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Studies of the Safety and Efficacy of Hydroxyurea
Two encouraging studies of the safety and efficacy of Hydroxyurea have been reported. The first, published in the July/August issue of the Journal of Pediatric Hematology/Oncology, found that hydroxyurea, used to manage sickle cell disease in adults, is also safe and effective in children younger than 5 years of age who have the disease. The second study, presented by Egyptian researchers at the 28th World Congress of the International Society of Hematology, reported that hydroxyurea is not associated with any chronic organ damage when given continuously for as long as 5 years. Both studies were reported on medscape.com.

Another first: Healthy twins born to carriers of sickle cell disease
May 11, 1999

Another first: Healthy twins born to carriers of sickle cell disease Technique tests embryos before they are implanted.

NEW YORK (CNN) -- A New York-area couple who are both carriers of sickle cell disease have twin babies who are completely free of the sickle cell gene, thanks to a technique called pre-implantation genetic diagnosis (PGD), in which fertilized embryos are tested for the disorder before implantation in the woman's uterus.

This first successful use of PGD to eliminate sickle cell disease was reported in Tuesday's Journal of the American Medical Association.
One of every 625 babies born to African-Americans has the blood disorder, which causes repeated episodes of severe pain, and a lowered life expectancy.
The 34-year-old woman who successfully gave birth to the healthy twins had already had two abortions because the fetuses were affected with sickle cell anemia. The lead author of the JAMA report, Kangpu Xu, Ph.D., of Weill Medical College, wrote that the couple then went through extensive counseling and decided to try PGD
. On the second try at in vitro fertilization, doctors tested seven embryos for the sickle cell gene. Four were normal, two were carriers, and diagnosis was unclear for one embryo.
Three disease-free embryos were implanted, and the woman gave birth to healthy twins after 39 weeks of pregnancy.
Genetic test of embryos still experimental.
Xu and his colleagues at Cornell University in New York stressed that the PGD test was still experimental in looking for single gene defects, such as sickle cell disease. But with further refinement, researchers said, it will become a powerful diagnostic tool.
Tests already exist to check a fetus for sickle cell during pregnancy. But some couples have strong personal objections to abortion when a pregnancy is already established. Pre-implantation genetic diagnosis could provide couples with another way to avoid passing on sickle cell disease. When both parents are carriers, they face a 25 percent chance of having a child with the disease, and half of their children may carry the gene. Sickle cell is a blood disorder that affects people of African heritage and several other ethnic groups from around the Mediterranean region.
People with the disease have recurring episodes of intense pain; an increased susceptibility to infections, strokes and organ failure; and a lowered life expectancy.
Cost may be an issue.
Despite the success of PGD testing, Xu and his co-authors suggested that its high cost may limit how widely it can be used. And the in vitro fertilization procedure itself is fairly expensive.
Beyond sickle cell anemia, several other hereditary diseases can be diagnosed in an embryo using PGD, including Tay-Sachs disease, Down's syndrome, cystic fibrosis, thalassemia and Fanconi's anemia. And researchers hope soon to add Fragile X syndrome and Huntington's chorea to the list of illnesses that can be detected in a human embryo.

Medical Correspondent Rhonda Rowland contributed to this report.
http://cnn.com/HEALTH/9905/11/sickle.cell.success/index.html
RELATED STORY:
Boy receives first cord blood transplant for sickle cell anemia
December 14, 1998
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Drugs May Ease Sickle Cell Crises

June 22, 1999
By WARREN E. LEARY

WASHINGTON -- The worst part of sickle cell disease is the numbing, painful episodes that can strike any time, searing the body with waves of agony as cells in crucial organs, starved for oxygen and nutrients by blocked blood vessels, wither and die.
Doctors and patients can do little but endure until a crisis has run its course. Powerful pain-killing drugs can help, as can blood transfusions. But, basically, it is something to be tolerated until it subsides.
Some researchers believe they have found ways to be more than sympathetic bystanders when the acute, painful episodes occur. They are conducting human tests with several new types of agents, the products of years of basic research, that may result in the first drugs to attack the basic mechanisms of the sickle cell crisis itself and interrupt the attack once it has started.
Two small biotechnology companies are developing drugs they say have shown promise in clinical trials in lessening the impact of sickle crises. Although each company's drug works in different ways, researchers developing each preparation say they appear to improve blood flow through small vessels and limit tissue damage.
Their developers say the drugs, which appear to be relatively nontoxic with few adverse effects, may be able to decrease the duration of pain, reduce the length of hospital stays and lessen the use of strong pain killers, including narcotics.
Doctors at Harvard Medical School in Boston are also conducting a trial to see if breathing nitric oxide gas during a crisis will shorten the event and reduce the formation of sickle blood cells, as laboratory tests suggest. Dr. Kenneth R. Bridges, head of the joint sickle cell center at Brigham and Women's Hospital and the Massachusetts General Hospital, said 11 of an expected 60 patients have been enrolled in a double-blind trial to be completed by this fall that involves hospitals in five cities.
A number of drugs and compounds in trials, or about to be tested, show some promise in reducing the impact of sickle cell crises, said Dr. Martin M. Steinberg, an expert at the University of Mississippi Medical Center in Jackson who wrote a recent review of sickle cell therapies in The New England Journal of Medicine. "There were few things like this in the works 5 or 10 years ago and we are seeing the results of a lot of basic research. We're entering a very hopeful period."
Sickle cell disease is a family of inherited blood disorders afflicting millions worldwide, primarily those with ancestors from Africa, the Mediterranean and India. In this country, the disease afflicts an estimated 80,000 African-Americans, and about 8 percent of blacks carry a genetic tendency -- termed sickle cell trait -- for the disease.
The disorders involve the production of abnormal forms of hemoglobin, the oxygen-carrying component of red blood cells. When depleted of oxygen, this sickle hemoglobin forms rigid polymers that cause the normally pliable blood cells to stiffen and contort into jagged shapes. These sickle-shaped cells block small vessels and cause vascular inflammation and other changes that further inhibit blood transport.
Lack of blood flow results in ischemia, the damage and death of cells and tissues deprived of oxygen and nutrients, and acute episodes of severe pain in the chest, back, abdomen or extremities. Experts say repeated crises result in damage to such organs as the kidneys and blood vessels.
To reduce the impact of sickle episodes, the CytRx Corporation of Norcross, Ga., is testing a compound called Flocor that it says improves blood flow in ischemic tissue by inhibiting adhesive interactions and lowering blood viscosity. The company says early tests indicate the chemical can shorten crises by acting as a lubricant, allowing sickled blood cells to flow more easily through tight vessels.
Dr. R. Martin Emanuele, the company's vice president for research, said Flocor was a highly purified version of poloxamer 188, an emulsifying chemical used in food products and other drugs to change the surface tension of oil-water mixtures.
Flocor is being tested at 46 hospitals around the country in a trial involving sickle cell patients in crisis. So far, 166 of a planned 224 patients have been enrolled. The study is expected to be completed by the end of the year.
Flocor, given intravenously, coats the blood cells and vessel walls and appears to keep them apart so that adhesive receptors in the blood vessels cannot hook onto the sickled cells, he said. The compound, he said, also changes the membranes of normal and sickled red cells, making them more bendable for maneuvering through small vessels.
"There is a direct effect on the cell membrane that is difficult to characterize," Dr. Emanuele said. "It probably has something to do with a change in the surface tension of the cell in the presence of Flocor, but we don't yet know the exact mechanism."
If the human trial succeeds, CytRx hopes to submit a new drug application to the Food and Drug Administration for approval by the middle of next year, said Jack J. Luchese, the company president. With quick approval, the drug could be for sale early in 2001, he said.
Cypros Pharmaceutical Corporation of Carlsbad, Calif., is also conducting a Phase III trial of a drug called Cordox, a natural fruit-sugar compound known as fructose 1-6 diphosphate. Research indicates extra intravenous doses of the compound, produced naturally in the body while a common sugar called glucose is metabolized, helps protect ischemic tissue from death, said Dr. Paul J. Marangos, chairman and chief executive officer.
"The pain and degenerative aspect of a sickle cell crisis is caused by cell death," Dr. Marangos said. "We are providing additional energy to these cells to keep them alive while their blood supply is restricted." Laboratory tests also suggest that the treatment reduces red cell sickling and improves blood flow, he added.
The trial, which began last year and will involve 280 patients at 40 medical centers, has enrolled 15 patients so far and evaluated 100 more who will be included when they next have a sickle crisis, he said.
The company hopes to finish the trial by the middle of next year and, if successful, seek F.D.A. approval, which could still be several years away, he added.
Dr. Steinberg, of the University of Mississippi, said the real value was in early intervention. Even if the new treatments prove effective in their emergency room tests, he said, the real benefit could come in developing versions that patients could use at the first sign of a crisis.

http://www.nytimes.com/library/national/science/062299hth-sickle-cell.html

Related Articles
Embryos Can Now Be Analyzed for Sickle Cell Gene (May 12)
Gene-Altered Mice Are Called First True Sickle Cell Model (Oct 31, 1997)
Transfusions Prevent Strokes in Children With Sickle Cell Disease, Study Finds (Sep. 19, 1997)

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