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The Ability of Filgrastim to Mitigate Mortality Following LD50/60 Total-body Irradiation Is Administration Time-Dependent
Open accessAbstract
The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 h following total body irradiation in a non-human primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gy, (target lethal dose 50/60) delivered at 0.80 Gy min, using linear accelerator-derived 6 MV photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg d) or the control (5% dextrose in water) was administered subcutaneously daily through effect (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 h post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 h after irradiation, did not improve survival (2.5% increase, p = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure.
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Subsequent studies have shown a loss in Neupogen effectiveness when treatment initiation was extended to 48 hours post-exposure (e.g., 2.5% increase, p = 0.8230).
“Subsequent studies have shown a loss in effectiveness when treatment initiation was extended to 48-h post-exposure (e.g., 2.5% increase, p = 08,230) (Farese et al., 2014) as well as in the absence of whole blood transfusions (31% versus 36% survival in the Neupogen® versus control arms, respectively) (Gluzman-Poltorak et al., 2014).”
From Medical countermeasures for the hematopoietic-subsyndrome of acute radiation syndrome in space (2022) · cites this paper as Farese et al., 2014
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Filgrastim improves survival in lethally irradiated nonhuman primates
Farese, A. M., Cohen, M. V., Katz, B. P., Smith, C. P., Gibbs, A., Cohen, D. M., & MacVittie, T. J. (2013) · Radiation Research · doi:10.1667/rr3049.1 · Cited by 187
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Singh, V. K., Newman, V. L., Berg, A. N., & MacVittie, T. J. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1023290 · Cited by 139
Self-citationPegfilgrastim improves survival of lethally irradiated nonhuman primates
Hankey, K. G., Farese, A. M., Blaauw, E. C., Gibbs, A. M., Smith, C. P., Katz, B. P., Tong, Y., Prado, K. L., & MacVittie, T. J. (2015) · Radiation Research · doi:10.1667/rr13940.1 · Cited by 129
Self-citationMedical countermeasures for the hematopoietic-subsyndrome of acute radiation syndrome in space
Kernagis, D. N., Balcer-Kubiczek, E., Bazyar, S., Orschell, C. M., & Jackson, I. L. (2022) · Life Sciences in Space Research · doi:10.1016/j.lssr.2022.06.002 · Cited by 16
Metadata
- Authors
- Farese, A. M., Brown, C. R., Smith, C. P., Gibbs, A. M., Katz, B. P., Johnson, C. S., Prado, K. L., & MacVittie, T. J.
- Affiliations
- University of Maryland, Baltimore (US)
- Indiana University Indianapolis (US)
- Corresponding author
- Farese, Ann M.
- Brown, Cassandra R.
- Smith, Cassandra P.
- Gibbs, Allison M.
- Prado, Karl L.
- MacVittie, Thomas J.
- Venue
- Health Physics
- Published
- 2014-01
- Volume
- 106
- Issue
- 1
- Pages
- 39-47
- ISSN
- 0017-9078 (ISSN-L)
- PMC
- PMC3888641
- OpenAlex
- W2327499930
- Cited by
- 56
- References
- 1
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 2
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Health Physics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001108)
- National Institute of Allergy and Infectious Diseases (HHSN272201000046C)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiation Dose and Imaging
- Keywords
- filgrastim, total body irradiation, radiation sickness, hematopoietic syndrome, medical countermeasures, administration timing, survival, neutropenia, nonhuman primate model, radiation lethality
- MeSH terms
- Filgrastim, Animals, Blood Platelets, Erythrocytes, Lethal Dose 50, Macaca mulatta, Male, Neutrophils, Recombinant Proteins, Time Factors, Whole-Body Irradiation, Survival Rate, Granulocyte Colony-Stimulating Factor
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