Assessment of drug-induced QT interval prolongation in conscious rabbits

Kijtawornrat, Anusak; Özkanlar, Yunusemre; Keene, Bruce W.; Roche, Brian; Hamlin, David M.; Hamlin, Robert L.

doi:10.1016/j.vascn.2005.04.013

Cited by 14 publications

(14 citation statements)

References 13 publications

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“…The use of conscious rabbit model and rabbits with heart diseases to test for torsadogenic compounds has been demonstrated previously (Kijtawornrat et al, 2006a(Kijtawornrat et al, , 2006b(Kijtawornrat et al, , 2012Hamlin and Kijtawornrat, 2008). The present study also demonstrated the potential utility of the anesthetized rabbit for detecting the liability of test articles to lengthen or shorten QT/QTc intervals in humans.…”

Section: Discussionsupporting

confidence: 65%

“…In SQT model, the drugs tested in order to shorten QT interval were nicorandil (0.3, 0.5 and 1.0 mg/kg/min, n = 7), pinacidil (0.1, 0.3 and 1.0 mg/kg/min, n = 5) and cromakalim (0.001, 0.003 and 0.01 mg/kg/min, n = 5). All doses were selected from our previous publications because they are known to lengthen and shorten QT intervals (Kijtawornrat et al, 2006a(Kijtawornrat et al, , 2006bPanyasing et al, 2010). All doses were infused intravenously over a period of 10 min.…”

Section: Experimental Protocolmentioning

confidence: 99%

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Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

et al. 2017

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-The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for druginduced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

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Section: Discussionsupporting

confidence: 65%

Section: Experimental Protocolmentioning

confidence: 99%

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

et al. 2017

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“…Therefore, the aim of this study was to assess the importance of enrofloxacin using the in vivo clinically healthy rabbit model with the normal dose and in a 10 times higher dose injection with various electrocardiographic parameters including RR, PQ, and QT intervals; QRS duration; QT/QTc prolongation; or TdP. Some authors speculated that increases in heart rate (HR), with accompanying decreases in QT intervals, could be masking an inherent increase in QT interval, identified with numerous drugs (Haverkamp et al, 2000;De Ponti et al, 2001;Redfern et al, 2003;Kijtawornrat et al, 2006;Ozkanlar et al, 2014). The reason for this was that a correction formula that adequately corrected QT intervals was used in the current study.…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxic effects of enrofloxacin on electrophysiological activity, cardiac markers, oxidative stress, and haematological findings in rabbits

Durgut¹,

Öztürk²,

Nacar³

et al. 2016

Turk J Zool

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IntroductionProlongation of the QT interval is commonly used as a surrogate marker of torsades de pointes (TdP), which is a known clinical risk factor for the development of severe, life-threatening, ventricular arrhythmias (Abi-Gerges et al., 2004). Noncardiovascular drug-induced prolongation of the QT interval is often associated with the onset of TdP (Haverkamp et al., 2000;De Ponti et al., 2001). Fluoroquinolones are among the drugs of choice for the treatment of common bacterial infections due to their wide spectrum against respiratory, gastrointestinal, and genitourinary pathogens (Elmas et al., 2006). QT interval prolongation is also a class effect of fluoroquinolones but there are great differences between the various members of this group (Camm, 2005). Thus, there are significant differences in the potency to prolong QT interval among the fluoroquinolones and the risk of arrhythmia varies between drugs and with co-risk factors (Frothingham, 2001;Owens and Ambrose, 2002). Because a QT prolongation and potentially fatal ventricular arrhythmias associated with quinolones such as grepafloxacin due to several cases of sudden death and TdP have been encountered retrospectively, enrofloxacin needs to be further investigated in detail. Therefore, the purpose of this study was to investigate the effect of normal and high doses of enrofloxacin on basal electrocardiographic parameters including heart rate (HR), P, QRS, QT, and RR intervals and corrected QT (QTc) values as well as biochemical and haematological findings in healthy conscious rabbits. Materials and methods ApprovalsThis study was approved by the Institutional Laboratory Animal Care and Use Committee of Mustafa Kemal University (2011 -01 -09). ChemicalsAll chemicals were obtained from Sigma Chemical Co, and solutions were prepared fresh daily from concentrated stock solutions. Animal preparationAfter 1 week of quarantine and acclimatisation, a total of 21 healthy New Zealand rabbits of both sexes, 12-18 months old, and of 2-4 kg body weight were used. The rabbits were housed individually in stainless-steel wire mesh cages and provided with food and water ad libitum. All rabbits were

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“…An equation relating QT to RR interval and its regression coefficient (r2) can be calculated using a simple regression model of the generic form QT = β × RRα. QTc can be normalized for the preceding RR interval using the formula QTc = QT/RRα, where α is the adjustment to produce a regression line with a slope of zero, indicating that this correction removes the influence of HR (Kijtawornrat et al, 2006). This method could be suitable for a population with a wide range of HR variation providing good correction and allows precise determination of drug-induced changes in QT (Tattersall et al, 2006).…”

Section: Methods Of Qtc Assessmentmentioning

confidence: 99%

Tomenendalova J: How to approach the QT interval in dogs - the state of the heart: a review

Agudelo¹,

Scheer²,

Tomenendálová³

2011

Vet. Med. - Czech

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ABSTRACT:The QT interval has been the objective of exhaustive attention in the past and also in recent times. A number of conditions, congenital and acquired, can have a direct effect on cardiac repolarization. Also drug regulatory agencies have showed increasing interest in the topic because certain drugs can prolong the QT interval to a level that produces ventricular arrhythmias. The dog is a species that shares some similarities with the human electrical system and has been used in human and veterinary research. We here present the current recommendations for QT measurement in dogs for use in clinical and experimental practice.

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Assessment of drug-induced QT interval prolongation in conscious rabbits

Cited by 14 publications

References 13 publications

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

Cardiotoxic effects of enrofloxacin on electrophysiological activity, cardiac markers, oxidative stress, and haematological findings in rabbits

Tomenendalova J: How to approach the QT interval in dogs - the state of the heart: a review

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