Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice

Elliott, Thomas B.; Bolduc, David L.; Ledney, G D; Kiang, Juliann G.; Fatanmi, Oluseyi O.; Wise, Stephen Y.; Romaine, Patricia L. P.; Newman, Victoria L.; Singh, Vijay K.

doi:10.3109/09553002.2015.1054526

Cited by 16 publications

(12 citation statements)

References 51 publications

(61 reference statements)

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“…The treatment also improved body weight, numbers of platelets, neutrophils, eosinophils, spleen weights and numbers of splenocytes only after combined injury (24). The efficacy was independent of gentamicin and levofloxacin (25). Unlike other effective therapeutics for combined injury, including mesenchymal stem cells (26, 27), ghrelin (28) and ciprofloxacin (29–31), which are capable of accelerating wound healing, Alxn4100TPO lacks this capability (24).…”

Section: Introductionmentioning

confidence: 99%

Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma

et al. 2017

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Exposure to ionizing radiation alone or combined with traumatic tissue injury is a crucial life-threatening factor in nuclear and radiological incidents. Radiation injuries occur at the molecular, cellular, tissue and systemic levels; their mechanisms, however, remain largely unclear. Exposure to radiation combined with skin wounding, bacterial infection or burns results in greater mortality than radiation exposure alone in dogs, pigs, rats, guinea pigs and mice. In the current study we observed that B6D2F1/J female mice exposed to 60Co gamma-photon radiation followed by 15% total-body-surface-area skin wounds experienced an increment of 25% higher mortality over a 30-day observation period compared to those subjected to radiation alone. Radiation exposure delayed wound healing by approximately 14 days. On day 30 post-injury, bone marrow and ileum in animals from both groups (radiation alone or combined injury) still displayed low cellularity and structural damage. White blood cell counts, e.g., neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets, still remained very low in surviving irradiated alone animals, whereas only the lymphocyte count was low in surviving combined injury animals. Likewise, in surviving animals from radiation alone and combined injury groups, the RBCs, hemoglobin, hematocrit and platelets remained low. We observed, that animals treated with both pegylated G-CSF (a cytokine for neutrophil maturation and mobilization) and Alxn4100TPO (a thrombopoietin receptor agonist) at 4 h postirradiation, a 95% survival (vehicle: 60%) over the 30-day period, along with mitigated body-weight loss and significantly reduced acute radiation syndrome. In animals that received combined treatment of radiation and injury that received pegylated G-CSF and Alxn4100TPO, survival was increased from 35% to 55%, but did not accelerate wound healing. Hematopoiesis and ileum showed significant improvement in animals from both groups (irradiation alone and combined injury) when treated with pegylated G-CSF and Alxn4100TPO. Treatment with pegylated G-CSF alone increased survival after irradiation alone and combined injury by 33% and 15%, respectively, and further delayed wound healing, but increased WBC, RBC and platelet counts after irradiation alone, and only RBCs and platelets after combined injury. Treatment with Alxn4100TPO alone increased survival after both irradiation alone and combined injury by 4 and 23%, respectively, and delayed wound healing after combined injury, but increased RBCs, hemoglobin concentrations, hematocrit values and platelets after irradiation alone and only platelets after combined injury. Taken together, the results suggest that combined treatment with pegylated G-CSF and Alxn4100TPO is effective for mitigating effects of both radiation alone and in combination with injury.

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Section: Introductionmentioning

confidence: 99%

Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma

et al. 2017

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“…Interestingly, with radiation alone, ciprofloxacin delayed onset of mortality, but by 30 days, did not improve survival, suggesting interplay between the effects of ciprofloxacin and the wound healing response mechanism. This survival benefit is specific to ciprofloxacin, as levofloxacin and amoxicillin administrations did not produce similar results (98). These data make a case for the further exploration of repurposing ciprofloxacin for a radiation combined injury indication.…”

Section: Session Iii: New Indications For Generic Productsmentioning

confidence: 85%

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments

DiCarlo

Cassatt

Dowling³

et al. 2018

Radiation Research

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The risk of a radiological or nuclear public health emergency is a major growing concern of the U.S. government. To address a potential incident and ensure that the government is prepared to respond to any subsequent civilian or military casualties, the U.S. Department of Health and Human Services and the Department of Defense have been charged with the development of medical countermeasures (MCMs) to treat the acute and delayed injuries that can result from radiation exposure. Because of the limited budgets in research and development and the high costs associated with bring promising approaches from the bench through advanced product development activities, and ultimately, to regulatory approval, the U.S. government places a priority on repurposing products for which there already exists relevant safety and other important information concerning their use in humans. Generating human data can be a costly and time-consuming process; therefore, the U.S. government has interest in drugs for which such relevant information has been established (e.g., products for another indication), and in determining if they could be repurposed for use as MCMs to treat radiation injuries as well as chemical and biological insults. To explore these possibilities, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop including U.S. government, industry and academic subject matter experts, to discuss the challenges and benefits of repurposing products for a radiation indication. Topics covered included a discussion of U.S. government efforts (e.g. funding, stockpiling and making products available for study), as well unique regulatory and other challenges faced when repurposing patent protected or generic drugs. Other discussions involved lessons learned from industry on repurposing pre-license, pipeline products within drug development portfolios. This report reviews the information presented, as well as an overview of discussions from the meeting.

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“…The strain differences outlined above suggest that radiation countermeasures should be tested in more than one mouse strain; in terms of countermeasures for ARS, one resistant (C57BL/6 or CD2F1) and another sensitive strain (C3H/HeN or BALB/c) should be tested for other 'delayed-type' response patterns, specific, pathology-susceptible strains need to be considered and utilized in testing. The mouse model has been used to study combined injury (radiation plus wound, burn, or hemorrhage) as well as for the evaluation of countermeasures effective against combined injuries (Kiang et al 2012(Kiang et al , 2014aElliott et al 2015). Efficacy of several radiation countermeasures such as captopril, PEGylated G-CSF, ghrelin, ciprofloxacin etc., has been established using the combined injury model in mice (Jiao et al 2009;Kiang et al 2010Kiang et al , 2014bSwift et al 2015).…”

Section: Micementioning

confidence: 99%

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

Singh

Seed²

2017

International Journal of Radiation Biology

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144

103

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Purpose: The increasing global risk of nuclear and radiological accidents or attacks has driven renewed research interest in developing medical countermeasures to potentially injurious exposures to acute irradiation. Clinical symptoms and signs of a developing acute radiation injury, i.e. the acute radiation syndrome, are grouped into three sub-syndromes named after the dominant organ system affected, namely the hematopoietic, gastrointestinal, and neurovascular systems. The availability of safe and effective countermeasures against the above threats currently represents a significant unmet medical need. This is the first article within a three-part series covering the nature of the radiation subsyndromes, various animal models for radiation countermeasure development, and the agents currently approved by the United States Food and Drug Administration for countering the medical consequences of several of these prominent radiation exposure-associated syndromes. Conclusions: From the U.S. and global perspectives, biomedical research concerning medical countermeasure development is quite robust, largely due to increased government funding following the 9/11 incidence and subsequent rise of terrorist-associated threats. A wide spectrum of radiation countermeasures for specific types of radiation injuries is currently under investigation. However, only a few radiation countermeasures have been fully approved by regulatory agencies for human use during radiological/nuclear contingencies. Additional research effort, with additional funding, clearly will be needed in order to fill this significant, unmet medical health problem. ARTICLE HISTORY

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Combined immunomodulator and antimicrobial therapy eliminates polymicrobial sepsis and modulates cytokine production in combined injured mice

Cited by 16 publications

References 51 publications

Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma

Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

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