Characterization of inhibition of platelet function by paracetamol and its interaction with diclofenac and parecoxib

....................................................................................................................................6 List of original publications ...................................................................................................7 Abbreviations and defi nitions ................................................................................................8 Introduction ..............................................................................................................................9 Review of the literature ........................................................................................................ 10 Biosynthesis of prostaglandins .................................................................................. 10 Structure and function of cyclooxygenase .............................................................. 11 Pharmacologic inhibition of COX isoforms .......................................................... 14 Analgesic effect of paracetamol ................................................................................ 15 Analgesic effect of NSAIDs ...................................................................................... 16 Combination of paracetamol and NSAIDs ............................................................ 17 Pharmacokinetic properties of paracetamol, diclofenac and parecoxib ............. 17 Platelet function and haemostasis ............................................................................. 18 Infl uence on platelet function of paracetamol and NSAIDs ............................... 22 Platelet function tests .................................................................................................. 22 Aims of the study ................................................................................................................. 23 Methods .................................................................................................................................. 24 Study designs ................................................................................................................ 24 Sampling and drug infusions ...................................................................................... 24 Cold pressor test .......................................................................................................... 25 Laboratory tests............................................................................................................ 25 Schild-plot and isobolographic analysis .................................................................... 26 Statistics ......................................................................................................................... 27 Results ..................................................................................................................................... 28 Inhibition of platelet function by paracetamol (II, III) ......................................... 28 Interaction of paracetamol and diclofenac (I, II) ................................................... 29 Interaction of paracetamol and parecoxib (IV) ...................................................... 29 Analgesic effect of paracetamol and diclofenac (I, III) ......................................... 30 Discussion .............................................................................................................................. 31 Inhibition of platelet function by paracetamol ....................................................... 31 Interaction between paracetamol and diclofenac or parecoxib ............................ 32 Other triggers of aggregation .................................................................................... 33 Release of thromboxane B2 from activated platelets ............................................. 34 PFA-100 ........................................................................................................................ 34 Analgesic effect of paracetamol, diclofenac and the combination ...................... 34 Clinical considerations ................................................................................................ 35 Conclusions ............................................................................................................................ 37 Acknowledgements ............................................................................................................... 38 References .............................................................................................................................. 40 Appendix. Receptor ligand interactions ............................................................................ 51