thromboxane-b2 and tolfenamic-acid

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

To study the production of prostacyclin (PGI2) and thromboxane A2 (TxA2) in endometriosis in vitro, samples of endometriotic tissue taken during operation from 6 women were superfused for 4.5 hours in 95% O2/5% CO2 at 37 degrees C, and the stable metabolites of PGI2 (=6-keto-PGF1 alpha), and TxA2 (=TxB2) were measured by radioimmunoassays from the superfusates. All samples studied produced 6-keto-PGF1 alpha in the range from 0.2 to 10.5 nanograms/gram of dry tissue/minute with a mean of 3.6 ng/g/min during the whole experiment. TxB2 was also released by each sample at rates between 0.2 and 11.9 ng/g/min (mean 2.6 ng/g/min). The production of these prostanoids tended to be greater in the serosal (n = 2) than in the ovarian (n = 4) endometriosis. The addition of indomethacin of 10(-5) - 10(-3) moles/l to the superfusion medium inhibited concentration-dependently the synthesis of these prostanoids. Apart from these in vitro data implying the production of PGs in endometriosis, 18 patients with pelvic endometriosis sustained no relief for their endometriotic symptoms from the treatments with three anti-prostaglandins (acetylsalicylic acid, indomethacin, tolfenamic acid) in a double-blind, placebo-controlled trial.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Clinical Trials as Topic; Endometriosis; Epoprostenol; Female; Humans; In Vitro Techniques; Indomethacin; ortho-Aminobenzoates; Prostaglandin Antagonists; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan) in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TX)B2 and inflammatory exudate prostaglandin (PG)E2 were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8 mgkg-1 tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB2 synthesis and the duration of inhibition was dose-related. A dose of 2 mgkg-1 tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE2 synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short tmax (0.94-2.04 h), a high estimated Vdarea (1.79-3.20 Lkg-1), an estimated t1/2 beta of 8.01-13.50 h and Cl beta of 0.142-0.175 Lkg-1h-1. The actions of tolfenamic acid in inhibiting PGE2 synthesis and in attenuating two of the cardinal signs of inflammation (heat and swelling) suggest that a dosage of 2 mgkg-1 administered intramuscularly should be effective clinically as an anti-inflammatory agent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Dinoprostone; Disease Models, Animal; Inflammation; Irritants; Male; ortho-Aminobenzoates; Skin Diseases; Skin Temperature; Thromboxane B2

Pharmacokinetic/pharmacodynamic modelling was applied to a study in which tolfenamic acid was administered intravenously to calves at a dose rate of 2 mg kg-1. The drug had a shorter mean (SEM) elimination half-life (T1/2 beta) of 2.5 (0.95) hours and a larger volume of distribution (Vdarea) of 0.98 (0.28) litre kg-1 than other non-steroidal anti-inflammatory drugs. Its body clearance was high with a mean value of 0.30 (0.06) litre kg-1 h-1. It had inhibitory effects on inflammatory exudate PGE2 and beta-glucuronidase, serum TxB2 and bradykinin-induced swelling but it did not affect exudate LTB4 concentrations. Its mean EC50 values were lower for exudate PGE2, beta-glucuronidase and bradykinin-induced swelling inhibition (0.077 [0.018]; 0.040 [0.017] and 0.030 [0.020] microgram ml-1, respectively) than for serum TxB2 inhibition (0.137 (0.079) microgram ml-1). There were also differences in its equilibration halflife, which was short for the inhibition of serum TxB2, intermediate for exudate PGE2 and beta-glucuronidase and longer for bradykinin-induced swelling. These differences may be explained by the existence of three distribution compartments relating to the different sites of action of the drug.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Cattle; Dinoprostone; Glucuronidase; Half-Life; Inflammation; Injections, Intravenous; Metabolic Clearance Rate; Models, Biological; ortho-Aminobenzoates; Thromboxane B2

Tolfenamic acid was administered to beagle dogs at 2, 4 and 8 mg/kg bodyweight i.m. and the concentration of drug in plasma and in inflamed (administered carrageenan) and non-inflamed subcutaneous tissue cage fluid was measured. The concentration of thromboxane B2 in serum from blood allowed to clot under standardized conditions was determined and the concentrations of prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and leucocyte numbers were measured in fluid from the carrageenan administered tissue cages. Skin temperature was also measured over each tissue cage following administration of drug. Tolfenamic acid displayed linear pharmacokinetics since the area under the plasma concentration time curve (AUC) values were 13.74 +/- 1.88, 29.82 +/- 6.53 and 50.52 +/- 5.73 micrograms/ml.h following administration of 2, 4 and 8 mg/kg, respectively. Tolfenamic acid proved to be a potent inhibitor of ex vivo thromboxane B2 generation in clotting blood. Maximal inhibition was greater than 80% at all dose rates and 97% at the 8 mg/kg dose rate 1 h after drug administration. It also proved to be a potent inhibitor of prostaglandin E2 production in inflammatory exudate, and significantly (P < 0.05) decreased prostaglandin E2 production at all dose levels. Tolfenamic acid did not significantly alter 12-HETE generation or white blood cell accumulation in inflammatory exudate. Tolfenamic acid significantly reduced the elevated skin temperature over carrageenan administered cages at all dose levels.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Count; Dinoprostone; Dogs; Dose-Response Relationship, Drug; Exudates and Transudates; Female; Hydroxyeicosatetraenoic Acids; Inflammation; Injections, Intramuscular; Leukocyte Count; Male; ortho-Aminobenzoates; Skin Temperature; Thromboxane B2

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

Tolfenamic acid and tenidap have been reported to be dual inhibitors of cyclo-oxygenase and 5-lipoxygenase. In this study inhibition of 5-lipoxygenase by tenidap and tolfenamic acid in plasma-free leukocyte suspensions (IC50 values = 10 microM) required concentrations more than 100 fold higher than those which inhibited cyclo-oxygenase (IC50 values = 0.05 and 0.02 microM respectively). The potencies of tolfenamic acid and tenidap as cyclo-oxygenase inhibitors were markedly reduced in blood (IC50 = 6.5 and 10 microM respectively) and neither significantly inhibited 5-lipoxygenase. Since both drugs also failed to inhibit 5-lipoxygenase in rat blood ex vivo, we conclude that, at physiological levels of plasma proteins, tolfenamic acid and tenidap are selective cyclo-oxygenase inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Blood Proteins; Cyclooxygenase Inhibitors; Humans; In Vitro Techniques; Indoles; Leukocytes; Lipoxygenase Inhibitors; ortho-Aminobenzoates; Oxindoles; Rats; Thromboxane B2

Special interest has been focused on the development of dual inhibitors of the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism. In contrast to other classic NSAIDs, some fenamates in clinically achievable concentrations have been shown to inhibit synthesis of 5-lipoxygenase products in vitro. In the present work, we studied the effect of orally administered tolfenamic acid (600 mg) on Ca ionophore A 23187 -induced leukotriene synthesis in isolated human polymorphonuclear leukocytes. Leukotriene production was reduced in all 14 subjects studied, the mean inhibition of LTB4 synthesis being 16 +/- 3% and that of LTC4 33 +/ 7%. The inhibition correlated positively with serum acid concentrations. We suggest that inhibition of leukotriene synthesis is an additional mechanism of the anti-inflammatory, antimigraine and antidysmenorrhoeic effects of tolfenamic acid, and a possible explanation for its rare gastric and bronchoconstrictive side-effects.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Calcimycin; Female; Humans; Leukotriene B4; Male; Neutrophils; ortho-Aminobenzoates; SRS-A; Thromboxane B2

The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Carbazoles; Diclofenac; Dinoprostone; Guanidines; Humans; Indomethacin; Naproxen; ortho-Aminobenzoates; Prednisolone; Prostaglandins; Prostaglandins E; Quinazolines; Synovial Fluid; Thromboxane B2