The pharmacology of ebselen.

Ebselen has been demonstrated to be an effective anti-inflammatory agent in a variety of experimental models in vivo which differ from classical tests in that the aetiological roles of hydroperoxides and/or lipoxygenase products appear to be greater. Indeed, ebselen exhibits only weak anti-inflammatory activity in the traditional prostaglandin-dominated models, such as carrageenan paw oedema, adjuvant arthritis and yeast paw hyperalgesia [50]. The major targets of this anti-inflammatory activity appear to be plasma exudation and infiltration, possibly as a result of the inhibition of the hydroperoxide and/or leukotriene effects on leukocyte-endothelium interactions. Both reactive oxygen species [24] and LTB [51, 52] enhance granulocyte adhesiveness to endothelium and ebselen inhibits the generation of reactive oxygen species, catalyses the breakdown of hydroperoxides, inactivates LTB by isomerization and inhibits 5-lipoxygenase [9-11, 13-16, 27-29]. Consequently, any or all of these mechanisms of action, together with inhibition of hypoxic-reperfusion injury [53], could contribute to the anti-inflammatory activity of ebselen. With regard to tissue injury, the inhibitory action of ebselen on gastric mucosal injury clearly bodes well for its clinical use and offers a big advantage over current NSAIDs. In vitro findings indicate that the compound may inhibit gastric acid secretion directly [54]. As an inhibitor of hepatic pancreatic and cerebral tissue injury, ebselen also opens up new perspectives for therapy which are being actively pursued. Studies on the mechanism of action of ebselen in these experimental tissue injury models point towards inhibition of 5-lipoxygenase products, though the GSH-Px like action may also play a role. In experimental liver injury, tumor necrosis factor (TNF) has been shown to be the final mediator of endotoxin action [55] and it will be of interest to see whether ebselen is able to affect the actions of this cytokine, both in the liver and at other sites, including TNF-induced leukocyte adhesion [56]. The last word on the pharmacology of ebselen is far from being spoken or written! [ABSTRACT FROM AUTHOR]