Abstract:
INTRODUCTION:The aim of this experiment was to establish the usefulness of assessing temporal variability of the QT interval and changes in the T wave morphology in dogs as markers of pro-arrhythmic risk in humans. For this purpose, the electrocardiographic effects of astemizole and cisapride, two well known pro-arrhythmic drugs in humans, were assessed in dogs. METHODS:Astemizole was administered intravenously at single doses of 1 and 3 mg/kg whilst cisapride was administered orally at doses of 1.5 and 6 mg/kg. Electrocardiograms (ECG) were recorded before and after treatment. From each ECG tracing, QT intervals were recorded over 100 beats for calculation of the mean and standard deviation (SD) of QT and mean corrected QT (QTc). The coefficient of variation of QT (CV=SD/mean) was calculated as an indicator of QT temporal variability. The changes in T wave morphology were assessed in precordial lead CV5RL. RESULTS:Astemizole increased both the QTc interval and the CV of QT. Increases in these parameters also occurred after cisapride, but were less marked than after astemizole. In addition, both compounds produced a notching of the T wave, consisting of the presence of two peaks. DISCUSSION:The effects of astemizole and cisapride on the CV of QT and their propensity to induce of T wave notching are consistent with the blocking of I(Kr) channels and indicate, respectively, an increase in temporal variability of cardiac repolarization and an increased heterogeneity of the repolarization of cardiac cells across the myocardium. These changes are key triggers of arrhythmic events and are thus consistent with the pro-arrhythmic properties of these drugs. This study therefore indicates that the evaluation of CV of QT and T wave morphology in dogs may help in predicting drug-induced pro-arrhythmic risk in humans.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Hanton G,Yvon A,Racaud Adoi
10.1016/j.vascn.2008.03.001subject
Has Abstractpub_date
2008-05-01 00:00:00pages
194-201issue
3eissn
1056-8719issn
1873-488Xpii
S1056-8719(08)00022-1journal_volume
57pub_type
杂志文章abstract:INTRODUCTION:MEKK1 is a 196-kDa serine-threonine kinase activated in response to a variety of stimuli, including EGF, lysophosphatidic acid, osmotic stress, UV light, and microtubule toxins. However, there are few reports about the expression level of MEKK1 in cancers. METHODS:In this report, a direct competitive ELIS...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2004.08.004
更新日期:2005-03-01 00:00:00
abstract::A method for the rapid detection of intracellular nitric oxide (NO) generation in dissociated cerebellar granule cells using dichlorofluorescin (DCFH) and flow cytometry was developed. DCFH can be oxidized specifically by NO and this was assessed by 1) the use of SIN-1 (10 nM-100 microM), an NO donor, that induced a c...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/s1056-8719(97)00066-x
更新日期:1997-10-01 00:00:00
abstract:INTRODUCTION:Fosmidomycin is a phosphonic acid derivative originally isolated as a natural antibiotic from Streptomyces lavendulae. It was originally used as an antibiotic, and later on as an antimalarial drug. A simple, sensitive, selective and reproducible bioassay based on colorimetric method was developed for the d...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2010.02.012
更新日期:2010-05-01 00:00:00
abstract:INTRODUCTION:In experimental pain research the effect of opioids is normally assessed by verbal subjective response to analgesia. However, as many confounders in pain assessment exist, objective bed-side assessment of the effect is highly warranted. Therefore, we aimed to assess the effect of morphine on three objectiv...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.vascn.2015.01.005
更新日期:2015-05-01 00:00:00
abstract:INTRODUCTION:Quantification of lactate dehydrogenase (LDH) release is a widely accepted assay for the quantitative determination of cell viability and late-stage apoptosis. Major disadvantages of commercially available LDH assay kits include proprietary formulations, limited options for optimization and high cost, all ...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2015.02.001
更新日期:2015-05-01 00:00:00
abstract::The objective of this research is to determine whether the administration of a complete soft food formula to sub-lethal irradiated animals from three different transgenic mouse strains over a period of 21 consecutive days will have a significant impact on the clinical signs, and the general survival rate of the animal...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.12.003
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:Embryonic rat aortic smooth muscle cells, A7r5, have been used extensively as an in vitro vascular smooth muscle cell model. They are usually provided at 11th passage by supplier and generally used before 25th passage. However, the exact passage number (P#) used is not reported in general. METHODS:In this...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.03.001
更新日期:2014-07-01 00:00:00
abstract::High-content screening (HCS) systems can be used for high-throughput screening of drugs in human embryonic stem cells (hESCs). However, hESCs require immunofluorescence staining with stemness markers (e.g., Oct-4) prior to HCS, which can be time consuming and labor intensive. In this study, we employed transgenic hESC...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2020.106913
更新日期:2020-01-01 00:00:00
abstract:INTRODUCTION:Reversible protein cysteine oxidation is recognised as a pivotal post-transitional modification that transduces physiological as well as pathological signalling. Pharmacological interventions that target specific sources of oxidant formation are currently being trialled to ascertain their potential ability...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2013.07.001
更新日期:2013-11-01 00:00:00
abstract:INTRODUCTION:Drug-induced QT interval prolongation has been one of the critical issues for developing new chemical entities and pharmaceutical companies need to evaluate the risk early in the development stage. At such stage, guinea pigs are appropriate due to their small size requiring only small amounts of test drugs...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2006.11.002
更新日期:2007-05-01 00:00:00
abstract:INTRODUCTION:A variety of in vitro tests to replace the Draize test have been developed; however, there is no available method for assessing the full spectrum of Globally Harmonized System (GHS) categories. Human cornea-like three-dimensional (3D) reconstructed tissue models are the most promising in vitro systems. The...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2018.02.007
更新日期:2018-01-01 00:00:00
abstract:INTRODUCTION:Excitation of Acetylcholine-mediated (Ach) transmission (especially if irreversible) may pose life-threatening adverse events by increasing neuronal network activity. Unfortunately, adequate detection of this liability during early drug development is hampered, because published ex vivo electrophysiologica...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.12.001
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:The analytical solutions to compartmental pharmacokinetic models are well known, but have not been presented in a form that easily allows for complex dosing regimen and changes in covariate/parameter values that may occur at discrete times within and/or between dosing intervals. METHODS:Laplace transforms...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2015.03.004
更新日期:2015-05-01 00:00:00
abstract:INTRODUCTION:Drug-induced prolongation of the electrocardiographic QT interval (long QT syndrome) has been associated with increased risk of a serious ventricular arrhythmia, torsade de pointes. Inhibition of hERG, a cardiac potassium channel that controls action potential repolarization, is the most common cause of QT...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2008.10.004
更新日期:2009-01-01 00:00:00
abstract::The application of microdialysis technique for the investigation of pharmacokinetics and pharmacodynamics of drugs requires careful assessment of probe performance to ensure validity of the data obtained using this technique. The aim of this study was to establish and validate the microdialysis technique for investiga...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/s1056-8719(00)00117-9
更新日期:2000-11-01 00:00:00
abstract::The isolated perfused mammalian heart preparation was established in 1897 by Oscar Langendorff. The method was developed on the basis of the isolated perfused frog heart established by Elias Cyon at the Carl Ludwig Institute of Physiology in Leipzig, Germany in 1866. Observations made using both methods at the end of ...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 历史文章,杂志文章,评审
doi:10.1016/j.vascn.2006.05.006
更新日期:2007-03-01 00:00:00
abstract:INTRODUCTION:Dipeptidyl peptidases (DPPs) 8 and 9 are homologous, cytoplasmic postproline-cutting enzymes, which have similar enzymatic activity and preferred substrates as DPP4. DPP4 is a well-known target for treating diabetes mellitus. With the increased concern of non-selectivity and toxicities caused by DPP4 inhib...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.11.002
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds t...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2016.06.004
更新日期:2016-09-01 00:00:00
abstract:INTRODUCTION:Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. METHODS:The test substances cisapride, dofetilide, haloperidol, a...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2006.02.009
更新日期:2007-01-01 00:00:00
abstract::In many circumstances, rapid information is required about the effects of drugs on neurotransmitter release in brain, and a common method used is measurement of radiolabelled release from superfused brain slices or synaptosomes in vitro. However, the method requires expensive equipment and is not readily adapted to th...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/s1056-8719(97)00010-5
更新日期:1997-04-01 00:00:00
abstract:INTRODUCTION:A custom designed HD exposure system was used to deliver controlled inhaled doses to an animal model through an endotracheal tube. METHODS:Target HD vapor challenges were generated by a temperature controlled bubbler/aerosol trap, while concentration was monitored near real-time by gas chromatography. Ani...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2014.09.009
更新日期:2015-01-01 00:00:00
abstract::The purpose of this study was to develop a simple and noninvasive method for the quantitative evaluation of neuromuscular blockade in mice. The sciatic nerve in anesthetized animals (etomidate, 50 mg/kg or mephenesin, 250 mg/kg) was stimulated using transcutaneous electrodes; repetitive supramaximal stimulations (3 Hz...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/1056-8719(92)90033-w
更新日期:1992-05-01 00:00:00
abstract::In this study a new model of cerebral ischemia, based on a middle cerebral artery (MCA) thrombosis in rats is described. Furthermore, the effect of the novel plasminogen activator (SUN9216), a plasminogen-plasminogen activator chimera, comprising the fibrin kringle 1 domain of a plasminogen, and the two kringles, and ...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/1056-8719(93)90068-p
更新日期:1993-06-01 00:00:00
abstract::Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by vid...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2019.106611
更新日期:2019-01-01 00:00:00
abstract:INTRODUCTION:Different methods for the analysis of behavioral observation data were compared to evaluate how the interpretation of a data set may depend on the analysis method employed. METHODS:Three methods of analysis were used to evaluate the same four sets of rodent behavioral FOB data: (1) evaluation by a trained...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2010.06.001
更新日期:2010-09-01 00:00:00
abstract:INTRODUCTION:The aim of this investigation was to evaluate methods for increasing Caco-2 cell throughput for assessing drug intestinal absorption. The use of 6-, 12-, and 24-well membranes and the effect of membrane size on permeability and the integrity of the Caco-2 cell monolayer were assessed. In an effort to optim...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/s1056-8719(01)00161-7
更新日期:2001-07-01 00:00:00
abstract::Escherichia coli produces a heat-stable (STa) enterotoxin that belongs to a family of peptides that mediate several diarrheal diseases, including traveler's diarrhea and epidemic diarrhea in infants and newborns. The STa enterotoxin consists of 18 or 19 amino acids and is encoded by genes specified on a transposon. In...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章,评审
doi:10.1016/1056-8719(92)90049-7
更新日期:1992-09-01 00:00:00
abstract:INTRODUCTION:Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple salin...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2015.09.006
更新日期:2016-01-01 00:00:00
abstract:INTRODUCTION:Accurate preclinical modeling of diabetic complications such as retinopathy, nephropathy and neuropathy is crucial to enable the development of novel preventative therapies. The aims of this study were to establish a model of long-term diabetes with sustained medium scale hyperglycemia and characterize the...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2015.11.003
更新日期:2016-03-01 00:00:00
abstract:INTRODUCTION:Detection of drug effects on neuronal synapses is important for predicting their adverse effects. We have used drebrin as a marker to detect the synaptic changes in cultured neurons. High concentration of glutamate decreases the amount of drebrin in synapses. To increase the availability of this method for...
journal_title:Journal of pharmacological and toxicological methods
pub_type: 杂志文章
doi:10.1016/j.vascn.2019.106607
更新日期:2019-01-01 00:00:00