tolfenamic-acid and flunixin

The pharmacodynamics of the non-steroidal anti-inflammatory drugs flunixin, tolfenamic acid and ketoprofen were studied in calves after intravenous administration. An acute inflammatory reaction was induced in tissue cages by the intracaveal injection of the mild irritant carrageenan, and the inhibition of inflammatory mediators and enzymes was investigated. The substances measured in the exudate included the enzymes (active and total metalloproteases, serine and cysteine proteases, acid phosphatase [AP], lactate dehydrogenase [LDH] and beta-glucuronidase) and the eicosanoids (prostaglandin [PG]E2 and leukotriene [LT]B4). Studies were also made of inhibition of the synthesis of serum thromboxane (Tx)B2 ex vivo, of bradykinin-induced oedema in vivo and of the generation of superoxide anions (O2-) in vitro. None of the drugs affected the concentration of LTB4, or the activities of metalloproteases, cysteine and serine proteases, AP or LDH in the exudate. All the drugs inhibited the synthesis of serum TxB2 and exudate PGE2 and inhibited the release of beta-glucuronidase. They also decreased the oedematous response to intradermally injected bradykinin and inhibited the generation of O2- ions by neutrophils in vitro. These actions may contribute to the anti-inflammatory effects of the drugs and hence to their clinical efficacy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Cattle Diseases; Clonixin; Cross-Over Studies; Dinoprostone; Edema; Glucuronidase; Ketoprofen; Neutrophils; ortho-Aminobenzoates; Superoxides; Thromboxane B2

The objective of this study was to analyse the effects of 4 nonsteroidal anti-inflammatory drugs (NSAIDs) on the production of beta-glucuronidase (beta-glu), tumour necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), interleukin-1 (IL-1) and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated equine synoviocytes. The agents studied were flunixin, tolfenamic acid, S(+)ketoprofen (KTP) and R(-)ketoprofen. LPS-induced release of beta-glu from synoviocytes was inhibited in a concentration dependent manner by all 4 compounds, tolfenamic acid being the most potent. Of the 2 KTP enantiomers, S(+)KTP exerted the greatest inhibitory effect. Tolfenamic acid and flunixin increased the production of IL-6-like activity by LPS-stimulated synoviocytes only at the highest concentration studied (1000 mumol/l). Lower concentrations produced no effect on IL-6. Flunixin, tolfenamic acid and S(+)KTP produced statistically significant and concentration related increases in the release of IL-1-like activity by LPS-stimulated synoviocytes. Prostaglandin E2 synthesis was markedly inhibited in a concentration dependent manner by the 4 NSAIDs. However, R(-)KTP was effective only at the highest concentrations investigated (1000 and 100 mumol/l). The present findings are compatible with the possibility that longterm use of NSAIDs in arthropathies, by removing the regulator role of PGE2 on IL-1 synthesis, might enhance the pathological process of cartilage degeneration.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Clonixin; Dinoprostone; Dose-Response Relationship, Drug; Drug Interactions; Glucuronidase; Horses; Interleukin-1; Interleukin-6; Ketoprofen; Lipopolysaccharides; ortho-Aminobenzoates; Synovial Membrane; Tumor Necrosis Factor-alpha

A study was made to compare the effects of two nonsteroidal antiinflammatory drugs (NSAIDs), flunixin and tolfenamic acid, on the leukotriene B4 (LTB4) production and migration of human polymorphonuclear leukocytes (PMNs) as well as on platelet aggregation and thromboxane B2 (TxB2) production during blood clotting. Tolfenamic acid inhibited LTB4 production in PMNs as well as FMLP- and LTB4-induced PMN migration (IC50 values 23 +/- 3, 39 +/- 11, and 68 +/- 13 microM, respectively), whereas flunixin inhibited these cell functions only with the highest concentration tested (100 microM). On the other hand, flunixin was clearly a more potent inhibitor of TxB2 production and adrenaline-induced platelet aggregation than tolfenamic acid, the IC50 values in TxB2 production being 0.28 +/- 0.02 microM and 2.6 +/- 0.3 microM for flunixin and tolfenamic acid, respectively. We suggest that inhibition of PMN functions may be an additional mechanism in the antiinflammatory action of tolfenamic acid. At least in human PMNs and platelets, flunixin seems to be only an inhibitor of cyclooxygenase.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Coagulation; Blood Platelets; Cell Movement; Clonixin; Humans; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; ortho-Aminobenzoates; Platelet Aggregation; Thromboxane B2