Methods: The five in vivo studies outsourced were the conscious d

Methods: The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic

cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model. Results: The results obtained indicated that each of the studies could be performed with comparable statistical power HM781-36B research buy and could achieve a similar outcome, independent of facility. Discussion: The consistency of results obtained from these models across multiple facilities was high thus providing Selonsertib confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B. (C) 2013 Elsevier Inc. All rights

“Objectives: To review evidence supporting the involvement of interleukin-6 in the pathophysiology of anemia of chronic disease, to discuss the possible molecular mechanisms driving this condition in patients with end-stage renal disease and rheumatoid arthritis, and to review clinical manifestations in these patients.

Methods: A literature search was performed using MEDLINE and the reference lists check details of relevant review articles. The following keywords were used in the MEDLINE search: interleukin-6, “”anemia of chronic disease”" OR “”anemia of inflammation,”" “”pathophysiology,”" “”end-stage renal disease,”" and “”rheumatoid

arthritis.”" The search was limited to English-language articles.

Results: Interleukin-6 is a multifunctional cytokine that regulates the hepatic acute-phase response, the immune response, inflammation, and hematopoiesis. Interleukin-6 appears to be the central mediator of anemia of chronic disease in a range of inflammatory diseases, including end-stage renal disease and rheumatoid arthritis, through increased generation of hepcidin and the resultant alterations in iron metabolism. Clinically, patients with anemia of chronic disease are more likely to experience increased disease severity and duration than patients who have chronic disease without anemia.

Conclusions: The integral role of interleukin-6 in the pathogenesis of anemia of chronic disease suggests that it could be an important therapeutic target. Currently available treatments target interleukin-1, and tumor necrosis factor-alpha and its receptors, and have been only partially successful. Given the complexity of the cytokine pathways that are involved in the pathogenesis of inflammatory disease, further studies are required to test other molecular targets. (C) 2009 Elsevier Inc. All rights reserved.

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