More on the need for circadian,circaseptan and circannual optimization of cyclosporine therapy

Summary Cyclosporine chronotherapy of pancreas-allotransplanted rats revealed, beyond a circadian stage-dependence of equal daily doses, further gain in graft function from doses varying from day to day with an about 7-day periodicity, the first highest dose being given on the 3rd or 5th day after surgery.     

In vivo effect of sodium valproate on mouse liver

The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.     

Estrogenic inhibition of testicular growth by R2858 in preweanling rats

Daily injections of physiologic doses of R2858 into preweanling rats from the 10th to the 19th day of age resulted in reduced testicular growth compared to controls. Body weights and other organ weights were unaffected. Leydig cells were smaller and less numerous, and showed distinct changes in ultrastructural morphology. Results of this study suggest that alpha-fetoprotein permits normal testicular development during postnatal life.     

The effect of methaqualone on prenatal development in the rat

Methaqualone treatment of pregnant rats in doses of 100-200 mg/kg day produces resorption and a series of anomalies whose incidence increases with the dose-level employed.     

Teratogenic interactions between cadmium and radiation in mice

Summary Mouse embryos were exposed to various doses of cadmium and/or X-rays on day 8 of gestation. The combined treatment exerted an antagonistic effect regarding the teratogenic action of the two agents.     

Placental permeability of arsenate ion during early embryogenesis in the hamster

Summary Sodium arsenate crosses the placental barrier in pregnant Syrian hamsters following injection in teratogenic or tracer doses on the 8th day of gestation.This work was supported by USPHS grant ES-00697.     

DNA fragmentation in leukocytes following subacute lowdose nerve agent exposure

The objective of the present study was to determine levels of DNA fragmentation in blood leukocytes from guinea pigs by single-cell gel electrophoresis (comet assay) after exposure to the chemical warfare nerve agent (CWNA), soman, at doses ranging from 0.1 LD₅₀ to 0.4 LD₅₀, once per day for either 5 or 10 days. Post-exposure recovery periods ranged from 0 to 17 days. Leukocytes were imaged from each animal, and the images analyzed by computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA-treated guinea pigs compared with saline-injected control animals at all doses and time points examined. Notably, significantly increased DNA fragmentation was observed in leukocytes 17 days after cessation of soman exposure. Our findings demonstrate that leukocyte DNA fragmentation assays may provide a sensitive biomarker for low-dose CWNA exposure.Received 29 July 2003; accepted 14 August 2003     

Bombesin promotes pancreatic growth in suckling rats

The pancreatic growth promoting effect of long term administration of bombesin was investigated in suckling rats. The authors showed that bombesin given in 10 micrograms/kg b.wt doses s.c. every 8 h for 10 days from the day of parturition stimulated pancreatic growth: it increased pancreatic weight, protein and DNA content, trypsin and amylase activity and trypsin/DNA ratio. Conclusion: Bombesin is an effective stimulator of pancreatic growth in suckling rats.     

Effect of low dose of 70 kVp X-rays on the intrauterine development of mice

Pregnant Swiss albino mice were exposed to low doses of X-rays (approximately 9 mGy) in the range used for diagnostic exposure, on day 3.5 of gestation (preimplantation period), day 6.5 (early organogenesis period) or day 11.5 (late organogenesis period). The fetuses were examined on the 18th day of gestation. Exposure at 3.5 days post coitus (d.p.c.) resulted in a significant increase in prenatal mortality, and an increased incidence of retarded fetuses was observed after exposure at 3.5 and 6.5 d.p.c. The major effect of exposure at 11.5 d.p.c. was a significant decrease in the fetal head size and brain weight.     

Effect of progesterone on male and female sex behavior induced by steroid hormones in adult ovariectomized ewes]

Ovariectomized adult Ewes daily treated with I/M injections of testosterone propionate (10 mg/day) or oestradiol benzoate (200 microgram/day) show male-like sexual behaviour and simultaneously a permanent female receptivity. Additional daily treatment with 100 mg of progresterone results in a rapid decrease in male sexual responses both when Ewes are treated with testosterone and with oestradiol. No effect is observed on the female receptivity. Cyproterone acetate (100 mg/day) given to Ewes in addition to daily injection of testosterone propionate (10 mg/day) has effects similar to those of progesterone. These results show that progesterone has antiandrogen and antioestrogen properties and that this hormone administered at high doses is able to inhibit male activity.     

Low doses of 2,4,5-trichlorophenoxyacetic acid are behaviorally teratogenic to rats

Pre-natal exposure of rats to 2,4,5-T has long-term effects on behavior. A test for novelty responding detects abnormalities after exposure to a single dose as low as 6 mg/kg on day 8 of gestation. This is well below doses reported to be morphologically teratogenic, and raises concern for human exposure.     

Low doses of 2,4,5-trichlorophenoxyacetic acid are behaviorally teratogenic to rats

Summary Pre-natal exposure of rats to 2,4,5-T has long-term effects on behavior. A test for novelty responding detects abnormalities after exposure to a single dose as low as 6 mg/kg on day 8 of gestation. This is well below doses reported to be morphologically teratogenic, and raises concern for human exposure.     

Effect of low dose of 70 kVp X-rays on the intrauterine development of mice

Summary Pregnant Swiss albino mice were exposed to low doses of X-rays (9 mGy) in the range used for diagnostic exposure, on day 3.5 of gestation (preimplantation period), day 6.5 (early organogenesis period) or day 11.5 (late organogenesis period). The fetuses were examined on the 18th day of gestation. Exposure at 3.5 days post coitus (d.p.c.) resulted in a significant increase in prenatal mortality, and an increased incidence of retarded fetuses was observed after exposure at 3.5 and 6.5 d.p.c. The major effect of exposure at 11.5 d.p.c. was a significant decrease in the fetal head size and brain weight.     

The effect of methaqualone on prenatal development in the rat

Summary Methaqualone treatment of pregnant rats in doses of 100–200 mg/kg day produces resorption and a series of anomalies whose incidence increases with the dose-level employed.Acknowledgment. Supported by the National Research Council of Canada, grant No. A0292. Methaqualone was generously supplied by W. H. Rorer, Canada, Ltd.     

Effects of low doses of ochratoxin A after intratesticular injection in the rat.

The toxic effect of various doses of ochratoxin A on the rat testis was investigated after a single intratesticular injection. At time of sacrifice (day 10) degenerating changes occur in the testicular tissues: seminiferous tubules dilatation, cytolysis of the seminiferous epithelium, hyperplasia of the interstitial tissue, vascular thrombosis. The relations between the blood supply disturbances and the observed lesions are discussed.     

Effects of low doses of ochratoxin A after intratesticular injection in the rat

Summary The toxic effect of various doses of ochratoxin A on the rat testis was investigated after a single intratesticular injection. At time of sacrifice (day 10) degenerating changes occur in the testicular tissues: seminiferous tubules dilatation, cytolysis of the seminiferous epithelium, hyperplasia of the interstitial tissue, vascular thrombosis. The relations between the blood supply disturbances and the observed lesions are discussed.     

Bombesin promotes pancreatic growth in suckling rats

Summary The pancreatic growth promoting effect of long term administration of bombesin was investigated in suckling rats. The authors showed that bombesin given in 10 g/kg b.wt doses s.c. every 8 h for 10 days from the day of parturition stimulated pancreatic growth: it increased pancreatic weight, protein and DNA content, trypsin and amylase activity and trypsin/DNA ratio. Conclusion: Bombesin is an effective stimulator of pancreatic growth in suckling rats.     

Estrogenic inhibition of testicular growth by R2858 in preweanling rats

Summary Daily injections of physiologic doses of R2858 into preweanling rats from the 10th to the 19th day of age resulted in reduced testicular growth compared to controls. Body weights and other organ weights were unaffected. Leydig cells were smaller and less numerous, and showed distinct changes in ultrastructural morphology. Results of this study suggest that -fetoprotein permits normal testicular development during postnatal life.The authors would like to thank Dr Deltour of Roussel UCLAF for the gift of R2858.     

Inhibition of post-hemicastration hypertrophy of the remaining testis by testosterone or aqueous testicular extract treatments in the young rat]

In the 10 day old hemicastrated Rat daily injections of testosterone (total doses of 0.04 to 4 mg/Rat) or of proteinaceous extract of Rat testis (4 mg/Rat) inhibit compensatory hypertrophy of the remaining testis. Both testosterone and testicular proteinaceous extract could be involved in the growing processes of the testis, locally or by means of modification of gonadotropin secretion. Results have been analysed by covariance analysis to eliminate the influence of body weight variations.     

Bacterial endotoxin and impaired fetal development

Summary Small doses ofE. coli endotoxin given to pregnant mice on the 13th day of pregnancy caused only a mild maternal illness but induced resorption of approximately half the number of fetuses in each mouse. The remaining live fetuses developed normally and showed no evidence of retarded growth or malformations. The weights of their placentas and maternal spleens increased significantly. Endotoxin given on the 6th day of pregnancy caused a small reduction in fetal weights.Acknowledgments. I am indebted to Mrs.Heather Sandison for technical assistance and to Mr.M. J. R. Healy for statistical examination of the results. Dr.A. B. G. Lansdown kindly advized on the interpretation of histological findings.