Effects of fluoroquinolones on HERG channels and on pancreatic β-cell ATP-sensitive K+ channels

Zünkler, Bernd J.; Claassen, Sonja; Wos-Maganga, Maria; Rustenbeck, Ingo; Holzgrabe, Ulrike

doi:10.1016/j.tox.2006.09.002

Cited by 22 publications

(14 citation statements)

References 23 publications

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“…This agrees with our previous results from APD prolonging extent in isolated papillary muscles from guinea pig, namely, SPX > LVFX > AX [11]. However, the values of IC 50 for HERG inhibition induced by SPX and LVFX obtained in this study are less than other investigations [12–14]. To our knowledge, the differences might be derived from the use of different cell line, different experimental conditions or co‐transfection of MiRP1.…”

Section: Discussionsupporting

confidence: 90%

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

Guo¹,

Han

Liu³

et al. 2010

Basic Clin Pharma Tox

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The administration of certain fluoroquinolone antibacterials has recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. In this study, the effects of a novel fluoroquinolone, antofloxacin hydrochloride (AX) on human-ether-à-go-go-related gene (HERG) encoding potassium channels and the biophysical mechanisms of drug action were performed with whole-cell patch-clamp technique in transiently transfected HEK293 cells. The administration of AX caused voltage-and time-dependent inhibition of HERG K + current (I HERG ⁄ MiRP1 ) in a concentration-dependent manner but did not markedly modify the properties of channel kinetics, including activation, inactivation, deactivation and recovery from inactivation as well. In comparison with sparfloxacin (SPX), levofloxacin lactate (LVFX), the potency of AX to inhibit HERG tail currents was the least one, with an IC 50 value of 460.37 lM. By contrast, SPX was the most potent compound, displaying an IC 50 value of 2.69 lM whereas LVFX showed modest potency, with an IC 50 value of 43.86 lM, respectively. Taken together, our data suggest that AX only causes a minor reduction of I HERG ⁄ MiRP1 at the estimated free plasma level.The human-ether-à-go-go-related gene (HERG) encodes the pore-forming a-unit of the K + channel that resembles the rapid component of the delayed rectifier current I Kr in cardiac myocytes and non-cardiac cells [1]. It is well established that the inhibition of cardiac I Kr is associated with druginduced QT prolongation torsades de pointes arrhythmias (TdP) and sudden cardiac death. Indeed, it is now known that structurally diverse drugs associated with LQT syndromes (LQTS), including class III anti-arrhythmics, antimicrobials, prokinetic drugs, antihistamines, antidepressants and antipsychotic agents as well, share a common ability of blockage on HERG K + channels, resulting in a delay of cardiac repolarisation [2]. The fluoroquinolone class of antibacterials is widely prescribed for the treatment of infections due to their broad-spectrum antibiotic activity. However, the administrations of certain fluoroquinolone antibacterials have recently been linked to QT interval prolongation, raising the clinical concerns over the cardiotoxicity of these agents. For instance, sparfloxacin (SPX) and grepafloxacin (GPX) have been shown to prolong QT interval on electrocardiogram (ECG) at clinical doses [3][4][5]. In addition, they can induce TdP, a life-threatening ventricular arrhythmia [6,7], resulting in their withdrawn from the market in most countries. Antofloxacin hydrochloride (AX) is a newly developed fluoroquinolone antibiotic in China ( fig. 1). Compared with other available fluoroquinolones in clinical use, AX was well tolerated and demonstrated rapid absorption, highserum concentration, broad tissue distribution, and a long elimination half-life in both animal and human beings from a pharmacokinetic point of view [8,9]. This study aimed to examine the effects of AX on HERG currents het...

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Section: Discussionsupporting

confidence: 90%

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

Guo¹,

Han

Liu³

et al. 2010

Basic Clin Pharma Tox

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“…E.g., fluoroquinolones C1 and C3 effectively depolarized the plasma membrane, but had only modest effects on KATP channel activity under closely similar conditions [28]. Also, there were obvious discrepancies between the depolarizing effect and the effect on secretion.…”

Section: Page 11 Of 30mentioning

confidence: 99%

The insulinotropic effect of fluoroquinolones

Ghaly¹,

Gunda²,

Sahin³

et al. 2009

Biochemical Pharmacology

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“…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: …”

Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

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

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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Effects of fluoroquinolones on HERG channels and on pancreatic β-cell ATP-sensitive K+ channels

Cited by 22 publications

References 23 publications

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

The Action of a Novel Fluoroquinolone Antibiotic Agent Antofloxacin Hydrochloride on Human‐Ether‐à‐go‐go‐Related Gene Potassium Channel

The insulinotropic effect of fluoroquinolones

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

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