SPID#: 61 Four studies were conducted on adolescent male rhesus monkeys (Macaca mulatta) to determine the effects of acute administration of growth hormone (GH) antagonists (As) on a number of physiological parameters including serum concentrations of insulin-like growth factor-I (IGF-I), IGF binding protein 3 (IGFBP-3), and the antigenicity of the GHAs. Based on studies in mice, a dose of 1.0 mg/kg of the GHA B-2036-PEG was hypothesized to be maximally effective. Study I determine the time course of changes in IGF-I and IGFBP-3 following placebo administration or treatment with 1.0 mg/kg B2036-PEG given either SC or IV. The decline in these growth factors was evident within 8 hours of treatment with levels reaching nadir concentrations by day 4 and remaining suppressed through day 7 before increasing to baseline values by day 14. Study II investigated how varying doses (0, 0.03, 0.10, 0.30, and 1.0 mg/kg) of B2036-PEG and G120K-PEG affected IGF-I and IGFBP-3. Results indicated that only the 0.3 and 1.0 mg/kg dose of B2036-PEG effectively lowered serum IGF-I by day 3 from treatment (-40 % and -80% of baseline, respectively). However, serum IGF-I had returned to baseline values by day 7 following the 0.3 mg/kg dose but remained suppressed by the maximum dose of B2036-PEG. The third study investigated the effects of varying doses (0, 0.1, 0.3, and 1.0 mg/kg) of B2036-PEG administered at 7 day intervals for 7 weeks. Samples were obtained at 7 day intervals also just prior to the next treatment. Under this sampling regimen, only the maximum dose lowered serum IGF-I. An analysis of serum GH concentrations indicated that there was an inverse relationship between serum GH and the degree to which serum IGF-I was suppressed by B2036-PEG. In contrast, this maximum dose of B2036-PEG had no effect on fasting concentrations of other metabolic and clinical parameters. Antigenicity of each GHA (G120K, G120K-PEG, B2024, B2024-PEG, B2036, B2036-PEG) was assessed by administering the 1.0 mg daily for 14 days. The antigenicity data were not made available for this report. However, the treatment with this concentration of B2036-PEG, which equaled a dose of ~0.2 mg/kg, effectively suppressed serum IGF-I and IGFBP-3 up to 7 days after the treatment. None of the other GHAs had an effect on these growth factors. These data indicate that a dose of 1.0 mg/kg of B2036-PEG administered weekly can suppress IGF-I and its primary binding protein for up to 7 days following treatment and that such treatment has no observed side effects in other metabolic parameters. Additional studies are needed to determine if a smaller dose administered more frequently can maintain the suppression of the GH axis.
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