title: Effects of non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte functions in vitro: focus on fenamates.
abstract: Prostanoid-independent anti-rheumatic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are a matter of debate. The aim of the present study was to compare the effects of chemically different NSAIDs (diclofenac, indomethacin, ketoprofen, paracetamol, piroxicam and four fenamates: flufenamic, meclofenamic, mefenamic and tolfenamic acids) on human polymorphonuclear leukocyte (PMN) functions, i.e. calcium ionophore A23187-triggered degranulation, leukotriene B4 (LTB4) release, platelet-activating factor (PAF) production and migration towards LTB4. The four fenamates caused a dose-dependent inhibition of each of the PMN functions tested. Flufenamic, meclofenamic and tolfenamic acids were about equipotent to inhibit PMN degranulation (IC50S 21-32 microM) and LTB4 release (IC50s 21-25 microM) whereas mefenamic acid achieved similar effects at somewhat higher drug concentrations. Tolfenamic and meclofenamic acids were the most potent fenamates to inhibit PAF synthesis (IC50s 37 and 51 microM) as well as migration towards LTB4 (IC50s 61 and 92 microM). Out of the other NSAIDs, diclofenac (which is chemically related to fenamates) suppressed degranulation as well as LTB4 and PAF production. Indomethacin inhibited LTB4 and PAF synthesis whereas ketoprofen reduced degranulation. The inhibitory effects of the non-fenamate NSAIDs occurred only at drug concentrations far higher than those achieved clinically. Paracetamol and piroxicam (up to 300 microM) did not influence the PMN functions tested. We conclude that NSAIDs with a fenamate structure differ from other NSAIDs by inhibiting PMN functions induced either by receptor-mediated stimulus (LTB4) or calcium ionophore (A23187) at micromolar drug concentrations.
authors.affiliation: Department of Biomedical Sciences, Univesity of Tampere, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Kankaanranta
authors.forename: E
authors.initials: E
authors.lastname: Moilanen
authors.forename: H
authors.initials: H
authors.lastname: Vapaatalo
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005439:Flufenamic Acid / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects*; D008469:Meclofenamic Acid / Q000494:pharmacology; D008528:Mefenamic Acid / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D062367:ortho-Aminobenzoates; D008528:Mefenamic Acid; D000001:Calcimycin; D008469:Meclofenamic Acid; D005439:Flufenamic Acid; C001209:fenamic acid; D005966:Glucuronidase