ADDITIVE IN-VITRO EFFECTS OF ANTI-SICKLING DRUGS

To study the effect of anti-sickling drugs on cellular dehydration ind uced by entry of Ca, sickle cells were subjected to cyclical oxygenati on-deoxygenation for 15 h in Ca-containing buffer. The consequential l oss of cation (K) via the Ca-dependent K efflux (Gardos) channel cause d cell dehydration and loss of deformability. Inhibition of a specific fraction of Ca entry by verapamil had no rheologically protective eff ect, whereas inhibition of the Gardos channel by clotrimazole or nitre ndipine had a marked protective effect. When Gardos channel inhibition (by either clotrimazole or nitrendipine) was combined with stabilizat ion of the oxyconformation of sickle haemoglobin (by the substituted b enzaldehyde 12C79), an additive protective rheological effect was achi eved with 60-78% reduction in clogging rate of 5 mu m diameter pores w hen compared with no drug. Therapeutic use of anti-sickling compounds in combination may achieve increased efficacy with lower toxicity.