title: Low-dose polymyxin: an option for therapy of Gram-negative sepsis.
abstract: Endotoxins are the major components of the outer membrane of most Gram-negative bacteria and are one of the main targets in inflammatory diseases. The presence of endotoxins in blood can provoke septic shock in case of pronounced immune response. Here we show in vitro inactivation of endotoxins by polymyxin B (PMB). The inflammatory activity of the LPS-PMB complex in blood was examined in vitro in freshly drawn blood samples. Plasma protein binding of PMB was determined by ultracentrifugation using membranes with different molecular cut-offs, and PMB clearance during dialysis was calculated after in vitro experiments using the AV1000S filter. The formed LPS-PMB complex has lower inflammatory activity in blood, which results in highly reduced cytokine secretion. According to in vitro measurements, the appropriate plasma level of PMB for LPS inactivation is between 100 and 200 ng/ml. Furthermore, the combination of cytokine removal by adsorbent treatment with LPS inactivation by PMB dosage leads to strong suppression of inflammatory effects in blood in an in vitro model. Inactivation of endotoxins by low-dose intravenous PMB infusion or infusion into the extracorporeal circuit during blood purification can be applied to overcome the urgent need for endotoxin elimination not only in treatment of sepsis, but also in liver failure.
authors.affiliation: Department for Health Sciences and Biomedicine, Danube University Krems, Krems, Austria Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria stephan.harm@donau-uni.ac.at.
authors.forename: Stephan
authors.initials: S
authors.lastname: Harm
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Gabor
authors.affiliation: Department for Health Sciences and Biomedicine, Danube University Krems, Krems, Austria.
authors.forename: Jens
authors.initials: J
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000627:therapeutic use; D001691:Biological Therapy / Q000639:trends; D001773:Blood Cells / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000378:metabolism*; D016905:Gram-Negative Bacterial Infections / Q000150:complications / Q000276:immunology* / Q000628:therapy; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D017093:Liver Failure / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D011112:Polymyxin B / Q000378:metabolism* / Q000627:therapeutic use; D011485:Protein Binding; D006435:Renal Dialysis / Q000379:methods; D018805:Sepsis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D011112:Polymyxin B
keywords: Inflammation; Polymyxin; cytokines; endotoxin; lipopolysaccharide; sepsis