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Endothelin
receptor antagonists are a new class of drugs for the treatment
of a number of major diseases, including pulmonary
arterial hypertension. Endothelin is a peptide made by the body
in the endothelium (a layer of cells which line the heart and blood
vessels). Endothelin constricts blood vessels and elevates blood
pressure. Endothelin is a potent vasoconstrictor that plays an important
role in blood flow.
Endothelin
and Pulmonary Arterial Hypertension (PAH):
In PAH, the body produces excess endothelin, contributing to the
constriction of blood
vessels and affecting the blood pressure in the lungs. Although
endothelin is present in healthy people, high concentrations of
the substance have been found in the plasma and lungs of patients
with PAH suggesting it is capable of causing PAH or increasing the
symptoms of PAH
How ETRAs
Work:
Endothelin must connect with an endothelin receptor in order to
be activated. Endothelin receptor antagonists block endothelin receptors,
thereby limiting harmful excess endothelin in the blood vessels.
There are two classes of endothelin receptors: Endothelin A ET-A
and Endothelin ET-B receptors, which play significantly different
roles in regulating blood vessel diameter. The binding of endothelin
to ET-A receptors located on smooth muscle cells causes vasoconstriction,
whereas the binding of endothelin to ET-B receptors located on the
vascular endothelium causes vasodilatation through the production
of nitric oxide. This latter activity of the ET-B receptor is thought
to be counter-regulatory and protects against excessive vasoconstriction.
Two Kinds of ETRAs:
Two types of ETRAs have been developed: dual ETRAs, which block
the receptors for both ET-A and ET-B, and selective ETRAs, which
block only the ET-A receptor.
There is debate over whether dual ETRAs or selective ETRAs are
more therapeutically useful. The argument for dual ETRAs is that
both endothelin receptors constrict blood vessels, but that ET-B
also dilates the vessels. Blocking both receptors limits the amount
of endothelin in the blood vessels. The argument for ET-A selective
ETRAs is that ET-B dilates the vessels and also removes excess endothelin
from circulation, so blocking only the ET-A receptor is the most
effective treatment.
Dual Endothelin Receptor Antagonist:
The first generation ETRAs are non-selective and block both the
ET-A and ET-B receptors. Tracleer is the first FDA approved ETRA
and it is a dual ETRA.
Selective Endothelin Receptor Antagonist:
Second generation ETRAs bind to the ET-A receptor in preference
to the ET-B receptor.
Letairis™ (Ambrisentan)
Tracleer®
(Bosentan)
Tracleer™ Frequently
Asked Questions
Recent items from the PHCentral Newsroom:
-
Phase III Study Initiated With Actelion-1
(Actelion) -- Actelion Ltd announced today the initiation of the phase III study SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) for its highly potent, tissue-targeting endothelin receptor antagonist (ERA) Actelion-1 (ACT-064992). The study is designed to evaluate the safety and efficacy of Actelion-1 in delaying disease progression and mortality in patients with pulmonary arterial hypertension (PAH).
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The
information in this page was last updated: 08/22/2006 |
