title: A new orally active, aminothiol radioprotector-free of nausea and hypotension side effects at its highest radioprotective doses.
abstract: OBJECTIVE
  A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721).
  
  
  METHODS
  PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension.
  
  
  RESULTS
  Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 μg/g body weight (equivalent to the human amifostine dose of 910 mg/m(2)), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats.
  
  
  CONCLUSIONS
  The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.
authors.affiliation: ProCertus BioPharm, Inc., Madison, WI, USA.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Soref
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.forename: William E
authors.initials: WE
authors.lastname: Fahl
mesh_terms: D000284:Administration, Oral; D004999:Amifostine / Q000008:administration & dosage; D000818:Animals; D003959:Diamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D005260:Female; D005289:Ferrets; D007022:Hypotension / Q000139:chemically induced*; D007261:Infusions, Intra-Arterial; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008813:Mice, Inbred ICR; D009325:Nausea / Q000139:chemically induced*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced*
chemical_list: C570582:3-(methylamino)-2-((methylamino)methyl)propane-1-thiol; D003959:Diamines; D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; D004999:Amifostine