Antiarrhythmic properties of ivabradine in an experimental model of Short‐QT‐ Syndrome

The I_f channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether‐a‐go‐go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short‐QT‐syndrome. Twelve rabbit hearts were isolated and Langendorff‐perfused. After obtaining baseline data, pinacidil, an I_K‐ATP channel opener, was infused (1 μmol/L). Eight endo‐ and epicardial monophasic action potentials and a 12‐lead ECG showed a significant abbreviation of QT interval (?32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; ?22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; ?20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 μmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post‐repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short‐QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR.     

An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk

Owing to its association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe, effective medicines. Genetic and pharmacological evidence highlighting the pivotal role the human ether-a-go-go-related gene (hERG) channel was a critical step in understanding how to start addressing this issue. It led to the development of hERG assays with the rapid throughput needed for the short timescales required in early drug discovery. The resulting volume of hERG data has fostered in silico models to help chemists design compounds with reduced hERG potency. In early drug discovery, a pragmatic approach based on exceeding a given potency value has been required to decide when a compound is likely to carry a low QT risk, to support its progression to late-stage discovery. At this point, the in vivo efficacy and metabolism characteristics of the potential drug are generally defined, as well its safety profile, which includes usually a dog study to assess QT interval prolongation risk. The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man. Further data may be required to refine the risk assessment before making the major investment decisions for full development. The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies.This article is commented on by Guth and Rast, pp. 22–24 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

L539 fs/47, a truncated mutation of human ether‐a‐go‐go‐related gene (hERG), decreases hERG ion channel currents in HEK 293 cells

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Reducing QT liability and proarrhythmic risk in drug discovery and development

Drug-induced torsades de pointes (TdP), a rare, life-threatening, polymorphic, ventricular tachycardia associated with prolongation of the QT interval, has been the main safety reason for the withdrawal of medicines from clinical use over the last decade. Most often, drugs that prolong the action potential and delay ventricular repolarization do so through blockade of outward (repolarizing) currents, predominantly the rapid delayed rectifying potassium current, I_Kr. While QT interval prolongation is not a safety concern per se, in a small percentage of people, it has been associated with TdP, which either spontaneously terminates or degenerates into ventricular fibrillation. Furthermore, recent data suggest that shortening of the QT interval may also be a new safety issue waiting to surface. This review article summarizes the presentations given at a symposium entitled ‘Reducing QT liability and proarrhythmic risk in drug discovery and development’, which was part of the Federation of the European Pharmacological Societies congress, Manchester, UK, 13–17 July 2008. The objective of this symposium was to assess the effects of implementing the latest regulatory guidance documents (International Conference on Harmonization S7A/B and E14), as well as new scientific and technical trends on the ability of the pharmaceutical industry to reduce and manage the QT liability and associated potential proarrhythmic risk, and contribute to the discovery and development of safer medicines. This review outlines the key messages from communications presented at this symposium and attempts to highlight some of the key challenges that remain to be addressed.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

Itraconazole‐induced Torsade de Pointes in a patient receiving methadone substitution therapy

Issues. Methadone, a pharmacological agent used to treat heroin dependence is relatively safe, but may cause cardiac arrhythmias in the concurrent presence of other risk factors. Approach and Key Findings. This case report highlights the risk of Torsade de Pointes, a life‐threatening cardiac arrhythmia, in a heroin‐dependent patient receiving methadone substitution therapy who was prescribed itraconazole for vaginal thrush. The patient presented to the accident and emergency department for chest discomfort and an episode of syncope following two doses of itraconazole (200 mg). Electrocardiogram monitoring at the accident and emergency department showed prolonged rate‐corrected QT interval leading to Torsade de Pointes. The patient was admitted for cardiac monitoring, and electrocardiogram returned to normal upon discontinuation of methadone. Implication. This cardiac arrhythmia was most likely as a result of a drug interaction between methadone and itraconazole because the patient presented with no other risk factors. Conclusion. Given the benefits of methadone as a substitution treatment for heroin‐dependent individuals, the association between methadone and cardiac arrhythmias is of great concern. Physicians treating heroin‐dependent patients on methadone substitution therapy should therefore be cautious of the potential risk of drug interactions that may lead to fatal cardiac arrhythmias.[NoorZurani MHR, Vicknasingam B, Narayanan S. Itraconazole‐induced Torsade de Pointes in a patient receiving methadone substitution therapy. Drug Alcohol Rev 2009;28:688–690]     

西酞普兰致QT间期延长的研究综述

目的综述了西酞普兰致QT间期延长的研究进展。西酞普兰通过阻断心脏相关离子通道，可剂量依赖性地引起QT间期延长，大剂量时可引起致命性的尖端扭转型室性心动过速。西酞普兰应用大剂量、女性、65岁以上人群、电解质紊乱、先天性长QT间期综合症是产生QT间期延长的风险因素。为安全合理地应用西酞普兰，应对其安全性进行持续的监测和评价。     

NS1643 enhances ionic currents in a G604S‐WT hERG co‐expression system associated with long QT syndrome 2

Loss of function mutations in the human ether‐a‐go‐go‐related gene (hERG) cause long QT syndrome type 2 (LQT2). Most LQT2 patients are heterozygous mutation carriers in which the mutant hERG exerts potent dominant‐negative effects. 1, 3‐bis‐(2‐hydroxy‐5‐trifluoromethyl‐phenyl)‐urea (NS1643) is known to enhance IKr in WT‐hERG. We investigated its actions following lipofectamine‐induced expression of both mutant G604S‐ and WT‐hERG in the heterologous HEK293 expression system. Cells transfected with pcDNA3‐G604S‐hERG did not lead to any expression of detectable currents whether before or following NS1643 challenge. Cells transfected with both pcDNA3‐WT‐hERG and pcDNA3‐G604S‐hERG showed reduced hERG currents compared to those transfected with pcDNA3‐G604S‐hERG consistent with the reduced trafficking and formation of modified heteromeric WT‐G604S channels reported on earlier occasions. Nevertheless, NS1643 then continued to produce concentration‐ and voltage‐dependent increases in hERG current amplitude. It did not affect the voltage dependence of activation, recovery from inactivation and deactivation. However, NS1643 (30 μmol/L) slowed steady state inactivation and shifted the steady state half maximal activation voltage (V_1/2) of the inactivation curve by +10 mV, and significantly increased the time constants of inactivation. Our present experimental results suggest that NS1643 significantly increases ion current and attenuates its inactivation in cells co‐expressing G604S‐hERG and WT‐hERG. These findings raise the possibility that hERG channel activators offer potential treatment strategies for inherited LQT2.     

QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience

Background: Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. Discussion: This has fostered discussion on the molecular mechanisms underlying the class-III anti-arrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk–benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H₁-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III anti-arrhythmic agents). Future perspectives for drug research and development are also briefly outlined. Received: 4 October 1999 / Accepted in revised form: 13 January 2000     

Non-antiarrhythmic drugs prolonging the QT interval: considerable use in seven countries

AIMS: Many drugs belonging to different therapeutic classes appear to share a potentially fatal side-effect: ventricular tachyarrhythmias associated with QT prolongation. The aim of this study was to assess the relevance and the magnitude of the problem in seven countries by grouping all nonantiarrhythmic drugs according to the type of evidence on QT prolongation and analysing their sales data. METHODS: We divided all nonantiarrhythmic QT-prolonging agents into the following categories (in increasing order of clinical relevance): group A, drugs with published clinical or preclinical evidence on QT prolongation or with relevant official warnings; group B, drugs with published clinical or preclinical evidence; group C, drugs with published clinical evidence; group D, drug with published clinical evidence on torsades de pointes or ventricular arrhythmias associated with QT prolongation; group E, drugs belonging to group D with official warnings. We retrieved 1998 sales data from community pharmacies in seven countries (Australia, Denmark, England, Germany, Greece, Italy and Sweden). Data for individual agents were expressed as defined daily doses per 1000 inhabitants per day (DDD/1000/day). Overall use in each country was calculated for each drug group. Groups D and E were considered as the most clinically relevant. RESULTS: Among the 102 nonantiarrhythmic agents meeting at least one of the inclusion criteria, 33 drugs had sales data > or =1 DDD/1000/day and 71 drugs had a use > or =0.1 DDD/1000/day in at least one country. Among the 37 nonantiarrhythmic agents with published reports of ventricular arrhythmias associated with QT prolongation, 12 compounds had sales data > or =1 DDD/1000/day. Total consumption in each country ranged: from 51.9 to 94.7 DDD/1000/day for group A; from 51.6 to 92.7 DDD/1000/day for group B; from 37.1 to 76.6 DDD/1000/day for group C; from 12.9 to 29.1 DDD/1000/day for group D; and from 5.8 to 15.3 DDD/1000/day for group E. CONCLUSIONS: In spite of wide variations in the sales of individual agents, the overall extent of use of nonantiarrhythmic QT-prolonging drugs was of the same order of magnitude in all countries. The significant use of drugs belonging to categories D and E should prompt careful risk/benefit assessment of each agent.     

乙酰半胱氨酸引起QTc延长

1例68岁女性患者,因肺间质纤维化口服乙酰半胱氨酸片0.6 g,tid。用药第3天患者诉心前区疼痛、心慌、胸闷。心电图示短阵房性心动过速、ST-T改变、QT间期延长,QTc 503 ms。心梗三项、电解质、BNP均在正常范围内。遂停用乙酰半胱氨酸片,其余治疗继续,停药第2天患者未再出现心慌等不适症状,复查QTc 446 ms。停药第3天患者病情好转出院。     

The genetics of pro-arrhythmic adverse drug reactions

Ventricular arrhythmia induced by drugs (pro-arrythmia) is an uncommon event, whose occurrence is unpredictable but potentially fatal. The ability of a variety of medications to induce these arrhythmias is a significant problem facing the pharmaceutical industry. Genetic variants have been shown to play a role in adverse events and are also known to influence an individual''s optimal drug dose. This review provides an overview of the current understanding of the role of genetic variants in modulating the risk of drug induced arrhythmias.     

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study

AIMS

To assess the steady-state pharmacokinetic and QT_c effects of domperidone and ketoconazole, given alone and together.

METHODS

A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects.

RESULTS

Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QT_cF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QT_cF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QT_c was positively correlated with plasma drug concentrations, in both men and women. ΔQT_cF increased by about 2 ms per 10 ng ml^–1 rise in domperidone concentration, and per 1 µg ml^–1 rise in ketoconazole concentration.

CONCLUSIONS

Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QT_cF in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained.     

In vitro evaluation of the effects of anti‐fungals,benzodiazepines and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone: implications on doping control analysis

We have studied whether the phase II metabolism of 19‐norandrosterone, the most representative metabolite of 19‐nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti‐Doping Agency. In detail, we have evaluated the effect of non‐prohibited drugs belonging to the classes of anti‐fungals, benzodiazepines, and non‐steroidal anti‐inflammatory drugs on the glucuronidation of 19‐norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl‐transferase were designed and performed to monitor the formation of 19‐norandrosterone glucuronide from 19‐norandrosterone. Determination of 19‐norandrosterone (free and conjugated fraction) was performed by gas chromatography – mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert‐butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed‐phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non‐prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19‐norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti‐fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non‐steroidal anti‐inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.     

Metal‐mediated Targeting in the Body

Metal ions are important for many biological processes and are steadily available in the human body. Metal concentrations can be extremely high in diseased areas of various pathological conditions. Some synthetic and natural drugs need to be activated by metal ions as prodrugs. In this review, we provide a few examples to illustrate how metal ions activate and mediate drug targeting in the body. This knowledge may be helpful for the development of more effective drugs and pharmaceutical formulations.     

Drug‐resistant epilepsy and topiramate: Plasma concentration and frequency of epileptic seizures

Topiramate (TPM) is a second‐generation antiepileptic drug (AED), acting on drug‐resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (C_p), and frequency of epileptic seizures. A cross‐sectional analytical study was developed with patients aged 18‐60 years, for diagnosis of drug‐resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty‐seven patients were included, 83.8% of the patients presented C_p below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 μg/mL in TPMC_p, while the use of inducers predicted a reduction of 2.97 μg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 μg/mL in TPMC_p decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with C_p below the therapeutic range, the mean number of seizures per month was greater than those with C_p within the therapeutic range. The prescribed dose and the use of AED inducers influence C_p of TPM, likewise the low C_p of first‐line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures.