DERMAL INFLAMMATION IN PRIMATES, MICE, AND GUINEA-PIGS - ATTENUATION BY 2ND-GENERATION LEUKOTRIENE-B-4 RECEPTOR ANTAGONIST, SC-53228

Granulocyte infiltration is a prominent feature of human psoriasis. Ps oriatic lesional skin contains abnormally high amounts of immunoreacti ve leukotriene B-4 (LTB(4)), a potent granulocyte chemotaxin in vivo a nd in vitro. SC-53228 )-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propano ic acid], a second-generation LTB(4) receptor antagonist, was tested t opically and orally in phorbol ester-induced dermal inflammation in th ree species. Skin inflammation was induced by topical application of p horbol-12-myristate-13-acetate-(PMA/TPA and assessed by ear thickness, levels of the neutrophil marker enzyme myeloperoxidase (MPO) and hist ological examination. In mice, SC-53228 inhibited inflammation with a topical ED(50) value of 200 +/- 18 mu g. When applied to guinea pigs, SC-53228 (100 mu g) inhibited the MPO increase by 86%, while 1000 mu g abrogated inflammation in rhesus macaques with no plasma accumulation of the drug. A 1% gel formulation was also efficacious in guinea pig PMA-induced epidermal inflammation. Furthermore, single oral dose admi nistration to mice was efficacious (ED(50) < 2.5 mg/kg) as was multido se administration to rhesus macaques. PMA-induced skin inflammation po ssesses some of the attributes of human psoriasis and an agent such as SC-53228 may have utility in the medical management of this condition .