The detonation by a terrorist of an improvised nuclear device would expose hundreds of thousands of citizens to acute radiation syndrome (ARS), which untreated leads to death. There are currently no approved drugs available for the prevention or treatment of ARS. Effective drugs with acceptable safety profiles that can be easily stored and self-administered and which have a long shelf life are a high priority for development. Humanetics will develop BIO 600, a simple and stable aminothiol, as a drug that can be given prior to radiation exposure to prevent lethal effects and/or that can act as a therapeutic following exposure. In addition to research performed by Humanetics, others have documented a radioprotective effect with BIO 600. It is orally bioavailable, stable at room temperature, a potent antioxidant and has a favorable and tested safety profile in humans. BIO 600 has the potential to be a truly effective and safe medical radiation countermeasure that might ultimately rescue hundreds of thousands of people from death due to the lethal effects of ARS. The damage to the hematopoietic system by whole body radiation exposure is the result of oxidative damage and the onset of apoptosis in hematopoietic stem cell lines. For the past two years Humanetics has been involved in a program to discover safe and potentially effective antioxidant drug candidates that also inhibit apoptosis thereby preventing the hematopoietic syndrome of ARS. Using a bioassay that utilizes murine intestinal crypt stem cells, a series of candidate compounds were screened for their ability to promote stem cell survival after irradiation. We have discovered that treatment with BIO 600 results in a dramatic 5-fold greater decrease in apoptosis compared to the irradiation only group and a 3-fold greater decrease when compared to amifostine, a well-known radioprotectant. Here in Phase I we will assess the compound's efficacy as a medical radiation countermeasure. A series of experiments will be conducted to document BIO 600's ability to improve survival versus placebo in an LD90/30 murine irradiation model for BIO 600 given prior to exposure and as a therapeutic following exposure (Specific aims 1 and 2). In Aim 3 we will focus on determining the therapeutic blood levels and pharmacokinetics and the calculation of the dose reduction factor (DRF). In Phase II we will complete the efficacy studies in small and large animals under the guidelines of the FDA Animal Rule and the clinical safety studies needed for the filing of a New Drug Application (NDA) with the FDA. The goal of the Phase I and Phase II research is to document the safety and efficacy of BIO 600 in order to go towards FDA approval for the drug as a medical radiation countermeasure for ARS.
Public Health Relevance: The detonation by a terrorist of an improvised nuclear device in a crowded urban area would expose hundreds of thousands of citizens to acute radiation syndrome (ARS) which untreated leads to death. There are currently no approved drugs available for the prevention or treatment of ARS. Humanetics is working to develop the small stable molecule BIO 600 as a radioprotective countermeasure to protect people from death due to the lethal effects of ARS.
Public Health Relevance Statement: Project Narrative The detonation by a terrorist of an improvised nuclear device in a crowded urban area would expose hundreds of thousands of citizens to acute radiation syndrome (ARS) which untreated leads to death. There are currently no approved drugs available for the prevention or treatment of ARS. Humanetics is working to develop the small stable molecule BIO 600 as a radioprotective countermeasure to protect people from death due to the lethal effects of ARS.
NIH Spending Category: Biodefense; Emerging Infectious Diseases; Infectious Diseases; Prevention; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human
Project Terms: 2-Aminoethanethiol; 5-BrdU; 5-Bromo-2'-deoxyuridine; 5-Bromodeoxyuridine; 5-Bromouracil deoxyriboside; 5-Bromouracil-2-deoxyriboside; 5-Budr; APAETP; Acute; Alza Brand of Amifostine; Amifostine; Aminopropylaminoethylthiophosphoric Acid; Animals; Antioxidants; Apoptosis; Apoptosis Pathway; Assay; BUdR; Bioassay; Bioavailable; Biologic Assays; Biological Assay; Blood; Blood Plasma; Blood Precursor Cell; BrdU; Bromodeoxyuridine; Bromodeoxyuridine (BUDR); Bromouracil Deoxyriboside; Broxuridine; Cell Death, Programmed; Cell Line; Cell Lines, Strains; Cell Survival; Cell Viability; CellLine; Cessation of life; Characteristics; Clinical; Crowding; Cysteamine; Cysteinamine; Cystinosis; Death; Development; Devices; Dose; Drug Approval; Drug Kinetics; Drugs; Essex Brand of Amifostine; Ethanethiol, 2-((3-aminopropyl)amino)-, dihydrogen phosphate (ester); Ethanethiol, 2-amino-; Ethiofos; Ethyol; Evaluation; Evaluation Research; Exposure to; Food and Drug Administration Drug Approval; Frequencies (time pattern); Frequency; Gammaphos; Goals; Guidelines; Hematologic Body System; Hematopoietic; Hematopoietic Body System; Hematopoietic System; Hematopoietic stem cells; Human; Human, General; Killings; Life; Lilly Brand of Amifostine; Mammals, Mice; Man (Taxonomy); Man, Modern; Medical; Medication; Mercamine; Mercaptamine; Mice; Microscopic; Modeling; Mother Cells; Murine; Mus; Nuclear; Oral; Organ System, Hematologic; Orphan Drugs; PBO; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Placebos; Plasma; Prevention; Process; Progenitor Cells; Progenitor Cells, Hematopoietic; Programs (PT); Programs [Publication Type]; Radiation; Radiation Syndromes; Radiation, Whole-Body; Relative; Relative (related person); Research; Research, Evaluation; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; S-(N-(3-Aminopropyl)-2-aminoethyl)thiophosphoric Acid; Safety; Schering-Plough Brand of Amifostine; Screening procedure; Self-Administered; Series; Serum, Plasma; Sham Treatment; Staining method; Stainings; Stains; Stem cells; Syndrome; Syndromes, Radiation; System; System, LOINC Axis 4; Temperature; Therapeutic; Therapeutic Studies; Therapy Research; Time; Total Body Irradiation; US Bioscience Brand of Amifostine; Uridine, 5-bromo-2'-deoxy-; Whole-Body Irradiation; Work; aminothiol; animal rule; anti-oxidant; base; beta-Mercaptoethylamine; cultured cell line; cystine storage disease; drug candidate; drug/agent; experiment; experimental research; experimental study; improved; intestinal crypt; irradiation; knowledge base; oxidative damage; pre-clinical; preclinical; prevent; preventing; programs; public health relevance; ray (radiation); research study; safety study; safety testing; screening; screenings; sham therapy; urban area
