[Repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910) by oral administration to rats].
Four-, 13- and 52-week repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910), a thyrotropin-releasing hormone(TRH) analogue, were carried out in rats. Through the three studies, TA-0910 solution was administered orally at doses of 3, 30 and 300 mg/kg/day. The animals receiving TA-0910 showed hyperlocomotion, grooming and wet dog shaking which were attributable to the central effects similar to those of TRH, but there was no death nor obvious deterioration of health caused by the treatment. Body weights decreased in males of 300 mg/kg group, and food consumption was on the upward trend in females in 300 mg/kg group. In 13- and 52-week studies, females receiving 300 mg/kg showed elongated estrous cycle, although it was not an evident change. Blood examinations revealed increases in erythrocyte count, hemoglobin and hematocrit in 300 mg/kg group. Reductions in serum(plasma) proteins and lipids, and drug-metabolizing enzyme activity of the liver were regarded as non-specific changes, as they were sporadic and slight in 300 mg/kg group. Salivary gland and adrenal weights increased in 300 mg/kg group. For the thyroid, weights increased in 300 mg/kg group in the 4- and 13-week studies, and increases of microfollicles and cell debris were observed microscopically in each treated group in the 52-week study. These changes seemed to be related with hormonal action of TA-0910, but the effects on animals were judged slight from plasma TSH and thyroid hormone levels after 4 weeks of dosing. The non-toxic dose was estimated to be 30 mg/kg/day, through the rat repeated dose toxicity studies. All the above changes were alleviated or abolished by 4-week recovery period.
Inui
T
T
Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Fujiwara
T
T
Susami
M
M
Hishida
N
N
Kuwamura
Y
Y
Kuse
H
H
Kawai
Y
Y
Kudow
S
S
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D006120:Grooming / Q000187:drug effects; D006948:Hyperkinesis / Q000139:chemically induced; D008297:Male; D018697:Nootropic Agents / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D013997:Time Factors
D018697:Nootropic Agents; C065049:TA 0910; D013973:Thyrotropin-Releasing Hormone