Background — DNA variants appearing to predispose drug-associated “acquired” long-QT syndrome (aLQTS) have been reported in congenital disease genes. However, the incidence of these genetic risk factors has not systematically evaluated a large set patients with aLQTS. We previously identified functionally important genes encoding K + channel ancillary subunits 11% an aLQTS cohort. Methods and Results The coding regions pore-forming proteins KvLQT1, HERG, SCN5A were screened (1) same cohort...

Background —Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests deaths have been noticed during treatment with cisapride, a newly developed gastrointestinal prokinetic agent. The rapid ( I Kr ) slow Ks components delayed rectifier current K are candidate ionic currents to explain cisapride-related toxicity because their role repolarization ventricular myocytes. Our objectives were (1) characterize effects cisapride on two major time-dependent outward potassium...

Background —Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some these events, we hypothesized that domperidone may unsuspected electrophysiological effects predisposing patients to proarrhythmia. Methods Results —Studies were undertaken 9 isolated guinea pig...

Torsades de pointes have been observed during treatment with droperidol, a butyrophenone neuroleptic agent. Our objectives were (1) to characterize the effects of droperidol on cardiac repolarization and (2) evaluate major time-dependent outward potassium current involved in (I(K)r).Isolated, buffer-perfused guinea pig hearts (n = 32) stimulated at different pacing cycle lengths (150 250 msec) exposed concentrations ranging from 10 300 nmol/L. Droperidol increased monophasic action potential...

Proarrhythmia has been observed with the antipsychotic agent thioridazine (THIO). The mechanisms underlying these effects are unknown. objectives of this study were 1) to characterize THIO on cardiac repolarization and 2) determine whether lengthening Q-T interval could be explained by blocking major K+-repolarizing currents. Isolated, buffer-perfused guinea pig hearts (n = 32) stimulated at various pacing cycle lengths (150-250 ms) exposed concentrations ranging from 300 nM 3 microM....

Cases of QT prolongation, torsades de pointes, and sudden death have been reported with arsenic trioxide (As2O3), a highly effective agent for acute promyelocytic leukemia. In this study, we evaluated the effects As2O3 on repolarizing cardiac ion currents.In HERG- or KCNQ1+KCNE1-transfected CHO cells (n=32; total), caused concentration-dependent block both IKr IKs, an IC50 tail current 0.14+/-0.01 micromol/L 1.13+/-0.06 IKs. contrast to other QT-prolonging drugs, also activated...

Pembrolizumab is a monoclonal antibody (mAb) approved for treating Non-Small Cell Lung Cancer (NSCLC), melanoma and lymphomas. Commercialized in single-size (100 mg/4 mL) vials, the pembrolizumab solution contains no preservative. As such, manufacturer recommends using vials only once, thus, to rapidly dispose of any unused portion. Thus, appreciable amounts this costly product are wasted. To evaluate physical, chemical microbiological stability vial leftovers stored at room temperature or 4...

Background —Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes ischemia could account for some these deaths, we hypothesized that may unsuspected electrophysiological effects predisposing proarrhythmia. Methods and Results —Studies were undertaken 10 isolated guinea pig hearts demonstrated prolongation repolarization a reverse use-dependent manner by 30 μmol/L. Action potential duration increased...

Abstract QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch‐clamp technique was used assess the I Kr ‐, Ks Na ‐blocking effects of Langendorff retroperfusion on isolated guinea‐pig hearts evaluate MAPD 90 MAP amplitude‐, phase 0 d V /d t ECG‐modulating bupropion two gap junction intercellular communication inhibitors: glycyrrhetinic acid heptanol. To their communication, fluorescence recovery...

Treatment with second generation histamine H1 receptor antagonists has been associated lengthening of the Q-T interval and proarrhythmia. Similarly, reported in patients after overdosing diphenhydramine (DPH), a first agent. Therefore, our study was designed 1) to assess effects DPH on cardiac repolarization 2) characterize drug major voltage-dependent K+ currents. First, we noticed that oral administration at usual dosages healthy volunteers or (prior angioplasty) prolongation Q-Tc...

Cases of QT prolongation and sudden death have been reported with risperidone, a neuroleptic agent increasingly prescribed worldwide. Although hypokalemia was present in some these events, we hypothesized that risperidone may unsuspected electrophysiologic effects predisposing patients to proarrhythmia. In six isolated guinea pig hearts, elicited cardiac repolarization: action potential duration increased from baseline value 128 ms ± 5 147 (15%) 1 μM during pacing at 250-ms cycle length,...

Abstract CYP3A4, the most abundant cytochrome P450 enzyme in human liver and small intestine, is responsible for metabolism of about 50% all marketed drugs. Numerous pathophysiological factors, such as diabetes obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition altered type 1 (T1D) 2 (T2D). The objective was evaluate effect T1D T2D on hepatic intestinal CYP3a drug‐metabolizing activity/expression mice. Hepatic microsomes prepared from streptozotocin‐induced...

Common deoxyribonucleic acid polymorphisms that modulate normal cardiac electrophysiologic characteristics have previously been identified in long QT syndrome disease genes. In this study we screened an additional gene encoding the potassium channel KCNA5 (underlying I(Kur)) 3 ethnic groups and evaluated functional consequences of variants identified.The coding region was by single-stranded conformational polymorphism analysis direct sequencing, nonsynonymous were studied patch-clamping...

Introduction: Paliperidone (9-hydroxyrisperidone) is a second-generation antipsychotic. As observed with risperidone, QT interval prolongation was reported paliperidone. Objective: The aim to evaluate the effects of paliperidone on cardiac ventricular repolarization. Methods: (1) Patch-clamp experiments: Human ether-a-go-go-related gene (HERG)- or KCNQ1 + KCNE1-transfected cells were exposed 0.1-100 μmol/L (N = 39 cells, total) assess drug effect HERG and KCNE1 currents. (2) Langendorff...

In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts modulating role on CYP3A, in our hypothesis.To evaluate effect of activity/expression guinea pigs.Hepatic microsomes prepared from male Hartley pigs fed with control, high-fat high sucrose (HFHS) or fructose diet (HFHF). Domperidone was...

Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management motor phonic tics associated Tourette syndrome. To further elucidate mechanism underlying these clinical observations, effects pimozide on monophasic action potential duration (MAPD 9 O) potassium currents involved repolarization native isolated myocytes were examined. Methods Results: Studies undertaken eight guinea pig hearts that...

Background: Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that structurally similar to clonidine (α 2 -adrenergic agonist) but not other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine. Objective: To evaluate the effects of tizanidine on ventricular repolarization. Methods: (1) Whole-cell patch-clamp experiments: HERG- KCNQ1+KCNE1-transfected cells were exposed...

Expression of voltage-gated K channel, shaker-related subfamily, member 5 (KCNA5) underlies the human atrial ultra-rapid delayed rectifier current (I(Kur)). The KCNA5 polymorphism resulting in P532L C terminus generates I(Kur) that is indistinguishable from wild type at baseline but strikingly resistant to drug block. In present study, truncating generated a channel with wild-type sensitivity, which indicated P532 not drug-binding site. Secondary structure prediction algorithms identified...

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) hydroxyeicosatetraenoic (HETEs-cardiotoxic). Type II diabetes is well-recognized risk factor for developing cardiovascular disease. A mouse model of (C57BLKS/J-db/db) was used. After sacrifice, livers hearts were collected, washed, snap frozen. Total proteins extracted. Western blots performed...