Leukotriene B4 (
LTB4) is a potent neutrophil activator and
chemotaxin that is present in increased concentrations in the colonic tissue and rectal
dialysates of acute
ulcerative colitis patients. Cotton-top tamarins (CTTs) with confirmed active
colitis were treated with the second generation
LTB4 receptor antagonist,
SC-53228 ((+)-(S)-7-[3-(2-cyclopropyl-methyl)-3-methoxy-4-[(methylamino) carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-
benzopyran-2-
propanoic acid), 20 mg/kg bodyweight by gavage, twice daily for 56 days. End points were
body weights, stool consistency, colonic endoscopy, assay of inflammatory mediators, and haematology and clinical chemistry tests.
LTB4 and
prostaglandin E (
PGE) values were measured in rectal
dialysates at pretreatment, 28 day and 56 day time points.
LTB4 concentrations were reduced from pretreatment mean (SEM) values of 37.3 (0.8) ng/ml to 3.7 (0.8) ng/ml (p < 0.001) and 2.3 (0.5) ng/ml (p < 0.01) at days 28 and 56, respectively. On the other hand, mucosal protective
PGE values remained constant or slightly increased during
SC-53228 treatment (pre: 6.9 (2.2) ng/ml; day 28: 6.7 (1.4) ng/ml; day 56: 9.9 (1.6) ng/ml). Furthermore, assessment of a panel of 35 clinical chemistry and haematology parameters throughout the treatment showed there were no significant untoward effects of
drug treatment. Six CCTs finished the eight week treatment and five of six gained weight (ranging from 27-121 grams each) while one CTT lost weight (50 g). Stool condition improved in five of six animals while one of six remained unchanged. All CCTs showed dramatic improvement histologically, with no or only minimally active
colitis after treatment. The histological changes plus significant
weight gains and improvement of stool condition (quality of life parameters) after eight weeks of
SC-53228 treatment were remarkable. Furthermore, in follow up biopsies seven months
after treatment ceased, three of six CTTs had no active
colitis. This is the first time afflicted CTTs have not had recurring colitic exacerbations after a treatment regimen was stopped. It is concluded that in colitic CTTs,
SC-53228 has shown both an immediate and a long acting anticolitic activity. It is also concluded that reduced
LTB4 concentrations during treatment inhibited neutrophil infiltration of the colonic tissue and this, coupled with the maintenance of mucosal protective
prostaglandins, contributed to the dramatic anticolitic efficacy. The treatment was safe over eight weeks. A compound such as
SC-53228 may be useful in the medical treatment of human
inflammatory bowel disease.