Isonicotinic Acid Hydrazide 및 Cycloserine의 長期投與가 白鼠의 各 臟器에 미치는 形態學的 硏究 = Morphological Studies of Prolonged Administration of Isonicotinic Acid Hydrazide and Cycloserine Upon the Various Organs of Rats

다국어 초록 (Multilingual Abstract)

Although among the various antituberculosis drugs, Isonicotinic Acid Hydrazide (isoniazid) is an excellent drug for the treatment of tuberculosis, in some patients, it may cause toxic reactions. The first, more common type of reaction is seen in the nervous system and is manifested by peripheral neuritis. This neurotoxicity varies in incidence and severity with the dosage of the drug. The second, less common toxic reactions are thought to be allergic in nature. The original reports on isoniazid described the occurence of toxic manifestations in animals and in man (Benson et al., 1952; Bernstein et al., 1952; Elmendorf et al., 1952; Rubin et al., 1952; Steenken & Wolinsky, 1952). After receiving toxic doses animals showed signs of central nervous system stimulation followed by clonic and tonic convulsions, and death resulted from respiratory failure. Different animal species vary considerably in their sensitivity to isoniazid. Clinically the principal form of toxicity is peripheral neuritis, as first reported by Biehl and Skavlem (1953) and Biehl and Nimits (1954). No toxic effects on the peripheral blood or on, kidneys have been reported, although a mild transient. liver dysfunction was observed. Epileptic patients would seem to be particularly susceptible to the convulsant toxic effect of isoniazid, and a fatality in such a patient was reported (Fetterhoff et al., 1952).
The symptoms of isoniazid toxicity resemble those of vitamin B6 deficiency, and Biehl and Vilter (1954) showed that patients receiving large doses of isoniazid excreted a large amount of pyridoxine, and they found that the complication of peripheral neuritis could be prevented by administering pyridoxine along with isoniazid. In common with the convulsions of B6 deficiency, hydrazideinduced convulsions can be suppressed immediately by pyridoxine or its congeners (Balzer et al., 1960; Jenney et al 1953; Ross, 1958). Moreover, pyridoxine does not seem to interfere with the antibacterial action of isoniazid (Crowle & Riemensnider, 1960; Grunberg & Blencowe, 1955; Ungar et al., 1954). The mode of action of isoniazid in producing peripheral neuropathy is not fully understood, but probably isoniazid competes with pyridoxal phosphate for the enzyme, apotryptophanase (Boone & Woodward 1953; Lichstein, 1955), and thus disturbs the metabolism of the neurone.
Neurological symptoms which are seen frequently after therapeutic dosage, are among the most important of the toxic effects of cycloserine. Also cycloserine produced convulsive seizures and ataxia in mice and rabbits (Fust, 1958). The toxic action of this tuberculostatic drug, cycloserine, can be explained, at least in part, by its inhibition of B6-catalyzed enzymatic reactions (Epstein et al., 1959). Pyridoxine reduces also cycloserine toxicity (Epstein et al,, 1959; Robitzek & Nenashev, 1957). The incidence of acute toxicity following the administration of cycloserine is low, and continued studies in rats, cats, dogs and monkeys showed no toxic effects in the prolonged drug- administration except for a temporary anemia and reticulocytosis in dogs and monkeys (Anderson et at., 1956).
Most studies of the toxic action of isoniazid and cycloserine have dealt mainly with clinical, biochemical and antibacterial changes, there are only a few reports of the morphological changes in various organs following prolonged administration of isoniazid and- cycloserine. These changes are confined to the nervous system, and simple description of liver, kidney and bone narrow in rats and dogs. Moreover, the mechanism involved in the metabolic and biochemical relationship
between isoniazid and cycloserine in large and prolonged doses, and pyridoxine deficiency is poorly understood and still obscure. Very little attention had been paid to the mechanism for the development of organic lesions produced by chronic toxicity of isoniazid and cycloserine.
Using different experimental conditions, therefore, a detailed morphological study of the lesions of the various organs was made. And special emphasis was made on the effects of prolonged administration of isoniazid and cycloserine which are known to be related particularly to pyridoxine metabolism. Furthermore, there is still very little known about the mode of action of the factors which cause the organic lesions after prolonged administration of these antituberculosis drugs in rats.
The purpose of this study is to characterize the patterns and define the nature of the morphological changes in various organs in rats, after prolonged administration, of isoniazid and cycloserine. It seeks to clarify the effect of isoniazid administration, the effect of cycloserine administration, their relationship, and, moreover, the effect of the additional administration of synthetic pyridoxine hydrochloride.