title: 17α-Ethynylestradiol-3-sulfate treatment of severe blood loss in rats.
abstract: BACKGROUND
  From 2001-2011, >80% of potentially survivable United States battlefield deaths were due to severe hemorrhage. We subjected male rats to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and measured survival and also mean arterial pressures (MAP).
  
  
  METHODS
  After controlled removal of 60% circulating blood volume (10-11 mL) over approximately 45 min, rats received EE-3-SO4 at 0 (vehicle controls), 0.1, 0.3, 1.0, or 3.0 mg/kg in 40 μL/100 g BW saline intravenously. MAP was recorded for 40 min after drug administration and survival was recorded for 6 h.
  
  
  RESULTS
  The dose response curve was bell shaped with optimum survival at 1 mg/kg EE-3-SO4. Median survival times of rats receiving 1 mg/kg (360 min) were approximately 6 times that of the control group (57 min): P = 0.0001. The number of animals alive at 6 h was 16 of 20 (80%) in the 1 mg/kg group versus 0 of 20 (0%) in the control group. Early increases in MAP correlated with longer survival times.
  
  
  CONCLUSIONS
  Administration of a single dose of 1 mg/kg EE-3-SO4 in 0.4 mL/kg of saline after controlled severe hemorrhage increased survival in rats by 6-fold. Partial recovery of blood pressure values correlated with longer survival time. These results, coupled with similar findings in a companion study in minipigs, support the further product development of EE-3-SO4 for: (1) severe hemorrhage when standard resuscitative fluids are not available, and (2) situations in which prolonged transportation periods are required for definitive treatment of the injured.
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: William
authors.initials: W
authors.lastname: Hubbard
authors.affiliation: Keith Pharmacology Research Group, LLC, Andover, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Keith
authors.affiliation: Fast-Track Drugs and Biologics LLC, North Potomac, Maryland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berman
authors.affiliation: Texas A&M Institute for Preclinical Studies, Texas A&M University, College Station, Texas.
authors.forename: Matthew
authors.initials: M
authors.lastname: Miller
authors.affiliation: Fast-Track Drugs and Biologics LLC, North Potomac, Maryland.
authors.forename: Charles
authors.initials: C
authors.lastname: Scott
authors.affiliation: NDA Partners LLC, Falls Church, Virginia.
authors.forename: Carl
authors.initials: C
authors.lastname: Peck
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: ichaudry@uabmc.edu.
authors.forename: Irshad H
authors.initials: IH
authors.lastname: Chaudry
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy*; D006863:Hydrogen-Ion Concentration; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000097:blood; D008297:Male; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology; D015996:Survival Rate; D015599:Trauma Severity Indices
chemical_list: D001786:Blood Glucose; C025810:ethinylestradiol-3-sulfate; D019344:Lactic Acid; D004997:Ethinyl Estradiol; D012965:Sodium Chloride
keywords: Ethynylestradiol sulfate; Rat; Severe shock; Survival