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15-epi-Lipoxin-A4 (15-epi-LXA4) "aspirin-triggered Lipoxin" (ATL) Figure 2.12 Generation of 15-(R)-HETE in endothelial cells by acetylated COX-2 (COX-2-Ac) and its transcellular conversion to 15-epi-lipoxin A4 (15-epi-LXA4) or aspirin-triggered lipoxin by 5-lipoxygenase (5-LO) of polymorphonuclear cells (modified after [122]).

involved in endothelial protection (Section 2.3.1) and, possibly represents a new class of anti-inflammatory and proresolving lipid mediators [123]. The most recent finding that ATL contributes to the control of innate immunity by inducing proteaso-mal degradation of a tumor necrosis factor receptor-associated factor-6 (TRAF-6) requires particular attention [124]. In addition, ATL appears also to be gastroprotective during repeated or long-term aspirin use, possibly associated with enhanced COX-2 expression in the stomach mucosa(Section3.2.1). However, most of the available evidence so far comes from in vitro or animal studies, and clinical data are still missing.

The generation of (R)-precursors of biologically active eicosanoids by aspirin is not limited to arachidonic acid but was also seen with docosahexaenoic acid and eicosapentaenoic acid, two precursors of series "3" prostaglandins. Interaction with aspirin-treated COX-2 in human endothelial cells resulted in the generation of 17-(R)-hydroxydocosahexaenoic acid, 17-(R)-HDHA. Human neutrophils transform COX-2-aspirin-derived 17-(R)-HDHA into two sets of novel di- and trihydroxy products - the resolvins. Analogous pathways exist for eicosapentaenoic acid. The name resolvins was given because these products of transcellular biosynthesis, similar to ATL, dampen inflammatory events. They are generated within the inflammatory resolution phase and downregulate leukocytic exudate cell numbers to prepare for orderly and timely resolution [125, 123].

Generation of New "Aspirin-Like Drugs" After elucidation of the molecular mechanism of aspirin action, many drugs were developed with the intention to inhibit COX-dependent prostaglandin formation - the so-called "aspirin-like drugs" or nonsteroidal anti-inflammatory drugs, including indo-methacin, diclofenac, ibuprofen, and many others. In contrast to aspirin, indomethacin-type compounds are reversible inhibitors of the enzyme and compete with the substrate arachidonic acid for binding at the catalytic site [108, 126].

Inhibition of ASA-Induced COX-1 Inhibition by Reversibly Acting NSAIDs The binding of NSAIDs and aspirin to similar sites in the lining of the COX-active site may result in drug interactions with particular relevance to the antiplatelet effects of aspirin. This interaction, first shown for indometh-acin [104, 128], was later confirmed for other NSAIDs (Section 2.3.1) and, most recently, pyra-zoles, such as dipyrone (metamizol) [129]. If these compounds are given shortly before aspirin, they may occupy salicylate binding sites inside the COX protein and prevent the access of aspirin to its acetylation site (Figure 2.13). Since NSAIDs act reversibly, the duration of this interaction is determined by the half-life of the particular compounds, in most cases only a few hours. However, this time is sufficient for deacetylation of aspirin by esterases that occurs within 30 min. Thus, aspirin might have lost its antiplatelet activity because the active form is no longer present when the acetylation site at the enzyme becomes available again. Functionally, this results in a prevention of antiplatelet effects of aspirin (Section 2.3.1) or aspirin "resistance" (Section 4.1.6). Interestingly, the inhibitory effect of dipyrone on aspirin-induced inhibition of platelet aggregation is seen also during continuous aspirin intake, probably as result of a higher affinity of dipyrone than salicylic acid to the (nonspecific) hydrophobic binding sites in the COX-1 channel

COX-2 differs from COX-1 by the presence of a side pocket in the substrate channel. Compounds that fit into this side pocket, such as coxibs, are COX-2 selective. Attempts have been made to create "aspirin-like," that is, irreversibly acting compounds, with a higher COX-2 selectivity by modifying the side chain in a way that increases affinity for the COX-2 protein. These compounds bind covalent to the enzyme and act irreversibly, like aspirin, but have a certain COX-2 selectivity in vitro and in animal models [127]. However, their efficacy is lower than that of the specific coxibs, and no data about clinical testing have been published so far.

Figure 2.13 The inhibition by ibuprofen of aspirin-induced inhibition of platelet COX-1. Evidence for inhibition of aspirin binding by ibuprofen (IBU) (for further explanation, see the text) (modified after [130, 131]).

(cf. Figure 4.24). No such interactions exist for selective COX-2 inhibitors [130].

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