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Acetylsalicylic acid (ASA) causes adverse haemorrhagic reactions in the upper gastrointestinal (GI) tract, and previous results have suggested that combination therapy with 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) could provide protection in this scenario. Based on this hypothesis, our aim was to develop a new compound from ASA and Tris precursors and to characterize the biological effects of ASA-Tris and the derivatives ASA-bis- and mono-hydroxymethyl-aminomethane (ASA-Bis, ASA-Mono, respectively) using in vivo and in vitro test systems. ASA or ASA conjugates (0.55mmol/kg, each) were administered intragastrically to Sprague-Dawley rats. Changes in the mucosal structure and in the serosal microcirculation were detected by in vivo imaging techniques, the plasma TNF-alpha, tissue xanthine oxidoreductase and myeloperoxidase activities, and liver cytochrome c changes were also determined. In two separate series, platelet aggregation and carrageenan arthritis-induced inflammatory pain were measured in control, ASA and ASA-Tris-treated groups. Severe mucosal injury and a significant decrease in serosal red blood cell velocity developed in the ASA-treated group and an ~2-fold elevation in proinflammatory mediator levels evolved. ASA-Tris did not cause bleeding, microcirculatory dysfunction, mucosal injury or an elevation in proinflammatory markers. The ASA-Mono and ASA-Bis conjugates did not cause macroscopic bleeding, but the inflammatory activation was apparent. ASA-Tris did not influence the cyclooxygenase-induced platelet aggregation significantly, but the inflammatory pain was reduced as effectively as in the case of equimolar ASA doses. ASA-Tris conjugation is an effective approach through which the GI side-effects of ASA are controlled by decreasing the cytokine-mediated progression of pro-inflammatory events., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We investigated the effects of exogenous phosphatidylcholine (PC) and non-steroidal diclofenac supplementation on polymorphonuclear cell influx in carrageenan-induced arthritis in rats. The microcirculatory consequences were evaluated by a novel method developed for direct intravital microscopic observation of the synovial membrane. Arthritis was induced by injection of a mixture of 2% lambda-carrageenan and 4% kaolin into the knee joints and the animals were treated orally with PC (150 mg/kg twice daily), sodium diclofenac (0.5mg/kg twice daily) or saline vehicle. Intravital videomicroscopy was used to investigate the leukocyte-endothelial interactions directly in the synovial membrane at 6h after the challenge. The inflammation-induced thermal and mechanical secondary hyperalgesic reactions were assessed at 24h, and the knee volume changes at 48h after the insult. The development of arthritis was accompanied by a significant increase in the number of adherent leukocytes in the synovial postcapillary venules, but this increase was reduced significantly (by approximately 40%) by PC, and slightly (by 22%) by diclofenac treatment. The perivascular infiltration of the neutrophil leukocytes and the intercellular adhesion molecule-1 (ICAM-1) expressions were reduced only by PC treatment. The significant decrease (45%) in the thermal nociceptive latency, the 3-fold increase in the mechanical touch sensitivity and the knee cross-sectional area (which was increased by 35% by the arthritis induction) were significantly ameliorated by both treatments. The present study demonstrated the anti-inflammatory effects of PC in experimental arthritis. The therapeutic potential may be linked to the reduction of neutrophil leukocyte-mediated microcirculatory inflammatory reactions.

The effect of co-administration with polyene phosphatidylcholine (Phospholipon 100) on the oral gastrotoxicity of various non-steroidal anti-inflammatory drugs (NSAIDs) was studied in the rat. The highly unsaturated phospholipid reduced gastric mucosal lesions measured 3.5 h after oral administration of aspirin, indomethacin, phenylbutazone, diclofenac, piroxicam and sudoxicam to rats which had received a 3 day bread diet followed by 24 h fasting. The extent of reduction of gastrotoxicity varied amongst the individual NSAIDs. Phospholipon 100 also reduced gastric lesions induced by 3 day oral piroxicam and diclofenac administration. A trend towards reduction of oral diclofenac gastrotoxicity was observed following intravenous Phospholipon 100 administration. Phospholipon 100 H (100% saturated phosphatidylcholine) was less effective than Phospholipon 100 in improving acute gastric tolerance to oral phenylbutazone, diclofenac and piroxicam. Administration of the NSAID-Phospholipon 100 combination produced little change in the anti-inflammatory activities of diclofenac on carrageenan paw oedema and diclofenac and piroxicam on adjuvant arthritis in the rat. Combination with Phospholipon 100 offers a novel means for reducing the gastric side-effects of NSAID therapy.