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The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.
- Source :
-
PloS one [PLoS One] 2015 Sep 14; Vol. 10 (9), pp. e0135388. Date of Electronic Publication: 2015 Sep 14 (Print Publication: 2015). - Publication Year :
- 2015
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Abstract
- There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.
- Subjects :
- Animals
Bone Marrow drug effects
Bone Marrow radiation effects
Female
Hematopoiesis
Intestinal Mucosa drug effects
Intestinal Mucosa radiation effects
Macaca mulatta
Male
Peptides administration & dosage
Peptides pharmacology
Radiation-Protective Agents administration & dosage
Radiation-Protective Agents pharmacology
Acute Radiation Syndrome drug therapy
Peptides therapeutic use
Radiation-Protective Agents therapeutic use
Toll-Like Receptor 5 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26367124
- Full Text :
- https://doi.org/10.1371/journal.pone.0135388