Abstract
Purpose: Opioid agonists are commonly used for chronic pain management, but debilitating constipation is a frequent dose-limiting side effect. Guanylate cyclase-C (GC-C) agonists are a new class of drug candidates for the treatment of gastrointestinal (GI) disorders. SP-333, a proteolysis-resistant analog of uroguanylin, activates GC-C to stimulate production of cyclic GMP (cGMP), a second messenger that promotes intestinal secretion and gut motility. Nonclinical toxicology studies have shown that repeated oral doses of SP 333 are well-tolerated in mice and monkeys. SP-333 is currently under clinical development for the treatment of ulcerative colitis. In the current study, the efficacy of SP-333 was assessed in a rat model of opioid-induced bowel dysfunction. Methods: Female CD rats (170-210 g; n=10-12/group) received an intraperitoneal dose of vehicle (water) or 2.5 mg/kg morphine followed by an oral dose of 0 (vehicle), 0.5, 5, or 50 mg/kg of SP-333. A charcoal meal was administered 10 min later, rats were euthanized after an additional 10 min, and GI transit was measured (distance traveled by leading edge of charcoal divided by total length of small intestine). Results: A single dose of morphine significantly reduced GI transit in rats (23.4% in morphine-treated vs 53.3% in vehicle-treated; p≤0.001). SP-333 produced a dose-dependent improvement in gut transit in morphine-treated rats, restoring transit to near normal levels following doses of 5 mg/kg (45.8%) or 50 mg/kg (48.4%) (p≤0.001 for both groups). Conclusion: Treatment with SP-333 accelerated gut transit in morphine-administered rats in a dosedependent manner, possibly via the known cGMP-mediated mode of action. In combination with previously completed toxicology studies, these data support the potential utility of SP 333 and other GC-C agonists as safe oral drug candidates for the treatment of opioid-induced bowel dysfunction. Disclosure - Mr. Kramer, Dr. Palejwala, Dr. Foss and Dr. Shailubhai are employees of Synergy Pharmaceuticals, Inc.Figure
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