title: Combination benefit of a pyrimidylpiperazine derivative (Y-40138) and methotrexate in arthritic rats.
abstract: Anti-tumor necrosis factor-alpha (TNFalpha) antibody in combination with methotrexate dramatically decreases joint destruction in rheumatoid arthritis. The aim of this study was to examine combined treatment with N-[1-(4-([4-(pyrimidin-2-yl)piperazin-1-yl]methyl)phenyl)cyclopropyl] acetamide HCl (Y-40138) and methotrexate in rat adjuvant-induced arthritis. The increase in hindpaw volume and joint destruction was suppressed by single therapeutic administration (days 15-20) of Y-40138 (30 mg/kg, p.o.), but not by prophylactic administration (days 1-9). However, arthritic progression was suppressed by single prophylactic administration of methotrexate (0.3 mg/kg, p.o.), but not by therapeutic administration. Combined administration (days 10-20) of Y-40138 (0.3-1 mg/kg) and methotrexate (0.03 mg/kg) synergistically suppressed the increase in hindpaw volume and joint destruction. We concluded that Y-40138 in combination with methotrexate synergistically suppressed arthritic progression. These data suggest that combined treatment with Y-40138 and methotrexate may increase efficacy of therapy for rheumatoid arthritis.
authors.affiliation: Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Hisadome.Masao@mm.m-pharma.co.jp
authors.forename: Masao
authors.initials: M
authors.lastname: Hisadome
authors.forename: Tetsuko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Kunitomo
authors.initials: K
authors.lastname: Adachi
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Komatsu
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006614:Hindlimb; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000081:Acetamides; D000906:Antibodies; D018501:Antirheumatic Agents; D010879:Piperazines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; D008727:Methotrexate