ascorbic-acid and benoxaprofen

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.

Topics: Anti-Inflammatory Agents; Ascorbic Acid; Cell Movement; Chemotaxis, Leukocyte; Hexosephosphates; Humans; Levamisole; Luminescent Measurements; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxidation-Reduction; Peroxidase; Propionates

Incubation of human blood polymorphonuclear leucocytes (PMNL) with benoxaprofen at concentrations of greater than 1 X 10(-5)M caused inhibition of random and leucoattractant-induced migration of these cells in vitro. The drug at the same concentrations and in the absence of an added stimulant caused increased PMNL oxidative metabolism measured by chemiluminescence, hexose-monophosphate shunt activity and myeloperoxidase release. Furthermore benoxaprofen also induced PMNL auto-oxidation detected by cellular auto-iodination. Co-incubation of PMNL with the anti-oxidants ascorbate or levamisole prevented benoxaprofen-mediated inhibition of PMNL migration and cellular auto-oxidation. The drug per se was not an oxidising agent and its inhibitory effects on PMNL motility were dependent upon intact cellular oxidative metabolism. The inhibitory effects of benoxaprofen on PMNL migration in vitro are caused by the proxidant activity of the drug.

Topics: Adult; Antioxidants; Ascorbic Acid; Cell Movement; Chemotaxis, Leukocyte; Cytoplasmic Granules; Humans; In Vitro Techniques; Luminescent Measurements; Neutrophils; Oxidation-Reduction; Pentose Phosphate Pathway; Propionates

Concanavalin A (con A) and the non-steroidal anti-inflammatory drug benoxaprofen caused increased oxidative metabolism and suppressor activity in human mononuclear leukocytes in vitro. The relationship between enhanced oxidative metabolism and suppressor activity in MNL was investigated using the water-soluble anti-oxidants ascorbate and cysteine at fixed concentrations of 1 X 10(-3) M. Ascorbate and cysteine inhibited both the induction of suppressor activity and increased oxidative metabolism in MNL caused by con A and benoxaprofen. It is proposed that ascorbate and cysteine prevent the induction of non-specific suppressor activity in MNL by an anti-oxidant mechanism.

Topics: Anti-Inflammatory Agents; Ascorbic Acid; Concanavalin A; Cysteine; Humans; Lymphocyte Activation; Lymphocytes; Oxidation-Reduction; Propionates; T-Lymphocytes, Regulatory