ライフサイエンスコーパス: dofetilide

1 re early (<3 days), all of which were TdP on dofetilide.

2 EAG into HERG removed high-affinity block by dofetilide.

3 channel (BEAG) is 100-fold less sensitive to dofetilide.

4 rologously in Xenopus oocytes, is blocked by dofetilide.

5 nt quinidine and by the specific IKr blocker dofetilide.

6 ion with class III antiarrhythmic drugs like dofetilide.

7 centrations of the potassium channel blocker dofetilide.

8 nd like KCR1, ALG10 diminished HERG block by dofetilide.

9 ntial duration and QT prolongation caused by dofetilide.

10 estradiol is not involved in the response to dofetilide.

11 terdepolarizations induced in this region by dofetilide.

12 rrhythmic methanesulfonanilide drugs such as dofetilide.

13 regnant myometrium, the ERG channel blockers dofetilide (1 microM), E4031 (1 microM) and Be-KM1 (100

14 .0-3.5 mmol/L) in the absence or presence of dofetilide (1 mumol/L).

15 h AF who received two identical infusions of dofetilide: 1) before elective direct current cardiovers

16 for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (fo

17 ic-action-potential duration increased after dofetilide (2.3+/-0.2 to 6.3+/-0.7 ms; P<0.0001) but not

18 o Torsade de Pointes (TdP) by class III drug dofetilide, 3, 10, and 30 microg/kg, was compared in 6 c

19 zed multicenter study of one of two doses of dofetilide (4 or 8 micrograms/kg body weight) or placebo

20 P<0.0001), similar to the QT prolongation by dofetilide (511+/-22 to 703+/-45 ms [+38%, P<0.0001]).

21 ith atrial flutter had a greater response to dofetilide (54% conversion rate) than those with atrial

22 We continuously infused dofetilide (6-9 mug/kg bolus+6-9 mug/kg per hour IV infu

23 QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associat

24 Dofetilide, a methanesulfonanilide derivative, is a pote

25 Dofetilide, a new class III antiarrhythmic agent, is mod

26 nd efficacy of a single bolus of intravenous dofetilide, a pure class III antiarrhythmic agent, for t

27 ative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used fo

28 ounds for agents that increase the IC(70) of dofetilide, a well characterized hERG blocker.

29 Dofetilide acts as a slow-onset/slow-offset open channel

30 We hypothesized that chronic dofetilide administration to intact dogs prolongs repola

31 than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration.

32 K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation wer

33 PVT was more common among patients receiving dofetilide, although total VT incidence was similar in t

34 Dofetilide (an IKr blocker) induced early afterdepolariz

35 Acute exposure to dofetilide, an IKr blocker without other recognized elec

36 f hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence.

37 identified in 15/87 (17%) patients receiving dofetilide and 5/87 (6%) patients on placebo (p < 0.05).

38 event was 22 days (range 6 to 107 days) for dofetilide and 99 days (range 34 to 207 days) for placeb

39 Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarization- and

40 There were 15 late events, 10 on dofetilide and five on placebo (p = 0.29).

41 her at 1 year in those patients continued on dofetilide and in those patients who experienced TdP whi

42 did decrease sensitivity to the IKr blockers dofetilide and quinidine 2- to 5-fold.

43 exhibited high-affinity block by cisapride, dofetilide, and MK-499, similar to wild-type channels fo

44 The pharmacology is also similar; dofetilide appears to primarily block activated channels

45 e Kv11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were

46 he increase in APD90 induced by 10(-8) mol/L dofetilide at cycle length=1000 ms was significantly les

47 TdP occurred in patients admitted to reload dofetilide at the same dose as previously tolerated, dos

48 ults indicate that important determinants of dofetilide binding are localized to the pore region of H

49 ound to be negative allosteric modulators of dofetilide binding to the Kv11.1 channel, with LUF7244 s

50 osition HERG 620 may participate directly in dofetilide binding; however, an intact C-type inactivati

51 Using [(3)H]dofetilide-binding assays with membranes of human Kv11.1

52 ]o from 1 to 8 mmol/L increased the IC50 for dofetilide block from 2.7 +/- 0.9 to 79 +/- 32 nmol/L an

53 t hydrophobic interactions are essential for dofetilide block in hIRK.

54 localization of a site that is critical for dofetilide block in hIRK.

55 A similar mechanism may explain dofetilide block in other ion channels, including IKr.

56 Verapamil antagonized dofetilide block of HERG channels, which suggests that t

57 Dofetilide block was slow and greatly attenuated at posi

58 To identify the molecular determinants for dofetilide block, we first engineered chimeras between H

59 Molecular models suggest that oestrogen and dofetilide blockade can concur simultaneously in the hER

60 Dofetilide blocked the triply mutated bEAG T432S/A443S/A

61 diol levels were unrelated to the effects of dofetilide, but as testosterone levels increased, the do

62 IRKs, with ROMK1-M2 increased unblocking of dofetilide by 10-20-fold in hIRK.

63 cessary to transform low-affinity binding of dofetilide by the related bovine ether a-go-go channel b

64 Intravenous dofetilide can convert sustained atrial fibrillation or

65 rtality was higher in patients who continued dofetilide compared with those who discontinued use (haz

66 1 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the

67 At 10(-)(6) mol/L dofetilide (cycle length=1 second), the incidence of ear

68 During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms v

69 The I(Kr)-specific blockers, E-4031 and dofetilide, do not inhibit KvLQT1, whereas clofilium, a

70 occurred in 2 patients admitted to increase dofetilide dosage (0% versus 6.7%; P=0.050).

71 Dofetilide dose adjustment or discontinuation was requir

72 rhythmic methanesulfonanilide drugs, such as dofetilide, E4031, and MK-499, at submicromolar concentr

73 e, but as testosterone levels increased, the dofetilide effect to increase APD diminished, as did ear

74 Dofetilide effectively terminated the arrhythmia in 31%

75 Increased INa-L contributes to chronic dofetilide effects in vivo.

76 Acute and chronic dofetilide effects on action potential duration (APD) we

77 linositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem ce

78 cohort of 1404 patients initially loaded on dofetilide for atrial fibrillation suppression at the Cl

79 d Drug Administration is expected to approve dofetilide for clinical use soon, and it is currently re

80 VU0405601 increased the IC(50) of dofetilide from 38.7 to 76.3 nM.

81 Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsi

82 Dofetilide has been approved for the conversion and main

83 ed at >>+20 mV, and were highly sensitive to dofetilide (IC50 of 46.9 nM).

84 study determined the efficacy and safety of dofetilide in converting atrial fibrillation (AF) or atr

85 and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricula

86 benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.

87 rrhythmic HERG blockers (sotalol, quinidine, dofetilide) in both cardiac and noncardiac cell lines.

88 Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interf

89 RP 58866 < or = 1 mumol/L and dofetilide increased AP duration symmetrically, consiste

90 nt was blocked by the IKr-specific inhibitor dofetilide, indicating that it represented recovery from

91 y protect normal females against the risk of dofetilide-induced arrhythmia.

92 rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretre

93 either block a specific ionic current (e.g., dofetilide-induced blockade of the rapidly activating co

94 SEA-0400 stabilized dofetilide-induced lability of repolarization and suppre

95 rowth factor-beta treatment also rescued the dofetilide-induced phenotype toward normal.

96 Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block

97 on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently.

98 and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP),

99 Dofetilide infusion during >/=210 minutes inhibited Akt

100 In four patients (group I), the SR dofetilide infusion was terminated early because QT prol

101 ding was compared with patients admitted for dofetilide initial loading.

102 Dofetilide is a highly selective blocker of the rapid co

103 he extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardiov

104 Although dofetilide is widely used in the United States for rhyth

105 Although dofetilide labeling states that the drug must be initiat

106 Dofetilide loading has a low but finite risk of TdP and

107 Dofetilide loading was stopped for 105 patients (7.5%) b

108 Dofetilide monotonically increased QTc and APD throughou

109 ndomized ICD patients to placebo (n = 87) or dofetilide (n = 87).

110 ere randomized to 125, 250, or 500 microgram dofetilide or placebo twice daily.

111 ing effects of a hormone and a hERG blocker, dofetilide, or hERG mutations.

112 This pattern suggested that dofetilide preferentially blocks open (or activated) cha

113 Low concentrations of dofetilide produced block of bEAG T432S/A443S; unlike HE

114 In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) a

115 The I(Kr) blocker dofetilide prolonged APD in female and ORCH more than in

116 c (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by incr

117 idence was strong for ibutilide, flecainide, dofetilide, propafenone, amiodarone, and quinidine.

118 Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo.

119 lained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81;

120 METHODS AND Patients admitted for dofetilide reloading for atrial arrhythmias were retrosp

121 Of 138 patients admitted for dofetilide reloading for atrial arrhythmias, 102 were re

122 presence of trained personnel, the risks of dofetilide reloading justifying repeat hospitalization h

123 The incidence of TdP in dofetilide reloading was compared with patients admitted

124 and support the need for hospitalization for dofetilide reloading.

125 n AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible.

126 D generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intr

127 , 0.37, 0.58 for 125, 250, and 500 microgram dofetilide, respectively, and 0.25 for placebo (500 micr

128 for KCR1-mediated glycosylation because the dofetilide response of glycosylation-deficient HERG(N598

129 Dofetilide resulted in cycle length--dependent and dose-

130 The most sensitive K+ channel target for dofetilide seems to be IKr, the rapid component of the r

131 nary-perfused canine hearts, the addition of dofetilide (selective IKr blocker) to pilsicainide (sele

132 Moreover, dofetilide-sensitive K(+) currents with distinctive 'hoo

133 ult is supported by in vitro studies of HERG dofetilide sensitivity by using coexpression of HERG wit

134 Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback

135 ock animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 d

136 ization delay as the selective I(Kr) blocker dofetilide, the combined ion-channel blocker AZD1305 ind

137 At 10(-6) mol/L dofetilide, the incidence of early afterdepolarizations

138 uggest that in ICD patients either long-term dofetilide therapy is associated with an increased risk

139 decreased sensitivity to the I(Kr) inhibitor dofetilide, these changes could not be correlated with d

140 evating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolar

141 Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased

142 qual to values previously reported by us for dofetilide-treated normal males.

143 Both in vivo and in vitro, dofetilide treatment, over a narrow window of time, enti

144 0 for the methanesulfonanilide I(Kr) blocker dofetilide was 12 +/- 2 nM.

145 to 3 S631A subunits, whereas the potency of dofetilide was a graded function of the number of S631A

146 Specific binding of [3H]dofetilide was saturable and fit a one-site binding isot

147 atives of the class III antiarrhythmic agent dofetilide was synthesized and assessed for hERG affinit

148 In all dogs, the selective I(Kr) blocker dofetilide was used to examine susceptibility to acquire

149 ersion rates for 125, 250, and 500 microgram dofetilide were 6.1%, 9.8%, and 29.9%, respectively, ver

150 rcent of pharmacological cardioversions with dofetilide were achieved in 24 hours and 91% in 36 hours

151 "Early after-depolarizations" induced by dofetilide were also completely eliminated by 3 microM P

152 creased the affinity of BEAG K+ channels for dofetilide, whereas C-type inactivation could not be rec

153 d by external quaternary ammonium cations or dofetilide, which approached the hERG selectivity filter

154 s was confirmed by specific I(Kr) block with dofetilide, which prolonged AP significantly more in LVH

155 protein and not to the direct interaction of dofetilide with the respective mutated site chains.

156 blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L.