ABSTRACT
Currently available treatments for radiation-induced nausea and vomiting either are ineffective or reduce performance. The new antiemetic and gastrokinetic agent zacopride was tested in rhesus monkeys to assess its behavioral toxicity and its ability to inhibit radiation-induced emesis. Zacopride (intragastric, 0.3 mg/kg) or a placebo was given blindly and randomly in the basal state and 15 min before a whole-body 800 cGy 60Co gamma-radiation dose (except for the legs which were partially protected to permit survival of some bone marrow). We determined (1) gastric emptying rates; (2) the presence and frequency of retching and vomiting; and (3) the effect of zacopride on the performance of a visual discrimination task in nonirradiated subjects. No vomiting, retching, or decreased performance was observed after either placebo or zacopride in the control state. Following irradiation plus placebo, 70 emeses were observed in 5 of 6 monkeys, and 353 retches were observed in all 6 monkeys. In contrast, only 1 emesis was observed in 1 of 6 monkeys and 173 retches were seen in 4 of 6 monkeys after irradiation plus zacopride (P less than 0.01). Zacopride also significantly inhibited radiation-induced suppression of gastric emptying. When given after the first vomiting episode in a separate group of irradiated monkeys, zacopride completely prevented any subsequent vomiting. The present results demonstrate that intragastric administration of zacopride significantly inhibited radiation-induced retching, vomiting, and suppression of gastric emptying in rhesus monkeys and did not cause detectable behavioral side effects when given to nonradiated monkeys. This observation has important implications in the treatment of radiation sickness.
Subject(s)
Benzamides/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/therapeutic use , Bridged-Ring Compounds/therapeutic use , Gastrointestinal Diseases/etiology , Radiation Injuries, Experimental/complications , Animals , Behavior, Animal/drug effects , Benzamides/pharmacology , Benzamides/toxicity , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds/toxicity , Discrimination, Psychological/drug effects , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/prevention & control , Macaca mulatta , MaleABSTRACT
As a prelude to neurobehavioral toxicologic studies in neonatal minipigs, normal maturational changes in the visual evoked response (VER) were determined in 6 Hormel-bred minipigs. The VER were highly variable for the 1st several days of life, but were reasonably stable by the 2nd weeks. All adult waveform components were present at birth, and maturational changes primarily affected waveform latency and consistency. Only one waveform (Pi) was sufficiently distinct and consistent for statistical evaluation. At birth the latency to Pi was about 102 ms. The latency of Pi rapidly decreased to about 56 ms during the next 25 days, and subsequent changes were minimal. Comparison with other species indicates many cross-species relationships of specific VER components, with the minipig VER having many maturational and topographic similarities to the human VER.
