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Genetic Linkage

Cialis Comes Full Circle – Help for Muscular Dystrophy

One symptom of Becker muscular dystrophy is fatigue and injury of exercising muscles, such as in gripping a weight.
Becker muscular dystrophy is a muscle-wasting disease that is rarer and less severe than the more familiar Duchenne type. Both conditions are basically untreatable. But according to a study published today in Science Translational Medicine, Cialis may alleviate the associated muscle fatigue and damage.

Yes, Cialis. The erectile dysfunction drug.

To anyone who’s followed the Viagra story, use of its cousin Cialis to treat muscle disease is not so much repurposing as it is a logical extension, based on regulating blood flow.

Viagra, developed in 1989, began its ascent three years later, when participants in a clinical trial to treat angina, which is chest pain due to blocked blood flow, reported strikingly improved erections. Taking a pill to treat what was about to evolve from “impotence” to “erectile dysfunction” trumped penile implants and injections, or older approaches of ingesting camel hump fat, jackal bile, or various herbs. Pfizer introduced Viagra to the world in 1998.

The biochemistry is actually fairly complicated. Here’s a short version (skip to next section if you like.)

In order for blood to fill out a vessel, nitric oxide, a simple gas, relaxes the smooth muscle in the vessel wall by binding cGMP (cyclic guanosine 3’5’-monophosphate). Drugs like Viagra and Cialis inhibit the enzyme (phosphodiesterase 5) that breaks down cGMP. So with more available cGMP, the vessel widens, providing more oxygen to the surrounding muscle.

Different phosphodiesterases work in different body parts. Blocking the enzyme in a penis sustains an erection; in the lungs, it counters high blood pressure. And now a team led by Ronald Victor, MD, at Cedars-Sinai Medical Center, has successfully tested Cialis on men with Becker muscular dystrophy. Their work adds an important new piece to the picture of the biochemistry behind control of blood flow.

Maintaining supplies of NO requires another enzyme, appropriately-named nitric oxide synthase (NOS). It must nestle into the smooth muscle cell’s outer membrane (sarcolemma) to produce the needed NO, and another protein, dystrophin, does this. Dystrophin is what is missing, abnormal, or misplaced in Duchenne and Becker muscular dystrophies. Without its escort, what little NOS remains ends up in the cytosol, the liquidy insides of the smooth muscle cell, rather than in the sarcolemma, where it must be tethered to function.

Cialis keeps cGMP around longer, giving what little NO is produced more of a chance to work. And it does.

Cialis improved muscle function in mdx mice, which have the same dystrophin mutations as people. “From the mouse paper we thought the drug could be a blockbuster in humans,” for muscular dystrophy, Dr. Victor told me.

The new study was straightforward. First, the researchers compared blood flow to the forearm at rest in 10 BMD patients and 7 healthy controls – it was the same.

Next the men performed a handgrip exercise while the lower halves of their bodies were in a chamber that had negative pressure, a common test to simulate cardiovascular stress. Normally the body maintains blood pressure by countering the ballooning of blood vessels in the legs with constriction elsewhere, but it tempers the constriction so that other body parts still get blood. The healthy men did this. But in the men with BMD, the blood vessels in the exercised forearm stayed narrowed, impairing blood flow. This is why the disease causes muscle damage and fatigue with exercise.

In a second experiment, each man with BMD took one Cialis (aka tadalafil) or placebo pill, had blood flow to the exercised forearm assessed, waited 2 weeks, then took the opposite pill.

“The tadalafil effect was both marked and immediate, occurring with a single dose,” the researchers write, in 8 of the 10 men, with no effect of placebo. The other two men had unusual mutations that might indicate their disease was too mild to show a response. Dr. Victor hopes that an ongoing multicenter prospective trial will support the findings of success.

He’s understandably ecstatic; he’s worked on this problem for two decades. “So little research has been done on Becker because it’s so rare. I hope we’ll provide the evidence to make this another indication for the drug. We finally have some hope for a therapeutic benefit for people with muscular dystrophy, and it’s really exciting.”

Dr. Victor is, however, concerned that patients with muscle disorders will seek the drugs before the larger trial can validate the findings. Yet at the same time, he and his co-workers envision additional new markets, pointing to the work of Ronald Cohn, MD, at Johns Hopkins University. His team’s work suggests that the drugs may be useful in boosting blood flow in neuropathies such as amyotrophic lateral sclerosis and spinal muscular atrophy, in the low-muscle-tone hypotonias, and in a host of myopathies (metabolic, mitochondrial, congenital, inflammatory, steroid-induced and critical illness associated).

The research may actually veer back to non-human animals, thanks to Dr. Cohn’s discovery that hibernating ground squirrels maintain blood flow to muscles in a way that other mammals can’t. “Squirrels can still target NOS. There must be some important secrets there,” Dr. Victor said.

Because many people have muscle conditions and many men take Cialis or Viagra, I wondered whether anyone had inadvertently discovered that their ED pills relieved their tired muscles. A guest blog, "Viagra for muscular dystrophy and publicity for accidental insight", indeed tells such a tale.

In 2005, a 57-year-old man with limb-girdle muscular dystrophy asked his doctor, Jeoffry B. Gordon, MD, MPH of San Diego, for Viagra for the usual reason. The patient reported back that in addition to an improved sex life, his muscles felt stronger. He happily did standing push-ups and chair and balance exercises to test his new abilities, which waxed and waned with the taking of the blue pills.

I tried to find Dr. Gordon but got caught up in the morass of doc websites that never actually provide any info. But his blog laments the medical journals, media outlets, organizations, and even Pfizer itself, that ignored his report of a beneficial effect of Viagra on muscle strength, seven years ago.

The lack of interest in Dr. Gordon’s anecdotal blog, low on the totem pole of medical publishing, bodes well for my concern that when the news breaks (if it does, one can never tell) about Cialis and Becker muscular dystrophy, men (and maybe some women) will go the Lance Armstrong route and try to use the pills to boost athletic performance.

But it probably won’t work!

“The drug doesn’t enhance performance, it doesn’t make people supernormal. These drugs seem to work under stressful conditions, such as exercise of diseased muscles,” Dr. Victor cautions.

I think repurposed drugs are the greatest thing since Spanx. I recently blogged here about the repurposing of a shelved childhood brain tumor drug finding new use to treat the ultra-rare rapid-aging disease progeria, and perhaps the millions with run-of-the-mill atherosclerosis. I love that erectile dysfunction drugs – considered more reimbursable on some health insurance plans than birth control pills for women (don’t get me started) – may help people with muscle diseases.

My interest in repurposing is somewhat of a turnaround, because for the past few years I’ve been immersed in writing my book, "The Forever Fix: Gene Therapy and the Boy Who Saved It" (shameless holiday-time book plug, paperback due out 1/8). Gene therapy is about as opposite repurposing drugs as one can get.

The book’s title comes from Lori Sames, whose little girl Hannah has giant axonal neuropathy. And even though Hannah’s Hope Fund is trying desperately to raise funds for a phase 1 clinical trial of gene therapy, reports on the first approved gene therapy – in Europe, for Glybera, on November 2 – are sobering.

Glybera is a gene therapy to treat lipoprotein lipase deficiency, which causes pancreatitis. The cost is staggering: about $2 million per patient. Even if it is a “forever fix,” who can afford it?

So I think a bioinformatics approach makes more sense. Wed the information pouring out of human genome sequencing to the stockpiles of drugs, those on the market and those warehoused awaiting homes. Using what we’ve already got makes more sense in treating patients now – particularly those with rare diseases who lie under the radar of new drug discovery.

This blog was published at Public Library of Science on November 28.
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