Anti-leukotriene effects of WY-50,295 tromethamine in isolated guinea pig pulmonary tissues

Inability of Short‐duration Treatment with a 5‐Lipoxy‐genase Inhibitor to Reduce Clinical Signs of Canine Atopy

“…Failure of WY-50295 to inhibit canine 5-lipoxygenase. Although this compound was not specifically tested on 5-LO in a canine model, it produces notable inhibition of 5-LO and/or blockade of tissue LTD, receptors in all other species tested, including, rat, mouse, guinea pig, sheep, and human beings (7)(8)(9)(10)(11). Thus, we believe this is an unlikely reason for its failure in dogs.…”

“…Insufficient duration of therapy. The action of WY-50295 on free 5-LO or 5-LO in isolated tissue in vitro is essentially immediate (8,9) and in in oivo models, its effects can be demonstrated with 1-4 h of a single oral dose (7,9,11). However, in symptomatic dogs, there is already a massive inflammatory response underway in the skin, involving numerous inflammatory mediators, cytokines, and an infiltrate of inflammatory cells with their associ-ated mediators.…”

“…The investigational antiallergenic drug WY-50295 is a potent and specific inhibitor of the arachidonic acid cascade enzyme 5-lipoxygenase (5-LO). When WY-50295 was evaluated in several animal models of inflammation, it was able to greatly reduce the production of proinflammatory leukotrienes, and also to inhibit leukotriene-induced airway smooth muscle contraction via antagonism of leukotriene D, receptors (7)(8)(9)(10)(11). Because it is possible that these leukotrieneblockade effects could reduce inflammation in canine skin, this study sought to preliminary determine the efficacy of WY-59295 in the management of pruritus due to allergic inhalant dermatitis (atopy) in the dog.…”

Pulmonary pharmacology of WAY-126299A: A dual-acting 5-lipoxygenase inhibitor and leukotriene D4 antagonist

“…Methods for determining the antagonism of LTD4-induced contractions of isolated guinea-pig trachea and for the inhibition of calcium ionophore-induced LTB4 production in human whole blood have been described previously in detail [3,7]. Methods for the inhibition of aerosol antigen-induced leukotriene-dependent bronchoconstriction in anesthetized and ventilated guinea pigs also have been described previously in detail [8].…”

“…For this reason we previously sought a compound which could simultaneously act as a 5-lipoxygenase (5-LO) inhibitor and a leukotriene D 4 (LTD4) receptor antagonist. WY50295 tromethamine (WY-50295T) exhibited this unique dual mechanism of action in vitro and in vivo, including the inhibition of leukotriene production in human neutrophils, rat whole blood and guinea-pig lung fragments [2,3]. However, WY-50295T was recently found to be inactive in human whole blood, presumably due to a high degree of plasma protein binding.…”