scholarly journals In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome

2007 ◽  
Vol 76 (2) ◽  
pp. 247-256 ◽  
Author(s):  
D GALLACHER ◽  
A VANDEWATER ◽  
H VANDERLINDE ◽  
A HERMANS ◽  
H LU ◽  
...  
Keyword(s):  
Torsades De Pointes ◽  
Canine Model ◽  
Drug Induced

scholarly journals Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

2020 ◽  
Author(s):  
Richard S Varga ◽  
Tibor Hornyik ◽  
Zoltán Husti ◽  
Zsófia Kohajda ◽  
Gábor Krajsovszky ◽  
...  
Keyword(s):  
Torsades De Pointes ◽  
Coronary Artery Occlusion ◽  
Canine Model ◽  
Artery Occlusion ◽  
Class I ◽  
Class Iii ◽  
Drug Induced ◽  
Pharmacological Management ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion, reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged frequency corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations and blocked IKr in isolated cardiomyocytes (Class III effects), reduced maximum rate of depolarization (Vmax) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent re-entry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

scholarly journals A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium

2018 ◽  
Vol 38 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Emmanuel Boulay ◽  
Matthew M. Abernathy ◽  
Ray Chui ◽  
Gregory S. Friedrichs ◽  
Nicolas Gendron-Parra ◽  
...  
Keyword(s):  
Ion Channel ◽  
Sodium Current ◽  
Torsades De Pointes ◽  
Channel Blockers ◽  
Drug Induced ◽  
Ion Channel Blockers ◽  
Channel Inhibition ◽  
Concept Evaluation ◽  
Preclinical Species

Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. Methods: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). Results: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. Discussion: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.

scholarly journals Drug-induced long QT syndrome: Assessment by the in vivo canine model.

2000 ◽  
Vol 116 (supplement) ◽  
pp. 82-87
Author(s):  
Atsushi Sugiyama ◽  
Yoshioki Satoh ◽  
Keitaro Hashimoto
Keyword(s):  
Long Qt Syndrome ◽  
Canine Model ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Syndrome

scholarly journals Effects of Ravuconazole Treatment on Parasite Load and Immune Response in Dogs Experimentally Infected with Trypanosoma cruzi

2010 ◽  
Vol 54 (7) ◽  
pp. 2979-2986 ◽  
Author(s):  
Lívia de Figueiredo Diniz ◽  
Ivo Santana Caldas ◽  
Paulo Marcos da Matta Guedes ◽  
Geovam Crepalde ◽  
Marta de Lana ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Half Life ◽  
Serological Test ◽  
Parasite Load ◽  
Interleukin 10 ◽  
Canine Model ◽  
Drug Induced ◽  
Antibody Levels

ABSTRACT In this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts. Ravuconazole was well tolerated, as no significant side effects were observed during the treatment using 6.0 mg/kg twice a day (12 mg/kg/day) for up to 90 days. In all treated animals, parasitemia was permanently suppressed by the first day of treatment, independently of the parasite strain. Cultures of blood obtained posttreatment were negative for 90% of the animals, confirming that the drug induced a marked reduction in the parasite load. The results of PCR tests for T. cruzi in blood performed 1 month posttreatment were consistently negative for three of five and two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas' disease, probably due to its unfavorable pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas' disease.

Electrophysiological safety of DW-286a, a novel fluoroquinolone antibiotic agent

2005 ◽  
Vol 24 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Eun-Joo Kim ◽  
Ki-Suk Kim ◽  
Won-Ho Shin
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Torsades De Pointes ◽  
Hill Coefficient ◽  
High Dose ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Ovary Cells ◽  
Sd Rats

Inhibition of the potassium current IKr, and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 μM significantly ( P <0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00±37.85 μM with a Hill coefficient ( nH) of −0.97 ±0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 μM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 μM (concentration in serum).

Comparison of High Purity Factor IX Concentrates and a Prothrombin Complex Concentrate in a Canine Model of Thrombogenicity

1991 ◽  
Vol 66 (05) ◽  
pp. 609-613 ◽  
Author(s):  
I R MacGregor ◽  
J M Ferguson ◽  
L F McLaughlin ◽  
T Burnouf ◽  
C V Prowse
Keyword(s):  
High Purity ◽  
Time Course ◽  
Prothrombin Complex Concentrate ◽  
Degradation Products ◽  
Canine Model ◽  
Factor Ix ◽  
In Vitro Tests ◽  
Albumin Infusion

SummaryA non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.

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