ライフサイエンスコーパス: dofetilide

1 estradiol is not involved in the response to dofetilide.

2 terdepolarizations induced in this region by dofetilide.

3 rrhythmic methanesulfonanilide drugs such as dofetilide.

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

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

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

7 At 1 year, 43% remained on dofetilide.

8 rologously in Xenopus oocytes, is blocked by dofetilide.

9 nt quinidine and by the specific IKr blocker dofetilide.

10 rescribed AAD for AF followed by sotalol and dofetilide.

11 ed block but not by the common hERG1 blocker dofetilide.

12 il) as well as the arrhythmogenic effects of dofetilide.

13 ion with class III antiarrhythmic drugs like dofetilide.

14 centrations of the potassium channel blocker dofetilide.

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

16 ntial duration and QT prolongation caused by dofetilide.

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

18 creased I(Kv) (11.1) despite the presence of dofetilide (1 muM) in WT K(v)11.1 cells.

19 tment (24-48 hour) with LUF7244 (10 muM) and dofetilide (1 muM) increased I(Kv11.1) compared with non

20 entration (20 mumol/L) or supplementing with dofetilide (1 mumol/L) failed to convert PsAF to sinus r

21 .0-3.5 mmol/L) in the absence or presence of dofetilide (1 mumol/L).

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

23 trafficking defective G601S-K(v)11.1 cells, dofetilide (10 muM) or dofetilide + LUF7244 (10 + 5 muM)

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

25 Sotalol (23.2%) and dofetilide (19.2%) were each more commonly prescribed th

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

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

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

29 s was rescued by 10 muM dofetilide or 10 muM dofetilide + 5 muM LUF7244.

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

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

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

33 e-concordant AAD use by drug was as follows: dofetilide 93%, sotalol 66%, flecainide 68%, propafenone

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

35 Dofetilide, a methanesulfonanilide derivative, is a pote

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

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

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

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

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

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

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

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

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

45 Dofetilide (an IKr blocker) induced early afterdepolariz

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

47 Treatment of PAH rats with dofetilide, an Kv11.1 channel blocker approved by the US

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

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

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

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

52 heir modulation by temperature, pentamidine, dofetilide and extracellular K(+) .

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

54 polarizing potassium current (I(Kr)) blocker dofetilide and I(Na-L) and I(Kr) at baseline.

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

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

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

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

59 Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically signifi

60 erter defibrillator candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF

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

62 Dofetilide at a concentration of 2 nM increased signific

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

64 n I(Kr) was reduced by the selective blocker dofetilide at IC(50) concentrations, but not when equiva

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

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

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

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

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

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

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

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

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

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

75 for drugs and currents (e.g., 10.4-fold for dofetilide block of hERG current and 4-fold for mexileti

76 Dofetilide block was slow and greatly attenuated at posi

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

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

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

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

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

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

83 Intravenous dofetilide can convert sustained atrial fibrillation or

84 Dofetilide challenge prolonged APD at much lower concent

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

86 1 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the

87 Supraphysiological dofetilide concentrations substantially increased K(v) 1

88 eric modulator/activator in combination with dofetilide corrected both congenital and acquired K(v)11

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

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

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

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

93 Dofetilide dose adjustment or discontinuation was requir

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

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

96 Dofetilide effectively terminated the arrhythmia in 31%

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

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

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

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

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

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

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

104 Dofetilide has been approved for the conversion and main

105 We tested in silico five drugs (astemizole, dofetilide, ibutilide, bepridil, and diltiazem) and comp

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

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

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

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

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

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

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

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

114 a concentration of 1 nM exaggerated further dofetilide-induced APD90 prolongation (696 9 ms, n=81, P

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

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

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

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

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

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

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

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

123 Dofetilide infusion during >/=210 minutes inhibited Akt

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

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

126 Dofetilide is a highly selective blocker of the rapid co

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

128 Dofetilide is one of the only anti-arrhythmic agents app

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

130 Although dofetilide labeling states that the drug must be initiat

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

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

133 itoring performance was assessed in a public dofetilide-loading data set with serial ECGs.

134 G601S-K(v)11.1 cells, dofetilide (10 muM) or dofetilide + LUF7244 (10 + 5 muM) also restored K(v)11.1

135 During continuous dofetilide monitoring, predictions correlated with groun

136 Dofetilide monotonically increased QTc and APD throughou

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

138 The effect of dofetilide on APD90 (616 54 ms, n=7 versus 526 54 ms, n=

139 of WT K(v)11.1 levels was rescued by 10 muM dofetilide or 10 muM dofetilide + 5 muM LUF7244.

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

141 In a real-world cohort of outpatients on dofetilide or sotalol presenting to the hospital or emer

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

143 We conclude that dofetilide plus LUF7244 rescues K(v)11.1 trafficking and

144 imed to test the ability of a combination of dofetilide plus LUF7244, a K(v)11.1 allosteric modulator

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

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

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

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

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

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

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

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

153 The protective effect of dofetilide raises the possibility of repurposing this an

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

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

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

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

158 and support the need for hospitalization for dofetilide reloading.

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

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

161 Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward traff

162 , 0.37, 0.58 for 125, 250, and 500 microgram dofetilide, respectively, and 0.25 for placebo (500 micr

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

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

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

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

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

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

169 seline APD but increased I(Kr) and increased dofetilide sensitivity.

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

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

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

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

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

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

176 physiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating a

177 rature, extracellular K(+) concentration and dofetilide through opposing acute (millisecond) effects

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

179 Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased

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

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

182 0 for the methanesulfonanilide I(Kr) blocker dofetilide was 12 +/- 2 nM.

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

184 Dofetilide was discontinued before hospital discharge in

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

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

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

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

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

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

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

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

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

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

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