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Dermal inflammation in primates, mice, and guinea pigs: Attenuation by second-generation leukotriene B4 receptor antagonist, SC-53228

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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 μg. When applied to guinea pigs, SC-53228 (100 μg) inhibited the MPO increase by 86%, while 1000 μg 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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Authors and Affiliations

  1. Department of Inflammatory Diseases Research, Searle Research and Development, 4901 Searle Parkway, 60077, Skokie, Illinois

    D. J. Fretland

  2. Department of Pharmaceutical Sciences, Searle Research and Development, 4901 Searle Parkway, 60077, Skokie, Illinois

    R. Gokhale & L. Mathur

  3. Department of Safety Assessment, Searle Research and Development, 4901 Searle Parkway, 60077, Skokie, Illinois

    D. A. Baron

  4. Department of Pharmacokinetics Bioanalytical and Radiochemistry, Searle Research and Development, 4901 Searle Parkway, 60077, Skokie, Illinois

    S. K. Paulson & J. Stolzenbach

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  1. D. J. Fretland
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Fretland, D.J., Gokhale, R., Mathur, L. et al. Dermal inflammation in primates, mice, and guinea pigs: Attenuation by second-generation leukotriene B4 receptor antagonist, SC-53228. Inflammation 19, 333–346 (1995). https://doi.org/10.1007/BF01534391

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