Evaluation of Possible Proarrhythmic Potency: Comparison of the Effect of Dofetilide, Cisapride, Sotalol, Terfenadine, and Verapamil on hERG and Native <i>I</i>Kr Currents and on Cardiac Action Potential

Orvos, Péter; Kohajda, Zsófia; Szlovák, Jozefina; Gazdag, Péter; Árpádffy-Lovas, Tamás; Toth, Daniel; Geramipour, Amir Mohammad; Tálosi, László; Jost, Norbert; Varró, András; Virág, László

doi:10.1093/toxsci/kfy299

Cited by 55 publications

(51 citation statements)

References 74 publications

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“…Only two platforms (used in 3 of 17 test assay results) obtained recordings at near physiologic temperatures (35 °C), with experiments on other platforms conducted at either unspecified (room) temperature or a range of temperatures (Table 1). It is well known that block of hERG with some drugs is temperature dependent 29,43,44 , and this may differentially affect IC 50 determinations. Little is known regarding the temperature sensitivity of drug block of other cardiac currents.…”

Section: Differences In Intracellular Buffer Composition the Componementioning

confidence: 99%

Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells

Kramer

Himmel

Lindqvist³

et al. 2020

Sci Rep

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Automated patch clamp (APC) instruments enable efficient evaluation of electrophysiologic effects of drugs on human cardiac currents in heterologous expression systems. Differences in experimental protocols, instruments, and dissimilar site procedures affect the variability of IC 50 values characterizing drug block potency. this impacts the utility of Apc platforms for assessing a drug's cardiac safety margin. We determined variability of Apc data from multiple sites that measured blocking potency of 12 blinded drugs (with different levels of proarrhythmic risk) against four human cardiac currents (heRG [i Kr ], hCav1.2 [L-Type I ca ], peak hNav1.5, [Peak I na ], late hNav1.5 [Late I na ]) with recommended protocols (to minimize variance) using five APC platforms across 17 sites. IC 50 variability (25/75 percentiles) differed for drugs and currents (e.g., 10.4-fold for dofetilide block of hERG current and 4-fold for mexiletine block of hNav1.5 current). Within-platform variance predominated for 4 of 12 hERG blocking drugs and 4 of 6 hNav1.5 blocking drugs. hERG and hNav1.5 block. Bland-Altman plots depicted varying agreement across Apc platforms. A follow-up survey suggested multiple sources of experimental variability that could be further minimized by stricter adherence to standard protocols. Adoption of best practices would ensure less variable Apc datasets and improved safety margins and proarrhythmic risk assessments. The characterization of drug effects on human currents using automated patch clamp (APC) platforms employing single-or multi-hole planar patch techniques 1-5 has revolutionized the assessment of electrophysiologic (and potential proarrhythmic) effects of new drug candidates. This increasingly popular experimental approach

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Section: Differences In Intracellular Buffer Composition the Componementioning

confidence: 99%

Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells

Kramer

Himmel

Lindqvist³

et al. 2020

Sci Rep

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“…The higher IC 50 values of THC and 11-nor-9-carboxy-THC than that of CBD in hERG current measurement in our study does not necessarily mean that CBD is more potent in other type of experiments since potency can www.nature.com/scientificreports/ differ from a target to another 12 . However, in our study due to technical limitations we focused our investigations to examine the effects of CBD in more depth.…”

Section: Discussionmentioning

confidence: 63%

“…The hERG channel current was measured by planar technology in HEK 293 cell line by the whole-cell configuration using an automated patch clamp system (Patchliner, Nanion Technologies GmbH., Munich, Germany) at room temperature as described previously 12 . The following solutions were used during automated patch-clamp recording (compositions in mM): internal solution: KCl 50, NaCl 10, KF 60, EGTA 20, HEPES 10, pH 7.2 (KOH); external solution: NaCl 140, KCl 4, glucose-monohydrate 5, MgCl 2 1, CaCl 2 3, HEPES 10, pH 7.4 (NaOH).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, formal drug development requires an early screening of whether the potential drug candidates bear any activities on the hERG channels 11 . However, drug effects on cardiac repolarization cannot be accurately estimated by measuring hERG channel currents alone 12 , since drug responses on native I Kr channel and action potential can be different from those measured in hERG.…”

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confidence: 99%

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The electrophysiological effect of cannabidiol on hERG current and in guinea-pig and rabbit cardiac preparations

Orvos

Pászti

Topál

et al. 2020

Sci Rep

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Cannabis use is associated with cardiovascular adverse effects ranging from arrhythmias to sudden cardiac death. The exact mechanism of action behind these activities is unknown. The aim of our work was to study the effect of cannabidiol (CBD), tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol on cellular cardiac electrophysiological properties including ECG parameters, action potentials, hERG and IKr ion channels in HEK cell line and in rabbit and guinea pig cardiac preparations. CBD increased action potential duration in rabbit and guinea pig right ventricular papillary muscle at lower concentrations (1 µM, 2.5 µM and 5 µM) but did not significantly change it at 10 µM. CBD at high concentration (10 µM) decreased inward late sodium and L-type calcium currents as well. CBD inhibited hERG potassium channels with an IC50 value of 2.07 µM at room temperature and delayed rectifier potassium current with 6.5 µM at 37 °C, respectively. The frequency corrected QT interval (QTc) was significantly lengthened in anaesthetized guinea pig without significantly changing other ECG parameters. Although the IC50 value of CBD was higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that hERG and potassium channel inhibition might have a role in the possible proarrhythmic adverse effects of cannabinoids in situations where metabolism of CBD impaired and/or the repolarization reserve is weakened.

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“…In the past, several drugs have been withdrawn from major markets because of their proarrhythmic effect. At present, to avoid severe cardiotoxicity, every new compound must go through preclinical safety testing determined by the U. S. Food and Drug Administration, the European Medicines Agency and other regulatory entities [16].…”

Section: Introductionmentioning

confidence: 99%

GIRK channel activity of Hungarian mushrooms: From screening to biologically active metabolites

et al. 2019

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In the current study effects of fungal extracts on the G-protein-activated inwardly rectifying potassium channel (GIRK1/4) were screened using the automated patch-clamp method. 40 organic (n-hexane, chloroform, and 50% methanol) and aqueous extracts were prepared from 10 mushroom species native to Hungary. Among the examined fungal fractions of different polarities some n-hexane and chloroform extracts exerted considerable ion channel activity. One of the most active fungal species, Hypholoma lateritium was selected for further detailed examination to determine the compounds responsible for the observed pharmacological property. Evaluation of the ion channel activity of mushroom metabolites 1-10 revealed that lanosta-7,9(11)-diene-12β,21α-epoxy-2α,3β,24β,25-tetraol (5) demonstrates remarkable blocking activity on GIRK current (IC 50 395.1 ± 31.8 nM). Investigation of the selectivity of the GIRK inhibitory effect proved that lanosta-7,9(11)-diene-12β,21α-epoxy-2α,3β,24β,25-tetraol (5) has only weak inhibitory activity on hERG channel (7.9 ± 2.8% at 100 μM), exerting more than three orders of magnitude lower blocking activity on hERG channel than on GIRK channel.

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Evaluation of Possible Proarrhythmic Potency: Comparison of the Effect of Dofetilide, Cisapride, Sotalol, Terfenadine, and Verapamil on hERG and Native IKr Currents and on Cardiac Action Potential

Cited by 55 publications

References 74 publications

Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells

Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells

The electrophysiological effect of cannabidiol on hERG current and in guinea-pig and rabbit cardiac preparations

GIRK channel activity of Hungarian mushrooms: From screening to biologically active metabolites

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