New Dogmas Or Old? B J R Whittle
Total Page：16
File Type：pdf, Size：1020Kb
1379 THE COX CONTROVERSY: VIEWPOINT 2 Gut: first published as 10.1136/gut.52.9.1379 on 11 August 2003. Downloaded from New dogmas or old? B J R Whittle ............................................................................................................................. Gut 2003;52:1379–1381 Recent experimental studies may undermine our NSAIDs came from the work of Whitehouse and understanding of the gastrointestinal side effects of Haslam some 40 years ago, who proposed that non-steroidal anti-inflammatory drugs and cast a these drugs in high concentrations can uncouple oxidative phosphorylation.5 Such work was subse- shadow on the original concept that underpins the quently used to formulate early theories of the bio- development of the recent addition to the clinical chemical and toxicological basis of the local 67 anti-inflammatory armamentarium, the COX-2 selective irritancy of these drugs. It is gratifying therefore that this early work has been reconfirmed by Bjar- inhibitors. But is this just a passing cloud or a total nason et al and forms an essential part of their own eclipse of the COX theory? new dogma.89 With the discovery by Vane and colleagues in .......................................................................... 1971 that aspirin and NSAIDs prevent the 10 ust when we had thought that the problems production of prostaglandins by inhibiting COX, with understanding the gastrointestinal side a general hypothesis on the mechanism of their Jeffects of non-steroidal anti-inflammatory therapeutic actions and side effects was devel- drugs (NSAIDs) had all been solved, along comes oped, although caveats to the universal applicabil- experimental data that apparently undermines ity were clearly recognised at that time by this the whole concept. Thus as Bjarnason and group. It was apparent for example that such COX colleagues1 discuss in the accompanying view- inhibition could not be the sole process by which 711 point 1 in this issue of Gut [see page 1376], NSAIDs provoked gastric mucosal injury. experimental studies using isoform selective Indeed, the well established gastric barrier cyclooxygenase (COX) inhibitors and COX gene breaking action of salicylates identified in the deleted rodents have cast a shadow on the 1960s by Davenport12 was always considered original concept that underpins the development likely to be independent of COX inhibition as of the recent addition to the clinical anti- these actions were shared by diverse irritants inflammatory armamentarium, the COX-2 selec- such as ethanol, detergents, and bile salts. These http://gut.bmj.com/ tive inhibitors. The question we must ask is topical irritant actions, particularly shown by the whether this is just a passing cloud or a total chemically acidic NSAIDs, which disrupt the gas- eclipse of the COX theory? tric epithelial cell barrier and allow the back The mechanistic interpretation of the experi- diffusion of acid into the mucosa, were considered mental data may indeed reveal inadequacies or to result from their physicochemical properties even flaws in the working concept. However, as interacting with the surface phospholipids.13 pointed out, these would not affect the clinical Local changes in epithelial oxidative respiration findings or therapeutic benefit of COX-2 inhibi- followed their accumulation in these cells.6 on September 25, 2021 by guest. Protected copyright. tors as anti-inflammatory and analgesic agents in “ terms of the more favourable gastrointestinal side The concept of synergistic interactions effect profile seen in most, but it should be said between topical irritancy and COX not all, of the published clinical studies.2–4 inhibition in mucosal injury was developed Irrespective of that being the case, we must all in the late 1970s” agree it is still important from a scientific and It was very clear that such topical gastric effects academic viewpoint to understand more fully the would largely, if not exclusively, occur only after role of COX inhibition in the pathogenesis of such oral administration. Moreover, it was known that side effects. So, where did we all go wrong in our many of the newer NSAIDs available at that time thinking, if indeed we really did? could provoke injury via the parenteral route, “It is still important from a scientific and suggesting that other biochemical mechanisms academic viewpoint to understand more must also operate, with COX inhibition being a fully the role of COX inhibition in the likely contender. Thus the concept of synergistic pathogenesis of such side effects” interactions between topical irritancy and COX inhibition in mucosal injury was developed in the It is of course very important, as Bjarnason et al late 1970s.7 This working theory can thus explain point out,1 to consider the historical perspectives why orally ingested low dose aspirin in cardiovas- behind the development of any scientific concept. cular therapy can still give rise to worrisome gas- Interpretation of the information on such histori- tric damage on long term usage, as the minimal cal milestones will however depend on the direc- tion from which one is approaching them. Some insight may also be gained by looking closely at ................................................. the older maps of the area. Abbreviations: NSAIDs, non-steroidal anti-inflammatory An early stage in the understanding of the drugs; NO, nitric oxide; iNOS, inducible nitric oxide biochemical actions that could be exerted by synthase; AS, ankylosing spondylitis. www.gutjnl.com 1380 Whittle topical effects can synergise with the consequences of local or indicated that COX inhibition could not be the sole factor in this systemic COX inhibition.14 complex pathology. Thus profound COX inhibition with aspirin It also became apparent from early work that site selectivity itself did not regularly cause such subacute injury, in contrast Gut: first published as 10.1136/gut.52.9.1379 on 11 August 2003. Downloaded from of COX inhibition could be achieved, which could also influence with agents such as indomethacin.22 It would appear that the gastric side effect profile. Thus sodium salicylate and an enterohepatic recirculation of many NSAIDs allows a more pro- experimental COX and lipoxygenase dual inhibitor did not longed contact with the intestinal mucosa, so local irritant inhibit gastric mucosal COX and did not provoke mucosal injury effects may be of relevance in these slowly evolving lesions, although these agents did inhibit prostanoid production at especially in rodents.923 Recent detailed studies in mice using inflammatory sites where they exerted anti-inflammatory COX-1 and COX-2 inhibitors and COX knockout mice have now 7 actions. It was predicted that anti- inflammatory COX suggested that as in the gastric mucosa, inhibition of both iso- inhibitors that had an attenuated ability to inhibit COX in the forms is required for the development of the characteristic jeje- mucosa, or had reduced topical irritant activity, would yield unal lesions seen over 48 hours with NSAIDs.24 novel NSAIDs displaying a lower propensity to damage the Early vascular changes are evident in the small intestine stomach, while agents having both attributes would be consid- following NSAIDs but it is not clear if these are solely the 711 erably superior. Such work was the precursor to the COX result of acute COX inhibition.25 Studies with antibacterial selectivity concept developed some 10 year later. agents have shown that the ingress of luminal bacteria is The experimental work with the newly identified selective involved in this enteropathy,23 26 confirming early work with COX-2 inhibitors, including celecoxib and rofecoxib, supported germ free animals.21 Thus an early breach in the intestinal the concept that inhibition of the constitutive COX-1 isoform barrier defence with subsequent translocation of the bacteria was a necessary component of the initiation of gastric 15 16 and release of endotoxin gives rise to expression of the nitric damage. Hence it was considered that COX-2 selective agents oxide (NO) synthase isoform, inducible nitric oxide synthase would be essentially free of such actions while retaining anti- (iNOS).26 The NO so formed appears to combine with the oxy- inflammatory properties as a consequence of reducing proin- gen moiety, superoxide, to form the highly reactive and cyto- flammatory prostanoids synthesised by the inducible COX-2 toxic species, peroxynitrite, which is responsible for the isoform. Indeed, in the preclinical models, the COX-2 selective further development of the fulminant intestinal lesions agents had a superior safety profile on the gut compared with following the initial challenge with the NSAID.27 28 the other NSAIDs.15 16 This was borne out in many clinical trials, 17–19 Are the COX-2 selective inhibitors considered completely free particularly those using endoscopic techniques. This work of such actions on the small intestine? The answer is quite sim- did not exclude however that mitigation of other factors such as ply, no. Indeed, the preclinical and safety data of the topical irritation by these essentially chemically non-acidic new submissions to the Food and Drug Administration (see agents could also contribute, especially when the agents were www.fda.gov/cder/approval/index.htm) for the first generation compared with standard NSAIDs given orally. In addition, the COX-2 inhibitors, celecoxib and rofecoxib, or to the European inability of the COX-2 selective inhibitors to affect platelet 4 Medicines Evaluation Agency (see www.emea.eu.int/)