NPC 15669, an inhibitor of neutrophil recruitment, is efficacious in acetic acid-induced colitis in rats.
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.
Noronha-Blob
L
L
Scios-Nova Pharmaceutical Corporation, Baltimore, Maryland.
Lowe
V C
VC
Muhlhauser
R O
RO
Burch
R M
RM
D000085:Acetates; D019342:Acetic Acid; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D003907:Dexamethasone / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000032:analysis / Q000378:metabolism; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D019804:Mesalamine; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000032:analysis / Q000378:metabolism
D000085:Acetates; D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005449:Fluorenes; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D007975:Leukotriene B4; C080486:N-(9H-(fluoren-9-ylmethoxy)carbonyl)glycine; D019804:Mesalamine; D013929:Thromboxane B2; D009637:Masoprocol; D003907:Dexamethasone; D009195:Peroxidase; D007930:Leucine; D019342:Acetic Acid; D005998:Glycine; D006854:Hydrocortisone