We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic inflammation in rat paw skin. We compared the effect of lipoxygenase (LOX) and cyclo‐oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80.

Intravenous (i.v.) pre‐treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl‐leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a five‐lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S‐transferase inhibitor (ethacrynic acid) significantly inhibited (40 to 60%) the development of neurogenic oedema, but did not affect cutaneous blood flow. Intradermal (i.d.) injection of LOX inhibitors reduced SP‐induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating effect.

Indomethacin and rofecoxib, a highly selective COX‐2 inhibitor, did not affect neurogenic and SP‐induced oedema. Surprisingly, the structurally related COX‐2 inhibitors, NS 398 and nimesulide, significantly reduced both neurogenic and SP‐induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP‐induced oedema, respectively).

COX‐2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation.

A mast cell stabilizer, cromolyn, and a H1 receptor antagonist, mepyramine, significantly inhibited neurogenic (51% and 43%, respectively) and SP‐induced oedema (67% and 63%, respectively).

The co‐injection of LOX inhibitors and compound 48/80 did not alter the effects of compound 48/80. Conversely, ethacrynic acid had a significant potentiating effect. The pharmacological profile of the effect of COX inhibitors on compound 48/80‐induced oedema was similar to that of neurogenic and SP‐induced oedema.

The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not affect neurogenic or SP‐induced oedema.

Thus, (i) SP‐induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene‐mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a significant role in this process.

British Journal of Pharmacology (2001) 132, 1581–1589; doi:10.1038/sj.bjp.0703950

01 Aug 1997·The Journal of pharmacology and experimental therapeutics

Evaluation of the antiinflammatory activity of a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitor, RWJ 63556, in a canine model of inflammation.

Article

Author: Ansell, J ; Stewart, A ; Wachter, M P ; Wu, W ; Beers, S A ; Argentieri, D C ; Barbone, A G ; Kirchner, T ; Malloy, E ; Singer, M ; Steber, M ; Ritchie, D M

Sterile perforated polyethylene spheres (wiffle golf balls) were implanted s.c. in beagle dogs. A local inflammatory reaction was elicited within the spheres by injecting carrageenan. Changes in leukocyte count, prostaglandin E2, thromboxane B2 and leukotriene B4 levels were monitored in fluid samples collected over a 24-hr period. Blood samples were also collected at various time points and analyzed for prostaglandin E2 and leukotriene B4 production after ex vivo calcium ionophore treatment. Effects of standard antiinflammatory agents (aspirin, indomethacin, dexamethasone, tenidap and zileuton) and newer cyclooxygenase-2 (COX-2) selective agents (nimesulide, nabumetone and SC-58125) were determined after oral administration. Ex vivo inhibition of cyclooxygenase product synthesis (prostaglandin E2, thromboxane B2) in whole blood was used as an indicator of activity for the constitutive COX-1 isoform, although inhibition of the synthesis of these mediators in the chamber exudate during an inflammatory process is believed to represent COX-2 inhibition. Treatment effects on leukotriene B4 production were also determined both ex vivo in whole blood and in the fluid. All of the compounds tested, except aspirin, inhibited leukocyte infiltration into the fluid exudate. Inhibitors that exert their effects on both isozymes of cyclooxygenase attenuate production of cyclooxygenase metabolites in both the inflammatory exudate and in peripheral blood ex vivo, although COX-2 selective inhibitors only demonstrated activity in the exudate. A 5-lipoxygenase inhibitor (zileuton), a corticosteroid (dexamethasone) and a dual COX-2 selective/5-lipoxygenase inhibitor (RWJ 63556) had similar profiles in that they all inhibited cell infiltration and eicosanoid production in the fluid and also attenuated leukotriene B4 production in both the fluid and blood.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	US	R.W. Johnson Pharmaceutical Research Institute	-

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