Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

Bruin, Marie L. De; Pettersson, Magnus; Meyboom, R.H.B.; Hoes, Arno W.; Leufkens, Hubert G.M.

doi:10.1093/eurheartj/ehi092

Cited by 217 publications

(105 citation statements)

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“…Another important use for this method is validation of a pharmacological hypothesis about the mechanism of occurrence of ADRs. A nice example was the investigation of anti-human ether-a-go-go-related gene (HERG) activity of 52 proarrhythmic drugs and the risk of drug-induced arrhythmias [8]. The study was performed using the database of the WHO International Drug Monitoring Program.…”

Section: Drug Of Interest (X)mentioning

confidence: 99%

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

Montastruc

Sommet

Bagheri

et al. 2011

Brit J Clinical Pharma

355

373

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Section: Drug Of Interest (X)mentioning

confidence: 99%

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

Montastruc

Sommet

Bagheri

et al. 2011

Brit J Clinical Pharma

355

373

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“…One study estimated the odds ratio for cardiac events at 1.93 (95% CI: 1.89 -1.98) for each unit increase in HERG blocking activity. 45 Drug effect on potassium channels may also be potentiated by a variety of milieurelated factors, such as ancillary drug use, 1 hypocalcemia, hypokalemia and hypomagnesemia related to diet, medical conditions, 19 diuretic use, and recent cardioversion of atrial fibrillation causing sudden heart rate slowing.…”

Section: Drug-induced Lqtsmentioning

confidence: 99%

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

Modell

Lehmann

2006

Genetics in Medicine

146

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Long QT syndrome (LQTS) refers to a group of "channelopathies"-disorders that affect cardiac ion channels. The "family" concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470ϩ allelic mutations induce loss-of-function in the passage of mainly K ϩ ions, and gain-of-function in the passage of Na ϩ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with subpopulation depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A

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“…As also stated by Viswanathan and Rudy, 15 early after-depolarization occurs due to longer repolarization and in phase 3, the inability of K+ ions to leave the cells upon ondansetron blocking the human Ether-à-go-go-Related Gene (HERG) K1 channel, 6,[16][17][18][19] which facilitates the fast component of the potassium current (Ikr) to occur during the formation of the action potential in the heart. In our study, after the injection of diltiazem, QTc measurements reversed (increased if it was decreasing, decreased if it was increasing) in 10 out of 11 rats.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Electrocardiography After Combined Use of Ondansetron and Diltiazem in Anesthetized Rats

Deni̇z¹,

Sertöz²,

Pehlivan³

et al. 2013

Turkiye Klinikleri J Med Sci

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A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : This study investigated the changes in electrocardiograms in rats after combined use of ondansetron and diltiazem. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : Seventeen rats were included in the study but data were collected from 11 rats with available data. After anesthesia, electrocardiogram records of rats for the initial 5 minutes were considered "Baseline" record. Following this, rats received intravenous ondansetron injection and their electrocardiograms were recorded for another 5 minutes. The same procedure was repeated with intravenous diltiazem injection. R Re es su ul lt ts s: : After ondansetron injection QTc from 9 rats were longer and 2 rats were shorter compared to baseline (before the administration of ondansetron). When diltiazem was given after ondansetron, in 10 rats out of 11, the QTc time was correlated negatively with measurements obtained before diltiazem. There was no statistically significant difference between the baseline QTc measurements and the QTc obtained after the administration of diltiazem. C Co on nc cl lu us si io on n: : The combined use of ondansetron and diltiazem does not lead to any change in rat electrocardiography.K Ke ey y W Wo or rd ds s: : Ondansetron; diltiazem; electrocardiography Ö ÖZ ZE ET T A Am ma aç ç: : Bu çalışmada, sıçanlarda ondansetron ve diltiazemin birlikte kullanımının elektrokardiyografide oluşturabileceği değişikliklerin araştırılması amaçlandı. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Çal-ışmaya 17 sıçan dâhil edilmekle birlikte, veriler 11 sıçandan toplanabildi. Anesteziden sonraki ilk 5 dakika boyunca sıçanlardan elde edilen elektrokardiyogram kayıtları bazal kayıt olarak kabul edildi. Bu işlemden sonra sıçanlara intravenöz ondansetron enjekte edildi ve bunu izleyen 5 dakika boyunca elektrokardiogram kayıtları alındı. Aynı işlemler intravenöz diltiazem enjeksiyonu ile tekrar edildi. B Bu ul lg gu ul la ar r: : Ondansetron verildikten sonra QTc bazal değerlere (ondansetron verilmeden önce) kıyasla 9 sıçanda daha uzun ve 2 sıçanda daha kısa bulundu. Ondansetrondan sonra diltiazem verildiğinde 11 sıçanın 10'unda QTc süreleri diltizem verilmesinden önceki ölçüme göre negatif korelasyon gösterdi. Bazal elektrokardiyografi QTc değerleri ile diltiazem verilmesinden sonra elde edilen QTc değerleri arasında istatistiksel olarak anlamlı bir fark saptanmadı. S So on nu uç ç: : Ondansetron ile diltiazemin birlikte kullanılmasının, sıçan elektrokardiografisinde değişiklik oluşturmadığı sonucuna varıldı.A An na ah ht ta ar r K Ke el li im me el le er r: : Ondansetron; diltiazem; elektrokardiyografi T Tu ur rk ki iy ye e K Kl li in ni ik kl le er ri i J J M Me ed d S Sc ci i 2 20 01 13 3; ;3 33 3( (3 3) ): :8 87 74 4--8 8

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Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

Abstract: Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.

Cited by 217 publications

References 10 publications

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

Evaluation of Electrocardiography After Combined Use of Ondansetron and Diltiazem in Anesthetized Rats

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