New directions in cyclooxygenase research and their implications for NSAID-gastropathy.
The observations reported in this paper have led to the formulation of a new hypothesis concerning the action of NSAIDs updating the concept first put forward in the early 70's. The new paradigm is that COX 1, a constitutive enzyme is thought to be a housekeeping protein, and to be important in generating prostaglandins necessary for physiological purposes, amongst which may be suppression of gastric acid secretion. In contrast, the induced COX 2 enzyme appears mainly after cell injury and inflammation and is responsible for generating the prostaglandins which mediate inflammatory episodes. In this model, inhibition of COX 1 is thought to produce the undesirable side effects of NSAID therapy, whereas inhibition of COX 2 is thought to be responsible for the anti-inflammatory effects. COX 2, therefore, appears to be the enzyme that should be targeted in anti-inflammatory drug therapy. By designing or screening for specific COX 2 inhibitors, it should be possible to develop drugs which are at least as effective anti-inflammatory agents as the current NSAIDs, but that are much safer in terms of gastrointestinal and other side effects. Early preclinical experience with highly selective inhibitors of COX 2, indeed, suggests that these compounds are anti-inflammatory, but have an ulcer sparing effect. Clinical data with meloxicam also suggest that this theoretical effect is also translated into patient benefit. The selective inhibition of COX 2 is a very attractive new concept that has revitalised NSAID research and promises future hope for the treatment of inflammatory disease without gastric side effects.
Flower
R J
RJ
Dept. Biochemical Pharmacology, William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, England.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins; D010544:Peroxidases / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D010544:Peroxidases; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases