The D-penicillamine-induced autoimmune syndrome observed in Brown Norway (BN) rats is similar to an idiosyncratic reaction seen in some patients. We have previously shown that pretreatment of BN rats with aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and misoprostol, a prostaglandin E (PGE) analog, completely prevented the development of D-penicillamine-induced autoimmunity. In an effort to further understand the role of arachidonic acid metabolism and iNOS in the pathogenesis of D-penicillamine-induced autoimmunity we had 3 objectives: (1) to test whether aminoguanidine and misoprostol could reverse D-penicillamine-induced autoimmunity; (2) whether BN rats that had previously developed D-penicillamine-induced autoimmunity could be protected on re-challenge with drug by pretreatment with aminoguanidine and misoprostol and (3) whether non-steroidal anti-inflammatory drugs, which inhibit PGE synthesis, would potentiate D-penicillamine-induced autoimmunity. We found that neither aminoguanidine nor misoprostol had any significant effect on the speed of recovery from D-penicillamine-induced autoimmunity. Prevention of disease on re-challenge after a 4 week recovery was less effective than on initial treatment with 7/8 animals pretreated with aminoguanidine getting sick again, while only 5/13 animals pretreated with misoprostol became ill. The effect of aminoguanidine was not significantly different from control (16/17) but that of misoprostol was (P=0.002). A single dose of the non-selective cyclooxygenase (COX) inhibitor, ketoprofen, decreased the time to onset of D-penicillamine-induced autoimmunity and continuous treatment significantly increased the incidence (P=0.024). Diclofenac, which is more selective, did not have a significant effect, and one dose of the selective inhibitor, rofecoxib, actually appeared to lower the incidence of D-penicillamine-induced autoimmunity (P=0.001). In this animal model of drug-induced autoimmunity, non-selective COX inhibitors appear to increase the incidence of disease. However, once the reaction occurs, prostaglandins are not effective for treatment and are only partially protective in an already sensitized animal.

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http://dx.doi.org/10.1016/s0300-483x(03)00160-4DOI Listing

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