Radiation countermeasure agents: an update (2011 – 2014)

Abstract

IntroductionDespite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government.Area coveredThis article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period.Expert opinionA number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future.

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

“…In general, mouse models appear quite appropriate for the initial efficacy testing of new radiation countermeasures, as screening protocols are well established and general response patterns documented within radiobiological literature. A large number of radiation countermeasures for ARS have been investigated in murine models (Singh et al 2013(Singh et al , 2014a(Singh et al , 2014bRosen et al 2015). 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.…”

“…Radiomitigators are administered soon after radiation exposure in order to stimulate recovery of injured tissues, but prior to the appearance of overt symptoms. Radiomitigators include immunomodulating agents such as 5-androstenediol, interleukin-12, G-CSF, PEGylated G-CSF, GM-CSF, and CBLB502 (truncated flagellin), as well as and angiotensin-converting enzyme inhibitors (ACE; captopril) (Seed 2005;Dumont et al 2010;Singh et al 2012Singh et al , 2014aMoulder 2014). Radiation therapeutics are agents administered once symptoms manifest in order to accelerate regeneration of tissue and organs Wagemaker et al 1998;Farese et al 2001Farese et al , 2013Drouet et al 2004;Herodin et al 2007;Dumont et al 2010).…”

Radiation Countermeasures: Current Status

“…GranulocyteColony Stimulating Factor (G-CSF) and GranulocyteMonocyte-Colony Stimulating Factor (GM-CSF) are likely to receive FDA approval 15 in near future. G-CSF provides protection against radiation induced hematopoietic as well as gastrointestinal injuries and testicular dysfunction [16][17] .…”

“…G-CSF stimulate different progenitor cells such as lymphoid progenitor, erythroid progenitor, basophil progenitor and eosinophil progenitors which further give rise to lymphocyte, erythrocyte, basophils, respectively 18 . The efficacy of G-CSF has been evaluated in mice, canines (beagle), NHPs and mini pigs 15 . Survivability and radioprotection has been improved by G-CSF across species 18,19 .…”

Excellence is the Real Enemy of Practicality! Relevance to Radiation Countermeasure Development

“…Since from 1959, hundreds of chemical and natural compounds have been evaluated for their radioprotective activities in USA and other parts of world including Europe and Russia. However, US scientists have taken lead in radiation countermeasure development [43][44][45] resulted eight molecules have been granted IND status and another four are under advance stage of development as shown in Fig. 5.…”