Maas J.E.,Medical College of Wisconsin |
Wan T.C.,Medical College of Wisconsin |
Figler R.A.,Clinical Data Inc. |
Gross G.J.,Medical College of Wisconsin |
Auchampach J.A.,Medical College of Wisconsin
Journal of Molecular and Cellular Cardiology | Year: 2010
Ischemic preconditioning (IPC) is a protective phenomenon in which brief ischemia renders the myocardium resistant to subsequent ischemic insults. Here, we used A2BAR gene knock-out (A2BKO)/β-galactosidase reporter gene knock-in mice and the A2BAR antagonist ATL-801 to investigate the potential involvement of the A2BAR in IPC, focusing on the acute phase of protection. Cardioprotection provided by acute IPC elicited by two 3-min occlusion/3-min reperfusion cycles was readily apparent in an isolated, Langendorff-perfused mouse heart model in studies using hearts from A2BKO mice. IPC equivalently improved the recovery of contractile function following 20min of global ischemia and 45min of reperfusion in both WT and A2BKO hearts by ~30-40%, and equivalently decreased the release of cardiac troponin I during the reperfusion period (from 5969±925 to 1595±674ng/g and 4376±739 to 2278±462ng/g using WT and A2BKO hearts, respectively). Similarly, the infarct size-reducing capacity of acute IPC in an in vivo model of infarction was fully manifested in experiments using A2BKO mice, as well as in experiments using rats pretreated with ATL-801. We did observe, however, a marked reduction in infarct size in rats following administration of the selective A2BAR agonist BAY 60-6583 (~25% reduction at a dose of 1.0mg/kg). While supportive of its concept as a cardioprotective receptor, these experiments indicate that the mechanism of the early phase of IPC is not dependent on signaling by the A2BAR. We present the idea that the A2BAR may contribute to the later stages of IPC dependent on the induction of stress-responsive genes. © 2010 Elsevier Ltd.
Pierz K.A.,Clinical Data Inc. |
Thase M.E.,University of Pennsylvania
Primary Care Companion to the Journal of Clinical Psychiatry | Year: 2014
Objective: To review the mechanism of selective serotonin reuptake inhibitor (SSRI)-mediated serotonergic neurotransmission, focusing on serotonin 1A (5-HT1A) autoreceptors, which are proposed to be involved in delaying therapeutic efficacy. Vilazodone was specifically designed to function both as an SSRI and a partial agonist at 5-HT1A receptors. This combined mechanism is proposed to decrease time to efficacy, minimize sexual side effects, and provide concomitant anxiolytic properties. Data Sources: A PubMed search of all English-language articles from January 1990 to January 2013 was conducted using the search termsdepression and 5-HT1A, depressionand buspirone, depression andpindolol, and vilazodone. Study Selection: We found 47 articles and abstracts that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol, buspirone, and vilazodone in depression. Data Extraction: This review summarizes current literature involving antidepressant activity, the role of 5-HT1A autoreceptors, and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists, with a focus on vilazodone. Results: Vilazodone has demonstrated efficacy in 2 large, randomized, double-blind, placebo-controlled trials in major depressive disorder. Results suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety. A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy. Conclusions: If future studies corroborate the clinical benefits attributed to its mechanism of action, vilazodone may show potential advantages in terms of onset of action, sexual side effects, and anxiolytic activity in patients with major depressive disorder. © 2014 Physicians Postgraduate Press, Inc.
Clayton A.H.,University of Virginia |
Kennedy S.H.,University of Toronto |
Edwards J.B.,Forest Laboratories |
Gallipoli S.,Clinical Data Inc. |
Reed C.R.,Clinical Data Inc.
Journal of Sexual Medicine | Year: 2013
Introduction. Sexual dysfunction is common in major depressive disorder (MDD), and many serotonergic antidepressants adversely affect sexual function. Vilazodone, a novel serotonin (5-HT) reuptake inhibitor and 5-HT1A partial agonist approved for MDD, exerts its effects at the 5-HT transporter and at both presynaptic and postsynaptic 5-HT1A receptors. This mechanism may limit sexual dysfunction. Aim. To summarize effects of vilazodone (40mg/day, with food) on sexual function in adults with MDD. Methods. Data sources were three Phase III studies: two 8-week, placebo-controlled studies (NCT00285376 and NCT00683592) and a 52-week open-label study (NCT00644358). Sexual function was assessed by analyzing changes from baseline to end of treatment (EOT) using validated measures. Main Outcome Measure. Arizona Sexual Experience Scale or Changes in Sexual Functioning Questionnaire. Results. Population included 869 patients (vilazodone, 436; placebo, 433) from placebo-controlled studies and 599 patients from the open-label study. Sexual dysfunction prevalence was high (50%, men; 68%, women) before treatment and declined during treatment in vilazodone and placebo groups, indicating improvement on average. At EOT, stable/improved sexual function was observed in ≥91% of patients in placebo-controlled studies; treatment group differences in sexual dysfunction at EOT were not statistically significant for either sex. Differences vs. placebo in changes from baseline of sexual function scores were small and were generally not statistically significant; effect sizes (Cohen's D) were generally of low magnitude. In the placebo-controlled studies, 8.0% of vilazodone-treated patients and 0.9% of placebo-treated patients reported ≥1 sexual-function-related treatment-emergent adverse event (P<0.001). Conclusion. Half of men and two thirds of women with MDD had sexual dysfunction at baseline; sexual function improved on average in both vilazodone and placebo groups. Results suggest that vilazodone may have a small adverse impact on sexual function in adults with MDD relative to the high prevalence of sexual dysfunction at baseline. © 2012 International Society for Sexual Medicine.
Nagao R.,Kyoto University |
Ashihara E.,Kyoto University |
Ashihara E.,Kyoto Prefectural University of Medicine |
Kimura S.,Saga University |
And 9 more authors.
Cancer Letters | Year: 2011
We investigated the effect of a novel Wnt/β-catenin signaling inhibitor, AV65 on imatinib mesylate (IM)-sensitive and -resistant human chronic myeloid leukemia (CML) cells in vitro. AV65 inhibited the proliferation of various CML cell lines including T315I mutation-harboring cells. AV65 reduced the expression of β-catenin in CML cells, resulting in the induction of apoptosis. Moreover, AV65 inhibited the proliferation of hypoxia-adapted primitive CML cells that overexpress β-catenin. The combination of AV65 with IM had a synergistic inhibitory effect on the proliferation of CML cells. These findings suggest that AV65 could be a novel therapeutic agent for the treatment of CML. © 2011 Elsevier Ireland Ltd.
PubMed | Stanford University, Healthcare Global, A-Life Medical, New York University and Clinical Data Inc.
Type: Journal Article | Journal: The American journal of cardiology | Year: 2016
Several randomized trials and decision analysis models have found that remote monitoring may reduce health care utilization and expenditures in patients with cardiac implantable electronic devices (CIEDs), compared with in-office monitoring. However, little is known about the generalizability of these findings to unselected populations in clinical practice. To compare health care utilization and expenditures associated with remote monitoring and in-office monitoring in patients with CIEDs, we used Truven Health MarketScan Commercial Claims and Medicare Supplemental Databases. We selected patients newly implanted with an implantable cardioverter defibrillators (ICD), cardiac resynchronization therapy defibrillator (CRT-D), or permanent pacemaker (PPM), in 2009, who had continuous health plan enrollment 2 years after implantation. Generalized linear models and propensity score matching were used to adjust for confounders and estimate differences in health care utilization and expenditures in patients with remote or in-office monitoring. We identified 1,127; 427; and 1,295 pairs of patients with a similar propensity for receiving an ICD, CRT-D, or PPM, respectively. Remotely monitored patients with ICDs experienced fewer emergency department visits resulting in discharge (p = 0.050). Remote monitoring was associated with lower health care expenditures in office visits among patients with PPMs (p = 0.025) and CRT-Ds (p = 0.006) and lower total inpatient and outpatient expenditures in patients with ICDs (p <0.0001). In conclusion, remote monitoring of patients with CIEDs may be associated with reductions in health care utilization and expenditures compared with exclusive in-office care.
Athanasiou M.C.,Clinical Data Inc. |
Dettling M.,Charité - Medical University of Berlin |
Cascorbi I.,University of Kiel |
Mosyagin I.,University of Kiel |
And 10 more authors.
Journal of Clinical Psychiatry | Year: 2011
Objective: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA). Method: Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls). Results: Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not. Conclusions: A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine. © Copyright 2010 Physicians Postgraduate Press, Inc.
Callis T.E.,Clinical Data Inc. |
Jensen B.C.,University of North Carolina at Chapel Hill |
Weck K.E.,University of North Carolina at Chapel Hill |
Willis M.S.,University of North Carolina at Chapel Hill
Expert Review of Molecular Diagnostics | Year: 2010
Cardiomyopathies are an important and heterogeneous group of common cardiac diseases. An increasing number of cardiomyopathies are now recognized to have familial forms, which result from single-gene mutations that render a Mendelian inheritance pattern, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Recently, clinical genetic tests for familial cardiomyopathies have become available for clinicians evaluating and treating patients with these diseases, making it necessary to understand the current progress and challenges in cardiomyopathy genetics and diagnostics. In this review, we summarize the genetic basis of selected cardiomyopathies, describe the clinical utility of genetic testing for cardiomyopathies and outline the current challenges and emerging developments. © 2010 Expert Reviews Ltd.
Voloshyna I.,Winthrop University |
Carsons S.,Winthrop University |
Littlefield M.J.,Winthrop University |
Rieger J.M.,Clinical Data Inc. |
And 2 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2013
The adenosine A2A receptor (A2AR) plays an important role in the regulation of inflammatory and immune responses. Our previous work has demonstrated that A2AR agonists exhibit atheroprotective effects by increasing expression of reverse cholesterol transport proteins in cultured human macrophages. This study explores the impact of pharmacologic activation/inhibition and gene silencing of A2AR on cholesterol homeostasis in both THP-1 human monocytes/macrophages and primary human aortic endothelial cells (HAEC). THP-1 human monocytes/macrophages and HAEC exposed to the A2AR-specific agonist ATL313 exhibited upregulation of proteins responsible for cholesterol efflux: the ABCA1 and G1 transporters. Further, activation of A2AR led to upregulation of the cholesterol metabolizing enzyme P450 27-hydroxylase, accompanied by intracellular changes in level of oxysterols. We demonstrate that anti-atherogenic properties of A 2AR activation are not limited to the regulation of lipid efflux in vasculature, but include protection from lipid overload in macrophages, particularly via suppression of the CD36 scavenger receptor. The reduced lipid accumulation manifests directly as a diminution in foam cell transformation. In THP-1 macrophages, either A2AR pharmacological blockade or gene silencing promote lipid accumulation and enhance foam cell transformation. Our pre-clinical data provides evidence suggesting that A2AR stimulation by ATL313 has the potential to be a viable therapeutic strategy for cardiovascular disease prevention, particularly in patients with elevated risk due to immune/inflammatory disorders. © 2012 Elsevier B.V. All rights reserved.
PubMed | Clinical Data Inc.
Type: Journal Article | Journal: The primary care companion for CNS disorders | Year: 2014
To review the mechanism of selective serotonin reuptake inhibitor (SSRI)-mediated serotonergic neurotransmission, focusing on serotonin 1A (5-HT1A) autoreceptors, which are proposed to be involved in delaying therapeutic efficacy. Vilazodone was specifically designed to function both as an SSRI and a partial agonist at 5-HT1A receptors. This combined mechanism is proposed to decrease time to efficacy, minimize sexual side effects, and provide concomitant anxiolytic properties.A PubMed search of all English-language articles from January 1990 to January 2013 was conducted using the search terms depression and 5-HT 1A, depression and buspirone, depression and pindolol, and vilazodone.We found 47 articles and abstracts that were selected for inclusion on the basis of information about the pharmacology of 5-HT1A receptors and the clinical data on pindolol, buspirone, and vilazodone in depression.This review summarizes current literature involving antidepressant activity, the role of 5-HT1A autoreceptors, and clinical trials involving serotonin reuptake inhibition in conjunction with 5-HT1A agonists and partial agonists, with a focus on vilazodone.Vilazodone has demonstrated efficacy in 2 large, randomized, double-blind, placebo-controlled trials in major depressive disorder. RESULTS suggest that vilazodone has a low incidence of sexual side effects and is effective in patients with high levels of anxiety. A pooled analysis shows evidence of significant symptom reduction after only 1 week of therapy.If future studies corroborate the clinical benefits attributed to its mechanism of action, vilazodone may show potential advantages in terms of onset of action, sexual side effects, and anxiolytic activity in patients with major depressive disorder.