title: A novel antifolate, MX-68, inhibits the development of autoimmune disease in MRL/lpr mice.
abstract: We compared a novel unpolyglutamable antifolate, MX-68, with polyglutamable antifolate, methotrexate (MTX), for treatment of an autoimmune kidney disease which develops spontaneously in MRL/Mp-lpr/lpr (MRL/lpr) mice. Oral administration of either MX-68 or MTX was commenced in 8-week-old female mice and continued 3 times a week until they reached 30 weeks of age. MX-68 delayed the onset of proteinuria and prolonged life span dose-dependently. Furthermore, it suppressed the elevation of serum blood urea nitrogen and cholesterol levels. MX-68 was as effective as MTX at ameliorating events which accompany the development of lupus nephritis, despite that MX-68 did not undergo polyglutamation. These ameliorative effects of MX-68 and MTX did not occur via inhibition of either autoantibody production or cell proliferation. Neither compound suppressed age-dependent elevation of immune complexes or antibodies for single-stranded DNA and TNP in serum nor did they influence the associated enlargement of lymph nodes and spleen. We conclude that MX-68 is beneficial for the treatment of autoimmune kidney disease in mice and may be useful for other related diseases such as systemic lupus erythematosus.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mihara
authors.forename: N
authors.initials: N
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Urakawa
authors.forename: Y
authors.initials: Y
authors.lastname: Moriya
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
mesh_terms: D015074:2-Aminoadipic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000936:Antigen-Antibody Complex / Q000032:analysis; D001323:Autoantibodies / Q000032:analysis / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000517:prevention & control; D001806:Blood Urea Nitrogen; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D008181:Lupus Nephritis / Q000188:drug therapy / Q000517:prevention & control; D008198:Lymph Nodes / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010851:Picrates / Q000276:immunology; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D004277:DNA, Single-Stranded; 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; D010851:Picrates; D015074:2-Aminoadipic Acid; D002784:Cholesterol; C005858:picric acid; D008727:Methotrexate