Results of a proof-of-concept study indicate that drugs such as tadalafil (Cialis, Eli Lilly) and sildenafil (Viagra, Pfizer) that inhibit phosphodiesterase type 5 (PDE5) may represent a promising new treatment strategy for boys with Duchenne muscular dystrophy (DMD).
Functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand, is impaired in patients with DMD, producing functional muscle ischemia despite corticosteroid and/or cardioprotective therapy. Researchers now report that tadalafil alleviates this ischemia in a dose-dependent manner.
Sildenafil, another PDE5 inhibitor, replicated the effect of tadalafil, strongly supporting PDE5 inhibition as the mechanism of action, the authors, led by Michael D. Nelson, PhD, The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, conclude.
“The new data add to a compelling body of preclinical mouse research, and, despite some limitations, “have informed the design of a pivotal multicenter clinical trial to determine whether chronic daily tadalafil can preserve muscle function in boys with DMD,” the authors write.
Their study was published online May 7 in Neurology.
New Drug Target
The nitric oxide (NO)-cyclic guanosine 3′,5′-monophosphate (cGMP) pathway represents a new drug target for DMD. A large body of preclinical research shows that PDE5 inhibitors, which prolong the half-life of cGMP — the downstream target of NO in vascular smooth muscle — benefit limb, respiratory, and cardiac muscles in mouse models.
The new human study involved 10 ambulatory boys with DMD aged 8 to 13 years with normal left ventricular ejection fraction and 10 healthy male controls matched for age, body mass index, blood pressure, and left ventricular ejection fraction. All boys with DMD were receiving therapy with glucocorticoids, and 5 were also receiving prophylactic cardiac medication.
For the case-control part of the study, researchers measured brachial artery blood flow in skeletal muscles of all participants when at rest and when doing handgrip exercises. The tests showed that the boys with DMD had impaired blood flow even though they were taking steroids.
“That sympatholysis is impaired in contemporary patients with DMD confirms and extends our earlier observations made well over a decade ago before patients with DMD were treated with any medication,” the authors note.
In another part of the study, boys with DMD, but not the healthy controls, received single doses of sildenafil or tadalafil in an open-label crossover design with a 2-week washout period before crossover. The order of the drugs was random. Participants received 0.5 mg/kg (not to exceed 20 mg) of either oral drug on day 1, followed by 1.0 mg/kg of the drug (not to exceed 40 mg) on day 2.
This analysis showed that tadalafil restored functional sympatholysis in patients with DMD. “[T]he seminal finding of this study is that tadalafil rescues sympatholysis in boys with DMD, providing added putative benefit beyond that afforded by the current standard of care,” the authors write. “The effect is marked, immediate and dose dependent.”
Tadalafil also normalized exercise-induced hyperemia, which was markedly blunted in the boys with DMD.
From a pharmacokinetic analysis of 9 of the boys with DMD, researchers determined that sildenafil, which was the main PDE5 inhibitor used in the preclinical studies, was nearly identical to tadalafil in the ability to restore sympatholysis.
Because the 2 drugs have different chemical structures, this “strongly implicates” PDE5 inhibition as the mechanisms of action, write the authors.
Because PDE5 is a cGMP-specific phosphodiesterase, “our data support the hypothesis that PDE5 inhibition boosts a residual NO-cGMP signal arising from cytosolic neuronal NO synthase, which, in the absence of dystrophin is misplaced from the sarcolemma,” the authors say.
Facial flushing occurred with both doses of either PDE 5 inhibitor. There were 2 cases of prolonged erections.
The authors note that the study did not address the “crucial question” of whether restoring normal blood flow regulation will preserve dystrophic skeletal muscle and slow disease progression.
The study was supported by Parent Project Muscular Dystrophy and the National Institutes of Health/National Center for Advancing Translational Sciences. Dr. Nelson has disclosed no relevant financial relationships.