Prolonged pharmacodynamic effects of S-0139, an intravenously administered endothelin A (ET) antagonist, in the human forearm blood flow model.
OBJECTIVE
To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.


METHODS
Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first.


RESULTS
Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2.


CONCLUSIONS
S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.
Discovery Medicine, GSK R&D, Harlow, UK.
Martin W
MW
Lunnon
Sharon M L
SM
Wallace
Joanne E
JE
Palmer
Andrew
A
Francis-Lang
Bart E
BE
Laurijssens
Prafull
P
Mistry
Bruce
B
Albala
Toshiaki
T
Nagafuji
Ian B
IB
Wilkinson
Kay
K
Maltby
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010991:Plethysmography; D016037:Single-Blind Method; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D055815:Young Adult
D002109:Caffeic Acids; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C086421:S 0139; D014662:Vasoconstrictor Agents; D009828:Oleanolic Acid