Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis

Abstract

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

A Novel Phenotype of Nonsteroidal Anti-Inflammatory Drug Hypersensitivity

“…Interestingly, among low COX inhibitors, acetaminophen was most commonly incriminated, followed by nimesulide, meloxicam, and less frequently, the coxibs, the more selective drugs sparing COX-1 (Figure 2). This is in agreement with the rates of inhibition of COX-1 in vitro,[11] with the exception of acetaminophen that inhibits another isoenzyme, COX-3, which is closely related to COX-1 [12-14]. …”

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…Indeed, stress has been shown to increase extracellular glutamate concentrations in many brain areas (Lowy et al, 1993;Moghaddam et al, 1994;SteinBehrens et al, 1994), an effect that is proposed to result from compromised activity of the energy-dependent excitatory amino acid transporters. On the other hand, it has recently been shown that glutamate release is mainly due to reversed operation of neuronal glutamate transporters in processes such as brain ischemia and others (Warner et al, 1996;Jabaudon et al, 2000;Rossi et al, 2000). Thus, in stress, this is one among the various mechanisms, which, alone or combined, may be responsible for glutamate release (Lawrence and Sapolsky, 1994) although we have not seen modifications in glutamate uptake in neurons (EAAT-3).…”

The pharmacological properties and clinical use of valdecoxib, a new cyclo‐oxygenase‐2‐selective inhibitor

“…8 These values are at least 10-fold greater than the COX-1 ⁄ COX-2 ratios obtained with nonselective NSAIDs. 9 The primary hydroxylated metabolite of valdecoxib, SC-66905, which accounts for 10-15% of the parent compound in human plasma (Pharmacia, on file 2000), has lower COX-2 inhibitory activity than that of valdecoxib and does not contribute significantly to the clinical effects of valdecoxib. Valdecoxib and its metabolite SC-66905 are also the active moieties of a new parenteral COX-2-selective inhibitor, parecoxib sodium.…”

“…in the group receiving valdecoxib when compared with that receiving placebo. The reduction in blood glucose, however, was not clinically significant (Pharmacia, on file 1999) 9 . A drug interaction study with valdecoxib (40 mg b.d.…”