| セッション情報 |
International Forum 1(Gastrointestinal tract) 3.Pathogenesis of NSAIDs-enteropathy
|
| タイトル |
IF1-3-I (Keynote lecture) Intestinal permeability and NSAID-enteropathy
|
| 演者 |
Ingvar Bjarnason（King's College HospitalLondonUK） |
| 共同演者 |
|
| 抄録 |
The main concern with long-term ingestion of NSAIDs is their gastrointestinal side effects． The gastricside effects （dyspepsiaerosions and ulcersbleeding and perforation） of these drugs are well recognisedand continue to drive the pharmaceutical industry to develop safer alternatives． However important theupper gastrointestinal side effects of NSAIDs are it is clear that the side effects on the small bowel（NSAID-enteropathy） are equally common and of similar clinical significance． Accordingly 700／o of pa-tients on long-term NSAIDs have NSAID-enteopathy （inflammationerosions and ulcers）which is associ-ated with small bowel bleedingprotein loss and at times with perforation and strictures． The pathogene-sis of NSAID enteropathy has been studied in detail and the overall picture is that NSAIDs initially causebiochemical damage to the enterocytes． This damage is then reflected on a tissue level and characterisedby increased intestinal permeability． This permeability increase in turn allows luminal substances （bile ac-idsbacterial degradation productsetc． ） access to the mucosa thereby leading to inflammation． The in-aammation may then progress to erosions and ulcers and the latter in particular have the propensity toeause serious events （significant bleeding and perforations）． Each stage （biochemicalcellulartissue） isimportant in the overall pathogenesis of the damage and the pathogenic mechanisms vary accordingly．Intestinal permeability is thought to be the central end essential mechanism of translating the biochemi-cal／cellular events of NSAIDs over to a tissue reaction． The intact intestinal barrier effectively excludesluminal toxins access to the mucosa． ln general there are over 30 situations whereby intestinal permeabil-ity is increased and this is always followed by an inflammatory reaction （enteropathy） ． These enteropa-thies can not be easily distinguished from each other suggesting that this（increased intestinal permeab且一ity leading to inflammation） is a common final pathway for a number of small bowel disease．The biochemical action of NSAIDs have been deducted from experimental work mainly in animalsThereare 2 main actions of NSAIDs． Firstly all conventional NSAIDs are weak acids and invariably lipophilic．This renders them with detergent properties and an ability to uncouple mitochondrial oxidative phospho-rylation which in fact underlie their “topical” toxicity． The former action causes direct damage to the sur-face epithelium by an interaction with phospholipids and the latter reduced intracellular ATP productionwhich results in loss of intercellular integrity and hence increased intestinal permeability． SecondlyNSAIDs inhibit COX-1 and COX-2． The precise consequence of COX-1 inhibition is uncertainbut it issuggested that this reduces microvascular blood flow and hence causes ischemia． COX-2 inhibition ap-pears to be proinflammatory in the gut． The interaction of these biochemical effects then lead to the gas-tric and small bowel damage via increased intestinal permeability．Increased intestinal permeability in man is seen after all conventional NSAIDs with 24 hours of ingestion．The permeability changes are dose dependent and at therapeutic doses there are no differences in theprevalence or severity of the permeability changes between the drugs when given short一 or long-term． ltis however controversial whether aspirin causes increased intestinal permeability and nabumetoneanon-acidic pro-NSAIDdoes not increase permeability． Neither aspirin or nabumetone cause NSAID-en-teropathy when taken long term． COX-2 selective agents do not increase intestinal permeability whentaken short-termbut most of them are non-acidic and therefore do not cause the “topical” effect．Various methods have been employed in order to attempt to abolish the permeability changes caused byNSAIDs as this may avoid the side effects on the small bowel． Unfortunately no drugs have been success-ful in this regard （sulphasalazinemetronidazoleH2 receptor antagonistsPPI’smisoprostoletc）．Prevent-ing the permeability changes and thereby abolishing the enteropathy remains a maj or challenge． |
| 索引用語 |
|
