Modulation of arachidonic acid metabolism by orally administered morniflumate in man.
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.
Civelli
M
M
Department of Pharmacology, Chiesi Farmaceutici S.p.A., Parma, Italy.
Vigano
T
T
Acerbi
D
D
Caruso
P
P
Giossi
M
M
Bongrani
S
S
Folco
G C
GC
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009544:Niflumic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015289:Leukotrienes; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D009544:Niflumic Acid; D013929:Thromboxane B2; C027859:morniflumate