A novel leukotriene B4-receptor antagonist in endotoxin shock: a prospective, controlled trial in a porcine model.
OBJECTIVE
To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B4-receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin.


METHODS
Prospective, randomized, controlled trial.


METHODS
Laboratory at a large university medical center.


METHODS
Twenty-five, immature, random-bred swine.


METHODS
Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 micrograms/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value.


RESULTS
Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration.


CONCLUSIONS
These data suggest that leukotriene B4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB4 receptors.
Fink
M P
MP
Department of Surgery, University of Massachusetts Medical Center, Worcester.
O'Sullivan
B P
BP
Menconi
M J
MJ
Wollert
P S
PS
Wang
H
H
Youssef
M E
ME
Fleisch
J H
JH
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004927:Escherichia coli Infections / Q000150:complications*; D015633:Extravascular Lung Water / Q000737:chemistry; D006439:Hemodynamics / Q000187:drug effects*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008297:Male; D009195:Peroxidase / Q000032:analysis; D011506:Proteins / Q000032:analysis; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D012772:Shock, Septic / Q000150:complications*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000097:blood
D011506:Proteins; D013777:Tetrazoles; D007975:Leukotriene B4; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D009195:Peroxidase; C063823:LY 255283