Dermal inflammation in primates, mice, and guinea pigs: attenuation by second-generation leukotriene B4 receptor antagonist, SC-53228.
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 micrograms. When applied to guinea pigs, SC-53228 (100 micrograms) inhibited the MPO increase by 86%, while 1000 micrograms 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.
Fretland
D J
DJ
Department of Inflammatory Diseases Research, Searle Research and Development, Skokie, Illinois 60077, USA.
Gokhale
R
R
Mathur
L
L
Baron
D A
DA
Paulson
S K
SK
Stolzenbach
J
J
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D004195:Disease Models, Animal; D003875:Drug Eruptions / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004431:Ear, External; D004487:Edema / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005782:Gels; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000037:antagonists & inhibitors; D011565:Psoriasis / Q000188:drug therapy*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001578:Benzopyrans; D005782:Gels; D018102:Receptors, Leukotriene B4; C082206:7-(3-(2-(cyclopropylmethyl)-3-methoxy-4-((methylamino)carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate