항결핵제가 취 외분비기능에 미치는 영향에 대한 실험적 연구

Abstract

[한글]결핵치료에 획기적인 계기를 마련한 것은 SM개발을 선두로 하여 PAS 및 INH개발로 인한 다 하겠다. 그후에도 계속 약제 개발이 진행되어 최근에는 rifampicin이 출품되기 까지에 이르렀다.

최초에 항결핵제인 streptomycin이 부작용으로 난청, 이명, 현훈이 있다고 보고한 다음 계속 부작용에 대한 보고가 있었다. INH의 말초신경염, ethambutol의 후안구성시신경염, rifampicin의 위장장애, 간독성, 혈소관감소증 등을 들수가 있다. 이와 같이 많은 독작용을 연구하였으나 특히 선장기에 대한 것은 찾아보기 힘든다. Singh등(1972)이 취장절편을 배양하여 분비액 속의 amylase치는 증가되고 조직내에는 감소됨을 보고하였다. 생체실험은 찾아 볼 수가 없으나 최(1972)가 항암제를 가지고 취담액 분비기능에 대하여 실험하

여 methotrexate 투여군에서 현저한 amylase치의 감소를 보고한 바 있다.

실험동물로 체중 150∼250gm의 흰쥐를 사용하였다. 실험약제는 수용성인 SM, INH, ethambutol, cycloserine, VM, KM 및 Pyrazinamide와 비수용성인 rifampicin을 사용하였다.

가) 흰쥐 복강내에 약제를 각각 10마리씩 대량(치료량의 10배이상) 을 주입하였다 그리고 secobarbital(30mg/kg)을 복강내에 주입하여 마취를 하고 실험대에 배면으로 고정하였다. 복부중앙선에 절개를 넣어서 미세한 polyethylene관을 담취관 내에 삽입 고정하고 담취액을 두시간 채취하였다.

나) 장기투여 실험에 있어서는 rifampicin(10mg/kg 경구), SM(150mg/kg, 복강내), 및 ethambutol(25mg/kg, 복강내)을 주 2회씩 계속 투여하고, 제1주와 제4주에 각각 단회 투여 실험과 같은 절차를 밟았다. 실험후 간장과 취장을 적출하여 10% formalin으로 고정하여

paraffine 절편을 만들어 Hematoxylin-Eosin 염색을 하였다.

다) 담즙 및 효소측정: Bilirubin과 cholate 측정은 Irvin 등(1944)과 Magee 등(1952)의 방법을 사용하였다.

Amylase는 전분기질에서 유리되는 maltose를 Summer(1924)법으로 측정하여 mgmaltose로 산출하고 lipase 측정은 Cherry 및 Crandall(1932)법으로 olive유 기질에서 유리되는 유리지방산을 Titrator TTT2b(radiometer, Denmark)를 이용한 적정에 쓰인 N/20 NaOH의 소비량으로 표시 하였다.

임상적으로 사용되는 항결핵제를 흰쥐에 단회 혹은 반복투여하여 초래된 간 및 취장의 분비기능의 변동을 검색하였다.

1) 담취외분비량은 SM, INH, cycloserine, rifampicin, viomycin 투여군에서 감소되었는데 특히 viomycin 투여군에서 현저하였다.

2) Bilirubin 농도는 ethambutol, KM, 및 cycloserine 투여군에서 증가 되었으나 SM투여군에서는 감소되었다.

3) 담취액 amylase치는 VM과 rifampicin 투여군에서 현저히 감소되었고, SM투여군에서는 약간 감소를 나타냈다.

4) 담취액 lipase치는 SM과 rifampcin 투여군에서 현저히 감소되었으나, cycloserine KM 및 pyrazinamide 투여군에서는 증가를 나타내었다.

5) 담취액 cholate치는 ethambutol 투여군에서 감소를, VM 투여군에서는 증가를 나타냈다.

6) 장기투여 실험에 있어서 담취외분비량은 ethamubutol은 1주투여군에서 현저히 감소되고, rifampicin은 1주 및 4주 투여군에서 약간 감소되었다.

7) 장기투여에서 담취액 amylase와 lipase치가 ethambutol 1주투여군에서 현저한 감소를 나타냈다. Rifampicin 4주 투여군에서는 amylase치의 경한 감소를 나타냈다.

8) 병리조직 소견은 지방변성이 SM 1주 투여군, 4주투여군 및 ethambutol 1주 투여군에서 약간 볼 수가 있었다. 취장에는 특별한 이상이 없었다.

[영문]The first evidence of human tuberculosis had been noted in bones of mumies since the age of neolithic. "Phthisis" which was the first nomenclature of tuberculosis was introduced into the history in ancient Greek ers. Laennec(1804) described the

pathologic process of tuberculosis, and Villemin(1865) had successful transmited the disease to the experimental animal. Koch(1882) declared his famous Koch's postulation and reconfirmed that tuberculosis was an infectious disease.

New turning point of chemotherapy against tuberculosis was made after introduction of streptomycin, para-aminosalicylic acid, and isonia acid, subsequently various drugs have been developed for clinical use. Rifampicin is the most recent antibiotic developed for tuberculosis.

Mclitor(1949) reported side reactions induced by streptomycin such as hearing difficulty, tinnitus, vertigo, and etc.

Waksman(1958) also reported some side reactions caused by kanamycin, capreomycin, and viomycin. INH which is the most potent and least toxic drug, might also cause serious peripheral neuritis, and rarely cause hepatic necrosis which is almost

fatal. Ethambutol is another less toxic drug, but it might cause retrobulbar optic neuritis. The latest rifampicin has rather bizzare untoward reactions which includes digestive disturbances, hepatotoxicity, and thrombocytopenia.

So far various toxicities of anti-tuberculous drugs such as in gastrointestinal, hepatic, and nervous systems have been studied, but few studies were attempted for the secretory function of glands, particularly about the pancreas. Sometimes, we notice an over diabetes while we treat tuberculosis patients with one or more of following drugs such as ethambutol, prothionamide, and pyrazinamide.

Singh(1972) experimented with a sliced pancreas of rat for excretory function through incubation, and reported that streptomycin increased amylase secretion and decreased tissue content.

Choi(1972) studied an in vivo pancreatico-biliary function with several anti-cancer drugs such as bleomycin, 5-FU, ICRF-159, and methotrexate, and reported that amylase secretion was remarkably increased in methotrexate treated group.

So far, there is no definite study of pancreatico-biliary function on influence of vaious anti-tuberculous drugs, and this study is particularly designed for this purpose.

Method and Materials:

1. Experimental animal: Albino rats with body weight ranging from 150 to 250 grams were used.

Pancreatico-biliary juice was collected for 2 hours after cannulation.

2. Experimental group:

a. Experiment 1: single massive dose of anti-tuberculous drugs(I.P.) administred.

1) Control group, saline.

2) Streptomycin, 100mg/kg.

3) INH, 100mg/kg.

4) Ethambutol, 200mg/kg.

5) Cycloserine, 200mg/kg.

6) Viomycin, 100mg/kg.

7) Pyrazinamide, 600mg/kg.

8) Rifampicin, 200mg/kg. (in DMSO solution and oral)

b. Experiment 2: Repeated administration(I.P.) of anti-tuberculous drugs were used in this series of experiments.

1) Rifampicin, 100mg/kg, p.o., twice a weekly

2) Streptomycin, 15mg/kg, i.p. twice a weekly

3) Ethambutol, 25mt/kg, i.p., twice a weekly

Similar experiment were conducted both first and fourth weeks respectively, and liver and pancreas were taken out for pathologic examination.

c. Determination of enzymes:

Bilirubin and cholate values were checked by methed modified by Irvin at al(1994) and Magee et al(1952).

Amylase determination was made by Sumner's method(1924).

Lipase determination was made by Cherry and Crandall's method(1932).

Results:

The effect of anti-tuberculous drugs on the pancreatico-biliary function were studied using albino rats. The drugs were administered in two ways: single toxic dose and repeated therapeutic doses.

The followings are summary of results obtained from the experiment:

1. Pancreatico-bilary secretion was remarkably inhibited in viomycin and rifampicin treated group and significant inhibition was observed in streptomycin, isoniazid, cycloserine treated groups. Ethambutol, kanamycin, and pyrazinamide treated groups showed no significant changes to compare with the control group.

2. Bilirubin concentration was significantly increased in ethambutol, kanamycin, and cycloserine treated groups, however, it was somethat decreased in streptomycin group.

3. Amylase secretion was remarkably decreased both in viomycin and rifampicin treated groups, and it was significantly decreased in streptomycin treated group.

4. Lipase secretion was remarkably decreased both in streptomycin and rifampicin treated groups, but it was significantly increased in cycloserine, kanamycin, and

pyrazinamide treated groups.

5. Cholate secretion was decreased in ethambutol treated group, but it was rather increased in viomycin treated group.

6. In repeated therapeutic doses, pancreatico-biliary secretion was remarkably decreased in one week in ethambutol treated group. But rifampicin treated group showed slight decrease both in one week and four weeks after treatment. There were little changes in bilirubin.

7. In repeated therapeutic doses, amylase secretion was remarkably decreased in ethambutol treated group for one week, and slightly decreased in rifampicin treated group for four weeks. Lipase sercetion was remarkably decreased in ethambutol

treated group for one week.

8. Pathological examination of excised live showed some degree of fatty degeneration in streptomycin treated groups for one and four weeks and in ethambutol treated group for one week.