Research: New Directions

Treatment of the sickling disorders has been unsatisfactory ever since its original description because medical science had no effective treatments for either the degree of sickling or for the vascular obstruction that is responsible for the signs and symptoms of these diseases. All medicine had to offer patients were fluids and analgesics while waiting for the painful episodes to resolve. Specific treatments are needed in three areas of the disease manifestations:

1. Treatments that would shorten the duration of the painful episodes.
2. Treatments that would prevent the events leading to painful episodes.
3. Treatments that would prevent damage to organs like the kidneys, lungs, brain and so forth.

Cage Johnson, M.D.

Professor of Hematology, L.A. County/USC Medical Center Comprehensive Sickle Cell Center Director, SCDFC Medical Director, and Camp Medical Director.

The recent data showing that hydroxyurea produces a reduction in the number of acute painful events, as well as, fewer episodes of the acute chest syndrome, has been widely heralded as a major advance for these patients. The success of hydroxyurea has led to a search for additional therapies that might have the same, if not better, effect but with less toxicity. That search has resulted in a number of new therapies that have been developed in very recent times. Although none of these treatments have been subjected to the rigorous testing of hydroxyurea, they appear promising and certainly deserve further study.

Cytrx Corporation of Norcross, Georgia is sponsoring a trial of their agent Flocor for the treatment of acute painful events. Flocor is a polaxamer that is extremely slippery; it coats sickled cells and possibly endothelial cells so that sickle cell adhesion to endothelium is blocked wherein the flow properties of the blood is greatly improved. Preliminary studies at several centers have shown that this drug can be given by vein during an acute attack and that it may reduce the length of time the vascular occlusion is present by improving blood flow. The first patients should be enrolled in this study during April 1998; the results might be available as early as the year 2000.

Fructose 1.6-Diphosphate: Cypros Pharmaceutical Corporation of Carlsbad, California has initiated studies of Cordox, a "natural substance" in the acute painful event. Organization of a rigorous clinical trial is just beginning, interim results are expected in late 1999/2000 and final results from this Phase III trial in late 2000. Little is known about the drug at this time, but it appears to reduce the degree of sickling of red blood cells, as well as, protect tissues from damage due to oxygen starvation. Like glutamine, fructose 1.6-diphosphate should have little toxicity.

Glutamate: Sickled cells have marked increase in the metabolism of this natural foodstuff. Glutamate is used within the red blood cell to detoxify naturally occurring oxidant substances. Giving glutamate increases the ability of the sickled cell to prevent oxidative damage to the cell; such damage is an important part of why sickled cells produce vascular obstruction. Preliminary studies with this agent show that sickle cell adhesion to endothelium is reduced, and that the frequency of painful events may be reduced as well. Potential toxicity with this agent seems very low when compared to other drugs like hydroxyurea. A trial of this agent under the direction of Dr. Yutaka Niihara at Harbor/UCLA Medical Center in Los Angeles will be starting later in 1998. Results might be available as early as 2001.

Flocor, Nitrous Oxide and Fructose 1.6-diphosphate are all directed at shortening the duration of a painful event. Should any of them be proven to be effective, they will provide an important addition to our therapeutic options. Glutamate, like hydroxyurea, is aimed at preventing painful episodes. Should it be proven effective, it is entirely possible that combining glutamate with hydroxyurea would be more potent than neither agent alone. This would allow for lower doses of hydroxyurea to be given. The lower doses would alleviate the concern over the long-term toxicity of hydroxyurea and would permit its use in less severe patients. Such a situation would be extremely beneficial to our patients.