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.

CONCLUSION:

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: Salvatore Cuzzocrea, Emanuela Mazzon, Rosanna di Paola, Tiziana Genovese, Carmelo Muià, Achille P Caputi, Daniela Salvemini
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 52 Issue 12 Pg. 3755-60 (Dec 2005) ISSN: 0004-3591 [Print] United States
• PMID: 16320326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Antirheumatic Agents
• Cytokines
• Organometallic Compounds
• imisopasem manganese
• Manganese
• Superoxide Dismutase
• Methotrexate

Topics

• Animals
• Antioxidants (chemistry, pharmacology)
• Antirheumatic Agents (pharmacology)
• Arthritis, Experimental (drug therapy, pathology)
• Cytokines (blood)
• Drug Synergism
• Drug Therapy, Combination
• Male
• Manganese
• Methotrexate (pharmacology)
• Molecular Mimicry
• Organometallic Compounds (chemistry, pharmacology)
• Rats
• Rats, Inbred Lew
• Superoxide Dismutase (chemistry)
• Weight Gain (drug effects)