In a national cooperative study led by Dr. Eugene P. Orringer of the University of North Carolina at Chapel Hill School of Medicine, PP188 was shown to make the painful episodes end sooner than they otherwise would.
"While the effect wasn't profound, it clearly shortened crises," said Orringer, a sickle cell disease expert and executive associate dean of medicine. "The beneficial effect of PP188 was particularly apparent in two specific subgroups of patients. One group was patients who were already taking the drug hydroxyurea, and the other was children."
A report on the findings appears in the Nov. 7 issue of the Journal of the American Medical Association. About 40 U.S. medical centers participated in the research. Dr. Kenneth I. Ataga, instructor in medicine, helped run the project at UNC.
In 1995, Orringer was one of 20 U.S. researchers who carried out a clinical trial that tested hydroxyurea in sickle cell patients. Based on that study, which found a 50 percent reduction in the number of crises, the Food and Drug Administration made hydroxyurea the first therapy approved as a specific treatment for sickle cell disease.
"Results of this new study suggest combining PP188 with hydroxyurea could further help these patients," he said.
As they grow into adulthood, children with sickle cell disease eventually develop a variety of health problems including damage to major organs such as kidneys, liver and lungs.
"If we could reduce the frequency or severity of crises during childhood, we might be able to protect these patients from much of the organ damage that typically appears later in adult life," Orringer said. "That possibility is particularly exciting."
Researchers enrolled 255 patients with sickle cell disease in a double-blinded, placebo-controlled study of PP188. The clinical trial, which lasted from March 1998 to October 1999, was the first such study to include both adults and young children.
To participate in the trial, each subject had to be experiencing a crisis severe enough to require hospitalization and painkillers. Half the enrolled subjects were given PP188, the study medication, and half received an inactive salt solution. The latter group of "control" subjects enabled researchers to determine if the new medication had the beneficial effects predicted by a variety of earlier laboratory studies.
At the project’s end, researchers determined the proportion of patients whose pain had subsided within a week.
They then compared those results with records of who received PP188 and who did not. About 50 percent more patients had their pain disappear within a week if they had received PP188 than those who received the inactive saline solution.
"The proportion of children who achieved resolution was markedly higher in the PP188-treated group (22 of 37, or 59.5 percent) than in those who received placebo (10 of 36, or 27.8 percent)," the authors wrote. Forty-six percent of patients who received hydroxyurea at the same time achieved resolution within a week, compared with 14.3 percent of patients who got hydroxyurea but not PP188.
One problem with sickle cell crises is that they are so unpredictable, Orringer said. In some patients, they can be rare, while in others they are frequent.
"A large NIH-funded study that followed 5,000 sickle cell patients reported an average of one to 1.5 crises per year," he said. "However, some patients can have one or more crises per week and require extensive painkillers. Patients can be feeling fine and then an hour or two later experience pain so severe they have to go to an emergency room and require hospital admission."
Sickle cell disease is not contagious, Orringer said. Rather, it is a genetic illness passed from parents to children. In the United States, it occurs almost exclusively in people whose ancestors came from Africa.
A child born to two parents, each of whom is a carrier of the sickle cell gene, has a 25 percent chance of being born with sickle cell disease. He or she has a 50-50 chance of being a carrier of the sickle cell gene (referred to as sickle cell trait) and a 25 percent chance of being entirely normal.
The CytRx Corp. of Norcross, Ga., chiefly sponsored the study. Other participating institutions included Johns Hopkins University School of Medicine and medical schools at the universities of Alabama at Birmingham, California at Davis, Illinois at Chicago, Mississippi and South Carolina. East Carolina University and the Medical College of Georgia also took part.
Note: Orringer can be reached at (919) 843-9485 or EPO@med.unc.edu.
Contact: David Williamson, (919) 962-8596 or david_williamson@unc.edu
Journal
JAMA