Cardiovascular monkey telemetry: Sensitivity to detect QT interval prolongation

Chaves, Alysia; Keller, William J.; O’Sullivan, Saoirse E.; Williams, M.A.; Fitzgerald, L.E.; McPherson, Holly; Goykhman, Dina; Ward, P Dorrington; Hoe, Chao-Min; Mixson, Lori; Briscoe, Richard J.

doi:10.1016/j.vascn.2006.03.004

Cited by 54 publications

(26 citation statements)

References 20 publications

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“…They offer a robust measure of channel activity, but lack voltage control and temporal resolution. In two reports, using either HEK-293 or CHO-K1 cells stably expressing recombinant hERG channels, IC 50 values determined in a Rb + flux assay were approximately 10-fold higher than those determined by electrophysiology, but the rank order of compounds according to potency was similar for the two assay types. 29,30 Fluorescence-based assays.…”

Section: Medium and High Throughput Herg Assaysmentioning

confidence: 98%

“…48 If metabolite profiles are expected to differ between man and dog, ECG measurements can also be made in primates. 49,50 In addition to the choice of species, the most important choice for ECG measurements is between the use of conscious animals implanted with telemetry devices and anesthetized animals. 51 Advantages of the anesthetized animals include greater reproducibility of the data and the potential for electrical pacing to study effects of heart rate.…”

Section: Evaluation Of Cardiac Riskmentioning

confidence: 99%

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Role of hERG potassium channel assays in drug development

Priest¹,

Bell²,

García³

2008

Channels

109

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Section: Medium and High Throughput Herg Assaysmentioning

confidence: 98%

Section: Evaluation Of Cardiac Riskmentioning

confidence: 99%

Role of hERG potassium channel assays in drug development

Priest¹,

Bell²,

García³

2008

Channels

109

View full text Add to dashboard Cite

“…According to the guideline on safety pharmacology core battery studies (ICH S7A, 2000), it is desirable to perform in vivo safety pharmacology studies using unanesthetized and unrestrained animals for examining effects of new drug candidates on the important vital functions of the respiratory system, cardiovascular system, and central nervous system. Further, in the current in vivo safety pharmacology core battery studies, it is recommended that nonhuman primates be used as generally resembling humans in data regarding pharmacokinetics (Ward and Smith, 2004;Terao, 2009), tissue cross-reactivity of antibody drugs (Ryan et al, 1999), and susceptibility to proarrhythmic drugs (Chaves et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Measurement of respiratory function using whole-body plethysmography in unanesthetized and unrestrained nonhuman primates

et al. 2010

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-Extended term, continuous measurement and observation of drug responses were performed to examine the feasibility of a custom-made whole-body plethysmograph for measuring respiratory function in unanesthetized, unrestrained monkeys. Using this apparatus, respiratory function (respiration rate, tidal volume, and minute volume) was observed for 23 hr in unanesthetized, unrestrained cynomolgus monkeys (Macaca fascicularis). The respiration rate, tidal volume, and minute volume in the light period (7:00 to 19:00) reached approximately 30% to 50% higher values than in the dark period (19:00 to 7:00), thus clearly exhibiting circadian variation in the cynomolgus monkey respiratory functions. Administration of morphine (10 mg/kg, s.c.) resulted in sustained reduction in tidal volume and minute volume, and ketamine (30 mg/kg [sub-anesthetic dose], i.m.) also produced sustained reduction in respiration rate, tidal volume, and minute volume. With dimorpholamine (1 mg/kg, i.v.) or caffeine (10 mg/kg, s.c.), respiration rate, tidal volume, and minute volume increased. Physiological saline (1 ml/kg, s.c. and 0.1 ml/ kg, i.v.) and chlorpromazine (10 mg/kg, s.c.) produced no clear-cut changes in respiration rate, tidal volume, or minute volume. From the above results, we conclude that our custom-made whole-body plethysmograph is useful for measuring respiratory function in unanesthetized and unrestrained monkeys.

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“…Moxifloxacin, a fluoroquinolone antibiotic known to prolong QT interval (Balfour and Wiseman, 1999), has been used as the standard positive compound to evaluate the sensitivity of clinical studies to detect small but significant increases in the QT interval (Shah, 2005), and data on the effect of moxifloxacin on QT interval in clinic is abundant at present. Thus, when demonstrating the appropriateness of preclinical assays for predicting QT risk in human, it is necessary to confirm the reactivity of moxifloxacin and compare it with clinical outcomes (Chen et al, 2005;Chaves et al, 2006;Holzgrefe et al, 2007;Komatsu et al, 2010). To our knowledge, however, there are no such reports at present regarding the guinea pig Langendorff model.…”

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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Cardiovascular monkey telemetry: Sensitivity to detect QT interval prolongation

Cited by 54 publications

References 20 publications

Role of hERG potassium channel assays in drug development

Role of hERG potassium channel assays in drug development

Measurement of respiratory function using whole-body plethysmography in unanesthetized and unrestrained nonhuman primates

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

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