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肺結核에 對한 化學療法의 理論과 實際

Basic Knowledge of anti-Tuberculous Agents and Their Clinical Application

최신의학 1961년 4권 4호 p.87 ~ 92
이효근,
소속 상세정보
이효근 (  ) - 세브란스병원 흉곽내과

Abstract


It is important that the principles of the chemotherapy of tuberculosis should be presanted to the medical profession in comprehensive yet precise fashion.
Streptomycin(SM) is stable in acid or neutyal solution(pH 3 to 7). In contrast, DHSM is stable in alkaline medium. Actually, very little precise information is available concerning the metabolic fate of SM. A chemical method of analysis demonstrated that only 60 to 90 per cent of an injected dose could be accounted for in the 24 hour urine of human subjects given a single parenterally injected dose of SMI). SM metabolic pattern, as reflected in blood concentrations, shows marked variation between individual subjects. SM is distributed in extracellular water only2). In the absence of meningeal inflammation, the drug does not enter the cerebrospinal fluid in appreciable quantities, if at all. In the presence of meningitis, however, SM does appear in the cerebrospinal fluid in signifcant concentration. The antimicrobial activity of SM is optimum at pH 7.7 to 7.8; significant reduction of activity occurs at pH 7.0, and activity is reduced 90 to 95 per cent at pH 5.5 to 6.0d> Although SM is distributed widely throughout body fluids, its ability to reach intracellular fluid is limlted. Concentrations of SM required to kill intracellular tubercle bacilli are 20 times those required to inhibit bacillary growth in systemic culture media4>.
Para-aminosalicylicylic acid(PAS): Certain antacid preparations which are used to overcome the gastrointestinal upset caused by PAS have been found to interfere with the absorption of PAS. It has been suggested that the delayed absorption allows extensive chemical breakdown of the drug in the gastrointinal tracts). PAS is metabolized primarily by acetylation and as much as 10 to 75 per cent of the total serum amines after oral administration of PAS may be in the from of acetylated drug(s). The bacteriostatic action of PAS is due to the interference of microbial metabolism of p-amino-benzoic acid7). Its tuberculostatic activity varies somewhat with the strain of tubercle bacilli. Some strains, as well as saprophytic acid-fast bacilli, are not inhibited by as much as 1000 mcg./ m17>. PAS penetrates caseous and infected tissues in significant concentrations but cellular products in caseous tissue and pus inhibit the antimicrobial activity of PAS. Moreover, PAS has little or no effect on intracellular tubercle bacilli8 >. ,
Isoniazid(INH): Most of the orally administered INH is metabolically converted to derivatives that posses no antimicrobial activity´). Individual patients vary widely in the degree to which they metabolically alter
isoniazid. Despites,this wide variation among different persons, an individual demonstrates the same general type of metabolic pattern11). Of patients observed so far, about 40 per cent of Americans(white) are rapid inactivators. On the otherhand, Koreans are about 70 per cent12). In general, a person who has lower serun concentrations of biologically active drug(i.e., a rapid inactivator) demonstrates suboptimal response to INH therapy. In contrast, the patient who does not extensively metabolize the drug(i.e., a slow inactivator) is much more likely to achieve optimal response to INH therapy13,14), INH is widely distributed in both intracellular and extracellular fluids. INH has an affinity for caseous tissue and concentrations in infected organs were greater than in normalss). Apparently, the development of peripheral neuritis is directly proportional to the concentrations of free-INH present in biological fluid. *It has been suggested that free-INH interferes with the metabolism of pyridoxine (Vitamin 131. 15)). A experiment indicates the bactericidal effect of INH when glucose is provided as a metabolic substrate16). INH thus appears to be a bactericidal agent at concentrations and under conditions that might be attained in the body.
Resistance to 10 mcg./ml. has been the most widely accepted criterion but it is now believed that resistance to concentrations as low as 2.5 mcg./ml. may be clinically significantl%). The previously accepted dividing line of 10 mcg./ml. is probably too high, a more realistic value being 2.0 to 3.5 Meg. /M117). The level of significant resistance to INH has been widely set at 5 mcg./ml.; several authorities now feel that resistance to level as low as 0.2 mcg./ml. are clinically significant17). An excellent correlation exists between laboratory findings and clinical response, especially regarding the use of SM and PASO. Less clear correlation exists between clinical response and INH-resistance, even with the high levels of INH-resistance. Indeed, cotinued improvement is often observed and severe progression of disease is rare when INH therapy is continued, even in the presence of INH-resistance; this may be related to the unique correlation between INH-resistance, catalase activity, and pathogenicity18), Tubercle bacilli that are susceptible to low concentrations of INH contain large amounts of endogenous catalase(catalase -positive) and are characteristically pathogenic for both man and experimental animals. Strains resistant to high concentrations of INH no longer contain largeamounts of catalase (catalase negative) and usually have redused virulence and pathogenicity (19. 20. 21. 22. 23).
If the individual under age 4(some say 2) with tuberculin hypersensitivity without other roentgenographical, bacteriological, or clinical evidence of active disease a considerable risk of disseminated tuberculosis may be assumed to be present; therefore, treatment should be undertaken.
At present time, steroid therapy, is indicated during chemotherapy in the following situations; 1) menigitis, especially in children in whom coma; 2) fulminating pulmonary or disseminated tuberculosis; 3) serous membrane tuberculosis; 4) tuberculous erythema nodosum; and 5) hypersensitivity to anti-tuberculous drugs.
From the standpoint of high effectiveness and low toxicity, the best allround dru. is INH. The most effective regimen available today is high dosage(12 or more mg./kg./day) INH, daily SM and PAS continued for no less than 12 months and often as long as two or three years, with the daily SM reduced to twice a week either after 90 days, after apperance of eighth nerve toxicity, or after reversal of infectiousness by culture.

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