Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia.
Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.
Ataga
Kenneth I
KI
Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Room 3149, Physicians Office Building, CB# 7305, Chapel Hill, NC 27599-7305, USA. kataga@med.unc.edu
Stocker
Jonathan
J
D000081:Acetamides / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D030801:Animals, Genetically Modified; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D014320:Triphenylmethyl Compounds / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity
D000081:Acetamides; D014320:Triphenylmethyl Compounds; C472774:senicapoc