Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate.

Abstract

BACKGROUND:

The triggering receptor expressed on myeloid cells-1 is an immunoreceptor that amplifies the inflammatory response mediated by toll-like receptors engagement. Triggering receptor expressed on myeloid cells-1 inhibitory peptides such LR12 have been shown to prevent hyperresponsiveness and death in several experimental models of septic shock.

METHODS:

Twelve adult male Cynomolgus (Macaca fascicularis) monkeys exposed to an intravenous bolus of endotoxin (10 μg/kg) were randomized to receive LR12 or placebo (n = 6 per group) as an initial intravenous bolus followed by an 8-h continuous intravenous infusion. An additional group of four only received vehicle infusion. Vital signs were monitored for 8 h. Blood was sampled at H0, 1, 2, 4, and 8 for analysis of clinical chemistries, leukocyte count, coagulation parameters, and cytokine plasma concentration.

RESULTS:

LR12 showed no effect on heart rate and body temperature. By contrast to the placebo group, which experienced a 25 to 40% blood pressure decrease after endotoxin administration, LR12-treated monkeys remained normotensive. Endotoxin induced leukopenia at 2 h (mean leukocyte count, 7.62 g/l vs. 21.1 at H0), which was attenuated by LR12. LR12 also attenuated cytokine production.

CONCLUSIONS:

The triggering receptor expressed on myeloid cells-1 inhibitor LR12 is able to mitigate endotoxin-associated clinical and biological alterations, with no obvious side effects. This study paves the way for future phases Ia and Ib trials in humans.

• Authors: Marc Derive, Amir Boufenzer, Sébastien Gibot
• Journal: Anesthesiology (Anesthesiology) Vol. 120 Issue 4 Pg. 935-42 (Apr 2014) ISSN: 1528-1175 [Electronic] United States
• PMID: 24270127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Lauric Acids
• Oligopeptides
• Rhodamines
• nangibotide

Topics

• Animals
• Blood Pressure (drug effects)
• Disease Models, Animal
• Endotoxins (blood)
• Injections, Intravenous
• Lauric Acids (administration & dosage, blood, pharmacokinetics)
• Leukopenia (blood, chemically induced, drug therapy)
• Macaca fascicularis
• Male
• Myeloid Cells (metabolism)
• Oligopeptides
• Random Allocation
• Rhodamines (administration & dosage, blood, pharmacokinetics)
• Shock, Septic (blood, chemically induced, drug therapy)