Copper-indomethacinate associated with zwitterionic phospholipids prevents enteropathy in rats: effect on inducible NO synthase.
Intestinal toxicity exerted by indomethacin was compared to that induced by copper-indomethacinate, free or associated to zwitterionic phospholipids. A single high dose of indomethacin (15 or 20 mg/kg), copper-indomethacinate (15 or 20 mg/kg), or copper-indomethacinate liposomes or nanocapsules (15 mg/kg) was orally administered. Then 24 hr later jejunoileal tissue was taken for macroscopic observation, ex vivo nitrite production, and determination of myeloperoxydase and iNOS activities. Antiinflammatory activity of the drugs was investigated using the carrageenan-induced paw edema model. Indomethacin induced penetrating ulcerations of the intestine that were maximal at hour 24. Copper-indomethacinate induced significantly less ulceration than indomethacin with no significant difference in MPO and iNOS activities. The injurious action of indomethacin on the small intestine was further reduced when copper-indomethacinate was administered as the phospholipid-associated state while similar anti-inflammatory action was observed on rat paw edema. The antiulcerogen effect of copper-indomethacinate seems to be linked to its free radical scavenging effect without any modification of nitric oxide release.
Bertrand
V
V
Département de Pharmacologie, CNRS URA 1534, Hôpital Cochin, Paris, France.
Guessous
F
F
Le Roy
A L
AL
Viossat
B
B
Fessi
H
H
El Abbouyi
A
A
Giroud
J P
JP
Roch-Arveiller
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology*; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008081:Liposomes; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D010743:Phospholipids; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008081:Liposomes; D009942:Organometallic Compounds; D010743:Phospholipids; C063001:cupric(indomethacinate)4complex; D003300:Copper; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007213:Indomethacin