Benoxaprofen: a pro-oxidant anti-inflammatory drug?
Benoxaprofen inhibited the random motility and migration to the leucoattractants endotoxin-activated serum (EAS) and f-met-leu-phe of human polymorphonuclear leucocytes (PMNL) in vitro. Inhibition of random and leucoattractant-induced migration was observed at drug concentrations of greater than 1 X 10(-6) M and 1 X 10(-5) M respectively. Benoxaprofen per se was not leucotactic but was pro-oxidative in that it stimulated PMNL hexose-monophosphate shunt activity, chemiluminescence, myeloperoxidase-mediated iodination reactions and degranulation. The drug also mediated auto-oxidation of PMNL as measured by cellular auto-iodination. The relationship between benoxaprofen-mediated inhibition of PMNL migration and activation of oxidative metabolism was investigated using the anti-oxidants ascorbate and levamisole at concentrations of 10(-2) M and 10(-3) M respectively. These agents prevented the decreased motility and auto-oxidation of PMNL induced by 10(-4) M benoxaprofen. Benoxaprofen (10(-4) M) did not inhibit the migration of PMNL from 3 children with chronic granulomatous disease thus showing that intact PMNL oxidative metabolism is required for the induction of drug-mediated inhibition of cell motility. Ingestion of therapeutic doses of benoxaprofen for 7 days by normal adults gave serum drug concentrations greater than those required for detectable effects on PMNL functions in vitro (mean serum value 126 micrograms/ml). Co-incubation of normal PMNL with serum from individuals who had ingested the drug caused decreased cell migration and increased chemiluminescence. These results show that benoxaprofen inhibits PMNL migration as a consequence of pro-oxidant properties and despite its withdrawal may be the prototype of the pro-oxidative anti-inflammatory drug.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006600:Hexosephosphates / Q000097:blood; D006801:Humans; D007978:Levamisole / Q000494:pharmacology*; D008163:Luminescent Measurements; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011422:Propionates / Q000097:blood / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D006600:Hexosephosphates; D011422:Propionates; C011677:benoxaprofen; D007978:Levamisole; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D001205:Ascorbic Acid