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Previous Volume 328:81-86 January 14, 1993 Number 2 Next

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ABSTRACT

Background Fetal-globin (-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the -globin chains that are defective or absent in patients with the -thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in -globin-gene expression in the developing fetus, cultured cells, and animal models.

Methods To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with -thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of -globin messenger RNA (mRNA) were determined before and during treatment.

Results In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P<0.01). The proportion of F reticulocytes increased about twofold, and the level of -globin mRNA increased twofold to sixfold. The increase in -globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations.

Conclusions In patients with -hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate -globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or -thalassemia.

Source Information

From the Children's Hospital Oakland Research Institute, Oakland, Calif. (S.P.P., H.E.W., E.P.V.); the Hospital for Sick Children, Toronto (N.F.O.); the University of Minnesota School of Medicine, Minneapolis (G.D.G.); Boston University School of Medicine, Boston (D.V.F.); Howard Hughes Medical Institute, University of California, San Francisco (T.I., S.C.); and Johns Hopkins University School of Medicine, Baltimore (G.H.D.).

Address reprint requests to Dr. Perrine at Children's Hospital Oakland Research Institute, Rm. 115, 747 52nd St., Oakland, CA 94609.

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N Engl J Med 1995; 333:1287-1288, Nov 9, 1995. Correspondence

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• Brauer, M., Al-Momen, A.-K., Faller, D. V., Olivieri, N. F. (1995). Butyrate Treatment in {beta}-Hemoglobinopathies. NEJM 333: 1287-1288 [Full Text]  
• Sher, G. D., Ginder, G. D., Little, J., Yang, S., Dover, G. J., Olivieri, N. F. (1995). Extended Therapy with Intravenous Arginine Butyrate in Patients with {beta}-Hemoglobinopathies. NEJM 332: 1606-1610 [Abstract] [Full Text]  
• Galanello, R., Cao, A., Olivieri, N. (1994). Induction of Fetal Hemoglobin in the Presence of Increased 3-Hydroxybutyric Acid Associated with {beta}-Ketothiolase Deficiency. NEJM 331: 746-747 [Full Text]  
• Brown, A. K., Sleeper, L. A., Miller, S. T., Pegelow, C. H., Gill, F. M., Waclawiw, M. A. (1994). Reference Values and Hematologic Changes From Birth to 5 Years in Patients With Sickle Cell Disease. Arch Pediatr Adolesc Med 148: 796-804 [Abstract]  
• Griffin, T. C., McIntire, D., Buchanan, G. R. (1994). High-Dose Intravenous Methylprednisolone Therapy for Pain in Children and Adolescents with Sickle Cell Disease. NEJM 330: 733-737 [Abstract] [Full Text]  
• Desforges, J. F. (1993). My Life at the Journal, 1961-1993. NEJM 329: 1038-1039 [Full Text]  
• Lowrey, C. H., Nienhuis, A. W. (1993). Treatment with Azacitidine of Patients with End-Stage {beta}-Thalassemia. NEJM 329: 845-848 [Full Text]  
• Weatherall, D.J. (1993). The Treatment of Thalassemia -- Slow Progress and New Dilemmas. NEJM 329: 877-879 [Full Text]  
• Blau, C. A. (1993). Therapy for Globin-Chain Disorders. NEJM 329: 364-364 [Full Text]  
• (1993). NEW APPROACHES TO SICKLE-CELL ANEMIA AND BETA- THALASSEMIA. JWatch General 1993: 7-7 [Full Text]  
• Bunn, H. F. (1993). Reversing Ontogeny. NEJM 328: 129-131 [Full Text]  
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