title: Reduced mucosal side-effects of acetylsalicylic acid after conjugation with tris-hydroxymethyl-aminomethane. Synthesis and biological evaluation of a new anti-inflammatory compound.
abstract: 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.
authors.affiliation: Institute of Surgical Research, Faculty of Medicine, University of Szeged, H-6720, Szeged, Szőkefalvi-Nagy Béla u. 6, Hungary. Electronic address: varga.gabriella.1@med.u-szeged.hu.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Varga
authors.affiliation: Institute of Surgical Research, Faculty of Medicine, University of Szeged, H-6720, Szeged, Szőkefalvi-Nagy Béla u. 6, Hungary. Electronic address: lajkonorbert91@gmail.com.
authors.forename: Norbert
authors.initials: N
authors.lastname: Lajkó
authors.affiliation: Institute of Surgical Research, Faculty of Medicine, University of Szeged, H-6720, Szeged, Szőkefalvi-Nagy Béla u. 6, Hungary. Electronic address: lindaugocsai@gmail.com.
authors.forename: Melinda
authors.initials: M
authors.lastname: Ugocsai
authors.affiliation: Institute of Surgical Research, Faculty of Medicine, University of Szeged, H-6720, Szeged, Szőkefalvi-Nagy Béla u. 6, Hungary. Electronic address: erces.daniel@med.u-szeged.hu.
authors.forename: Dániel
authors.initials: D
authors.lastname: Érces
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Szeged, H-6720, Szeged, Dóm tér 10, Hungary. Electronic address: horvath.gyongyi@med.u-szeged.hu.
authors.forename: Gyöngyi
authors.initials: G
authors.lastname: Horváth
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Szeged, H-6720, Szeged, Dóm tér 8, Hungary. Electronic address: toth.gabor@med.u-szeged.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Tóth
authors.affiliation: Institute of Surgical Research, Faculty of Medicine, University of Szeged, H-6720, Szeged, Szőkefalvi-Nagy Béla u. 6, Hungary. Electronic address: boros.mihaly@med.u-szeged.hu.
authors.forename: Mihály
authors.initials: M
authors.lastname: Boros
authors.affiliation: Pax Forschung GmbH, Im Rapsfeld 23, 50933 Cologne, Germany. Electronic address: ghyczy@t-online.de.
authors.forename: Miklós
authors.initials: M
authors.lastname: Ghyczy
mesh_terms: D000818:Animals; D001241:Aspirin / Q000009:adverse effects* / Q000138:chemical synthesis / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D003576:Electron Transport Complex IV / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005756:Gastritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008744:Methylamines / Q000737:chemistry*; D008833:Microcirculation / Q000187:drug effects; D059225:Nociception / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D008744:Methylamines; D008315:Malondialdehyde; C027451:methylamine; D003576:Electron Transport Complex IV; D001241:Aspirin
keywords: Aspirin; Cytokines; Gastritis; Inflammation; Microcirculation; Rat