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The effect of antiarthritic drugs on hindpaw edema and enhanced IL-1 production by macrophages from adjuvant arthritic (AA) rats was determined. Hindpaw edema was inhibited by indomethacin (INDO), methotrexate (MTX) or prednisolone (PRED) but not by D-penicillamine (D-PEN) or chloroquine (CQ). IL-1 production by splenic adherent cells was decreased by MTX and PRED; whereas, IL-1 production by peritoneal exudate cells was decreased by PRED, INDO and D-PEN. This normalization in IL-1 production is not caused by a direct inhibition of IL-1 production by the drugs but most likely reflects clinical improvement in the disease. Whether reduction in IL-1 levels provides a more meaningful parameter than paw edema for assessing clinical efficacy of disease-modifying drugs remains to be determined.

A series of substituted 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles were synthesized and evaluated in the rat adjuvant-induced arthritis and mouse oxazolone-induced contact sensitivity assays to determine the potential of these compounds for use as immunoregulatory antiinflammatory agents. This class of compounds was derived by combining salient structural features of the antiinflammatory agent flumizole and the immunoregulatory drug levamisole. Unlike the latter two, a number of compounds in the target series were found to possess the desired combination of activities. Exploration of structure-activity relationships in the adjuvant-induced arthritic rat assay revealed that optimal potency was exhibited by symmetrically substituted 5,6-diaryl compounds having one of the following alkyl heteroatom or halogen functions at the para position: methoxy, ethoxy, methylthio, N-ethyl-N-methylamino, fluoro, or chloro. Scrambling of these two substituent classes to yield the asymmetrically substituted 5,6-diaryl compounds resulted in potent activity only with the 5-alkyl heteroatom, 6-halo-substituted regioisomers. However in the oxazolone-induced contact sensitivity assay, no consistent relationship of variation in activity with structural change was apparent. The initial target compound 5,6-bis(4-methoxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole (1) was compared with its progenitors in additional models of inflammation and immunoregulation.

SK&F D-39162, a potential chrysotherapeutic agent, on oral administration was effective in suppressing the development of inflammatory lesions and 7S anti-sheep red blood cell antibody formation in adjuvant arthritic rats. Oral absorption of SK&F D-39162 was indicated by the presence of serum gold levels. In contrast to orally administered SK&F D-39162, gold sodium thiomalate administered intramuscularly at equivalent gold doses, appeared to be less effective in suppressing the primary and secondary lesions of adjuvant arthritis, produced relatively higher levels of gold in both serum and kidneys and produced marked toxicity. Other pharmacologic properties of SK&F D-39162 distinguishing it from gold sodium thiomalate which may have clinical significance include potent inhibitory activity on antibody-forming cells, immediate hypersensitivity reactions and extracellular release of lysosomal enzymes. In further contrast to gold sodium thiomalate, SK&F D-39162 is not a potent inhibitor of sulfhydryl group reactivity. In pharmacokinetic studies, the daily oral administration of SK&F D-39162 to normal rats produced greater stability of blood gold levels and less kidney gold accumulation than parenterally administered gold sodium thiomalate.

Adjuvant-induced arthritis (AA) in rats is associated with a number of immunologic abnormalities which include a marked decrease in spleen cell mitogenic responses. In this study we investigated the altered production of interleukins in arthritic rats and evaluated the effects of auranofin treatment on disease progression and aberrant interleukin production. The capacity of the AA rat spleen cells to produce interleukin (IL) 2 and IL-3 was found to decrease during the development of the arthritic lesion, with maximum suppression occurring 16 to 17 days after adjuvant injection. In contrast, the production of IL-1 by splenic adherent cells from arthritic rats was markedly increased. Prophylactic treatment of AA rats with auranofin resulted in a slight reduction in paw edema, a complete normalization of the depressed IL-2 production, and a reduction of the elevated IL-1 production, but had no effect on the depressed IL-3 production. In contrast, auranofin administered to normal rats, in the same dosing regimen, did not affect interleukin production. Therapeutic administration of auranofin to AA rats with established disease resulted in normalization of IL-1 production without affecting the suppressed IL-2 and IL-3 levels. In contrast, while indomethacin treatment effectively decreased paw edema, it did not appreciably affect the systemic aberrant interleukin production. Taken together, these results suggest that disease-associated abnormalities in interleukin production may be mediated by different mechanisms with differential sensitivity to the effects of the disease-modifying drug auranofin. Furthermore, defining the relationship between drug-mediated normalization of aberrant immune parameters and clinical improvement will provide a basis for the elucidation of the mechanism of action of disease-modifying antiarthritic drugs as well as for assessment of clinical efficacy of drug treatment.

The dual inhibitors of arachidonic acid metabolism, Smith Kline & French (SK&F) 86002, SK&F 104351, and phenidone; the corticosteroid, dexamethasone; and the selective cyclooxygenase inhibitors, ibuprofen, indomethacin, naproxen, and piroxicam were evaluated for their antiarthritic potency in the murine, collagen-induced arthritis model. The ability of these compounds to alter the severity of arthritic lesions and to reduce serum levels of the acute-phase reactant, serum amyloid P component (SAP) were monitored. Serum concentrations of SAP were found to correlate strongly (r = 0.985) with disease severity at day 35 postimmunization. Treatment with SK&F 86002, SK&F 104351, phenidone, or dexamethasone significantly reduced disease severity, as judged by clinical score (55%, 72%, 41%, and 45% inhibition, respectively) and SAP levels (62%, 94%, 52%, and 94% inhibition, respectively) in arthritic mice. This profile of activity was not shared by the selective cyclooxygenase inhibitors, which did not uniformly inhibit disease activity by both parameters. The results suggest that dual inhibitors of 5-lipoxygenase and cyclooxygenase may prove more effective than selective cyclooxygenase inhibitors as anti-arthritic agents.

We demonstrated previously that variables of macrophage activation are associated with the development and progression of the arthritic lesion in the model of adjuvant induced arthritis. This association was investigated further by assessing the ability of antiarthritic agents to modulate variables of macrophage activation in direct comparison to effects on the arthritic lesion. Whereas indomethacin effectively reduced hindpaw edema, it had no significant effect on Ia expression or on any measurement of activation. Prednisolone inhibited hindpaw edema and the production of interleukin-1 (IL-1) by splenic macrophages. Only methotrexate inhibited hindpaw edema and all variables of macrophage activation (PGE2 and IL-1 production, cyanine dye accumulation) as well as the influx of Ia positive macrophages into synovial tissue.

Disease-associated alterations in macrophage functions were assessed by investigating the stages of activation of peritoneal macrophages obtained from adjuvant-induced arthritic rats. The stages of activation were established by defining several functional parameters in macrophages obtained from normal, sterile-irritant injected and Propionibacterium acnes injected animals. Peritoneal macrophages taken from arthritic rats 17 days post adjuvant injection displayed parameters characteristic of activated, but not elicited or resident macrophages. Specifically, an increased number of macrophages was recovered from arthritic rats which spread readily in culture, exhibited enhanced Fc receptor-mediated phagocytosis, increased leucine aminopeptidase ectoenzyme activity, enhanced secretion of prostaglandin E2 and interleukin 1, and ability to lyse tumor cells spontaneously. In addition, these macrophages were impaired in their ability to secrete superoxide anion. These data demonstrate distinct differences in parameters of peritoneal macrophage activation in rats compared to mice and that macrophage activation is associated with disease progression in adjuvant-induced arthritic rats.

Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium also exhibits antiarthritic and immunoregulatory activities after p.o. administration to rats. Spirogermanium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered p.o. before or after the development of the arthritic lesions. After termination of spirogermanium administration, the adjuvant-injected hindleg lesions remained significantly suppressed for at least 2 weeks postdrug treatment; whereas, the uninjected, immune-mediated hindleg inflammation tended to increase postdrug treatment. In multiparameter ex vivo studies, untreated arthritic rats exhibited enhanced cyanine dye fluorescence in peripheral blood monocytes, enhanced interleukin (IL)-1 production by adherent spleen cells and depressed IL-2 and IL-3 production by splenic lymphocytes. Spirogermanium normalized these changes to various degrees, with the exception of the depressed IL-2 and IL-3 production. Spirogermanium administered to normal nonarthritic rats decreased mitogenic responses of spleen cells to Concanavalin A which was found to be caused, at least in part, by enhanced suppressor cell activity. The antiarthritic and immunoregulatory profile of spirogermanium appeared to be different from the profiles of the antiarthritic agents, auranofin and indomethacin.

The association between the induction and progression of adjuvant-induced arthritis (AA) and the development of synovial and systemic macrophage activation was assessed by studying the temporal development of these parameters in a rat model. Rats with AA developed significant edema of the uninjected hind leg beginning 10 days post-adjuvant injection, with progressive increases in edema continuing through day 17. Several parameters of macrophage activation, including the enhanced ability to secrete interleukin-1 and prostaglandin E2, kill tumor cells, accumulate fluorescent cyanine dyes, emigrate into the peritoneal cavity and synovium, and express Ia antigen, as well as the decreased ability to secrete superoxide anion, were associated temporally with the development of the arthritic lesion. In addition to the temporal association between macrophage activation and development of arthritis, a positive correlation between macrophage activation and arthritis induction was seen with the use of synthetic adjuvants at arthritogenic and nonarthritogenic doses. These data taken together suggest that induction and progression of AA in rats is associated with both systemic (blood, spleen, and peritoneal cavity) and local (synovium) macrophage activation.