TUCARESOL INCREASES OXYGEN-AFFINITY AND REDUCES HEMOLYSIS IN SUBJECTSWITH SICKLE-CELL-ANEMIA

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-fo rmyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde , was designed to interact with haemoglobin to increase oxygen affinit y and has been shown to inhibit sickling in vitro. We administered tuc aresol to sickle cell patients in the steady state to examine the anti -sickling effect in vivo. Oral doses of tucaresol or placebo were give n to nine stable sickle cell patients (aged 17-39 years; tucaresol, si x; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 o r 300 mg for the next 6 d. Due to concerns over the sharp rise in haem atocrit in one patient, subsequent cohorts received 300 mg tucaresol d aily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patient s on tucaresol, haemolysis was reduced with rises in haemoglobin of 0. 9 - 3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16-52% , and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1-2 weeks following discontinuation of the drug. Three of the six patients on tucaresol d eveloped fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.