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Notes: Abstract In comparative clinical studies of auranofin (AF, oral gold) and parenteral gold in the treatment of rheumatoid arthritis, no difference in efficacy was detected. Since the pharmacologic profiles of these compounds are different, we studied their combined effect on adjuvant arthritis (AA). The effect of AF alone and combined with gold sodium thiomalate (GTM) or gold sodium thiosulfate (GTS) on the excretion of urinary hydroxyproline (UHP) and urinary calcium (UCa), and the articular index of arthritic rats was followed during five weeks of treatment. The excretion of UHP and UCa was significantly inhibited (P〈0.005) in rats treated with AF combined with GTM or GTS as compared with animals treated with the individual gold compounds. However, the articular index only decreased significantly (P〈0.02) in the group of rats treated with AF + GTS. The present studies open the possibility that combined treatment with oral and injectable gold provide a new approach for chrysotherapy with an increased antiarthritic potency.

Notes: Abstract We have observed an antiarthritic effect of combined chrysotherapy in adjuvant arthritis. Since superoxide radicals (O 2 − ) are potent mediators of rheumatoid inflammation, we studied the combined effect of auranofin (AF) and injectable golds on luminol-dependent chemiluminescence (LDCL) and O 2 − generation by cytochrome-c reduction of activated leukocytes by different receptor-mediated stimuli: phorbol myrystic acetate, 10−6 M; f-Met-Leu-Phe, 10−6 M; and poly-L-histidine, 10−5 M. AF, 0.6 and 0.9 Μg Au/ml, inhibited 34 and 58% of O 2 − generation, respectively; the addition to AF of 0.3 Μg Au/ml of gold thiosulfate (GTS) increased this inhibition to 84 and 97% of the oxygen burst. Similar synergistic potentiation inhibition was obtained by LDCL. When the inhibition of O 2 − generation by the combined action of AF and GTS was compared with AF + gold sodium thiomalate (GTM), only GTS showed an activation on AF's inhibition of the oxygen burst of human leukocytes. The ligand thiosulfate in equimolar concentrations to GTS had a statistically significant (P〈0.01) inhibitory effect on AF's blockade of O 2 − generation during the first 5 min of the interaction with the PMNs; thiomalate had no effect. Sequential pretreatment of PMNs with AF and GTS on O 2 − generation revealed that for synergism of combined gold action to take place, the cell membrane had to be subjected first to the action of oral gold or to the simultaneous combined action of oral and parenteral gold. The in vitro studies showing a synergistic potentiation in the inhibition of the oxygen burst of human PMNs by AF + GTS and not with GTM points out a different role of the injectable gold ligands in the biological potentiation of the synergistic gold complex.

Notes: Abstract Human blood leukocytes and platelets and mouse peritoneal macrophages emit very rapid and very intense Luminol-dependent chemiluminescence (CL) signals when treated with streptococci, staphylococci, or with zymosan, which have been preopsonized with arginine-rich histone, dextran sulfate or polyanetholesulfonate (liquoid). Liquoid alone at 10–30μg/2×105 leukocytes also triggers intense CL responses in the absence of a carrier. Strong CL can also be triggered, and at the same levels, when the various polyelectrolytes are simply mixed with the bacteria or zymosan and added to the leukocyte suspensions. The CL responses induced by the polyelectrolyte-bacteria complexes greatly exceed those triggered in leukocytes by antibody-complement-coated particles. Liquoid also shows a unique property of markedly augmenting CL signals which have already been induced by other ligand-coated bacteria or zymosan particles. Streptococci and staphylococci were found to be much superior to zymosan, Gram-positive bacilli, orE. coli as carriers for the various polyelectrolytes in the CL reaction. Neither protamine sulfate, lysozyme, myeloperoxidase, crystalline ribonuclease (all cationic in nature), chondroitin sulfate, heparin, nor alginate sulfate acted as ligands for triggering CL, when used to opsonize bacteria or zymosan. The induction of CL in blood leukocytes by the various ligand-coated bacteria is markedly inhibited by azide, KCN catalase, aminotriazole, and EDTA, agents known to inhibit the production of oxygen radicals following stimulation of leukocytes by opsonized bacteria. Two children diagnosed for chronic granulomatous diseases (CGD) of childhood and an apparently healthy sister of one of the male patients completely failed to respond with CL either to the polyelectrolyte-bacteria complexes, liquoid or antibody-coated bacteria and zymosan. It is proposed that liquoid be employed for the rapid screening of defects in certain oxygen-dependent metabolic processes in both PMNs and macrophages. It is also suggested that polyelectrolytes like the ones described in this study may markedly enhance the bactericidal properties of leukocytes and macrophages towards both extracellular and intracellular microorganisms and may perhaps also augment the tumoricidal effects of activated macrophages.