An experimental study of the antileprosy activity of a series of thioamides in the mouse.

A series of substituted thioamides have been studied to establish whether their structure-activity pattern against Mycobacterium leprae is similar to that displayed against M. tuberculosis. Antileprosy activity was evaluated in the mouse foot pad using both the kinetic and continuous methods. Ethionamide and prothionamide were found to be the most active compounds and to be of approximately equal potency. Thioisonicotinamide was about five times less active. 2-t-Butyl-thioisonicotinamide, 2-dimethylamino-thioisonicotinamide, and pyrazine carbonic thioamide were inactive at the dosages tested. High-pressure liquid chromatographic methods were devised to study the potential influence of pharmacological factors on their in vivo activity. Fecal measurements suggested that all of the thioamides were well absorbed when fed in the diet. After intravenous administration, all of the thioamides were rapidly eliminated from the mouse. The differences in their elimination rates probably played only a minor role in affecting their relative antileprosy activities. It was concluded that the structural requirements for antileprosy and antituberculosis activity of the thioamides are probably similar.

A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man.

The blood levels and urinary excretion of the anti-mycobacterial drugs ethionamide and prothionamide have been compared after oral dosage in man. High pressure liquid chromatographic methods were used to determine the two closely related thioamides and their microbiologically active sulphoxide metabolites after the ingestion of both single and combined doses of the two drugs. Both drugs were rapidly eliminated from the body, the half-life for the urinary excretion and removal from the plasma of prothionamide being slightly less than that of ethionamide. Less than 0.1% of the orally administered doses were excreted unchanged in the faeces. Plasma concentrations of ethionamide and its sulphoxide metabolite were substantially higher than those of prothionamide and prothionamide sulphoxide. The implications of these findings for the use of ethionamide or prothionamide in the treatment of lepromatous leprosy are discussed.

The nose in lepromatous leprosy; bacteriological and histopathological studies of patients treated with dapsone monotherapy for varying periods of time.

A clinical, bacteriological and histopathological investigation of 62 patients with lepromatous leprosy attending a hospital in South India is reported, with particular emphasis on the activity of the disease in the nose. Twelve of the patients were from a group of 34 new patients who had been originally examined 5 years previously, and subsequently treated with dapsone (DDS) monotherapy. A further 50 lepromatous patients were also examined, who had been treated for periods ranging from 3 months to 10 years. With a few exceptions, there was good correlation between the clinical and histopathological findings in the skin and nose. Evidence of disease activity was demonstrated among three-quarters of the patients who had been treated for over a year. Failure to achieve quiescence was explained in most of the patients by failure to collect their dapsone treatment or to ingest it regularly as demonstrated by the determination of DDS/creatinine ratios on urine samples collected at the time of their visit to the clinic. Although the compliance of most patients was relatively satisfactory during the first 12 months of treatment, thereafter it deteriorated markedly. In contrast to the clinical, bacteriological, and histopathological evidence of disease activity in the skin and nose of most patients, in only one of the patients treated for more than a year was a positive nose-blow encountered. This suggests that the infectivity of DDS-treated lepromatous patients within this time and this diminished infectivity often persists despite poor drug compliance and continuing disease activity.