In additional dog studies, compound 44 (L-163,191) was active (a fourfold increase of peak GH over baseline) orally at 0.0675 mg/kg (1:2 responded), at 0.125 mg/kg (6:8 responded) and at 0.25 mg/kg (7:8 responded). Following intravenous administration 4:4 dogs responded at the 0.025 mg/kg level. In a balanced crossover study using eight beagles, compound 44 given orally increased peak GH concentrations in a dose responsive manner with a 5.3-fold increase at 0.25 mg/kg, a 9.0-fold increase at 0.50 mg/kg, and a 15.8-fold increase at 1.0 mg/kg. After a single oral 1 mg/kg dose in three dogs, GH levels remained elevated out to 360 min and insulin-like growth factor (IGF-1) was significantly elevated 30% at 480 min (59).
Because the GH response to compound 44 in pituitary cell culture is rapidly desensitized, chronic in vivo studies were important. When compound 44 was orally administered daily to six beagles for four days at a 1 mg/kg dose, mean GH peak and AUC on day 4 were significantly higher than vehicle treated controls although reduced by 79 and 75%, respectively. GH secretion remained pulsatile throughout the experiment. Importantly, mean IGF-1 levels measured just before dosage on day 4 had increased from the vehicle control level of 50 ± 13.4 ng/mL to 108.8 ± 26.9 ng/mL (60).
The selectivity of L-163,191 (44) had been demonstrated earlier in over 50 in vitro assays in which its IC50 values exceeded 10 ^M. These included receptors for ligands known to affect GH release such as acetyl choline, galanin, somatostatin, met-enkepha-lin, and clonidene (14). It was also shown that growth hormone releasing hormone (GHRH) would not displace [35S] L-163,191 from its receptor (29). The in vivo selectivity of L-163,191 was examined in dogs (59). When it was given as a single 0.25 mg/kg intravenous dose to eight beagles, the GH mean peak level was increased 20.4-fold while cortisol levels were elevated from 2.6 ± 0.2 ^g/dL for the saline control to 6.2 ± 0.5 ^g/dL. This increase was not unexpected since cortisol elevations had been seen with GHRP-6 (6) and with the benzolactam L-692,429 (3) in dogs (30) and in humans although within normal ranges (32,33). Also, insulin and glucose levels were slightly elevated in dogs with a 1 mg/kg oral dose of L-163,191 and there were no significant changes in luteinizing hormone, prolactin or thyroxine levels (59). Thus, with the exception of moderate cortisol elevation, the other hormonal and metabolic parameters were not significantly changed by L-163,191 in dogs at 1 mg/kg oral dose.
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