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TNF alpha measurement in rat and human whole blood as an in vitro method to assay pyrogens and its inhibition by dexamethasone and erythromycin.

To ensure the safety of potential drugs, pyrogen tests are traditionally performed in rabbits. New methods have been developed as alternatives to the test to reduce the use of experimental animals. Among these methods there are the Limulus amoebocyte lysate test and the determination of cytokine production by human leukocytes and whole blood. When exposed to a range of concentrations of endotoxins, human and rat whole blood release TNFalpha at amounts that are detectable by a commercially available enzyme-linked immunosorbent assay (ELISA). Our results show that the sensitivity of human and rat blood to endotoxins from Salmonella abortus equi and Escherichia coli is similar. In rat blood, TNFalpha was detected after contact with the pyrogens only in fresh blood, collected on the same day of incubation with the pyrogenic substances. The measurement of TNFalpha production would be a reliable alternative to the rabbit pyrogen test. However, given that the addition of erythromycin and dexamethasone inhibited the production of this cytokine, this method is limited when parenteral formulations contain these two drugs. Similar inhibition has been observed in the rabbit test. Additional experiments will be necessary to demonstrate that the rat whole blood test system is useful and reliable for the pyrogens evaluation.