S-0139

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.AIMSTo estimate the pharmacologically active dose range of a new investigational compound S‐0139, a selective endothelin A (ETA) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.METHODSVenous occlusion plethysmography was performed to assess changes in forearm blood flow following intra‐brachial administration of endothelin‐1 (ET‐1). ETAantagonists 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.RESULTSIntravenously 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.CONCLUSIONSS‐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.

Background and Purpose— Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET A ) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA. Methods— Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke. Results— The combination therapy of S-0139 and rtPA significantly ( P <0.01) reduced infarct volume (24.8±0.9% versus 33.8±1.5% in control) and hemorrhagic area (7.1±6.1 μm 2 versus 36.5±19.2 μm 2 in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels. Conclusions— These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.