Promising therapies in sickle cell disease

Cardiovascular and Hematological Disorders - Drug Targets

Volumn 9, Issue 1, 2009, Pages 1-8

  Raghupathy, Radha ^a   Billett, Henny H ^a  

^a MONTEFIORE MEDICAL CENTER   (United States)

Author keywords

Review; Sickle cell anemia therapy

Indexed keywords

2,2 BIS(4 FLUOROPHENYL) 2 PHENYLACETAMIDE; 5 AZA 2' DEOXYCYTIDINE; ACETYLCHOLINE; ALPHAVBETA5 INTEGRIN; ANTIOXIDANT; ARGININE; AZACITIDINE; BUTYRIC ACID; CALCIUM ACTIVATED POTASSIUM CHANNEL; CELL ADHESION MOLECULE; EPTIFIBATIDE; FIBRINOGEN RECEPTOR ANTAGONIST; HEMOGLOBIN F; HEMOGLOBIN S; HEPARINOID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYDROXYUREA; IMIDAZOLE; INTERCELLULAR ADHESION MOLECULE 1; LENALIDOMIDE; NITRIC OXIDE; NITROPRUSSIDE SODIUM; OXIPURINOL; POLOXAMER; POMALIDOMIDE; POTASSIUM CHLORIDE COTRANSPORTER; PYROGLUTAMATE MAGNESIUM; PYROGLUTAMIC ACID; SILDENAFIL; UNINDEXED DRUG;

ABDOMINAL PAIN; ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION; BLOOD VESSEL OCCLUSION; CELL VOLUME; CLINICAL TRIAL; DIARRHEA; DRUG MEGADOSE; DRUG WITHDRAWAL; ENZYME INHIBITION; ERYTHROCYTE ADHESIVENESS; GENE THERAPY; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYDRATION; INTRACELLULAR MEMBRANE; ION EXCHANGE; LOW DRUG DOSE; NONHUMAN; PROTEIN POLYMERIZATION; REVIEW; SICKLE CELL ANEMIA; ANIMAL; CELL ADHESION; DRUG DELIVERY SYSTEM; DRUG EFFECT; METABOLISM; PATHOPHYSIOLOGY; VASODILATATION;

ANEMIA, SICKLE CELL; ANIMALS; CELL ADHESION; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; HEMOGLOBIN, SICKLE; HUMANS; VASODILATION;

EID: 65549088927     PISSN: 1871529X     EISSN: None     Source Type: Journal    
DOI: 10.2174/187152909787581354     Document Type: Review

References (85)

1. Platt, O.S.; Brambilla, D.J.; Rosse, W.F.; Milner, P.F.; Castro, O.; Steinberg, M.H.; Klug, PP. Mortality in sickle cell disease- life expectancy and risk factors for early death. N. Engl. J. Med., 1994, 330, 1639-1644
2. Ingram, V.M. A specific chemical difference between the globins of normal human and sickle-cell anemia haemoglobin. Nature, 1956, 178, 792-794
3. Gallais, D.; Lonsdorfer, J.; Bogui, P.; Fattoum, S. Point counterpoint. Sickle cell trait should/should not be considered asymptomatic and as a benign condition during physical activity. J. Appl. Physiol., 2007, 103, 2137-2138
4. Pasvol, G.; Weatherall, D.J.; Wilson, R.J. Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria Nature, 1978, 274, 701-703
5. Friedman, M.J. Erythrocytic mechanism of sickle cell resistance to malaria. Proc. Natl. Acad. Sci. USA, 1978, 75, 1994-1997
6. Frenette, P.S. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr. Opin. Hematol., 2002, 9, 101-106.
7. Cawein, M.J.; O'Neill, R.P.; Danzer, L.A.; Lappat, E.J.; Roach, T. A study of the sickling phenomena and oxygen dissociation curve in patients with hemoglobins SS, SD, SF and SC. Blood, 1969, 34, 682-690.
8. Samuel, R.E.; Salmon, E.D.; Briehl, R.W. Nucleation and growth of fibres and gel formation in sickle cell haemoglobin. Nature, 1990, 345, 833-835.
9. Goodman, S.R. The irreversibly sickled cell: a perspective. Cell Mol. Biol., 2004, 50, 53-58.
10. Ballas, S.K.; Larner, J.; Smith, E.D.; Surrey, S.; Schwartz, E.; Rappaport, E.F. Rheologic predictors of the severity of the painful sickle cell crisis. Blood, 1988, 72, 1216-1223.
11. Kaul, D.K. Sickle red cell adhesion: many issues and some answers. Transfus. Clin. Biol., 2008, 15, 51-55.
12. Kaul, D.K.; Hebbel, R.P. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J. Clin. Invest., 2000, 106, 411-420.
13. Reiter, C.D.; Wang, X.; Tanus-Santos, J.E.; Hogg, N.; Cannon, R.O, 3rd; Schechter, A.N.; Gladwin, M.T.Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med., 2002, 8, 1383-1389.
14. Ohene-Frempong, K.; Weiner, S.J.; Sleeper, L.A.; Miller, S.T.; Embury, S.; Moohr, J.W.; Wethers, D.L.; Pegelow, C.H.; Gill, F.M. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood, 1998, 91, 288-294.
15. Castro, O.; Brambilla, D.J.; Thorington, B.; Reindorf, C.A.; Scott, R.B.; Gillette, P.; Vera, J.C.; Levy, PS. The acute chest syndrome of sickle cell disease: incidence and risk factors. The Co-operative Study of Sickle Cell Disease. Blood, 1994, 84, 643-649.
16. Fadlon, E.; Vordermeier, S.; Pearson, T.C.; Mire-Sluis, A.R.; Dumonde, D.C.; Phillips, J.; Fishlock, K.; Brown, K.A.Blood polymorphonuclear leukocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD64. Blood, 1998, 91, 266-274.
17. Kurantsin-Mills, J.; Ofosu, F.A.; Safa, T.K.; Siegel, R.S.; Lessin, LS. Plasma factor VII and thrombin-antithrombin III levels indicate increased tissue factor activity in sickle cell patients. Br. J. Haematol., 1992, 81, 539-544.
18. Solovey, A.; Gui, L.; Key, N.S. Tissue factor expression by endothelial cells in sickle cell anemia. J. Clin. Invest., 1998, 101, 1899-1904.
19. Beurling-Harbury, C.; Schade, S.G. Platelet activation during pain crisis in sickle cell anemia patients. Am. J. Hematol., 1989, 31, 237-241.
20. Francis, R.B., Jr. Protein S deficiency in sickle cell anemia. J. Lab. Clin. Med., 1988, 111, 571-576.
21. Chiu, D.; Lubin, B.; Roelofsen, B. Sickled erythrocytes accelerate clotting in vitro: an effect of abnormal membrane lipid asymmetry. Blood, 1981, 58, 398-401.
22. Bernaudin, F.; Socie, G.; Kuentz, M.; Chevret, S.; Duval, M.; Bertrand, Y.; Vannier, J.P.; Yakouben, K.; Thuret, I.; Bordigoni, P.; Fischer, A.; Lutz, P.; Stephan, J.L.; Dhedin, N.; Plouvier, E.; Margueritte, G.; Bories, D.; Verlhac, S.; Esperou, H.; Coic, L.; Vernant, J.P.; Gluckman, E. SFGM-TC.Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood, 2007, 110, 2749-2756.
23. Pinto, F.O.; Roberts, I. Cord blood stem cell transplantation for haemoglobinopathies. Br. J. Hematol., 2008, 141, 309-324.
24. Hanna, J.; Wernig, M.; Markoulaki, S.; Sun, C.W.; Meissner, A.; Cassady, J.P.; Beard, C.; Brambrink, T.; Wu, L.C.; Townes, T.M.; Jaenisch, R.Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science, 2007, 318, 1920-1923.
25. Pataryas, H.A.; Stomatoyannopoulos, G. Hemoglobins in human fetuses: Evidence of adult hemoglobin production after the 11th gestational week. Blood, 1972, 39, 688-696.
26. Kutlar, A.; Hattori, Y.; Bakioglu, I.; Kutlar, F.; Kamel, K.; Huisman, T.H. Hematological observations on Arabian SS patients with a homozygosity or heterozygosity for a..S chromosome with haplotype #31. Hemoglobin, 1985, 9, 545-557.
27. Pagnier, J.; Mears, J.G.; Dunda-Belkhodja, O.; Schaefer-Rego, K.E.; Beldjord, C.; Nagel, R.L.; Labie, D. Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc. Natl. Acad. Sci. USA, 1984, 81, 1771-1773.
28. Kulozik, A.E.; Wainscoat, J.S.; Serjeant, G.R.; Kar, B.C.; Al-Awamy, B.; Essan, G.J.F.; Falusi, A.G.; Haque, S.K.; Hilali, A.M.; Kate, S.; Ranasinghe, W.A.E.P.; Weatherall, D.J. Geographical survey of β S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am. J. Hum. Genet., 1986, 39, 239-244.
29. Nagel, R.L.; Erlingsson, S.; Fabry, M.E.; Croizat, H.; Susuka, S.M.; Lachman, H.; Sutton, M.; Driscoll, C.; Bouhassira, E.; Billett, H.H. The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients. Blood, 1991, 77, 1371-1375.
30. Yin, W.; Barkess, G.; Fang, X.; Xiang, P.; Cao, H.; Stamatoyannopoulos, G.; Li, Q. Histone acetylation at the human β-globin locus changes with developmental age. Blood, 2007, 110, 4101-4107.
31. DeSimone, J.; Heller, P.; Hall, L.; Zwiers, D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc. Natl. Acad. Sci. USA, 1982, 79, 4428-4431.
32. Mabaera, R.; Greene, M.R.; Richardson, C.A.; Conine, S.J.; Kozul, C.D.; Lowrey, C.H. Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood, 2008, 111, 411-420.
33. Ley, T.J.; DeSimone, J.; Noguchi, C.T.; Turner, P.H.; Schechter, A.N.; Heller, P.; Nienhuis, A.W. 5-Azacytidine increases γ-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood, 1983, 62, 370-380.
34. Carr, B.I.; Garrett Reilly, J.; Smith, S.S.; Winberg, C.; Riggs, A. The tumorigenicity of 5-azacytidine in the male Fischer rat. Carcinogenesis, 1984, 5, 1583-1590.
35. Letvin, N.L.; Linch, D.C.; Beardsley, G.P.; McIntyre, K.W.; Nathan, D.G. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N. Engl. J. Med., 1984, 310, 869-873.
36. Platt, O.S.; Orkin, S.H.; Dover, G.; Beardsley, G.P.; Miller, B.; Nathan, D.G. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J. Clin. Invest., 1984, 74, 652-656.
37. Stamatoyannopoulos, G. Control of globin gene expression during development and erythroid differentiation. Exp. Hematol., 2005, 33, 259-271.
38. Cokic, V.P.; Smith, R.D.; Beleslin-Cokic, B.B.; Njoroge, J.M.; Miller, J.L.; Gladwin, M.T.; Schechter, A.N. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J. Clin. Invest., 2003, 111, 231-239.
39. Hillery, C.A.; Du, M.C.; Wang, W.C.; Scott, J.P. Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytes to thrombospondin and laminin. Br. J. Haematol., 2000, 109, 322-327.
40. Steinberg, M.H.; Barton, F.; Castro, O.; Pegelow, C.H.; Ballas, S.K.; Kutlar, A.; Orringer, E.; Bellevue, R.; Olivieri, N.; Eckman, J.; Varma, M.; Ramirez, G.; Adler, B.; Smith, W.; Carlos, T.; Ataga, K.; DeCastro, L.; Bigelow, C.; Saunthararajah, Y.; Telfer, M.; Vichinsky, E.; Claster, S.; Shurin, S.; Bridges, K.; Waclawiw, M.; Bonds, D.; Terrin, M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA, 2003, 289, 1645-1651.
41. Charache, S.; Terrin, M.L.; Moore, R.D.; Dover, G.J.; Barton, F.B.; Eckert, S.V.; McMahon, R.P.; Bonds, D.R. 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, 1317-1322.
42. Perrine, S.P.; Greene, M.F.; Faller, D.V. Delay in the fetal globin switch in infants of diabetic mothers. N. Engl. J. Med., 1985, 312, 334-338.
43. Weinberg, R.S.; Ji, X.; Sutton, M.; Perrine, S.; Galperin, Y.; Li, Q.; Liebhaber, S.A.; Stamatoyannopoulos, G.; Atweh, G.F. Butyrate increases the efficiency of translation of γ-globin mRNA. Blood, 2005, 105, 1807-1809.
44. Atweh, G.F.; Sutton, M.; Nassif, I.; Boosalis, V.; Dover, G.J.; Wallenstein, S.; Wright, E.; McMahon, L.; Stamatoyannopoulos, G.; Faller, D.V.; Perrine, S.P. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood, 1999, 93, 1790-1797.
45. Dover, G.J.; Brusilow, S.; Charache, S. Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood, 1994, 84, 339-343.
46. Fathallah, H.; Atweh, G.F. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology, 2006, ASH education book.
47. Resar, L.M.; Segal, J.B.; Fitzpatric, L.K.; Friedmann, A.; Brusilow, S.W.; Dover, G.J. Induction of fetal hemoglobin synthesis in children with sickle cell anemia on low-dose oral sodium phenylbutyrate therapy. J. Pediatr. Hematol. Oncol., 2002, 24, 737-741.
48. Saunthararajah, Y.; Hillery, C.A.; Lavelle, D.; Molokie, R.; Dorn, L.; Bressler, L.; Gavazova, S.; Chen, Y.H.; Hoffman, R.; DeSimone, J. 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, 3865-3870.
49. Carr, B.I.; Rahbar, S.; Asmeron, Y.; Riggs, A.; Winberg, C.D. Carcinogenicity and hemoglobin synthesis induction by cytidine analogues. Br. J. Cancer, 1988, 57, 395-402.
50. List, A.; Dewald, G.; Bennett, J.; Giagounidis, A.; Raza, A.; Feldman, E.; Powell, B.; Greenberg, P.; Thomas, D.; Stone, R.; Reeder, C.; Wride, K.; Patin, J.; Schmidt, M.; Zeldis, J.; Knight, R. Myelodysplastic Syndrome-003 Study Investigators.Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N. Engl. J. Med., 2006, 355, 1456-1465.
51. Schey, S.A.; Fields, P.; Bartlett, J.B.; Clarke, I.A.; Ashan, G.; Knight, R.D.; Streetly, M.; Dalgleish, A.G. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol., 2004, 22, 3269-3276.
52. Moutouh-de Parseval, L.A.; Vehelle, D.; Glezer, E.; Jensen-Pergakes, K.; Ferguson, G.D.; Corral, L.G.; Morris, C.L.; Muller, G.; Brady, H.; Chan, K. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J. Clin. Invest., 2008, 118, 248-258.
53. Brugnara C. Erythrocyte membrane transport physiology. Curr. Opin. Hematol., 1997, 4, 122-127.
54. Lauf, P.K.; Adragna, N.C. K-Cl cotransport: properties and molecular mechanism. Cell Physiol. Biochem., 2000, 10, 341-354.
55. + efflux is highly expressed in young human red cells containing normal hemoglobin or HbS. J. Membr. Biol., 1987, 97, 97-105.
56. Olukoga, A.O.; Adewoye, H.O.; Erasmus, R.T.; Adedoyin, M.A. Erythrocyte and plasma magnesium in sickle-cell anaemia. East Afr. Med. J., 1990, 67, 348-354.
57. Hankins, J.S.; Wynn, L.W.; Brugnara, C.; Hillery, C.A.; Li, C.S.; Wang, W.C. Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia. Br. J. Hematol., 2008, 140, 80-85.
58. Gardos, G. The function of calcium in the potassium permeability of human erythrocytes. Biochem. Biophys. Acta, 1958, 30, 653-654
59. Alvarez, J.; Montero, M.; Garcia-Sancho, J. High affinity inhibition of Ca(2+)-dependent K+ channels by cytochrome P-450 inhibitors. J. Biol. Chem., 1992, 267, 11789-11793.
60. Brugnara, C. 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, 1227-1234.
61. Stocker, J.W.; De Franceschi, L.; McNaughton-Smith, G.A.; Corrocher, R.; Beuzard, Y.; Brugnara, C. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood, 2003, 101, 2412-2418.
62. Ataga, K.I.; Smith, W.R.; De Castro, L.M.; Swerdlow, P.; Saunthararajah, Y.; Castro, O.; Vichinsky, E.; Kutlar, A.; Orringer, E.P.; Rigdon, G.C.; Stocker, J.W.; ICA-17043-05 Investigators. Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood, 2008, 111, 3991-3997.
63. Romero, J.R.; Suzuka, S.M.; Nagel, R.L.; Fabry, M.E. Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity. Blood, 2002, 99, 1103-1108.
64. Rector, T.S.; Bank, A.J.; Mullen, K.A.; Tschumperlin, L.K.; Sih, R.; Pillai, K.; Kubo, S.H. Randomized, double-blind, placebocontrolled study of supplemental oral L-arginine in patients with heart failure. Circulation, 1996, 93, 2135-2141.
65. Fabry, M.E.; Nagel, R.L. Heterogeneity of red cells in the sickler: a characteristic with practical clinical and pathophysiological implications. Blood Cells, 1982, 8, 9-15.
66. Kaul, D.K.; Fabry, M.E.; Nagel, R.L. Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications. Proc. Natl. Acad. Sci. USA, 1989, 86, 3356-3360.
67. Montes, R.A.; Eckman, J.R.; Hsu, L.L.; Wick, T.M. Sickle erythrocyte adherence to endothelium at low shear: Role of shear stress in propagation of vaso-occlusion: Am. J. Hematol., 2002, 70, 216-227.
68. Embury, S.H.; Matsui, N.M.; Ramanujam, S.; Mayadas, T.N.; Noguchi, C.T.; Diwan, B.A.; Mohandas, N.; Cheung, A.T. The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood, 2004, 104, 3378-3385.
69. Matsui, N.M.; Varki, A.; Embury, S.H. Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin. Blood, 2002, 100, 3790-3796.
70. Matsui, N.M.; Borsig, L.; Rosen, S.D.; Yaghmai; M.; Varki, A.; Embury, S.H. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood, 2001, 98, 1955-1962.
71. Mankelow, T.J.; Spring, F.A.; Parsons, S.F.; Brady, R.L.; Mohandas, N.; Chasis, J.A.; Anstee, D.J. Identification of critical aminoacid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to alpha V integrins. Blood, 2004, 103, 1503-1508.
72. 3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood, 2000, 95, 368-374.
73. Zennadi, R.; Moeller, B.; Whalen, E.J.; Batchvarova, M.; Xu, K.; Shan, S.; Delahunty, M.; Dewhirst, M.W.; Telen, M.J. Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo. Blood, 2007, 110, 2708-2717.
74. Finnegan, E.M.; Barabino, G.A.; Liu, X.D.; Chang, H.Y.; Jonczyk, A.; Kaul, D.K. Small-molecule cyclic ..v..3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion. Am. J. Physiol. Heart Circ. Physiol., 2007, 293, 1038-1045.
75. Lee, S.P.; Ataga, K.I.; Zayed, M.; Manganello, J.M.; Orringer, E.P.; Phillips, D.R.; Parise, L.V. Phase I study of eptifibatide in patients with sickle cell anemia. Br. J. Haematol., 2007, 139, 612-620.
76. 3-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. Am. J. Physiol. Cell Physiol., 2006, 291, C922-930.
77. Orringer, E.P.; Casella, J.F.; Ataga, K.I. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA, 2001, 286, 2099-2106.
78. Canalli, A.A.; Franco-Penteado, C.F.; Saad, S.T.; Conran, N.; Costa, F.F. Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation. Haematologica, 2008, 93, 605-609.
79. Reiter, C.D.; Wang, X.; Tanus-Santos, J.E.; Hogg, N.; Cannon, R.O, 3rd; Schechter, A.N.; Gladwin, M.T. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med., 2002, 8, 1383-1389.
80. Morris, C.R.; Vichinsky, E.P.; Warmerdam, J.V.; Machado, L.; Kepka-Lenhart, D.; Morris, S.M., Jr.; Kuypers, F.A. Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease. J. Pediatr. Hematol. Onc., 2003, 25, 629-634.
81. Michelakis, E.D.; Tymchak, W.; Noga, M.; Webster, L.; Wu, X.C.; Lien, D.; Wang, S.H.; Modry, D.; Archer, S.L. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation, 2003, 108, 2066-2069.
82. Machado, R.F.; Martyr, S.; Kato, G.J., Barst, R.J.; Anthi, A.; Robinson, M.R.; Hunter, L.; Coles, W.; Nichols, J.; Hunter, C.; Sachdev, V.; Castro, O.; Gladwin, M.T. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br. J. Haematol., 2005, 130, 445-453.
83. Kato, G.J.; Gladwin, M.T. Evolution of novel small molecule therapeutics targeting sickle cell vasculopathy. JAMA, 2008, 300, 2638-2646.
84. Switzer, J.A.; Hess, D.C.; Nichols, F.T.; Adams, R.J. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol., 2006, 5, 501-512
85. Kaul, D.K,; Liu, X.D.; Zhang, X.; Ma, L.; Hsia, C.J.; Nagel, R.L. Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants. Am. J. Physiol. Heart Circ. Physiol., 2006, 291, 167-175.