Gastric effects of the CCK-B/gastrin receptor ligand CI-988 in cynomolgus monkeys.

We have previously demonstrated that the CCK-B/gastrin receptor ligand CI-988 induces gastric gland degeneration and atrophy in cynomolgus monkeys, an effect consistent with gastrin receptor antagonism and inhibition of gastrin's trophic effects on oxyntic mucosa. However, gastrin receptor ligands of the dipeptoid chemical series to which CI-988 belongs have been reported to act as agonists or antagonists towards gastrin-related events, depending on the animal model and the functional endpoint examined. To investigate further these apparently conflicting data, basal gastric acid secretion was monitored acutely in conscious monkeys given CI-988 orally at 10 mg/kg or intravenously at 0.01 mumol/kg/hr and histological changes in gastric mucosa were evaluated in monkeys given CI-988 orally at 5, 25 or 75 mg/kg/day for 4 weeks. Degeneration and atrophy of gastric glands occurred at 25 and 75 mg/kg with statistically significant decrements in gastric mucosal height at 75 mg/kg. In addition, CI-988 stimulated gastric acid secretion when given either orally or intravenously. Co-administration of the structurally unrelated CCK-B/gastrin antagonist L-365,260 completely blocked CI-988-stimulated acid secretion, confirming that CI-988's agonist effect on acid secretion is mediated by the gastrin receptor. Assuming that gastric mucosal degeneration is the result of inhibition of gastrin's trophic activity, CI-988 appears to induce paradoxical agonist and antagonist gastrin-receptor mediated effects.

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.

Early detection of positive blood cultures by the acridine orange staining technique.

Staining 2,205 macroscopically negative blood cultures with acridine orange after 6 to 17 h of inoculation and incubation was as sensitive as an early subculture in detecting positive blood cultures. Of the 179 positive blood cultures, 30 (16.8%) were detected by acridine orange alone, 19 (10.6%) were detected by early subculture alone, 84 (46.9%) were detected by both techniques, and 46 (25.7%) were not detected by either method. The latter group includes cultures that became positive after 48 h of incubation. Acridine orange staining of smears prepared from macroscopically negative blood cultures after 6 to 17 h is a rapid, reliable method to detect positive blood cultures.

Regulation of female sexual behavior in the golden hamster: behavioral effects of mating and ovarian hormones.

In the female hamster, sexual receptivity was abbreviated following copulation. Short-term effects of mating, lasting approximately 24-48 hr, were observed in females mated in either estradiol- or estradiol-and-progesterone-induced estrus. Long-term effects of copulation, of 9 days or more in duration, were apparent only in females chronically treated with both estradiol and progesterone, suggesting that progesterone exposure prolongs the inhibitory effects of mating. When progesterone stimulation was intermittent through the use of short-acting injection procedures, recovery from mating could be detected in 48 hr and was complete within 96 hr after copulation. The pattern of behavioral response to ovarian hormones in unmated females was also documented, replicating the "biphasic" effect of progesterone in this species. The inhibitory effects of mating and progesterone summate to produce consistent decrements in female sexual receptivity. It is postulated that short-term postcopulatory abbreviations in receptivity would reduce the vulnerability of the estrous female while long-term inhibitions, interacting with sustained progesterone stimulation, would reduce the probability of mating during pregnancy when hormone levels are elevated for a prolonged period.