(Unpublished data, 2009) The effect of losartan in the skeletal muscle morphology of Golden Retriever Muscular Dystrophy: a promising drug for dystrophic muscle regeneration? *
Marina Brito da Silva - research conducted to get the Master of Science in Department of Surgery of the Sao Paulo University, Faculty of Veterinary Medicine and Animal Science, Sao Paulo, SP, Brazil under orientation of Maria Angelica Miglino.
Duchenne Muscular Dystrophy (DMD) has the substitution of the muscle by connective tissue as its most relevant characteristic. Once fibrotic proliferation is a major obstacle to the efficacy of therapy for muscular dystrophies, early interventions to prevent it will probably be necessary as part of an effective treatment. A significant correlation between fibrosis and the expression of TGF-beta 1, a multifunctional cytokine, in Duchenne muscular Dystrophy has been reported, emphasizing the role of cytokine in the development of muscle fibrosis, and suggesting it as target for fibrosis therapies. In this study we evaluated the effect of losartan over the development of connective tissue on the skeletal musculature of the canine model GRMD. One dystrophic dog was previously used in the pilot study to estipulate the dosage and side effects caused by losartan. Five dystrophic dogs, two male and two female and one control animal were used in the experiment. A dose of 50mg of losartan was orally given once a day. The clinical and laboratorial exams did not show any adverse effect through the experimental period. Therefore losartan utilization showed to be safe therapy. Muscle biopsy fragments have been removed before starting losartan (T0) and after (Tf) were used for histology and TGF beta-1 imunohistochemistry to compare this two times. The evaluations range of motion and limb circunference measures within imunohistochemistry and collagen quantification results helped to infer about losartan effect in the dystrophyc muscle fibrosis. Range of motion and limb circumference values did not show statistical difference. Although the percentage of connective tissue deposition area in the animals in Tf was statistically lower lower than T0. The decrease of TGF beta-1 signalization showed in imunohystochimestry pictures within the decrease of connective tissue deposition, after losartan, suggest an inhibitory effect of this medication through this cytokine in the studied GRMD muscle.
* NOTE: the dogs were treated for 2 months on average.
Dr. Chris Spurney, cardiologist at CNMC in Washington, DC is suppose to run the losartan trial at CNMC. He may be coordinating all efforts with the Hopkins team. Atleast this is my understanding from a recent meeting I attended. I have no idea when this trial will launch off the ground. My son is taking 50mg at bedtime and tolertaing the drug without experiencing any adverse side effects thus far. He was started on the drug in July 2009. I handed Dr. Leshner, our son's neurologist at CNMC, several articles re: the losartan's effects in muscle in mdx models and then dog models. He finally consented to writing the prescription for the drug. At first, our son was prescribed 12.5mg daily then the dosage was slowly increased to where he is now, at 50mg daily. Feel free to inbox me if you are interested in receiving the articles. I can email them to you.
I don't know when the group at Hopkins is planning to start their Losartan trial, but there's another one already underway:
ACE Inhibitor vs. Losartan
Five centers are collaborating in a double-blind randomized study to determine if the ACE inhibitor lisinopril is more effective than losartan in treating heart function in Duchenne. Investigators will also determine if the participants who receive losartan show any improvements in muscle strength. The study will be recruiting 150 boys and men of all ages with a positive diagnosis of Duchenne. Participants must show less than 5% normal levels of dystrophin in their muscles and also have cardiac ejection fractions below 50%. Participating centers include Nationwide Children’s Hospital in Columbus, Boston Children’s, St. Louis Children’s, University of Minnesota and UC Davis. The study is recruiting now.
I will try to find out where you can inquire about participation and a blurb about this study will also appear in the upcoming PPMD newsletter. This study was funded by MDA.