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

Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m(2) and >80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.
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PMID:Pharmacokinetics of laropiprant and glucuronide metabolite in patients with severe renal insufficiency. 1943 74

Laropiprant (LRPT), a prostaglandin D2 receptor 1 antagonist shown to reduce niacin-induced flushing symptoms, is being developed in combination with niacin for the treatment of dyslipidemia. This study assessed the pharmacokinetics/pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose LRPT. Thirteen subjects received 2 treatments in random order separated by > or =10-day washout: (1) multiple-dose LRPT 40 mg/d for 12 days (days -5 to 7) with coadministered single-dose warfarin 30 mg (day 6) and (2) single-dose warfarin 30 mg (day 1). R+- and S(-)-warfarin and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. Comparability was declared if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR; warfarin + LRPT/warfarin alone) of area under the plasma concentration curve from zero to infinity (AUC0-infinity) for R+- and S(-)-warfarin were contained within (0.80, 1.25). The estimated GMRs of AUC0-infinity (90% CIs) were 1.02 (0.96, 1.09) and 1.04 (0.98, 1.09) for R+- and S(-)-warfarin, respectively. The estimated GMRs of maximum plasma concentration (Cmax) (90% CIs) were 1.13 (1.02, 1.26) and 1.11 (0.99, 1.24) for R+- and S(-)-warfarin, respectively. The estimated GMRs of area under the prothrombin time INR curve from 0 to 168 hours on day 21 (INR AUC0-168 h) and average maximum observed prothrombin time INR (INRmax) were 1.02 (0.99, 1.05) and 1.04 (0.98, 1.10), respectively. There was no evidence of clinically meaningful alterations in the pharmacokinetics and pharmacodynamics (ie, INR) of R(+)- or S(-)-warfarin after coadministration of multiple-dose LRPT and single-dose warfarin.
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PMID:Influence of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the pharmacokinetics and pharmacodynamics of warfarin. 1945 60

There are many factors that increase the risk of cardiovascular disease, and a prominent factor among these is dyslipidemia. The following literature review focuses on the use of niacin therapy in order to treat dyslipidemia and how to control the associated "niacin flush." The associated studies gathered are reviews and randomized control trials. They were obtained by using electronic searches. Certain keywords took precedence, and articles focusing on niacin therapy were chosen. Recent research has found promising insight into more effective prevention of the niacin-mediated flush through a selective antagonist for the prostaglandin D2 receptor, laropiprant. Aspirin (or NSAIDs) also provide some prevention for flushing, although recent studies have shown that it is not as effective as laropiprant. There is a need for further research in order to come to a clear conclusion regarding combined therapies of aspirin and laropiprant pretreatment, as well as exact dosage requirements.
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PMID:Mechanisms of flushing due to niacin and abolition of these effects. 1987 84

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