Interaction between anti-inflammatory drugs and reactive oxygen metabolites must be considered in the course of pharmacological studies intended to develop new compounds. Effects of indomethacin, aspirin, and 3,5-diisopropylsalicylic acid (3,5-DIPS) and their copper complexes on PMNL oxidative metabolism and the evolution of an acute inflammatory reaction were studied in the rat. Experiments were performed in vitro by assessment of superoxide generation and reduction of chemiluminescence by PMNLs incubated or not (control) in medium containing various concentrations of these compounds. A dose-related decrease of these parameters was observed, however, copper complexes were found to be more effective than their parent drugs or Cu gluconate. Copper complexes were also more effective anti-inflammatory agents than their parent ligands or Cu gluconate when the volume of exudate and number of exudate PMNLs were assessed after induction of pleurisy in rats by injection of isologous serum. It is concluded that modulation of the PMNL oxidative burst by copper complexes offers an accounting for the anti-inflammatory activity of these compounds.
Antiinflammatory activities and modulations of PMNL responses produced by treatment with tetrakis-mu-2-[3-(trifluoromethyl)-phenyl]aminonicotinatodicopper (II) [Cu(II)2(niflumate)4] and niflumic acid were studied in isologous serum-induced rat pleurisy. Doses of 10 or 30 mg/kg (35 or 106 mumol/kg) of niflumic acid or Cu(II)2(niflumate)4 (8 or 23 mumol/kg) caused significant (p < 0.01) reductions in pleural exudate and number of polymorphonuclear leukocytes (PMNLs) in the exudate. While both doses of Cu(II)2(niflumate)4 produced significant dose-related reductions in both parameters, only the higher dose of niflumic acid produced a significant dose-related reduction in both parameters. Boyden chamber measurements of N-formyl-methionyl-leucyl-phenylalanine (f-MLP) chemotaxis by PMNLs incubated with 10 or 30 micrograms/ml niflumic acid (35 or 106 nmol/ml) or Cu(II)2(niflumate)4 (8 or 23 nmol/ml) were significantly (p < 0.01 to p < 0.001) decreased in dose-related fashions. Chemotaxis of PMNLs from pleuritic rats treated orally with 10 or 30 mg/kg niflumic acid or Cu(II)2(niflumate)4 was significantly (p < 0.001) inhibited by the larger dose of niflumic acid and both doses of Cu(II)2(niflumate)4. Opsonized zymosan (OZ)-stimulated chemiluminescence (CL) of PMNLs from pleuritic rats treated orally with these same doses of niflumic acid or Cu(II)2(niflumate)4 was only significantly (p < 0.05 or p < 0.01 respectively) decreased by the larger doses. Superoxide (O2-) production by these cells was significantly decreased by the larger dose of niflumic acid (p < 0.05) while both doses of Cu(II)2(niflumate)4 produced significant (p < 0.05 to p < 0.01) decreases.(ABSTRACT TRUNCATED AT 250 WORDS)
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