best, for mild to moderate pain. Its site of action has recently been identified as a COX-3 isoenzyme, a variant of the COX-1 enzyme (Chandrasekharan et al., 2002; Schwab et al., 2003; Ayoub et al., 2004). This discovery raises the possibility of developing more potent and selective drugs targeting the site. A number of arguments counted against the COX-3 hypothesis: COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1, but they are as good at reducing fever as older NSAIDs. The fever response has also been clearly associated with a rapid induction of COX-2 expression and an associated increase in prostaglandin E2 production, with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to fit in well with those sites associated with fever, and the protein should be present within the hypothalamus rather than the cerebral cortex. All these considerations appeared to argue against COX-3 being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results could be read as showing that paracetamol acts at a different site than the other NSAIDs and that more than one COX isoform contribute to the fever response. Finally, the discovery of the frame-shift mechanism has made it highly unlikely that COX-3 plays a role in inflammation and fever in humans. References Further reading . –13931. EC 1.14.99 Integral membrane proteins