Nova droga anti-inflamatória previne as alterações musculares em camundongos com distrofia e melhora os resultados do tratamento com células tronco
Itália – o mesmo grupo italiano que descreveu bons resultados com células tronco em camundongos e cães realizou esta pesquisa associando uma droga nova com a terapia com células tronco. A droga nova é chamada de HCT 1026, um anti-inflaamatório derivado do flurbiproen e que libera óxido nítrico. É uma droga segura com poucos efeitos colaterais para o estômago e tolerada para tratamento a longo prazo. A droga foi administrada por um ano a camundongos, em dois modelos de distrofia, camundongo mdx, sem distrofina, e o camundongo sem a proteína alfa sarcoglican. Houve melhora das alterações dos músculos, dos níveis de CK e da fadiga muscular com retardo da evolução da doença. Os resultados nos camundongos foram melhores que os obtidos com corticóides. Os camundongos tratados com HCT 1026 e que receberam células tronco tiveram quatro vezes mais células tronco migrando para os músculos. Este tratamento experimental com HCT 1026 demonstrou ser muito eficiente, com resultados positivos a longo prazo. O resumo do artigo e as informações adicionais, em inglês, podem ser lido abaixo:
(IN PRESS: PNAS 2007, 104(1):264-9) Nitric oxide release combined with nonsteroidal antiinflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy
Silvia Brunelli, Clara Sciorati, Giuseppe D’Antona, Anna Innocenzi, Diego Covarello, Beatriz G. Galvez, Cristiana Perrotta, Angela Monopoli, Francesca Sanvito, Roberto Bottinelli, Ennio Ongini, Giulio Cossu and Emilio Clementi – Italy
Duchenne muscular dystrophy is a relatively common disease that affects skeletal muscle, leading to progressive paralysis and death. There is currently no resolutive therapy. We have developed a treatment in which we combined the effects of nitric oxide with nonsteroidal antiinflammatory activity by using HCT 1026, a nitric oxide-releasing derivative of flurbiprofen. Here, we report the results of long-term (1-year) oral treatment with HCT 1026 of two murine models for limb girdle and Duchenne muscular dystrophies (alpha-sarcoglycan-null and mdx mice). In both models, HCT 1026 significantly ameliorated the morphological, biochemical, and functional phenotype in the absence of secondary effects, efficiently slowing down disease progression. HCT 1026 acted by reducing inflammation, preventing muscle damage, and preserving the number and function of satellite cells. HCT 1026 was significantly more effective than the corticosteroid prednisolone, which was analyzed in parallel. As an additional beneficial effect, HCT 1026 enhanced the therapeutic efficacy of arterially delivered donor stem cells, by increasing 4-fold their ability to migrate and reconstitute muscle fibers. The therapeutic strategy we propose is not selective for a subset of mutations; it provides ground for immediate clinical experimentation with HCT 1026 alone, which is approved for use in humans; and it sets the stage for combined therapies with donor or autologous, genetically corrected stem cells.
ADDITIONAL INFORMATIONS:
“HCT 1026, a derivative of flurbiprofen, one of the most potent nonsteroidal antiinflammatory drugs, that releases NO and does not have the severe side effects of corticosteroids. Of importance for an immediate testing in the clinic is the fact that HCT 1026 is safe at the gastrointestinal level, and it has been approved for use in humans; it is effective on oral administration, and it is thus suited for long-term treatment.”
“Two decades after the identification of the molecular defect responsible for Duchenne muscular dystrophy, there are still no effective cures for the disease. The failure of all previous pharmacological treatments has left corticosteroids as the only available drug treatment. Therapy with corticosteroids, despite current attempts to ameliorate the protocols of administration, is still of limited clinical benefits, and it is accompanied by severe side effects. The treatment we tested here meets several criteria for an effective therapy, including the ability to block or at least significantly delay the progress of the disease, produce little or no side toxicity, be cost-effective, and, eventually, resolve the underlying genetic defect. In particular, the administration of HCT 1026 was sufficient on its own to delay significantly and persistently the progression of muscular dystrophy in two different models relevant to muscular dystrophy in humans. The drug was effective in correcting biochemical and morphological alterations and in limiting inflammation. Most importantly, the drug increased muscle strength and significantly increased the ability of animals to perform on different motility tests. This functional amelioration was persistent after 12 months of treatment, when disease in untreated animal was severe, clearly demonstrating the efficacy of the treatment in slowing disease progression. Long-term beneficial effects have not been reported for any of the experimental treatments of muscular dystrophy investigated so far.”
