Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 6). 2- and 4-weeks administration study of haloperidol.

Haloperidol, a neuroleptic, was orally given to Sprague-Dawley rats for 2 or 4 weeks, starting at 8 and 6 weeks of age. The dose levels were 0, 30 and 60 mg/kg/day for the 4-week treatment groups, and 0, 30, 60 and 80 mg/kg/day for the 2-week treatment groups. On the day after the last administration, rats were anesthetized and sacrificed at 10 weeks of age. The absolute weights of the testes and epididymides were decreased after 2- and 4-weeks at 30 mg/kg/day or above. The absolute and relative weights of the prostate and seminal vesicles were also decreased after 2-weeks at 60 mg/kg/day or above, and 4-weeks at 30 mg/kg/day or above. The histopathological alterations observed after 2-weeks at 30 mg/kg/day were as follows: atrophy of Leydig cells, numerous necrotic pachytene spermatocytes in seminiferous tubules of stage VII, retention of mature spermatids, exfoliation of round spermatids in lumina of seminiferous tubules, cell debris in lumina of the epididymis. At 60 mg/kg/day or above, these alterations were pronounced. Histopathological changes were comparable to those detected after 4-weeks treatment. It was concluded that alterations of the male reproductive organs are detectable by a 2-week administration of haloperidol in rats to almost the same degree as after 4-weeks treatment.

Suppressive effects of Y-24180, a long-acting antagonist for platelet-activating factor, on allergic pulmonary eosinophilia in mice.

We studied the effects of (+/-)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethy l-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180), a long-acting antagonist for platelet-activating factor (PAF), on antigen-induced eosinophil infiltration and interleukin-5 (IL-5) release in the bronchoalveolar lavage fluid (BALF) of mice. Mice actively sensitized with ovalbumin (OA) were challenged by injecting intratracheally OA 3 times every fourth day. Both the number of eosinophils and level of IL-5 were significantly increased in the BALF 24 hr after the last OA challenge. Either Y-24180 or prednisolone was orally administered once a day for 10 days beginning one day before the first OA challenge. WEB2086, another PAF antagonist, was orally administered once or twice a day for 10 days. Y-24180 (0.3 - 3 mg/kg) suppressed the eosinophil infiltration in a dose-dependent manner and suppressed the IL-5 release at the highest dosage. Prednisolone (10 mg/kg) significantly suppressed both the eosinophil infiltration and IL-5 release. In contrast, WEB2086 affected neither the eosinophil infiltration nor IL-5 release when administered once a day (10 - 100 mg/kg/day). This drug never affected the IL-5 release but significantly suppressed eosinophil infiltration even when administered twice a day (30 - 200 mg/kg/day). These results indicate that the suppressive effect of Y-24180 on allergic pulmonary eosinophilia is due to not only to its long-lasting PAF-antagonism but also due to its suppressive effect on IL-5 release.