A means of increasing the tolerated dose of isoniazid in mice.

Abstract

Attempts have been made to find a means of increasing the amount of isoniazid (INH) which mice will tolerate. In the DBA strain of mice; INH alone was lethal for 45% of the animals when 5 mg/20 g mouse (250 mg/kg) were given orally. With an 8 mg dose of INH, lethal per se, simultaneous administration of as little as 25 mg glycine and 10 mg sodium glucuronate mono-hydrate was sufficient to keep alive all the animals tested. By the use of appropriate amounts of the 2 detoxifying chemicals, all mice survived either a single oral dose of 25 mg INH, or 3 doses of 8 mg daily, or 13 doses of 10 mg each given at 72-hour intervals. Larger amounts were not tolerated. A study of the blood plasma concentrations of INH showed that, whereas 24 hours after a 4-mg dose alone only a negligible amount remained, appreciably higher concentrations, approximately 6-fold, persisted for a longer period following 8 or 10 mg INH in combined treatment. In the proportions tested, sodium glucuronate and glycine had no effect on the bacteriostatic action of INH in vitro on one human strain of tubercle bacilli.