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  • 1
    Publication Date: 2014-05-15
    Description: Objective— Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results— We observed that the nicotinic acid–induced increase in blood flow was substantially reduced in Trpv1 –/– knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions— Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.
    Keywords: Other Vascular biology
    Print ISSN: 1079-5642
    Electronic ISSN: 1524-4636
    Topics: Medicine
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  • 2
    Publication Date: 2015-03-13
    Description: Introduction Past studies of network meta-analysis focused on evaluating drug combinations in treating type 2 diabetes but not on evaluating antidiabetic drugs in monotherapy. Clinical guidelines (eg, NICE (National Institute of Health and Care Excellence) clinical guidelines 66 and 87) were based only on the findings of individual clinical trials and pairwise meta-analysis in evaluating monotherapy. This study aims to fill this gap of research by conducting a Bayesian network meta-analysis to compare major antidiabetic drugs, including metformin, glimepiride, glyburide, glipizide, repaglinide, nateglinide, sitagliptin, vildagliptin, saxagliptin and SGLT-2 (sodium-glucose transporter-2) inhibitors. Methods and analyses Randomised controlled trials (RCTs) on the drug therapy of type 2 diabetes with outcome measures including glycosylated haemoglobin or fasting blood glucose will be included. The quality of included RTCs will be evaluated according to the Cochrane Collaboration's risk of bias tool. Traditional pairwise meta-analysis and Bayesian network meta-analysis will be conducted to compare the efficacies of antidiabetic drugs. Sensitivity analysis on the sample size of RCTs, meta-regression analysis on the follow-up periods, dosages and baselines of outcome measure, contradiction analysis between pairwise and network meta-analyses, and publication bias analysis, will be performed. Ethics and dissemination Ethical approval is not required because this study includes no confidential personal data and interventions on the patients. Pairwise and network meta-analyses are based on the published RCT reports of eligible drugs in treating type 2 diabetes. The results of this study will be disseminated by a peer-reviewed publication. Protocol registration number PROSPERO CRD42014010567.
    Keywords: Open access, Evidence based practice, Health informatics, Pharmacology and therapeutics, Diabetes and Endocrinology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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