Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic analysis has shown that the slower than normal rhythmic defecation behavior of the clk-1 mutants of Caenorhabditis elegans is the result of altered lipoprotein metabolism. We show here that this phenotype can be suppressed by drugs that affect lipoprotein metabolism, including drugs that affect HMG-CoA reductase activity, reverse cholesterol transport, or HDL levels. These pharmacological effects are highly specific, as these drugs affect defecation only in clk-1 mutants and not in the wild-type and do not affect other behaviors of the mutants. Furthermore, drugs that affect processes not directly related to lipid metabolism show no or minimal activity. Based on these findings, we carried out a compound screen that identified 190 novel molecules that are active on clk-1 mutants, 15 of which also specifically decrease the secretion of apolipoprotein B (apoB) from HepG2 hepatoma cells. The other 175 compounds are potentially active on lipid-related processes that cannot be targeted in cell culture. One compound, CHGN005, was tested and found to be active at reducing apoB secretion in intestinal Caco-2 cells as well as in HepG2 cells. This compound was also tested in a mouse model of dyslipidemia and found to decrease plasma cholesterol and triglyceride levels. Thus, target processes for pharmacological intervention on lipoprotein synthesis, transport, and metabolism are conserved between nematodes and vertebrates, which allows the use of C. elegans for drug discovery.
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PMID:Evolutionary conservation of drug action on lipoprotein metabolism-related targets. 1790 68

Bile-acid sequestrants augment cholesterol excretion via enhanced conversion to bile acids, and act to lower low-density lipoprotein cholesterol (LDL-C), especially when combined with other cholesterol-lowering drugs. Colesevelam hydrochloride (HCL) has become the preferred drug of this class due to fewer gastrointestinal adverse effects. This article reviews the use of colesevelam in the treatment of dyslipidemia. Bile-acid sequestrants are a class of drugs developed to lower LDL-C levels. Two of the bile-acid sequestrants, colestyramine resin and colestipol, have been used since the 1980s, and have proven effective and safe as nonsystemic approaches to cholesterol reduction. However, tolerability and compliance issues related to palatability and gastrointestinal side effects have limited the use of these sequestrants. Colesevelam HCL (Daiichi Sankyo, Inc., Parsippany, NJ) is a nonabsorbed lipid-lowering agent that can be used in monotherapy or in combination with an HMG-CoA reductase inhibitor to reduce LDL-C in patients with primary hypercholesterolemia (Fredrickson type IIa). This article reviews the clinical efficacy and use of colesevelam HCL for the management of dyslipidemia.
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PMID:The use of colesevelam hydrochloride in the treatment of dyslipidemia: a review. 1793 Oct 91

Amlodipine/atorvastatin (Caduet) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.
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PMID:Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia. 1830 38

The metabolic syndrome increases the risk of atherothrombotic cardiovascular disease (CVD) and diabetes. In turn, diabetes promotes the development of atheroma and is regarded as a coronary heart disease risk equivalent. A multifactorial therapeutic strategy is advocated for patients with the metabolic syndrome to improve cardiovascular risk factor profiles and to reduce the chances of developing type 2 diabetes. Individual components of the syndrome must be addressed using safe, efficacious, and cost-effective measures. There is general agreement that lifestyle modifications, including control of body weight, avoidance of central adiposity, adoption of an antiatherogenic diet, and regular physical activity, are crucial. However, as the magnitude of the individual components of the metabolic syndrome increases with time, lifestyle measures are often insufficient. An individual with metabolic syndrome will often require drug treatment for hyperglycemia, atherogenic dyslipidemia, and high blood pressure, together with antiplatelet therapy. Reducing the need for polypharmacy is an increasingly important consideration for clinicians and the pharmaceutical industry; to date, no single therapy has emerged that targets the root cause(s) of the syndrome. HMG-CoA reductase inhibitors are important agents that reduce CVD morbidity and mortality, in people with impaired fasting glucose or metabolic syndrome. Selective cannabinoid receptor antagonists appear promising because they improve or attenuate several key defects of the syndrome. Thiazolidinediones and metformin are presently licensed for treatment of type 2 diabetes but may prove to have a broader role in future. Novel insulin-sensitizing drugs are under investigation. Drugs that act to prevent or reverse endothelial dysfunction may be of particular utility in preventing cardiovascular disease, especially if initiated before tissue damage has become irreversible. Insulin therapy, which has antiinflammatory and endothelial protective properties, has been shown to reduce morbidity and mortality in high-risk nondiabetic patients during critical illness. Potential synergy between different classes of drugs with metabolic and/or cardiovascular protective properties merits further investigation.
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PMID:Prevention of cardiovascular complications of the metabolic syndrome: focus on pharmacotherapy. 1837 Jul 50

The HMG-CoA reductase inhibitor (statin) rosuvastatin (Crestor) is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed the progression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention, although more data are needed from trials examining the effects of the drug on cardiovascular endpoints. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients (although it should be noted that it has not yet been established that atherosclerotic regression translates into improved cardiovascular outcomes). Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients.
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PMID:Rosuvastatin: a review of its effect on atherosclerosis. 1842 95

The primary role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is to treat dyslipidemia. The clinical benefits with statin therapy have been demonstrated in the primary and secondary prevention of atherosclerotic vascular diseases. More recently, it has been observed that pleiotropic effects of statins (which may or may not be associated with lipid lowering) have been described as treatment of various cardiovascular disease processes and in noncardiac disease processes. This article evaluates the potential mechanisms for these effects in the management of heart failure and postulates their clinical and beneficial use.
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PMID:Investigations of statins in heart failure: inflammatory biomarkers and hormones. 1843 97

The incidence of chronic kidney disease (CKD) in the U.S. continues to increase, and now over 10% of the U.S. population has some form of CKD. Although some patients with CKD will ultimately develop renal failure, most patients with CKD will die of cardiovascular disease before dialysis becomes necessary. Patients with CKD have major proatherogenic lipid abnormalities that are treatable with readily available therapies. The severe derangements seen in lipoprotein metabolism in patients with CKD typically results in high triglycerides and low high-density lipoprotein (HDL) cholesterol. Because of the prevalence of triglyceride disorders in patients with CKD, after treating patients to a low-density lipoprotein goal, non-HDL should be calculated and used as the secondary goal of treatment. A review of the evidence from subgroup analysis of several landmark lipid-lowering trials supports treating dyslipidemia in mild to moderate CKD patients with HMG-CoA reductase inhibitors. The evidence to support treating dyslipidemia in hemodialysis patients, however, has been mixed, with several outcome trials pending. Patients with CKD frequently have mixed dyslipidemia and often require treatment with multiple lipid-lowering drugs. Although statins are the cornerstone of therapy for most patients with CKD, differences in their pharmacokinetic properties give some statins a safety advantage in patients with advanced CKD. Although most other lipid-lowering agents can be used safely with statins in combination therapy in patients with CKD, the fibrates are renally metabolized and require both adjustments in dose and very careful monitoring due to the increased risk of rhabdomyolysis. After reviewing the safety and dose alterations required in managing dyslipidemia in patients with CKD, a practical treatment algorithm is proposed.
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PMID:Managing dyslipidemia in chronic kidney disease. 1989 3

Rosuvastatin is a potent HMG-CoA reductase inhibitor that has proven to be effective in the treatment of dyslipidemia. Rosuvastatin is cleared from the body by both biliary and renal clearance, the latter believed to be due to active tubular secretion. Whereas the mechanisms of hepatic clearance of rosuvastatin are well documented, those of renal clearance are not. Because rosuvastatin (and other statins) may alter proximal tubular function, this study aimed to characterize the mechanisms of tubular rosuvastatin secretion to define the factors that could influence the presence/concentration of rosuvastatin in proximal tubular cells. Hereto, polarized monolayers of primary human tubular cells were used. We found rosuvastatin net secretion across proximal tubule cells, which was saturable (K50=20.4+/-4.1 microM). The basolateral uptake step was rate-limiting and mediated by OAT3. Rosuvastatin efflux at the apical membrane was mediated by MRP2/4 and ABCG2 together with a small contribution from MDR1 or P-glycoprotein. These data, obtained in an intact human tubule cell model, provide a detailed insight into rosuvastatin's renal handling and the possible factors influencing it.
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PMID:Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. 1861 79

Dyslipidemia and the contributions of oxidized low-density lipoproteins (ox-LDL) are independent cardiovascular risk factors. There is growing evidence that dyslipidemia contributes not only to cardiovascular disease but also to the progressive decline of renal function in diabetic and non-diabetic kidney disease. Ox-LDL, by generating inflammation and oxidative stress, contributes to a pro-atherogenic mileu and leads to endothelial dysfunction, subsequent glomerular filtration barrier damage, and progressive renal injury. Chronic kidney disease (CKD), in turn, induces deleterious effects on lipid metabolism. Therefore, by inhibiting cholesterol synthesis and reducing ox-LDL, HMG CoA reductase inhibitors (statins) are attractive therapeutic options to preserve renal function. Current evidence demonstrates a reduction in cardiovascular risk and improved renal outcomes especially in patients with mild to moderate impairment of renal function. Evidence supports a beneficial role of statins thought to extend beyond their lipid-lowering effect, referred to as pleiotropic actions. These actions include modulatory effects on inflammation, oxidative stress and thrombosis, derived from their ability to prevent the formation of isoprenoid intermediates involved in cellular signaling, posttranslational modification of proteins and cellular function. This translates to potential reductions in the rate of decline in GFR in CKD and adverse effects of type 2 diabetes mellitus in the kidney. This review examines the role of statins for reno-protection as well as cardiovascular benefit in patients with CKD.
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PMID:HMG CoA reductase inhibitors and renoprotection: the weight of the evidence. 1912 95

The risk of cardiovascular disease increases with declining glomerular filtration rate. Hyperlipidemia and dyslipidemia, characterized by increased triglycerides and low levels of high-density lipoprotein, are both associated with cardiovascular outcome as well as the risk of progression of loss of renal function. Both hyperlipidemia and dyslipidemia respond to pharmacologic therapy, including hydroxymethylglutaryl-CoA reductase inhibitors and fibric acid derivatives, to alteration in diet as well as to extreme measures such as bariatric surgery. However, the effects of these modalities on cardiovascular or renal outcomes are dependent upon the level of renal function. There is strong evidence that patients with stages 1-3 chronic kidney disease attain benefit from lipid-lowering therapy both with reduction in cardiovascular risk and possibly reduction in the rate of decline in renal function. Among dialysis patients little risk reduction appears to be achieved by treatment of low-density lipoprotein cholesterol level. Bariatric surgery reduces hyperlipidemia in patients with chronic kidney disease, but has also been associated with subsequent rapid decline in renal function secondary to oxalate deposition.
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PMID:New insights into lipid metabolism in chronic kidney disease: what are the practical implications? 1916 24


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