PDF《RESEARCH PAPER》

AOU'

Policlinico G. Martino, Via C. Valeria Gazzi,

98125 Messina, Italy. E-mail: [email protected] Received

26 February 2009;

accepted

3 March

2009 British Journal of Pharmacology (2009), 157, 1410C1418 ?

2009 The Authors Journal compilation ?

2009 The British Pharmacological Society All rights reserved 0007-1188/09 www.brjpharmacol.org Both COX and LOX pathways are of particular clinical relevance. COX exists in two distinct isoforms, COX-1 and COX-2, the latter being inducible and primarily involved in in?ammation and cell proliferation (Botting, 2006). There is also a third isoform, COX-3, which is a splicing variant of COX-1 with an additional

34 amino acids. This variant has been cloned, partially characterized and appears to be suscep- tible to inhibition by analgesic compounds such as paraceta- mol (acetaminophen) (Botting, 2006). Other variants exist, but have not been well characterized speci?cally in vivo. In recent years, selective COX-2 inhibitors that are as ef?cacious as traditional non-steroidal anti-in?ammatory drugs (NSAIDs), but minimize the risk of unwanted gastrointestinal side effects have been developed (Hinz and Brune, 2002). Unfortunately, a new set of side effects have been identi?ed for this class of NSAIDs related to kidney and cardiovascular dysfunction (Sanghi et al., 2006). Both traditional NSAIDs and the newer coxibs directly inhibit the COX enzymes affecting AA metabolism, but emerging information has suggested an important role of another AA metabolic pathway, 5-LOX and its effect on in?ammatory response (Clària and Romano, 2005). In addition, it is becoming clear that NSAIDs shunt AA metabolism towards the 5-LOX pathway and synthesis of LT (Maxis et al., 2006). The 5-LOX metabolic pathway produces both vasocontric- tive LTs such as LTC4, LTD4 and LTE4 best recognized for their roles in bronchoconstriction (Peters-Golden, 2008), as well as chemoattractant LTB4 which attracts leucocytes to the site of tissue damage to perform needed repair functions (Ford- Hutchinson et al., 1980;

Yokomizo et al., 1997). NSAID- induced gastric in?ammation has been associated with shunting of the AA to generate LTB4 from 5-LOX (Hudson et al., 1993;

Celotti and Durand, 2003). In cardiovascular animal disease models treated with COX pathway inhibitors, 5-LOX production of LT from cells present in plaques has been shown to promote in?ammation in endothelial cells via the in?ux of leucocytes and vasoconstriction of arteries (Mehrabian et al., 2002;

B?ck, 2008). And in the kidney, chronic use of COX inhibitors leads to renal dysfunction (Perazella and Eras, 2000), and damage is partly mediated by an up-regulation of 5-LOX and LTB4-induced in?ux of leucocytes (Maccarrone et al., 1999). The shunting of AA metabolism down the 5-LOX pathway may therefore add or exacerbate adverse events while a patient is taking a traditional NSAID or selective COX-2 inhibitor. Inhibition of the biosynthesis of such in?ammatory media- tors by blocking the AA-processing activities of COX and 5-LOX is considered as a promising approach to manage osteoarthritis (OA) (Celotti and Laufer, 2001). Recently, reports have appeared regarding so-called '

dual inhibitors'

, agents that inhibit not only COX-1 and COX-2, but also 5-LOX-mediated AA metabolism (Celloti and Durand, 2003;

Shelly and Hawkey, 2003;

Brune, 2004). These agents may be particularly effective for minimizing both gastric and cardio- vascular side effects by balancing AA metabolism in the body (Martel-Pelletier et al., 2003;