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De Pointes (de + pointe)
Kinds of De Pointes Selected AbstractsCardiac side effects of psychiatric drugs,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S1 2008Paul Mackin Abstract This review describes the common effects of psychotropic drugs on the cardiovascular system and offers guidance for practical management. Selected reports from the literature describing common side effects associated with psychotropic drugs are reviewed, and suggestions for further reading are given throughout the text. Orthostatic hypotension is the most common adverse autonomic side effect of antipsychotic drugs. Among the atypical antipsychotics the risk of orthostatic hypotension is highest with clozapine and among the conventional drugs the risk is highest with low potency agents. Rarely, orthostatic hypotension may result in neurocardiogenic syncope. QTc prolongation can occur with all antipsychotics but an increased risk is seen with pimozide, thioridazine, sertindole and zotepine. QTc prolongation is a marker of arrhythmic risk. Torsade de pointe, a specific arrhythmia, may lead to syncope, dizziness or ventricular fibrillation and sudden death. Heart muscle disease presents most commonly in the elderly as chronic heart failure, but myocarditis and cardiomyopathy, although relatively rare, are devastating, but potentially reversible complications of psychotropic drug therapy have been particularly linked to clozapine treatment. Patients with severe mental illness (SMI) are a ,high risk' population with regard to cardiovascular morbidity and mortality. It is probable that many patients accumulate an excess of ,traditional' risk factors for the development of cardiovascular disease, but other mechanisms including psychotropic drugs may also be influential in increasing risk in this vulnerable group. These risks need to be seen in the context of the undoubted therapeutic efficacy of the psychotropic armamentarium and the relief that these drugs bring to those suffering from mental disorder. Copyright © 2007 John Wiley & Sons, Ltd. [source] Testosterone shortens QT interval on ECG in both genders and may underlie lower incidence of torsades de pointes in malesACTA PHYSIOLOGICA, Issue 3-4 2006Ari-Pekka Koivisto No abstract is available for this article. [source] Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapineACTA PSYCHIATRICA SCANDINAVICA, Issue 4 2005W. V. R. Vieweg Objective:, Describe potential cardiac complications of low-dose quetiapine and other atypical antipsychotic drugs. Method:, We present a case report of a 45-year-old Black woman with multiple medical and psychiatric problems taking low-dose quetiapine. Results:, Coincident with a generalized seizure, the patient developed ,ventricular fibrillation'. She was countershocked with restoration of normal sinus rhythm. The initial electrocardiogram showed QT interval prolongation. Shortly thereafter, classical torsade de pointes appeared, lasted 10 min, and resolved spontaneously. Hypomagnesemia was present. A cardiac electrophysiologist was concerned that the very slow shortening of the prolonged QTc interval after magnesium replacement implicated quetiapine as a risk factor for QTc interval prolongation and torsade de pointes. A psychosomatic medicine consultant asserted that the fragmented medical and psychiatric care almost certainly contributed to the patient's medical problems. We discuss other cases of QT interval prolongation by newer antipsychotic drugs and previous reports by our group concerning the association of psychotropic drugs, QT interval prolongation, and torsade de pointes. Conclusion:, Atypical antipsychotic drug administration, when accompanied by risk factors, may contribute to cardiac arrhythmias including torsade de pointes. [source] Cardiac arrhythmia during propofol sedationEMERGENCY MEDICINE AUSTRALASIA, Issue 5 2008Robert J Douglas Abstract Recent articles have described the increasing frequency of use of propofol as a sedating agent in the ED, and praise the safety profile of propofol when used in this manner. We describe a patient who developed torsade de pointes followed by ventricular fibrillation while undergoing propofol sedation for closed reduction of a mid-shaft fracture of the tibia and fibula. Possible reasons for the event are discussed, and suggestions are made for areas of further research. [source] Evidences of the gender-related differences in cardiac repolarization and the underlying mechanisms in different animal species and humanFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2006Jianhua Cheng Abstract Clinical and experimental studies have shown that gender differences exist in cardiac repolarization in various animal species and human, as is evidenced by significantly longer QT, JT intervals and action potential duration in females than in males due to a reduced repolarization reserve in females. The latter is shown by the relatively greater increase in ventricular repolarization and higher incidence of torsades de pointes (TdP) in preparations from females by drugs blocking repolarizing K+ currents. These results can be modulated by gonadectomy, suggesting that gonadal steroids are important determinants of gender difference in repolarization. In human subjects, QT and JT intervals are longer in women, whereas QT dispersion and Tp-e interval (the interval from the peak to the end of T wave) are longer in men. At slow heart rates greater prolongation in QT and increase in transmural repolarization heterogeneity (i.e. increase in Tp-e) may predispose to TdP tachycardias in women. In healthy postmenopausal women, hormone replacement therapy with estrogen alone usually produced a prolongation of QT interval, while estrogen plus progesterone had no significant effects on QT interval but reduced QT dispersion. Along with these, there are still conflicting data reported. Further work is needed before the elucidation of the basis of gender differences in ventricular repolarization. [source] Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic propertiesJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2009Sebastian Polak Abstract The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug,hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC50) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC50 values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high-quality data set for further studies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Proarrhythmia as a Class Effect of Quinolones: Increased Dispersion of Repolarization and Triangulation of Action Potential Predict Torsades de PointesJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2007PETER MILBERG M.D. Background: Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via IKr blockade in an intact heart model of proarrhythmia. Methods and Results: In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 ,M to 1,000 ,M were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP90/50) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. Conclusion: Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP. [source] The Mechanism of Pause-Induced Torsade de Pointes in Long QT SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 9 2005JINQIU LIU M.D. Introduction: Torsade de pointes (TdP), is often preceded by a short-long cycle length sequence. However, the causal relationship between the pause associated with a short-long cycle length sequence and TdP is not completely understood. This study tests the hypothesis that a pause enhances both dispersion of repolarization and EAD formation; however, EADs that form where APD is longest will be less likely to initiate TdP. Methods and Results: We used optical mapping to measure transmural action potentials from the canine left ventricular wedge preparation. D-sotalol and ATX-II were used to mimic LQT2 and LQT3, respectively. The pause significantly enhanced mean APD (from 356 ± 20 to 381 ± 25 msec in LQT2, P < 0.05; from 609 ± 92 to 675 ± 98 msec in LQT3, P < 0.05) and transmural dispersion (from 35 ± 9 to 46 ± 11 msec in LQT2, P < 0.05; from 121 ± 85 to 171 ± 98 msec in LQT3, P < 0.05) compared to steady state pacing. Under LQT3 condition EADs, EAD-induced triggered activity, and TdP were more likely to occur following a pause. Interestingly, the triggered beat following a pause always broke through at the region of maximum local repolarization gradient. Conclusion: These data suggest that a pause accentuates transmural repolarization gradients and facilitates the formation of EADs and EAD-induced triggered activity. In contrast to our hypothesis, the findings of this study support the concept that M-cells (where APD is longest) can play an important role in both the origination of EAD-induced triggered activity and unidirectional block associated with TdP. [source] Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (IKr) ChannelJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2004CHRISTINA DAVIE Ph.D. Introduction: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG IKr channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. Methods and Results: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33,35°C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on IKr (rapidly activating delayed rectifier potassium current), INa (sodium current), and ICa (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 ,M elicited early afterdepolarizations (EADs) but had little affect on ICa or INa. E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 ,M loratadine, desloratadine, and cetirizine had little effect on APD or IKr. Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited ICa at 1 ,M. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35°C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. Conclusion: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel. [source] Drug-Induced Torsades de Pointes and Implications for Drug DevelopmentJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2004Ph.D., ROBERT R. FENICHEL M.D. Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475-495, April 2004) [source] Block of IKs Does Not Induce Early Afterdepolarization Activity but Promotes ,-Adrenergic Agonist-Induced Delayed Afterdepolarization ActivityJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2000ALEXANDER BURASHNTKOV Ph.D. Block of IK Does Not Induce EADs.Introduction: An early afterdepolarization (EAD)-induced triggered heat is thought to precipitate torsade de pointes (TdP) in the long QT syndrome (LQTS). Previous studies demonstrated the development of EAD activity and dispersion of repolarization under LQT2 (reduced IKr) and LQT3 (augmented late INa). but not LQTl (reduced IKs), conditions. The present study examines these electrophysiologic characteristics during IKs block. Methods and Results: Canine epicardial (Epi), M, and endocardial (Endo) tissues and Purkinje fibers isolated from the canine left ventricle were studied using standard microelectrode recording techniques. The IKs blocker chromanol 293B (293B, 30 ,M), produced a homogeneous rate-independent prolongation of action potential duration (APD) in Epi, M, and Endo, but little to no APD prolongation in Purkinje. Chromanol 293B I to 30 ,M failed to induce EADs or delayed afterdepolarizations (DADs) in any of the four tissue types. Isoproterenol (ISO, 0.1 to 1.0 ,M) in the presence of 293B 30 ,M significantly prolonged the APD of the M cell (basic cycle length , sec), abbreviated that of Purkinje, and caused little change in that of Epi and Endo. The combination of 293B 30 ,M and ISO 0.2 ,M did not induce EADs in any of the four tissue types, but produced DAD activity in 4 of 8 Epi, 7 of 10 M cells, and 3 of 8 Endo. Conclusion: Our results indicate that IKs block alone or in combination with ,-adrenergic stimulation does not induce EADs in any of the four canine ventricular tissue types, but that the combination of the two induces DADs as well as accentuated dispersion of repolarization. [source] Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychoticsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2005Vincenzo Calderone The prolongation of the cardiac repolarization process, a result of the blocking of the Human Ether-a-go-go Related Gene potassium channel, is an undesired accessory property shared by many pharmacological classes of non-cardiovascular drugs. Often the delayed cardiac repolarization process can be identified by a prolongation of the QT interval of the electrocardiograph. In these conditions, premature action potentials can trigger a dangerous polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which occasionally can result in lethal ventricular fibrillation. In this work, brief descriptions of the electrophysiological basis of torsade de pointes and of the several pharmacological classes of torsadogenic drugs are given. Attention is focused on antipsychotics, with a deeper overview on the experimental and clinical reports about their torsadogenic properties. [source] Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramideJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2003Erika Hanada ABSTRACT Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10,100 ,m) and erythromycin (100 ,m) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 ,m) and Ito (IC50 = 20.9 + 0.13 ,m) while erythromycin reduced IK (IC50 = 60.1 + 0.29 ,m) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration. [source] Influence of Extracellular K+ Concentrations on Quinidine-induced K+ Current Inhibition in Rat Ventricular MyocytesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2000MICHIKO HIROTA Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (IK), the transient outward current (Ito), and the inward rectifier potassium current (IK1), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on IK, Ito, and IK1 were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both IK and Ito, which were barely influenced by changes in [K+]o, IK1 was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both IK and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 ,M (IK), and 17.6 and 17.3 ,M (Ito). Although higher concentrations of quinidine were required to inhibit IK1, the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types IK, Ito and IK1 is barely influenced by changes in [K+]o. These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect IK or Ito, it can inhibit IK1 and can result in QT prolongation in-vivo. [source] Challenges of Diagnosis of Long-QT Syndrome in ChildrenPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 9 2007EWA MORIC-JANISZEWSKA Ph.D. We describe the clinical and genetic characteristics of the family, in which the diagnosis of LQT1 had been made. The electrocardiogram (ECG) characteristics of this patient indicated the likelihood of LQTS1. Polymorphic ventricular extrasystolies and episodes of polymorphic non-sustained ventricular tachycardia were confirmed by Holter ECG monitoring. On the exertional electrocardiogram polymorphic ventricular tachycardia (torsade de pointes) was recorded. Direct sequencing of both DNA strands revealed the absence of mutations or polymorphisms in the KCNQ1, HERG, and SCN5A genes. [source] Sudden Cardiac Death with Left Main Coronary Artery Occlusion in a Patient Whose Presenting ECG Suggested Brugada SyndromePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 11 2003TADAYOSHI HATA This article describes a patient who died suddenly during Holter ECG monitoring. A ventricular premature systole with an extremely short coupling interval of 240 ms was immediately followed by torsades de pointes, soon degenerating into ventricular fibrillation. Retrospective survey of the patient's medical records revealed an incomplete right bundle branch block (iRBBB) configuration with fluctuating saddle back-type ST elevation in leads V1 and V2, these suggesting Brugada syndrome. Autopsy showed complete thrombotic occlusion of the left main coronary artery. (PACE 2003; 26:2175,2177) [source] New-Onset QT Prolongation and Torsades De Pointes Accompanied by Left Ventricular Dysfunction Secondary to Acute PancreatitisPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2003PIROOZ S. MOFRAD A 70-year-old woman presented with acute pancreatitis and new-onset QT prolongation with subsequent torsades de pointes. Coronary catheterization was performed and was unremarkable. After persistent QT prolongation, despite temporary atrial pacing, a permanent dual chamber cardioverter defibrillator was implanted. In addition to the QT prolongation, significant depression in the left ventricular function was noted. Both resolved once the pancreatitis abated. (PACE 2003; 26:1765,1768) [source] Levofloxacin Induced Polymorphic Ventricular Tachycardia with Normal QT IntervalPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 5 2001BRENDON PALTOO PALTOO, B., et al.: Levofloxacin Induced Polymorphic Ventricular Tachycardia with Normal QT Interval. Polymorphic ventricular tachycardia (PVT) is a form of ventricular tachycardia characterized by QRS complexes that seem to change direction during the tachycardia. If associated with a prolonged QT interval, it is called torsades de pointes. In the absence of a congenital long QT syndrome, torsades is seen with certain drugs such as antiarrythmic agents (Class IA, IC, III), psychotropic medications, antidepressants, antihistamines, and electrolyte disturbances. We report the first case of polymorphic ventricular tachycardia with normal QT interval associated with the oral use of levofloxacin in the absence of other etiologies known to cause these arrhythmias. [source] Pro arrhythmic Effects of Ibutilide in a Canine Model of Pacing Induced CardiomyopathyPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 2 2000MING-HSIUNG HSIEH The authors developed a canine model of pacing induced cardio my apathy to study the possible mechanisms of ibutilide induced torsades de pointes (TP) in heart failure. Thirteen dogs received intravenous ibutilide after acute AV block for 60 minutes, and after implantation of a VVI pacemaker, with a rate of 270 beats/min for 2,3 weeks. Twelve-lead ECG and right and left ventricle monophasic action potentials were recorded at different right ventricle pacing cycle lengths from 600 ms to 1200 ms during the study. The results showed ibutilide could significantly prolong ventricular repolarization and increase the dispersion in a dose dependent and reverse use dependent manner. Furthermore, after ihutilide administration, cardiomyopathic dogs had a greater dispersion of ventricular repolarization, and also had higher incidences of early afterdepolarizations and spontaneous or pacing induced TP than acute AV block dogs. [source] Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndromePEDIATRICS INTERNATIONAL, Issue 2 2006KENJI HOSHINO Abstract Background: Administration of magnesium sulfate (MgSO4) is an effective and safe treatment for torsades de pointes (TdP) associated with acquired long QT syndrome (LQTS) in adults. As for children, there are few reports focusing on it. The authors discuss the efficacy of MgSO4 for TdP in children with congenital and acquired LQTS. The authors also discuss the optimal administration dosage and serum magnesium (SMg) concentration during MgSO4 therapy. Methods: The authors studied seven consecutive LQTS children undergoing MgSO4 therapy for TdP. Of the seven children, five were congenital LQTS and two were acquired LQTS. A bolus injection of MgSO4 was given intravenously over 1,2 min followed by continuous infusion for the next 2,7 days. Results: Of the seven patients, six responded completely to the initial bolus. The bolus dosage was 5.9 ± 3.8 mg/kg (range, 2.3,12 mg/kg) in these six, and the other remaining one (neonate with congenital LQTS) required a total of 30 mg/kg until complete abolishment. The continuous infusion was given at rates of 0.3,1.0 mg/kg per h and patients did not show recurrence of TdP. The SMg concentration was 3.9 ± 1.0 mg/dL (2.9,5.4 mg/dL) immediately after bolus injection. The mean corrected QT (QTc) interval before and after bolus injection did not show significant difference. Conclusion: Intravenous infusion of MgSO4 was effective for TdP in children with LQTS, and MgSO4 abolished TdP without shortening the QTc interval. The optimal bolus dosage, infusion rates and SMg concentration were 3,12 mg/kg, 0.5,1.0 mg/kg per h and 3,5 mg/dL, respectively. [source] Frequency of high-risk use of QT-prolonging medications,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2006Nancy M. Allen LaPointe PharmD Abstract Purpose Prolongation of the QT interval has been associated with increased risk of torsades de pointes and death. Concurrent use of more than one QT-prolonging drug or a QT-prolonging drug with a drug that alters its pharmacokinetic profile is an important risk factor for adverse outcomes. Methods Using a representative sample of 2 million health plan members from 10 health maintenance organizations with pharmacy benefits between January 1999 and July 2001, we identified potential drug interactions involving QT-prolonging medications. Prescription claims overlapping by at least 7 days for either 2 or more QT-prolonging drugs or a QT-prolonging drug with a drug that alters its clearance were considered potential drug interactions. We determined the number of drug interactions overall and the number of these interactions involving patients with other risk factors for torsades de pointes. Results A total of 48,465 potential drug interactions were identified in 10,415 (4.6%) of the 228,550 patients with at least one prescription for a QT-prolonging drug. Amitriptyline was involved in 37,859 (78.1%) of the drug interactions. Of all potential drug interactions, 43,689 (90.1%) occurred in patients with at least one other risk factor for torsades de pointes, and 1053 (2.2%) were listed as a contraindicated combination in product labeling. Conclusion Potential drug interactions involving currently marketed QT-prolonging drugs occurred in 4.6% of patients who had a prescription for a QT-prolonging medication. The findings suggest several areas for targeted interventions to decrease the potential risk from QT-prolonging medications. Copyright © 2005 John Wiley & Sons, Ltd. [source] Recurrent torsades de pointes in association with a very low calorie dietANAESTHESIA, Issue 8 2009E-J. T. Crawford Summary The use of very low calorie diets under medical supervision is becoming increasingly popular in the UK, as the incidence of obesity continues to rise. We report the case of torsades de pointes developing during such a diet. Torsades de pointes has been reported in association with very low calorie diets in the past but to our knowledge, this is the first report since the introduction of newer, nutritionally complete versions of the diet. We review the intensive care management of recurrent torsades de pointes resistant to standard therapy and its relationship to dieting and obesity. [source] Dofetilide-Induced Long QT and Torsades de PointesANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 3 2007Mehmet K. Aktas M.D. Dofetilide, a new class III antiarrhythmic agent, has been approved as an antiarrhythmic agent for the treatment of atrial fibrillation and atrial flutter. Dofetilide selectively inhibits the rapid component of the delayed rectifier potassium current resulting in a prolongation of the effective refractory period. Like other drugs that affect potassium currents, the prolonged QT interval occurring in the patients treated with dofetilide can be complicated by torsades de pointes. We report four cases of dofetilide-induced QT prolongation and torsades de pointes. We discuss the risk factors for the development of dofetilide-induced long QT and torsades de pointes and review the current literature. [source] Differences between Ventricular Repolarization in Men and Women: Description, Mechanism and ImplicationsANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2003Borys Surawicz M.D., M.A.C.C. The purpose of this review article is to discuss the differences between ventricular repolarization in males and females in terms of morphology, possible mechanism, and practical significance. The interest in the subject increased when it became known that in comparison to men, women have a higher incidence of torsade de pointes (tdp) and a greater lengthening of QT-interval after administration of class III antiarrhythmic drugs. Before puberty, the QT intervals and the patterns of ventricular repolarization in boys and girls are similar. At puberty, in boys the QT interval shortens, and a typical male pattern of ventricular repolarization develops. This pattern is characterized by a higher amplitude of the J-point, a shorter and steeper ST segment course, a steeper ascent, and a higher amplitude of the T wave. This pattern is prevalent in >90% of young males. With increasing age the prevalence of the male pattern in males declines gradually and drops to 14% in the oldest age group. The rise and fall of the prevalence of the male pattern appears to parallel the rise and decline of testosterone in males. The female pattern of ventricular repolarization is prevalent in about 80% of females in all age groups. The hormonal effects on ventricular repolarization have been studied in normal and castrated rabbits of both sexes. The available evidence indicates that the females have greater divergence of L calcium current among different layers of the myocardium and a lower density of the repolarizing Kr and Ks currents. The clinical significance of the repolarization differences among genders remains to be determined. Of particular interest is the question whether the males with female pattern are at the same risk of tdp as the females or whether the females with male pattern are at lower risk of tdp than the females with female pattern. [source] Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2006Mireille Canal-Raffin Abstract Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright © 2006 John Wiley & Sons, Ltd. [source] Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8-year periodBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Emanuel Raschi WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Several noncardiovascular drugs with QT liability are currently on the market. , Previous epidemiological studies have shown significant exposure of the general population to drugs with QT liability with similar consumption in many European countries. , Several regulatory measures have concerned medicinal products carrying a pro-arrhythmic risk in humans. WHAT THIS STUDY ADDS , The list of antibacterial agents with documented QT liability has grown over the last few years. , Notwithstanding stringent regulatory measures, population exposure to antibiotics with QT liability is still significant in several countries. , The magnitude of the problem is clearly heterogeneous, with remarkable diversity between Northern and Southern countries (lower and higher exposure, respectively). AIMS (i) To classify antibacterial agents with QT liability on the basis of the available evidence, and (ii) to assess trends in their consumption over an 8-year period (1998,2005) in 14 European countries. METHODS Current published evidence on QT liability of antibiotics was retrieved through MEDLINE search and joined to official warnings from regulatory agencies. Each drug was classified according to an already proposed algorithm based on the strength of evidence: from group A (any evidence) to group E (clinical reports of torsades de pointes and warnings on QT liability). Consumption data were provided by the European Surveillance of Antibacterial Consumption (ESAC) project and were expressed as defined daily doses per 1000 inhabitants per day (DID). RESULTS Among 21 detected compounds, nine [six fluoroquinolones (FQs) and three macrolides (MACs)] belonged to group E. Use of group E drugs ranged from 1.3 (Sweden) to 4.1 DID (Italy) in 1998 and from 1.2 (Sweden) to 6.5 DID (Italy) in 2005. Significant exposure was observed in Italy and Spain (6.5 and 3.8 DID, respectively, in 2005). Only Denmark, Sweden and UK showed a slight decrease in use. Exposure to clarithromycin increased in 10 out of 14 countries, with a marked increment in Italy (3 DID in 2005). CONCLUSIONS Notwithstanding regulatory measures, in 2005 there was still significant exposure to antibacterials with strong evidence of QT liability and, in most countries, it was even increased. This warrants further investigation of appropriateness of use and suggests closer monitoring of group E drugs. Physicians should be aware when prescribing them to susceptible patients. [source] Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest FranceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Mariam Molokhia WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drug-induced long-QT syndrome (LQTS) is a potentially fatal condition that has led to a number of postmarketing withdrawals in recent years. , However, many cases may not survive long enough to reach hospital, and only a small proportion are reported to pharmacovigilance agencies. , The extent to which genetic determinants of susceptibility to LQTS are specific to particular drugs, or common to several classes of drug, remains to be determined. WHAT THIS STUDY ADDS , We estimated population prevalence of drug-induced LQTS in the Midi-Pyrenees region, southwest France, using five different institutions and assessed feasibility of tracing potential cases (in addition to pharmacovigilance data), using hospital data and rigorous case definition. , These methods can be adapted to a wider region, used to augment pharmacovigilance reporting, and offer researchers the opportunity to study genetic susceptibility to drug-induced LQTS. AIMS The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely. [source] Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Ruth Dixon WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes. , Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder. , Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients. WHAT THIS STUDY ADDS , This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines. , The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia's and Bazett's). , The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man. AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic,pharmacodynamic (PK,PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo ,7.48 ms, 90% CI ,10.49, ,4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK,PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50,200 mg b.d.) were not associated with QT prolongation in healthy subjects. [source] Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for IKsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010J Ducroq Introduction:, Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods:, The effects of moxifloxacin (100 µM) and doxorubicin (30 µM), with or without dexrazoxane (from 3 to 30 µM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results:, Moxifloxacin (100 µM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 µM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 µM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications:, Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes. 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 [source] Relevance of anaesthesia for dofetilide-induced torsades de pointes in ,1 -adrenoceptor-stimulated rabbitsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2008D Vincze Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or ,-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in ,1 -adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or ,-chloralose were infused simultaneously with the ,1 -adrenoceptor agonist phenylephrine (15 ,g kg,1 min,1, i.v.) and dofetilide (0.04 mg kg,1 min,1, i.v.). The electrocardiographic QT interval, the Tpeak,Tend interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15,0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with ,-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with ,-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the ,-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared. British Journal of Pharmacology (2008) 153, 75,89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007 [source] | |||||||||||||||||||||||||||||||