Impaired responses to Mycobacterium leprae antigens in rhesus monkeys experimentally inoculated with simian immunodeficiency virus and M. leprae.

Seven of eight rhesus monkeys (RM) coinfected with simian immunodeficiency virus (SIV) and Mycobacterium leprae harboured acid-fast bacilli (AFB) at sites of dermal inoculation and/or at disseminated sites at times of humane sacrifice (up to 270 days post-M. leprae inoculation) due to SIV-induced debilitation or, in one long term survivor's case, to date over 3 years post-M. leprae inoculation. Detectable AFB were cleared in biopsies of inoculation sites of RM inoculated with M. leprae alone after 63 days postinoculation; these sites have, so far, remained AFB-negative, thereafter. Compared to animals infected with M. leprae alone, RM coinfected with SIV plus M. leprae showed: 1, completely suppressed serum antibody responses to M. leprae-specific PGL-I antigen, but strong anti-SIV Gp120 antibody responses; 2, impaired sensitization of blood mononuclear cells (MNC) to in vitro recognition of M. leprae-specific antigens in blastogenic stimulation assays; 3, impaired in vitro responses of blood MNC to nonspecific (ConA) blastogenic stimuli; and 4, early post-M. leprae inoculation, there was a significant incremental diminution of percentages of blood CD4+CD29+ T-cells in addition to the existing SIV-induced diminished percentages of CD4+CD29+ T-cells. The results indicate that humoral and cellular immune responses to M. leprae antigens are compromised in M. leprae-inoculated RM previously infected with SIV. These results provide an immunologic basis for the demonstration of enhanced M. leprae persistence or leprosy susceptibility in SIV-M. leprae coinfected RM.

Relative bioavailability of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in rats and monkeys.

4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) is being evaluated for its anticancer activities in melanoma, breast cancer, Kaposi's sarcoma and lymphoproliferative disorders. A single oral dose of 1 g/kg of A-007 in rats resulted in prolonged and low plasma levels, typically less than 150 ng/ml for several days. Similarly, a single oral dose of 5 g/kg of A-007 in monkeys resulted in prolonged and low plasma levels, typically less than 22 ng/ml for several days. Oral bioavailability data suggests that this is not an efficient mode of drug administration and availability diminishes as one progresses from rodents to primates (relative oral bioavailability 2%); thus suggesting an alternative form of drug delivery is required in higher species. A-007 is not detected in plasma after a 0.25% gel is applied topically to the skin daily for 28 days. Early clinical support the topical use of A-007 to treat cutaneous metastasis for human breast cancer. The present data further support a dermal approach for the use of A-007 to treat metastatic cutaneous cancers.