A pilot study in rhesus macaques to assess the treatment efficacy of a small molecular weight catalytic metalloporphyrin antioxidant (AEOL 10150) in mitigating radiation-induced lung damage.

Abstract

The objective of this pilot study was to explore whether administration of a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy of whole thorax lung irradiation in a non-human primate model. Thirteen animals were irradiated with a single exposure of 11.5 Gy, prescribed to midplane, and delivered with 6 MV photons at a dose rate of 0.8 Gy min. Beginning at 24 h post irradiation, the AEOL 10150 cohort (n = 7) received daily subcutaneous injections of the catalytic antioxidant at a concentration of 5 mg kg for a total of 4 wk. All animals received medical management, including dexamethasone, based on clinical signs during the planned 180-d in-life phase of the study. All decedent study animals were euthanized for failure to maintain saturation of peripheral oxygen > 88% on room air. Exposure of the whole thorax to 11.5 Gy resulted in radiation-induced lung injury in all animals. AEOL 10150, as administered in this pilot study, demonstrated potential efficacy as a mitigator against fatal radiation-induced lung injury. Treatment with the drug resulted in 28.6% survival following exposure to a radiation dose that proved to be 100% fatal in the control cohort (n = 6). Computed tomography scans demonstrated less quantitative radiographic injury (pneumonitis, fibrosis, effusions) in the AEOL 10150-treated cohort at day 60 post-exposure, and AEOL 10150-treated animals required less dexamethasone support during the in-life phase of the study. Analysis of serial plasma samples suggested that AEOL 10150 treatment led to lower relative transforming growth factor-Beta-1 levels when compared with the control animals. The results of this pilot study demonstrate that treatment with AEOL 10150 results in reduced clinical, radiographic, anatomic, and molecular evidence of radiation-induced lung injury and merits further study as a medical countermeasure against radiation-induced pulmonary injury.

• Authors: Michael C Garofalo, Amanda A Ward, Ann M Farese, Alexander Bennett, Cheryl Taylor-Howell, Wanchang Cui, Allison Gibbs, Karl L Prado, Thomas J MacVittie
• Journal: Health physics (Health Phys) Vol. 106 Issue 1 Pg. 73-83 (Jan 2014) ISSN: 1538-5159 [Electronic] United States
• PMID: 24276551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• AEOL 10150
• Antioxidants
• Metalloporphyrins
• Radiation-Protective Agents
• Transforming Growth Factor beta1
• Dexamethasone
• Oxygen

Topics

• Animals
• Antioxidants (administration & dosage, chemistry, pharmacology, therapeutic use)
• Catalysis
• Dexamethasone (pharmacology)
• Lung (drug effects, pathology, physiopathology, radiation effects)
• Macaca mulatta
• Male
• Metalloporphyrins (administration & dosage, chemistry, pharmacology, therapeutic use)
• Molecular Weight
• Oxygen (metabolism)
• Pilot Projects
• Radiation Injuries, Experimental (blood, drug therapy, pathology, physiopathology)
• Radiation Pneumonitis (blood, drug therapy, pathology, physiopathology)
• Radiation-Protective Agents (administration & dosage, chemistry, pharmacology, therapeutic use)
• Respiration (drug effects, radiation effects)
• Survival Rate
• Tomography, X-Ray Computed
• Transforming Growth Factor beta1 (blood)