[Repeated dose toxicity studies of taltirelin tetrahydrate (TA-0910) with oral administration to dogs].
Taltirelin tetrahydrate (TA-0910), novel thyrotropin-releasing hormone (TRH) analogue, was orally administered to dogs as dose levels 0.5, 5, and 50 mg/kg for 13 weeks and 0.15, 1.5 and 15 mg/kg for 52 weeks. Blood concentrations of test substance measured in 52-week study revealed that absorption of TA-0910 was with dose-dependent manner and not changed through the treatment period. These toxicokinetics suggested that there were no alterations on metabolism of TA-0910 with repeated treatment. The animals receiving 5 or 50 mg/kg showed decrease in body weight or suppression of body weight gain, and decrease in food intake (13-week study). As an abnormality in general conditions, vomiting and salivation (5 mg/kg or more, both in 13- and 52-week studies), increase in behavior as water intake (5 mg/kg or more, 13-week study), and hyperlocomotion (50 mg/kg) were observed. Elevating GPT values were noted temporally in the animals treated with 5 mg/kg or more (both in 13- and 52-week studies) without abnormal findings in histopathology. The thyroid weights were increased in treated animals receiving 5 or 50 mg/kg in 13-week study, but no histopathological changes were noted. Electron microscopy revealed dilatation of granular endoplasmic reticulums in follicular cells of thyroid from 50 mg/kg group in 13-week study. It was concluded that no-effect levels of 13- and 52-week studies were 0.5 mg/kg and 1.5 mg/kg, respectively.
Inui
T
T
Safety Research Laboratory, Tanabe Seiyaku, Co., Ltd., Osaka, Japan.
Yuasa
H
H
Adachi
T
T
Kawai
Y
Y
Kudow
S
S
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced; D008297:Male; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D012472:Salivation / Q000187:drug effects; D013961:Thyroid Gland / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D018697:Nootropic Agents; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone; D000410:Alanine Transaminase