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SK&F 86002 [6-(4-fluorophenyl)2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole], a dual inhibitor of arachidonic acid metabolism, administered orally to rats prevented the development of carrageenan-induced edema, immune- and nonimmune-mediated inflammation of adjuvant-induced arthritis (AA) and reduced established inflammation in AA and collagen type II-induced arthritis. A similar profile of activity was observed following treatment with the cyclooxygenase inhibitor, indomethacin. However, unlike other nonsteroidal antiinflammatory drugs, SK&F 86002 exhibited antiinflammatory activity in inflammation models that are insensitive to cyclooxygenase inhibitors such as the established inflammation in carrageenan-induced edema and the edema induced by arachidonic acid and platelet activating factor. Moreover, SK&F 86002, but not indomethacin, inhibited the immune-mediated inflammatory responses evoked in sensitized animals by challenge with purified protein derivative. In addition, SK&F 86002 produced dose-related analgesia in mice, which was not reversed by the narcotic antagonist, naltexone. SK&F 86002 thus represents an orally active antiarthritic and analgesic compound with novel antiinflammatory properties.

Arachidonic acid (AA) injected into hindpaws of Lewis rats produces a severe edematous response. Treatment with corticosteroids (dexamethasone, prednisolone), dual inhibitors of arachidonate metabolism (phenidone, SK & F 86002), anti-histamine/serotonin agents (chlorpheniramine, cyproheptadine) and a gold compound (auranofin) inhibited AA-induced edema. In contrast, administration of high doses of cyclooxygenase inhibitors (indomethacin, piroxicam, naproxen, ibuprofen, meclofenamic acid and tiflamizole) did not affect AA-induced hind paw edema. The involvement of lipoxygenase products and mast cell mediators in the edematous response to arachidonic acid render this model potentially useful for studying antiinflammatory agents with a mechanism of action different from that of cyclooxygenase inhibitors.

Oral administration of spirogermanium (Sg), inhibits the development of immune-mediated hindpaw inflammation in the rat model of adjuvant arthritis (AA) and DTH responses to PPD (30 mg/kg/day). A similar dosing protocol inhibits hindleg paralysis in experimental autoimmune encephalomyelitis (EAE). The spleens of these animals and those of normal rats contain radiation resistant (2000 R) non-specific suppressor cells (SC) which bear some similarity to those generated following total lymphoid irridiation (TLI). These cells do not appear to be mature T cells, they are partially adherent to plastic, sephadex G10 and nylon wool, insensitive to indomethacin and are enriched in a 1.07 g/ml fraction of a Percoll density gradient.

Adjuvant arthritis (AA) was induced in male Lewis rats by a single FCA (M. but yricum) injection into the tail. At various time periods post FCA injection, AA and control rats were anesthetized and administeredE. coli endotoxin (30 mg/kg, i.v.). Plasma samples were obtained at 30, 60, 90, 120 and 150 min following endotoxin administration and assayed for TNFα levels by ELISA. Compared to control rats, AA rats exhibited enhanced EIPT levels (706% of control,p<0.05) which was associated with the onset of inflammatory lesions on days 12–14 post FCA, and remained significantly elevated (>300% of control,p<0.05) for at least 30 days post FCA. There were no significant correlations between EIPT levels and hindpaw volumes or body weights. The results of this study support previous observations that AA is associated with macrophage activation and suggest that EIPT levels in AA rats may be a useful parameter for the evaluation of novel antiarthritic agents.

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 byd-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 andd-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.

Arachidonic Acid (AA) injected into a hindpaw of Lewis rats produces high levels of tissue myeloperoxidase (MPO), a biochemical marker for PMN leukocytes. Treatment with a corticosteriod (prednisolone) or dual 5-LO/CO inhibitors of AA metabolism (phenidose, SKF 86002) produced dose-related inhibition of AA-induced elevations in paw tissue MPO levels. In contrast, administration of high pharmacologic doses of selective cyclooxygenase inhibitors (indomethacin, ibuprofen, naproxen), anti-histamine/serotonin agents (cyproheptadine, chlorpheniramine) or an anti-arthritic gold compound (auranofin) produced only slight or moderate effects. Thus, AA-induced hindpaw inflammation is a useful method for determining pharmacologic effects of 5-LO/CO inhibitors on PMN leukocyte infiltrationin vivo.