Disease relevance of Tikosyn

• Dofetilide for atrial fibrillation [1].
• Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group [2].
• There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group [2].
• CONCLUSIONS: In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure [2].
• There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group [3].

Psychiatry related information on Tikosyn

• In dofetilide-treated patients, a baseline QTc interval <429 ms was associated with a significant risk reduction (risk ratio 0.4, 95% CI 0.3 to 0.8) [4].

High impact information on Tikosyn

• INTERPRETATION: In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not affect all-cause mortality, cardiac mortality, or total arrhythmic deaths [3].
• Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial [3].
• This clinical result is supported by in vitro studies of HERG dofetilide sensitivity by using coexpression of HERG with wild-type and I447V KCR1 cDNAs [5].
• Electrophysiological effects of dofetilide in an in vitro model of "border zone" between normal and ischemic/reperfused myocardium [6].
• BACKGROUND: To evaluate both class III activity and antiarrhythmic action of dofetilide at the level of the "border zone," we investigated its electrophysiological effects on guinea pig ventricular strips submitted partly to normoxia (normal zone, NZ) and partly to simulated severe ischemia, then reperfusion (altered zone, AZ) [6].

Chemical compound and disease context of Tikosyn

• AIMS: This study compared the efficacy and safety of intravenous dofetilide with amiodarone and placebo in converting atrial fibrillation or flutter to sinus rhythm [7].
• This study evaluates the effects of the class IC antiarrhythmic drug flecainide, and of dofetilide, a new class III drug, on conversion rate and flutter cycle length in patients with atrial flutter [8].
• Further, RSD1235's ability to reverse the pro-arrhythmic actions of the class III agents dofetilide and clofilium was assessed in isolated Purkinje fibers and an in vivo model of torsades de pointes (TdP) [9].
• Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 microM dofetilide (n = 6) or with 100 microM glibenclamide (a blocker of ATP sensitive K+ channels, n = 6), or not pretreated (n = 6) [10].
• Torsade de pointes ventricular tachycardia was reported in up to 3.3% of patients who received oral dofetilide in the DIAMOND (Diamond Investigations of Arrhythmia and Mortality on Dofetilide) studies, although only a small proportion of patients in these studies had atrial fibrillation; most episodes occurred within the first 3 days [11].

Biological context of Tikosyn

• Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans [12].
• The activating currents displayed inward rectification and deactivating current tails were voltage-dependent, saturated at >>+20 mV, and were highly sensitive to dofetilide (IC50 of 46.9 nM) [13].
• To assess physiological significance, dofetilide-sensitive currents were recorded during application of simulated action potential clamps [14].
• OBJECTIVES: To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and QTc prolongation on the surface electrocardiogram after oral and intravenous administration [15].
• This pattern suggested that dofetilide preferentially blocks open (or activated) channels and that the fast inactivation may competitively slow the binding kinetics [16].

Anatomical context of Tikosyn

• METHODS AND RESULTS: In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial tumor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical IKr is the major delayed rectifier and can be readily recorded in isolation from other currents [17].
• Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker [18].
• Using constructs heterologously expressed in Xenopus oocytes, we found that transplantation of the S5-S6 linker from BEAG into HERG removed high-affinity block by dofetilide [19].
• Effect of dofetilide on cardiac repolarization in patients with ventricular tachycardia. A study using simultaneous monophasic action potential recordings from two sites in the right ventricle [20].
• High affinity open channel block by dofetilide of HERG expressed in a human cell line [16].

Associations of Tikosyn with other chemical compounds

• Elevating [K+]o from 1 to 8 mmol/L increased the IC50 for dofetilide block from 2.7 +/- 0.9 to 79 +/- 32 nmol/L and for quinidine block from 0.4 +/- 0.1 to 3.8 +/- 1.2 mumol/L [21].
• Thus, the serine in position HERG 620 may participate directly in dofetilide binding; however, an intact C-type inactivation process seems to be crucial for high-affinity drug binding [19].
• HERG/I(Kr) channels are blocked selectively by class III antiarrhythmic methanesulfonanilide drugs such as dofetilide [22].
• Corresponding baseline recording periods, Ch and C1, matched by time with Dh and D1 were selected from the control ECG recording in the absence of dofetilide [23].
• Recent data show that maintenance of sinus rhythm after successful cardioversion is enhanced by the use of class III drugs including amiodarone and dofetilide [24].

Gene context of Tikosyn

• Dofetilide did not significantly inhibit CYP2C9, CYP2D6, or CYP3A4 at concentrations up to 100 microM in vitro [25].
• Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively [26].
• The MERG B current was blocked by the selective IKr blocker, dofetilide, with an IC50 of 54 nmol/L [27].
• We developed a cellular model in which ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively [28].
• Here we show that hIRK, a member of the two-transmembrane-segment family of inward K+ rectifiers that we have cloned from human heart, is a target for dofetilide. hIRK currents, expressed heterologously in Xenopus oocytes, are blocked by dofetilide at submicromolar concentrations (IC50 = 533 nmol/L at 40 mV and 20 degrees C) [29].

Analytical, diagnostic and therapeutic context of Tikosyn

• Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89) [2].
• We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study [2].
• During reperfusion, dofetilide at 5, 10, and 50 nmol/L exhibited concentration-dependent class III effects, as it did in the NZ, and did not modify the incidence of spontaneous arrhythmias [6].
• METHODS AND RESULTS: Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study [12].
• To identify the molecular determinants for dofetilide block, we first engineered chimeras between HERG and BEAG and then used site-directed mutagenesis to localize single amino acid residues responsible for block [19].

References