NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects.
BACKGROUND
A novel class of nitric oxide-releasing nonsteroidal anti-inflammatory drug (NO-NSAID) derivatives has recently been described which exert anti-inflammatory activities but produce significantly less gastrointestinal injury than the parent NSAID from which they are derived. The present studies were performed to determine if a nitroxybutylester derivative of naproxen was less ulcerogenic to the gastrointestinal tract than its parent NSAID, and if it exerted comparable analgesic and anti-inflammatory properties to the parent NSAID.


METHODS
The two drugs were compared in an acute gastric injury model, an antral ulcer model and after twice-daily administration for 18 days (small intestinal damage model). Anti-inflammatory activity was examined in the carrageenan-induced paw oedema model, while analgesia was examined in the acetic acid-induced writhing model. The pharmacokinetic profiles of naproxen vs. NO-naproxen were compared by HPLC analysis.


RESULTS
NO-naproxen was found to produce significantly less gastric damage despite inducing similar increases in plasma TNF alpha to naproxen. With chronic administration, small intestinal damage was markedly less with NO-naproxen than with the parent NSAID. However, NO-naproxen exerted superior analgesic and comparable anti-inflammatory effects to naproxen. NO-naproxen was not completely converted to naproxen, but the reduced plasma levels of the latter was not the underlying reason for reduced gastrointestinal toxicity of NO-naproxen.


CONCLUSIONS
NO-naproxen represents a novel, gastrointestinal-sparing NSAID derivative with superior analgesic and comparable anti-inflammatory properties to naproxen.
Davies
N M
NM
Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.
Røseth
A G
AG
Appleyard
C B
CB
McKnight
W
W
Del Soldato
P
P
Calignano
A
A
Cirino
G
G
Wallace
J L
JL
D000700:Analgesics / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000633:toxicity*; D007077:Ileal Diseases / Q000097:blood / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D009288:Naproxen / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D010437:Peptic Ulcer / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D009288:Naproxen