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Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist.

Abstract
The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.
AuthorsK T Kruse-Elliott, D H Albert, J B Summers, G W Carter, J J Zimmerman, J E Grossman
JournalShock (Augusta, Ga.) (Shock) Vol. 5 Issue 4 Pg. 265-73 (Apr 1996) ISSN: 1073-2322 [Print] United States
PMID8721386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipopolysaccharides
  • Platelet Activating Factor
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • Prodrugs
  • Pyridinium Compounds
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Thiazoles
  • platelet activating factor receptor
  • Thromboxane B2
  • ABT 299
  • Peroxidase
Topics
  • Animals
  • Blood Pressure (drug effects)
  • Cardiac Output (drug effects)
  • Dose-Response Relationship, Drug
  • Lipopolysaccharides (toxicity)
  • Lung (drug effects, enzymology, pathology)
  • Peroxidase (drug effects, metabolism)
  • Platelet Activating Factor (metabolism, pharmacology)
  • Platelet Aggregation Inhibitors (administration & dosage, pharmacology)
  • Platelet Membrane Glycoproteins (agonists, antagonists & inhibitors)
  • Prodrugs (administration & dosage, pharmacology)
  • Pyridinium Compounds (administration & dosage, pharmacology)
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Shock, Septic (drug therapy, mortality, physiopathology)
  • Stroke Volume (drug effects)
  • Swine
  • Thiazoles (administration & dosage, pharmacology)
  • Thromboxane B2 (blood)
  • Vascular Resistance (drug effects)

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