Acute and Subacute Toxicities of Theophylline are ...

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ment, spasm and hyperpnea were observed at more than 150 flg/mi Animals died after tonic eonvulsion at ISO pg/ml In the repeated dose toxieity study, the ...
Reprinted tYom: Methods Find Exp Clin Pharmacol 2000. 22(3): 173-178 Ci)pyriglu © 2()()() Pious Science CCC: 037y-()355/2()()()

Acute and Subacute Toxicities of Theophylline are Directly Reflected by its Plasma Concentration in Dogs M. Shibatci, M. Wcichi, M. Kcigciwa, J. Kojima' and K. Onodera^ Toxicology Group, Omiya Research Laboratory, Nikken Chemicals Co., Ltd., Saitama; 'Department of Medical Development, Nikken Chemicals Co., Ltd., Tokyo; and -Department of Pharmacology, Tohoku University School of Dentistry, Sendai, Japan

S U M M A R Y

The purpose of this study was to evaluate the relationship between aeiite and suhaeute toxieity and blood levels of theophylline in do^s. Theophylline was administered intravenously into dogs onee (at doses of 50, 100 and 150 mg/kg) or for 4 weeks (at doses of 20, 55 and 70 mg/kg/dav). In the single dose toxieity study, by inereasing the dose of theophylline, plasma coneentration inereased and the severity of toxie symptoms were inten sified. After a single dosing of theophylline, aeeentuated heart rate and vomiting were observed at a eoneentration of more than 67 flg/nd, and exeitement, spasm and hyperpnea were observed at more than 150 flg/mi Animals died after tonic eonvulsion at ISO pg/ml In the repeated dose toxieity study, the plasma eoneentration of theophylline inereased dependent on dosage, and was not ajfeeted by repeated dosing. Even under these eonditions, the toxie symptoms were quite similar to those of the single dose, except for an additional decrease in movement, body weight reduction and myocar dial lesion. These present results suggest that the severity of theophylline toxieity is dependent on its plasma concent rations rather than accumulated

dosages. The blood concentration of theophylline-treated patients should be maintained within the therapeutic range in order to diminish risk. © 2()()() I'rous Science. All rights reserved.

Key words: Theophylline - Toxicity - Dogs - Toxicokinetics

INTRODUCTION

Theophylline preparations have been used widely for

(15-17). Since Theodrip® does not include ethylenedi

the treatment of slight and serious asthma and other air

amine, it will be effective for patients whose allergy is caused as a result of aminophylline (and/or ethylenedi

way-obstructed patients. An injectable form of aminophylline (the ethylenediamine salt of theophylline) is used for patients with acute asthma. Under these circum stances, the optimal therapeutic range of aminophylline

amine). In rats or mice orally administered a high dose of theophylline, toxic effects on clinical signs, body weight and histopathology were observed (18-20). In another

is narrow in instillation (1). A theophylline overdose

induces many adverse effects such as nausea, vomiting, tachycardia, headache, seizures, agitation, etc. (2-5). Based on long-term use experience in man, there is like ly to be a close relationship between the severity of toxic symptoms and the blood concentration of theophylline (6-9). On the other hand, theophylline clearance is affect ed by age, smoking, concurrent illnesses, coadministra tion of other medications and food (10-12). Therefore, a

monitoring of blood concentrations and also an adjust ment of its dose for each patient will be effective in reducing adverse effects (7, 13). Recently, a new injection formulation of theophylline (Theodrip®) was developed (Nikken Chemicals Co.,

report, theophylline-induced toxicity was not noticed in dogs to which theophylline was administered orally or intravenously for 12 weeks at a dose of 20 mg/kg/day (21). The relation between toxicity and blood concentra tion of theophylline is unknown in these toxicity studies. We reported that the risk of teratogenic and fetal toxicity

caused by theophylline is directly reflected by its blood level, rather than its dosage, in rabbits (22). In this study, we evaluated the relationship between acute and suba cute toxicity and blood level of theophylline in dogs.

M AT E R I A L S

AND

METHODS

Ltd.) as a substitute for aminophylline injection (14).

Animals

Aminophylline occasionally causes hypersensitivity due to the presence of ethylenediamine in the compound

Male and female Beagle dogs, 6 or 7 months of age (Oriental Maruichi Kyodo Co., Ltd., Shizuoka, Japan),