Stimulant Drugs of Abuse and Cardiac Arrhythmias

Nonmedical use of prescription and nonprescription drugs is a worldwide epidemic, rapidly growing in magnitude with deaths because of overdose and chronic use. A vast majority of these drugs are stimulants that have various effects on the cardiovascular system including the cardiac rhythm. Drugs, like cocaine and methamphetamine, have measured effects on the conduction system and through several direct and indirect pathways, utilizing multiple second messenger systems, change the structural and electrical substrate of the heart, thereby promoting cardiac dysrhythmias. Substituted amphetamines and cocaine affect the expression and activation kinetics of multiple ion channels and calcium signaling proteins resulting in EKG changes, and atrial and ventricular brady and tachyarrhythmias. Preexisting conditions cause substrate changes in the heart, which decrease the threshold for such drug-induced cardiac arrhythmias. The treatment of cardiac arrhythmias in patients who take drugs of abuse may be specialized and will require an understanding of the unique underlying mechanisms and necessitates a multidisciplinary approach. The use of primary or secondary prevention defibrillators in drug abusers with chronic systolic heart failure is both sensitive and controversial. This review provides a broad overview of cardiac arrhythmias associated with stimulant substance abuse and their management.

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Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

Frontiers in Immunology ◽

10.3389/fimmu.2021.663061 ◽

2021 ◽

Vol 12 ◽

Author(s):

Stephanie M. Matt ◽

Emily A. Nickoloff-Bybel ◽

Yi Rong ◽

Kaitlyn Runner ◽

Hannah Johnson ◽

...

Keyword(s):

Substance Abuse ◽

Drugs Of Abuse ◽

Receptor Gene ◽

Myeloid Cells ◽

Fluorescent Imaging ◽

Public Health Issue ◽

Common Mechanism ◽

Drug Abusers ◽

Drug Induced ◽

Dopamine Signaling

Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

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Faculty Opinions recommendation of Efficacy and safety of ivabradine in patients with chronic systolic heart failure and diabetes: an analysis from the SHIFT trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725794915.793512854 ◽

2016 ◽

Author(s):

Michael Kapiloff

Keyword(s):

Heart Failure ◽

Systolic Heart Failure ◽

Efficacy And Safety ◽

Shift Trial ◽

Chronic Systolic Heart Failure

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QRS duration in evaluating ventricular dyssynchrony in patients with chronic systolic heart failure

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.00161 ◽

2010 ◽

Vol 30 (2) ◽

pp. 161-164

Author(s):

Yan-ping GUI ◽

De-ning LIAO ◽

Jia-you ZHANG

Keyword(s):

Heart Failure ◽

Systolic Heart Failure ◽

Ventricular Dyssynchrony ◽

Chronic Systolic Heart Failure ◽

Qrs Duration

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Liver and Statins: A Critical Appraisal of the Evidence

Current Medicinal Chemistry ◽

10.2174/0929867325666180327095441 ◽

2019 ◽

Vol 25 (42) ◽

pp. 5835-5846 ◽

Cited By ~ 6

Author(s):

Anna Licata ◽

Antonina Giammanco ◽

Maria Giovanna Minissale ◽

Salvatore Pagano ◽

Salvatore Petta ◽

...

Keyword(s):

Adverse Events ◽

Association Studies ◽

Organic Anion ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Organic Anion Transporting Polypeptide ◽

Treatment And Prevention ◽

Genome Wide ◽

Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

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Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV

Cell Death Discovery ◽

10.1038/s41420-021-00530-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qingying Tang ◽

Shuxia Chen ◽

Hui Wu ◽

Honghua Song ◽

Yongjun Wang ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Granule Cells ◽

Spine Density ◽

Drug Induced ◽

Distinct Cell Type ◽

Cognitive Behaviors ◽

Dentate Granule Cells ◽

Rat Pups ◽

Cognitive Deficiency ◽

Underlying Mechanisms

AbstractCongenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.

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Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18137139 ◽

2021 ◽

Vol 18 (13) ◽

pp. 7139

Author(s):

Yue Wu ◽

Jieqiang Zhu ◽

Peter Fu ◽

Weida Tong ◽

Huixiao Hong ◽

...

Keyword(s):

Machine Learning ◽

Autoimmune Diseases ◽

Odds Ratio ◽

Area Under Curve ◽

Predictive Performance ◽

Drug Induced ◽

Drug Candidates ◽

Daily Dose ◽

Structural Alerts ◽

Underlying Mechanisms

An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.

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Neurogenic Erectile Dysfunction. Where Do We Stand?

Medicines ◽

10.3390/medicines8010003 ◽

2021 ◽

Vol 8 (1) ◽

pp. 3

Author(s):

Charalampos Thomas ◽

Charalampos Konstantinidis

Keyword(s):

Erectile Dysfunction ◽

Large Cohort ◽

Sexual Performance ◽

Drug Induced ◽

Underlying Mechanisms

Erectile Dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance, causing tremendous effects on both patients and their partners. The pathophysiology of ED remains a labyrinth. The underlying mechanisms of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic. Neurogenic ED consists of a large cohort of ED, accounting for about 10% to 19% of all cases. Its diversity does not allow an in-depth clarification of all the underlying mechanisms nor a “one size fits all” therapeutical approach. In this review, we focus on neurogenic causes of ED, trying to elucidate the mechanisms that lie beneath it and how we manage these patients.

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