[Clinical trials of new therapeutic pharmacology for sickle cell disease].
Following the generation of transgenic mouse models of sickle cell disease, pre-clinical trials have shown the beneficial effects of various potential therapeutic molecules for the acute or chronic manifestations of the disease. Several molecules are upon evaluation in phase I to phase III clinical trials. These therapeutic approaches target: 1) membrane cation transport systems and channels involved in sickle cell dehydration; 2) adherence of erythrocytes to endothelium; 3) activation of circulating and endothelial cells participating in the vasoocclusive events and local ischemia. The Gardos channel (calcium activated potassium channel KCNN4) is inhibited by the clotrimazole metabolite ICA17043, in phase III trial. The K-Cl co-transport (KCC1/3/4) activated by the depletion of erythrocyte magnesium is inhibited by Magnesium pidolate; dipyridamole inhibits ion transports upon deoxygenation. Sulfasalazyne (inhibitor of the NF-jB pathway) inhibits the abnormal activation of endothelial cells. Nitric oxide (NO) is the most potent vasodilator. It prevents the activation of leucocytes, platelets and endothelial cells in patients with sickle cell disease and vascular remodelling. The L-arginine, the NO precursor, provides could be beneficial in sickle cell patients.
Brugnara
Carlo
C
Department of Laboratory Medicine and Pathology, Children's Hospital, Harvard Medical School, Boston, MA, USA. carlo.brugnara@childrens.harvard.edu
de Franceschi
Lucia
L
D000081:Acetamides / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D002986:Clinical Trials as Topic; D003022:Clotrimazole / Q000627:therapeutic use; D004176:Dipyridamole / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004903:Erythrocyte Aggregation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors; D007511:Ischemia / Q000517:prevention & control; D049990:Membrane Transport Modulators / Q000627:therapeutic use; D051379:Mice; D009569:Nitric Oxide / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011761:Pyrrolidonecarboxylic Acid / Q000627:therapeutic use; D027981:Symporters / Q000037:antagonists & inhibitors; D014320:Triphenylmethyl Compounds / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use; D000096922:K Cl- Cotransporters
D000081:Acetamides; D001120:Arginine; D003022:Clotrimazole; D004176:Dipyridamole; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D049990:Membrane Transport Modulators; D009569:Nitric Oxide; D010975:Platelet Aggregation Inhibitors; D011761:Pyrrolidonecarboxylic Acid; D027981:Symporters; D014320:Triphenylmethyl Compounds; D014665:Vasodilator Agents; D000096922:K Cl- Cotransporters; C496923:KCNN4 protein, human; C472774:senicapoc