Galantamine (Reminyl®) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current

Vigneault, Patrick; Bourgault, Sarah; Kaddar, Nisrin; Caillier, Bertrand; Pilote, Sylvie; Patoine, Dany; Simard, Chantale; Drolet, Benoît

doi:10.1016/j.ejphar.2012.02.002

Cited by 15 publications

(19 citation statements)

References 14 publications

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“…Donepezil has also caused significant inhibition of delayed rectifier Kv currents and fast transient Kv currents in rat dissociated hippocampal neurons (Yu and Hu, 2005) and in molluscan neurons (Solntseva et al, 2007). Although some acetylcholinesterase inhibitors, such as galantamine are known to cause QT interval prolongation by blocking the hERG current (Vigneault et al, 2012), to the best of our knowledge, the effects of donepezil on hERG currents remain unknown. Since hERG channels are highly expressed in both the heart and the brain (Vandenberg et al, 2012), we studied the effect of donepezil on hERG currents using the patch-clamp technique to determine the electrophysiological basis for cardiac and neuronal action.…”

Section: Introductionmentioning

confidence: 99%

Effects of donepezil on hERG potassium channels

et al. 2015

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Section: Introductionmentioning

confidence: 99%

Effects of donepezil on hERG potassium channels

et al. 2015

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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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“…Given the structural diversity of the alkaloids included in this study, deriving structural features critical for hERG inhibition was not possible. However, it seems that alkaloids with an aporphine (17)(18)(19)(20) or benzophenanthridine (21)(22)(23)(24) scaffold are particularly prone to hERG block.…”

Section: Resultsmentioning

confidence: 97%

“…Also, the hERG inhibitory activity of galanthamine (32) and ephedrine had been previously reported. When assayed in HEK293 cells, galanthamine (32) had been classified as weak hERG blocker (IC 50 : 760.2 µM) [18], whereas ephedrine showed no hERG block at 10 µM [15]. (−)-Ephedrine (7) and (−)-galanthamine (32) were, therefore, used as negative controls in our study and indeed induced no hERG inhibition in the oocyte assay (l " Table 1).…”

Section: Resultsmentioning

confidence: 98%

“…The initial test concentration was 100 µM (l " Table 1). Of the alkaloids tested, protopine (16), (+)-bulbocapnine (18), (+)-N-methyllaurotetanine (19), (+)-boldine (20), (+)-corynoline (24), and reserpine (31) reduced I hERG by more than 60 % (inhibition of I hERG by 88.4 ± 1.9 %, 72.0 ± 1.6 %, 81.4 ± 2.9 %, 65.8 ± 5.3%, 72.6 ± 2.4 %, and 66.9 ± 0.3 %, respectively). (+)-Chelidonine (23) and yohimbine (30) were somewhat less active (inhibition of I hERG by 56.8 ± 8.2 % and 52.6 ± 3.0 %, respectively).…”

Section: Resultsmentioning

confidence: 99%

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Natural Products as Potential Human Ether-A-Go-Go-Related Gene Channel Inhibitors – Screening of Plant-Derived Alkaloids

et al. 2014

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Inhibition of the cardiac human ether-a-go-go-related gene channel is a problematic off-target pharmacological activity and, hence, a major safety liability in clinical practice. Several non-cardiac drugs have been restricted in their use, or even removed from the market due to this potentially fatal adverse effect. Comparatively little is known about the human ether-a-go-go-related gene inhibitory potential of plant-derived compounds. In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by ≥ 50% at 100 µM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.

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Galantamine (Reminyl®) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current

Cited by 15 publications

References 14 publications

Effects of donepezil on hERG potassium channels

Effects of donepezil on hERG potassium channels

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

Natural Products as Potential Human Ether-A-Go-Go-Related Gene Channel Inhibitors – Screening of Plant-Derived Alkaloids

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