title: Cyclooxygenase Inhibitors as a New Therapeutic Strategy in Small Bowel Transplantation.
abstract: BACKGROUND
  The long-term outcome of intestinal transplantations is still not favorable, which is partly due to the intestinal susceptibility to ischemia. There are several indications that the inflammatory response to ischemia-reperfusion injury is mediated by cyclooxygenases and that their inhibition may be associated with improved organ function. The aim of this study was to analyze if cyclooxygenase (COX) inhibitors could improve the early posttransplant outcome after orthotopic small bowel transplantation.
  
  
  METHODS
  Small bowel transplantation was performed between rats to test the impact of nonselective (Piroxicam), preferential (Meloxicam), and selective COX-2 inhibitors (Parecoxib). The donor intestines were either perfused and stored with inhibitor or had inhibitor administered intravenously after transplantation.
  
  
  RESULTS
  Using COX inhibitors, a sequential increase of posttransplantation intestinal integrity could be shown, with Parecoxib the least effective and Meloxicam the most effective treatment. These differences were in line with the downregulation of COX-2 activity by the inhibitors. Functionally, the same tendency could be seen in diminished expression of proinflammatory molecules, decreased leucocyte inflammation, and significantly improved graft microcirculation. In most cases, the intravenous administration was more effective. However, the COX inhibitors used were shown to cause relevant hepatotoxicity under nearly all conditions, but particularly under intravenous administration. Only Meloxicam in histidine-tryptophan-ketoglutarate was demonstrated to be a safe drug without hepatotoxic side effects.
  
  
  CONCLUSIONS
  The activity of COX contributes to ischemia-reperfusion injury after intestinal transplantation. In this comparative study, the administration of the preferential COX-2 inhibitor Meloxicam via histidine-tryptophan-ketoglutarate showed the best graft-protective attributes and the lowest hepatotoxic side effects.
authors.affiliation: 1 Institute of Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany. 2 Department of Surgery, University of Bonn Medical Center, Bonn, Germany. 3 Surgical Research Division, Department of Surgery, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Frank Alexander
authors.initials: FA
authors.lastname: Schildberg
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Mamdouh
authors.initials: M
authors.lastname: Afify
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.forename: Pascal
authors.initials: P
authors.lastname: Paschenda
authors.forename: Nico
authors.initials: N
authors.lastname: Schäfer
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Kalff
authors.forename: Thomas
authors.initials: T
authors.lastname: Minor
authors.forename: René Hany
authors.initials: RH
authors.lastname: Tolba
mesh_terms: D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005947:Glucose / Q000494:pharmacology; D007421:Intestine, Small / Q000637:transplantation*; D007422:Intestines / Q000098:blood supply; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D000077239:Meloxicam; D008833:Microcirculation; D011189:Potassium Chloride / Q000494:pharmacology; D011343:Procaine / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013843:Thiazines / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
chemical_list: C039984:Bretschneider cardioplegic solution; D016861:Cyclooxygenase Inhibitors; D013843:Thiazines; D013844:Thiazoles; D008353:Mannitol; D011343:Procaine; D011189:Potassium Chloride; D005947:Glucose; D000077239:Meloxicam