The effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.
BACKGROUND
The pathogenesis of NSAID-induced enteropathy may involve dual inhibition of the cyclooxygenase (1 and 2) and a topical effect with sequential increased intestinal permeability, development of inflammation and ulcers. It has been suggested that nitric-oxide donating drugs cause significantly less gastrointestinal injury by counteracting for NSAID-induced reductions in blood flow.


OBJECTIVE
To compare the effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.


METHODS
Single doses of AZD3582, naproxen (dose range 10-300 micromol/kg) or vehicle were given to male Sprague Dawley rats. Intestinal permeability (51CrEDTA) and intestinal inflammation (granulocyte marker protein) was quantitated and ulcer counts made.


RESULTS
Intestinal permeability (all doses) and inflammation (highest dose of the drugs) increased significantly from control levels following naproxen and AZD3582 and there was no significant difference between the drugs. Median ulcer counts were, however, significantly (p < 0.01) lower with AZD3582 (4 +/- 2) than with naproxen (17 +/- 4).


CONCLUSIONS
Naproxen and AZD3582 are equally associated with increased small intestinal permeability and inflammation, which is the consequence of their topical effect. The reduced small bowel ulcer counts with AZD3582 accords with the suggestion that vascular factors are the main driving force for NSAID-induced ulcer formation.
Guy's, King's and St Thomas' School of Medicine, Department of Gastroenterology, King's College Hospital Foundation Trust, Denmark Hill, London SE5 9PJ, London, UK.
M
M
Walley
G
G
Sigthorsson
C
C
Hotz-Behofsits
R
R
Simpson
I
I
Bjarnason
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004751:Enteritis / Q000517:prevention & control; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D009288:Naproxen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; C111751:naproxen-n-butyl nitrate; D009288:Naproxen