Incidence of tuberculosis in Japan is the highest among developed countries and its decreasing rates have slowed down since 1977. Such tuberculosis status in Japan might be resulted from rapid increase of the proportion in general population of the elderly generations, who had been infected with tubercle bacilli in the past and at risk of reactivation of tuberculosis, and also from the increased incidence among young persons in urban areas. Further, homeless, alcoholics and jobless personsare increasing among newly diagnosed tuberculosis patients from urban areas. Rapid identification and efficient treatment of the patients are the critical strategies of the control of tuberculosis.

　Six-months short-course chemotherapy containing pyrazinamide has been established as the standard regimen for the initial treatment of tuberculosis patients all over the world. But, in Japan, pyrazinamide has not been included in the standard regimen until quite recently, though several clinical trials carried out in Japan during 1880's had confirmed its efficacy. At the beginning of its introduction, pyrazinamide was generally used to treat relapsed or failure cases in combination with ethionamide and /or cycloserine, both of which are more or less hepatotoxic, in larger dose as 2.0g/day for rather longer period in Japan as well as in USA and European countries. As a consequence, high frequency of liver dysfunction, some were fatal, was reported among the patients treated with pyrazinamide-containing regimens. Because of such historical backgrounds, most of the Japanese physicians were very timid to accept 6-months short-course regimens containing pyrazinamide and preferred much longer regimens without pyrazinamide The longer the treatment, the worse the patients' adherence to the treatment. To improve such situations, we conducted a clinical trial from January 1991 to December 1993.

　Initial treatment cases of pulmonary tuberculosis who admitted Fukujuji Hospital, Japan Anti-Tuberculosis Association, from January 1991 to December 1993 were enrolled to the trial. Exclusion criteria were: age more than 80 years old, complication of severe liver diseases, especially liver cirrhosis, and resistance to INH and/or RFP. The regimen consisted of 2HRZS(E)/4HRE. The dose of pyrazinamide was 1.2g/day b.i.d. irrespective of body weight, gender and age. Sputum examinations (smear for AFB and culture) were carried out on three consecutive days on the admission and once a month thereafter. Chest X-ray, audiometry, visual field examination, and blood chemistry including liver function tests were examined on the admission and once a month thereafter. During the early phase of the treatment, liver function tests were examined on the admission and once a month thereafter. During the early phase of the treatment, liver functions were examined every other week.

Demographic characteristics:

　319 patients were enrolled for the trial. Mean age of 248 male patients was 46.6 years old and that of 71 female patients was 43.7 years old. 67 patients were complicated with diabetes mellitus, 2 patients were coinfected with HIV, 11 patients were suffered from malignant tumor of any sites, 14 patients had a history of gastrectomy, 3 patients were suffered from psychotic diseases, and 4 patients had a history of taking adrenocorticosteroids.
　219 (68.7%) patients were smear and culture positive and 71 (22.3%)were smear negative and culture positive. Overall , 90.9% of the patients were culture positive. Tubercle bacilli resistant to at least one anti-tuberculosis drug were isolated from 18 patients(5.6%). As for the chest X-ray findings, 51(16.0%) were far advanced, 166(52.0%) were not-far-advanced but cavitary and 101(31.7%) were non-cavitary.

Bacteriological negative conversion by the treatment and relapse:

　Negative conversion rate after two months treatment among 164 bacillary cases who completed the treatment was 91.5% and all patients converted on fifth month. In case of the patients treated with standard regimen without pyrazinamide , negative conversion rate at the second month was 90.0% and 100% conversion was achieved on the sixth month.
　Among 148 cases who completed the treatment without any change in the drugs, only one patients relapsed during average 18.5 month of follow-up. This patient was complicated with diabetes mellitus, and relapsed 45 months after the complicated with diabetes mellitus, and relapsed 45 month after the completion of chemotherapy. Tubercle bacilli isolated from this patient at the start of the treatment and also at the relapse were both susceptible to all anti-tuberculosis drugs.

Efficacy of the pyrazinamide-containing regimen:

　Of total 319 enrolled patients, 254 completed the treatment with success, 1 was still continuing anti-tuberculosis therapy because of multi-drug resistant tuberculosis, 25 were non-adherent to the treatment , 11 died of active tuberculosis, 7 died of other diseases than tuberculosis and 21 were lost from further follow-up.
　The overall efficacy of this regimen is 91.1%, when calculated on the bases of 291 patients excluding 28 patients of last 2 categories.

Adverse reactions:

　Allergic reaction occurred in 17(5.3%), but the causative drugs were discontinued in 9 (2.8%) only. 61(19.1%) revealed abnormal liver function tests, but the causative drugs were stopped in 26(8.2%). Disturbance of the VIIth cranial nerve occurred in 3(1.2%) of 207 patients on streptomycin, and streptmycin was discontinued in all of 3. Elevated serum uric acid level was observed in 89/ 207(40.3%) of male patients and 31/58(53.5%) of female patients, Only male patient complained arthralgia and pyrazinamide was discontinued.
　To introduce pyrazinamide into the standard regimen in Japan, it seems very important to clarify the frequency and severity of liver dysfunction caused by this drug. Among 274 who showed normal live function at the start of the treatment , 53 (19.3%) revealed elevated serum transaminase level higher than 50 IU/ml, of whom 16(5.8%) revealed the level higher than 150IU/ml.Clinical symptoms appeared in 11 patients(4.0%). Clinical symptoms appeared more frequently in the patients with higher level of serum transminase.
　Of all enrolled cases, 45 (14.1%) revealed elevated serum transaminase level higher than 50 IU/ml at the start of therapy. Pyrazinamide was stopped in 11, and wad continued in remaining 34 patients of whom only 2 patients showed further elevation of serum transaminase level higher than 150 IU/ml.
　As a whole, pyrazinamide was discontinued in 35(11.0%). The reasons of discontinuation were liver dysfunction in 25, fever in 3, skin rush in 3, arthralgia in 1, gastrointestinal distress in 1 and others in 2.

　In summary, the regimen including pyrazinamide is effective and safe. The negative conversion rate at the second month of treatment was 95.1%, higher than the rate (90.0%) achieved by the (former) standard 9 months regimen without pyrazinamide.
　After completion of this regimen, only one (0.7%) relapsed bacteriologically.
　Adverse reactions occurred in 39 (12.2%) including liver dysfunction in 18 (5.6%). Most of the adverse reactions were mild of moderate, and fatal liver dysfunction did not occur during this trial.