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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective.

Two classes of antipyretic analgesics were developed about 100 years ago, namely the acidic aspirin-like drugs and non-acidic acetaminophen-phenazone-like compounds. Since then, research has aimed at improving the side-effect profile of the acidic anti-inflammatory aspirin-like drugs and improving the anti-inflammatory efficacy of the non-acidic acetaminophen-phenazone-like compounds. Both drug classes inhibit the cyclooxygenase (COX)-1 and -2 enzymes non-selectively. The aspirin-like drugs achieve particularly high concentrations in inflamed tissue, which is assumed to account for their superior anti-inflammatory potency. These acidic drugs also reach comparatively high concentrations in the stomach wall, kidney cortex and blood, resulting in the well-known side effects that occur with acidic compounds but not with acetaminophen and phenazone. Following the discovery of the two differentially distributed and regulated COXs, two non-acidic COX-2-selective compounds--celecoxib and rofecoxib--were introduced. They proved to be less toxic to the gastrointestinal tract compared with, for example, diclofenac or naproxen. These non-acidic drugs distribute homogeneously throughout the body--a cause for concern since COX-2 has been found to be present constitutively in many organ systems, including brain, bone and the genito-urinary tract. It appears desirable to combine the tissue-targeted distribution of the highly protein-bound acidic aspirin-type drugs with the selectivity of the COX-2 inhibitors, in order to achieve improved anti-inflammatory activity and at the same time reduce the risk of side effects. Such agents should be devoid of COX-1-related side effects in, for example, the inhibition of blood coagulation and should only weakly affect COX-2 related functions of the central nervous system, due to slow blood-brain barrier penetration. We therefore propose that a drug combining the pharmacokinetic characteristics of, for example, ibuprofen with the COX-2 selectivity of rofecoxib is likely to be a superior anti-inflammatory analgesic.[1]


  1. Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective. Brune, K., Neubert, A. Clinical and experimental rheumatology. (2001) [Pubmed]
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