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Hydroxyurea and other disease-modifying therapies in sickle cell disease

Griffin P Rodgers, MD
Section Editors
Stanley L Schrier, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of vasoocclusion, many of which cannot be reversed (eg, tissue infarction). (See "Overview of the clinical manifestations of sickle cell disease".)

The development of vasoocclusion is the result of a number of factors, beginning with the polymerization of deoxyhemoglobin S (HbS) and ending with the subsequent interactions between the sickled erythrocyte and the vascular endothelium. Factors that influence such hemoglobin polymerization include cellular dehydration, which increases the concentration of HbS and the sickling process; the level of gamma globin chains, which inhibit the polymerization of HbS; intracellular acidosis; and oxygen saturation. (See "Sickle hemoglobin polymer: Structure and functional properties" and "Mechanisms of vasoocclusion in sickle cell disease".)

Hydroxyurea and other agents that have been employed to decrease these processes and prevent irreversible complications of SCD will be reviewed here. Overviews of the treatment of SCD, the use of transfusion in SCD, and hematopoietic cell transplantation, the only curative treatment for SCD, are presented separately. (See "Overview of the management and prognosis of sickle cell disease" and "Hematopoietic cell transplantation in sickle cell disease" and "Red blood cell transfusion in sickle cell disease".)


Rationale for using disease-modifying therapies — A definitive cure is not currently available for most patients with sickle cell disease (SCD), and therapies directed at symptom relief do not alter the natural history of the disease. Thus, therapies are needed that prevent complications without subjecting patients to the morbidity and mortality of highly aggressive approaches such as hematopoietic cell transplantation (HCT).

Gene therapy for SCD is especially formidable, due to the necessity for erythroid-specific, high level, and balanced globin gene expression and the difficulty in transducing hematopoietic stem cells. As a result, increasing attention has been focused on the use of HCT. (See 'Gene therapy' below and 'Hematopoietic cell transplantation' below and "Hematopoietic cell transplantation in sickle cell disease".)


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  1. Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342:83.
  2. Vichinsky E. New therapies in sickle cell disease. Lancet 2002; 360:629.
  3. Perrine RP, Pembrey ME, John P, et al. Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann Intern Med 1978; 88:1.
  4. Wood WG, Pembrey ME, Serjeant GR, et al. Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin. Br J Haematol 1980; 45:431.
  5. Brittenham G, Lozoff B, Harris JW, et al. Sickle cell anemia and trait in southern India: further studies. Am J Hematol 1979; 6:107.
  6. Diop S, Thiam D, Cisse M, et al. New results in clinical severity of homozygous sickle cell anemia, in Dakar, Senegal. Hematol Cell Ther 1999; 41:217.
  7. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325:11.
  8. Fabry ME, Suzuka SM, Weinberg RS, et al. Second generation knockout sickle mice: the effect of HbF. Blood 2001; 97:410.
  9. Hankins J, Aygun B. Pharmacotherapy in sickle cell disease--state of the art and future prospects. Br J Haematol 2009; 145:296.
  10. Jane SM, Cunningham JM. Understanding fetal globin gene expression: a step towards effective HbF reactivation in haemoglobinopathies. Br J Haematol 1998; 102:415.
  11. Steinberg MH, Rodgers GP. Pharmacologic modulation of fetal hemoglobin. Medicine (Baltimore) 2001; 80:328.
  12. Mischiati C, Sereni A, Lampronti I, et al. Rapamycin-mediated induction of gamma-globin mRNA accumulation in human erythroid cells. Br J Haematol 2004; 126:612.
  13. Akinsheye I, Alsultan A, Solovieff N, et al. Fetal hemoglobin in sickle cell anemia. Blood 2011; 118:19.
  14. Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders. Blood 2012; 120:2945.
  15. Saunthararajah Y, Lavelle D, DeSimone J. DNA hypo-methylating agents and sickle cell disease. Br J Haematol 2004; 126:629.
  16. Trompeter S, Roberts I. Haemoglobin F modulation in childhood sickle cell disease. Br J Haematol 2009; 144:308.
  17. Halsey C, Roberts IA. The role of hydroxyurea in sickle cell disease. Br J Haematol 2003; 120:177.
  18. Brawley OW, Cornelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008; 148:932.
  19. Lanzkron S, Strouse JJ, Wilson R, et al. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med 2008; 148:939.
  20. Platt OS, Orkin SH, Dover G, et al. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 74:652.
  21. Dover GJ, Humphries RK, Moore JG, et al. Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production. Blood 1986; 67:735.
  22. Charache S, Dover GJ, Moyer MA, Moore JW. Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia. Blood 1987; 69:109.
  23. Xu J, Zimmer DB. Differential regulation of A gamma and G gamma fetal hemoglobin mRNA levels by hydroxyurea and butyrate. Exp Hematol 1998; 26:265.
  24. Cokic VP, Smith RD, Beleslin-Cokic BB, et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 2003; 111:231.
  25. Costa FC, da Cunha AF, Fattori A, et al. Gene expression profiles of erythroid precursors characterise several mechanisms of the action of hydroxycarbamide in sickle cell anaemia. Br J Haematol 2007; 136:333.
  26. Flanagan JM, Steward S, Howard TA, et al. Hydroxycarbamide alters erythroid gene expression in children with sickle cell anaemia. Br J Haematol 2012; 157:240.
  27. Zhu J, Chin K, Aerbajinai W, et al. Hydroxyurea-inducible SAR1 gene acts through the Giα/JNK/Jun pathway to regulate γ-globin expression. Blood 2014; 124:1146.
  28. Green NS. A step forward back to (induced) fetal. Blood 2014; 124:993.
  29. Gladwin MT, Shelhamer JH, Ognibene FP, et al. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol 2002; 116:436.
  30. Nahavandi M, Tavakkoli F, Wyche MQ, et al. Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea. Br J Haematol 2002; 119:855.
  31. Iyamu EW, Cecil R, Parkin L, et al. Modulation of erythrocyte arginase activity in sickle cell disease patients during hydroxyurea therapy. Br J Haematol 2005; 131:389.
  32. Cokic VP, Beleslin-Cokic BB, Tomic M, et al. Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells. Blood 2006; 108:184.
  33. Westerman M, Pizzey A, Hirschman J, et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br J Haematol 2008; 142:126.
  34. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996; 75:300.
  35. Kasschau MR, Barabino GA, Bridges KR, Golan DE. Adhesion of sickle neutrophils and erythrocytes to fibronectin. Blood 1996; 87:771.
  36. Benkerrou M, Delarche C, Brahimi L, et al. Hydroxyurea corrects the dysregulated L-selectin expression and increased H(2)O(2) production of polymorphonuclear neutrophils from patients with sickle cell anemia. Blood 2002; 99:2297.
  37. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003; 289:1645.
  38. Bridges KR, Barabino GD, Brugnara C, et al. A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy. Blood 1996; 88:4701.
  39. Steinberg MH, Nagel RL, Brugnara C. Cellular effects of hydroxyurea in Hb SC disease. Br J Haematol 1997; 98:838.
  40. Hillery CA, Du MC, Wang WC, Scott JP. Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytes to thrombospondin and laminin. Br J Haematol 2000; 109:322.
  41. Bartolucci P, Chaar V, Picot J, et al. Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation. Blood 2010; 116:2152.
  42. The management of sickle cell disease. National Institutes of Health; National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. NIH publication 04-2117, revised 2004. This reference is available for downloading or purchase at www.nhlbi.nih.gov/health/prof/blood/sickle/ (Accessed on April 01, 2008).
  43. Stettler N, McKiernan CM, Melin CQ, et al. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015; 313:1671.
  44. Goldberg MA, Brugnara C, Dover GJ, et al. Treatment of sickle cell anemia with hydroxyurea and erythropoietin. N Engl J Med 1990; 323:366.
  45. Franco RS, Yasin Z, Palascak MB, et al. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood 2006; 108:1073.
  46. Setty BN, Kulkarni S, Dampier CD, Stuart MJ. Fetal hemoglobin in sickle cell anemia: relationship to erythrocyte adhesion markers and adhesion. Blood 2001; 97:2568.
  47. Ballas SK, Dover GJ, Charache S. Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 1989; 32:104.
  48. Rodgers GP, Dover GJ, Noguchi CT, et al. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990; 322:1037.
  49. Orringer EP, Blythe DS, Johnson AE, et al. Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia. Blood 1991; 78:212.
  50. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992; 79:2555.
  51. Ware RE, Eggleston B, Redding-Lallinger R, et al. Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 2002; 99:10.
  52. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332:1317.
  53. Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial. Blood 1996; 88:1960.
  54. Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004; 103:2039.
  55. Davies S, Olujohungbe A. Hydroxyurea for sickle cell disease. Cochrane Database Syst Rev 2001; :CD002202.
  56. Moore RD, Charache S, Terrin ML, et al. Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Am J Hematol 2000; 64:26.
  57. Ferster A, Tahriri P, Vermylen C, et al. Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 2001; 97:3628.
  58. Hankins JS, Ware RE, Rogers ZR, et al. Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Blood 2005; 106:2269.
  59. Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics 2008; 122:1332.
  60. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 2010; 115:2354.
  61. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008; 358:1362.
  62. Steinberg MH. Sickle cell disease and hydroxyurea: the good, the bad, and the future (editorial). Blood 2005; 105:441.
  63. Zumberg MS, Reddy S, Boyette RL, et al. Hydroxyurea therapy for sickle cell disease in community-based practices: a survey of Florida and North Carolina hematologists/oncologists. Am J Hematol 2005; 79:107.
  64. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood 2010; 115:5300.
  65. Candrilli SD, O'Brien SH, Ware RE, et al. Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease. Am J Hematol 2011; 86:273.
  66. Haywood C Jr, Beach MC, Bediako S, et al. Examining the characteristics and beliefs of hydroxyurea users and nonusers among adults with sickle cell disease. Am J Hematol 2011; 86:85.
  67. Bakanay SM, Dainer E, Clair B, et al. Mortality in sickle cell patients on hydroxyurea therapy. Blood 2005; 105:545.
  68. Gulbis B, Haberman D, Dufour D, et al. Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience. Blood 2005; 105:2685.
  69. Wang WC, Wynn LW, Rogers ZR, et al. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001; 139:790.
  70. Thornburg CD, Dixon N, Burgett S, et al. A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. Pediatr Blood Cancer 2009; 52:609.
  71. Thornburg CD, Calatroni A, Panepinto JA. Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. J Pediatr Hematol Oncol 2011; 33:251.
  72. Thompson BW, Miller ST, Rogers ZR, et al. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer 2010; 54:250.
  73. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011; 377:1663.
  74. Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood 2012; 120:4304.
  75. Heeney MM, Whorton MR, Howard TA, et al. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol 2004; 26:179.
  76. Rana S, Houston PE, Wang WC, et al. Hydroxyurea and growth in young children with sickle cell disease. Pediatrics 2014; 134:465.
  77. Rogers ZR, Wang WC, Luo Z, et al. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial. Blood 2011; 117:2614.
  78. Ware RE, Despotovic JM, Mortier NA, et al. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 2011; 118:4985.
  79. Wang WC, Oyeku SO, Luo Z, et al. Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics 2013; 132:677.
  80. Little JA, McGowan VR, Kato GJ, et al. Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica 2006; 91:1076.
  81. Polycythemia vera. Hematol Oncol Clin North Am 2003; 17:1191.
  82. Ferster A, Sariban E, Meuleman N, Belgian Registry of Sickle Cell Disease patients treated with Hydroxyurea. Malignancies in sickle cell disease patients treated with hydroxyurea. Br J Haematol 2003; 123:368.
  83. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010; 85:403.
  84. McGann PT, Howard TA, Flanagan JM, et al. Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure. Br J Haematol 2011; 154:134.
  85. Archer N, Galacteros F, Brugnara C. 2015 Clinical trials update in sickle cell anemia. Am J Hematol 2015; 90:934.
  86. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci U S A 1982; 79:4428.
  87. Ley TJ, DeSimone J, Noguchi CT, et al. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood 1983; 62:370.
  88. Dover GJ, Charache SH, Boyer SH, et al. 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. Prog Clin Biol Res 1983; 134:475.
  89. Mabaera R, Greene MR, Richardson CA, et al. Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood 2008; 111:411.
  90. Koshy M, Dorn L, Bressler L, et al. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 2000; 96:2379.
  91. DeSimone J, Koshy M, Dorn L, et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 2002; 99:3905.
  92. Saunthararajah Y, Hillery CA, Lavelle D, et al. Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 2003; 102:3865.
  93. Saunthararajah Y, Molokie R, Saraf S, et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol 2008; 141:126.
  94. al-Khatti A, Umemura T, Clow J, et al. Erythropoietin stimulates F-reticulocyte formation in sickle cell anemia. Trans Assoc Am Physicians 1988; 101:54.
  95. Nagel RL, Vichinsky E, Shah M, et al. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Blood 1993; 81:9.
  96. Rodgers GP, Dover GJ, Uyesaka N, et al. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993; 328:73.
  97. el-Hazmi MA, al-Momen A, Kandaswamy S, et al. On the use of hydroxyurea/erythropoietin combination therapy for sickle cell disease. Acta Haematol 1995; 94:128.
  98. Faller DV, Perrine SP. Butyrate in the treatment of sickle cell disease and beta-thalassemia. Curr Opin Hematol 1995; 2:109.
  99. Weinberg RS, Ji X, Sutton M, et al. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood 2005; 105:1807.
  100. Perrine SP, Miller BA, Faller DV, et al. Sodium butyrate enhances fetal globin gene expression in erythroid progenitors of patients with Hb SS and beta thalassemia. Blood 1989; 74:454.
  101. Perrine SP, Rudolph A, Faller DV, et al. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci U S A 1988; 85:8540.
  102. Constantoulakis P, Knitter G, Stamatoyannopoulos G. On the induction of fetal hemoglobin by butyrates: in vivo and in vitro studies with sodium butyrate and comparison of combination treatments with 5-AzaC and AraC. Blood 1989; 74:1963.
  103. Fathallah H, Weinberg RS, Galperin Y, et al. Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. Blood 2007; 110:3391.
  104. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328:81.
  105. Sher GD, Ginder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. N Engl J Med 1995; 332:1606.
  106. Stamatoyannopoulos G, Blau CA, Nakamoto B, et al. Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood 1994; 84:3198.
  107. Little JA, Dempsey NJ, Tuchman M, Ginder GD. Metabolic persistence of fetal hemoglobin. Blood 1995; 85:1712.
  108. Liakopoulou E, Blau CA, Li Q, et al. Stimulation of fetal hemoglobin production by short chain fatty acids. Blood 1995; 86:3227.
  109. Reich S, Bührer C, Henze G, et al. Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia. Blood 2000; 96:3357.
  110. Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol 2016; 175:141.
  111. Abdulmalik O, Safo MK, Chen Q, et al. 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol 2005; 128:552.
  112. http://www.clinicaltrials.gov/ct2/show/NCT01987908 (Accessed on August 29, 2014).
  113. Cerami A, Manning JM. Potassium cyanate as an inhibitor of the sickling of erythrocytes in vitro. Proc Natl Acad Sci U S A 1971; 68:1180.
  114. Walder JA, Zaugg RH, Walder RY, et al. Diaspirins that cross-link beta chains of hemoglobin: bis(3,5-dibromosalicyl) succinate and bis(3,5-dibromosalicyl) fumarate. Biochemistry 1979; 18:4265.
  115. Abraham DJ, Perutz MF, Phillips SE. Physiological and x-ray studies of potential antisickling agents. Proc Natl Acad Sci U S A 1983; 80:324.
  116. Head CA, Brugnara C, Martinez-Ruiz R, et al. Low concentrations of nitric oxide increase oxygen affinity of sickle erythrocytes in vitro and in vivo. J Clin Invest 1997; 100:1193.
  117. Brugnara C, Bunn HF, Tosteson DC. Regulation of erythrocyte cation and water content in sickle cell anemia. Science 1986; 232:388.
  118. Schwartz RS, Musto S, Fabry ME, Nagel RL. Two distinct pathways mediate the formation of intermediate density cells and hyperdense cells from normal density sickle red blood cells. Blood 1998; 92:4844.
  119. Canessa M, Spalvins A, Nagel RL. Volume-dependent and NEM-stimulated K+,Cl- transport is elevated in oxygenated SS, SC and CC human red cells. FEBS Lett 1986; 200:197.
  120. Olivieri O, Vitoux D, Galacteros F, et al. Hemoglobin variants and activity of the (K+Cl-) cotransport system in human erythrocytes. Blood 1992; 79:793.
  121. Gibson JS, Speake PF, Ellory JC. Differential oxygen sensitivity of the K+-Cl- cotransporter in normal and sickle human red blood cells. J Physiol 1998; 511 ( Pt 1):225.
  122. Culliford SJ, Ellory JC, Gibson JS, Speake PF. Effects of urea and oxygen tension on K flux in sickle cells. Pflugers Arch 1998; 435:740.
  123. Lew VL, Hockaday A, Sepulveda MI, et al. Compartmentalization of sickle-cell calcium in endocytic inside-out vesicles. Nature 1985; 315:586.
  124. Lew VL, Ortiz OE, Bookchin RM. Stochastic nature and red cell population distribution of the sickling-induced Ca2+ permeability. J Clin Invest 1997; 99:2727.
  125. Rivera A, Jarolim P, Brugnara C. Modulation of Gardos channel activity by cytokines in sickle erythrocytes. Blood 2002; 99:357.
  126. Rosa RM, Bierer BE, Thomas R, et al. A study of induced hyponatremia in the prevention and treatment of sickle-cell crisis. N Engl J Med 1980; 303:1138.
  127. Brugnara C. Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. Curr Opin Hematol 1995; 2:132.
  128. Bennekou P, Pedersen O, Møller A, Christophersen P. Volume control in sickle cells is facilitated by the novel anion conductance inhibitor NS1652. Blood 2000; 95:1842.
  129. Bennekou P, de Franceschi L, Pedersen O, et al. Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease. Blood 2001; 97:1451.
  130. Stocker JW, De Franceschi L, McNaughton-Smith GA, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 2003; 101:2412.
  131. Brugnara C, de Franceschi L, Alper SL. Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J Clin Invest 1993; 92:520.
  132. De Franceschi L, Saadane N, Trudel M, et al. Treatment with oral clotrimazole blocks Ca(2+)-activated K+ transport and reverses erythrocyte dehydration in transgenic SAD mice. A model for therapy of sickle cell disease. J Clin Invest 1994; 93:1670.
  133. Brugnara C, Gee B, Armsby CC, et al. Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 1996; 97:1227.
  134. Ataga KI, Smith WR, De Castro LM, et al. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 2008; 111:3991.
  135. Ataga KI, Reid M, Ballas SK, et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol 2011; 153:92.
  136. Brugnara C, Tosteson DC. Inhibition of K transport by divalent cations in sickle erythrocytes. Blood 1987; 70:1810.
  137. De Franceschi L, Beuzard Y, Jouault H, Brugnara C. Modulation of erythrocyte potassium chloride cotransport, potassium content, and density by dietary magnesium intake in transgenic SAD mouse. Blood 1996; 88:2738.
  138. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 1997; 100:1847.
  139. De Franceschi L, Bachir D, Galacteros F, et al. Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease. Br J Haematol 2000; 108:284.
  140. De Franceschi L, Cappellini MD, Graziadei G, et al. The effect of dietary magnesium supplementation on the cellular abnormalities of erythrocytes in patients with beta thalassemia intermedia. Haematologica 1998; 83:118.
  141. De Franceschi L, Bachir D, Galacteros F, et al. Dietary magnesium supplementation reduces pain crises in patients with sickle cell disease (abstract). Blood 1997; 90:264a.
  142. Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood 2015; 126:1651.
  143. Wambebe C, Khamofu H, Momoh JA, et al. Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder. Phytomedicine 2001; 8:252.
  144. Cordeiro NJ, Oniyangi O. Phytomedicines (medicines derived from plants) for sickle cell disease. Cochrane Database Syst Rev 2004; :CD004448.
  145. Fawibe AE. Managing acute chest syndrome of sickle cell disease in an African setting. Trans R Soc Trop Med Hyg 2008; 102:526.
  146. Oniyangi O, Cohall DH. Phytomedicines (medicines derived from plants) for sickle cell disease. Cochrane Database Syst Rev 2010; :CD004448.
  147. Iyamu EW, Turner EA, Asakura T. In vitro effects of NIPRISAN (Nix-0699): a naturally occurring, potent antisickling agent. Br J Haematol 2002; 118:337.
  148. Iyamu EW, Turner EA, Asakura T. Niprisan (Nix-0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions. Br J Haematol 2003; 122:1001.
  149. Perampaladas K, Masum H, Kapoor A, et al. The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan. BMC Int Health Hum Rights 2010; 10 Suppl 1:S11.
  150. Telen MJ, Wun T, McCavit TL, et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 2015; 125:2656.
  151. Pawliuk R, Westerman KA, Fabry ME, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 2001; 294:2368.
  152. Mansilla-Soto J, Rivière I, Sadelain M. Genetic strategies for the treatment of sickle cell anaemia. Br J Haematol 2011; 154:715.
  153. Wu LC, Sun CW, Ryan TM, et al. Correction of sickle cell disease by homologous recombination in embryonic stem cells. Blood 2006; 108:1183.
  154. Nienhuis AW. Development of gene therapy for blood disorders. Blood 2008; 111:4431.
  155. Perumbeti A, Higashimoto T, Urbinati F, et al. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood 2009; 114:1174.
  156. Zou J, Mali P, Huang X, et al. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood 2011; 118:4599.
  157. Blouin MJ, Beauchemin H, Wright A, et al. Genetic correction of sickle cell disease: insights using transgenic mouse models. Nat Med 2000; 6:177.
  158. Campbell AD, Cui S, Shi L, et al. Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proc Natl Acad Sci U S A 2011; 108:18808.
  159. Wilber A, Hargrove PW, Kim YS, et al. Therapeutic levels of fetal hemoglobin in erythroid progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer. Blood 2011; 117:2817.
  160. Xu J, Peng C, Sankaran VG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 2011; 334:993.
  161. Lan N, Howrey RP, Lee SW, et al. Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors. Science 1998; 280:1593.
  162. Alami R, Gilman JG, Feng YQ, et al. Anti-beta s-ribozyme reduces beta s mRNA levels in transgenic mice: potential application to the gene therapy of sickle cell anemia. Blood Cells Mol Dis 1999; 25:110.
  163. Weatherall DJ. Gene therapy: repairing haemoglobin disorders with ribozymes. Curr Biol 1998; 8:R696.
  164. Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood 2015; 125:2597.