QT drug

Recent experimental data shows that hesperetin, a citrus flavonoid, affects potassium channels and can prolong the QTc interval in humans. Therefore, in the present study we investigated the effects of hesperetin on various transmembrane ionic currents and on ventricular action potentials. Transmembrane current measurements and action potential recordings were performed by patch-clamp and the conventional microelectrode techniques in dog and rabbit ventricular preparations. At 10 µM concentration hesperetin did not, however, at 30 µM significantly decreased the amplitude of the IK1 , Ito , IKr potassium currents...

OBJECTIVE: Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. METHODS AND RESULTS: We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs...

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation...

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride...

Fluoroquinolones, a popular antibiotic class that inhibits nucleic acid synthesis of bacteria by disrupting the activity of the enzyme's topoisomerase IV and DNA gyrase, are used to treat bacterial infections. However, the widespread use of these drugs has allowed for the development of microbial resistance in recent years. Quinolones also have many clinically relevant side effects, including psychosis, confusion, seizures, headaches, dizziness, and nausea. Common side effects include tendinitis, myopathy, depression, and fatigue...

Aim: Drug-induced long QT syndrome (diLQTS), an adverse effect of many drugs, can lead to sudden cardiac death. Candidate genetic variants in cardiac ion channels have been associated with diLQTS, but several limitations of previous studies hamper clinical utility. Materials & methods: Thus, the purpose of this study was to assess the associations of KCNE1 -D85N, KCNE2 -I57T and SCN5A -G615E with diLQTS in a large observational case-control study (6,083 self-reported white patients treated with 27 different high-risk QT-prolonging medications; 12...

PURPOSE: To investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). PARTICIPANTS AND METHODS: In two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01-0.1 mmol gadolinium/kg body weight) or placebo...

INTRODUCTION: Invasive fungal infections, especially candidemia and invasive candidiasis, continue to cause substantial morbidity and mortality. In addition, the emergence of drug-resistant Candida species, notably C. glabrata and C. auris , along with limitations in available treatments, highlights the urgent need for novel, effective antifungal agents. AREAS COVERED: This review discusses the results of in vitro studies evaluating the spectrum and highlights the pharmacokinetic/pharmacodynamic properties...

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid...

BACKGROUND: The aim of this study was to evaluate the association between CDK4/6 inhibitors and QT interval prolongation (QTp) and Torsades de Pointes (TdP) in breast cancer patients. METHOD: The cases with breast cancer from 2015 to 2022 were extracted from the FDA adverse event database (FARES) and further divided into a CDK4/6 inhibitor group and a positive control group. The associations between CDK4/6 inhibitors and QTp and TdP adverse events were evaluated using the reporting odds ratio (ROR) and the information component (IC)...

The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low threshold to initiate, and have quick delivery of decision quality data. We have aimed to profile compounds with diverse mechanism of actions (MoAs) of "non-QT" cardiovascular drug effects and evaluate the ability of nonclinical in vivo cardiovascular models to detect clinically reported effects...

Drug withdrawal post-marketing due tocardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity isthroughinhibition of cardiac ion channels, leading to prolongation of the QT intervaland sometimes fatal arrythmias. Recently, oxylipinsignaling compounds have been shown to bind toand alter ion channel function,and disruption in their cardiac levels may contribute to QTprolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes,where it oxidizes arachidonic acid to cardioprotectiveepoxyeicosatrienoic acids (EETs)...

In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model...

INTRODUCTION: Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability and safety profiles become critically important for medication selection. AREAS COVERED: This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the United States...

BACKGROUND: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine...

BACKGROUND: The use of SGLT-2 inhibitors has revolutionized heart failure therapy. Evidence suggests a reduced incidence of ventricular and atrial arrhythmias in patients with dapagliflozin or empagliflozin treatment. It is unclear to what extent the reduced arrhythmia burden is due to direct effects of the SGLT2 inhibitors or is solely a marker of improved cardiac function. METHODS: One hundred five rabbit hearts were allocated to eight groups and retrogradely perfused, employing a Langendorff setup...

Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non-alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT-interval prolongation with mitiperstat using concentration-QT (C-QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372)...

Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug-drug interactions (DDIs). Real-world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation...

AIMS: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. METHODS AND RESULTS: We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss of function KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 loss of function allele G643S, or siRNAs reducing KCNQ1 expression...

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15...