterial thrombosis and thus may play a cardinal role in the pathogenesis of myocardial and cerebral infarction. In 18 patients with coronary artery disease and hypercholesterolemia resistant to low-lipid diet a 12 week treatment with lovastatin (HMG-CoA reductase inhibitor) leads to the reduction of total cholesterol, LDL-cholesterol and triglycerides but also to a marked increase of platelet activity. Lovastatin is an inactive lacton prodrug which must be enzymatically or chemically transformed to the active form. In in-vitro experiments, it was discovered that both chemically hydrolysed lovastatin and plasma containing lovastatin metabolites stimulate induced platelet aggregation in whole blood samples. "Essential" phospholipids (Lipostabil) added to the blood samples in concentrations according to those which are used clinically prevent this stimulation. This corresponds to data obtained earlier from Lipostabil-treated ischemic heart disease patients. Besides a lipid-lowering effect Lipostabil showed a 50% reduction of spontaneous aggregates in plasma, an increase of the susceptibility threshold to aggregation inducers and a decrease of the platelet aggregation amplitude in whole blood samples. Therefore, it would be promising to combine the therapy by lovastatin with "essential" phospholipids possessing a remarkable improving effect on the platelet function based on a molecular action independent of their moderate lipid-reducing action.
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PMID:Evidence of combined therapy of dyslipoproteinemia by HMG-CoA reductase inhibitors and "essential" phospholipids. 833 Apr 75

Hyperlipidemia following successful renal transplantation is a frequent and persistent disorder, and lipid abnormalities are associated with ischemic heart disease. Correlates have been found to cyclosporine and steroids as the major causes of lipid disorders. Cardiovascular disease is currently the major cause of death among renal graft recipients in the long run. Therefore, lipid lowering therapy appears to be useful in those patients without cardiovascular disease (primary prevention) and is mandatory in those with established coronary artery disease (secondary prevention). Because of the multiplicity of other cardiovascular risk factors, hyperlipidemia might only be of minor importance. On the other hand, lipids may even accelerate the development of arteriosclerosis in a preinjured vascular endothelium. Dietary modification or reduction of dietary fat is considered to be the first line of antilipemic therapy. Unfortunately, hyperlipidemia appears not to be responsive to modification of dietary fat without weight reduction. In general, patients taking immunosuppressive drugs after organ transplantation are grouped under high risk population when pharmacological intervention is selected, since only some lipid lowering drugs are safe and efficacious in short-term studies and when used with precaution. Low-dose HMG-CoA reductase inhibitor is the drug of choice for lowering LDL cholesterol. Immunosuppression withdrawal protocols have successfully been used to control massive hyperlipidemia in immunologically stable patients in the long term. Although evidence from prospective controlled intervention studies is lacking, it is reasonable to adopt the principle of a broad-based approach aimed at reducing LDL cholesterol as well as other major risk factors for cardiovascular disease in this patient population. The likelihood is that effective control of serum lipids and lipoproteins may achieve a similar beneficial reduction in absolute mortality in renal transplant recipients as already demonstrated in individuals without kidney disease but with cardiovascular damage.
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PMID:Clinical utility of antilipidemic therapies in chronic renal allograft failure. 858 86

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n = 11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16 +/- 1.15 to 3.53 +/- 0.99 mmol/L (P < .001). The total cholesterol concentration decreased from 9.90 +/- 1.32 to 5.43 mmol/L (P < .001). HDL cholesterol concentration increased from 1.19 +/- 0.31 to 1.49 +/- 0.43 mmol/L (P < .001). Triglyceride concentrations decreased from 1.34 +/- 0.66 to 0.88 +/- 0.36 mmol/L (P < .01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Atorvastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH.
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PMID:Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia. 930 31

Hyperlipidemia is recognized as one of the major risk factors for the development of coronary artery disease and progression of atherosclerotic lesions. Dietary therapy together with hypolipidemic drugs are central to the management of hyperlipidemia, which aims to prevent atherosclerotic plaque progression, induce regression, and so decrease the risk of acute coronary events in patients with pre-existing coronary or peripheral vascular disease. In patients at high risk of coronary artery disease but without evidence of atherosclerosis, treatment is designed to prevent the premature development of coronary artery disease, whereas in those with hypertriglyceridemia, treatment aims to prevent the development of hepatomegaly, splenomegaly, and pancreatitis. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most potent lipid-lowering agents currently available, and their use in the treatment of hyperlipidemia provides the focus for this review. Particular emphasis is given to cerivastatin, a new HMG-CoA reductase inhibitor that combines potent cholesterol-lowering properties with significant triglyceride-reducing effects. Recently completed primary and secondary intervention trials have shown that the significant reductions in low-density lipoprotein (LDL) cholesterol achieved with statins result in significant reductions in morbidity and mortality associated with coronary artery disease as well as reductions in the incidence of stroke and total mortality. Such benefits occur early in the course of statin therapy and have led to suggestions that these drugs may possess antiatherogenic effects over and above their capacity to lower atherogenic lipids and lipoproteins. Experimental studies have also shown statin-induced improvements in endothelial function, decreased platelet thrombus formation, improvements in fibrinolytic activity, and reductions in the frequency of transient myocardial ischemia.
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PMID:Current and future treatment of hyperlipidemia: the role of statins. 973 40

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatin's high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.
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PMID:Preclinical review of cerivastatin sodium--a step forward in HMG-CoA reductase inhibition. 981 Nov 53

The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5 micrograms/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.
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PMID:Overview of the use of CoQ10 in cardiovascular disease. 1041 41


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