Various Drugs with or without an Antisickling Effect in the In Vitro Tests Showed a Strong Antisickling Effect in the In Vivo Studies in Transgenic Sickle Mice.

Since its inception in 1997, the NHLBI Sickle Cell Disease (SCD) Reference Laboratory (Ref Lab) has received over 150 candidate drugs from over 30 researchers, universities and companies for evaluation. All candidate drugs are evaluated for both their beneficial and adverse effects in vitro using more than 10 sophisticated methods. Specifically, each candidate drug is studied to see whether it inhibits cell sickling, prolongs the delay time prior to deoxy-hemoglobin (Hb) S polymerization, increases the solubility of deoxy-Hb S, hydrates red blood cells (RBCs), prevents dehydration of RBCs, shifts the oxygen equilibrium curve (OEC) toward the left, reduces the adhesion of RBCs to endothelial cells, promotes the synthesis of Hb F, causes hemolysis, promotes formation of met-Hb and increases the denaturation of intracellular Hb S. With this new approach, we have found more than 10 new antisickling agents that showed beneficial effects without significant adverse effects in the in vitro tests. Of these, five drugs were further studied in vivo using transgenic mice that produce human Hb S, and all five drugs inhibited the formation of sickled cells in the blood and significantly prolonged their survival time under acute hypoxic conditions. The five drugs are NIPRISAN (plant extracts) [Brit. J. Haematol. (BJH) 122:1001,2003], MX-1520 (prodrug of vanillin) (