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 pathophysiology of intermittent claudication (IC) and the role of pentoxifylline and cilostazol for treating IC are discussed. IC, a result of inadequate blood flow to the musculature, is the primary symptom of occlusive peripheral vascular disease (PVD). Patients with IC often have a decreased quality of life because of mobility limitations. PVD is a sign of generalized atherosclerosis and increases the risk of cardiac morbidity and mortality. Smoking, hypertension, diabetes mellitus, and increasing age may hasten the progression of PVD. Strategies for treating IC are aimed at improving symptoms and reducing the progression of atherosclerosis and include risk-factor modification, exercise, and antiplatelet therapy. Cilostazol and pentoxifylline are the only two drugs with FDA-approved labeling for use in treating IC. Both drugs have been shown to increase pain-free walking time and total distance walked, although there is some conflicting evidence for pentoxifylline. Cilostazol and pentoxi-fylline are fairly well tolerated; the most common adverse effects involve the gastrointestinal tract and central nervous system. Inhibitors of cytochrome P-450 isoenzymes 3A4 and 2C19 should be used cautiously in patients taking cilostazol, and this drug is contraindicated in patients with congestive heart failure. Cilostazol is more costly than pentoxifylline. Initiation of therapy with either pentoxifylline or cilostazol may be reasonable if risk-factor modifications, lifestyle changes, and antiplatelet therapy are not effective. The mainstays of therapy for IC are risk-factor modification, exercise, and antiplatelet therapy. If these prove inadequate, treatment with pentoxifylline or cilostazol may be reasonable.
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PMID:Treatment of intermittent claudication with pentoxifylline and cilostazol. 1181 75

Mechanisms for the regulation of intracellular cholesterol levels in various types of brain and vascular cells are of considerable importance in our understanding of the pathogenesis of a variety of diseases, particularly atherosclerosis and Alzheimer's disease (AD). It is increasingly clear that conversion of brain cholesterol into 24-hydroxycholesterol and its subsequent release into the periphery is important for the maintenance of brain cholesterol homeostasis. Recent studies have shown elevated plasma concentrations of 24-hydroxycholesterol in patients with AD and vascular dementia, suggesting increased brain cholesterol turnover during neurodegeneration. The oxygenases involved in the degradation and excretion of cholesterol, including the cholesterol 24-hydroxylase and the 27-hydroxylase, are enzymes of the cytochrome P-450 family. This review focuses on the newly recognized importance of cholesterol and its oxygenated metabolites in the pathogenesis of ischemic stroke and AD. The reduction in stroke and AD risk in patients treated with cholesterol-lowering statins is also discussed.
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PMID:Cholesterol in neurologic disorders of the elderly: stroke and Alzheimer's disease. 1521 22

Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de-esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P-450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10-80 mg dose-dependently reduced diastolic blood pressure (DBP). Troughto-peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once-daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24-h DBP and SBP were similar to those of cuff DBP measurement. In mild-to-moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24-h blood pressure. In lowering DBP olmesartan medoxomil, at 10-20 mg/day, was as effective as atenolol at 50-100 mg/day. In mild-to-moderate hypertensive patients, olmesartan medoxomil, at 5-20 mg once daily, was more effective than captopril at 12.5-50 mg twice daily. At 20-40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5-10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases.
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PMID:Clinical and experimental aspects of olmesartan medoxomil, a new angiotensin II receptor antagonist. 1559 75

Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 (CYP) metabolites synthesized from the essential fatty acid arachidonic acid to generate four regioisomers, 14,15-, 11,12-, 8,9-, and 5,6-EET. Cultured human coronary artery endothelial cells (HCAECs) contain endogenous EETs that are increased by stimulation with physiological agonists such as bradykinin. Because EETs are known to modulate a number of vascular functions, including angiogenesis, we tested each of the four regioisomers to characterize their effects on survival and apoptosis of HCAECs and cultured human lung microvascular endothelial cells (HLMVECs). A single application of physiologically relevant concentration of 14,15-, 11,12-, and 8,9-EET but not 5,6-EET (0.75-300 nM) promoted concentration-dependent increase in cell survival of HLMVECs and HCAECs after removal of serum. The lipids also protected the same cells from death via the intrinsic, as well as extrinsic, pathways of apoptosis. EETs did not increase intracellular calcium concentration ([Ca2+]i) or phosphorylate mitogen-activated protein kinase p44/42 when applied to these cells, and their protective action was attenuated by the phosphotidylinositol-3 kinase inhibitor wortmannin (10 microM) but not the cyclooxygenase inhibitor indomethacin (20 microM). Our results demonstrate for the first time the capacity of EETs to enhance human endothelial cell survival by inhibiting both the intrinsic, as well as extrinsic, pathways of apoptosis, an important underlying mechanism that may promote angiogenesis and endothelial survival during atherosclerosis and related cardiovascular ailments.
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PMID:Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature. 1661 27

Coronary heart disease (CHD) is the leading cause of death in Western civilizations, in particular in chronic kidney disease (CKD) patients. Serum total cholesterol and LDL have been linked to the development of atherosclerosis and progression to CHD in the general population. However, the reductions of total and LDL cholesterol in the dialysis population have not demonstrated the ability to reduce the morbidity, mortality, and cost burden associated with CHD. The patients at greatest risk include those with pre-existing CHD, a CHD-risk equivalent, or multiple risk factors. However, data in the dialysis population are much less impressive, and the relationship between plasma cholesterol, cholesterol reduction, use of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, and reduction in incidence of CHD or effect on progression of renal disease have not been proven. Adverse event information from published trials indicates that agents within this class share similar tolerability and adverse event profiles. Hepatic transaminase elevations may occur in 1 to 2% of patients and is dose related. Myalgia, myopathy, and rhabodmyolysis occur infrequently and are more common in kidney transplant patients and patients with CKD. This effect appears to be dose related and may be precipitated by administration with agents that inhibit cytochrome P-450 isoenzymes. Caution should be exercised when coadministering any statin with drugs that metabolize through cytochrome P-450 IIIA-4 in particular fibrates, cyclosporine, and azole antifungals. Elderly patients with CKD are at greater risk of adverse drug reactions, and therefore the lowest possible dose of statins should be used for the treatment of hyperlipidemia.
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PMID:The efficacy and safety of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in chronic kidney disease, dialysis, and transplant patients. 2139 88


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