論文 - 大谷　壽一

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年09月

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年08月

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年07月

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 & Drug Disposition （Biopharmaceutics & Drug Disposition）  16 （ 9 ） 745 - 753 1995年12月

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年04月

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年12月

ISSN  02898055