The purpose of this study is to evaluate the safety and efficacy of TBC11251Na in patients with pulmonary arterial hypertension. Pulmonary arterial hypertension is a condition in which the blood pressure is abnormally high in the blood vessels that go from the heart to the lungs (the pulmonary arteries). The increased blood pressure in the lungs places a strain on the heart. The strain causes the heart to pump less blood into the lungs, causing shortness of breath, tiredness, and as heart failure develops, swelling in the feet and abdomen. Although the cause of this high blood pressure is unknown, previous studies have shown that endothelin (ET-1) is increased in patients with pulmonary arterial hypertension. Endothelin causes pulmonary vasoconstriction, e.g. closes the blood vessels in the lungs, thereby decreasing the blood pressure in the lungs. Previous studies demonstrated that continuous intravenous infusion of prostacyclin in patients with pulmonary arterial hypertension improved quality of life, improved survival and decreased the blood pressure in the lungs. Prostacyclin, subsequently, was approved by the Food and Drug Administration for long term treatment of pulmonary arterial hypertension. Unfortunately, chronic prostacyclin can only be given by continuous intravenous infusion 24 hours a day. Despite therapy with chronic continuous infusion of prostacyclin substantially improving survival and quality of life, this treatment is associated with significant risks due to the delivery system, including infection with subsequent hospitalizations. TBC11251Na, is a potent selective ETa receptor antagonist. The effects of endothelin are controlled by two different receptors: ETa and ETb. ETa receptors cause pulmonary vasoconstriction and ETb receptors cause pulmonary vasodilation. TBC11251Na is available in an oral preparation, in addition to an intravenous form. TBC11251Na is potentially capable of decreasing the high blood pressure in the lungs. Previous studies in patents with chronic heart failure and secondary pulmonary hypertension demonstrated that TBC11251Na lowers pulmonary arterial hypertension without any clinically significant side effects. Because of the potential for the therapeutic effect and an urgent need for an alternative effective treatment, the safety and efficacy of TBC11251Na will be evaluated in patients with pulmonary arterial hypertension. The study design is to evaluate the effects of a single oral dose of TBC11251Na in patients with pulmonary arterial hypertension as well as the safety and efficacy of 12 weeks of therapy (in all patients who tolerate the single dose). The efficacy of TBC11251Na will be evaluated by assessing its effects on exercise, symptoms of pulmonary hypertension as well as measurements of pulmonary artery pressure. Prior to the study, TBC11251Na has been given to 48 healthy volunteers and 48 patients with congestive heart failure .
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