The project proposed will make use of recently discovered antiarthritic agents of the amidine type to investigate the pathogenesis of joint inflammation and to develop new avenues of treatment. A suitable proven experimental model is available in the Lewis rat where a single systemic application of streptococcal cell wall-derived peptidoglycan-polysaccharide fragments leads to recurrent erosive polyarthritis. The disease shares many features with human rheumatoid arthritis the etiology of which is still unknown and for which there exists no curative therapy. Interest in amidines arose when preliminary experimental studies showed that BABIM (bis-(5-amidino-2-benzimidazolyl)methane) can block completely the arthritic events. Organic synthetic amidines of the class proposed are highly potent inhibitors of trypsin and other arginyl- or lysyl- directed estero-proteases. Their beneficial effect in inflammation is attributed to interference with the action of humoral and/or cell-associated proteases. The major aims of this proposal are: 1) To establish in the arthritis model an optimal dosing schedule for the pilot compound BABIM. 2) To investigate in detail the influence of BABIM On the histopathologic and immunopathologic parameters. 3) To test for their therapeutic properties a series of additional promising amidines and to try to correlate effectiveness with blockage of a given enzyme. 4) To examine in vivo and in vitro whether the anti-inflammatory properties of amidines are based on interference with specific functions of macrophages and/or neutrophilic polymorphonuclear leukocytes. The results of the planned in vivo and in vitro studies will provide deeper insight into the etiologic factors involved in the arthritic process, the mechanism of bone and joint destruction, and the cause of the characteristic recurrences and remissions of the disease. By extrapolation, there will also be a clearer understanding of arthritis in man, and there is great promise for obtaining an effective agent for treatment of diseases such as rheumatoid arthritis.
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| Dieter Geratz, J; Pryzwansky, K B; Schwab, J H et al. (1993) Suppression of local and systemic responses in streptococcal cell wall-induced acute inflammation of the air pouch by cyclosporine A. Comparison with the effects of two anti-inflammatory bis-benzimidazoles. Am J Pathol 142:1227-37 |
| Geratz, J D; Tidwell, R R; Lombardy, R J et al. (1991) Streptococcal cell wall-induced systemic disease. Beneficial effects of trans-bis(5-amidino-2-benzimidazolyl)ethene, a novel, macrophage-directed anti-inflammatory agent. Am J Pathol 139:921-31 |
| Geratz, J D; Tidwell, R R; Schwab, J H et al. (1990) Sequential events in the pathogenesis of streptococcal cell wall-induced arthritis and their modulation by bis(5-amidino-2-benzimidazolyl)methane (BABIM). Am J Pathol 136:909-21 |
