Channick, R. N. et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 358, 1119-1123

Duke University, Durham, North Carolina, United States
The Lancet (Impact Factor: 45.22). 10/2001; 358(9288):1119-23. DOI: 10.1016/S0140-6736(01)06250-X
Source: PubMed


Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension.
In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg 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, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.
In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks 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(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups.
Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

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    • "Two approved ERAs have been used during the past years to treat patients with PAH, bosentan (Tracleer) and ambrisentan (Letairis/Volibris) [13], [14]. In 2013, the novel dual ERA macitentan (Opsumit) [15] demonstrated efficacy in a long-term event-driven phase 3 clinical trial [16] and has recently received marketing authorisation in many countries. "
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    ABSTRACT: The competitive endothelin receptor antagonists (ERA) bosentan and ambrisentan, which have long been approved for the treatment of pulmonary arterial hypertension, are characterized by very short (1 min) occupancy half-lives at the ETA receptor. The novel ERA macitentan, displays a 20-fold increased receptor occupancy half-life, causing insurmountable antagonism of ET-1-induced signaling in pulmonary arterial smooth muscle cells. We show here that the slow ETA receptor dissociation rate of macitentan was shared with a set of structural analogs, whereas compounds structurally related to bosentan displayed fast dissociation kinetics. NMR analysis showed that macitentan adopts a compact structure in aqueous solution and molecular modeling suggests that this conformation tightly fits into a well-defined ETA receptor binding pocket. In contrast the structurally different and negatively charged bosentan-type molecules only partially filled this pocket and expanded into an extended endothelin binding site. To further investigate these different ETA receptor-antagonist interaction modes, we performed functional studies using ETA receptor variants harboring amino acid point mutations in the presumed ERA interaction site. Three ETA receptor residues significantly and differentially affected ERA activity: Mutation R326Q did not affect the antagonist activity of macitentan, however the potencies of bosentan and ambrisentan were significantly reduced; mutation L322A rendered macitentan less potent, whereas bosentan and ambrisentan were unaffected; mutation I355A significantly reduced bosentan potency, but not ambrisentan and macitentan potencies. This suggests that - in contrast to bosentan and ambrisentan - macitentan-ETA receptor binding is not dependent on strong charge-charge interactions, but depends predominantly on hydrophobic interactions. This different binding mode could be the reason for macitentan's sustained target occupancy and insurmountable antagonism.
    PLoS ONE 09/2014; 9(9):e107809. DOI:10.1371/journal.pone.0107809 · 3.23 Impact Factor
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    • "The most frequent severe side effect of bosentan is known to be liver toxicity [4-8]. The package insert of bosentan indicates that the incidence of liver toxicity is 14.3% in Japanese clinical studies and 11% in US clinical studies [9]. "
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    ABSTRACT: Introduction Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation. Case presentation We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud’s phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy. Conclusions These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan.
    Journal of Medical Case Reports 07/2014; 8(1):250. DOI:10.1186/1752-1947-8-250
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    • "Sildenafil improves exercise capacity and reduces PAP [6]. Bosentan reduces PAP and improves exercise capacity as well as functional class in patients with PAH [7] [8]. A combination of a PDE-5 inhibitor and endothelin-1 receptor antagonist is standard therapy for advanced PAH [9]. "

    Pharmacology & Pharmacy 12/2013; 04(07):542-548. DOI:10.4236/pp.2013.47078
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