Effect of levetiracetam on cardiac repolarization in children with epilepsy

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia’s formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = −0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

Download Full-text

The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

Archives of Toxicology ◽

10.1007/s00204-021-03086-0 ◽

2021 ◽

Author(s):

Leila Topal ◽

Muhammad Naveed ◽

Péter Orvos ◽

Bence Pászti ◽

János Prorok ◽

...

Keyword(s):

Side Effects ◽

Action Potentials ◽

Oral Intake ◽

Potassium Currents ◽

Delayed Rectifier ◽

Cardiac Repolarization ◽

Cardiovascular Side Effects ◽

Channel Inhibition ◽

Repolarization Reserve ◽

Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

Download Full-text

Impact of ISK Voltage and Ca2+/Mg2+-Dependent Rectification on Cardiac Repolarization

Biophysical Journal ◽

10.1016/j.bpj.2020.06.022 ◽

2020 ◽

Vol 119 (3) ◽

pp. 690-704

Author(s):

Peter Bronk ◽

Tae Yun Kim ◽

Iuliia Polina ◽

Shanna Hamilton ◽

Radmila Terentyeva ◽

...

Keyword(s):

Cardiac Repolarization

Download Full-text

Study of cardiac repolarization in healthy volunteers performed with mizolastine, a new H 1 ‐receptor antagonist

British Journal of Clinical Pharmacology ◽

10.1046/j.1365-2125.1999.00927.x ◽

1999 ◽

Vol 47 (5) ◽

pp. 515-520 ◽

Cited By ~ 17

Author(s):

Chaufour ◽

Caplain ◽

Lilienthal ◽

L’Héritier ◽

Deschamps ◽

...

Keyword(s):

Healthy Volunteers ◽

Receptor Antagonist ◽

Cardiac Repolarization

Download Full-text

Abstract 1352: Gender Differences In Cardiac Repolarization In Transgenic Long QT Syndrome 2 (LQT2) Rabbits

Circulation ◽

10.1161/circ.116.suppl_16.ii_277-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Katja E Odening ◽

Mohammad Hajjiri ◽

Michael Brunner ◽

Peem Lorvidhaya ◽

Lorraine Schofield ◽

...

Keyword(s):

Gender Differences ◽

Cardiac Repolarization ◽

Adult Women ◽

Male Adult ◽

Clinical Events ◽

Transgenic Rabbits ◽

Surface Ecg ◽

Electrophysiological Studies ◽

Genotype Difference

Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic rabbits over-expressing pore mutants of the human KvLQT1 (LQT1) and HERG (LQT2) selectively in the heart. We report the gender differences in cardiac repolarization, incidence of polymorphic VT and SCD in these cohorts. Methods: Adult female and male LQT1, LQT2, and littermate controls (ages 5 to 33 mo were similar in f/m, LQT2 were younger due to higher mortality) underwent telemetric ECG monitoring, surface ECG and in vivo electrophysiological studies under general anaesthesia with isoflurane (2–5%). Results: Monitoring data showed a steeper QT/RR slope in female (0.745 ± 0.05, n=4) than in male (0.513 ± 0.06, n=9; p<0.05) LQT2 rabbits. No significant gender differences were observed in QT/RR slopes in either LQT1 or WT rabbits. QT-, QTpeak-index and Tp-e were significantly longer in female than in male LQT2 rabbits (females, n=6: QT: 129.2% ± 3.9; QTp: 105.9% ± 2.1; Tp-e: 42.9ms ± 4.1 vs. males, n=8: QT: 117.5% ± 4.3; p<0.05; QTp: 93.5% ± 5.6, p<0.05; Tp-e: 29.5ms ± 2.9, p<0.02). EP studies revealed significantly longer atrial (AERP) and ventricular (VERP) refractory periods in LQT2 females compared to males (females, n=4: AERP: 143.3 ± 5.8 ms; VERP: 212.5 ± 22.2 ms vs. males, n=8: AERP: 102.5 ± 7.7 ms, p<0.01; VERP: 178.1 ± 7.8 ms, p<0.05). AERP and VERP were significantly longer in LQT2 females than in LQT1 females (LQT1 females, n=7: AERP: 101.4 ± 7.7 ms, p<0.01, VERP: 156.9 ± 6.2, p<0.001), whereas in male LQT rabbits this genotype difference was only found in VERP but not in AERP. Survival was significantly shorter in female LQT2 rabbits compared to LQT1 or WT controls, with 4 sudden deaths among 10 LQT2, 1 among 19 WT and no SCD in 13 LQT1 females (p<0.02). No gender difference was observed in mortality. All cases of SCD occurred after sexual maturation and two LQT2 females died during lactation. Monitoring revealed the cause of SCD was polymorphic VT. Conclusions: Monitoring of LQT rabbits reveal gender differences in LQT2 rabbits. QT/RR slope is steeper in female than in male adult LQT2 rabbits. AERP and VERP are longer in LQT2 females than in males. Finally, in LQT2 females, SCD was associated with lactation, but not pregnancy.

Download Full-text

Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01292-21 ◽

2021 ◽

Author(s):

Lori M. Newman ◽

Martin Kankam ◽

Aya Nakamura ◽

Tom Conrad ◽

John Mueller ◽

...

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Cardiac Repolarization ◽

Cardiac Safety ◽

Double Blind ◽

Thorough Qt Study ◽

Regulatory Guidelines ◽

Clinically Significant ◽

The One ◽

Global Threat

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.

Download Full-text