Effect of the leukotriene B4 receptor antagonist SC-41930 on colonic inflammation in rat, guinea pig and rabbit.
Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes ulcerative colitis and Crohn's disease. Leukotriene B4 is thought to be a prominent proinflammatory mediator in these diseases, in that leukotriene B4 levels are increased in the colonic mucosa of inflammatory bowel disease patients and there is increased polymorphonuclear leukocyte infiltration of these tissues. We evaluated the efficacy of 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-3,4-dihydro-8-propyl -2H-1-benzopyran-2-carboxylic acid (SC-41930), a potent, orally active leukotriene B4 receptor antagonist, in a model of inflammatory bowel disease. Colonic mucosal inflammation was induced in rats, guinea pig and rabbits by rectal instillation of a dilute solution of acetic acid. Twenty-four hours later, mucosal levels of myeloperoxidase (a marker enzyme for neutrophil infiltration) and extravasation of i.v. administered Evans blue dye (a marker of vascular disruption and increased permeability) were measured. Tissues were also evaluated histologically. The animals received either SC-41930 or vehicle, intrarectally, 30 min after or 1 hr before and 1 hr after the acetic acid. When given 30 min after acetic acid instillation SC-41930 prevented the rise in myeloperoxidase and dye extravasation observed in the acetic acid inflammed tissue. The SC-41930-treated tissues were less edematous and had fewer neutrophils within the subepithelial space. Median effective dose (ED50) values for vascular protection were approximately 20 mg/kg for both rat and guinea pig. ED50 values for inhibition of granulocyte accumulation were 20 mg/kg for rat, 24 mg/kg for guinea pig and 30 mg/kg for rabbit. These data indicate that SC-41930 is effective locally to prevent acute colonic inflammation.
Fretland
D J
DJ
Department of Gastrointestinal Diseases Research, Searle Research Development Skokie, Illinois.
Widomski
D
D
Tsai
B S
BS
Zemaitis
J M
JM
Levin
S
S
Djuric
S W
SW
Shone
R L
RL
Gaginella
T S
TS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D003092:Colitis / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D009195:Peroxidase / Q000032:analysis; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000187:drug effects*; D018102:Receptors, Leukotriene B4
D001578:Benzopyrans; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C059950:SC 41930; D007975:Leukotriene B4; D009195:Peroxidase