NPC 15669, an inhibitor of neutrophil recruitment, is efficacious in acetic acid-induced colitis in rats

Abstract

Background: The efficacy of the leukocyte recruitment inhibitor, N-[9H-2,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669) was compared with drugs used to treat inflammatory bowel diseases in a rat model, acetic acid-induced colitis.

Methods: Colonic damage assessed by visual inspection, histological quantitation of tissue injury, vascular permeability, myeloperoxidase (MPO) accumulation, and synthesis of inflammatory mediators were measured.

Results: Intrarectal pretreatment with NPC 15669 results in a significant reduction of all measured indices of inflammation. The median effective dose (ED50) of NPC 15669 for inhibition of MPO accumulation and vascular permeability is 13.2 mg/kg and 31 mg/kg, respectively. The active moiety of sulfasalazine, 5-aminosalicylic acid (5-ASA), the antioxidant/5-lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) and the corticosteroids dexamethasone and hydrocortisone, yielded ED50 values (MPO accumulation) of 68 mg/kg, 95 mg/kg, 0.7 mg/kg, and 13 mg/kg, respectively. When formulated suspensions of NPC 15669, 5-ASA, or dexamethasone were used, potency was increased 10-40-fold. Furthermore, NPC 15669 (10 mg/kg) administered 7 hours after acetic acid and evaluated 24 hours after acetic acid administration significantly attenuated neutrophil influx (70% inhibition of MPO accumulation), whereas 5-ASA (100 mg/kg) displayed no therapeutic effects.

Conclusions: NPC 15669 may be useful in the treatment of inflammatory disorders.