Abstract
Summary
1. Two isoniazid derivatives, N-isonicotinoyl - N'- (salicylidene) hydrazine (INSH) and N-isonicotinoyl-N'-(2, 2-dimeth-yl-3-hydroxypropylidene) hydrazine (IHPH), were found to have an in vitro tuberculostatic effect similar to that of INH but both exhibited cross resistance with the parent compound. H37Rv tubercle bacilli were easily made resistant to INSH by serial passage in drug-containing liquid medium, after which the strain was found to have lost its former virulence for guinea pigs. Resistance was much slower to appear, however, in medium containing a combination of INH plus INSH. 2. P-amino-salicylic acid hydrazide (PASH) showed about the same in vitro effect as, and cross resistance with, PAS, but there was no cross resistance with INH. Tubercle bacilli could easily be made resistant to PASH by serial passage in drug-containing medium. This compound demonstrated very little beneficial effect in mice infected intravenously with the H37Rv strain. 3. INSH produced therapeutic results similar to those seen with INH in experimental tuberculosis of rabbits infected intravenously with a virulent bovine strain. 4. Guinea pigs were infected subcutaneously with 4 INH-resistant strains of tubercle bacilli; 3 were human strains isolated from patients treated with the drug, and the 4th, a bovine strain isolated from a rabbit treated with INH. Treatment with INH, INSH, or IHPH produced good results in the animals infected with the 2 strains showing least in vitro resistance, but very little beneficial effect in those infected with the 2 strains containing at least 1.0% of individual organisms resistant to 5 μg/ml. There was no significant difference in the results obtained in any of the 4 groups with INH or either of its 2 derivatives.
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