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Prolonged pharmacodynamic effects of S‐0139, an intravenously administered endothelin A (ET A ) antagonist, in the human forearm blood flow model
Author(s) -
Lun Martin W.,
Wallace Sharon M. L.,
Palmer Joanne E.,
FrancisLang Andrew,
Laurijssens Bart E.,
Mistry Prafull,
Albala Bruce,
Nagafuji Toshiaki,
Wilkinson Ian B.,
Maltby Kay
Publication year - 2010
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03590.x
Subject(s) - medicine , pharmacodynamics , vasoconstriction , antagonist , anesthesia , plethysmograph , forearm , brachial artery , endothelin receptor , endothelin receptor antagonist , placebo , blood flow , pharmacokinetics , pharmacology , blood pressure , surgery , receptor , alternative medicine , pathology
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Using the technique of venous occlusion plethysmography, endothelin (ET) antagonists have been shown to block the vasoconstrictive effects of intra‐brachial ET‐1 infusion on forearm blood flow. • Effects have been reported only when significant plasma concentrations of the antagonists are present. WHAT THIS STUDY ADDS • S‐0139 is a selective ET antagonist given by intravenous administration. • In this study it is shown to have a prolonged duration of pharmacodynamic activity beyond that expected from its pharmacokinetic profile. AIMS 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 µg kg −1 min −1 ), (2) a randomized study to confirm dose–response (placebo, 2.5, 6.67 and 15 µg kg −1 min −1 ), and (3) a delayed administration study (15.7 µg 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.