scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Vol 118 (20) ◽  
pp. e2024215118
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Life Threatening ◽  
Approved Drugs ◽  
Voltage Sensing Domain ◽  
Action Potential Repolarization ◽  
Antiarrhythmic Effects

Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

Cardiovascular Safety of Psychiatric Agents: A Cautionary Tale

Angiology ◽  
2018 ◽  
Vol 70 (2) ◽  
pp. 103-129 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Antonis S. Manolis
Keyword(s):  
Psychiatric Patients ◽  
Torsade De Pointes ◽  
Close Monitoring ◽  
Drug Induced ◽  
The Metabolic Syndrome ◽  
Psychotropic Agents ◽  
Individualized Approach ◽  
Life Threatening ◽  
Coronary Syndromes ◽  
Therapy Modification

Psychiatric agents are among the most commonly prescribed medications. Despite the advent of newer generation agents, patients receiving them still experience cardiovascular (CV) side effects. However, these agents may have heterogeneous properties, calling for an individualized approach based on efficacy and also on the particular side effect profile of each specific agent. Proarrhythmic effects arising from drug-induced long-QT syndrome and consequent potentially life-threatening polymorphic ventricular arrhythmias in the form of torsade de pointes, the metabolic syndrome contributing to atherosclerosis and acute coronary syndromes, and drug-induced orthostatic hypotension raise major concerns. Of course, it is also crucial that fear of potential CV adverse effects does not deprive psychiatric patients of appropriate drug therapy. Modification of CV risk factors in psychiatric patients together with optimal management of their CV diseases and appropriate selection of psychotropic agents with greater efficacy and least CV toxicity are of paramount importance in mitigating CV risks and enhancing safety. Identifying patients at high risk of CV complications and close monitoring of all patients receiving these agents are crucial steps to prevent and manage such complications. All these issues are herein reviewed, relevant guidelines are discussed, and schemas are depicted that illustrate the interrelated connections among the psychotropic agents and their CV effects.

scholarly journals Deep learning analysis of drug-induced ECG changes to inform arrhythmia risk and improve diagnosis of congenital long QT syndrome

2021 ◽  
Author(s):  
Edi Prifti ◽  
Ahmad Fall ◽  
Giovanni Davogustto ◽  
Alfredo Pulini ◽  
Isabelle Denjoy ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Torsade De Pointes ◽  
Original Method ◽  
Limited Information ◽  
Long Qt ◽  
Drug Induced ◽  
Life Threatening ◽  
Electrocardiogram Ecg ◽  
Learning Analysis ◽  
Congenital Long Qt Syndrome

Abstract Congenital or drug-induced long-QT syndromes can cause Torsade-de-Pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy to identify individuals at high risk of TdP consists on measuring the QT duration on the electrocardiogram (ECG), shown to provide limited information. We propose an original method, including training deep neural networks to recognize ECG alterations induced by QT-prolonging drugs, as a comprehensive evaluation of TdP risk. These models accurately detected patients taking QT prolonging drugs during ECGs, while discriminating for the presence and type of congenital long-QT. Moreover, they enhanced prediction of drug-induced TdP events in addition to QT measurement. Analyses of these models revealed footprints of the torsadogenic risk and clinically relevant patient stratification.

scholarly journals New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 434
Author(s):  
Tomohiro Yamashita ◽  
Sawako Kamikaseda ◽  
Aya Tanaka ◽  
Hidetoshi Tozaki-Saitoh ◽  
Jose M. M. Caaveiro ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Intrathecal Administration ◽  
Chemical Library ◽  
P2x7 Receptors ◽  
Approved Drugs ◽  
Cardinal Symptom

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca2+ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca2+ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.

scholarly journals Drug Induced Pneumonitis Secondary to Treatment with Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (VIEKIRA PAK®) for Chronic Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Shih Yea Sylvia Wu ◽  
Bridget Faire ◽  
Edward Gane
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Kidney Injury ◽  
Complete Recovery ◽  
Final Diagnosis ◽  
Community Acquired Pneumonia ◽  
Drug Induced ◽  
First Case ◽  
Life Threatening

VIEKIRA PAK (ritonavir-boosted paritaprevir/ombitasvir and dasabuvir) is an approved treatment for compensated patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection. This oral regimen has minimal adverse effects and is well tolerated. Cure rates are 97% in patients infected with HCV GT 1a and 99% in those with HCV GT 1b. We report the first case of life-threatening allergic pneumonitis associated with VIEKIRA PAK. This unexpected serious adverse event occurred in a 68-year-old Chinese female with genotype 1b chronic hepatitis C and Child-Pugh A cirrhosis. One week into treatment with VIEKIRA PAK without ribavirin, she was admitted to hospital with respiratory distress and acute kidney injury requiring intensive care input. She was initially diagnosed with community acquired pneumonia and improved promptly with intravenous antibiotics and supported care. No bacterial or viral pathogens were cultured. Following complete recovery, she recommenced VIEKIRA PAK but represented 5 days later with more rapidly progressive respiratory failure, requiring intubation and ventilation, inotropic support, and haemodialysis. The final diagnosis was drug induced pneumonitis.

scholarly journals A Review of Adverse Cutaneous Drug Reactions Resulting from the Use of Interferon and Ribavirin

2009 ◽  
Vol 23 (10) ◽  
pp. 677-683 ◽  
Author(s):  
Nisha Mistry ◽  
Jonathan Shapero ◽  
Richard I Crawford
Keyword(s):  
Side Effects ◽  
Drug Reactions ◽  
Drug Induced ◽  
Common Cause ◽  
Injection Site Reactions ◽  
Drug Eruptions ◽  
Fixed Drug ◽  
Life Threatening ◽  
Cutaneous Drug Reactions ◽  
Systemic Drug

Drug-induced cutaneous eruptions are named among the most common side effects of many medications. Thus, cutaneous drug eruptions are a common cause of morbidity and mortality, especially in hospital settings. The present article reviews different presentations of drug-induced cutaneous eruptions, with a focus on eruptions reported secondary to the use of interferon and ribavirin. Presentations include injection site reactions, psoriasis, eczematous drug reactions, alopecia, sarcoidosis, lupus, fixed drug eruptions, pigmentary changes and lichenoid eruptions. Also reviewed are findings regarding life-threatening systemic drug reactions.

scholarly journals Toxic epidermal necrolysis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 951 ◽  
Author(s):  
Wolfram Hoetzenecker ◽  
Tarun Mehra ◽  
Ieva Saulite ◽  
Martin Glatz ◽  
Peter Schmid-Grendelmeier ◽  
...  
Keyword(s):  
Cell Death ◽  
Mortality Rate ◽  
Toxic Epidermal Necrolysis ◽  
Human Leukocyte ◽  
Best Supportive Care ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Mucosal Involvement ◽  
Keratinocyte Cell ◽  
Life Threatening

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

scholarly journals Drug-induced QT interval prolongation in cancer patients

2011 ◽  
Vol 4 (4) ◽  
pp. 223
Author(s):  
Torben K. Becker ◽  
Sai-Ching J. Yeung
Keyword(s):  
Cancer Patients ◽  
Qt Interval ◽  
Alkylating Agents ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Vascular Disruption ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Multiple Drugs

Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

scholarly journals A case of nimesulide induced toxic epidermal necrolysis

2020 ◽  
Vol 9 (5) ◽  
pp. 810
Author(s):  
Suja Xaviar ◽  
Mirunalini Ravichandran
Keyword(s):  
Mortality Rate ◽  
Toxic Epidermal Necrolysis ◽  
Skin Disease ◽  
The Body ◽  
Drug Induced ◽  
Over The Counter ◽  
Life Threatening ◽  
Cox 2 ◽  
Adequate Management ◽  
Possible Cause

Toxic epidermal necrolysis (TEN) is a rare life-threatening drug-induced mucocutaneous skin disease with a mortality rate of approximately 30%. Nimesulide is a preferential cyclo-oxygenase (COX-2) inhibitor which is frequently used for its antipyretic, anti-inflammatory and analgesic activity. Here, we report a case of nimesulide induced toxic epidermal necrolysis in a 57 years old male patient. This patient was admitted in the hospital with symptoms of epidermal sloughing and fluid filled blisters all over the body following over the counter intake of nimesulide for fever. The drug was promptly stopped, and patient was managed with steroids, antibiotics and other adequate supportive measures. The patient showed significant recovery following stoppage of drug and adequate management. This case highlights the importance of nimesulide and other NSAIDs as possible cause of TEN.

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