oxadiazoles and Constipation

1. Naldemedine is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation. 2. This phase 1 study investigated the absorption, distribution, metabolism and excretion of naldemedine, following a single oral 2-mg dose of [oxadiazole-

Topics: Administration, Oral; Adult; Area Under Curve; Carbon Radioisotopes; Constipation; Healthy Volunteers; Humans; Inactivation, Metabolic; Intestinal Absorption; Male; Naltrexone; Nausea; Oxadiazoles; Tissue Distribution

SC-27166 is the result of continuing efforts to discover selective and orally active antidiarrheal agents. SC-27166, which is chemically unrelated to opiates or neuroleptics, possesses potent constipating and antidiarrheal activity in several animal models. Tolerance to the constipating actions of SC-27166 did not develop in mice. On the other hand, gut tolerance rapidly developed to morphine sulfate and loperamide. The basic mechanism of the antidiarrheal action of SC-27166 is a consequence of increased intestinal circular muscle contractile activity. Supportive pharmacological studies indicated that SC-27166 has equivocal analgesia in mice which is manifested at near toxic dose levels. SC-27166 was also evaluated for potential dependence liability in morphine abstinence-induced jumping in mice. The abstinence-induced jumping was suppressed to a far lesser extent by SC-27166 than by either loperamide or diphenoxylate at equal doses. SC-27166 was also devoid of anticbholinergic activity. When compared with the reference standards morphine and diphenoxylate, these pharmacological studies indicated that SC-27166 has a high degree of separation of undesirable central nervous system actions from its antidiarrheal properties and may have important therapeutic potential.

Topics: Analgesics; Animals; Antidiarrheals; Behavior, Animal; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Constipation; Diarrhea; Diphenoxylate; Diuresis; Dogs; Female; Gastrointestinal Motility; Haplorhini; Humans; Macaca mulatta; Male; Mice; Morphine; Naloxone; Oxadiazoles; Parasympatholytics; Rats; Substance Withdrawal Syndrome

Topics: Constipation; Coronary Disease; Humans; Oxadiazoles; Sodium; Sulfuric Acids