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East Northport, NY, United States

Lu Z.,State University of New York at Stony Brook | Wu C.-Y.C.,State University of New York at Stony Brook | Jiang Y.-P.,State University of New York at Stony Brook | Ballou L.M.,State University of New York at Stony Brook | And 4 more authors.
Science Translational Medicine | Year: 2012

Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K +) current I Kr. Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K + currents I Kr and I Ks, the L-type calcium ion (Ca 2+) current I Ca,L, and the peak sodium ion (Na +) current I Na and increased the persistent Na + current I NaP. Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in / NaP. These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.

Hattler B.,University of Denver | Messenger J.C.,University of Denver | Shroyer A.L.,Northport Veterans Affairs Medical Center | Collins J.F.,Cooperative Studies Program Coordinating Center | And 5 more authors.
Circulation | Year: 2012

Background-The Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial compared clinical and angiographic outcomes in off-pump versus on-pump coronary artery bypass graft (CABG) surgery to ascertain the relative efficacy of the 2 techniques. Methods and Results-From February 2002 to May 2007, the ROOBY trial randomized 2203 patients to off-pump versus on-pump CABG. Follow-up angiography was obtained in 685 off-pump (62%) and 685 on-pump (62%) patients. Angiograms were analyzed (blinded to treatment) for FitzGibbon classification (A=widely patent, B=flow limited, O=occluded) and effective revascularization. Effective revascularization was defined as follows: All 3 major coronary territories with significant disease were revascularized by a FitzGibbon A-quality graft to the major diseased artery, and there were no new postanastomotic lesions. Off-pump CABG resulted in lower FitzGibbon A patency rates than on-pump CABG for arterial conduits (85.8% versus 91.4%; P=0.003) and saphenous vein grafts (72.7% versus 80.4%; P<0.001). Fewer off-pump patients were effectively revascularized (50.1% versus 63.9% on-pump; P<0.001). Within each major coronary territory, effective revascularization was worse off pump than on pump (all P≤0.001). The 1-year adverse cardiac event rate was 16.4% in patients with ineffective revascularization versus 5.9% in patients with effective revascularization (P<0.001). Conclusions-Off-pump CABG resulted in significantly lower FitzGibbon A patency for arterial and saphenous vein graft conduits and less effective revascularization than on-pump CABG. At 1 year, patients with less effective revascularization had higher adverse event rates. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00032630. © 2012 American Heart Association, Inc.

Snider A.J.,Northport Veterans Affairs Medical Center | Snider A.J.,Health Science University
International Journal of Clinical Rheumatology | Year: 2013

Sphingolipids and their metabolizing enzymes are beginning to be recognized as critical mediators in biological processes, specifically in inflammation and autoimmunity. Sphingosine kinases (SKs) and their lipid product sphingosine-1-phosphate (S1P) play essential roles in inflammatory signaling processes, as well as disease development and progression. SKs can be activated by numerous growth factors and cytokines, including TNF-α and IL-1β, leading to the generation of S1P. S1P exerts its biological effects on intracellular and extracellular targets, such as S1P receptors. In addition to roles in inflammatory signaling pathways SKs, S1P and S1P receptors have been implicated in immune cell function and trafficking, specifically in lymphocytes. This review will discuss the contribution of the bioactive sphingolipid S1P, its generating enzyme SK, and its cell surface receptors in the inflammatory and autoimmune diseases systemic lupus erythematosus, arthritis and inflammatory bowel disease. © 2013 Future Medicine Ltd.

Choi E.,Northport Veterans Affairs Medical Center
American Journal of Health-System Pharmacy | Year: 2012

Purpose. The pharmacology and pharmacokinetics of the antidepressant vilazodone (approved for U.S. marketing in 2011) are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. Summary. Vilazodone (marketed as Viibryd by Forest Pharmaceuticals) is a dualacting serotonergic agent that combines the antidepressant effects of a selective serotonin-reuptake inhibitor (SSRI) with partial serotonin (5-HT)1A-receptor agonist activity. In two published eight-week Phase III trials involving a total of 878 adults with major depressive disorder (MDD), vilazodone use was found to yield significant symptomatic improvements relative to placebo use, as determined by mean changes from baseline in scores on the Hamilton Depression Rating Scale and other widely used clinical assessment instruments. Vilazodone hydrochloride therapy should be initiated at a dosage of 10 mg once daily and incrementally adjusted over 14 days to the recommended target daily dose of 40 mg; for optimal bioavailability and effectiveness, it should be taken after a light or high-fat meal. The adverse effects most commonly reported in clinical trials of vilazodone were diarrhea, nausea, vomiting, and insomnia. Conclusion. Vilazodone is an efficacious and safe new antidepressant for the treatment of MDD. Its relatively high cost and adverse-effect profile, as well as a lack of data demonstrating that vilazodone can produce long-term MDD remission and offer significant advantages over the current standard of care, may limit the usefulness of vilazodone in clinical practice. Copyright © 2012, American Society of Health-System Pharmacists, Inc. All rights reserved.

Walsh-Irwin C.,Northport Veterans Affairs Medical Center
AACN Advanced Critical Care | Year: 2012

Brugada syndrome can lead to lethal cardiac arrhythmias and is often difficult to diagnose because the ECG can be masked. Abnormal STsegment changes in the precordial leads should be recognized and investigated further. A good history of any syncopal episodes as well as a family history of SCD in young family members can be instrumental in helping identify patients at risk. Patients younger than 45 years with symptoms or with a family history of SCD are predictors of poor outcomes. 13 Psychosocial support and referral to an electrophysiologist, as well as genetic counseling, should be considered. © 2012, AACN.

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