The effects of diphenyl dimethyl dicarboxylate (PMC) on oral tolerance to ovalbumin (OVA) were investigated in C3H/HeN and BALB/c mice. Mice orally received 20 mg OVA or 2% starch solution were immunized 7 days later with an i.p. injection of 0.1 mg OVA in complete Freund's adjuvant (CFA). The effects of oral OVA and PMC on antibody production were assessed by ELISA of immunoglobulin (Ig) subclass level in serum collected 7 days after immunization. Oral tolerance was obtained enough on day 7 after immunization and was more effective in C3H strain than in BALB strain, associated mainly with decreases of anti-OVA IgG, IgG1, IgG2a and IgM levels. After oral OVA, oral administrations of PMC for 6 days significantly elevated anti-OVA IgG, IgG1, IgG2a and IgM levels in mice hyposensitized by the oral OVA. These findings indicate that PMC is an useful modulator of oral tolerance to OVA in these two strains.
Pdn/+ female mice, mated with Pdn/+ males, were treated with 40 mg/kg body weight of all-trans-retinoic acid (RA) intraperitoneally on day 10 or 11 of gestation, and effects on the limb development were investigated. RA treatment induced the shortening of stylopodium and zygopodium. In the present experiment, we focused on the differences between genotypes in the shortening of stylopodium and zygopodium induced by RA. The effects of RA were milder in Pdn/Pdn than +/- (Pdn/+ and/or +/+) fetuses. The differences between genotypes in the effects of RA were more significant in the group treated on day 11 than on day 10 of gestation. Cartilage of stylopodium and zygopodium was longer in day-13 Pdn/Pdn embryos exposed to RA on day 11 of gestation than those in similarly treated +/- embryos. Many apoptotic cells were observed in the mesenchyme of the forelimb plates at 12 hr after injection of RA on day 11 of gestation. These results suggest than the Pdn gene might influence the apoptosis induced by RA in the mesenchymal cells of the limb, causing milder effects in the shortening of stylopodium and zygopodium in Pdn/Pdn fetuses.
Effects of repeated s.c. treatments with 50 μmol (approx. 31 mg)/kg/day of neomycin for 10 or 15 days were examined in mice. There were no significant differences between saline and neomycin treatment groups in the motor coordination assessed by rota-rod test and traction test. On tension recordings, an in vitro addition of d-tubocurarine inhibited the twitch tensions evoked by the nerve stimulations in both cases of saline or neomycin treatment. Neomycin treatments shifted the concentration-response curve between twitch tension and d-tubocurarine to the left, dependently on its injection days. These results suggest that repeated treatments with neomycin enhance the inhibitory effect of d-tubocurarine on the neuromuscular transmission in mice without eliciting motor incoodination and muscle relaxation.
Active oxygens cause major tissue damages in a number of distress syndromes. Pentoxifylline (POF) and its metabolites, a methylxanthine derivative, are inhibitors of superoxide anion production in stimulated human leukocytes. Examination was made of the effects of POF on the genotoxic actions of active oxygens. The frequency of sister-chromatid exchanges (SCEs) induced by paraquat (PQ), a generator of superoxide anions, was significantly reduced in cultured Chinese hamster lung cells (CHL/IU) pretreated with POF. POF metabolite samples were also effective. Superoxide anion scavenging effect of POF were found at 0.1 mM, and it was more potent than that of POF metabolite samples. POF and its metabolite sample inhibited xanthine oxidase (XOD) at 1 mM but not at 0.1 mM. POF would thus appear to protect cells from the toxic effects of active oxygens on chromosomes and tissue damage by not only inhibition of active oxygen production in leukocytes but also by scavenging activity of active oxygens.
The testicular toxicity of cyclophosphamide (Cp) in rats was evaluated by quantitative morphometry of spermatogenic cycle stage. Nine-week-old male Sprague-Dawley rats in Group 1 were given a single oral administration of 100 mg/kg of Cp, and were sacrificed at 1, 7, 14 and 21 days thereafter. Rats in Group 2 were orally given 100 mg/kg/day of Cp for 2 days, followed by 50 mg/kg/day for the next 3 days, and were sacrificed at 1 and 4 days after the last administration. The numbers of seminiferous epithelia were counted in the seminiferous tubules of stages II, V, VII and XII of the spermatogenic cycle. The data were expressed as numbers of spermatogenic cells per Sertoli cells per seminiferous tubule cross section. Animals in Group 1 showed decreased preleptotene spermatocytes at Day 7, decreased zygotene spermatocytes at Day 14, and decreased pachytene spermatocytes at Day 21. In group 2, testicular toxicity could also be clearly detected by this morphometric approach. The present morphometric study thus indicates that testicular toxicity can be detected from Day 7 even after a single administration of Cp.
The effects of nifedipine on the development of physical dependence on barbital and diazepam in rats were examined using the drug-admixed food method. Rats were chronically treated with either barbital- or barbital in combination with nifedipine-admixed food for 28 days, and with either diazepam- or diazepam in combination with nifedipine-admixed food for 26 days, on schedules of gradually increasing doses of barbital or diazepam. Withdrawal was conducted by substituting normal food for drug-admixed food on the last day of the treatment. Co-administration of nifedipine with barbital potentiated body weight loss and withdrawal scores after the termination of barbital treatment. However, the withdrawal signs after the termination of diazepam treatment were not affected by co-administration of nifedipine with diazepam. These results suggest that nifedipine potentiates the development of physical dependence on barbital but not diazepam. It is known that co-administration of dihydropyridine derivative nitrendipine suppresses the development of physical dependence on ethanol. Basing on the differences in sensitivity of central depressants, barbiturates, benzodiazepines and ethanol, to three types of voltage-dependent Ca2+ channels, such as L-, N- and T-types studied so far, the development of physical dependence on central depressants may be modified differently by L-type Ca2+ channel blockers, corresponding to respective depressants.