GASTRIC GLAND DEGENERATION INDUCED IN MONKEYS BY THE CCK-B GASTRIN RECEPTOR ANTAGONIST CI-988/

Gastric effects of subchronic treatment with the cholecystokinin-B (CC K-B)/gastrin receptor antagonist CI-988 were investigated in cynomolgu s monkeys. In preliminary range-finding studies, CI-988 was given oral ly to 1 monkey per sex for 14 days at doses of 50, 100, 200, and 500 m g/kg/day. Subchronic studies of CI-988 were subsequently conducted usi ng 5 monkeys per sex at doses of 0, 5, 25, and 75 mg/kg for 4 or 13 wk . High-dose monkeys were dosed initially at 100 mg/kg, but the dose wa s not well tolerated and was decreased to 75 mg/kg after 8 days of tre atment. One male monkey at 75 mg/kg was euthanatized in estremis on da y 23. In the range-finding study, minimal to moderate, multifocal to d iffuse degeneration of gastric glands, primarily in the fundic region, was observed at 100 mg/kg and above, with frank gastric mucosal atrop hy occurring at 200 and 500 mg/kg. Minimal to mild gastric gland degen eration was also observed in the subchronic study after 4 wk at 25 and 75 mg/kg, but histopathologic gastric changes were remarkably absent after 13 wk. Mucosal height in the stomach fundus was decreased 19.8% in 75-mg/kg males at week 4, and although gastric mucosa appeared hist ologically normal after 13 wk, mucosal height remained 28.6% less than that of controls. In females at 75 mg/kg, fundic mucosal height was d ecreased 7% and 5% at weeks and 13, respectively, but decreases were n ot statistically significant. Mean serum gastrin concentrations were i ncreased 10-fold in males only after 4 wk at 75 mg/kg, but were compar able to controls during week 13. CI-988-induced gastric gland degenera tion is consistent with antagonism of gastrin's trophic activity towar d gastric mucosa. Notwithstanding decrements in gastric mucosal height , disappearance of mild histopathologic findings despite continued tre atment with the ligand suggests some degree of adaptation to subchroni c CCK-B/gastrin inhibition, although the mechanism of accomodation has yet to be delineated.