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Children's Hospital Research Center Oakland Awarded $830,000 NIH Grant to Test New Treatment for Pulmonary Hypertension in Sickle Cell Patients

After garnering a highly competitive National Institutes of Health (NIH) grant awarded to only nine centers through out the country, Claudia Morris, MD, a clinical scientist at CHORI and a physician in the Emergency Department at Children's Hospital Research Center Oakland (CHRCO), will lead CHRCO's participation in the multi-center clinical trial to evaluate a new drug for the treatment of pulmonary hypertension in sickle cell patients.

"This is going to be the largest prospective data base of sickle cell patients ever," says Dr. Morris, who is collaborating on the study with CHORI clinical scientists Ward Hagar, MD, and Elliot Vichinsky, MD, fellow colleagues from the Department of Hematology/Oncology. "Over a thousand patients will be screened using blood banking, so the information we can get from that, not just for this trial, but for future research, is phenomenal."

Housing the country's largest, most innovative sickle cell disease treatment and research programs in the country and caring for over 600 adults and children with sickle cell disease, CHRCO was an ideal site location to participate in the multi-center trial to explore this novel treatment for pulmonary hypertension.

A rare but serious disorder in patients without sickle cell disease, pulmonary hypertension - high blood pressure in the blood vessels leading from the heart to the lungs - is the leading cause of morality in sickle cell patients, and a cause for serious alarm.

"Sickle cell patients have a very low tolerance to even mild forms of pulmonary hypertension, so what may look like mild pulmonary hypertension in patients without sickle cell, is very dangerous in patients with sickle cell," explains Dr. Morris. "There is a ten-fold risk of mortality even with mild pulmonary hypertension."

Studies have shown that ~ 50 percent of adult sickle cell patients who present with pulmonary hypertension die within 2 years of onset. Whether pulmonary hypertension was the actual cause of the mortality or only a symptom of disease severity has not yet been determined, however.

"There's a whole new area of research that has been coming to the surface in the last five years in which people have begun to realize that pulmonary hypertension is a significant problem in all hemoglobinopathies, including thalassemia and sickle cell disease, because of reduced nitric oxide and its substrate arginine," Dr. Morris explains.

Nitric oxide is what the body uses to regulate blood pressure and normal blood flow, among other critical functions, and in patients with hemolytic blood diseases, nitric oxide bioavailability is significantly depleted.

"The breakdown of red blood cells and the release of their contents during hemolysis is a key trigger of this process," explains Dr. Morris. "As the red blood cell ruptures it releases free hemoglobin which scavenges nitric oxide directly, and releases arginase - an enzyme that consumes nitric oxide's substrate - arginine."

This phenomenon is part of what contributes to the development of hemolysis-associated pulmonary hypertension and is itself is a key factor in the pathology of sickle cell disease that has only recently been appreciated.

The study drug, however, called Sildenafil, has been shown to actually increase the available nitric oxide in the body while simultaneously improving pulmonary arterial pressures and exercise capacity in preliminary trials.

The hope is that treatment with Sildenafil will not only improve pulmonary pressures and function, but the long-term outcome for sickle cell patients with pulmonary hypertension as well. The Sildenafil study will run through December of 2009, and will receive nursing staff and other infrastructure support through CHRCO's Clinical and Translational Science Institute (CTSI) Clinical Research Center, a new initiative of NIH to encourage clinical research and training, and to speed the delivery of new and effective therapies to patients.


Monday, May 16, 2011 11:33 PM

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