Perspectives on the cyclooxygenase-2/ cyclooxygenase-1 hypothesis

The introduction of the cyclooxygenase (COX) hypothesis to explain both the therapeutic effects and the toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) has provided direction for the development of preferential and highly selective COX-2 inhibitors, which retain efficacy against inflammation with reduced risk of toxicity. However, the complex physiologic responses to inflammation and disease suggest that COX-2 inhibition by NSAIDs is an action on only one several interrelated components of the inflammatory response, such as oxygen radical production, nitric oxide synthesis, and heme oxygenase activity, that may affect resolution of inflammation. Additionally, NSAIDs demonstrate actions independent of COX inhibition that may enhance their anti-inflammatory activity and be of benefit in the treatment or prevention of other diseases. Although much has yet to be learned regarding the roles of COX and the actions of NSAIDs, preferential and highly selective COX-2 inhibitors seem to provide an increase in gastrointestinal safety compared with standard NSAIDs. As more information becomes available from preclinical studies, clinical studies, and postmarketing surveillance, it may be necessary to modify the proposed model or re-evaluate the direction of the new drug development. In the meantime, these inhibitors provide useful tools for investigating the physiologic roles of the COX isoforms and raise our expectations that NSAIDs can be developed with greatly enhanced safety profiles.