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

Abstract

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 exerciseinduced 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 nearinfrared 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-fold: first, sympatholysis is impaired in boys with DMDproducing 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.

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

“…The reported reduced recruitment of sufficient blood flow in patients with BMD during muscle activity responsible for relative ischemia [37] is improved by PDE5 inhibition in some studies [22,38,39], but not in all of them [23,24], which may relate to variations in methods applied. Corresponding reduced brain blood flow recruitment during activation was hypothesized to be present in patients with BMD and restored by PDE5 inhibition; the current data partly support this hypothesis.…”

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…The administration of Tadalafil or Sildenafil resulted in beneficial effects in mdx mice and DMD patients [19,49,50]. Unfortunately, disappointing results came out on February 2016 from the phase III trial of Tadalafil, due to failure to prove evidence for efficacy in slowing the decline in the walking ability of DMD boys.…”

Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin‐Deficient Hearts

“…This is unfortunate because it would have been of great interest to follow the cardiac status of those patients as they approached the age of onset of cardiac symptoms, had they remained on the drug. The anticipated mechanism in the ambulatory trial, suggested by a combination of animal and human studies, 12,42,43 was to improve blood flow to exercising leg muscles by amplifying deficient nitric oxide signaling to vascular smooth muscle, thus preventing ischemia and preserving muscle. Although our dog studies did not focus on skeletal muscle function, we examined histology of diaphragm and quadriceps muscles from treated and untreated animals.…”

“…Tadalafil restores limb functional sympatholysis in patients with Becker muscular dystrophy 11 and DMD. 12 Based on these muscle benefits, a phase III clinical trial for the use of tadalafil in DMD was performed in patients exhibiting normal cardiac function (ClinicalTrials.gov identifier NCT01865084). Consequently, the impact of long-term PDE5 inhibition on the progression of cardiomyopathy in DMD is a topic of high and immediate clinical significance.…”