Inhibitory effects of the novel platelet activating factor receptor antagonist, 1-ethyl-2-[N-(2-methoxy)benzoyl-N-[(2R)-2-methoxy-3-(4- octadecylcarbamoyloxy) piperidinocarbonyloxypropyloxy]carbonyl] aminomethyl-pyridinium chloride, in several experimentally induced shock models.
E5880 (1-ethyl-2-[N-(2-methoxy)benzoyl-N-[(2R)-2-methoxy-3-(4- octadecylcarbamoyloxy) piperidinocarbonyloxypropyloxy] carbonyl]aminomethylpyridinium chloride, CAS 128420-61-1) is a novel analog-type antagonist of platelet activating factor (PAF). This paper describes the in vitro PAF antagonistic activity of E5880 and its in vivo effect in various experimentally induced shock models. Inhibition by E5880 of [3H]platelet activating factor (PAF) binding to human platelet PAF receptor was extremely potent; its IC50 value was 0.27 nmol/l, so that it was about 5 times more potent than PAF itself. Its IC50 value in inhibition of washed human platelet aggregation induced by PAF was 0.66 nmol/l. Intravenous treatment with E5880 dose-dependently reversed PAF-induced hypotension in rats and protected mice from lethality caused by PAF. Lipopolysaccharide (LPS)-induced hypotension in rats was inhibited by both pre- and post-treatment with E5880. It was also confirmed that blood PAF level, measured by the GC-NICI-MS method, was increased after LPS challenge in this model. Furthermore, E5880 was extremely effective in preventing passive anaphylactic lethality in mice. Blood PAF level in this model was also increased immediately after antigen challenge, and this was coincident with the time at which signs of shock became apparent. These findings support the concept that PAF is an important mediator in the development of LPS-induced shock and anaphylactic shock, and suggest that E5880, a novel and potent PAF antagonist, may be effective in clinical treatment for shock states.
Nagaoka
J
J
Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan.
Harada
K
K
Kimura
A
A
Kobayashi
S
S
Murakami
M
M
Yoshimura
T
T
Yamada
K
K
Asano
O
O
Katayama
K
K
Yamatsu
I
I
D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control; D008070:Lipopolysaccharides; D051379:Mice; D008813:Mice, Inbred ICR; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D012769:Shock / Q000188:drug therapy* / Q000503:physiopathology
D008070:Lipopolysaccharides; D010880:Piperidines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C072429:E 5880