Synergistic interaction between methotrexate and a superoxide dismutase mimetic: pharmacologic and potential clinical significance.
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.
Cuzzocrea
Salvatore
S
University of Messina, Messina, Italy. salvator@unime.it
Mazzon
Emanuela
E
di Paola
Rosanna
R
Genovese
Tiziana
T
Muià
Carmelo
C
Caputi
Achille P
AP
Salvemini
Daniela
D
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
D000975:Antioxidants; D018501:Antirheumatic Agents; D016207:Cytokines; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase; D008727:Methotrexate