Papers - Ohtani, Hisakazu

Inhibitory effects of the antihistamines epinastine, terfenadine, and ebastine on potassium currents in rat ventricular myocytes

Ohtani H., Hanada E., Hirota M., Sato H., Kotaki H., Sawada Y., Uemura H., Nakaya H., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology)  51 ( 9 ) 1059 - 1063 1999.09

ISSN  00223573

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We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (I(K)) and transient outward potassium current (I(to)) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit I(K) with IC50 values of 5.96, 15.3 and 145 μM, respectively. I(to) was suppressed by epinastine with an IC50 value of 69.5 μM. The order of arrhythmogenicity, assessed by the inhibition of I(K), was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

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Sustained QT prolongation induced by tacrolimus in guinea pigs

Minematsu T., Ohtani H., Sato H., Iga T.

Life Sciences (Life Sciences)  65 ( 14 ) PL197 - PL202 1999.08

ISSN  00243205

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Recently, clinical cases have been reported of QT prolongation and torsades de pointes associated with the use of tacrolimus (FK506). We examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs in order to evaluate the arrhythmogenicity of FK506 in comparison with quinidine (QND). FK506 (0.1 or 0.01 mg/hr/kg) or QND (30 mg/hr/kg) was intravenously infused to guinea pigs and time profiles of drug concentration in blood and QTc interval were examined during and after infusion. Both FK506 and QND evoked a significant QTc prolongation, and the dose-response relationship showed an anti-clockwise hysteresis, FK506-induced QTc prolongation persisted throughout the duration of the experiment despite a decline in the plasma FK506 concentration, whilst QND-induced QTc prolongation disappeared as plasma concentrations decreased. FK506 induced a sustained QTc prolongation in guinea pigs at drug concentrations in blood that correspond to its therapeutic range in human, suggesting that it might be of clinical significance to monitor the electrocardiogram, especially when patients have congenital or acquired QT-prolonging risk factors.

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Pharmacokinetic - pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats

Ohtani H., Sato H., Iga T., Kotaki H., Sawada Y.

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition)  20 ( 2 ) 101 - 106 1999.02

ISSN  01422782

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Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, E(max) and EC10 (ms) (where 10 ms of QT prolongation was evoked) of 0.73 μg/ml, 12.5 ms and 2.90 μg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

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Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada E., Ohtani H., Kotaki H., Sawada Y., Sato H., Iga T.

Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences)  88 ( 2 ) 234 - 240 1999.02

ISSN  00223549

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Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the E(max) model with an 'effect compartment' could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation)induced by coadministration of DP and EM in rats.

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Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats

Hirota M., Ohtani H., Hanada E., Kotaki H., Sawada Y., Iga T.

Life Sciences (Life Sciences)  62 ( 24 ) 2159 - 2169 1998.05

ISSN  00243205

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Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 μg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 ± 1.40 vs 56.60 ± 0.748 msec, mean ± SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

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Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection

Hanada E., Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Chromatography B: Biomedical Applications (Journal of Chromatography B: Biomedical Applications)  692 ( 2 ) 478 - 482 1997.05

ISSN  15726495

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A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 μl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 μg/ml for plasma and 0.5-100.0 μg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.

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A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats

Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology)  49 ( 4 ) 458 - 462 1997.04

ISSN  00223573

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The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with methane and α-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner; its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

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Pharmacokinetic-pharmacodynamic analysis of the electrocardiographic effects of terfenadine and quinidine in rats

Ohtani H., Hanada E., Yamamoto K., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin)  19 ( 9 ) 1189 - 1196 1996.09

ISSN  09186158

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In establishing a method of electrocardiographic (ECG) measurement for investigating drug-induced ECG changes, we examined the ECG effects and pharmacokinetics of terfenadine (TFN) and quinidine (QND) in rats. The time profiles of the plasma concentration and ECG parameters, such as the QT interval determined from limb lead II (QT-II) and the precordial chest lead (QT-V), heart rate and PR interval, were examined during constant intravenous infusion of TFN (5 or 15 mg/kg/h) or QND sulfate dihydrate (10 or 30 mg/kg/h). Both agents provided significant and concentration-dependent QT prolongation. The plasma concentrations (C10), where 10 ms of QT prolongation was observed, were 1.03 μM for TFN and 5.12 μM for QND, respectively. The calculated plasma unbound concentration of C10 (C(10·f)) was 10.3 nM for TFN and 3.82 μM for QND, which coincides with previously reported in vitro values of IC50 for potassium channels. The drug-induced QT prolongation was quantitatively reproduced in rats within the clinical concentration range. The usefulness of our methodology for the evaluation of arrhythmogenic hazards of the drugs was also demonstrated.

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Toxicodynamic analysis of cardiac effects induced by four cholinesterase inhibitors in rats

Yamamoto K., Shimizu M., Ohtani H., Hayashi M., Sawada Y., Iga T.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology)  48 ( 9 ) 935 - 939 1996.09

ISSN  00223573

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The cardiac effect of edrophonium (2-20 μmol kg-1), pyridostigmine (0.5-5 μmol kg-1), neostigmine (0.05-0.5 μmol kg-1) and ambenonium (0.02-0.3 μmol kg-1) was investigated after intravenous administration to rats. For pyridostigmine and neostigmine, the heart rate decreased in a dose-dependent manner, and then gradually recovered to the basal level at about 10 min. Rapid decrease of heart rate was observed after edrophonium and ambenonium administration, and rapid recovery to the basal level within 1 min. For ambenonium, a dose-dependent tachycardiac response was observed. The time-course of heart rate change was analysed by the effect-compartment model. Significant correlation was observed between bradycardiac EC50 values obtained by effect-compartment model analysis and inhibitory constant (K(i)) to acetylcholinesterase in-vitro, suggesting that the bradycardiac response was induced by inhibition of this enzyme and following elevation of acetylcholine concentration in the synaptic cleft. On the other hand, the tachycardiac EC50 values of edrophonium and ambenonium based on the effect-compartment model analysis were similar to dissociation constants (K(d)) of these drugs to muscarinic receptors in-vitro, suggesting that the tachycardiac activity of these drugs may be associated with antagonistic activity to postsynaptic muscarinic receptors. We conclude that, clinically, edrophonium and ambenonium are safer drugs than pyridostigmine and neostigmine, at least as regards muscarinic side-effects, including bradycardia.

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Quantitative determination of epinastine in plasma by high-performance liquid chromatography

Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Chromatography B: Biomedical Applications (Journal of Chromatography B: Biomedical Applications)  683 ( 2 ) 281 - 284 1996.08

ISSN  15726495

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A high-performance liquid chromatographic (HPLC) method for the quantitative determination of epinastine, a non-sedating histamine H1 receptor antagonist, in rat plasma, was developed. A 100-μl volume of plasma sample was spiked with a solution of internal standard (diphenidol) and extracted with dichloromethane under alkaline conditions. The extract was applied onto the HPLC system and detected by ultraviolet absorption at a wavelength of 220 nm. The linearity of the calibration curve was preserved over the concentration range of 20-1000 ng/ml. Both intra-assay variation and relative error were less than 5% for the plasma sample containing 50 ng/ml or 1000 ng/ml of epinastine hydrochloride. The analytical method presented here should be useful for the investigation of the pharmacokinetic properties of epinastine, which is of clinical significance.

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Lack of potentiation with felbinac patch on the convulsive toxicity of enoxacin in rats

Ohtani H., Noma S., Kawakami J., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin)  19 ( 7 ) 995 - 997 1996.07

ISSN  09186158

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We investigated the possible potentiation of the convulsive toxicity of enoxacin (ENX) by the concomitant topical application of a felbinac (FLB) patch in rats. A felbinac patch (Seltouch®; 0.5%, 3 cm x 4 cm) was attached on the back of rats where their hair has been removed. ENX was infused from the left jugular vein at 8 h after the application of FLB patch under an unanesthetized and unstrained condition. Blood, CSF and brain samples were collected at the occurrence of convulsion, and ENX concentrations of each part were determined. As a result, no significant potentiation by FLB patch was found in the onset time of convulsion or in the ENX concentration of each part. Moreover, based on the assumption that there are no inter-species differences in ENX concentration in the brain at the occurrence of a convulsion (C(br)), the predicted plasma ENX concentration required to elicit convulsions in humans, which was estimated from the C(br) and K(p) value of ENX in the brain of rats, was 20 times higher than the therapeutic plasma level.

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Antibronchospasmic, tachycardiac, and hypokalaemic effects of L‐isoproterenol in guinea‐pigs

Ohtani H., Yamamoto K., Sawada Y., Iga T.

Biopharmaceutics &amp; Drug Disposition (Biopharmaceutics &amp; Drug Disposition)  16 ( 9 ) 745 - 753 1995.12

ISSN  01422782

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The relationship between antibronchospasmic, tachycardiac, or hypokalaemic effects and plasma concentration of L‐isoproterenol (ISP) hydrochloride was investigated in guinea‐pigs in vivo. ISP was infused at the rate of 10, 30, 50, 100, and 300 ng kg−1 min−1. The antibronchospasmic effect was expressed as the attenuation of methacholine‐induced bronchospasm. The EC50 values of ISP for antibronchospasmic and tachycardiac effects were 5.12 nM and 3.95 nM, respectively. Although they were comparable to the values reported in vitro (7.23–0.358 nM, 1.77 nM), the concentration response relationship of ISP for antibronchospasmic effect was quite steep with a slope factor of more than six. Moreover, a decrease in plasma potassium level was not clearly detected. The experimental procedure in our present study was useful for evaluating antibronchospasmic and tachycardiac effects of beta‐agonists. Copyright © 1995 John Wiley & Sons, Ltd.

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Prediction of the therapeutic dose for β-stimulants based on preclinical data: Application of oral dosage forms and aerosols to asthmatic patients

Ito K., Yajima N., Ohtani H., Yamada Y., Nakamura K., Sawada Y., Iga T.

Journal of Pharmacokinetics and Biopharmaceutics (Journal of Pharmacokinetics and Biopharmaceutics)  21 ( 2 ) 133 - 144 1993.04

ISSN  0090466X

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The therapeutic doses of β-stimulants in the treatment of bronchial asthma show wide variation among the drugs. In the present study, we tried to construct a system for prediction of the optimum clinical dose of β-stimulants as oral dosage forms and aerosols using the data from preclinical pharmacological studies and pharmacokinetic data in humans. Values of EC50 (drug concentration that gives the half-maximum bronchodilator effect) in the in vitro studies based on isolated trachea of guinea pigs were collected from the literature. The ratios of the EC50 value of each drug to that of isoproterenol were used as the indicator of in vitro pharmacological activity. There were significant correlations between the EC50 ratios and the oral dose or the maximum plasma concentration after single oral administration, but the correlation coefficients were relatively small (r<.9). On the other hand, a linear log-log relationship was observed between the EC50 ratio and the maximum plasma unbound concentration (Cumax) (slope=0.907, r=.955, p<0.001). In the case of aerosols, a good correlation was observed between the EC50 ratio and the dose (slope=0.770, r=.900, p<0.01). The predicted concentration of β-stimulants in the lung after aerosol administration tended to be higher than the Cumax after oral administration, suggesting the contribution of nonspecific binding in the lung tissue. These findings indicate the possibility of predicting the appropriate dose of β-stimulants based on the preclinical pharmacological data and the pharmacokinetic data in humans. © 1993 Plenum Publishing Corporation.

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Information system for therapeutic drug monitoring - Information system in Pharmacy Department

Orii T., Yamamoto K., Sawada Y., Iga T., Ohtani H., Kohda Y.

Japan Journal of Medical Informatics (Japan Journal of Medical Informatics)  12 ( 1 ) 17 - 27 1992.12

ISSN  02898055