Co‐administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans

Abstract

Background and purpose: Current therapies for muscular dystrophy are based on corticosteroids. Significant side effects associated with these therapies have prompted several studies aimed at identifying possible alternative strategies. As inflammation and defects of nitric oxide (NO) generation are key pathogenic events in muscular dystrophies, we have studied the effects of combining the NO donor isosorbide dinitrate (ISDN) and the non-steroidal anti-inflammatory drug ibuprofen. Experimental approach: a-Sarcoglycan-null mice were treated for up to 8 months with ISDN (30 mg·kg -1 ) plus ibuprofen (50 mg·kg -1 ) administered daily in the diet. Effects of ISDN and ibuprofen alone were assessed in parallel. Drug effects on animal motility and muscle function, muscle damage, inflammatory infiltrates and cytokine levels, as well as muscle regeneration including assessment of endogenous stem cell pool, were measured at selected time points. Key results: Combination of ibuprofen and ISDN stimulated regeneration capacity, of myogenic precursor cells, reduced muscle necrotic damage and inflammation. Muscle function in terms of free voluntary movement and resistance to exercise was maintained throughout the time window analysed. The effects of ISDN and ibuprofen administered separately were transient and significantly lower than those induced by their combination. Conclusions and implications: Co-administration of NO and ibuprofen provided synergistic beneficial effects in a mouse model of muscular dystrophy, leading to an effective therapy. Our results open the possibility of immediate clinical testing of a combination of ISDN and ibuprofen in dystrophic patients, as both components are approved for use in humans, with a good safety profile.

Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies: evidence from Phase I studies in healthy volunteers

“…The results of the ISOFEN1 study confirmed the optimal tolerability of the combined therapy with ibuprofen and ISO previously documented in a pilot study in dystrophic patients 23. In mouse models of DMD, the effect of ISO plus ibuprofen is endowed with a synergistic therapeutic effect 25,26. The similar pharmacokinetic profiles of ibuprofen and ISO, when given alone or combined, allow us to exclude that the synergism between these two drugs is eventually related to an unmasked pharmacokinetic drug-to-drug interaction.…”

The nitric oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy

“…The pharmacological properties of molsidomine may also contribute to explain the higher efficacy of this drug with respect to other NOdonating or NO-generating drugs investigated in the past as therapeutic approaches to muscular dystrophy, i.e. the NOS substrate L-arginine and the NO donor isosorbide dinitrate (Barton et al, 2005;Hnia et al, 2008;Marques et al, 2005;Sciorati et al, 2010;Voisin et al, 2005). The release of NO from molsidomine has a slower onset and is more prolonged than with isosorbide dinitrate (Agvald et al, 1999) and, at variance with isosorbide dinitrate, it occurs independently of interactions with thiolcontaining compounds (Noack and Feelisch, 1989).…”

“…We found that for NO release to have significant and persistent therapeutic effects it has to be combined with non steroidal anti-inflammatory (NSAID) activity; the combination of these pharmacological activities resulted in an increased muscle progenitor differentiation, survival and selfrenewal and quenching of inflammation all contributing to effective muscle repair (Brunelli et al, 2007;Sciorati et al, 2010;Sciorati et al, 2011).…”

Nitric Oxide in Myogenesis and Therapeutic Muscle Repair

“…up to the end of the observation period, which was set at 12 months to mimic a chronic treatment in a clinical setting with patients. Several mechanisms synergised to yield the therapeutic effect of the combined therapy: significant reduction in both fibre damage and inflammation and increases in the myogenic precursor cells number and differentiation capacity, which preserve the long-term regeneration capacity of muscle [119][120][121]. Other actions of NO on skeletal muscle such as vasodilation and thus reduction of the ischaemia induced by nNOS displacement, increase in glucose uptake and in energy generation [106] may also have contributed to muscle repair.…”