The endothelin system and its role in pulmonary arterial hypertension (PAH)
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《胸》
1 Papworth Hospital, Cambridge, UK
2 University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK
Correspondence to:
Dr J Pepke-Zaba
Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge CB3 8RE, UK; jjm.zaba@ntlworld.com
Endothelin receptor antagonists represent a major advance in the treatment of PAH but much remains to be learned of their effectiveness in specific forms of pulmonary hypertension
Keywords: endothelin receptor antagonists; pulmonary arterial hypertension; bosentan
The endothelin system is emerging as an important mediator in pulmonary arterial hypertension (PAH) and the endothelin receptor antagonists represent a major advance in the treatment of this condition. PAH results from a massive proliferation of myofibroblast cells in the intima of small pulmonary arteries. Thickening of the media is also observed and abnormal proliferation of endothelial cells may result in plexiform lesions.
The endothelin system has been extensively studied over the 15 years since its initial discovery by Yanagisawa and co-workers in 1988. It is clear that endothelin 1 (ET-1) is a key mediator of pulmonary vascular biology and pathophysiology. It is a powerful vasoconstrictor and proliferative cytokine. In the early 1990s ET-1 was identified as an important mediator of PAH. Plasma ET-1 levels were found to be elevated in patients with pulmonary hypertension and correlated with the raised pulmonary vascular resistance.1 Furthermore, expression of ET-1 mRNA and protein was increased in endothelial cells comprising vascular lesions in primary pulmonary hypertension.2
The availability of ET-1 receptor antagonists allowed testing of these compounds in experimental models. In rat models of experimental pulmonary hypertension—including pulmonary hypertension induced by chronic (2–3 weeks) hypoxia3 and by the alkaloid monocrotaline—ET-1 antagonists prevent the development of PAH. More compelling is the finding that ET-1 antagonists can partly reverse established PAH in experimental models.4 These observations suggest that ET-1 antagonists can potentially reverse established pulmonary vascular remodelling rather than simply prevent vasoconstriction.5 In clinical PAH the main component of the increased pulmonary vascular resistance is remodelling rather than vasoconstriction. However, in animal models the predominant lesion is medial hypertrophy rather than intimal thickening, and it is unknown whether regression of these lesions occurs in man. Nevertheless, ET-1 antagonists provide a unique opportunity to target pulmonary vascular remodelling via their effects on vascular cell growth.
ENDOTHELIN RECEPTORS
Endothelin receptors exist in at least two separate isoforms, ETA and ETB. ETA receptors are generally present on smooth muscle cells and are responsible for vasoconstriction and cell proliferation whereas ETB receptors are found on both endothelial cells and smooth muscle cells. The role of ETB receptors is more complex. ETB receptor can mediate endothelium-dependent vascular relaxation by inducing nitric oxide (NO) and prostacyclin (PGI2) release and are therefore thought to induce vasodilatation; however, the potential of ETB receptors to mediate relaxation is not clear. The proportion of ETB receptors increases in small peripheral pulmonary arteries.6 It is this peripheral region comprising the resistance arteries of the lung that is the most important site for vascular remodelling in PAH. Pharmacological studies in human pulmonary resistance arteries suggest that the ETB receptor, as well as the ETA receptor, mediate vasoconstriction to ET-1 in man, although there appear to be species differences in ETB mediated contraction. Human pulmonary artery smooth muscle cells cultured from small pulmonary arteries (<1 mm external diameter) retain a high proportion of ETB binding (33%) and these receptors can be shown to mediate some of the growth response to ET-1.6 Patients with severe pulmonary hypertension exhibit increased ET receptor binding in peripheral pulmonary arteries.6 In patients with idiopathic pulmonary arterial hypertension (previously known as primary pulmonary hypertension) there appeared to be no change in the proportion of ETA:ETB receptors in peripheral pulmonary arteries as assessed by in vitro autoradiography.6 However, in chronic thromboembolic pulmonary hypertension, selective upregulation of ETB receptor mRNA has been reported in lung samples.7 Thus, a case has been made for dual ETA/ETB receptor antagonists in the inhibition of pulmonary vascular remodelling. Since ET-1 is produced by the neighbouring endothelium and in an autocrine manner by smooth muscle cells in the vascular wall, dual ETA/ETB receptor antagonism could block both receptor subtypes shown to be involved in ET-1 stimulated smooth muscle cell proliferation. Inhibition of ETB receptors on the endothelium could theoretically be detrimental because of the loss of ETB mediated NO/PGI2 release, although in vivo this effect has not been observed and the relative benefits of dual ETA/ETB versus ETA antagonism remain to be determined.
THERAPEUTIC POTENTIAL OF ENDOTHELIN RECEPTOR ANTAGONISTS
The critical importance of ET-1 in the spectrum of pulmonary hypertensive disorders has identified endothelin receptor antagonists as having obvious therapeutic potential. The oral dual endothelin receptor antagonist bosentan (Tracleer) has been studied in two randomised, placebo controlled, double blind studies.8,9 Patients with PAH (idiopathic or associated with connective tissue disease) in NYHA functional class III or IV were included. The primary end point (6 minute walking distance) was evaluated at 16 weeks. Patients treated with bosentan walked 36.4 metres further at 16 weeks compared with a reduction in walking distance of 7.8 metres in the placebo group, giving a treatment effect of 44.2 metres (CI 21 to 67 metres, p = 0.0002). Clinical worsening—defined by death, premature withdrawal from study, admission to hospital for worsening of PAH, or escalation of treatment to intravenous prostacyclin—occurred in 37% of placebo treated patients compared with 11% of bosentan treated patients (p = 0.0015). NYHA functional class improved significantly in more patients on bosentan than placebo.
An open label, uncontrolled, single and multiple dose study has been performed in children aged 4–17 years with PAH to assess the pharmacokinetics, tolerability, and safety of oral bosentan. In this preliminary study a significant improvement in haemodynamics was observed after 12 weeks of bosentan treatment in the 18 enrolled children, either alone or in combination with intravenous epoprostenol.10
Favourable clinical and haemodynamic results have recently been achieved with the use of bosentan in 11 patients with HIV-associated PAH.11 A study to assess the effects of bosentan in patients with Eisenmenger’s disease is also ongoing.
The most important adverse event described in patients taking bosentan is an increase in serum hepatic transaminase levels in 11% of patients. Abnormal hepatic function was found to be dose dependent, being more frequently reported in patients receiving 250 mg twice daily or higher than in those receiving 125 mg twice daily (14% and 5%, respectively). Due to the potential increase in liver enzymes, the US Food and Drug Administration (FDA) requires that liver function tests be performed at least monthly. Bosentan use may also be associated with mild anaemia.
Careful attention must be paid to the use of adequate contraception in women of childbearing age because of potential teratogenic effects. In addition, bosentan may decrease the efficacy of hormonal contraceptive techniques and, for this reason, they should not be used alone. There is concern that the endothelin antagonists as a class may be capable of causing testicular atrophy and male infertility. Younger men who may consider conceiving should be counselled regarding this possibility before taking these drugs.
Most recent data from two randomised, placebo controlled studies and two long term extensions show that bosentan treated patients in NYHA class III have improved survival at 2 years compared with that estimated by NIH equation.12
Bosentan has been approved for the treatment of NYHA class III and IV PAH in the USA and Canada. In Europe it has been approved by the EMEA for the treatment of NYHA class III PAH, specifying that efficacy has been demonstrated only in patients with IPAH patients and those with PAH associated with scleroderma without significant lung fibrosis.
The success of bosentan has seen the emergence of further endothelin receptor antagonists for the treatment of pulmonary hypertension. These include the selective ETA receptor antagonists sitaxsentan13,14 and ambrisentan15 which are currently undergoing phase III clinical trials. There is much debate as to whether ETA selectivity or dual ETA/ETB blockade possesses any clinical advantage. Sitaxsentan, a selective orally active ETA receptor antagonist, has a long duration of action (half life 5–7 hours) and is approximately 6500 times more selective as an antagonist for ETA than for ETB receptors. It has been assessed in one randomised clinical trial on 178 patients with PAH in NYHA class II, III and IV. The study showed improvements in exercise capacity compared with placebo, increased 6 minute walking distance of 35 metres and 33 metres with doses of 100 mg and 300 mg, respectively (p<0.01), haemodynamics and clinical events.14 An additional pilot study with this compound in 20 patients with PAH has shown similar results.13 However, a recent study showed an increase in the 6 minute walking distance of 65 metres (p = 0.0002) in patients with PAH in NYHA class III and IV.15 As with bosentan, liver function abnormalities occurred with sitaxsentan (10% in the 300 mg group).13
Ambrisentan, another selective orally active ETA receptor antagonist, has been evaluated in a pilot blinded dose comparison study in 64 patients with PAH.16 Two randomised clinical trials are currently ongoing.
Clearly, endothelin receptor antagonists represent a major advance in the treatment of PAH. However, much remains to be learned of their effectiveness in specific forms of pulmonary hypertension—for example, patients with inoperable chronic thromboembolic pulmonary hypertension.
As with systemic hypertension, it is likely that the optimum approach in pulmonary hypertension will involve the use of drug combinations, so more information is needed on the combined effects of endothelin receptor antagonists with other emerging and available treatments.17 In addition, we need to know whether these agents could prevent the progression of disease in patients with NYHA I/II symptoms.
The studies with the orally active non-selective endothelin receptor antagonist bosentan are a welcome addition to our therapeutic formulary. Early data on selective ETA blockade are encouraging and may result in alternative treatments.
REFERENCES
Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease. Ann Intern Med 1991;114:464–9.
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–9.
Bonvallet ST, Zamora MR, Hasunuma. et al BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 1994;266:H1327–1.
Miyauchi T, Yorikane R, Sakai S, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993;73:887–97.
Chen S-J, Chen Y-F, Opgenorth TJ, et al. The orally active nonpeptide endothelin A receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodelling in Sprague-Dawley rats. J Cardiovasc Pharmacol 1997;29:713–2.
Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002;165:398–405.
Bauer M, Wilkens H, Langer F, et al. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105:1034–6.
Channick R, Simonneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–23.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
Barst R, Ivy D, Widlitz AC, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003;73:372–82.
Sitbon O, Gressin V, Speich R, et al. Bosentan in pulmonary arterial hypertension associated with HIV infection. Eur Respir J 2003;22:563.
McLaughlin V, Sitbon O, Rubin LJ, et al. The effect of first-line bosentan on survival of patients with primary pulmonary hypertension. Am J Respir Crit Care Med 2003;167:A442.
Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 2002;121:1860–8.
Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441–7.
Frost A, Langleben D, Hill NS, et al. 6MW as an efficacy endpoint in PAH clinical trials: demonstration of a ceiling effect. Am J Respir Crit Care Med 2004;169:A176.
Rubin LJ, Galie N, Badesch BD, et al. Ambrisentan improves exercise capacity and clinical measures in pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2004; (in press).
Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: Breathe-2. Eur Respir J 2004;24:353–9.(J Pepke-Zaba1 and N W Mor)
2 University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK
Correspondence to:
Dr J Pepke-Zaba
Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge CB3 8RE, UK; jjm.zaba@ntlworld.com
Endothelin receptor antagonists represent a major advance in the treatment of PAH but much remains to be learned of their effectiveness in specific forms of pulmonary hypertension
Keywords: endothelin receptor antagonists; pulmonary arterial hypertension; bosentan
The endothelin system is emerging as an important mediator in pulmonary arterial hypertension (PAH) and the endothelin receptor antagonists represent a major advance in the treatment of this condition. PAH results from a massive proliferation of myofibroblast cells in the intima of small pulmonary arteries. Thickening of the media is also observed and abnormal proliferation of endothelial cells may result in plexiform lesions.
The endothelin system has been extensively studied over the 15 years since its initial discovery by Yanagisawa and co-workers in 1988. It is clear that endothelin 1 (ET-1) is a key mediator of pulmonary vascular biology and pathophysiology. It is a powerful vasoconstrictor and proliferative cytokine. In the early 1990s ET-1 was identified as an important mediator of PAH. Plasma ET-1 levels were found to be elevated in patients with pulmonary hypertension and correlated with the raised pulmonary vascular resistance.1 Furthermore, expression of ET-1 mRNA and protein was increased in endothelial cells comprising vascular lesions in primary pulmonary hypertension.2
The availability of ET-1 receptor antagonists allowed testing of these compounds in experimental models. In rat models of experimental pulmonary hypertension—including pulmonary hypertension induced by chronic (2–3 weeks) hypoxia3 and by the alkaloid monocrotaline—ET-1 antagonists prevent the development of PAH. More compelling is the finding that ET-1 antagonists can partly reverse established PAH in experimental models.4 These observations suggest that ET-1 antagonists can potentially reverse established pulmonary vascular remodelling rather than simply prevent vasoconstriction.5 In clinical PAH the main component of the increased pulmonary vascular resistance is remodelling rather than vasoconstriction. However, in animal models the predominant lesion is medial hypertrophy rather than intimal thickening, and it is unknown whether regression of these lesions occurs in man. Nevertheless, ET-1 antagonists provide a unique opportunity to target pulmonary vascular remodelling via their effects on vascular cell growth.
ENDOTHELIN RECEPTORS
Endothelin receptors exist in at least two separate isoforms, ETA and ETB. ETA receptors are generally present on smooth muscle cells and are responsible for vasoconstriction and cell proliferation whereas ETB receptors are found on both endothelial cells and smooth muscle cells. The role of ETB receptors is more complex. ETB receptor can mediate endothelium-dependent vascular relaxation by inducing nitric oxide (NO) and prostacyclin (PGI2) release and are therefore thought to induce vasodilatation; however, the potential of ETB receptors to mediate relaxation is not clear. The proportion of ETB receptors increases in small peripheral pulmonary arteries.6 It is this peripheral region comprising the resistance arteries of the lung that is the most important site for vascular remodelling in PAH. Pharmacological studies in human pulmonary resistance arteries suggest that the ETB receptor, as well as the ETA receptor, mediate vasoconstriction to ET-1 in man, although there appear to be species differences in ETB mediated contraction. Human pulmonary artery smooth muscle cells cultured from small pulmonary arteries (<1 mm external diameter) retain a high proportion of ETB binding (33%) and these receptors can be shown to mediate some of the growth response to ET-1.6 Patients with severe pulmonary hypertension exhibit increased ET receptor binding in peripheral pulmonary arteries.6 In patients with idiopathic pulmonary arterial hypertension (previously known as primary pulmonary hypertension) there appeared to be no change in the proportion of ETA:ETB receptors in peripheral pulmonary arteries as assessed by in vitro autoradiography.6 However, in chronic thromboembolic pulmonary hypertension, selective upregulation of ETB receptor mRNA has been reported in lung samples.7 Thus, a case has been made for dual ETA/ETB receptor antagonists in the inhibition of pulmonary vascular remodelling. Since ET-1 is produced by the neighbouring endothelium and in an autocrine manner by smooth muscle cells in the vascular wall, dual ETA/ETB receptor antagonism could block both receptor subtypes shown to be involved in ET-1 stimulated smooth muscle cell proliferation. Inhibition of ETB receptors on the endothelium could theoretically be detrimental because of the loss of ETB mediated NO/PGI2 release, although in vivo this effect has not been observed and the relative benefits of dual ETA/ETB versus ETA antagonism remain to be determined.
THERAPEUTIC POTENTIAL OF ENDOTHELIN RECEPTOR ANTAGONISTS
The critical importance of ET-1 in the spectrum of pulmonary hypertensive disorders has identified endothelin receptor antagonists as having obvious therapeutic potential. The oral dual endothelin receptor antagonist bosentan (Tracleer) has been studied in two randomised, placebo controlled, double blind studies.8,9 Patients with PAH (idiopathic or associated with connective tissue disease) in NYHA functional class III or IV were included. The primary end point (6 minute walking distance) was evaluated at 16 weeks. Patients treated with bosentan walked 36.4 metres further at 16 weeks compared with a reduction in walking distance of 7.8 metres in the placebo group, giving a treatment effect of 44.2 metres (CI 21 to 67 metres, p = 0.0002). Clinical worsening—defined by death, premature withdrawal from study, admission to hospital for worsening of PAH, or escalation of treatment to intravenous prostacyclin—occurred in 37% of placebo treated patients compared with 11% of bosentan treated patients (p = 0.0015). NYHA functional class improved significantly in more patients on bosentan than placebo.
An open label, uncontrolled, single and multiple dose study has been performed in children aged 4–17 years with PAH to assess the pharmacokinetics, tolerability, and safety of oral bosentan. In this preliminary study a significant improvement in haemodynamics was observed after 12 weeks of bosentan treatment in the 18 enrolled children, either alone or in combination with intravenous epoprostenol.10
Favourable clinical and haemodynamic results have recently been achieved with the use of bosentan in 11 patients with HIV-associated PAH.11 A study to assess the effects of bosentan in patients with Eisenmenger’s disease is also ongoing.
The most important adverse event described in patients taking bosentan is an increase in serum hepatic transaminase levels in 11% of patients. Abnormal hepatic function was found to be dose dependent, being more frequently reported in patients receiving 250 mg twice daily or higher than in those receiving 125 mg twice daily (14% and 5%, respectively). Due to the potential increase in liver enzymes, the US Food and Drug Administration (FDA) requires that liver function tests be performed at least monthly. Bosentan use may also be associated with mild anaemia.
Careful attention must be paid to the use of adequate contraception in women of childbearing age because of potential teratogenic effects. In addition, bosentan may decrease the efficacy of hormonal contraceptive techniques and, for this reason, they should not be used alone. There is concern that the endothelin antagonists as a class may be capable of causing testicular atrophy and male infertility. Younger men who may consider conceiving should be counselled regarding this possibility before taking these drugs.
Most recent data from two randomised, placebo controlled studies and two long term extensions show that bosentan treated patients in NYHA class III have improved survival at 2 years compared with that estimated by NIH equation.12
Bosentan has been approved for the treatment of NYHA class III and IV PAH in the USA and Canada. In Europe it has been approved by the EMEA for the treatment of NYHA class III PAH, specifying that efficacy has been demonstrated only in patients with IPAH patients and those with PAH associated with scleroderma without significant lung fibrosis.
The success of bosentan has seen the emergence of further endothelin receptor antagonists for the treatment of pulmonary hypertension. These include the selective ETA receptor antagonists sitaxsentan13,14 and ambrisentan15 which are currently undergoing phase III clinical trials. There is much debate as to whether ETA selectivity or dual ETA/ETB blockade possesses any clinical advantage. Sitaxsentan, a selective orally active ETA receptor antagonist, has a long duration of action (half life 5–7 hours) and is approximately 6500 times more selective as an antagonist for ETA than for ETB receptors. It has been assessed in one randomised clinical trial on 178 patients with PAH in NYHA class II, III and IV. The study showed improvements in exercise capacity compared with placebo, increased 6 minute walking distance of 35 metres and 33 metres with doses of 100 mg and 300 mg, respectively (p<0.01), haemodynamics and clinical events.14 An additional pilot study with this compound in 20 patients with PAH has shown similar results.13 However, a recent study showed an increase in the 6 minute walking distance of 65 metres (p = 0.0002) in patients with PAH in NYHA class III and IV.15 As with bosentan, liver function abnormalities occurred with sitaxsentan (10% in the 300 mg group).13
Ambrisentan, another selective orally active ETA receptor antagonist, has been evaluated in a pilot blinded dose comparison study in 64 patients with PAH.16 Two randomised clinical trials are currently ongoing.
Clearly, endothelin receptor antagonists represent a major advance in the treatment of PAH. However, much remains to be learned of their effectiveness in specific forms of pulmonary hypertension—for example, patients with inoperable chronic thromboembolic pulmonary hypertension.
As with systemic hypertension, it is likely that the optimum approach in pulmonary hypertension will involve the use of drug combinations, so more information is needed on the combined effects of endothelin receptor antagonists with other emerging and available treatments.17 In addition, we need to know whether these agents could prevent the progression of disease in patients with NYHA I/II symptoms.
The studies with the orally active non-selective endothelin receptor antagonist bosentan are a welcome addition to our therapeutic formulary. Early data on selective ETA blockade are encouraging and may result in alternative treatments.
REFERENCES
Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease. Ann Intern Med 1991;114:464–9.
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–9.
Bonvallet ST, Zamora MR, Hasunuma. et al BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 1994;266:H1327–1.
Miyauchi T, Yorikane R, Sakai S, et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993;73:887–97.
Chen S-J, Chen Y-F, Opgenorth TJ, et al. The orally active nonpeptide endothelin A receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodelling in Sprague-Dawley rats. J Cardiovasc Pharmacol 1997;29:713–2.
Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002;165:398–405.
Bauer M, Wilkens H, Langer F, et al. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105:1034–6.
Channick R, Simonneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–23.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
Barst R, Ivy D, Widlitz AC, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003;73:372–82.
Sitbon O, Gressin V, Speich R, et al. Bosentan in pulmonary arterial hypertension associated with HIV infection. Eur Respir J 2003;22:563.
McLaughlin V, Sitbon O, Rubin LJ, et al. The effect of first-line bosentan on survival of patients with primary pulmonary hypertension. Am J Respir Crit Care Med 2003;167:A442.
Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 2002;121:1860–8.
Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441–7.
Frost A, Langleben D, Hill NS, et al. 6MW as an efficacy endpoint in PAH clinical trials: demonstration of a ceiling effect. Am J Respir Crit Care Med 2004;169:A176.
Rubin LJ, Galie N, Badesch BD, et al. Ambrisentan improves exercise capacity and clinical measures in pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2004; (in press).
Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: Breathe-2. Eur Respir J 2004;24:353–9.(J Pepke-Zaba1 and N W Mor)