Inflammation of guinea pig dermis. Effects of leukotriene B4 receptor antagonist, SC-41930.
Neutrophil (PMNL) infiltration is a prominent feature of human psoriasis. Psoriatic skin lesions contain abnormally high amounts of leukotriene B4 (LTB4), itself a potent PMNL chemoattractant both in vivo and in vitro. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid), an orally active LTB4 receptor antagonist, was tested topically in models of skin inflammation induced by 200 nmol of the calcium ionophore A23187 or 200 micrograms phorbol-12-myristate-13-acetate (PMA) applied topically to the guinea pig ear as assessed by ear weight, levels of the PMNL marker enzyme myeloperoxidase (MPO), and histological examination (PMA model) at 4 and 18 h respectively. When coapplied topically with A23187 or PMA, SC-41930 significantly inhibited epidermal inflammation with ED50 values of 0.6 and 4 mg, respectively. SC-41930 treatment also was associated with lowered dermal LTB4 levels in both models. The PMA-induced skin inflammation model also was assessed histologically and revealed acanthosis, edema, PMNL infiltration, and rete ridge prominence as long as 96 h after a single application that was completely inhibited by SC-41930 topical coapplication. Furthermore, oral treatment (40 mg/kg) significantly reduced edema and inflammatory cell infiltration in both models. These models possess many of the characteristics of human psoriasis, and agents such as SC-41930 that demonstrate activity in these models may well have therapeutic utility in the treatment of human psoriasis.
Fretland
D J
DJ
Department of Gastrointestinal Diseases, Searle Research and Development, Skokie, Illinois.
Widomski
D L
DL
Zemaitis
J M
JM
Walsh
R E
RE
Levin
S
S
Djuric
S W
SW
Shone
R L
RL
Tsai
B S
BS
Gaginella
T S
TS
D000279:Administration, Cutaneous; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D000001:Calcimycin / Q000633:toxicity; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007249:Inflammation; D008297:Male; D011565:Psoriasis / Q000473:pathology; D011971:Receptors, Immunologic / Q000187:drug effects*; D018102:Receptors, Leukotriene B4; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D001578:Benzopyrans; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C059950:SC 41930; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate