Active clinical trials for "Endotoxemia"

The purpose of this study is to determine whether a phospholipid emulsion is effective in the treatment of chronic endotoxemia in hemodialysis patients.

Oxygen is a widely available gas that is cheap, easy to get and extensively used in medicine. From animal studies it has become apparent that increasing or lowering the degree of oxygen in the blood, the inflammatory response can be altered. We will investigate of this is also true in humans by increasing, lowering or keeping oxygen levels normal while giving healthy subjects a short inflammatory stimulus.

The human body knows a biphasic immunological reaction to sepsis. First, the pro-inflammatory reaction takes place, marked by the release of pro-inflammatory cytokines like TNF-α, as a reaction to the bacterial toxins. Secondly, the counter regulatory anti-inflammatory reaction arises. This phase is acting as negative feedback on the inflammation by inhibition of the pro-inflammatory cytokines. This is called "immunoparalysis", a pronounced immunosuppressive state, which renders patients vulnerable to opportunistic infections. Most of the septic patients survive the initial pro-inflammatory phase, but die during this second stage.Research in the past has shown that immunostimulatory therapy with GM-CSF or IFN-γ has promising effects on the pro-inflammatory reaction during immunoparalysis ex vivo. Both drugs are known for their immunostimulatory effects. Recent pilot studies have showed in septic patients, that long-lasting monocyte deactivation in sepsis ex vivo can be reversed by these two immunostimulants. However, the mechanism and extent of immunoparalysis recovery may be different between the two compounds. Previously it has been shown that human endotoxemia (induced by LPS), leads to marked immunosuppression in healthy individuals, characterized by a transient refractory state to a subsequent LPS challenge (endotoxin tolerance). Consequently, human endotoxemia can serve as a standardized, controlled model for sepsis-induced immunoparalysis. Until now, all studies have focused on the ex vivo tolerance. However, we have recently proved, that the ex vivo condition is not completely representative for the in vivo situation. Ex vivo, leukocyte tolerance to LPS resolves within one day, while the in vivo immunoparalysis persists for two weeks. In this project, we will investigate the effects of both GM-CSF and IFN-γ in a parallel double-blind placebo controlled randomized manner on the immunoparalysis following human endotoxemia, both in-vitro and in vivo. As a result, we hope to get more insight in the pathophysiology of sepsis-induced immunoparalysis and thereby develop new immunostimulatory therapies that improve patient outcome

The purpose of this study is to determine whether probiotic treatment of overweight volunteers consuming high fat diet is able to reduce plasma lipopolysaccharide concentration.

The purpose of this study is to assess the effect of the anti-hepcidin Spiegelmer NOX-H94 on iron homeostasis during systemic inflammation induced by endotoxin. In the human endotoxemia model, intravenously administered lipopolysaccharide elicits an inflammatory response with release of pro-inflammatory cytokines, such as IL-6 and TNF-alfa, with subsequent induction of hepcidin. As a consequence of hepcidin induction, serum iron concentrations decrease. This study in healthy subjects investigates the capacity of NOX-H94 to inactivate hepcidin and to prevent serum iron decrease in a pathophysiological model prior to studying the efficacy of NOX-H94 in patients with anemia of chronic disease.

Excessive inflammation, production of free radicals and vascular injury are considered the main contributors to the development of organ dysfunction in patients with severe infections and sepsis. The endogenously produced unconjugated bilirubin is one of the most powerful anti-oxidants of the human body and the administration of bilirubin in animal experiments has been shown to protect from inflammation-induced death. However, bilirubin for human administration is not yet available. Therefore, we wish to exploit one of the side effects of atazanavir, a registered drug currently used as a protease inhibitor in HIV infected patients. Atazanavir inhibits the enzyme UPD glucuronosyl transferase enzyme (UGT1A1) and therefore increases endogenously produced bilirubin levels moderately. To study the effect of hyperbilirubinemia during inflammation we will apply the human endotoxemia model. The human endotoxemia model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting. We hypothesize that atazanavir-induced hyperbilirubinemia has beneficial anti-inflammatory and vascular effects during human endotoxemia.

Vorapaxar is a recently approved protease activated receptor - 1 (PAR-1) inhibitor. Platelet inhibition may also exert positive results on coagulation activation and may beneficially influence the inflammatory response. Since vorapaxar is the first available substance of a new class of platelet inhibitors its effects on the human coagulation system and the inflammatory response will be assessed in the well-established human endotoxemia model.

Rationale: The vagus nerve exerts an anti-inflammatory effect in in vitro and animal experiments. This 'vagal anti-inflammatory pathway' is mediated by the nicotinergic α7nACh receptor that can be selectively stimulated by GTS-21. Activation of the cholinergic anti-inflammatory pathway via vagus nerve stimulation or α7nAChR agonists improves outcome in animal models of endotoxemia, sepsis and experimental arthritis. Up to now, the anti-inflammatory effects of oral administration of GTS-21 in humans in vivo has not been investigated. Objective: Primary aim: to investigate the anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response in the human endotoxemia model and the subsequent inflammation-induced subclinical organ dysfunction. Secondary aim: to measure the effect of LPS administration in the absence or presence of GTS-21 in human volunteers on vagal nerve activity measured by heart rate variability analysis. Study design: Double-blind placebo-controlled randomized cross-over intervention study in healthy human volunteers during experimental endotoxemia. Study population: Non-smoking healthy male volunteers, age 18-35 yrs Intervention: Subjects will be tested in a cross-over design in 2 separate sequential sessions, 2-4 weeks apart. A total of 12 subjects will be randomly assigned to one of two dosing groups in a 1:1 ratio: GTS-21 followed by Placebo n=6, Placebo followed by GTS-21 n=6. Subjects will receive 150mg GTS-21 or placebo orally tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 or placebo the morning of the day of LPS administration (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0). Before LPS injection, prehydration will be performed by infusion of 1.5 L 2.5% glucose/0.45% saline solution in 1 hour. One hour after the last dose of GTS-21 or placebo, LPS derived from E coli O:113 will be injected (2 ng/kg iv in 1 minute). There will be a 14 day washout period for patients in all groups. The last group of subjects will be subjected to an identical dose of LPS and placebo at two different moments 2-4 weeks apart to obtain time controls. Main study parameters/endpoints: Main study endpoint is the concentration of circulating cytokines after LPS in the absence and presence of GTS-21. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: A medical interview and physical examination is part of this study. Approximately 350 ml blood will be withdrawn and urine will be collected. There will be mild discomfort associated with participation in this study, as LPS induces flu-like symptoms for approximately 4 hrs. GTS-21 was found to be well tolerated at a dose of 150 mg three times daily (450 mg/day).

To compare the safety and efficacy of the PMX cartridge based on mortality at 28-days in subjects with septic shock who have high levels of endotoxin and are treated with standard medical care plus use of the PMX cartridge, versus subjects who receive standard medical care alone.

The purpose of this study is to determine the effects of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia.