Beneficial effects of a novel platelet-activating factor receptor antagonist, ST 899, on endotoxin-induced shock in mice.
The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock.
Ruggiero
V
V
Sigma Tau Industrie Farmaceutiche Riunite SpA, Department of Microbiology and Immunology, Pomezia, Italy.
Chiapparino
C
C
Manganello
S
S
Pacello
L
L
Foresta
P
P
Martelli
E A
EA
D000818:Animals; D001681:Biological Assay; D002087:Butyrates; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D000644:Quaternary Ammonium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis
D002087:Butyrates; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D000644:Quaternary Ammonium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C093670:ST 899; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D007371:Interferon-gamma