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PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy

Nelson, Michael D ; Rader, Florian ; Tang, Xiu ; Tavyev, Jane ; Nelson, Stanley F ; Miceli, M Carrie ; Elashoff, Robert M ; Sweeney, H Lee ; Victor, Ronald G

Neurology, 2014-06, Vol.82 (23), p.2085-2091 [Periódico revisado por pares]

Hagerstown, MD: American Academy of Neurology

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Título:
PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy
Autor: Nelson, Michael D ; Rader, Florian ; Tang, Xiu ; Tavyev, Jane ; Nelson, Stanley F ; Miceli, M Carrie ; Elashoff, Robert M ; Sweeney, H Lee ; Victor, Ronald G
Assuntos: Adolescent ; Biological and medical sciences ; Carbolines - administration & dosage ; Carbolines - adverse effects ; Carbolines - pharmacokinetics ; Carbolines - pharmacology ; Child ; Diseases of striated muscles. Neuromuscular diseases ; Exercise - physiology ; Forearm - blood supply ; Forearm - diagnostic imaging ; Humans ; Ischemia - drug therapy ; Ischemia - etiology ; Male ; Medical sciences ; Muscle, Skeletal - blood supply ; Muscle, Skeletal - drug effects ; Muscle, Skeletal - physiopathology ; Muscular Dystrophy, Duchenne - complications ; Muscular Dystrophy, Duchenne - drug therapy ; Muscular Dystrophy, Duchenne - physiopathology ; Neurology ; Phosphodiesterase 5 Inhibitors - administration & dosage ; Phosphodiesterase 5 Inhibitors - adverse effects ; Phosphodiesterase 5 Inhibitors - pharmacokinetics ; Phosphodiesterase 5 Inhibitors - pharmacology ; Piperazines - administration & dosage ; Piperazines - adverse effects ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Purines - administration & dosage ; Purines - adverse effects ; Purines - pharmacokinetics ; Purines - pharmacology ; Sildenafil Citrate ; Spectroscopy, Near-Infrared ; Sulfones - administration & dosage ; Sulfones - adverse effects ; Sulfones - pharmacokinetics ; Sulfones - pharmacology ; Sympathetic Nervous System - drug effects ; Sympathetic Nervous System - physiopathology ; Tadalafil ; Ultrasonography ; Vascular diseases and vascular malformations of the nervous system ; Vasoconstriction - drug effects ; Vasoconstriction - physiology
É parte de: Neurology, 2014-06, Vol.82 (23), p.2085-2091
Notas: Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Descrição: OBJECTIVE:To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). METHODS:In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. RESULTS:The major new findings are 2-foldfirst, sympatholysis is impaired in boys with DMD—producing functional muscle ischemia—despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. CONCLUSIONS:These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.
Editor: Hagerstown, MD: American Academy of Neurology
Idioma: Inglês

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PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy

Nelson, Michael D ; Rader, Florian ; Tang, Xiu ; Tavyev, Jane ; Nelson, Stanley F ; Miceli, M Carrie ; Elashoff, Robert M ; Sweeney, H Lee ; Victor, Ronald G

Hagerstown, MD: American Academy of Neurology

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