Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this double-blind, placebo-controlled cross-over design trial was to assess the safety of a multi-vitamin preparation containing nicotinic acid in a physiological dose. Seventy-two healthy volunteers took part in this trial. At six consecutive time-points, we systematically documented blood pressure, pulse, skin temperature and flushing symptoms after an oral dose of up to 50.1 mg nicotinic acid. The results suggest that nicotinic acid in a dosage of 16.7 mg does not cause flushing symptoms. In higher doses up to 50.1 mg, flushing symptoms are sporadically possible. There was no physiologically relevant change regarding the central metabolic parameters blood pressure, pulse and skin temperature.
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PMID:Investigation of niacin on parameters of metabolism in a physiologic dose: randomized, double-blind clinical trial with three different dosages. 1952 94

Extended-release (ER) niacin (nicotinic acid)/laropiprant is a once-daily fixed-dose combination tablet that has been evaluated (with or without an HMG-CoA reductase inhibitor [statin]) in the treatment of adults with dyslipidaemia or primary hypercholesterolaemia. Niacin (vitamin B3) is a lipid-modifying drug and laropiprant is an anti-flushing agent, which reduces flushing induced by niacin. In a randomized, double-blind, placebo-controlled, multicentre, 24-week trial, a significant (p < 0.001) reduction (18.4%) in plasma low-density lipoprotein cholesterol (LDL-C) levels (primary endpoint) was achieved with ER niacin/laropiprant 2000 mg/40 mg once daily (after an initial 4-week 1000 mg/20 mg once-daily regimen) compared with placebo (weeks 12-24) in adults with primary hypercholesterolaemia or mixed dyslipidaemia. ER niacin/laropiprant 2000 mg/40 mg plus simvastatin 20 mg or 40 mg once daily (after an initial 4-week lower-dose regimen) produced significant (p < 0.05) improvements, from baseline, in LDL-C levels (primary endpoint) compared with once-daily ER niacin/laropiprant 2000 mg/40 mg or simvastatin alone at week 12 in a randomized, double-blind, multicentre, factorial trial in adults with primary hypercholesterolaemia or mixed dyslipidaemia. The incidence and intensity of flushing (an efficacy endpoint) were significantly (p < 0.05) reduced with ER niacin/laropiprant compared with ER niacin in randomized trials. ER niacin/laropiprant, alone or in combination with a statin, was generally well tolerated for up to 24 weeks by adults with dyslipidaemia or primary hyercholesterolaemia.
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PMID:Extended-release niacin (nicotinic acid)/laropiprant. 1967 16

Although statins reduce cardiovascular morbidity and mortality further risk reduction is needed. In this respect low HDL-cholesterol concentrations and/or elevated triglyceride concentrations may be potential treatment targets. Niacin (nicotinic acid) is an effective drug which increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol and decreases the concentration of low-density lipoprotein (LDL)-cholesterol, triglycerides and lipoprotein(a). Clinical studies indicate that niacin can significantly reduce the risk for cardiovascular events. However, niacin is not very commonly used because of significant side effects (especially flushing). Laropiprant is a potent selective antagonist of PGD2-receptor subtype-1 and can thus reduce niacin-induced flushing. Although the addition of laropiprant will reduce the frequency of flushing, it will not completely eliminate this side effect. Laropiprant does not change the effect of niacin on lipids or other side effects of niacin (ie, gastro-intestinal problems, glucose elevation). The combination of niacin with laropiprant may therefore enable use of niacin at higher doses and therefore exploit the full potential of the drug. Endpoint studies that will be published over the next few years will show whether this treatment modality also translates into clinical effect in patients treated with statins. Until publication of these studies niacin/laropiprant should be used only in high-risk patients not achieving lipid goals on statins.
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PMID:Review of extended-release niacin/laropiprant fixed combination in the treatment of mixed dyslipidemia and primary hypercholesterolemia. 2001 45

Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D(2)-driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events.
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PMID:A "hot" topic in dyslipidemia management--"how to beat a flush": optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. 2036 Feb 95

There is a rising interest towards the old drug, nicotinic acid (niacin, vitamin B(3)), because at pharmacological concentrations it has a beneficial effect on HDL cholesterol. Its use, however, was limited due to its adverse effect, flushing. When the mechanism of flushing was solved, a combination of niacin and DP1 receptor antagonist or prostaglandin inhibitor is used, there has been a comeback of niacin with extensive clinical trials. This paper argues that the new strategy with niacin for the prevention of atherosclerosis should be re-evaluated, because vasodilatation of the peripheral vessels might be crucially important in the early primary prevention according to our "vasa vasorum hypoxia" hypothesis.
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PMID:Niacin in the prevention of atherosclerosis: Significance of vasodilatation. 2045 29

When cholesterol levels remain high despite appropriate lifestyle measures, the choice of lipid-lowering drug should focus on products that have been shown to prevent fatal and nonfatal cardiovascular events. On this basis, simvastatin and pravastatin, unlike sustained-release nicotinic acid, are first-line options. A fixed-dose combination of nicotinic acid and laropiprant is authorised in the European Union for the treatment of lipid disorders, either alone or together with a statin. The role of laropiprant, a type 1 prostaglandin D2 receptor antagonist, is to prevent the flushing caused by nicotinic acid. The nicotinic acid + laropiprant combination, used alone or simultaneously with a statin, has only been tested for its effect on surrogate lipid endpoints, not for its ability to prevent cardiovascular events. Three comparative trials in a total of about 4000 patients showed that laropiprant partly prevented the flushing due to sustained-release nicotinic acid. However, about one in three patients still had at least moderately intense flushing at the outset of treatment, while about half the patients subsequently had flushing on up to 3 days a week. Compared with sustained-release nicotinic acid alone, laropiprant + nicotinic acid combination therapy provokes more gastrointestinal disorders, more hypersensitivity reactions, and more transaminase and creatine phosphokinase elevations. Through its effect on prostaglandin D2 and thromboxane A2, laropiprant also has effects on blood coagulation, with uncertain clinical consequences. Animal and human data argue against the use of the nicotinic acid + laropiprant combination during pregnancy and breast-feeding. In practice, patients with hypercholesterolaemia need drugs with well-documented clinical efficacy, and this excludes the nicotinic acid + laropiprant combination.
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PMID:Nicotinic acid + larodiorant. Laropiprant adds its own adverse effects. 2045 30

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a-/- mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin.
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PMID:Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. 2066 68

Nicotinic acid (at a daily dose of grams) has been shown to induce potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional anti-atherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future.
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PMID:New evidence for nicotinic acid treatment to reduce atherosclerosis. 2093 32

Advances in clinical lipidology during the last 18 months include the establishment of high-sensitivity C-reactive protein (hsCRP) as an important risk marker for cardiovascular disease. Determining hsCRP levels should help the clinician single out patients at particularly high risk. However, more research needs to be done in this area. Furthermore, statins do not seem to be of benefit in patients with severe congestive heart failure, on chronic hemodialysis, or with aortic stenosis. Next, plasma triglyceride levels are now considered an important risk marker for cardiovascular disease, but the therapeutic benefits related to lowering triglyceride levels remain difficult to achieve. Also, nicotinic acid has gained more interest partly because recent studies have demonstrated positive effects on atherosclerosis development and partly because the side effect of flushing seems to be partially avoidable with the concomitant administration of laropiprant. Both the raising of high-density lipoprotein cholesterol by nicotinic acid and the additional lowering of low-density lipoprotein cholesterol by ezetimibe and eprotirome will need to demonstrate hard endpoint reductions in large-scale intervention trials. Trials of niacin/laropiprant (the AIM-HIGH and HPS2-THRIVE studies) and ezetimibe (the IMPROVE-IT study) are already under way.
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PMID:Recent advances in preventing cardiovascular disorders by managing lipid levels. 2117 59

Flushing and hepatotoxicity are important adverse effects of nicotinic acid. This article reviews the role of metabolism of nicotinic acid in the production of these side effects. The suggestion that nicotinic acid (NUA) formation produces flushing is traced to a correlation of flushing with NUA C(max) (maximal concentration) and the observation that aspirin inhibits NUA formation and flushing. The former does not establish causation and the latter can be explained by inhibition of prostaglandin formation. Recent characterization of the GPR109A receptor that mediates prostaglandin release by Langerhans cells to produce flushing has shown nicotinic acid, not NUA, is responsible. The suggestion that nicotinamide metabolites produce hepatotoxicity is not supported by any data. The mechanism of hepatotoxicity is unknown and a toxic metabolite of nicotinic acid has not been identified. Different nicotinic acid formulations produce different metabolite patterns due to nonlinear pharmacokinetics, but there is no evidence that these differences have any clinical importance.
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PMID:The role of nicotinic acid metabolites in flushing and hepatotoxicity. 2129 80


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