Abstract | BACKGROUND AND PURPOSE:
Indomethacin is a non-steroidal anti-inflammatory drug ( NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use. EXPERIMENTAL APPROACH: Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity ( luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy ( analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E(2) concentration) in rats with adjuvant-induced joint inflammation. KEY RESULTS: Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin. CONCLUSIONS AND IMPLICATIONS: The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.
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Authors | L M Lichtenberger, J J Romero, E J Dial |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 157
Issue 2
Pg. 252-7
(May 2009)
ISSN: 1476-5381 [Electronic] England |
PMID | 19366347
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Phosphatidylcholines
- Dinoprostone
- Indomethacin
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Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(adverse effects, pharmacokinetics, therapeutic use)
- Chromatography, High Pressure Liquid
- Dinoprostone
(analysis)
- Drug Administration Routes
- Gastrointestinal Hemorrhage
(chemically induced)
- Indomethacin
(adverse effects, blood, therapeutic use)
- Models, Animal
- Phosphatidylcholines
(chemistry)
- Radioimmunoassay
- Rats
- Stomach Ulcer
(chemically induced)
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