Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

Abstract

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I HERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC 50 Ͻ 0.1 M) included lidoflazine, terfenadine, and haloperidol; moderatepotency blockers (0.1 M Ͻ IC 50 Ͻ 1 M) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC 50 Ͼ 1 M) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC 50 Ͼ 300 M) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (Ͻ30 min of drug exposure per measurement). Since two of the drugs that were ineffective I HERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I HERG .

Development and Validation of Fluorescence-Based and Automated Patch Clamp–Based Functional Assays for the Inward Rectifier Potassium Channel Kir4.1

“…From dose-response experiments, an EC 80 concentration of 0.84 mM was determined, which represents only 15% of that used previously by our group. 22,23,34,35 Despite the use of lower Tl + concentrations, which tended to slightly increase the well-to-well variability in fluorescence and reduce the mean Z 0 score (data not shown), the assay generated robust screening statistics, indicating that it is suitable for HTS of chemical libraries. Our studies of VU717 show that the assay is clearly capable of identifying a *6 mM IC 50 inhibitor of Kir4.1 in a primary screen, which is a reasonable starting point to developing a submicromolar inhibitor suitable for in vitro and ideally in vivo pharmacology.…”

“…Prenylamine was formerly used clinically as a vasodilator in the treatment of angina pectoris, but it was discontinued because of its propensity to induce torsades de pointes by blocking hERG channels. 35 The potencies of VU717, prenylamine, and fluoxetine were compared across a threefold dilution series ranging from 300 nM to 100 mM. The mean -SEM CRCs for the three compounds are shown in Figure 6B.…”

Profiling Diverse Compounds by Flux- and Electrophysiology-Based Primary Screens for Inhibition of Human Ether-à-go-go Related Gene Potassium Channels

“…The IC 50 value of pyrilamine is 1.67 -0.04 mM by electrophysiological recording, but it is well above 10 mM in the Tl þ assay (data not shown). Pyrilamine is a previously known hERG blocker 39 and has no detectable fluorescence that may cause interference to the Tl þ -based measurement. Indeed, the degree of overlap between the assay results is a key parameter to gauge the effectiveness of the Tl þ -based assay.…”

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

“…PPB are either from published data (plain text) or measured in our laboratories (bold italics). [22]; c: [23]; d: [24,25]; e: [26]; f: [27]; g: [28]; h: [19]; i: [29]; j: [30]; k: [31]; l: [32]; m: [33]; n: [34]; o: [35]; p: [36]; q: [37]; r: [38]; s: [39]; t: [40]; u: [41]; v: [42]; w: [43]; x: [44]; y: [45]; z: [46]; aa: [47]; bb: [48]; cc: [49]; dd: [50]; ee: [51]; ff: [52]; gg: [53]; hh: [54]; ii: [55]; jj: [56]; kk: [57]; ll: [58]; mm: [59]; nn: [60]; oo: [61]; pp: [62]; qq: [63]; rr: [64]; ss: [65]; tt: [66]; uu: [67]; vv: [68]; ww: …”