A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.

Abstract

BACKGROUND:

Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome.

METHODS:

In a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 microg of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times.

RESULTS:

In subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 microg, p < .05). Tumor necrosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531.

CONCLUSIONS:

E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.

• Authors: E Bunnell, M Lynn, K Habet, A Neumann, C A Perdomo, L T Friedhoff, S L Rogers, J E Parrillo
• Journal: Critical care medicine (Crit Care Med) Vol. 28 Issue 8 Pg. 2713-20 (Aug 2000) ISSN: 0090-3493 [Print] United States
• PMID: 10966240 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Lipid A
• Lipopolysaccharides
• E 5531

Topics

• Adolescent
• Adult
• Double-Blind Method
• Endotoxemia (blood, drug therapy)
• Humans
• Lipid A (analogs & derivatives, therapeutic use)
• Lipopolysaccharides (antagonists & inhibitors)
• Male