Modulation of arachidonic acid metabolism by orally administered morniflumate in man

Abstract

Unlike other classic NSAIDs, some fenamates given at therapeutic concentrations, have been shown to inhibit, both in vitro and in vivo, the 5-lipoxygenase pathway of arachidonic acid cascade as well as the synthesis of cyclooxygenase products. This dual inhibitory property might represent an improvement in anti-inflammatory therapy. The aim of this work was to characterize the effect of morniflumate, administered at therapeutic dosages to normal human volunteers, on leukotriene B4 (LTB4) and thromboxane (TXB2) synthesis, both in purified PMNs and in whole blood. PMNs, isolated two hours after a single oral administration of morniflumate and at steady-state condition, fully retain their capacity to release LTB4 and TXB2. Since intracellular concentrations of the drug were undetectable, in spite of its elevated concentrations in platelet poor plasma, the results obtained using PMNs suggest a drug loss during the cells purification procedure. In whole blood experiments, morniflumate reduced blood LTB4 synthesis induced by Ca-ionophore A23187 Bx approximately 50%, both after single dose and at steady state; the degree of inhibition showed a pattern similar to the plasma levels of the bioactive metabolite of morniflumate (M1). The inhibition of serum TXB2 levels was higher than 85%. Hence, morniflumate is capable of reducing arachidonic acid metabolism acting both on cyclooxygenase and 5-lipoxygenase. This characteristic might provide a better approach in anti-inflammatory therapy.

Niflumic Acid Suppresses Interleukin-13–induced Asthma Phenotypes

“…An inhibitory effect on cyclooxygenase has been attributed to NA (34). We have studied the effect of another inhibitor of prostaglandin synthesis, indomethacin, on IL-13-induced asthma reaction, and indomethacin failed to attenuate the airway response to IL-13.…”

“…There were no significant differences in baseline values of airway pressure among the control, IL-13 instillation alone, and IL-13 plus NA groups. We conclude that NA inhibited not only goblet cell hyperplasia but also AHR and eosinophilic inflammation induced by IL- 13. It has been reported that NA has an inhibitory effect on cyclooxygenase (34). We studied the effect of indomethacin on IL-13-induced airway responses.…”

Monitoring eicosanoid biosynthesis via lipoxygenase and cyclooxygenase pathways in human whole blood by single HPLC run

“…In the present study, we introduced a simple analytical method to quantify LOX and COX products in HWB. As shown previously [16,21] stimulation of blood ex vivo and the evaluation of metabolites from AA represent a valuable model for the assessment of the in vivo efficiency of drugs acting on AA metabolism.…”

Anion channel blockers differentially affect t-type Ca2+ currents of mouse spermatogenic cells, ?1E currents expressed inXenopus oocytes and the sperm acrosome reaction

“…ACBs used in this work also inhibit cycloxygenases and lipoxygenases that participate in arachidonic acid metabolism [Civelli et al, 1991] and the 3␣-hydroxysteroid dehydrogenase involved in sex steroid metabolism [Penning et al, 1985]. Metabolites of the lipoxygenase, and cycloxygenase pathways positively modulate cation and anion channels [Diener et al, 1996;Kanli and Norderhus, 1998].…”