Rat adjuvant arthritis model

The above observations clearly indicate that IL-4 is an important neutrophil activator in vitro. Recently, one study was conducted in order to assess the capacity of IL-4 and IL-IO to block neutrophil activation in an ex vivo human model system, and to confirm their effect on neutrophil function in an animal model of arthritis [75]. In the rat adjuvant arthritis model, treatment with systemic murine IL-4 (mIL-4 and mIL-10) was found to be effective against even the most severely diseased [75]. IL-4 (and IL-10) was effective in lowering the absolute neutrophil cell number recovered and the neutrophil activation state in the joint synovia. Both cytokines reduced the phagocytic activation of human neutrophils in response to proinflammatory cytokines. Collectively, the results demonstrate that IL-4 (and IL-10) can exert powerful regulatory effects on neutrophil function that translate into a therapeutic response in a disease model of arthritis. The authors concluded that treatment with IL-4 (or IL-10) alone or in combination might therefore be very usefiil in the management of patients with rheumatoid arthritis [75]. 

L-167307 is an orally bioavailable inhibitor of p38 kinase. In vivo, it reduces secondary paw swelling in the rat adjuvant arthritis model with an ID50 of 7.4 mg/kg/day. Triarylpyrrole L-167307 was assembled using the Paal-Knorr pyrrole synthesis of a 1,4-diketone and ammonium acetate. ... 

Several other modifications have been explored for the targeted delivery of SOD. Chemical modification with hydrophilic monomethoxypolyethyleneglycol polymers (MPEG) resulted in a derivative with an increased molecular weight of 130 kDa, and hence a reduced renal elimination rate. The MPEG-SOD preparations reduced arthritic lesions in a complete adjuvant arthritis model in the rat, while native SOD did not show an anti-inflammatory effect [55]. 

In models of chronic inflammation, for which the rat adjuvant arthritis assay is frequently used, these selective COX-2 inhibitors... 

Models of rheumatoid arthritis (RA) were object to l,25(OH)2D3 treatment, providing additional support for the high potential of the hormone for the treatment of Thl-mediated diseases. As an example, in rat adjuvant arthritis l,25(OH)2D3 improved the inhibiting effect of cyclosporine A on arthritis onset as well as on arthritis aggravation [142]. The incidence and severity of type II collagen-induced arthritis was reduced in rats or mice orally treated with 25-(OH)2-D3, the 1,25 (OH)2D3 analog MC 1288 or l,25(OH)2D3 [143-145], l,25(OH)2D3 has further proven to be therapeutically effective in animal models of autoimmune thyroiditis [146], allogeneic transplantation [66, 147,148], rat Heymann nephritis [149] and autoimmune prostatitis [80]. Results from l,25(OH)2D3-related studies in animal models are summarized in Table 10.3. 

Holmdahl R, Lorentzen JC, Lu S, et al. Arthritis induced in rats with nonimmunogenic adjuvants as models for rheumatoid arthritis. Immunol Rev 2001 184 184-202. 

Barnes DA, Tse J, Kaufhold M, et al. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest 1998 101(12) 2910-2919. 

Genetically predisposed animals or induced animal models may also be used to study and predict chemical-induced autoimmunity. In induced models, a susceptible animal strain is immunized with a mixture of an adjuvant and an autoantigen isolated from the target organ. Examples are adjuvant arthritis (AA), experimental allergic encephalomyelitis (EAE) and experimental uveitis in the Lewis strain rat. Examples of spontaneous models... 

Corvo ML, Boerman OC, Oyen WJ, et al. Intravenous administration of superoxide dismutase entrapped in long circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis. Biochim Biophys Acta 1999 1419 325. 

In order to block the effects of spinally released CGRP, an antiserum against CGRP was tested in several models of chronic pain and was found to be antinociceptive in models of chronic inflammatory pain such as adjuvant-arthritis (Kuraishi et al., 1988) or carrageenan-induced hyperalgesia (Kawamura et al., 1989). In addition this antiserum inhibited the repeated cold stress-induced hyperalgesia in rats (Satoh et al., 1992). 

M and 1.1 x 10 M respectively. In addition WF 14861 inhibited mouse crude bone cathepsin with IC50 value of 4.0 x 10 M. The compound ameliorated the tissue damage and the bone destruction modes of low calcium diet fed mouse and adjuvant arthritis rat model. It lowered the plasma calcium concentration from 11.70 0.33 mg/dl to 9.88 0.57 mg/dl (84.0 4.87 %) when injected at the concentration of lOOmg/kg to low calcium diet fed mice [72]. 

Test Methods - As a model manifesting both an acute inflammatory response and disseminated secondary lesions, the adjuvant arthritis assay in rats has become widely accepted in many laboratories. The effect of various known agents on such parameters as the decrease in foot volume, the restoration of body-weight loss, the reduction of plasma "inflammation units", and the change in erythrocyte sedimentation rate has been described.i The relative potency of known drugs was estimated by Glenn as indomethacin (II), 81, hydro-... 

On the other hand, rat adjuvant-induced arthritis is a model of chronic inflammation frequently reported in screening for anti-arthritic agents. Adult rats are the animals of choice because the disease does not occur in hamsters, mice or guinea pigs. The clinical and pathological changes in adjuvant disease are comparable to those of rheumatic arthritis [56]. 

Collagenase production and release are partly responsible for the joint destruction that characterises human rheumatoid arthritis. Triterpenes from the lupane and a-amyrin groups have been studied in vitro to examine their effects on the release of the arthritic joint degradative enzyme collagenase using the rat osteosarcoma. This test and the rat synovial granuloma of adjuvant arthritis are similar both models are based on connective tissue tumours with bone-invasive properties. The pentacyclic triterpenes assayed have been shown to possess general antiproteolytic effects that can explain the anti-arthritic effects in adjuvant arthritis in rats [71,103]. 

The search for new and effective treatment modalities requires the availability of adequate screening tests. Although no model adequately reflects the events that occur in human arthritic conditions, several in vivo and in vitro assays are used. The most common in vivo animal assays measure the ability of anti-inflammatory drugs to inhibit edema induced in the rat paw by carrageenan (a mucopolysaccharide derived from a sea moss of the Chondrus species), to inhibit adjuvant arthritis in rats induced by Mycobacterium butyricum or M. tuberculosis, to inhibit granuloma formation usually induced by the implantation of a cotton pellet beneath the abdominal skin of rats, or to inhibit erythema of guinea pig skin as a result of exposure to ultraviolet radiation. In vitro techniques include the ability of NSAIDs to stabilize erythrocyte membranes or, more commonly, to inhibit the biosynthesis of prostaglandins, particularly in cultured human synoviocytes and chondrocytes, and monocyte culture fluid stimulated bovine synoviocytes and chondrocytes. 

In a more recent publication, Dompe discussed their efforts to identify follow-up compounds that produce more favorable PK characteristics than reparixin [132]. One such compound is trifluoromethanesulfonate 44, which inhibited both CXCL8- and CXCLl-induced PMN chemotaxis with equal potencies (IC50 8.4 and 26 nM, respectively) [133] and in addition gave excellent rat PK properties Cl 4.1 mlmin kg , P 72%) [134]. Extensive in vivo profiling showed 44 to be orally efficacious in a range of inflammatory disease models such as the rat adjuvant-induced arthritis model. 

Vitamin Ki and Vitamin Kg have activity in a number of anti-inflammatory models when administered parenterally. a-Tocopherol and linoleic acid inhibit the induction of adjuvant arthritis in the rat Ormotein, a protein-divalent metal chelate is reported in clinical trial as an antiinflammatory agent-] ... 

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