title: Protective effect of a novel, potent inhibitor of poly(adenosine 5'-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis.
abstract: OBJECTIVE
  To determine whether activation of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) synthetase (PARS) contributes to mortality rate, myocardial dysfunction, and cardiovascular collapse in a porcine model of sepsis induced by implantation of an infected clot.
  
  
  METHODS
  Prospective, random animal study.
  
  
  METHODS
  Research laboratory at Rush Presbyterian St. Luke's Medical Center.
  
  
  METHODS
  Twenty pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure, sonomicrometer crystals in the left ventricle to measure short axis diameter, an ultrasonic flow meter to measure cardiac output, and catheters in the pulmonary artery and aorta to measure blood pressures and collect samples.
  
  
  METHODS
  By using a randomized study design, we administered either the novel potent PARS inhibitor PJ34 (10 mg/kg for 1 hr, 2 mg x kg(-1) x hr(-1) for 96 hrs) or vehicle to pigs immediately before intraperitoneal implantation of Escherichia coli 0111.B4 (2.3 +/- 0.1 x 10(10) colony-forming units/kg)-laden fibrin clots to produce peritonitis and bacteremia.
  
  
  RESULTS
  In vehicle-treated pigs, 12% survival was recorded at 24 hrs, whereas 83% and 66% survival was recorded in the PJ34-treated animals at 24 and 96 hrs, respectively (p <.05). PJ34 treatment attenuated bacteremia-induced increases in systemic and pulmonary vascular resistances. In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-alpha. PJ34 treatment significantly attenuated this cytokine response. The formation of peroxynitrite and the activation of PARS were confirmed in hearts and lungs of the septic pigs by the immunohistochemical detection of nitrotyrosine and poly(ADP-ribose), respectively. Inhibition of PARS with PJ34 abolished poly(ADP-ribose) formation in septic animals.
  
  
  CONCLUSIONS
  Treatment with a potent PARS inhibitor improved survival and cardiovascular status and attenuated an important mediator component of the inflammatory response in a lethal porcine model of sepsis.
authors: Inotek Corporation, Beverly, MA 01915, USA.
authors: Roy D
authors: RD
authors: Goldfarb
authors: Anita
authors: A
authors: Marton
authors: Eva
authors: E
authors: Szabó
authors: László
authors: L
authors: Virág
authors: Andrew L
authors: AL
authors: Salzman
authors: Dana
authors: D
authors: Glock
authors: Imran
authors: I
authors: Akhter
authors: Robert
authors: R
authors: McCarthy
authors: Joseph E
authors: JE
authors: Parrillo
authors: Csaba
authors: C
authors: Szabó
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004927:Escherichia coli Infections / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy; D010616:Phenanthrenes / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha