Effects of the Endothelin Receptor Antagonist Bosentan on Hemodynamics, Symptoms and Functional Capacity in Japanese Patients With Severe Pulmonary Hypertension

Abstract

ulmonary arterial hypertension (PAH) is a rare and debilitating disease, characterized by an increase in pulmonary vascular resistance that ultimately leads to right heart failure and death. 1 When a definite cause can not be demonstrated, the condition is termed primary pulmonary hypertension (PPH), which predominantly affects women most commonly in their third decade of life. 2 No ethnic predisposition is apparent in the National Institutes of Health registry, and the proportions by ethnic group parallel those in the general population. 2 Similar pulmonary vascular lesions are produced by many illnesses such as scleroderma, human immunodeficiency virus infection, liver disease or the use of certain anorectic drugs, and these are now classified as types of PAH. 3 A limited number of innovative strategies for the treatment of PAH have been developed over the past decades, but their effectiveness is Circulation Journal Vol.69, February 2005 largely limited by their nonselectivity for the pulmonary vasculature and significant drawbacks have been reported. 5 Recently, it was shown that PAH is associated with increased concentrations of endothelin (ET)-1, a potent vasoconstrictor, in plasma and the lungs, 6,7 suggesting that inhibition of ET receptors is a potential therapeutic alternative for this life-threatening disorder. In fact, studies with Caucasian PAH patients have demonstrated significant clinical benefits of bosentan, a dual ET receptor antagonist. [8][9][10] In the present study, the effects of bosentan on cardiopulmonary hemodynamics, symptoms and functional capacity were assessed, as well as the 6-min walk test and the specific activity scale (SAS), in Japanese patients with PAH.The pharmacokinetics of bosentan are dose-proportional up to a dose of 500 mg and in Caucasians, the absolute bioavailability of bosentan is 50%, being mainly excreted via the bile in the form of metabolites. 11,12 However, ethnic differences in the pharmacokinetics of many drugs have been demonstrated. 13 Therefore, prior to the start of the clinical trial, the multiple-dose pharmacokinetics of bosentan were compared in Caucasian and Japanese subjects. Methods Comparative Study of the Ethnic Differences in the Pharmacokinetics of BosentanThis part of the study was performed at FOCUS GmbH

Effects of Long-Acting Beraprost Sodium (TRK-100STP) in Japanese Patients With Pulmonary Arterial Hypertension

“…Since lesions are observed in most of the pulmonary vascular system from the tunica intima and media to the adventitia, conventional vasodilators are only effective for the systemic vasculature and show almost no effect on the pulmonary vasculature. The only formulation which shows evidence of exerting a pulmonary vasodilator effect during the chronic period is an endothelin receptor antagonist [25][26][27][28][29][30][31][32][33][34] apart from prostacyclin 22,[35][36][37][38][39][40] and its derivatives. [15][16][17][18]41,42) The 6MW distance is widely used as an indicator of the functional severity of pulmonary hypertension in each individual as a clinical test for efficacy evaluation before and after administration of several pulmonary vasodilators.…”

“…However, the study was designed with an administration period set at 12 weeks, similar to other clinical studies of PAH therapy such as intravenous epoprestenol, 22) oral bosentan, 32) and sildenafil. 43) During continuous long-term therapy with conventional beraprost, a decrease in the extent of the increase in the 6MW distance was reported from 3 months to 12 months during administration to patients with PAH.…”

Bosentan Improved Syncope in a Hemodialysis Patient With Pulmonary Hypertension and Mild Aortic Stenosis

“…It has been reported that bosentan administration results in an improvement in a 6-minute walk after 4 weeks. 9,14) It is natural to attribute these effects to this endothelin receptor blocker, because no other conditions were changed in the 4 weeks of treatment. Although hemodynamic data were compared after 12 weeks in other studies, 9,14) we observed a hemodynamic improvement with bosentan even after 4 weeks and further improvement in pressure gradient of TR by echocardiography.…”

“…7,8) Meanwhile, a dual endothelin receptor antagonist, bosentan, has been available in Japan since 2005. 9) We report a case of IPAH in which repetitive syncope was successfully treated by bosentan. Syncopal attack in this patient was thought to be related mainly to PH and partially to hemodialysis and mild aortic stenosis.…”

Additional Effects of Bosentan in Patients With Idiopathic Pulmonary Arterial Hypertension Already Treated With High-Dose Epoprostenol

“…Current treatment algorithms recommend prostanoid analogs (iloprost, treprostinil), bosentan, sildenafil, and epoprostenol (EPO), depending on disease severity. 1,2 Although each of these drugs has been reported to improve hemodynamics and exercise capacity in PAH patients, [3][4][5][6][7][8][9][10][11][12][13][14][15] improvement of long-term survival in patients with idiopathic PAH (IPAH) has been achieved only with EPO, 4-6 treprostinil 13 and bosentan. 10 PAH is a complex disease with multifactorial pathophysiology.…”