Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Applying Pharmacogenomics in the Therapeutics of Pulmonary Diseases
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although it can occur at any age. People who are at increased risk for PH include
those with a family history, 120 those with certain diseases or conditions, 121 those who
use street drugs (e.g., cocaine) or certain diet medicines (e.g., fenfluramine), 122–127
and those who live at high altitudes. 128,129
Therapy for Pulmonary Hypertension
Treatments, including medicines, procedures, and other therapies, as well as lifestyle
changes have been targeted to relieve PH symptoms and slow the progress of the disease.
Among the five PH groups, PAH is the most studied group and, therefore, all of
the currently available drug classes, such as prostacyclin analogs, endothelin receptor
antagonists, and phosphodiesterase (PDE) type 5 inhibitors have been developed to
treat PAH. Notably, significant progress in the understanding of the pathogenesis of
PAH has resulted in a shift from vasodilator therapy to the development of specific
drugs targeting seminal molecular derangements of this disorder. However, limited
treatment data exist for the non-PAH forms of PH that are currently less studied. The
major classes of treatments for PAH are summarized as follows.
Prostanoids
Prostanoids, such as epoprostenol and treprostinil, have vasodilator, antiproliferative,
and immunomodulatory effects and represent established therapies for severe
cases of PAH. In particular, continuous intravenous epoprostenol is a standard care
for individuals with serious or life-threatening PAH, and is also the most effective
therapy to date. 130 Epoprostenol is a prostacyclin (also called prostaglandin I2 or
PGI 2 ), a prostaglandin member of the family of lipid molecules known as eicosanoids.
Prostacyclin prevents formation of the platelet plug involved in primary
hemostasis by inhibiting platelet activation, 131 thus acting as an effective vasodilator.
Endothelin Receptor Antagonists
Endothelin receptor antagonists, such as bosentan, ambrisentan, and macitentan,
have been used to treat PAH by improving exercise ability and decreasing clinical
worsening. For example, bosentan is an effective, safe drug used for patients
with PAH at a dose of 125 mg twice daily. 132 Recent meta-analysis further suggests
that bosentan can treat PAH effectively with an increased incidence of abnormal
liver function testing compared with the placebo. 133 In a recent multicenter, doubleblinded,
randomized, placebo-controlled, and event-driven phase III trial, macitentan,
a new ETA/ETB antagonist, was shown to significantly reduce morbidity
and mortality among patients with PAH. 134 Notably, macitentan represents the latest
addition to the drug therapies for PAH. 135 Compared with other analogs, macitentan
is characterized by fewer contraindications, use in hepatic impairment, and oncedaily
administration. 136
Phosphodiesterase Type-5 Inhibitors
PDE5 inhibitors inhibit the degradation of cyclic guanosine monophosphate (cGMP),
which is catalyzed by PDE5. 137 Randomized clinical trials in monotherapy or combination
therapy have been conducted in PAH patients with PDE5 inhibitors sildenafil
and tadalafil, both of which can significantly improve clinical status, exercise