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Results: 1 to 10 of 69

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In Silico Pharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers.
Cai C, Fang J, Guo P, Wang Q, Hong H, Moslehi J, Cheng F
(2018) J Chem Inf Model 58: 943-956
MeSH Terms: Antineoplastic Agents, Cardiovascular System, Computational Biology, Computer Simulation, Drug Discovery, Drug-Related Side Effects and Adverse Reactions, Humans, Molecular Targeted Therapy, Myocytes, Cardiac, Pluripotent Stem Cells, Product Surveillance, Postmarketing, Safety
Show Abstract · Added October 1, 2018
Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance.
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12 MeSH Terms
Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.
Griendling KK, Touyz RM, Zweier JL, Dikalov S, Chilian W, Chen YR, Harrison DG, Bhatnagar A, American Heart Association Council on Basic Cardiovascular Sciences
(2016) Circ Res 119: e39-75
MeSH Terms: American Heart Association, Cardiovascular Diseases, Cardiovascular System, Humans, Oxidation-Reduction, Oxidative Stress, Reactive Nitrogen Species, Reactive Oxygen Species, Signal Transduction, United States
Show Abstract · Added March 26, 2019
Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.
© 2016 American Heart Association, Inc.
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MeSH Terms
Dysfunctional vestibular system causes a blood pressure drop in astronauts returning from space.
Hallgren E, Migeotte PF, Kornilova L, Delière Q, Fransen E, Glukhikh D, Moore ST, Clément G, Diedrich A, MacDougall H, Wuyts FL
(2015) Sci Rep 5: 17627
MeSH Terms: Adult, Astronauts, Blood Pressure, Cardiovascular System, Humans, Male, Middle Aged, Posture, Space Flight, Vestibule, Labyrinth, Vision, Ocular
Show Abstract · Added October 14, 2016
It is a challenge for the human body to maintain stable blood pressure while standing. The body's failure to do so can lead to dizziness or even fainting. For decades it has been postulated that the vestibular organ can prevent a drop in pressure during a position change--supposedly mediated by reflexes to the cardiovascular system. We show--for the first time--a significant correlation between decreased functionality of the vestibular otolith system and a decrease in the mean arterial pressure when a person stands up. Until now, no experiments on Earth could selectively suppress both otolith systems; astronauts returning from space are a unique group of subjects in this regard. Their otolith systems are being temporarily disturbed and at the same time they often suffer from blood pressure instability. In our study, we observed the functioning of both the otolith and the cardiovascular system of the astronauts before and after spaceflight. Our finding indicates that an intact otolith system plays an important role in preventing blood pressure instability during orthostatic challenges. Our finding not only has important implications for human space exploration; they may also improve the treatment of unstable blood pressure here on Earth.
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11 MeSH Terms
Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia.
Moslehi JJ, Deininger M
(2015) J Clin Oncol 33: 4210-8
MeSH Terms: Aniline Compounds, Antineoplastic Agents, Cardiovascular System, Clinical Trials as Topic, Dasatinib, Fusion Proteins, bcr-abl, Humans, Hypertension, Imatinib Mesylate, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Molecular Targeted Therapy, Nitriles, Protein Kinase Inhibitors, Pyridazines, Pyrimidines, Quinolines
Show Abstract · Added March 6, 2016
For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.
© 2015 by American Society of Clinical Oncology.
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17 MeSH Terms
Vascular and Metabolic Implications of Novel Targeted Cancer Therapies: Focus on Kinase Inhibitors.
Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J
(2015) J Am Coll Cardiol 66: 1160-78
MeSH Terms: Animals, Cardiovascular System, Disease Models, Animal, Female, Humans, Male, Molecular Targeted Therapy, Neoplasms, Prognosis, Protein Kinase Inhibitors, Randomized Controlled Trials as Topic, Risk Assessment, Survival Analysis, Treatment Outcome
Show Abstract · Added March 6, 2016
Novel targeted cancer therapies, especially kinase inhibitors, have revolutionized the treatment of many cancers and have dramatically improved the survival of several types of malignancies. Because kinases not only are important in cancer development and progression, but also play a critical role in the cardiovascular (CV) system and metabolic homeostasis, important CV and metabolic sequelae have been associated with several types of kinase inhibitors. This paper reviews the incidences and highlights potential mechanisms of vascular and metabolic perturbations associated with 3 classes of commonly used kinase inhibitors that target the vascular endothelial growth factor signaling pathway, the ABL kinase, and the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway. We propose preventive, screening, monitoring, and management strategies for CV care of patients treated with these novel agents.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
High content screening for modulators of cardiovascular or global developmental pathways in zebrafish.
Williams CH, Hong CC
(2015) Methods Mol Biol 1263: 167-74
MeSH Terms: Animals, Animals, Genetically Modified, Cardiovascular System, Disease Models, Animal, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Organogenesis, Phenotype, Signal Transduction, Small Molecule Libraries, Zebrafish
Show Abstract · Added February 3, 2015
Major developmental pathways play critical roles in wide array of human pathologies. Chemical genomic screening allows for the discovery of novel tools not only to target known pathway interactors but also to discover new, chemically tractable targets for known pathways. The zebrafish has emerged as a useful model for developmental biology and has been well characterized. The zebrafish represents a hardy conglomerate of totipotent cells that are massively and simultaneously assessing all significant pathways in parallel in an endogenous context. This represents a gold standard for biological assays, chemically targeting select pathways without causing pleiotropic effects. Here, we describe methods used to develop high content screening assays implementing transgenic zebrafish to assess phenotypic changes that have identified several classes of novel compounds that effect developmental pathways.
1 Communities
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12 MeSH Terms
Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus.
Milian J, Goldfine AB, Zuflacht JP, Parmer C, Beckman JA
(2015) Acta Diabetol 52: 709-15
MeSH Terms: Adult, Antioxidants, Atazanavir Sulfate, Atherosclerosis, Bilirubin, Blood Pressure, Cardiovascular System, Cholesterol, LDL, Diabetes Mellitus, Type 1, Endothelium, Vascular, Female, Humans, Male, Middle Aged, Oxidative Stress, Risk Factors, Vasodilation
Show Abstract · Added January 15, 2016
AIMS - Vascular disease is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). We previously demonstrated that patients with T1DM have impaired endothelial function, a forme fruste of atherosclerosis, as a result of increased oxidative stress. Bilirubin has emerged as a potent endogenous antioxidant with higher concentrations associated with lower rates of myocardial infarction and stroke.
METHODS - We tested the hypothesis that increasing endogenous bilirubin using atazanavir would improve cardiometabolic risk factors and vascular function in patients with T1DM to determine whether targeting bilirubin may be a novel therapeutic approach to reduce cardiovascular disease risk in this population. In this single-arm, open-label study, we evaluated blood pressure, lipid profile, and conduit artery function in fifteen subjects (mean age 45 ± 9 years) with T1DM following a 4-day treatment with atazanavir.
RESULTS - As anticipated, atazanavir significantly increased both serum total bilirubin levels (p < 0.0001) and plasma total antioxidant capacity (p < 0.0001). Reductions in total cholesterol (p = 0.04), LDL cholesterol (p = 0.04), and mean arterial pressure (p = 0.04) were also observed following atazanavir treatment. No changes were seen in either flow-mediated endothelium-dependent (p = 0.92) or nitroglycerine-mediated endothelium-independent (p = 0.68) vasodilation, measured by high-resolution B-mode ultrasonography at baseline and post-treatment.
CONCLUSION - Increasing serum bilirubin levels with atazanavir in subjects with T1DM over 4 days favorably reduces LDL and blood pressure but is not associated with improvements in endothelial function of conduit arteries.
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17 MeSH Terms
Unravelling the causes of reduced peak oxygen consumption in patients with cancer: complex, timely, and necessary.
Koelwyn GJ, Jones LW, Moslehi J
(2014) J Am Coll Cardiol 64: 1320-2
MeSH Terms: Cardiovascular System, Colorectal Neoplasms, Exercise, Female, Humans, Male
Added March 4, 2015
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6 MeSH Terms
Cancer-drug discovery and cardiovascular surveillance.
Groarke JD, Cheng S, Moslehi J
(2013) N Engl J Med 369: 1779-81
MeSH Terms: Antineoplastic Agents, Cardiovascular System, Drug Discovery, Fusion Proteins, bcr-abl, Humans, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyridazines, Pyrimidines, Vascular Diseases
Added March 4, 2015
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1 Members
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12 MeSH Terms
Role of mitochondrial oxidative stress in hypertension.
Dikalov SI, Ungvari Z
(2013) Am J Physiol Heart Circ Physiol 305: H1417-27
MeSH Terms: Angiotensin II, Animals, Antihypertensive Agents, Antioxidants, Blood Pressure, Cardiovascular System, Humans, Hypertension, Mechanotransduction, Cellular, Mitochondria, NADPH Oxidases, Oxidative Stress, Reactive Oxygen Species, Renin-Angiotensin System, Risk Factors
Show Abstract · Added February 17, 2016
Based on mosaic theory, hypertension is a multifactorial disorder that develops because of genetic, environmental, anatomical, adaptive neural, endocrine, humoral, and hemodynamic factors. It has been recently proposed that oxidative stress may contribute to all of these factors and production of reactive oxygen species (ROS) play an important role in the development of hypertension. Previous studies focusing on the role of vascular NADPH oxidases provided strong support of this concept. Although mitochondria represent one of the most significant sources of cellular ROS generation, the regulation of mitochondrial ROS generation in the cardiovascular system and its pathophysiological role in hypertension are much less understood. In this review, the role of mitochondrial oxidative stress in the pathophysiology of hypertension and cross talk between angiotensin II signaling, pathways involved in mechanotransduction, NADPH oxidases, and mitochondria-derived ROS are considered. The possible benefits of therapeutic strategies that have the potential to attenuate mitochondrial oxidative stress for the prevention/treatment of hypertension are also discussed.
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15 MeSH Terms