Efficacy of mizoribine in the treatment of systemic lupus erythematosus in children.

BACKGROUND: Mizoribine (MZR) is a novel immunosuppressant developed in Japan. As MZR is reported to be less toxic than other cytotoxic drugs, it is frequently used in Japan in the treatment of adult patients with rheumatoid arthritis or lupus nephritis. The objective of this study was to evaluate the efficacy of MZR in children with SLE. Nine female children with lupus nephritis who had undergone renal biopsy before starting MZR, were involved in this study. Their mean disease duration was 4.8 years at the time MZR treatment was initiated. Patients who had received intensive medications, such as methyl-prednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, and/or other immunosuppressants, within the 4 months prior to the start of the study, were excluded. METHODS: Patients treated with 3 mg/kg per day of MZR were monitored every month for up to 1 year. The efficacy of MZR was evaluated by the changes from baseline values of serum C3, serum C4, anti-dsDNA antibody titer, erythrocyte sedimentation rate (ESR), urinary protein, dosage of prednisolone (PSL), and the sum of the scores defined by these parameters. RESULTS: Favorable changes were observed in C3 and ESR after 2 months and 3 months of MZR therapy, respectively. At 3 months of MZR therapy, the sum of scores defined by the parameters for disease activity indicated that MZR was more effective in non-class IV nephritis patients (n = 5) than in class IV nephritis patients (n = 4) (P = 0.0197). All nine children involved in the study tolerated the MZR therapy well during the study. CONCLUSION: MZR was safe in lupus children, but its efficacy was limited in patients with non-class IV nephritis. Further study is necessary, in which higher dosages and/or earlier use of MZR is provided to a larger number of children.

Effects of pure 2,4-dichlorophenoxyacetic acid on cultured rat embryos.

2,4-dichlorophenoxyacetic acid (2,4-D), a plant growth regulator, has been used worldwide as a herbicide. Previously we evaluated the prenatal developmental effects of 2,4-D by feeding it to pregnant rats and found that it is maternally toxic and embryolethal, and it induces urogenital malformations in rat fetuses. In the study presented here, we investigated the effects of pure 2,4-D on rat embryos in whole embryo culture. Rat embryos on day 9.5 of gestation were cultured for 48 h at several concentration levels with pure 2,4-D (50-500 microg/mL). 2,4-D caused a concentration-related increase in the incidence of each malformation. Significant decreases in the number of somites were observed at a concentration of 100 microg/mL or more. At the concentration of 100 microg/mL, there was normal yolk sac circulation. This result suggests that 2,4-D has a detrimental effect on somite development and directly damages developing embryos.

Effects of supplemental L-methionine on E-64 [trans-epoxysuccinyl-1-leucyl-amido (4-guanido) butane]-induced dysmorphology in rat embryos cultured in vitro.

E-64 [trans-epoxysuccinyl-1-leucyl-amido (4-guanido) butane] is teratogenic, inducing a spec-trum of malformations in vivo and producing similar effects in vitro. Numerous studies support the concept that E-64-induced malformations result from embryonic nutritionaldeficiency, without affecting the maternal nutritional status. This has provided a useful model with which to investigate the nutritional requirements of the early embryo, as well as the role of various nutrients in the etiology of congenital defects. In the current investigation, we examined effects of L-methionine on E-64-induced embryotoxicity in vitro. For these experiments, we cultured rat embryos 9.5 days postconception (p.c.) for 48 hours with E-64 and/or L-methionine. We found that the addition of L-methionine to E-64-exposed cultures reduced optic abnormality and increased embryo protein. These results suggest that embryopathy largely results from a deficiency of L-methionine although E-64 limits the supply of all amino acids to the embryo. Furthermore, although endocytosis and degradation of proteins by the visceral yolk sac (VYS) supply most amino acids to the embryo, free amino acids may be compensatory when this source is reduced. These results support those of previous investigations that suggest L-methionine is a limiting nutrient for embryonic development.