Finding of 8 New Therapeutic Agents by the Use of New High-Throughput Drug Screening Methods Established by the Nhlbi Sicke Cell Disease Reference Laboratory.

The NHLBI Sickle Cell Disease (SCD) Reference Laboratory (Ref Lab) was established in 1997 to facilitate rapid, efficient, accurate and economical evaluation of agents or therapies that may be beneficial for the treatment of patients with sickle cell disease. On the basis of the assumption that the unsuccessful finding of antisickling agents in the past was attributed to insufficient pre-clinical drug evaluation, the SCD Ref Lab proposed to screen drugs using more than 10 in vitro tests to study if a drug inhibits or promotes sickling, hydrates or dehydrates SS cells, prolongs or shortens the delay time prior to deoxy-Hb S polymerization, induces Hb F, increases or decreases the solubility of deoxy-Hb S; Hb oxygen affinity; membrane ion transport, adhesion of SS cells to endothelial cells; met-Hb S formation; hemolysis and the amount of intracellular denatured Hb S. In addition, drugs that showed a beneficial effect without significant adverse effects in these tests were further studied using transgenic mice that produce human sickle hemoglobin. To perform many in vitro tests efficiently, the SCD Ref Lab established a new high-throughput drug evaluation protocol by which many tests are conducted simultaneously using a small volume of SS blood samples or Hb S. To date, we have found 8 new antisickling agents. They are NS3623 (