[Four-week intravenous toxicity study of montirelin hydrate (NS-3) in dogs followed by 4-week recovery test].
A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.002, 0.02, 0.2, 2 and 20 mg/kg in males and 0, 0.2, 2 and 20 mg/kg in females. After discontinuation of the treatment, a 4-week recovery test was also conducted in the 0 and 20 mg/kg groups. No deaths related to the treatment were observed. There were no changes in body weight gain, and food and water consumptions. Nasal discharge was seen in all dose groups. Salivation, emesis and hypoactivity were observed in the 0.2 mg/kg group and over. Licking chops were seen in the 2 and 20 mg/kg groups. Trembling and agitated/restless behavior were seen in the 20 mg/kg group. Electrocardiographic examination revealed elevated heart rate in the 0.2 mg/kg group and over. Ophthalmoscopic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination disclosed increases in T3 level in the 2 and 20 mg/kg groups of males and in T4 level in the 0.2 mg/kg group and over of males. There were no pathological findings attributable to the treatment. The changes mentioned above were satisfactorily reversible. The nasal discharge seen in the 0.02 mg/kg group and below was considered to be of no toxicological significance. These results show that the NOAEL of montirelin hydrate is 0.02 mg/kg for 4-week repeated dose toxicity in dogs.
Harling
R J
RJ
Huntingdon Research Centre Ltd., Cambridgeshire, England.
Gopinath
C
C
Matthiesen
T
T
Ishibashi
S
S
Iwakura
K
K
Sumi
N
N
D017109:Akathisia, Drug-Induced; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D012472:Salivation / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D013997:Time Factors; D014202:Tremor / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
C031926:montirelin; D013973:Thyrotropin-Releasing Hormone