thromboxane-b2 and benoxaprofen

The effect on arachidonate metabolism of two compounds (BW755C and benoxaprofen) which have been reported to inhibit 5' lipoxygenase in leukocytes has been evaluated in human polymorphonuclear leukocytes (PMN) stimulated with the calcium ionophore A23187 and serum-treated zymosan (STZ). The syntheses of leukotriene B4 (LTB4) and thromboxane B2 (TXB2) from endogenous substrate were determined by specific radioimmunoassays as indicators of 5' lipoxygenase and cyclo-oxygenase activity in the PMN respectively. Benoxaprofen inhibited the synthesis of leukotriene B4 by human PMN stimulated with the calcium ionophore A23187, but it was approximately 5 times less potent than BW755C. However, benoxaprofen (IC50 1.6 X 10(-4)M) was approximately 100 times less potent than BW755C (IC50 1.7 X 10(-6)M) at inhibiting leukotriene B4 synthesis induced by serum-treated zymosan. Both drugs inhibited thromboxane synthesis by leukocytes stimulated with A23187 or serum-treated zymosan at similar concentrations (approximately 5 X 10(-6)M). The data obtained using STZ as stimulus are consistent with previous in vivo studies and indicate that benoxaprofen is a relatively selective inhibitor of cyclo-oxygenase. However, this selectivity was far less apparent when A23187 was used as a stimulus to release the eicosanoids which suggests that this inhibition could be via an indirect mechanism and therefore A23187 should be used with caution as a stimulus of 5' lipoxygenase for evaluating inhibitors of eicosanoid synthesis.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Arachidonate Lipoxygenases; Calcimycin; Humans; Leukotriene B4; Lipoxygenase; Neutrophils; Propionates; Pyrazoles; Thromboxane B2; Zymosan

Topics: Animals; Anti-Inflammatory Agents; Dinoprostone; Disease Models, Animal; Inflammation; Leukocyte Count; Leukotriene B4; Propionates; Prostaglandins E; Rats; Thromboxane B2

The effects of BW755C, benoxaprofen, indomethacin and piroxicam were studied on intravascular platelet aggregation using continuous platelet counting. Plasma levels of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 (6-keto PGF1 alpha) were measured by radioimmunoassay. BW755C, a dual inhibitor of arachidonic acid metabolism, potentiated or inhibited aggregation depending on dose. BW755C increased TxB2 and 6-keto PGF1 alpha plasma levels at low doses. At higher doses BW755C inhibited aggregation and reduced TxB2 plasma levels. At 16 mg/kg BW755C, 6-keto PGF1 alpha was detected. Benoxaprofen also potentiated collagen-induced aggregation. 8 mg/kg indomethacin was shown to have a short lasting increased inhibitory action on collagen-induced aggregation when compared with the more specific cyclooxygenase inhibitor, piroxicam. 6-keto PGF1 alpha was detected in plasma from rats treated with indomethacin and piroxicam. The results obtained using low doses of BW755C suggest that the lipoxygenase pathway is involved in platelet aggregation. Interpretation of the results obtained using higher doses of drugs also suggests this involvement though some nonspecific actions of the drugs must be taken into consideration. Further work is required to detail the role of lipoxygenase products in collagen-induced intravascular platelet aggregation.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Chromatography, Thin Layer; Collagen; Indomethacin; Piroxicam; Platelet Aggregation; Propionates; Pyrazoles; Radioimmunoassay; Rats; Thiazines; Thromboxane B2

Studies were performed in fasted rats to establish if the propensity of 4 non-steroidal anti-inflammatory (NSAI) drugs to elicit varying degrees of gastric mucosal damage following oral administration is related to their rate of absorption by the mucosal and subsequent inhibitory effects on prostaglandin (PG) production in vivo. Aspirin (200 mg/kg p.o.) and indomethacin (10 mg/kg p.o.) produced ultrastructural signs of damage at 10-60 min to the surface mucous cells, parietal cells and endothelial cells of sub-mucosal capillaries coincident with the relatively rapid absorption of the radiolabelled drugs and reduction in the mucosal content of PGE2 and 6-keto PGF1 alpha determined by gas chromatography/mass spectrometry. Azapropazone (100 mg/kg p.o.) failed to elicit mucosal damage either ultrastructurally or even visually up to 23 h after dosing and did not affect the content of PG's even though the drug was present in the mucosa in sufficient concentration to elicit reduction in prostaglandin synthesis in vitro. Benoxaprofen (110 mg/kg p.o.) reduced the content of PGE2 and somewhat variably, that of 6-keto PGF1 alpha, was more slowly absorbed c.f. aspirin and indomethacin, but failed to elicit appreciable mucosal damage. These results show that while reduction in PG synthesis is a factor in the development of damage by ulcerogenic drugs, it appears that the rate of absorption or other biochemical effects (including e.g. influences on the production of oxyradicals or 5-lipoxygenase products of eicosanoid metabolism) may contribute to the relatively low irritancy of drugs such as azapropazone or benoxaprofen.

Topics: Animals; Anti-Inflammatory Agents; Apazone; Aspirin; Chromatography, Gas; Dinoprostone; Gastric Mucosa; Indomethacin; Intestinal Absorption; Kinetics; Lipoxygenase; Male; Mass Spectrometry; Microscopy, Electron; Propionates; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2