Gastric gland degeneration induced in monkeys by the CCK-B/gastrin receptor antagonist CI-988.
Gastric effects of subchronic treatment with the cholecystokinin-B (CCK-B)/gastrin receptor antagonist CI-988 were investigated in cynomolgus monkeys. In preliminary range-finding studies, CI-988 was given orally to 1 monkey per sex for 14 days at doses of 50, 100, 200, and 500 mg/kg/day. Subchronic studies of CI-988 were subsequently conducted using 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 was not well tolerated and was decreased to 75 mg/kg after 8 days of treatment. One male monkey at 75 mg/kg was euthanatized in extremis on day 23. In the range-finding study, minimal to moderate, multifocal to diffuse degeneration of gastric glands, primarily in the fundic region, was observed at 100 mg/kg and above, with frank gastric mucosal atrophy occurring at 200 and 500 mg/kg. Minimal to mild gastric gland degeneration 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 histologically normal after 13 wk, mucosal height remained 28.6% less than that of controls. In females at 75 mg/kg, fundic mucosal height was decreased 7% and 5% at weeks 4 and 13, respectively, but decreases were not statistically significant. Mean serum gastrin concentrations were increased 10-fold in males only after 4 wk at 75 mg/kg, but were comparable to controls during week 13. CI-988-induced gastric gland degeneration is consistent with antagonism of gastrin's trophic activity toward gastric mucosa. Notwithstanding decrements in gastric mucosal height, disappearance of mild histopathologic findings despite continued treatment with the ligand suggests some degree of adaptation to subchronic CCK-B/gastrin inhibition, although the mechanism of accommodation has yet to be delineated.
Dethloff
L A
LA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Robertson
D G
DG
Tierney
B M
BM
Breider
M A
MA
Bestervelt
L L
LL
D000284:Administration, Oral; D000818:Animals; D001284:Atrophy; D048429:Cell Size / Q000187:drug effects; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D005755:Gastrins / Q000097:blood; D006727:Hormone Antagonists / Q000633:toxicity*; D007211:Indoles / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000633:toxicity; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D005755:Gastrins; D006727:Hormone Antagonists; D007211:Indoles; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine