T.P.6 Combination anti-inflammatory and anti-fibrotic treatment in muscular dystrophy – The more the better?

Abstract

Congenital muscular dystrophy is an incurable disorder with no effective treatment. Anti-inflammatory and anti-fibrotic agents have been suggested as potential therapies. As previously demonstrated by our group, Glatiramer acetate (GA), an anti-inflammatory agent and the anti-fibrotic agent Losartan exert their effect through different pathways and have distinct beneficial effects on strength, mobility and fibrosis. Thus, the aim of the present study was to evaluate the effect of combination therapy of GA with Losartan in the dy2J/dy2J mouse model of congenital muscular dystrophy. Fore and hind limb muscle strength, fibrosis and mobility parameters were assessed. dy2J/dy2J mice receiving the combination of GA/Losartan or GA alone showed mild improvement in forelimb muscle strength (11%) in contrast to treatment with Losartan alone (74%). Hind limb muscle strength was unchanged in dy2J/dy2J mice receiving the combination therapy, while the two drugs alone showed significant improvement in strength (GA; 52.7% vs. Losartan; 74%). The combined treatment showed only mild reduction in muscle fibrosis (20%) compared with Losartan alone (42.3%. No significant change for GA). GA/Losartan combination therapy or Losartan alone showed no change in mobility parameters. However, treatment with GA alone resulted in a marked improvement in mobility parameters. In conclusion, the improvements seen with GA/Losartan combination therapy were less noticeable than the improvements of each of the two agents administered as a single medication. We conclude that combination therapy should be administered with caution. Combining two medications with theoretical synergistic effect and previous positive effect may result in a reduction of the therapeutic effect compared to the use of each of these agents separately.