This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main objective of this study is to evaluate the safety and tolerability of multiple doses of 10mg/kg/day of ICL670 as a starting dose (with potential dose adjustments) relative to deferoxamine (DFO) in sickle cell disease (SCD) patients with transfusional hemosiderosis requiring chelation therapy. Sickle cell disease includes sickle cell anemia, the sicklec beta thalassemia syndromes and hemoglobinopathies in which HbS is in association with another abnormal hemoglobin. The two cardinal pathphysiologic features of sickle cell disorders are chronic hemolytic anermia and vaso-occlusion, which results in ischemic tissue injury. Sickle cell disease patients sometimes require long-term transfusional therpary to treat or prevent severe complications such as stroke and chronic congestive heart failure. The goal of a chronic transfusion program is to maintain the percent HbA above 50-70 percent. Repeated transfuiosn leads to rapid iron loading with excess iron being deposited in the liver, spleen, many endocrine organs, and the myocardium, leading to tissue damage and fibrosis. When excess iron overload is documented, chelation therapy with DFO is initiated. Poor patient compliance due to repeated subcutaneous infusions of DFO is a significant problem with chronic chelation therapy. The need for an iron chelator, which can be given orally, has been recognized for a long time. ICL670 is an N-substituted bis-hydroxphenyl-triazole of a new class of tridentate iron chelator. It is active after orally administration and exhibits high tolerability and potency in mobilizing tissue iron and promoting iron excretion, as demonstrated in in vitro and in vivo models.
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