"It should be mentioned that cisapride, dofetilide, and sotalol directly inhibit hERG channel activity whereas quinidine decreases the surface expression of hERG channels by suppressing hERG channel translocation to cell membrane surface XREF_BIBR."
"In addition to vanoxerine we profiled one non torsadogenic MICE comparator verapamil, one torsadogenic MICE comparator bepridil and the selective hERG blocker dofetilide."
"We identified a lower than reported EC 50 for the hERG blocker dofetilide, and sotalol (Peng, Lacerda, Kirsch, Brown, & Bruening-Wright) as well as for the Na + channel blocker flecainide."
"Protocol 2 was applied and these cells showed no peak in their inward current, i.e. no HERG currents (n = 3); dofetilide blocks HERG current immediately when applied to the inside of the cell and when HERG channels have been opened by holding the cell at 0 mV.In a second group of SHSY5Y cells, -50 mV was applied to the patch pipette before and during the establishment of the whole-cell recording configuration and cells were subsequently held at -60 mV."
"IC 50 variability (25/75 percentiles) differed for drugs and currents (e.g., 10.4-fold for dofetilide block of hERG current and 4-fold for mexiletine block of hNav1.5 current)."
"HERG channel inhibition by dofetilide and its derivatives."
"However, it is not yet proven whether dofetilide (blocker of the HERG like current) affects hypoxia induced depolarization and [Ca 2+] c."
"Of note, the similar levels of hERG potassium channel block induced by 2-3 nM dofetilide and 6.9 muM ranolazine (approximately 52%) induced> 200 ms of APDc and FPDc prolongation and multiple arrhythmic events in dofetilide treated cells, but only APDc and FPDc prolongation (< 150 ms) without arrhythmias in ranolazine treated cells."
"Dofetilide, cisapride, sotalol, terfenadine and verapamil blocked hERG channels at 37degreesC with an IC50 of 7nM, 18nM, 343muM, 165nM and 214nM, respectively."
"Verapamil antagonized dofetilide block of HERG channels, which suggests that they may share a common binding site."
"Thus, time series images were acquired for 20 s at 33 Hz to provide improved signal to noise as well as recording duration, and coupled with an automated image analysis to determine the effect of the hERG blockers dofetilide, E-4031 and sotalol."
"Many of the hERG blockers including dofetilide contain an ionizable basic aliphatic amine."
"Neither verapamil nor dofetilide inhibited trafficking of wild type hERG."
"Novel High-Throughput Quantitation of Potent hERG Blocker Dofetilide in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry : Application in a Phase 1 ECG Biomarker Validation Study."
"This conclusion agrees with the experimental finding that application of the hERG antagonist dofetilide initiates prolonged depolarisations [XREF_BIBR]."
"Acidification markedly potentiated dofetilide blockade of the HERG channels but weakened the inhibitory effects of quinidine and azimilide."
"A second, selective hERG antagonist Dofetilide [XREF_BIBR] (at 1muM) produced similar bradycardia in hearts from wt flies, also characterized by significantly prolonged diastolic intervals and not observed in sei mutants (XREF_FIG)."
"HERG channel inhibition by dofetilide and derivatives was studied in HEK293 cell lines stably expressing hERG channels using an automated planar patch system (see Methods)."
"15 This effect was inhibited by the hERG1 blocker dofetilide."
"Amiodarone, azimilide, dofetilide, quinidine and sotalol all produced a dose dependent inhibition of HERG current."
"This contrasts with other hERG blockers, such as dofetilide, that do not prevent the channel from closing and therefore remain bound when the membrane is polarized."
"All of the selected compounds, at both 10 and 50muM, significantly increased the dissociation of [3 H] dofetilide from the channel by 29-84% (XREF_SUPPLEMENTARY) implying their negative allosteric modulation of the channel inhibition by hERG blockers like dofetilide."
"In a study on dofetilide induced hERG blockade, it was reported that a blockade of 10% was associated with a 20-ms [95% confidence interval (CI) 12-32] increase in QT interval [XREF_BIBR]."
"Dofetilide and cisapride acutely inhibit hERG current."
"Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches, HERG currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L."
"When expressed heterologously, the HERG channel, like cardiac I Kr current, is inhibited by the methanesulfonanilide drugs, E-4031 and dofetilide."
"Application of 10muM dofetilide for 10min caused complete inhibition of both the chimaera and the hERG channel (XREF_FIG)."
"Dofetilide (n = 7), which inhibited hERG current with an IC 50 of 29nM, concentration-dependently prolonged APD in isolated Purkinje fibres, increased triangulation of the action potential and elicited early after-depolarizations starting at a concentration of 0.01 muM."
"Dofetilide, a class III anti-arrhythmic drug is a potent blocker of hERG and is widely used to distinguish hERG currents from other currents XREF_BIBR XREF_BIBR."
"These properties are compared with four known HERG channel blockers including verapamil, cisapride, ketoconazole and dofetilide in the XREF_TABLE."
"Both DC031050 and dofetilide potently inhibited hERG currents with IC (50) values of 2.3 +/- 1.0 and 17.9 +/- 1.2 nmol/L, respectively."
"While nonclinical studies have suggested that late sodium current block can reduce dispersion of repolarization from hERG block, we observed that ranolazine still had a dose dependent relationship with T wave morphology, in some cases having greater T wave morphology changes at equivalent amounts of QTc prolongation compa red with the pure hERG blocker dofetilide."
"Drugs illustrating this could include verapamil (hERG + calcium block), ranolazine (hERG + late sodium block), and some of the human immunodeficiency virus (HIV) protease inhibitors such as lopinavir and ritonavir, which block hERG, late sodium, and calcium.19 Amiodarone and its metabolite cause potent hERG block and QTc prolongation, often> 60-90 ms; however, it has been associated with a low risk of TdP despite its profound effects on repolarization, probably because it also blocks both late sodium and calcium currents.19 Thus, late sodium and calcium block shorten the action potential duration of ventricular cells20 (and QTc13, 14, 15); and, in the presence of QTc prolongation, blockage of these inward currents can prevent the initiation of TdP.21 Other evidence of the importance of late sodium current block in preventing TdP comes from a canine model of TdP, where coadministration of mexiletine, a late sodium current blocker, reduced QTc prolongation and the number of TdP events associated with sotalol, a predominant hERG blocker.16 In addition, previous clinical studies have demonstrated that mexiletine can mitigate QTc prolongation caused by the strong hERG blocker quinidine.13, 14, 15 This has been confirmed in recent clinical studies demonstrating that late sodium current blockers (mexiletine, lidocaine) can reduce drug induced QTc prolongation caused by the selective hERG blocker dofetilide,22 and also that mexiletine can mitigate recurrent TdP caused by the acquired long QT syndrome.18 Because there is now a comprehensive understanding of the ionic currents that play a role in QTc prolongation and the development of TdP, the CiPA initiative proposes a new mechanistic, model informed approach to cardiac safety assessment of new drugs."
"Under this paradigm, it will be important to differentiate QTc prolonging drugs with balanced ion channel effects, such as ranolazine (i.e. hERG potassium channel and late sodium current block), that are not associated with torsade from selective hERG potassium channel blockers, such as dofetilide, that are associated with torsade."
"Our data demonstrates that hERG blockers such as dofetilide and further high risk categorized compounds prolong the field potential duration."
"Our results confirm that in SHSY5Y cells dofetilide is unable to block HERG when the channels are closed."
"For dofetilide the selective block of hERG accounts for the proarrhythmia markers we observed experimentally and in simulations and by extension the drug 's torsadogenicity."
"For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments."
"In contrast, dofetilide blocked HERG currents in a voltage- and time independent manner under the steady state because of very slow unblocking at negative potentials, which also caused frequency independent block."
"In order to test the hypothesis that determinants of hERG activators might interact with hERG blockers, we mutated F557 and analysed the inhibition of potassium currents through mutant F557L by six " gold standard " hERG blockers dofetilide, haloperidol, terfenadine, astemizole, cisapride and amiodarone."
"The HERG like current was blocked by dofetilide (DOF) in a concentration dependent manner (IC (50) = 13 +/- 4 nM, mean +/- SE) and high concentrations of Ba (2+) (1 and 10 mM)."
"Model studies reproduced this feature in studies of hERG blockers such as dofetilide, KN-93 and other common high-affinity blockers (Durdagi etal."
"Dofetilide (0.3 microM) inhibited HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively."
"This latter point was subsequently confirmed through PK/pharmacodynamic modeling with the selective hERG blocker dofetilide."
"With the use of inside-out macropatches from oocytes, however, higher affinity dofetilide block of HERG current has been obtained (IC 50 35 nM, Kiehn et al., 1996)."
"Dofetilide, a class III antiarrhythmic drug with high potency and specificity for I Kr [5], inhibited HERG current with an IC 50 value of 1.53 x10 -8 mol/l."
"These results confirm that dofetilide can not block HERG channels while they are held closed at -60 mV."
"Imipramine a known Eag blocker induces apoptosis in acute myeloid leukaemia cells via the caspase-3 activation [XREF_BIBR] while it has been shown that HERG expressing cells are more sensitive to apoptosis induced by hydrogen peroxide, with reversal of effect on blocking with a HERG blocker dofetilide [XREF_BIBR]."
"Dofetilide blocked hERG current with an IC 50 of 29nM."
"XREF_FIG shows that dofetilide inhibited hERG current with an IC 50 of 29nm, markedly prolonged APD in isolated Purkinje fibres and largely prolonged APD and QT and elicited TdP in isolated hearts (XREF_FIG)."
"Cells prepared from normal cultures and following cryopreservation were compared with regard to time course of Rb+ efflux response at different concentrations of KCl, overall cell morphology, signal-to noise assay window, assay robustness, and 50% inhibitory concentration (IC50) of the hERG blocker dofetilide."
"In one simulation study, only a 10% hERG blockade by dofetilide corresponded to a QT prolongation of 20ms [95% confidence interval (CI) : 12-32ms] (Jonker et al., 2005)."
"We recently developed a detailed kinetically based model of the hERG blocker dofetilide by extending the consensus five-state Markov chain model that includes three closed states (C 3, C 2 and C 1), a conducting open state and (O) an inactivation state (I) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."
"This was measured by radioligand binding assays using the H-3 labeled class III antiarrhythmic drug and potent hERG blocker dofetilide together with HEK-293 cell membranes."
"Dofetilide completely blocked the HERG current, leaving only a small plateau current and caused a significant reduction in peak current (control =-737+/-107 pA; after dofetilide =-163+/-43 pA, mean +/-SEM (n = 3); P < 0.05)."
"Though majority of highly potent hERG blockers including dofetilide, astemizole, terfenadine, and cisapride, show from 2 to 70-fold higher affinity for the inactivated state than to the open conformational state of the channel."