Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics.

Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST.

Effects of terfenadine, astemizole and epinastine on electrocardiogram in conscious cynomolgus monkeys.

We examined the effects of non-sedative histamine H1 receptor antagonists on the electrocardiogram (ECG) in conscious cynomolgus monkeys. Terfenadine (3 mg kg(-1) h(-1), i.v.) and astemizole (0.3 and 1 mg kg(-1) h(-1), i.v.) caused significant time-dependent increases in the QT interval and QTc Bazett (QTc). However, normal ECG forms were found during a 60-min infusion of epinastine (3 mg kg(-1) h(-1) i.v.). A higher dose of epinastine (10 mg kg(-1) h(-1), i.v.) increased the QTc and PR interval only 5 min after the start of the infusion. The minimum plasma concentrations of terfenadine, astemizole and epinastine which caused QTc prolongation were 85, 35 and over than 3600 ng/ml, respectively. These drugs did not alter the PQ and QRS intervals and did not cause arrhythmia or atrioventricular block. Our results are consistent with the clinical observation that prolongation of QTc is caused by terfenadine and astemizole but not by epinastine. Thus, measurement of QTc in cynomolgus monkey appears to be a useful approach for evaluating the potential cardiotoxicity of histamine H1 receptor antagonists.

Effects of astemizole on ventricular activation, effective refractory periods, RT intervals, and programmed stimulation-induced ventricular arrhythmias in dog hearts with myocardial infarction.

To clarify the mechanisms of enhanced cardiotoxic effects of astemizole in ischemic hearts, we examined the effects of astemizole on ventricular activation, effective refractory periods (ERPs), RT intervals, and incidence of programmed electrical stimulation (PES)-induced ventricular arrhythmias in the dog heart after myocardial infarction. Myocardial infarction was produced by the two-stage ligation of left anterior descending coronary artery in dogs. At 7 days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and the normal zones for applying an electrical stimulation or recording the ventricular activation. Ventricular-activation delay was measured in a premature excitation, which was produced by a stimulation at a coupling interval between 300 and 140 ms on the ventricular surface of the normal zone. The ERP and the RT interval were determined during atrial pacing. The ventricular-activation delay increased after astemizole at doses of 0.3-3 mg/kg in the infarcted zone and at 3 mg/kg in the normal zone. Astemizole at doses of 0.3-3 mg/kg significantly prolonged the ERP to a greater extent in the infarcted zone than in the normal zone, and thus a dispersion of ERP between normal and infarcted zones increased. The RT interval in the normal zone significantly increased after astemizole to a greater extent at a long coupling interval. The RT interval in the infarcted zone also increased after astemizole at doses of 0.1-3 mg/kg to a greater extent than that in the normal zone. Astemizole at doses of 0.3-3 mg/kg increased the incidence of PES-induced ventricular arrhythmias. In conclusion, enhanced cardiotoxic effects of astemizole in ischemic hearts may be caused by increased activation delay in the ischemic regions and increased ERP dispersion in the ventricle.

Effects of magnesium sulfate on the canine cardiovascular system complicating astemizole overdose.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Effects of nonsedating antihistamine, astemizole, on the in situ canine heart assessed by cardiohemodynamic and monophasic action potential monitoring.

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetized in vivo canine model under the cardiohemodynamic and monophasic action potential monitoring. A dose of 0.3 mg/kg of iv astemizole (n = 7), which is close to the recommended dose for clinical use, showed a bradycardic effect and a reversed use-dependent lengthening of repolarization. The increase in the repolarization was greater than in the effective refractory period. These effects persisted even when the plasma drug concentration became undetectable. Additional administration of 3.0 mg/kg of iv astemizole (n = 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those observed by the lower dose. The decrease of the plasma concentration of astemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overdose may be related to proarrhythmic effects and the monitoring of plasma drug concentration will be less helpful in predicting the cardiac adverse effects of astemizole. The results provide some insights into the clinical cardiotoxicity of astemizole. Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthening of repolarization.

A study of the interaction between dirithromycin and astemizole in healthy adults.

The effect of a standard regimen of dirithromycin, a macrolide antibiotic, on the single-dose pharmacokinetics of the H (1) receptor blocker astemizole was evaluated in a sample of 18 healthy young adults (nine males and nine females). The study was conducted in a two-way cross-over fashion after the subjects had been randomly given either dirithromycin (two 250 mg tablets) or placebo (two tablets) every morning for 10 days. On the morning of the fourth dose of either dirithromycin or placebo each subject ingested a single 30-mg oral dose (three 10-mg tablets) of astemizole. The disposition kinetics of both astemizole and its major metabolite, N-desmethylastemizole, were characterized after measuring the concentrations of both analytes in the serum fraction of serial blood samples collected for 14 days after the astemizole dose. In addition, corrected QT (QT(c) ) intervals were estimated from electrocardiogram rhythm strips that were run 24 hours prior to the astemizole dose, 12 hours after the astemizole dose, and after the last treatment (dirithromycin or placebo) dose in both study periods. Pharmacokinetic parameters that were measured for both astemizole and N-desmethylastemizole during each treatment were: C(max), t(max), AUC (0-infinity), CL(oral), half-life, and volume of distribution (V). None of the parameters for N-desmethylastemizole was different when comparing data by ANOVA from the dirithromycin treatment period with that of the placebo treatment period. On the other hand, during dirithromycin treatment astemizole CL(oral) was 34% slower, volume of distribution was 24% larger, and half-life was 84% longer. Generally, all QT ( c ) intervals did not appear to be affected by dirithromycin treatment. The changes in astemizole kinetics could not be attributed to its N-demethylation since the dispositional kinetics of N-desmethylastemizole were unaffected by dirithromycin. Therefore, it is difficult to ascertain the clinical significance of the changes in astemizole kinetics. Since there were no significant differences for mean QT(c) intervals and no effect of dirithromycin treatment on N-desmethylastemizole kinetics, it is unlikely that a standard regimen of dirithromycin would place a patient taking astemizole at an increased risk of torsade de pointes or related ventricular arrhythmias.

Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.

OBJECTIVES: Proarrhythmic effects have been observed with the selective histamine1 (H1) receptor antagonist drug astemizole, a widely prescribed antihistamine. The metabolites of astemizole and those of other antihistamine compounds have not been implicated as causative agents of cardiac arrhythmias. The purpose of this study was to examine whether desmethylastemizole, the principal metabolite of astemizole, blocks delayed rectifier potassium (K+) channels. BACKGROUND: QT interval prolongation and torsade de pointes are associated with astemizole intake and have been ascribed to block the repolarizing K+ currents, specifically the rapidly activating component of the delayed rectifier iKr. Astemizole undergoes extensive first-pass metabolism, and its dominant metabolite, desmethylastemizole, has a markedly prolonged elimination time. We report the clinical observation of QT prolongation and torsade de pointes in a patient with undetectable serum concentrations of astemizole (< 0.5 ng/ml) and "therapeutic" concentrations of desmethylastemizole (up to 7.7 ng/ml or 17.3 nmol/liter). METHODS: The perforated patch clamp recording technique was used to study the effects of desmethylastemizole (20 nmol/liter) on action potentials and iKr in isolated rabbit ventricular myocytes. RESULTS: Desmethylastemizole produced action potential prolongation and the induction of plateau early afterdepolarizations. Under voltage clamp conditions, desmethylastemizole suppressed iKr amplitude by approximately 65%. The drug E-4031 (100 nmol/liter), which selectively blocks iKr, had a similar effect on current amplitude. CONCLUSIONS: Desmethylastemizole, the major astemizole metabolite, blocks the repolarizing K+ current iKr with high affinity. The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.

The effect of activated charcoal on the absorption and elimination of astemizole.

1. The effect of activated charcoal on the absorption and elimination of astemizole and its metabolites was studied in healthy volunteers. 2. Subjects were divided into three groups containing seven subjects each. One group received 30 mg of astemizole with water only (control) and another group with 25 g of activated charcoal. The third group received multiple doses (12 g) of charcoal from 6 h onwards twice daily for 8 days. The concentrations of astemizole and its metabolites in plasma were measured by radioimmunoassay for 192 h. 3. Activated charcoal, administered immediately after astemizole ingestion, reduced the absorption of astemizole by 85% (P < 0.001). Multiple doses of activated charcoal, administered throughout the period of astemizole elimination, had no significant effect on the rate of elimination or the area under the curve from 0 to 192 h. 4. The absorption of astemizole from the gastrointestinal tract can be effectively prevented with activated charcoal. Because astemizole is rapidly absorbed, charcoal should be administered as soon as possible in acute astemizole poisoning. Multiple doses of charcoal do not seem to shorten the elimination half-life of astemizole.

Does the histamine skin prick test identify patients at risk for toxicity after the ingestion of astemizole?

Astemizole is a widely prescribed nonsedating antihistamine that suppresses wheal and flare reactions from histamine prick testing. We report a two-year-old girl with a serum concentration-proven overdose of astemizole who nonetheless exhibited a significant wheal and flare reaction after histamine skin prick testing for at least 22 hours after the ingestion. These findings suggest that histamine skin prick testing should not be used as a screening test to evaluate whether an ingestion of astemizole has occurred.

Prolonged QT interval and torsade de pointes following astemizole overdose.

A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.

Detection and determination of free and plasma protein-bound astemizole by thin-layer chromatography: a useful technique for bioavailability studies.

A thin-layer chromatographic (TLC) procedure has been developed for the determination of astemizole in plasma as the free and as protein-bound substance. The detection and quantification were performed without using internal standards. In earlier described methods for the estimation of astemizole by high-performance liquid chromatography and radioimmunoassay, only free levels in plasma were quantified, at 3.3% of the total astemizole, with the remaining 96.7% bound to plasma protein and tissue. Our method employs proteolysis of plasma proteins by incubating plasma for 2 h in pepsin. After proteolysis the astemizole is extracted, and a known amount of the extract is spotted on precoated silica gel F 254 plates. Astemizole was quantified using a Shimadzu CS-930 dual-wavelength TLC scanner. The method provides a direct estimate of total astemizole present in the plasma.