[A fifty two-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in dogs].
A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a newly developed anti-allergic agent, was carried out in beagles by oral administration of 30, 90, 270 and 810 mg/kg/day for 52 weeks. The recovery study was carried out by the withdrawal for 5 weeks using control and the 810 mg/kg groups. The results are as follows: 1. Observation of general conditions revealed soft feces, mucous feces, and diarrhea in both sexes of the 270 and 810 mg/kg groups during the administration period, and these findings disappeared during the withdrawal period. One female of the 810 mg/kg group exhibited tremors in the legs and neck, staggering, a decrease of spontaneous motor activity, and clonic convulsions in Week 17 of administration and died on Day 118. One male of the same group exhibited whole body tremors and staggering from Week 32 to Week 52. 2. Body weight gain tended to be inhibited in males of the 810 mg/kg group during the administration period. The body weight of the female that died decreased rapidly after the appearance of neurological symptoms. The body weight of the male that exhibited neurological symptoms decreased after their appearance but later increased. 3. There were no abnormal changes in food consumption in all of the sacrificed dogs. The female that died did not eat at all after the appearance of neurological symptoms. The male that exhibited neurological symptoms did not eat at all for 1 week after their appearance, but the food consumption returned to normal thereafter. 4. Prothrombin times were prolonged in males of the 270 and 810 mg/kg groups at Week 26, and activated partial thromboplastin times were prolonged in males of the 810 mg/kg group at Week 52. 5. Plasma levels of alkaline phosphatase, GPT and LDH were elevated in some males and females of the 810 mg/kg groups. 6. No abnormalities due to IPD-1151T administration were found in urinalysis, opthalmological examination, electrocardiography, and fecal occult blood examination, or organ weights. 7. Autopsies including histopathological and electron microscopic examinations on the sacrificed dogs revealed no abnormalities. Subserosal hemorrhage in the base of the heart, congestion in the lungs, congestion and vacuolation in the liver and slight cell infiltration around vessels of the brain were found in the female that died.(ABSTRACT TRUNCATED AT 400 WORDS)
Aoki
M
M
Hatano Research Institute, Food and Drug Safety Center, Kanagawa, Japan.
Ohtaki
T
T
Seki
T
T
Kojima
K
K
Yoshimura
S
S
Ikeda
H
H
Kawaguchi
H
H
Katsumura
H
H
Yamaguchi
K
K
Inada
H
H
D000284:Administration, Oral; D000818:Animals; D001190:Arylsulfonates / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D013452:Sulfonium Compounds / Q000008:administration & dosage / Q000633:toxicity*
D001190:Arylsulfonates; D006633:Histamine Antagonists; D013452:Sulfonium Compounds; C073028:suplatast tosilate