Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonhuman primates have been used as models for testing the role of interleukin-1 (IL-1) in inflammatory diseases, including endotoxemia. The objective of this investigation was to develop a reproducible and rapid method for in vivo evaluation of IL-1 antagonists using cynomolgus monkeys. IL-1 alone can induce many of the symptoms of endotoxemia in monkeys including fever, loss of appetite, and lethargy, however, test animals are slow to recover and may become desensitized to IL-1. We have developed an ex vivo method using whole blood for analysis of IL-1 antagonists administered in vivo to the monkeys and report here results for the naturally occurring IL-1 receptor antagonist, IL-1ra. In this procedure, animals are given an i.v. infusion of IL-1ra, and blood samples are taken preinfusion and during the infusion. The samples are incubated with or without IL-1 beta and the subsequent ex vivo induction of IL-6 determined. This allows analysis of the effects of in vivo pharmacodynamics on the efficacy of antagonists without exposing the test animals to IL-1. In this ex vivo protocol, each animal serves as its own control, eliminating from the assessment the large animal to animal variation observed with in vivo responses. By testing various doses, we estimate that 50% inhibition of IL-1 induced IL-6 can be achieved with an infusion of IL-1ra at 5 micrograms/kg/15 min. This method allows simple and efficient analysis of inhibitors and antagonists of IL-1 and, potentially, other effectors.
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PMID:An ex vivo method for studying inflammation in cynomolgus monkeys: analysis of interleukin-1 receptor antagonist. 895 81

This study examined the role of the interleukin-1 (IL-1) type I receptor (IL-1RtI) in the acute phase response (APR) to inflammation in mice. Turpentine (100 microliters/mouse) injected subcutaneously induced fever, lethargy, body weight loss, and anorexia in IL-1RtI wild-type mice. Knockout mice lacking the IL-1RtI were resistant to these effects of turpentine, supporting a role for this receptor in the APR to local inflammation. The intraperitoneal injection of a low (50 micrograms/kg) or high (2.5 mg/kg) dose of lipopolysaccharide (LPS) induced similar APRs in IL-1RtI wild-type and knockout mice. IL-1RtI knockout mice were resistant to the APR induced by peripherally injected murine IL-1 beta, suggesting that it is not the interaction of endogenous IL-1 beta with IL-1RtII that induces an APR to LPS in these mice. We speculate that the absence of IL-1RtI in these knockout mice results in the sensitization of other cytokine pathways to mediate the APR to LPS.
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PMID:IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice. 899 68