Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist. Effects on microvascular permeability, hypotension and nephrosis.
The effects of a newly synthesized platelet-activating factor (PAF) antagonist, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11- dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine (E-6123, CAS 131614-02-3) on microvascular permeability, systemic hypotension and nephrosis were investigated. E-6123 inhibited PAF injection-induced microvascular permeability (edema) in guinea pigs after oral administration at 3 micrograms/kg. The inhibitory effects of E-6123 were very potent compared to those of other PAF antagonists. E-6123 reversed PAF and/or endotoxin injection-induced hypotension in rats after intravenous administration at 3 micrograms/kg. The increase in urinary protein excretion of rats in which nephrosis had been induced by intraperitoneal injection of aminonucleoside was not inhibited by oral administration of E-6123 at 10 mg/kg/d.
Sakuma
Y
Y
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Shirato
M
M
Nagaoka
J
J
Obaishi
H
H
Tsunoda
H
H
Katayama
S
S
Ono
H
H
Katayama
K
K
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D006168:Guinea Pigs; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000517:prevention & control*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011507:Proteinuria / Q000139:chemically induced / Q000652:urine; D011692:Puromycin Aminonucleoside; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D004731:Endotoxins; D010972:Platelet Activating Factor; D014230:Triazoles; C068033:E 6123; D011692:Puromycin Aminonucleoside