STIMULUS-DEPENDENT EFFECTS OF CI-986 ON ARACHIDONIC-ACID METABOLISM BY HUMAN NEUTROPHILS

CI-986 l)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione choline salt ) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B-4 (LTB(4) ) release in response to calcium ionophore A23187 was 15 to 35 fold gr eater than the responses to N-formyl-methionyl-leucyl-phenylalanine (F MLP) or serum-opsonized zymosan (SOZ), respectively, while the thrombo xane B-2 (TXB(2)) release response was similar for the three stimuli t ested CI-986 inhibited the release of LTB(4) and TXB(2) in response to A23187 with IC(50)s of 63.4 and 1.6 mu M, respectively. In comparison , the compound inhibited SOZ-stimulated LTB(4) release with an IC50 of 11.2 mu M, while having no effect on TXB(2) at concentrations up to 1 00 mu M. Conversely, CI-986 inhibited FMLP-stimulated LTB(4) release b y 42% at 100 mu M, while inhibiting TXB(2) release with an IC50 of 0.1 3 mu M. These results demonstrate a stimulus-dependent inhibitory effe ct of CI-986 on human neutrophil eicosanoid metabolism.