Tol??rance gastro-intestinale des anti-inflammatoires non-st??ro??diens

Abstract

Gastrointestinal Tolerability of Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective antipyretic, analgesic and anti-inflammatory agents. One of the major concerns regarding the use of these compounds is the incidence of gastrointestinal (GI) adverse effects, ranging from dyspepsia to the serious and potentially life threatening complications of ulcers, haemorrhages, and perforations. Thus, the prevention and/or treatment of upper GI damage is estimated to increase the overall cost of NSAID therapy by at least 40%. The pathogenesis of NSAID-induced gastroduodenal mucosal injury appears to involve both topical and systemic mechanisms. The former is related to the acidic nature of most NSAIDs, which promotes the accumulation of ionised molecules (ion trapping) within the mucosal cells. Topical mucosal injury may also occur as a result of biliary excretion of active NSAID metabolites. The systemic effect has, however, the predominant role. It is mediated through cyclo-oxygenase (COX) inhibition and a subsequent decrease in gastroprotective prostaglandins. Fortunately, 2 forms of COX enzymes, designated COX-1 and COX-2, have been recognised. COX-1 appears to function as a house-keeping enzyme, whereas COX-2 is primarily induced by inflammatory stimuli and mitogens in various cells, including macrophages and synovial cells. Accordingly, the inhibition of COX-2 would result in anti-inflammatory effects, whereas gastroduodenal ulceration is thought to be related to the inhibition of COX-1. Animal data have suggested that nabumetone has a low ulcerogenic potential in comparison with other available NSAIDs. This feature was further supported by controlled clinical trials as well as epidemiological studies. The relative GI safety of nabumetone may be attributed to its lack of direct and indirect topical effects because of its nonacidic nature and absence of enterohepatic recirculation. Furthermore, the active metabolite [6-methoxy-2-naphthylacetic acid (6-MNA)] may be gastro-sparing as a result of its property of COX-2 preferential inhibition. La toxicite digestive des anti-inflammatoires non-steroidiens (AINS) est la principale responsable de la morbidite, de la mortalite et du surcout lies a l'emploi de ces medicaments. Elle resulte d'une agression locale de la muqueuse par les AINS et, surtout, d'une action systemique, consecutive a l'inhibition de la synthese des prostaglandines cytoprotectrices dans le tractus gastro-duodenal. Tous les AINS disponibles exposent certes aux complications ulcereuses, hemorragiques et aux perforations mais les donnees experimentales, cliniques et epidemiologiques montrent que le risque varie selon les molecules. A ce titre, un faisceau convergent d'arguments plaide en faveur du faible potentiel ulcerogene de la nabumetone. Ce profil avantageux serait la consequence des caracteristiques physicochimiques (AINS prodrogue non-acide) et cinetiques (absence d'elimination biliaire) du produit, des lors denue de toxicite muqueuse directe. De plus, d'apres differents travaux, son metabolite actif, l'acide 6-methoxy-2-naphtylacetique (6-MNA), apparait comme un inhibiteur preferentiel de COX-2 de sorte qu'il epargnerait relativement COX-1, iso-enzyme impliquee dans la formation des prostaglandines dans l'estomac.