title: Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses.
abstract: BACKGROUND
  Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti-inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses.
  
  
  OBJECTIVE
  Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro.
  
  
  METHODS
  Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL-1β and IL-6 was assessed.
  
  
  RESULTS
  There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL-1β and IL-6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested.
  
  
  CONCLUSIONS
  We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration.
  
  
  CONCLUSIONS
  Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.
authors.affiliation: Department of Large Animal Clinical Studies, College of Veterinary Medicine, Michigan State University, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Schroeder
authors.forename: S J
authors.initials: SJ
authors.lastname: Holcombe
authors.forename: V L
authors.initials: VL
authors.lastname: Cook
authors.forename: M D
authors.initials: MD
authors.lastname: James
authors.forename: J C
authors.initials: JC
authors.lastname: Gandy
authors.forename: J G
authors.initials: JG
authors.lastname: Hauptman
authors.forename: L M
authors.initials: LM
authors.lastname: Sordillo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy / Q000662:veterinary*; D005260:Female; D015870:Gene Expression; D006339:Heart Rate / Q000187:drug effects; D006734:Horse Diseases / Q000097:blood / Q000139:chemically induced*; D006736:Horses / Q000097:blood*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D011773:Pyruvates / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011773:Pyruvates; C046522:ethyl pyruvate