A diuretic effect of the pentapeptide BW942C [Tyr-D-Met(O)-Gly-pNO2-Phe-Pro-NH2 HCl] was demonstrated in humans and rats; it was characterized pharmacologically using whole animal, isolated tissue and in vitro binding studies. A single 2-mg dose of BW942C increased urine output 5-fold over control values in humans. In Long-Evans rats, BW942C produced a biphasic dose-response curve for urine output with lower doses increasing and higher doses suppressing output. Low doses of naltrexone antagonized the antidiuresis, and high doses antagonized the diuresis produced by BW942C. BW942C was less efficacious in producing diuresis than the full kappa agonists bremazocine and U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate, hydrate). Furthermore, BW942C antagonized the diuretic effects of bremazocine and U50,488H. Rats tolerant to U50,488H-induced diuresis were cross-tolerant to BW942C. In Brattleboro rats, which are unable to synthesize vasopressin, BW942C failed to produce a diuretic effect, demonstrating the necessity of vasopressin for its diuretic response. In the kappa-selective rabbit vas deferens bioassay, BW942C was less efficacious than a full agonist, it was antagonized by naloxone and BW942C in nondepressant doses antagonized a full agonist. In binding studies, BW942C had the highest affinity for mu and delta opioid receptors and an intermediate affinity for kappa opioid receptors. The data suggest that BW942C has the property of a partial kappa opioid agonist in addition to being a mu agonist.

1988-04-01·Journal of Clinical Oncology1区 · 医学

Control of chemotherapy-induced diarrhea with the synthetic enkephalin BW942C: a randomized trial with placebo in patients receiving cisplatin.

1区 · 医学

Article

作者: R J Gralla ; L B Tyson ; M G Kris ; R A Clark ; S Groshen

Diarrhea commonly occurs following the administration of cisplatin. BW942C, a pentapeptide, is a synthetic enkephalin shown to control castor oil-induced and traveler's diarrhea. To assess the safety and efficacy of BW942C in controlling diarrhea caused by cisplatin, 30 adults with lung cancer who had already experienced diarrhea (three or more loose bowel movements) during the 24-hour period following a prior cisplatin administration were randomized to receive either BW942C or placebo during the next cisplatin course. All patients received a concomitant antiemetic regimen including metoclopramide, dexamethasone, and lorazepam during all courses. Patients administered BW942C experienced less diarrhea (27% v 67%, P = .02). Twenty-seven percent of patients given the pentapeptide had loose bowel movements as opposed to 93% who received placebo (P = .0002). There were no significant differences in the incidence and degree of vomiting and other treatment-related side effects observed between the placebo and treatment groups. We conclude that oral BW942C is more effective than placebo in controlling diarrhea following cisplatin chemotherapy.

1988-01-01·Gastroenterology1区 · 医学

Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum

1区 · 医学

Article

作者: Holger Martens ; Helen M. Berschneider ; Don W. Powell

BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.

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