title: Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates.
abstract: The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model. In this study, we evaluated GT3 pharmacokinetics (PK) and efficacy at different doses of cobalt-60 gamma radiation (0.6 Gy/min) using the nonhuman primate (NHP) model. The PK results demonstrated increased area under the curve with increasing drug dose and half-life of GT3. GT3 treatment resulted in reduced group mean neutropenia by 3-5 days and thrombocytopenia by 1-5 days. At 5.8 and 6.5 Gy total-body irradiation, GT3 treatment completely prevented thrombocytopenia. The capability of GT3 to reduce severity and duration of neutropenia and thrombocytopenia was dose dependent; 75 mg/kg treatment was more effective than 37.5 mg/kg treatment after a 5.8 Gy dose. However, the higher GT3 dose (75 mg/kg) was associated with higher frequency of adverse skin effects (small abscess) at the injection site. GT3 treatment of irradiated NHPs caused no significant difference in animal survival at 60 days postirradiation, however, low mortality was observed in irradiated, vehicle-treated groups as well. The data from this pilot study further elucidate the role and pharmacokinetics of GT3 in hematopoietic recovery after irradiation in a NHP model, and demonstrate the potential of GT3 as a promising radioprotector.
authors.affiliation: a   Department of Radiation Biology, F. Edward Hébert School of Medicine, "America's Medical School" Uniformed Services University of the Health Sciences, Bethesda, Maryland;|b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Singh
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Shilpa
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Oluseyi O
authors.initials: OO
authors.lastname: Fatanmi
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Wise
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Newman
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Patricia L P
authors.initials: PL
authors.lastname: Romaine
authors.affiliation: c   Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare Systems, Little Rock, Arkansas; and.
authors.forename: Howard
authors.initials: H
authors.lastname: Hendrickson
authors.affiliation: d   Veterinary Sciences Department, Armed Forces Radiobiology Research Institute, Bethesda, Maryland.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Gulani
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
authors.affiliation: b   Armed Forces Radiobiology Research Institute, Bethesda, Maryland;
authors.forename: K Sree
authors.initials: KS
authors.lastname: Kumar
authors.affiliation: c   Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare Systems, Little Rock, Arkansas; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D054508:Acute Radiation Syndrome / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002839:Chromans / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003037:Cobalt Radioisotopes; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D008253:Macaca mulatta; D011323:Primates; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000209:etiology / Q000473:pathology; D014481:United States; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D014916:Whole-Body Irradiation
chemical_list: D002839:Chromans; D003037:Cobalt Radioisotopes; D011837:Radiation-Protective Agents; D014810:Vitamin E; C013649:plastochromanol 8