Toxicity of the novel anti-peptic ulcer agent polaprezinc in beagle dogs.
A preliminary dose-range finding study, two 13-week studies and a 52-week study were performed in beagle dogs with polaprezinc (catena-(S)-[mu-[Na-(3-aminopropionyl)histidinato (2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7, Z-103), a novel anti-peptic ulcer agent, as part of a safety evaluation program. In the preliminary single-dose study, treatment-related findings were confined to one animal treated with 200 mg/kg and consisted in emesis and mucosal lesions in the stomach and upper small intestine. Based on these data, dosages were selected for the main 13-week study (0, 50, 120 and 300 mg/kg/day) and additional 13-week study (0, 8 and 20 mg/kg/day). The dosages for the 52-week study were 8, 20 and 50 mg/kg/day. In the 13-week studies, dosages of 50 mg/kg/day and above resulted in emesis, mild diarrhea and salivation; reduced food consumption and associated reduction in body weight gain for high dosed females; increased blood alkaline phosphatase and decreased urinary specific gravity; histopathological changes in the kidney of the high dosed group in males and females. These changes were no longer apparent following the withdrawal period. In the 52-week study, similar but milder and transient results were noted at the high dose of 50 mg/kg/day. From these results, the no-effect dose level was estimated to be 20 mg/kg b.w./day.
Matsuda
K
K
Department of Toxicology, Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
Yamaguchi
I
I
Wada
H
H
D000818:Animals; D000897:Anti-Ulcer Agents / Q000633:toxicity*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002336:Carnosine / Q000031:analogs & derivatives*; D004151:Dipeptides / Q000633:toxicity*; D004285:Dogs; D004435:Eating / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005123:Eye / Q000187:drug effects; D005260:Female; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009942:Organometallic Compounds / Q000633:toxicity*; D010437:Peptic Ulcer / Q000188:drug therapy*; D017967:Zinc Compounds
D000897:Anti-Ulcer Agents; D004151:Dipeptides; D009942:Organometallic Compounds; D017967:Zinc Compounds; C061957:polaprezinc; D002336:Carnosine