Preventive effect of a novel antifolate, MX-68, in murine systemic lupus erythematosus (SLE).
We evaluated the preventive effects of a novel nonpolyglutamatable antifolate, MX-68, on two experimental murine models of systemic lupus erythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-host disease (GVHD) mice, in comparison with classical antifolate methotrexate (MTX). The oral administration of 2 mg/kg MX-68, three times a week from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting from the development of lupus nephritis was also inhibited. However, MX-68 did not suppress the increase of serum anti-DNA or anti-TNP antibodies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVHD mice, MX-68 given three times a week from the day of first cell injection, for 9 weeks, dose-dependently delayed the appearance of proteinuria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DNA and anti-TNP antibodies was significantly inhibited, but this was not observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These beneficial effects of MX-68 were much greater than those of MTX in both models. These results suggest that MX-68 might be a more useful drug for the treatment of SLE.
Mihara
M
M
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Shizuoka, Japan.
Takagi
N
N
Urakawa
K
K
Moriya
Y
Y
Takeda
Y
Y
D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001806:Blood Urea Nitrogen; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000150:complications / Q000188:drug therapy; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008181:Lupus Nephritis / Q000517:prevention & control; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D008814:Mice, Inbred NZB; D011507:Proteinuria / Q000517:prevention & control
D001323:Autoantibodies; D005493:Folic Acid Antagonists; C104193:N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro -2H-1,4-benzothiazine-7-carbonyl)-L-2-aminoadipic acid; D015074:2-Aminoadipic Acid; D002784:Cholesterol; D008727:Methotrexate