Browsing by Subject "Niacin"

Now showing 1 - 5 of 5

Open Access
beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.
(J Clin Invest, 2009-05) Walters, Robert W; Shukla, Arun K; Kovacs, Jeffrey J; Violin, Jonathan D; DeWire, Scott M; Lam, Christopher M; Chen, J Ruthie; Muehlbauer, Michael J; Whalen, Erin J; Lefkowitz, Robert J
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.
Open Access
Impact of increases in high-density lipoprotein cholesterol on cardiovascular outcomes during the armed forces regression study.
(J Cardiovasc Pharmacol Ther, 2010-12) Devendra, Ganesh P; Whitney, Edwin J; Krasuski, Richard A
INTRODUCTION: high-density lipoprotein (HDL) cholesterol is a well-established inverse risk factor for cardiovascular disease. The extent to which cardiovascular risk can be modified through changes in HDL, however, is less clear. We further examined the role of aggressive HDL raising therapy on cardiovascular outcomes in the 143 patients enrolled in the Armed Forces Regression Study (AFREGS). METHODS: reanalysis of the AFREGS population. Patients with stable coronary disease were randomized to receive gemfibrozil, niacin, and cholestyramine in combination or matching placebos, on top of aggressive dietary and exercise modification for a 30-month period. Blood work was performed at baseline and repeated after 1 year of therapy. RESULTS: patients were divided into 3 groups based on their therapeutic response: no HDL increase, mild HDL increase, and large HDL increase (% change in HDL ≤ 0, ≤ the lower 2 tertiles of HDL increase, and > the upper tertile of HDL increase, respectively). A progressive decrease in cardiovascular events was noted across these groups (30.4%, 19.4%, and 3.2%, respectively, P = .01). Kaplan-Meier analysis according to percentage change in HDL demonstrated a similar improvement in event-free survival (P = .01). Proportional hazards modeling also demonstrated that increasing HDL predicted a lower hazard of cardiovascular events, even after adjusting for changes in low-density lipoprotein ([LDL] P < .01). For every 1% increase in HDL achieved, a 2% decrease in events was recognized. CONCLUSIONS: these data suggest that in a population of patients with stable atherosclerosis, the greater the percentage increase in HDL achieved, the greater the cardioprotective benefit. This further supports HDL raising as a beneficial therapeutic strategy.
Open Access
The effect of gemfibrozil, niacin and cholestyramine combination therapy on metabolic syndrome in the Armed Forces Regression Study.
(Am J Med Sci, 2011-05) Krasuski, Richard A; Devendra, Ganesh P; Cater, George; Whitney, Edwin J
INTRODUCTION: Metabolic syndrome is a powerful predictor of cardiovascular events independent of overt diabetes. Dietary restriction and weight loss modify metabolic syndrome components. This study addresses whether combination pharmacologic therapy focused on dyslipidemia provides additional benefit. METHODS: This study examines the effect of 1 year of gemfibrozil, niacin and cholestyramine therapy on a baseline of aggressive dietary and lifestyle intervention in 143 clinically stable, nondiabetic patients with coronary disease, randomized into a double-blind, placebo-controlled trial. RESULTS: Cohort characteristics included age 63 ± 7 years, 92% men, 43% with previous myocardial infarction, systolic blood pressure 139 ± 17 mm Hg, triglycerides 168 ± 81 mg/dL and high-density lipoprotein cholesterol 34 ± 6 mg/dL. The mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.5 ± 1.1, P < 0.001, and metabolic syndrome prevalence decreased from 38% to 18% (P < 0.001) for the entire cohort. In the lifestyle intervention and placebo group, the mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.9 ± 1.1 (P = 0.01), and prevalence of metabolic syndrome decreased from 44% to 30% (P = 0.15). A far more marked change was observed with lifestyle intervention and pharmacologic therapy: abnormal metabolic components decreased from 2.2 ± 0.9 to 1.0 ± 1.0 (P < 0.001), and prevalence of metabolic syndrome decreased from 32% to 6% (P < 0.001). CONCLUSIONS: The combination of gemfibrozil, niacin and cholestyramine has profound, beneficial effects on the components of metabolic syndrome. These benefits are additive to those seen with aggressive diet and lifestyle modification.
Open Access
Therapy and clinical trials.
(Curr Opin Lipidol, 2011-12) Elmallah, Wael; Krasuski, Richard A
Open Access
Therapy and clinical trials.
(Curr Opin Lipidol, 2013-06) Sodhi, Nishtha; Krasuski, Richard A