Disease relevance of Torsades de Pointes

• Polymorphic ventricular tachycardia (Torsade de Pointes) associated with the use of probucol [1].
• CONTEXT: Erythromycin is a widely used antibiotic that infrequently causes QT-prolongation and torsades de pointes cardiac arrhythmias [2].
• Long QT syndrome and torsade de pointes in a patient receiving fluconazole [3].
• CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine [4].
• Proarrhythmia occurred in three patients: one had torsade de pointes that disappeared when amiodarone administration was stopped; two with severe anatomic heart disease died suddenly during the loading period (one with atrial flutter and one with ventricular tachycardia) [5].

High impact information on Torsades de Pointes

• There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group [6].
• These data indicate that HERG is LQT2 and suggest a likely cellular mechanism for torsade de pointes [7].
• OBJECTIVES AND METHODS--To gain insight into possible mechanisms of and predisposing factors for torsades de pointes during terfenadine therapy, spontaneous reports in the US Food and Drug Administration's Spontaneous Reporting System database were examined [8].
• When cases of torsades de pointes were analyzed by individual drug, observed female prevalence was always greater than expected, representing a statistically significant difference (P < .05) for all agents except procainamide [9].
• This report describes the first association (exclusive of drug overdose) of symptomatic torsades de pointes occurring with the use of terfenadine in a patient who was taking the recommended prescribed dose of this drug in addition to cefaclor, ketoconazole, and medroxyprogesterone [10].

Chemical compound and disease context of Torsades de Pointes

• Torsades de pointes occurring in association with terfenadine use [11].
• Thioridazine-induced torsade de pointes. Successful therapy with isoproterenol [12].
• This report describes a case of thioridazine-induced torsade de pointes that was successfully managed with isoproterenol infusion after therapy with other agents was unsuccessful [12].
• Astemizole-induced torsade de pointes [13].
• Torsade de pointes with prenylamine: do we still need the drug [14]?

Biological context of Torsades de Pointes

• The data show a clear congruity between the conditions that predispose to torsade de pointes in the clinic and the conditions under which quinidine may induce triggered activity and marked action potential prolongation in isolated Purkinje fibers.(ABSTRACT TRUNCATED AT 400 WORDS)[15]
• Sex difference in risk of torsade de pointes with d,l-sotalol [16].
• Bepridil-induced prolongation of QT increased at slow heart rates, which could explain the greater incidence of torsades de pointes in bradycardia [17].
• METHODS: Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes [18].
• Both terfenadine and astemizole may have cardiotoxic effects (e.g., torsades de pointes) when serum concentrations rise due to overdosing or drug interactions [19].

Anatomical context of Torsades de Pointes

• Endocardial monophasic APD of left and right ventricle was measured and susceptibility to torsade de pointes was tested by infusing Dofetilide (0.025 mg/kg/5') [20].
• An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes [21].
• It has been demonstrated that quinidine, which also prolongs QT interval and induces torsade de pointes, produces early afterdepolarizations and triggered activity in canine Purkinje fibers driven at slow rates [22].
• QT prolongation and torsades de pointes have been documented in patients administered cisapride and its blocking of potassium channels in myocytes has been suggested as the mechanism [23].

Gene context of Torsades de Pointes

• Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia [24].
• BACKGROUND: The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride [25].
• It is concluded that modulation of this important K+ current is not the mechanism by which intravenous magnesium terminates drug-induced LQT and torsades de pointes [26].
• In most cases, the patients had preexisting risk factors for torsade de pointes and/or were receiving other medications known to inhibit the hepatic CYP3A4 enzyme system and the metabolism of cisapride [27].
• We propose that an increase in cardiac calcium current and reduced trafficking of hERG channels to the cell surface cause QT prolongation and torsade de pointes in patients treated with As(2)O(3) [28].

Analytical, diagnostic and therapeutic context of Torsades de Pointes

• METHODS: Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. D,L-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations [29].
• CONCLUSION: The accelerated titration regimen for sotalol can shorten the time to attain the dosage usually required to effectively control arrhythmias, without excessive QT prolongation and the associated increased risk of torsades de pointes [30].
• Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the 'QT interval' of the electrocardiogram (ECG), torsades de pointes and sudden death [31].
• Both in the animal model and in humans, treatment with magnesium, isoproterenol, or pacing, all of which suppress EADs, will also suppress torsade de pointes [32].
• Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion [21].

References