The study was performed without external funding.
Lugovik I.A., Shekunova E.V. Evaluation of the use of various formula for correction of the QT interval (QTC) and ECG reference intervals in anesthetized beagle dogs. Laboratory Animals for Science. 2022; 2. https://doi.org/10.29296/2618723X-2022-02-04
Safety pharmacology is an essential stage of preclinical testing strategy and includes studies evaluating the potential effects of a test substance on vital systems: the cardiovascular, respiratory and central nervous systems. When evaluating the effects of a test substance on cardiovascular system (CS) in vivo, it is necessary to estimate its effect on blood pressure (BP), heart rate and electrocardiogram (ECG). These assessments can be performed in conscious or anesthetized animals.
ICH Guideline S7B describes a non-clinical testing strategy for assessing the potential of a test substance to delay ventricular repolarization. The QT interval on the ECG (time from the earliest onset of the QRS complex to the latest end of the T wave) is a measure of the duration of ventricular depolarization and repolarization. To date, it is believed that with a delay in ventricular repolarization and prolongation of the QT interval, there is an increased risk of ventricular tachyarrhythmia, including fatal torsade de pointes. However, the QT interval shortens as the heart rate (HR) increases and lengthens as the heart rate slows. This circumstance make it difficult to assess the potential effect of a test substance on the QT interval at different HR in animals. In this regard, the QT interval should be corrected for HR. For this purpose, there are several clinically developed heart rate correction formulas, however, they may not fully reflect the QT-HR relationship for dogs, and therefore the most appropriate formula should be determined in each research center.
25 males and 17 females beagle dog were used in the experiment. The animals were housed under standard vivarium conditions. Registration of parameters was carried out in the morning (from 09:00 to 11:00). Medetomidine and propofol were used for the anesthesia. The results showed that, in relation to the conditions of this experiment, the assessment of the corrected QT (QTc) by means of several the most commonly used approaches (Bazett’s formula, Fridericia's formula, and Sagie’s formula) is not satisfactory.
Additionally, ECG main parameters (RR, P, PQ, QRS, QT duration (in ms) and amplitude R, P, Q, S, T (in mV)) and blood pressure reference intervals were set. In the future this will help to assess changes in the functional parameters of the cardiovascular system in dogs more accurately in the pharmacological safety testing.
The authors declare no conflicts of interest.
I.A. Lugovik — data collection and analysis, experimental manipulations, analysis of literary sources, writing the text of the article.
E.V. Shekunova — experimental manipulations, analysis of literary sources, writing the text of the article.
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