Drug shows promise in treating dangerous complication of erectile disorder

Thousands of men are afflicted with an embarrassing and painful condition that triggers spontaneous, long-lasting erections. There are limited treatment options, but a solution could be on the way thanks to new research at The University of Texas Health Science Center at Houston.

Priapism is a condition of persistent painful penile erection in the absence of sexual desire. It is highly associated with sickle cell disease, leukemia and other blood disorders. It can also result from vasoactive drug abuse. One of the most dangerous complications seen in priapic patients is penile fibrosis, which can lead to erectile dysfunction. Priapism can be an urgent urological condition and causes of the erections lasting at least four hours are unknown.

Biochemists in the laboratory of Yang Xia, M.D., Ph.D., an associate professor at The University of Texas Medical School at Houston, report that an FDA-approved drug called polyethylene glycol-linked adenosine deaminase (PEG-ADA) relieved symptoms and a major complication in a pre-clinical study. Current findings appear online and will be in the March 2010 print issue of The FASEB Journal, the journal of The Federation of American Societies for Experimental Biology.

Xia believes priapism is linked to elevated levels of a signaling molecule called adenosine. The link was discovered by Xia and her colleagues when they noticed that genetically-deficient mice with elevated levels of adenosine also had spontaneous erections lasting many hours. Xia's team described their unexpected finding last year in a paper published in The Journal of Clinical Investigation. Subsequent work from this group has appeared in two articles published in The Journal of Sexual Medicine.

"In this latest study, we show in mouse models that we can prevent a major complication of priapism called penile fibrosis, which is scarring of the penis and can lead to erectile dysfunction," Xia said. "We built on our earlier work, which showed that we can prevent and treat priapism in mouse models."

Mice were treated with PEG-ADA, a drug typically prescribed for patients with a deficiency of the adenosine deaminase enzyme, which degrades adenosine to maintain its normal levels. ADA deficient people have a condition called Severe Combined Immunodeficiency Disease (also known as SCID or the "Bubble Boy Disease") and are treated with PEG-ADA, which replaces the missing enzyme.

PEG-ADA was associated with reduced penile fibrosis in one set of mice with sickle cell disease features and in a second set with a deficiency of the ADA enzyme. No serious side effects were reported. "The next step could involve clinical trials," Xia said. "Because the drug has already been approved for use in people with SCID, the FDA approval process could be expedited."

Harinder Juneja, M.D., director of both the Division of Hematology at the UT Medical School at Houston and clinical hematology at Memorial Hermann - Texas Medical Center, said there are limited treatment options for his male sickle cell patients with priapism. "The main treatments are pain control, hydration and surgical intervention," Juneja said. Male sickle cell patients have about a 40 percent chance of getting priapism. "A medication that could prevent the advent of priapism or treat established priapism is definitely needed. "

"Taken together, substantial evidence now suggests a general role for adenosine signaling in normal penile erection as a vasorelaxant and neuromodulator," Xia said. "From this perspective it is not surprising that impaired adenosine signaling is associated with erectile dysfunction and excessive adenosine signaling is associated with priapism."

The study titled "Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling" was funded by the National Institutes of Health and the China Scholarship Council.

Other contributors to the study from the Department of Biochemistry and Molecular Biology at the UT Medical School include: Jiaming Wen, M.D., lead author, Yingbo Dai, M.D., Ph.D., Yujin Zhang, M.D., Ph.D., Tiejuan Mi, Prasad Phatarpekar, Rodney Kellems, Ph.D., and Michael Blackburn, Ph.D. Also collaborating on the study was Xianzhen Jiang, M.D., Yuxin Tang, M.D. and Hong Sun, M.D., of the Third Xiangya Hospital of Central South University, Changsha, Hunan, China.

October 30, 2009