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| Year : 2008
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| Current status of bosentan for treatment of pulmonary hypertension |
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Shahzad G Raja, Gilles D Dreyfus
Harefield Hospital, Middlesex, United Kingdom
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 Abstract | | |
Pulmonary arterial hypertension (PAH) is a debilitating disease associated with significant morbidity and a high mortality if left untreated. Over the past 5 years, there have been significant advances with regard to the understanding of the pathogenesis, diagnosis and classification of PAH. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both the quality of life and mortality. One of the recent drugs is an orally active dual endothelin receptor antagonist, bosentan; this drug has shown to improve the exercise capacity and survival in patients with PAH. This review article discusses the pharmacology of bosentan and summarises the current available evidence for the safety and efficacy of bosentan for the treatment of PAH. Keywords: Bosentan, endothelin, endothelin receptor antagonist, pulmonary arterial hypertension
How to cite this article:
Raja SG, Dreyfus GD. Current status of bosentan for treatment of pulmonary hypertension. Ann Card Anaesth 2008;11:6-14 |
How to cite this URL:
Raja SG, Dreyfus GD. Current status of bosentan for treatment of pulmonary hypertension. Ann Card Anaesth [serial online] 2008 [cited 2021 Nov 27];11:6-14. Available from: https://www.annals.in/text.asp?2008/11/1/6/38443 |
Pulmonary arterial hypertension (PAH) is a progressive disease with substantial morbidity and mortality. In the last few years, significant progress has been made in the understanding of the pathogenesis [Figure - 1] and course of the disease. One of the key peptides in the pathogenesis of PAH is endothelin. Endothelin is a potent endogenous vasoconstrictor that is increased in individuals with PAH. The development of bosentan (Tracleer® , Actelion), a novel, well-tolerated orally active endothelin antagonist, has significantly changed the therapeutic approach to PAH [1] [Table - 1]. Recent clinical trials have demonstrated that treatment with bosentan produces favourable effects on cardiopulmonary haemodynamics, exercise capacity, World Health Organization (WHO) functional class (Appendix I) and time to clinical worsening in PAH. This article focuses on the role of endothelin in the pathogenesis and progression of pulmonary vascular disease and the efficacy and safety of bosentan as an emerging therapeutic option for the treatment of PAH.
| Endothelin and the Pathogenesis of Pulmonary Hypertension | |  |
The endothelins are a family of 21 amino-acid peptides that play a key role in the regulation of the vascular tone. The first member of this family identified was endothelin-1 (ET-1), a 2492-dalton peptide with potent vasoconstrictor properties, isolated by Yanagisawa et al. in 1988. [2] Two additional endothelin isopeptides - ET-2 and ET-3 - were subsequently discovered. The ET-1 appears to play the most prominent role in vascular control.
The majority of ET-1 secreted from cultured endothelial cells occurs from the abluminal side of the cells towards the adjacent vascular smooth muscle cells that contain specific endothelin receptors. [3] Thus, it is important to note that although circulating ET-1 can be detected in the plasma and may have important clinical correlations with pulmonary vascular disease, these plasma levels may not necessarily reflect the paracrine action of ET-1 on adjacent smooth muscle cells. [4]
In patients with PAH, several derangements in ET-1 expression and activity have been demonstrated. Serum ET-1 levels are higher in patients with idiopathic pulmonary arterial hypertension (IPAH, formerly called primary pulmonary hypertension) compared with healthy controls [5] with a correlation between serum ET-1 levels and pulmonary haemodynamics. [6] In addition, lung specimens from patients with IPAH when compared to those from patients without pulmonary hypertension exhibit increased ET-1 staining of the muscular pulmonary arteries. [7] High levels of endothelin receptor A (ET A ) density and circulating ET-1 have also been observed in patients with congenital cardiac lesions, which in some instances decrease following the surgical correction of the cardiac lesions. [8]
Endothelin also has a pathogenetic role in chronic thromboembolic pulmonary hypertension [4] with increased activity of the ET-1 system observed in the pathological studies on both animals [9] and humans [10] .
Endothelin receptors
There are two distinct guanine nucleotide-binding (G) proteins-connected receptors, ET A and ET B , for the endothelin family of peptides. [11] These two receptors have unique locations [12] and binding affinities [13] for the endothelin peptides. The ET A receptors are expressed on pulmonary vascular smooth muscle cells, whereas ET B receptors are located on both pulmonary vascular endothelial cells and smooth muscle cells.
The activation of the ET A receptor located in pulmonary vascular smooth muscle cells mediates a potent vasoconstrictive response that is thought to occur via G-protein-induced phospholipase C activation: 1, 4, 5-inositol triphosphate formation with the consequent release of calcium (Ca 2+ ) from intracellular stores. [11] There is also evidence that the ET A receptor mediates increased intracellular calcium by activating nonselective calcium channels on the surface of the smooth muscle cells. [14] The vasoconstriction induced by ET A has been shown to persist even after ET-1 is removed from the receptor, likely due to the persistently elevated concentrations of intracellular Ca 2+ . [15]
ET-1 apart from having powerful vasoconstricting effects is also known to be a potent mitogen with the ability to induce cell proliferation in a number of cell types, including vascular smooth muscle cells. [16] It has been shown that the mitogenic actions of ET-1 are mediated by both the ET A [17] and ET B [18] receptors.
In the normal pulmonary vasculature, ET B receptors are predominantly expressed on endothelial cells. [19] The ET B receptors on endothelial cells mediate vasodilation via the increased production of nitric oxide and prostacyclin. [19],[20] Nitric oxide and prostacyclin also negatively feed back on ET-1 activity by the inhibition of preproendothelin-1 transcription. In addition, ET-1 is cleared by ET B receptors.
Data suggest that the ET B receptor does not exclusively mediate pulmonary vasodilation. Under certain circumstances, it may actually contribute to pulmonary vasoconstriction through a population of ET B receptors located on the vascular smooth muscle cells. [21] The vasoconstrictive actions of the ET B receptor may become more pronounced in the pathological setting of pulmonary hypertension, [22] possibly due to upregulation of ET B receptors in states of pulmonary hypertension. [23] The functions of both receptors under pathological conditions may therefore determine whether antagonising one or both receptors is preferable.
| Pharmacology of Bosentan | | |
Pharmacokinetics
Bosentan is a dual endothelin receptor antagonist, which competitively antagonises the binding of endothelin to both endothelin receptors ET A and ET B [24] [Figure - 2]. Bosentan is an orally active, highly substituted pyrimidine derivative (4-tert-butyl- N -[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide) with a molecular weight of 569.64 and the molecular formula C 27 H 29 N5 O6 S-H2 O. [25]
Bosentan attains peak plasma concentrations after approximately 3 h following oral administration. The absolute bioavailability is approximately 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. [26] During multiple-dose administration, bosentan has a volume of distribution of 30 L and a clearance of 17 L/h with approximately 98% bound to albumin. The terminal half-life after oral administration is 5.4 h and is unchanged at steady state. [26] Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, while plasma concentrations are decreased by approximately 50% because of a 2-fold increase in clearance, probably due to the induction of metabolising enzymes. Bosentan is mainly metabolised in the liver and its metabolites are excreted in the bile. Three metabolites have been identified to be formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following the administration of bosentan. [26]
The pharmacokinetics of bosentan are dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure to bosentan. Severe renal impairment (creatinine clearance: 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. [26]
Drug interactions
Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan induces CYP3A4 and/or CYP2C9 and hence decreases the exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50%. [26] The co-administration of ciclosporin and bosentan markedly increases the initial bosentan trough concentrations. The concomitant administration of ciclosporin and glibenclamide is contraindicated and not recommended due to an increase in the incidence of aminotransferase elevations. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin [Table - 2].
Pharmacodynamics
Bosentan is specific for ET receptors and does not interfere with receptors or binding of other neurotransmitters, peptides, growth factors or eicosanoids. [27] It produces systemic and pulmonary vasodilatation by acting as a competitive antagonist of ET to both ET A and ET B receptor subtypes, thereby blocking the biological consequences of ET receptor activation. [25] Binding and functional experiments with bosentan have demonstrated a receptor affinity ratio (ET A /ET B ) of 20:1, portending an enhanced vasodilatory role in PAH by reducing ET A receptor activation. [27]
Therapeutic efficacy of bosentan is also associated with pulmonary vascular remodelling as well as possible antifibrotic and anti-inflammatory properties within the pulmonary vasculature, as shown by studies on animals [Table - 3]. [9],[28],[29],[30],[31]
Adverse effects
The most significant adverse effects associated with bosentan use are the potential for serious liver injury and major birth defects, leading the FDA to mandate the manufacturer of bosentan, Actelion, to place a black box warning on the package labelling. [25] The dose-dependent asymptomatic elevation of serum aminotransferase concentrations and abnormal liver function were more frequently observed in patients receiving bosentan in study 351 [32] and BREATHE-1 trial. [33] However, serum aminotransferase concentrations returned to normal without discontinuation of the drug or change of the dose in study 351. [32]
Other most common adverse events experienced by patients receiving bosentan for treatment of PAH in the various trials were headache (22%), nasopharyngitis (11%), flushing (9%), hepatic function abnormality (8%) and lower extremity oedema (8%). Overall, the discontinuance of the therapy due to adverse events was greater in those receiving bosentan (5%) than placebo (3%). Abnormal liver function, defined as serum aminotransferase levels >5 times the upper limit of normal or increase in bilirubin ≥2 times the upper limit of normal, occurred in >1% of patients treated for PAH, requiring the discontinuation of bosentan. [25],[32],[33]
The paediatric safety data are extremely limited. In the retrospective study that reported long-term outcomes for children with PAH, who were treated with bosentan therapy with or without concomitant prostanoid therapy, the most frequent adverse event was peripheral oedema ( n = 7, 8%). [34] Systemic hypotension was reported in three patients (3%). Fatigue that lead to discontinuation was observed in two patients (2%) 9 and 11 months after starting bosentan; which resolved following the discontinuation of bosentan and two patients (2%) with unrepaired congenital heart disease discontinued bosentan 5 and 7 months after starting bosentan because of systemic arterial oxygen desaturation. The systemic arterial oxygen saturation returned to baseline following the discontinuation of bosentan in one of these two patients. [34] Other major adverse effect was the asymptomatic increase in liver transaminases (above 2× the upper limit of normal) reported in 10 patients (12%).
Warning in pregnancy
Bosentan is rated as a pregnancy-risk category X. Pregnancy-risk category X is defined as follows: studies in animals or humans have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. Therefore, a pregnancy-risk category X drug is contraindicated in women who are or may become pregnant. The impairment of fertility/testicular function and potential for birth defects was observed in studies on animal. [25]
Monitoring
Pregnancy must be excluded before starting treatment with bosentan. Oral, injectable and implantable oestrogen/progesterone contraceptives should not be used as the sole method of contraception. Plasma levels of oral, injectable and implantable oestrogen/progesterone contraceptives are likely to be decreased due to the inducible effects of bosentan on CYP3A4, the most common route of metabolism for these agents.
Liver aminotransferases should be obtained at the baseline and then monthly after the initiation of treatment. Adjustments in dosage are done according to aminotransferases levels. If clinical symptoms accompany the rise in aminotransferases levels, bosentan should be discontinued.
Haemoglobin levels should be monitored at 1 and 3 months and every 3 months thereafter. Decreases in haemoglobin were noticed during the first few weeks of treatment.
| Dosage and Administration | | |
The initial oral dose for bosentan therapy is 62.5 mg twice daily for 4 weeks; further, it is increased to a maintenance dose of 125 mg twice daily. For patients weighing <40 kg but >12 years of age, an initial and maintenance dose of 62.5 mg twice daily is recommended. Dosage adjustments are not required in patients with renal insufficiency. Monthly pregnancy tests are required for women with childbearing potential due to the risk of birth defects. [25]
Baseline and monthly liver function tests are required during the therapy. Patients with elevated liver enzyme levels should undergo biweekly assessment and the use of bosentan should be avoided in patients with moderate to severe hepatic insufficiency. Dosage adjustments are recommended by manufacturers in patients experiencing elevated serum aminotransferase concentrations during the therapy. [25]
The evidence of acute rebound pulmonary hypertension has not been observed following the abrupt withdrawal of therapy; however, given the limited clinical experience with abrupt discontinuance, a dose reduction of 62.5 mg twice daily for 3-7 days has been recommended. [25]
| Clinical Efficacy | | |
Evidence of usage in adult patients
Bosentan received FDA approval for use in PAH based on efficacy data published from two randomised, double-blind, multicentre, placebo-controlled trials. [32],[33] The first multicentre double-blind, randomised, placebo-controlled study of chronic oral bosentan (Study 351) was performed by Channick and colleagues. [32] They randomly assigned 32 patients with pulmonary hypertension (primary or associated with scleroderma) to bosentan (62.5 mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index (Appendix II), WHO functional class and withdrawal due to clinical worsening. Analysis was by intention to treat. The authors found that in patients administered with bosentan, the distance walked in 6 min improved by 70 m at 12 weeks as compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], P = 0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L/min/m 2 (95% CI 0.6-1.4, P < 0.0001) greater in patients administered with bosentan than in those administered with placebo. Pulmonary vascular resistance decreased by 223 dyne s cm -5 with bosentan, but increased by 191 dyne s cm -5 with placebo (difference -415 [-608 to -221], P = 0.0002). Patients administered with bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. There were three withdrawals from clinical worsening and all were in the placebo group ( P = 0.033), with similar number and nature of adverse events between the two groups.
The BREATHE-1 (Bosentan: Randomised Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension) trial was conducted in 213 patients with WHO class III ( n = 195) and IV ( n = 18) PAH despite the conventional therapy. [33] Subjects were randomised to receive bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg ( n = 74) or 250 mg ( n = 70) twice daily for 12 weeks or placebo ( n = 69). At week 16, patients treated with bosentan had an improved 6-min walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95% CI 21-67; P < 0.001). Bosentan also improved the Borg dyspnoea index and WHO functional class and increased the time to clinical worsening. [33]
Sitbon et al . [35] performed a 1-year follow-up of patients in Study 351. [32] In the follow-up study, 29 of the original 32 patients received bosentan for an additional year (62.5 mg b.i.d for 4 weeks and then 125 mg b.i.d). After 6 months, assessed patients who continued on bosentan treatment maintained the improvement in walking distance observed at the end of the previous study (mean ± SEM, 60 ± 11 m) and patients starting bosentan treatment improved their walking distance by 45 ± 13 m. Long-term treatment with bosentan for >1 year was associated with an improvement in haemodynamic parameters and modified NYHA functional class. Overall, bosentan treatment was well tolerated. No patient underwent transplantation or died. [35]
The Combination of bosentan with epoprostenol therapy in patients with PAH has also been shown to improve haemodynamics or clinical outcomes in a double-blind, placebo-controlled, prospective, randomised trial. [36] BREATHE-2 study assessed the efficacy and safety of combining bosentan and epoprostenol, a continuously infused prostaglandin, in the treatment of PAH. [36] Thirty-three patients with PAH started epoprostenol treatment (starting dose of 2 ng/kg/min up to 14 ± 2 ng/kg/min at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all the measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). The findings of the BREATHE-2 trial have been verified by a recently published prospective, nonrandomised, open-label study. [37]
Evidence of usage in paediatric patients
Data on bosentan therapy for PAH in children are extremely limited. In an open-label study involving children with PAH, the safety and efficacy of bosentan appeared comparable to the results previously reported in adult patients with PAH. [38] In this two-centre, open-label study, 19 paediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use. Patients weighing between 10 and 20 kg, 20 and 40 kg or greater than 40 kg received a single dose of 31.25, 62.5 or 125 mg, respectively on day 1, and this was followed by 4 weeks of treatment with the initial dose. The dose was then up-titrated to the target dose (31.25, 62.5 or 125 mg twice daily). Pharmacokinetic and haemodynamic parameters were obtained at baseline and after 12 weeks of treatment. Six-minute walking distance and cardiopulmonary exercise testing results were measured at baseline and at week 12 in children aged 8 years or older. The variability in exposure among the 3 groups was less than 2-fold after single- and multiple-dose administration. The exposure to bosentan decreased over time in all the groups. The covariates body weight, gender, age and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan. Bosentan produced haemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was -8.0 mmHg (95% CI -12.2 to -3.7 mmHg) and that in pulmonary vascular resistance index was -300 dyne s cm -5 m 2 (95% CI -576 to -24 dyne s cm -5 m 2 ). [38]
A recently published study reports the long-term outcome of children with PAH treated with bosentan therapy with or without concomitant prostanoid therapy. [34] In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. The data for haemodynamics, WHO functional class and safety were collected. At the cut-off date, 68 patients (79%) were still treated with bosentan, 13 (15%) discontinued the treatment and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients ( n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 ± 3 mmHg to 57 ± 3 mmHg, P = 0.005 and 20 ± 2 U m 2 to 15 ± 2 U m 2 , P = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at 1 and 2 years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. [34]
A recently published Cochrane systematic review also suggests that bosentan in conjunction with conventional therapy over 12-16 weeks can improve exercise capacity, Borg dyspnoea scores and several cardiopulmonary haemodynamics variables in patients mainly with idiopathic PAH. [39]
Current status of bosentan in the treatment algorithm of pulmonary arterial hypertension
Bosentan received approval in 2001/2002 by a number of regulatory agencies, both in Europe as well as in Canada and the United States of America. The approved indications are PAH, with functional class III or IV [Figure - 3]. For WHO functional class III and possibly early class IV patients who are not acutely vasoreactive or who have failed calcium channel blocker therapy, bosentan should be considered as the initial treatment of choice, based on compelling short- and long-term data. For patients with significant haemodynamic decline, particulary those with signs of overt right ventricular failure or those who progress to WHO functional class IV, epoprostenol remains the initial therapy of choice. The addition of bosentan to epoprostenol is a potentially attractive approach as the two agents work through different and possibly complementary mechanisms.
| Conclusion | | |
Bosentan is emerging as a promising therapeutic option for the treatment of pulmonary hypertension of varied origin. Because it is administered orally, bosentan offers convenient dosing and thereby avoids the complications as well as costs associated with the administration of intravenous medications requiring central venous access. However, rigorous, blinded, placebo-controlled, multicentre randomised clinical trials are required to establish the safety of long-term bosentan therapy as well as to confirm its efficacy as a combination therapy with other drugs available for the treatment of PAH.
| References | | |
| 1. | O'Callaghan D, Gaine SP. Bosentan: A novel agent for the treatment of pulmonary arterial hypertension. Int J Clin Pract 2004;58:69-73.  [PUBMED] [FULLTEXT] |
| 2. | Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al . A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411-5. [PUBMED] [FULLTEXT] |
| 3. | Yoshimoto S, Ishizaki Y, Sasaki T, Murota S. Effect of carbon dioxide and oxygen on endothelin production by cultured porcine cerebral endothelial cells. Stroke 1991;22:378-83. [PUBMED] |
| 4. | Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:62S-7S. [PUBMED] [FULLTEXT] |
| 5. | Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464-9. [PUBMED] |
| 6. | Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al . Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9. [PUBMED] [FULLTEXT] |
| 7. | Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998;114:208S-12S. [PUBMED] [FULLTEXT] |
| 8. | Ishikawa S, Miyauchi T, Sakai S, et al . Elevated levels of plasma endothelin-1 in young patients with pulmonary hypertension caused by congenital heart disease are decreased after successful surgical repair. J Thorac Cardiovasc Surg 1995;110:271-3. [PUBMED] [FULLTEXT] |
| 9. | Kim H, Yung GL, Marsh JJ, et al . Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000;15:640-8. [PUBMED] [FULLTEXT] |
| 10. | Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schafers HJ. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105:1034-6. |
| 11. | Takuwa Y, Kasuya Y, Takuwa N, Kudo M, Yanagisawa M, Goto K, et al . Endothelin receptor is coupled to phospholipase C via a pertussis toxin-insensitive guanine nucleotide-binding regulatory protein in vascular smooth muscle cells. J Clin Invest 1990;85:653-8. [PUBMED] [FULLTEXT] |
| 12. | Benigni A. Defining the role of endothelins in renal pathophysiology on the basis of selective and unselective endothelin receptor antagonist studies. Curr Opin Nephrol Hypertens 1995;4:349-53. [PUBMED] |
| 13. | Masaki T. The discovery of endothelins. Cardiovasc Res 1998;39:530-3. [PUBMED] [FULLTEXT] |
| 14. | Iwamuro Y, Miwa S, Zhang XF, Minowa T, Enoki T, Okamoto Y, et al . Activation of three types of voltage-independent Ca2 + channel in A7r5 cells by endothelin-1 as revealed by a novel Ca2 + channel blocker LOE 908. Br J Pharmacol 1999;126:1107-14. [PUBMED] [FULLTEXT] |
| 15. | Clarke JG, Benjamin N, Larkin SW, Webb DJ, Davies GJ, Maseri A. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989;257:H2033-5. [PUBMED] [FULLTEXT] |
| 16. | Chua BH, Krebs CJ, Chua CC, Diglio CA. Endothelin stimulates protein synthesis in smooth muscle cells. Am J Physiol 1992;262:E412-6. [PUBMED] [FULLTEXT] |
| 17. | Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, et al . ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002;165:398-405. [PUBMED] [FULLTEXT] |
| 18. | Sugawara F, Ninomiya H, Okamoto Y, Miwa S, Mazda O, Katsura Y, et al . Endothelin-1-induced mitogenic responses of Chinese hamster ovary cells expressing human endothelin A: The role of a wortmannin-sensitive signaling pathway. Mol Pharmacol 1996;49:447-57. |
| 19. | Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, et al . Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993;91:1367-73. [PUBMED] [FULLTEXT] |
| 20. | de Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, et al . Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1988;85:9797-800. [PUBMED] [FULLTEXT] |
| 21. | Masaki T. Possible role of endothelin in endothelial regulation of vascular tone. Annu Rev Pharmacol Toxicol 1995;35:235-55. [PUBMED] [FULLTEXT] |
| 22. | Dupuis J, Jasmin JF, Prie S, Cernacek P. Importance of local production of endothelin-1 and of the ET(B) Receptor in the regulation of pulmonary vascular tone. Pulm Pharmacol Ther 2000;13:135-40. |
| 23. | Kuc RE, Davenport AP. Endothelin-A-receptors in human aorta and pulmonary arteries are downregulated in patients with cardiovascular disease: An adaptive response to increased levels of endothelin-1? J Cardiovasc Pharmacol 2000;36:S377-9. [PUBMED] [FULLTEXT] |
| 24. | Clozel M, Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Ann Med 2005;37:2-12. [PUBMED] |
| 25. | Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother 2003;37:1055-62. [PUBMED] [FULLTEXT] |
| 26. | Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan: A dual endothelin receptor antagonist. Clin Pharmacokinet 2004;43:1089-15. [PUBMED] |
| 27. | Roux S, Breu V, Ertel SI, Clozel M. Endothelin antagonism with bosentan: A review of potential applications. J Mol Med 1999;77:364-76. [PUBMED] [FULLTEXT] |
| 28. | Chen SJ, Chen YF, Meng QC, Durand J, Dicarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995;79:2122-31. [PUBMED] [FULLTEXT] |
| 29. | Filep JG, Fournier A, Foldes-Filep E. Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: Involvement of ETA and ETB receptors. Br J Pharmacol 1995;115:227-36. |
| 30. | Holm P, Liska J, Clozel M, Franco-Cereceda A. The endothelin antagonist bosentan: Hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs. J Thorac Cardiovasc Surg 1996;112:890-7. [PUBMED] [FULLTEXT] |
| 31. | Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997;156:600-8. [PUBMED] [FULLTEXT] |
| 32. | Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, 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. [PUBMED] [FULLTEXT] |
| 33. | Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al . Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903. [PUBMED] [FULLTEXT] |
| 34. | Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, et al . Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005;46:697-704. [PUBMED] [FULLTEXT] |
| 35. | Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, et al . Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: A 1-year follow-up study. Chest 2003;124:247-54. [PUBMED] [FULLTEXT] |
| 36. | Humbert M, Barst RJ, Robbins IM, Channick RN, Galiθ N, Boonstra A, et al . Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-9. |
| 37. | Seyfarth HJ, Pankau H, Hammerschmidt S, Schauer J, Wirtz H, Winkler J. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest 2005;128:709-13. [PUBMED] [FULLTEXT] |
| 38. | Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al . Pharmacokinetics, safety and efficacy of bosentan in paediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003;73:372-82. [PUBMED] |
| 39. | Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev 2006 Jul 19;3:CD004434. |
Correspondence Address:
Shahzad G Raja
Department of Cardiothoracic Surgery, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB9 6JH
United Kingdom
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0971-9784.38443
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3] |
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