Studies of immediate adverse reactions to different doses of a slow-release preparation of isoniazid.

'Double-blind' studies were carried out to assess the incidence of immediate adverse reactions to different doses of a slow-release preparation of isoniazid (matrix isoniazid). Individual doses of 30 mg/kg matrix isoniazid were well-tolerated but higher doses resulted in giddiness, the incidence being dose-related. The giddiness was characterized by a late onset and was usually present even at 24 hours. A few patients complained of gastro-intestinal symptoms. It is concluded that matrix isoniazid can be given to Madras patients in doses of 30-40 mg/kg without risk of an undue incidence of immediate adverse reactions.

Two controlled studies of the efficacy of isoniazid alone in preventing relapse in patients with bacteriologically quiescent pulmonary tuberculosis at the end of one year of chemotherapy.

An earlier report showed that, in patients with bacteriologically quiescent pulmonary tuberculosis at the end of 1 year of chemotherapy, isoniazid alone in a single daily dose of 150-200 mg, given as maintenance therapy in the second year, did not markedly prevent relapse over a 4-year period of follow-up in patients who had had residual cavitation (the "open-negative" syndrome) at 1 year, but was highly effective in patients who had not. As a result of these findings, two controlled studies, reported here, were undertaken.The first study was undertaken in patients with bacteriologically quiescent disease and residual cavitation at 1 year, and investigated the value of isoniazid in a higher daily dose (400 mg) throughout the second year; this is known to be the optimum therapeutic dose when isoniazid is prescribed alone for 1 year in the initial treatment of the disease. The second study was carried out in patients with bacteriologically quiescent disease and no residual cavitation at 1 year, and sought to determine the value of a shorter duration (6 months) of chemotherapy in the second year with a daily dose of 300 mg of isoniazid. Neither of the two isoniazid regimens was highly satisfactory, although both appeared to have had some effect in preventing relapse during the 4-year period of follow-up.

Attack rate of tuberculosis in a 5-year period among close family contacts of tuberculous patients under domiciliary treatment with isoniazid plus PAS or isoniazid alone.

This report from the Tuberculosis Chemotherapy Centre, Madras, considers the risk, over a 5-year period, to close family contacts of sputum-positive patients treated at home for 1 year with a standard regimen of isoniazid plus PAS or one of 3 regimens of isoniazid alone. The attack rate of tuberculosis in the contacts did not appear to be influenced by the treatment received by the patients in the first year or by the duration in the 5-year period for which the patients had (1) positive sputum smears, (2) positive cultures, or (3) isoniazid-resistant cultures. Further, over half the cases of tuberculosis developed in the first year, many of these being in the first 3 months. These findings confirm the conclusions reached from an earlier study, namely, that the major risk to the contacts is from exposure to the infectious patient before diagnosis, and that the risks from the other possible sources of infection (the patient during treatment and the urban environment of Madras) are, in comparison, small.

A 5-year study of patients with pulmonary tuberculosis treated at home in a controlled comparison of isoniazid plus PAS with 3 regimens of isoniazid alone.

This report from the Tuberculosis Chemotherapy Centre, Madras, describes the progress, over a 5-year period, of 341 patients with newly diagnosed, sputum-positive tuberculosis. All the patients were treated on a domiciliary basis. In the first year, the patients received, on the basis of random allocation, a standard regimen of isoniazid plus PAS or 1 of 3 regimens of isoniazid alone. Previous reports have shown that the response in the first year was substantially superior with the standard regimen, and that the bacteriological relapse rates in the second year were fairly similar for the 4 regimens. The findings in the present report extend the latter conclusion to the end of 5 years. Further, when considered together with the findings in an earlier study, they have shown that isoniazid, given as maintenance chemotherapy in the second year, was highly effective in preventing bacteriological relapse in patients who, at 1 year, had bacteriologically quiescent disease and no residual cavitation; the effect was, however, less marked in patients with residual cavitation at 1 year.Patients who were clear-cut failures of the allocated chemotherapy and those who had a bacteriological relapse in the second or subsequent years were usually re-treated with streptomycin plus PAS or streptomycin plus pyrazinamide, and if this was ineffective, with cycloserine plus thioacetazone or cycloserine plus ethionamide.Considering the findings over the 5-year period for all patients, 16 died from non-tuberculous causes and 1 took his discharge prematurely. Of the remainder, 86% had bacteriologically quiescent disease at 5 years, 6% had bacteriologically active disease and 8% had died of tuberculosis. These findings confirm the value of well-organized domiciliary chemotherapy, which was established by an earlier report from the Centre, and are particularly encouraging for developing countries such as India, where tuberculosis is a major problem and resources are limited.

Effect of pyridoxine on vitamin B6 concentrations and glutamic-oxaloacetic transaminase activity in whole blood of tuberculous patients receiving high-dosage isoniazid.

An earlier report from the Tuberculosis Chemotherapy Centre, Madras, showed that, in tuberculous patients receiving high-dosage isoniazid (12.5-15.6 mg/kg body-weight), the concomitant administration of 6 mg of pyridoxine prevented peripheral neuropathy. In that study, biochemical determinations of B(6) concentrations and GOT activity in whole blood had been routinely undertaken on all patients on admission to treatment, and at 6, 12, 24 and 52 weeks thereafter; in addition, extra determinations were undertaken for patients who developed peripheral neuropathy. The present paper reports the findings of these investigations, which are: (a) peripheral neuropathy developed predominantly among slow inactivators of isoniazid, and was associated with a substantial reduction in GOT activity but no apparent change in B(6) concentration; (b) the reduction in GOT activity appeared to be due to deficiency of both the coenzyme (pyridoxal phosphate) and the apoenzyme; (c) the concomitant administration of pyridoxine (6 mg or 48 mg) with high-dosage isoniazid to 3 patients with peripheral neuropathy, 1 of whom had convulsions also, resulted in increased B(6) concentrations and GOT activity, and no further convulsions; and (d) the concomitant administration of pyridoxine 6 mg daily, as a prophylactic, resulted in a significant increase in B(6) concentrations and GOT activity and prevention of the neuropathy.These findings establish the existence of a definite association between the occurrence of isoniazid-induced toxicity and diminished pyridoxine function.

A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India.

This report is the last of a series of nine publications from the Tuberculosis Chemotherapy Centre, Madras, concerning various aspects of an investigation of the role of ambulatory chemotherapy for pulmonary tuberculosis. It presents the attack rates of tuberculosis over a 5-year period of follow-up of close family contacts of patients, all of whom were treated for one year with isoniazid plus PAS, half (selected at random) in sanatorium and half at home. The incidence of active tuberculosis and of tuberculous infections was no greater in the contacts of patients treated at home than in the contacts of patients treated in sanatorium, either in the first year or over the subsequent four years. The major risk to the contacts resulted from exposure to the patient before diagnosis. These findings reaffirm that close family contacts of patients treated at home were at no additional risk of developing tuberculosis, provided the patients received effective chemotherapy. Finally, this study has shown that it is possible in South India to obtain extremely good co-operation from a group of families over a period of several years.

A 5-year study of patients with pulmonary tuberculosis in a concurrent comparison of home and sanatorium treatment for one year with isoniazid plus PAS.

This report from the Tuberculosis Chemotherapy Centre, Madras, summarizes the progress over a 5-year period of 193 patients with newly diagnosed, sputum-positive pulmonary tuberculosis who were admitted to a concurrent comparison of home and sanatorium treatment for one year with isoniazid plus PAS. Previous reports have shown that, despite the traditional advantages of sanatorium treatment-rest, adequate diet, nursing and supervised drug-administration-the home patients responded nearly as well as the sanatorium patients in the first year; further, the relapse rates over a 2-year period of follow-up were similar. The findings in the present report are based on a 4-year period of follow-up and extend these conclusions, the relapse rates over the period being 7% for the home patients and 10% for the sanatorium patients.Patients who failed to respond to treatment in the first year and those who had a bacteriological relapse in the second or subsequent years were usually re-treated with reserve regimens, first with streptomycin plus pyrazinamide and, if this was ineffective, with cycloserine plus ethionamide. Considering the findings over the entire 5-year period, five home patients and three sanatorium patients died from non-tuberculous causes. Of the remainder, 5% of the home patients and 6% of the sanatorium patients died of tuberculosis, 4% in each series had bacteriologically active disease at five years and 90% and 89%, respectively, had bacteriologically quiescent disease at that time. These findings are very encouraging, particularly for developing countries such as India, where tuberculosis is a major problem and sanatorium beds are very few.