Abstract
In septic shock, iNOS activation and nitric oxide (NO) overproduction contribute to vascular hyporeactivity to adrenergic vasopressors. The consequent hypotension often necessitates high doses of catecholamine administration. However, this may lead to detrimental effects on tissue perfusion, immune function and myocardial function. Asymmetric dimethlyarginine (ADMA), an endogenous inhibitor of NO synthase, is extensively metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Competitive inhibition of the DDAH-1 isoform should thus reverse hypotension but, as this isoform is absent in immune cells, it should not compromise the immune effects of NO. Hence, we investigated whether L257, a novel DDAH-1 inhibitor, could spare norepinephrine dosing in a rat endotoxic shock model.
Highlights
Fibrinolytic shutdown plays a pivotalrole in the pathogenesis of multiple organ dysfunction syndrome (MODS) in disseminated intravascular coagulation (DIC)
Beneficial action is mainly believed through improvement of major antioxidant selenoenzymes, but could on the contrary be related to a therapeutic oxidant action reducing activity of hyperactivated circulating phagocytic cells [4]
It has been suggested that the absence of beneficial effect of high-dose Na SeO continuously administered [2] might be related to toxicity, especially on the lung, of too much selenium (Se) as mentioned in recent parenteral nutrition guidelines in intensive care
Summary
Fibrinolytic shutdown plays a pivotalrole in the pathogenesis of multiple organ dysfunction syndrome (MODS) in disseminated intravascular coagulation (DIC). In a separate set of experiments investigating the MOA, AB103 administration (5 mg/kg, given without antibiotics 2 hours post CLP) was associated with: a reduction in Th-1 cytokine levels in peritoneum (TNFα, IL-3, IL-17 and Rantes) and plasma (IL-3 and IL-6); a reduction in splenocyte proliferation, stimulated ex vivo with anti-CD3 and anti-CD28 antibodies; a reduction in neutrophil recruitment to the spleen, liver and kidney, as determined by MPO activity; and a reduced bacterial load in peritoneum, blood and tissues (kidney, liver, spleen) Conclusion These data demonstrate that attenuation of CD28 signaling is a viable therapeutic approach to the treatment of sepsis. Therapeutic dosing of AZD9773 bid from 24 to 60 hours (schedule/dose/route as previously) did not result in significantly different survival outcomes versus either DigiFab or imipenem alone (n = 60 per group) Conclusion These data demonstrate for the first time that TNFα neutralization in a murine CLP model improves survival in a severe sepsis setting.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
