A double-blind study to determine the maximum tolerated dose of ethionamide, when administered twice-weekly to patients with pulmonary tuberculosis

ATI earlier report from this Centre (Tuber-culosis Chemotherapy Centre, Madras, 1964) showed that a fully supervised twice-weekly regimen of streptomycin plus high-dosage isoniazid was highly effective in the treatment of patients with newly-diagnosed bacteriologi-cally confirmed pulmonary tuberculosis. How-ever, this regimen involves intramuscular injections of streptomycin and may not always be easy to organize, especially in rural areas and in developing countries with limited resources. For this reason, it was decided to investigate the possibility of replacing strepto-mycin in the twice-weekly regimen by two oral drugs, namely ethionamide and PAS. Ethiona-mide was chosen since, apart from isoniazid and streptomycin, it was the most potent drug available at the time, and PAS was included with a view to enhance the efficacy of the regimen. Finally, it was decided that the patients should be given an intensive phase of daily treatment with streptomycin, PAS and isoniazid for two weeks. Experiments in the guinea-pig had shown that the size of the individual dose of a drug needed to be increased as the interval between successive doses was increased (Dickinson & Mitchison, 1966). As PAS is bulky and the dosage of isoniazid in the twice-weekly regimen was already high, namely 15 mg./kg. body-weight, it was decided to explore the possibility of increasing the dosage of ethionamide to a level higher than that usually employed (0.5— 1.0 g.) in daily regimens. An investigation was therefore undertaken to determine the maximum tolerated dose of ethionamide. when administered twice-weekly together with isonia-zid plus PAS. Since the assessment of ethio-namide intolerance is largely subjective, the study was conducted ‘double-blind’ with respect to the dosage of ethionamide