title: Synergistic interaction between methotrexate and a superoxide dismutase mimetic: pharmacologic and potential clinical significance.
abstract: OBJECTIVE
  To investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen-induced arthritis (CIA) in rats.
  
  
  METHODS
  CIA was elicited in Lewis rats that had been assigned to different experimental groups, and the rats were treated daily, starting at the onset of arthritis (day 26), with M40403 2 mg/kg intraperitoneally, MTX 0.15 mg/kg orally, or combination therapy (M40403 2 mg/kg plus MTX 0.015 mg/kg).
  
  
  RESULTS
  The histopathologic features of CIA in type II collagen-challenged rats included erosion of the articular cartilage and bone resorption. Treatment of rats with MTX 0.15 mg/kg orally delayed the development of clinical signs (days 26-35) and improved histologic status in the knee and paw, as clearly demonstrated by a significant reduction in erosion of the articular cartilage at the joint margins and subchondral bone resorption. Furthermore, radiographic evidence of protection against bone resorption and soft tissue swelling was apparent in the tibiotarsal joints of rats treated with MTX 0.15 mg/kg daily. Furthermore, combination therapy with M40403 2 mg/kg plus MTX 0.015 mg/kg exerted significant protection against the development of arthritis, similar to that observed with MTX alone at a dose of 0.15 mg/kg. In contrast, no significant protection was observed in animals treated with M40403 2 mg/kg alone or with MTX 0.015 mg/kg alone.
  
  
  CONCLUSIONS
  This study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.
authors.affiliation: University of Messina, Messina, Italy. salvator@unime.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Rosanna
authors.initials: R
authors.lastname: di Paola
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Achille P
authors.initials: AP
authors.lastname: Caputi
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008297:Male; D008345:Manganese; D008727:Methotrexate / Q000494:pharmacology*; D018716:Molecular Mimicry; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013482:Superoxide Dismutase / Q000737:chemistry; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000975:Antioxidants; D018501:Antirheumatic Agents; D016207:Cytokines; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase; D008727:Methotrexate