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Lexington, KY, United States

Lofwall M.R.,University of Kentucky | Babalonis S.,University of Kentucky | Nuzzo P.A.,UK COM | Elayi S.C.,Gill Heart Institute | Walsh S.L.,University of Kentucky
Drug and Alcohol Dependence | Year: 2016

Background: The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Methods: Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30 mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60 mg, dronabinol 5, 10, 20, and 30 mg [decreased from 40 mg]). Placebo was substituted for oxycodone maintenance doses for 21 h before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Results: Oxycodone produced prototypic opioid agonist effects (i.e. suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10 mg produced effects most similar to placebo, while the 20 and 30 mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. Conclusion: CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. © 2016 Elsevier Ireland Ltd. Source

Nagareddy P.,Gill Heart Institute | Smyth S.S.,Gill Heart Institute
Current Opinion in Hematology | Year: 2013

PURPOSE OF REVIEW: This article will summarize recent observations that provide mechanistic insight into the molecular and cellular links between inflammation and thrombosis in the context of cardiovascular and other thromboinflammatory disease states. RECENT FINDINGS: Several disease conditions are characterized by a thromboinflammatory state in which interactions of blood cells and components with the vascular wall perpetuate both thrombotic and inflammatory pathways. Targeting these pathways may be of benefit in inflammatory conditions and cardiovascular disease. SUMMARY: Ongoing clinical trials should provide additional insight into the hypothesis that the thromboinflammatory state contributes to adverse clinical outcomes. Copyright © 2013 Lippincott Williams & Wilkins. Source

Deevska G.,University of Kentucky | Sunkara M.,Gill Heart Institute | Karakashian C.,University of Kentucky | Peppers B.,University of Kentucky | And 2 more authors.
Journal of Lipid Research | Year: 2014

In hepatocytes, aging-associated decline in GSH has been linked to activation of neutral SMase (nSMase), accumulation of bioactive ceramide, and inflammation. In this study, we seek to test whether dietary supplementation with the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTC), would correct the aging-associated differences in hepatic GSH, nSMase, and ceramide. Young and aged mice were placed on a diet that either lacked sulfur-containing amino acids (SAAs) or had 0.5% OTC for 4 weeks. Mice fed standard chow were used as an additional control. SAA-deficient mice exhibited significant aging-associated differences in hepatic GSH, GSH/GSSG, ceramide, and nSMase. C24:1 ceramide, the major ceramide species in liver, was affected the most by aging, followed by the less abundant C16:0 ceramide. OTC supplementation eliminated the aging-associated differences in hepatic GSH and GSH/GSSG ratio. Surprisingly, however, instead of decreasing, the nSMase activity and ceramide increased in the OTC-fed mice irrespective of their age. These effects were due to elevated nSMase-2 mRNA and protein and appeared to be direct. Similar increases were seen in HepG2 cells following treatment with OTC. The OTC-fed aged mice also exhibited hepatic steatosis and triacylglyceride accumulation. These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation. © 2014, American Society for Biochemistry and Molecular Biology Inc. All rights reserved. Source

Wallace E.L.,Gill Heart Institute | Ziada K.M.,Gill Heart Institute
Journal of Invasive Cardiology | Year: 2015

Percutaneous coronary interventions (PCI) of chronic total occlusions (CTOs) can be technically challenging, but are valuable in patients with severe angina. Recently, algorithms for CTO-PCI have been proposed to facilitate the selection of the PCI approach that can best achieve procedural success. When the ostium of the occluded vessel is ambiguous or not well visualized, the success rate of antegrade approaches is significantly diminished. In our case, we demonstrate the utility of intravascular ultrasound imaging in the localization of an ambiguous or (stump-less) ostial CTO in addition to providing real-time far-field imaging, which is helpful in tracking wire progress through the occluded segment. Adjunctive imaging was instrumental in achieving procedural success using the antegrade approach. Source

Panchatcharam M.,Gill Heart Institute | Miriyala S.,University of Kentucky | Salous A.,Gill Heart Institute | Wheeler J.,Gill Heart Institute | And 6 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. Methods and Results-We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain-and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. Conclusion-Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk. © 2012 American Heart Association, Inc. Source

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