Biochemical & histochemical changes relating to fibrosis following infection with Mycobacterium tuberculosis in the guinea pig.

Guinea pigs infected with M. tuberculosis were studied for parameters relating to fibrosis following infection. The infected animals were followed up to a period of 44 wk and the changes that occurred in the lung, liver and spleen were studied. Corresponding tissues from animals injected with bleomycin, an anti-mitotic drug which has the ability to produce pulmonary fibrosis, served as positive controls. Tissue collagen, elastin and hexosamines were estimated biochemically. The presence of granuloma and stainable collagen in paraffin sections of these tissues was also studied. Establishment of the infection was assessed bacteriologically by culturing the viable organisms from the spleen. It was observed that a self-limiting infection was established in the guinea pigs and none of the animals died of the infection. In the infected animals, collagen, elastin and hexosamines showed an initial decrease followed by an increase. While the elastin and the hexosamine levels returned to the basal levels in all the three organs, collagen levels increased in the lung and were comparable to those of the bleomycin control. Collagen stainable by Van Gieson's method was found to be increased in the lung from the 4th wk onwards. The present report indicates the potential of adopting this system for studying mechanisms of fibrogenesis in tuberculous infection.

The clearance of tubercle bacilli & mycobacterial antigen vis a vis the granuloma in different organs of guinea pigs.

In the present study, an attempt was made to define the relationship of intact tubercle bacilli and/or their antigenic fragments to a granuloma in the guinea pig in order to distinguish an active from a resolving granuloma. In one set of animals, granuloma was induced in the skin by injecting heat-killed Mycobacterium tuberculosis intradermally and in another set, granuloma was produced in the lung and spleen by injecting live M. tuberculosis intramuscularly. The animals were sacrificed at various time points and skin, lung and spleen from the two groups were subjected to histological examination for the presence of granuloma, bacilli and antigenic fragments. In the dermal lesion, intact acid fast bacilli were cleared first by day 42 followed by the removal of their antigenic fragments by day 63 and finally by day 84, the granuloma had resolved completely. In the guinea pigs infected with live M. tuberculosis, removal of the bacilli followed by the clearance of antigen was observed. Though the granuloma itself did not subside completely in these animals, it was found that there was a reduction in congestion and oedema of the granulomatous area. It is concluded from the results that the demonstration of antigen at the site of lesion may be potentially useful to discriminate between a persisting and a resolving tuberculous granuloma.

Induction of rifampicin metabolism during treatment of tuberculous patients with daily and fully intermittent regimens containing the drug.

Self-induction of rifampicin metabolism during daily and intermittent chemotherapy was studied by monitoring the changes in the serum half-life of the drug over a 4-week period in patients with pulmonary tuberculosis. Rifampicin 450 mg was administered to 8 patients who received treatment daily, 7 on thrice-weekly and 7 others on twice-weekly treatment. Serum half-life was computed from concentrations of the drug determined at 3, 4 1/2 and 6 hours after drug administration, on admission and at 1, 2 and 4 weeks after start of treatment. In the daily series, the mean serum half-life decreased from 4.9 hours on admission to 3.6 hours at 1 week (P = 0.02), and treatment beyond this had no further effect. In the thrice-weekly series, maximal induction was observed at the 2nd week, the mean values on admission and at 2 weeks being 5.8 and 3.7 hours, respectively (P less than 0.01). In the twice-weekly series, maximal induction was observed only at the 4th week, the mean values on admission and at 4 weeks being 4.9 and 3.7 hours, respectively (P less than 0.01). Serum activity of gamma glutamyl transferase was not found to be a suitable in vivo marker to monitor induction of the hepatic microsomal enzymes as no significant changes were observed in the activity of this enzyme in any of the 3 series during the 4-week period.