Cyclooxygenase and nitric oxide systems in the gut as therapeutic targets for safer anti-inflammatory drugs.
After a decade of intense pharmacological and drug development activity by the pharmaceutical industry, compounds derived from two key strategies for reducing gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) have been subjected to rigorous clinical appraisal. Despite the undoubted therapeutic and commercial success of the selective cyclooxygenase (COX)-2 inhibitors, known as the coxibs, with second-generation compounds already approved and launched, some concerns over their full gastrointestinal profile still linger, while the cardiovascular safety of this class has become a key issue. Likewise, Phase II evaluation of compounds incorporating a nitric oxide (NO)-donating moiety into standard NSAIDs (the NO-NSAIDs or CINODs) has created recent controversy over the full clinical profile of these compounds. Other approaches such as NO-COX-2 inhibitors and dual COX-lipoxygenase inhibitors are already warranting interest. It might therefore be too early to predict the eventual winning strategy for safer anti-inflammatory drugs.
Whittle
Brendan J R
BJ
William Harvey Research Institute, Bart's and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK. b.j.whittle@qmul.ac.uk
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004345:Drug Industry / Q000639:trends; D005767:Gastrointestinal Diseases / Q000201:enzymology*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D015337:Multicenter Studies as Topic; D009569:Nitric Oxide / Q000502:physiology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000502:physiology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases