Dermal inflammation in primates,mice, and guinea pigs: Attenuation by second-generation leukotriene B4 receptor antagonist,SC-53228 |
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Authors: | D. J. Fretland R. Gokhale L. Mathur D. A. Baron S. K. Paulson J. Stolzenbach |
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Affiliation: | (1) Department of Inflammatory Diseases Research, Searle Research and Development, 4901 Searle Parkway, 60077 Skokie, Illinois;(2) Department of Pharmaceutical Sciences, Searle Research and Development, 4901 Searle Parkway, 60077 Skokie, Illinois;(3) Department of Safety Assessment, Searle Research and Development, 4901 Searle Parkway, 60077 Skokie, Illinois;(4) Department of Pharmacokinetics Bioanalytical and Radiochemistry, Searle Research and Development, 4901 Searle Parkway, 60077 Skokie, Illinois |
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Abstract: | Granulocyte infiltration is a prominent feature of human psoriasis. Psoriatic lesional skin contains abnormally high amounts of immunoreactive leukotriene B4 (LTB4), a potent granulocyte chemotaxin in vivo and in vitro. SC-53228 [(+)-(S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy}propoxy)-3, 4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], a second-generation LTB4 receptor antagonist, was tested topically and orally in phorbol ester-induced dermal inflammation in three species. Skin inflammation was induced by topical application of phorbol-12-myristate-13-acetate-(PMA/TPA) and assessed by ear thickness, levels of the neutrophil marker enzyme myeloperoxidase (MPO) and histological examination. In mice, SC-53228 inhibited inflammation with a topical ED50 value of 200 ± 18 g. When applied to guinea pigs, SC-53228 (100 g) inhibited the MPO increase by 86%, while 1000 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 administration to mice was efficacious (ED50 < 2.5 mg/kg) as was multidose administration to rhesus macaques. PMA-induced skin inflammation possesses some of the attributes of human psoriasis and an agent such as SC-53228 may have utility in the medical management of this condition. |
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