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)

The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
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PMID:3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. 1866 82

Nicotinic acid has been used for several decades to treat dyslipidemia. In mice, the lipid-lowing effect of nicotinic acid is mediated by the Gi coupled receptor PUMA-G. In humans, high (GPR109A) and low (GPR109B) affinity nicotinic acid receptors have been characterized. Here we identify monomethylfumarate as a GPR109A agonist. Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. We show that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrate competitive binding with nicotinic acid. We show that GPR109A is highly expressed in neutrophils and epidermal keratinocytes, and that its expression is increased in human psoriatic lesions. Our findings provide evidence that GPR109A is a target for the drug Fumaderm and suggest that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders.
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PMID:The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. 1872 46

Metabolic syndrome (MS) is a common condition strongly associated with the development of type 2 diabetes and coronary heart disease (CHD). High triglycerides (TG) and low high density lipoprotein cholesterol (HDL-C) often occur together and represent the fundamental dyslipidemia of patients with MS. This abnormal lipoprotein profile is a major risk factor for premature cardiovascular disease. This review briefly discusses new findings on structure and functions of HDL in the atherogenic dyslipidemic condition known as MS. While the knowledge of the association between HDL-C and CHD began with the observation of an inverse relationship between HDL-C values and CHD risk, information in recent years shows the important role of HDL function in the pathogenesis of atherosclerosis. HDL particles are heterogeneous in structure, intravascular metabolism and antiatherogenic activity. Reductions in HDL-C concentrations, as seen in MS, are frequently associated with an abnormal HDL subclass distribution, altered HDL chemical composition, reduced antiinflamatory and antioxidative properties, and low capacity to promote cholesterol efflux. Deficiency of HDL particle number and attenuated antiaterogenic activity favor accelerated atherosclerosis. These data justify renewed emphasis on low HDL-C as a major risk factor in the prevention and treatment of CHD. Pharmacological interventions that increase HDL-C can also improve the quality and biological activities of HDL particles. Fibrates, nicotinic acid, cholesteryl ester transfer protein inhibitors, and reconstituted HDL are being investigated. Patients with MS constitute a high risk group that would particularly benefit from intervention to rise HDL-C.
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PMID:[Some physiopathologic features of metabolic syndrome]. 1893 96

Low levels of high-density lipoprotein cholesterol (HDL-C) represent a major cardiovascular risk factor, with a stronger relationship to coronary heart disease than that seen with elevated levels of low-density lipoprotein cholesterol (LDL-C). HDL-C has important antiatherogenic effects, including reverse cholesterol transport, inhibition of LDL-C oxidation, and antiplatelet and anti-inflammatory actions. Patients with low HDL-C are also at an amplified risk of coronary heart disease due to the common coexistence of other risk factors, including excess adiposity, metabolic syndrome, type 2 diabetes mellitus, hypertriglyceridemia, and the atherogenic dyslipidemia characterized by small dense LDL-C. First-line therapy of low HDL-C generally consists of nonpharmacologic measures such as improved fitness and weight loss. Current pharmaceutical options include statins, fibrates, and nicotinic acid. A host of novel approaches involving HDL-C and reverse cholesterol transport hold the promise of fundamentally changing the natural history of atherosclerosis, the most common and important chronic disease in humans.
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PMID:The importance of recognizing and treating low levels of high-density lipoprotein cholesterol: a new era in atherosclerosis management. 1912 82

Dyslipidemia is central to the process of atherosclerosis. Modification of the lipid profile by diet, exercise, or pharmacologic therapy has been demonstrated to reduce the risk from atherosclerosis in clinical studies in primary and secondary prevention. Nicotinic acid has been in clinical use for over 50 years. The administration of nicotinic acid has been demonstrated to reduce apolipoprotein B-containing lipoproteins (very low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and lipoprotein (a)). Nicotinic acid also exerts significant effects on high-density lipoprotein. In addition to improving dyslipidemia, nicotinic acid has been demonstrated to induce a number of nonlipid or pleiotropic effects. The recent discovery of the nicotinic acid receptor has improved knowledge relative to the mechanism of action and the adverse effect profile of nicotinic acid. Clinical trials utilizing clinical or angiographic end points demonstrated efficacy for the use of nicotinic acid in monotherapy or in combination with bile acid resins or statins.
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PMID:Nicotinic acid: a new look at an old drug. 1922 80

Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic acid stimulates the GPCR GPR109A and Gi/Go proteins, here we dissected the roles of G proteins and the adaptor proteins, beta-arrestins, in nicotinic acid-induced signaling and physiological responses. In a human cell line-based signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering of cAMP, recruitment of beta-arrestins to the cell membrane, an activating conformational change in beta-arrestin, and beta-arrestin-dependent signaling to ERK MAPK. In addition, we found that nicotinic acid promoted the binding of beta-arrestin1 to activated cytosolic phospholipase A2 as well as beta-arrestin1-dependent activation of cytosolic phospholipase A2 and release of arachidonate, the precursor of prostaglandin D2 and the vasodilator responsible for the flushing response. Moreover, beta-arrestin1-null mice displayed reduced cutaneous flushing in response to nicotinic acid, although the improvement in serum free fatty acid levels was similar to that observed in wild-type mice. These data suggest that the adverse side effect of cutaneous flushing is mediated by beta-arrestin1, but lowering of serum free fatty acid levels is not. Furthermore, G protein-biased ligands that activate GPR109A in a beta-arrestin-independent fashion may represent an improved therapeutic option for the treatment of dyslipidemia.
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PMID:beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. 1934 87

The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease. The core components of the dyslipidemia of the metabolic syndrome, which most likely initiate atherosclerosis, are the "lipid triad" of high plasma triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C), and a preponderance of small, dense low-density lipoprotein (LDL) particles. Postprandial lipemia is also recognized as an important component. Dysregulation of fat metabolism in the liver with overproduction of very-low-density lipoprotein 1 (VLDL1) particles is considered the hallmark of the dyslipidemia of the metabolic syndrome. The cornerstone of therapy is therapeutic lifestyle change. If this does not correct the dyslipidemia, drug therapy may be required. LDL-C lowering with statins is the first-line treatment; however, there is ongoing debate as to whether further aggressive LDL-lowering therapy with higher-dose statins as opposed to comprehensive lipid management is the optimal therapy to reduce cardiovascular risk in subjects with the metabolic syndrome. Combination of a statin with a fibrate and/or nicotinic acid can improve all components of the dyslipidemia. However, there are, as yet, no large cardiovascular outcome studies that show a reduction in cardiovascular morbidity or mortality using combination therapy. The current LDL-C goal in high-risk patients with the metabolic syndrome is below 100 mg/dL, with a non-HDL goal of below 130 mg/dL. However, in very high-risk patients, such as those with established cardiovascular disease, an LDL-C goal of below 70 mg/dL is recommended.
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PMID:Pathogenesis and management of the dyslipidemia of the metabolic syndrome. 1940 Jul 42

Diabetes mellitus type 2 is reaching epidemic proportions in western societies. The treatment of diabetic dyslipidemia to prevent cardiovascular disease is of increasing clinical and scientific interest. In the pathogenesis of this disease plasma triglycerides play a central role. Triglyceride rich particles by themselves are not considered atherogenic; however, they are hydrolysed to chylomicron and VLDL remnant particles. Furthermore, mediated by cholesteryl ester transfer protein (CETP), atherogenic small dense LDL particles (sdLDL) emerge, and HDL cholesterol decreases. All these factors yield into a significantly increased atherogenesis and cardiovascular risk. Weight reduction and low fat diets have shown positive effects in general, but a specific therapy to treat diabetic dyslipidemia is still missing. Studies so far have failed to show a reliable benefit for fibrates and for nicotinic acid. Thus, statin therapy to decrease LDL cholesterol to target is the essential treatment for diabetic dyslipidemia to reduce cardiovascular risk. Other lipid lowering drugs can be added optionally.
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PMID:[Diabetic dyslipoproteinemia: beyond LDL]. 1942 32

Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% and 30% for the salt form and free acid form, respectively. Following administration to the colon, the extent of absorption was further reduced. The data indicate that bioavailability from the DSB was limited by the solubility of the drug coupled with an absorption window, whilst absorption from the colon was limited by permeability. The study provided detailed information to support and guide the formulation strategy for a MR form of acipimox, which may improve the treatment of adult patients with type II diabetes and dyslipidemia.
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PMID:The assessment of human regional drug absorption of free acid and sodium salt forms of acipimox, in healthy volunteers, to direct modified release formulation strategy. 1979 34

Nicotinic acid (niacin) is one of the oldest drugs used to treat dyslipidemia. In addition to modestly lowering low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a), niacin is currently the most effective available agent for raising high-density lipoprotein cholesterol (HDL-C). Despite its well-documented beneficial effects on lipids, the clinical use of niacin has been limited by its side effect profile, notably flushing. This sensation of cutaneous vasodilatation and burning has limited patient compliance and is a frequent cause of discontinuation of the drug. While pretreatment with nonsteroidal anti-inflammatory agents, such as aspirin, may reduce the incidence of flushing, present-day niacin still results in flushing in many patients. Recent studies have elucidated what we currently understand as the molecular mechanism that mediates niacin-induced flushing, specifically that niacin acting through its receptor stimulates the production of several prostaglandins, including prostaglandin (PG) I(2), PGE(2) and PGD(2). Laropiprant is a potent, highly selective prostaoid DP(1) receptor antagonist that decreases the incidence and intensity of niacin-induced flushing without affecting its beneficial lipid effects. Thus, laropiprant, when used in conjunction with niacin, can improve the tolerability of niacin and aid in medication compliance. This paper reviews the data suggesting the importance of raising HDL with niacin, describes the pharmacology of the drug, and examines the potential beneficial effects of combining niacin with laropiprant.
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PMID:Niacin and laropiprant. 2057 6


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