Rat adjuvant arthritis (AA) was used as a model to evaluate several blood markers as possible predictive indicators of drug efficacy. AA was induced in Sprague-Dawley rats by the injection of complete Freund's adjuvant into the right hind foot pad. The rats were dosed p.o. from day 18 to day 31 with levamisole (10 mg/kg), indomethacin (1 mg/kg), diclofenac sodium (0.5 & 1 mg/kg), and prinomide (10 & 20 mg/kg). Disease severity was assessed by paw circumference on day 31. The following blood markers were analyzed: hyaluronate by ELISA, prostaglandin E2 by RIA, ESR by micro-dispette, total PMN by Technicon H-1, and albumin by BCG dye. Blood marker correlation (r) to disease severity was: hyaluronate (0.71), prostaglandin E2 (0.58), ESR (0.52), PMN (0.58), and albumin (-0.71). The relative rank order of drug efficacy (indomethacin, diclofenac sodium, and prinomide) did not differ using the change in paw circumference (day 31-day 17) or blood markers. Levamisole exacerbated the disease as measured by all the above parameters. Thus, these blood markers provide additional information for the statistical evaluation of drugs in rat adjuvant arthritis.
We have shown that during the developing phase of adjuvant disease (AD) in rats the expression of MHC class II (Ia) antigens on blood monocytes (BM) was enhanced. The results of a study in established AD are reported now. Four agents were tested: indomethacin and diclofenac-sodium (1 mg/kg/day); levamisole and prinomide (10 mg/kg/day), administered orally from day 18-31 after induction of AD. We assessed the following BM parameters: Ia expression, interleukin-1 (sIL-1) production, and membrane bound IL-1 (mIL-1). In AD Ia expression was enhanced, no changes occurred in mIL-1 or sIL-1. Indomethacin treatment reduced sIL-1 production, levamisole Ia expression and mIL-1 activity, prinomide all three parameters measured and diclofenac, though clinically effective, none.
Using rat peritoneal macrophages and blood monocytes we examined the relationship of developing adjuvant disease (AD) with the expression of class I and II antigens, release of interleukin-1 (IL-1) and production of prostaglandin E2 (PGE2). We observed that class I and II antigens initially decreased; class II remained low throughout, whereas class I returned to normal. PGE2 and IL-1 gradually increased. Treatment in vivo with the NSAID Na-diclofenac lowered PGE2 and IL-1 release and partly reversed the observed reduction of class I and II antigens. Also, exposure of the cells in vitro to lipopolysaccharide increased class I antigen expression.
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