The inhibin B response in male rats treated with two drug candidates.

BACKGROUND: Serum Inhibin B was measured in two studies of known testis-toxic drug candidates. METHODS AND RESULTS: Study 1 was for a compound for Hepatitis C, and utilized a 10-week dosing period, followed by mating and necropsy of half of each group, and then a 12-week recovery period for the remaining animals. At the postmating necropsy, 6 of 15 high-dose males had testis lesions; Inhibin B was significantly reduced in all animals in that group. The mid-dose group had no lesions but significantly reduced serum Inhibin B. At recovery, 9 of 15 high-dose males showed damage in testes; serum Inhibin B levels were not different from controls. Inhibin B appeared to both overreport and underreport testis damage in Study 1. Study 2 was an acute pathogenesis study for an antibacterial compound, using control and two dose levels and multiple time points (days 5, 8, 15, 22, and then untreated until day 71). At each time point blood was sampled from all remaining rats and five/group were killed for histologic evaluation. The low-dose group had minimal to moderate lesions, while serum Inhibin B was never changed. The high-dose animals progressed quickly from minimal lesions to being broadly and moderately affected; serum Inhibin B levels were reduced at days 8 and 15 only. In Study 2, Inhibin B appeared less sensitive than histology, except at the extremes of testis damage, when Inhibin B was routinely low. CONCLUSION: We conclude that in these two studies there was a poor correlation between changes in serum levels of Inhibin B and testis histopathology.

T-cell-dependent antibody response: assay development in cynomolgus monkeys.

The current study was designed to develop and test a T-cell dependent antibody response to keyhole limpet hemocyanin (KLH) in cynomolgus monkeys. In an optimization experiment, monkeys (3/sex) were given a single intramuscular injection of KLH at 10 mg/animal to evaluate the kinetics of the antibody response. Serum samples were collected pretest, and on Days 4, 6, 8, 11, 15 and 22 for measurement of anti-KLH IgM and IgG endpoint titers. In a subsequent experiment, female monkeys (3/group) were treated once daily by gavage with the immunosuppressive agent cyclosporine (Neoral) at 0, 10 and 50 mg/kg for 21 days, and the effects of drug treatment on anti-KLH IgM and IgG responses were determined. The effects of cyclosporine on hematology, biochemistry, bone marrow, organ weights, gross and histopathology, and peripheral lymphocyte subsets also were evaluated. Robust anti-KLH IgM and IgG responses were seen in monkeys given a single intramuscular injection of KLH at 10 mg/animal, with peak antibody responses at approximately 10-14 days post-immunization for anti-KLH IgM, and 14-21 days for anti-KLH IgG. Decreases in anti-KLH IgG endpoint titers were seen in 1 monkey given cyclosporine at 10 mg/kg, and 1 monkey dosed at 50 mg/kg. Relative to vehicle control animals, mild lymphoid depletion was evident in lymph nodes and tonsil of monkeys with suppressed anti-KLH IgG titers. Collectively, these findings in individual animals provided evidence of cyclosporine-induced immunosuppression. Cyclosporine at 10 and 50 mg/kg did not alter anti-KLH IgM production, hematology, biochemistry, bone marrow, organ weights, or peripheral lymphocyte subsets. Lastly, the results of this study demonstrated that KLH immunization at 10 mg/animal did not alter the standard toxicity endpoints evaluated in control animals.