Disease relevance of C07753

• Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment [1].
• Sustained polymorphic ventricular tachycardia occurred in 2 of the 64 patients who received ibutilide (3 percent), both of whom had an ejection fraction of 0.20 or less [1].
• Acute renal failure after ibutilide [2].
• Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators [3].
• Ibutilide and the treatment of atrial arrhythmias. A new drug--almost unheralded--is now available to US physicians [4].

Psychiatry related information on C07753

• OBJECTIVE: The primary objective of this piggyback cost-effectiveness analysis of the TIME study was to compare the cost per successful conversion of atrial fibrillation (AF) for ibutilide in the presence and absence of magnesium prophylaxis [5].
• METHODS: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 microg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women) [6].

High impact information on C07753

• MAIN OUTCOME MEASURE: QT interval, recorded from electrocardiogram at timed intervals during and after ibutilide infusion and standardized for variations in heart rate (QTc) [7].
• OBJECTIVES: To determine if the degree of QT prolongation in response to ibutilide varies with the menstrual cycle phase and to compare QT prolongation between women and men [7].
• RESULTS: Maximum (mean [SD]) millisecond increase in QTc after ibutilide infusion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compared with men (46 [16]; P =.002 vs menses and P =.007 vs ovulation) [7].
• BACKGROUND: Ibutilide is a class III drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsade de pointes [8].
• Despite QT-interval prolongation after ibutilide, only 1 episode of torsade de pointes occurred [8].

Chemical compound and disease context of C07753

• Amiodarone had fewer effects on atrial refractory period and conduction velocity than did ibutilide and propafenone, and it terminated atrial flutter in only 4 (33%) of 12 patients [9].
• Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy [8].
• OBJECTIVES: This multicenter study compared the efficacy and safety of ibutilide versus procainamide for conversion of recent-onset atrial flutter or fibrillation [10].
• Flecainide was given over 20 min at a dose of 2 mg/kg body weight (maximum 200 mg), ibutilide was infused at a dose of 1 mg (or 0.01 mg/kg if less than 60 kg) over 10 min, followed by a 10 min observation period and an identical second dose if AF did not convert to sinus rhythm (SR) [11].
• Pure class III antiarrhythmic drugs like d-sotalol, ibutilide and dofetilide show a high rate of torsade de pointes [12].

Biological context of C07753

• BACKGROUND: The selective class III antiarrhythmic agent ibutilide prolongs action potential duration and terminates atrial flutter (AFL) and fibrillation (AF), but the mechanism of its antiarrhythmic efficacy in humans has not been fully characterized [13].
• In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2 mg successfully converted the arrhythmia in 57% of patients [14].
• Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies [15].
• The pharmacokinetics of ibutilide are linear, its extravascular distribution is rapid and extensive, while its systemic clearance is high (elimination half-life 3-6 hours) [16].
• Electrophysiology and pharmacology of ibutilide [16].

Anatomical context of C07753

• However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block IKr but rather increases a slow inward sodium current [17].
• Electrograms and monophasic action potentials from the right atrium in 35 patients with spontaneous, sustained atrial flutter were recorded before, during and after intravenous ibutilide (0.005 to 0.025 mg/kg body weight, n = 25) or placebo (n = 10) [18].
• Monophasic action potential recordings were obtained from right and left ventricular endocardium/epicardium during and after three doses of ibutilide (0. 01, 0.02 and 0.05 mg/kg), at pacing cycle lengths of 300-1000 ms [19].
• Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear [20].
• Electrophysiological effects of ibutilide on the delayed rectifier K(+) current in rabbit sinoatrial and atrioventricular node cells [21].

Associations of C07753 with other chemical compounds

• Incremental pacing was performed to measure the conduction velocity along the isthmus and lateral wall, and extrastimulation was performed to evaluate atrial refractory period in the baseline state and after intravenous infusion of ibutilide, propafenone, and amiodarone [9].
• METHODS AND RESULTS: Right atrial monophasic action potentials were recorded during 148 episodes of AFL (n=89) or AF (n=59) in 136 patients treated with intravenous ibutilide (n=73) or placebo (n=22) as participants in randomized, double-blinded comparative studies or intravenous procainamide (n=53) in a concurrent open-label study [13].
• METHODS: Seventy-one patients with AF (n = 48) or AFL (n = 23), receiving propafenone 300 to 900 mg/day (n = 46) or flecainide 100 to 300 mg/day (n = 25), presented for ibutilide (2.0 mg) cardioversion [22].
• Structural determinants of HERG channel block by clofilium and ibutilide [23].
• Ten minutes after perfusion in the presence of vehicle or ibutilide, hearts were perfused with the ATP-dependent potassium channel opener, pinacidil (1.25 microM) and subjected to a 12-min hypoxic period followed by 40 min of reoxygenation, or until the onset of VF [24].

Gene context of C07753

• Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide.It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low [25].
• This is because ibutilide is not metabolised by CYP3A4 or CYP2D6 [25].
• Ibutilide prolongs MAPD and ERP of human atrium and ventricle without reverse use-dependency [26].
• CAVB biopsies had significantly longer APDs, a larger dispersion of repolarization and showed more EADs in the presence of ibutilide than SR biopsies [27].
• Ibutilide induced slowing of AF was more intense and more rapid in patients who converted to sinus rhythm than in those who did not (25 +/- 5% vs 18 +/- 14% drop in rate, t1/2 3.4 minutes vs 6.3 minutes, P = 0.002) [28].

Analytical, diagnostic and therapeutic context of C07753

• BACKGROUND: Ibutilide is an action potential-prolonging antiarrhythmic currently in clinical trials [17].
• The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter [3].
• This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group [29].
• However, antiarrhythmic doses of MK499 and ibutilide also consistently and significantly increased ventricular relative (+9.9 and +7.6%, respectively) and effective (+10.4 and +9.9%, respectively) refractory periods, rate-corrected ECG QTc (+6.7 and +7.8%, respectively), and paced QT (+7.3 and +8.5%, respectively) intervals [30].
• Safety data were reviewed from several controlled clinical trials of ibutilide, a new class III antiarrhythmic drug recently approved for the acute interruption of atrial fibrillation and flutter [31].

References