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Session 6: Actual Applications and Future Perspectives
of Dual ETA/ETB Antagonists
Benefits of dual endothelin receptor antagonists: Mechanisms
of action, current studies, and future directions
Martine Clozel
Actelion Pharmaceuticals Ltd., Drug Discovery Department, Switzerland
E-mail: martine.clozel@actelion.com
Over expression of endothelin (ET) and its receptors ETA and ETB
results in pathological changes including hypertrophy and fibrosis. These
changes are hallmarks of conditions such as pulmonary arterial
hypertension (PAH). Dual, but not single (ETA) endothelin receptor
antagonists (ERAs), have been shown to improve survival in animal
models of pulmonary hypertension and chronic heart failure. Hyper-
stimulation of ETB receptors following ETA receptor blockade by single
ERAs leads to increased vascular permeability and fluid retention. These
observations support the rationale that dual receptor antagonism may
have optimal efficacy and minimized risk of edema. Macitentan is a novel
dual ERA designed for optimized physicochemical properties, favoring
sustained receptor binding and enhanced tissue penetration. Macitentan
does not increase bile salts, the proposed underlying mechanism for
elevated liver enzymes observed with the dual ERA bosentan.
Macitentan was studied in the Phase III SERAPHIN trial, the first event-
driven, outcome trial in PAH. The study included over 740 patients.
Macitentan 10 mg reduced the risk of morbidity and mortality by 45%
versus placebo. Moreover, there was no difference in incidence of
peripheral edema or liver enzyme elevations between placebo and ma
citentan-treated patients. Current preclinical and clinical research on the
ET system highlights the potential for dual ERAs in other diseases. Future
directions may include the fields of scleroderma, pulmonary fibrosis,
heart diseases and oncology.
doi:10.1016/j.lfs.2013.12.109
Effects of bosentan on digital ulcers in patients with
systemic sclerosis
Yasushi Kawaguchi
Institute of Rheumatology, Tokyo Women's Medical University, Japan
E-mail: y-kawa@ior.twmu.ac.jp
Systemic sclerosis (SSc) is a connective tissue disease involving
tissue fibrosis and endothelial injury. In the 1990s, several studies
indicated that plasma endothelin (ET )-1 was elevated in patients
with SSc, which might contribute to endothelial injuries (i.e.:
Raynaud's phenomenon, digital ulcer, pulmonary hypertension, renal
dysfunction). Interestingly, ET-1 exerted a fibrotic effect inducing
collagen production in skin fibroblasts, suggesting that ET-1 might be
involved in both tissue fibrosis and endothelial injury in patients
with SSc. Digital ulcer in patients with SSc results from peripheral
vascular damage which related to an excessive vasoconstriction. That
may be refractory for the treatment with any prostanoids. The ability
of vasodilation in prostanoids could be almost equivalent to that in
endothelin receptor antagonist (ERA). However, prostanoids could
not exhibit anti-fibrotic properties, which may be different from the
effects of ERA. In this session, I am going to show the effects of
bosentan on digital ulcers in patients with SSc and to evaluate the
inhibitory effects of bosentan on the fibrogenic responses through
TGF-βin SSc fibroblasts.
doi:10.1016/j.lfs.2013.12.110
0024-3205/© 2013 The Authors. Published by Elsevier Inc.
Life Sciences 93 (2013) e28
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