Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

Tabo, Mitsuyasu; Nakamura, Mikiko; Kimura, Kazuya; S, Itó

doi:10.2131/jts.31.381

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…On the other hand, dl-sotalol has very weak hERG inhibitory potential with an IC 50 value of 278 μM (Kirsch et al, 2004), but apparently caused QTc interval prolongation at the free plasma concentration of 4.99 μM in common marmosets. dl-Sotalol also prolonged QTc intervals at a free plasma concentration of 7.2 μM in anesthetized dogs (Schnelle and Garrett, 1973;Tabo et al, 2006) and 5.3 μM in humans (Carr et al, 1995;Kimura et al, 1996). The reason why dl-sotalol shows such weak hERG blockade even though it prolongs QT interval via the I K blockade (Antonaccio and Gomoll, 1993) is unclear, but it is considered that the QT-prolonging effect of dl-sotalol might be caused, at least partially, through a mechanism other than direct hERG inhibition.…”

Section: Discussionmentioning

confidence: 99%

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

et al. 2008

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-Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.

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Section: Discussionmentioning

confidence: 99%

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

et al. 2008

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“…The following QT interval corrections (QTc) were applied: (QTc Bazett : QT/RR 0.5 ), Fridericia (QTc Fridericia : QT/RR 0.33 ), Tabo (QTc Tabo : QT/RR 0.3879 ), Van de Water (QTc Van de Water : QT −0.087 [RR −1]) (18), and Framingham (QTc Framingham : QT +0.154 [1 − RR]).…”

Section: Methodsmentioning

confidence: 99%

Autonomic Nervous System Activity Measured Directly and QT Interval Variability in Normal and Pacing-Induced Tachycardia Heart Failure Dogs

Piccirillo

Magrì

Ogawa

et al. 2009

Journal of the American College of Cardiology

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Objectives This study sought to find out more about the relationship between sympathetic and vagal nerve activity and the cardiac repolarization in a canine model of pacing-induced tachycardia congestive heart failure (CHF). Background The QT variability index (QTVI), a noninvasive marker of temporal cardiac repolarization dispersion, is among the risk factors for sudden death during CHF. Among factors influencing this variable are the myocardial damage and the autonomic nervous system activity typical of dilated cardiomyopathy. Methods We assessed autonomic nervous system activity recorded from an implanted data transmitter that monitored integrated left stellate-ganglion nervous activity, integrated vagus nerve activity, and electrocardiogram. We collected 36 segments recorded at baseline and 36 after induced CHF. We then arbitrarily identified recording segments as containing low or high sympathetic activity values, and we compared corrected QT intervals and the QTVI under a given sympathetic activity condition at baseline and after inducing CHF. Results In the high sympathetic activity subgroup, both QT variables increased from baseline to CHF (corrected QT intervals, p < 0.01; QTVI, p < 0.05) whereas in the low sympathetic activity subgroup they remained unchanged. The baseline QTVI correlated inversely with integrated vagus nerve activity (r2 = 0.16; β = −0.47; p < 0.05) whereas, during CHF, the QTVI correlated directly with integrated left stellate-ganglion nervous activity (r2 = 0.32; β = 0.27, p < 0.01). Conclusions During CHF, sympathetic activation is associated with an increase in the QT interval and QTVI. Because these changes vary over time, they could result from myocardial structural damage and sympathetic activation combined. Conversely, under normal conditions, no relationship exists between sympathetic activation and the QT variables.

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“…However, there is inadequate information about which equation corrects the QT interval appropriately for the RR interval in isolated guinea pig hearts. Cardio-acceleration by electrical pacing and/or treatment with drugs which change the heart rate were performed to construct a relationship between QT and RR intervals over a wide range to develop suitable QT/RR correction methods (Hamlin et al, 2003b;Tabo et al, 2006). Zatebradine is a specific bradycardiac agent that blocks the hyperpolarization-activated pacemaker current (I h ) and was reported to reduce the heart rate without changing the actual ventricular repolarization period in isolated guinea pig cardiac preparations (Kobinger et al, 1984;Hamlin et al, 2004), indicating that zatebradine would be appropriate for establishing plots of the ventricular repolarization period against the RR interval in isolated guinea pig hearts.…”

Section: Introductionmentioning

confidence: 99%

Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart

et al. 2010

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-The aims of this study were to determine a suitable method to correct the ventricular repolarization period against the RR interval in isolated perfused Langendorff guinea pig heart and to clarify the reliability of this model using several drugs. QT and RR intervals from an electrocardiogram and the epicardial monophasic action potential duration (MAP 90 ) were measured. Two drugs clinically known to be QT-prolonging (E-4031, moxifloxacin) and two known to be non-QT-prolonging (verapamil, zatebradine) were used for the study. To determine a method of correcting the ventricular repolarization period against RR interval, heart rates were slowed with 0.3 µM zatebradine, a specific bradycardiac agent, and then accelerated with atrial pacing to obtain a wide range of MAP 90 /RR relationships. An exponential rate-correction model elicited the most appropriate algorithm for the relationship among the four models tested. Based on linear regression analysis, the exponential showed superior dissociation of corrected MAP 90 s against RR intervals than generic Bazett's and Fridericia's formulae. E-4031 and moxifloxacin prolonged the corrected QT (QTc) intervals and MAP 90 under atrial pacing at a cycle length of 0.25 sec (MAP 90(pacing) ) dose-dependently; verapamil and zatebradine failed to prolong them, indicating that the reliability of this model was excellent. MAP 90(pacing) prolongation by moxifloxacin, the positive compound in the clinical "Thorough QT/QTc Study", was seen at around QTc-prolonging concentrations in clinic, suggesting that the sensitivity would be appropriate for QT evaluation. We therefore concluded that the isolated guinea pig heart model is sufficiently sensitive and useful for assessing the potential QT prolongation of drugs.

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Qt-Rr Relationships and Suitable Qt Correction Formulas for Halothane-Anesthetized Dogs

Cited by 7 publications

References 26 publications

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Autonomic Nervous System Activity Measured Directly and QT Interval Variability in Normal and Pacing-Induced Tachycardia Heart Failure Dogs

Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart

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