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Pulmonary Arterial Hypertension: Role of Ambrisentan

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Pulmonary Arterial Hypertension: Role of Ambrisentan American Journal of Advanced Drug Delivery www.ajadd.co.uk Review Article Pulmonary Arterial Hypertension: Role of Ambrisentan Pranay Wal*1, Ankita Wal2, Shweta Tripathi2 and Dr. Awani K Rai2 1Jodhpur National University, Jodhpur, India. 2Assistant Professor, Pranveer Singh Institute of Technology, bhauti road, Kanpur (U.P) 208020. India. Date of Receipt- 14/09/2013 ABSTRACT Date of Revision- 28/09/2013 Date of Acceptance- 29/09/2013 Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system.Ambrisentan (LU 208075)approved by the US Food and Drug Administration in 2007, a selective ETA-receptor antagonist, is an orally active diphenyl propionic acid derivative that was recently approved for treatment of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms.. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties. Therefore, blockade of ET receptors has been suggested as an attractive target in a number Address for of acute and chronic cardiovascular indications, including pulmonary Correspondence arterial hypertension (PAH), systemic hypertension, and heart failure. Jodhpur National In Phase III clinical trials in patients with PAH, ambrisentan (2.5–10 University, Jodhpur, mg orally once-daily) improved exercise capacity, time to clinical India. worsening, WHO functional class, and quality of life compared with Phone number: +91- placebo. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary 9795967709 . hypertensive diseases. E-mail: Keywords: Pulmonary Hypertension, Endothelin, Endothelin [email protected] receptor antagonist, Ambrisentan. American Journal of Advanced Drug Delivery www.ajadd.co.uk Wal et al_______________________________________________________ ISSN 2321-547X INTRODUCTION Pulmonary Arterial Hypertension (PAH) PAH differs from ordinary percent of patients), fatigue, dizziness, hypertension, which is high blood pressure syncope or fainting (present in 13 percent of throughout the body. In PAH, the high blood patients), weakness (present in 19 percent of pressure is in the arteries between the heart patients), peripheral edema, and chest pains and lungs. This causes the blood vessels that during physical activity. A key factor go from the heart to the lungs (or pulmonary underlying the increase in pulmonary arteries) to become tight, thick, and stiff. vascular resistance in PAH is thought to be Typically, the pulmonary arteries are open pulmonary endothelial dysfunction, and elastic, which creates no resistance to involving impaired production of blood flow.1 Pulmonary arterial vasodilators, such as nitric oxide (NO) and hypertension (PAH) is defined as a blood prostacyclin, and overexpression of pressure elevation in the vessels supplying vasconstrictors, such asendothelin-1.11 the lung. It is characterized by vasoconstriction and vascular obstruction The Venice 2003 Revised Classification that eventually lead to increased pulmonary system is12 : vascular resistance and right heart failure.2 WHO Group I - Pulmonary arterial As the disease progresses, patients hypertension experience a progressive rise in pulmonary WHO Group II - Pulmonary artery pressure and pulmonary vascular hypertension associated with left heart resistance which leads to heart failure and disease 3,4,5 premature death. These high pressures WHO Group III - Pulmonary make it difficult for the heart to pump blood hypertension associated with lung 6 through the lungs to be oxygenated. It was diseases and/orhypoxemia previously defined as mean pulmonary WHO Group IV - Pulmonary artery pressure (MPAP)>25 mmHg at rest or hypertension due to chronic thrombotic >30 mmHg with exercise, but the definition and/or embolicdisease was simplified to resting (MPAP) WHO Group V – Miscellaneous. ≥25mmHg based on a review of current 7 literature in 2008. At the same time, Over the last 13 years, 6 drugs pulmonary vascular tone may be increased comprising 3 different drug classes have and the ability of the pulmonary circulation been approved for the treatment of PAH in to dilate or recruit underutilized vessels in 8 the US (Table 1). response to increased flow is reduced. The five-group World Health These changes result in a progressive Organization (WHO) classification scheme increase in pulmonary vascular was last updated in 2008 at the 4th World resistance(PVR) that increases right Symposium on Pulmonary Hypertension ventricular afterload, reduces exercise (Table 2). Patients in WHO Group1 are tolerance and in most cases results in right 9 classified as having pulmonary arterial ventricular failure. hypertension (PAH), whereas patients in A key problem in treating PAH is 10 Groups 2 to 5 are classified as non-PAH or the difficulty in confirming the diagnosis. PH. Group 1 adds the criterion of pulmonary The early common symptoms include: arterial wedge pressure of ≤15 mmHg and breathlessness or dyspnea (present in 60 pulmonary vascular resistance (PVR) of ≥3 AJADD[1][4][2013]572-595 Wal et al_______________________________________________________ ISSN 2321-547X Wood’s units. Group 1 also include increase in vasoconstrictor and proliferative sidiopathic and drug- and toxin-induced mediators and a decrease in vasodilator and PAH.13 The World Health Organization antiproliferative mediators.23 (WHO) classification of PAH is based on Among the currently targeted patients’ function, with class I signifying therapies licensed in the U.S. for use in PAH no limitation of usual daily physical activity, are: the ETRAs (ambrisentan and bosentan), class II indicating mild limitation of physical the PDE-5s (sildenafil and tadalafil), and the activity, class III representing marked prostaglandins (epoprostenol, iloprost, and limitation of physical activity, and class IV treprostinil). Clinical trials with these indicating inability to perform any physical targeted therapies have demonstrated activity at rest, with possible signs of right- improvements in exercise capacity, ventricular failure.14 hemodynamics, symptoms, and quality of 24 The diagnosis of PAH is based on life. right heart catheterization demonstrating a Data suggesting a role of the mean pulmonary artery pressure (PAP) endothelins in the pathophysiology of PAH greater than 25 mm Hg with a normal left include elevated circulating levels of atrial pressure, as estimated by a pulmonary endothelin-1 (ET-1) in patients with PAH capillary wedge pressure (PCWP) less than and increased expression of ET-1 in plexi 25 15 mm Hg, and pulmonary vascular form lesions. Occluding the distal resistance (PVR) greater than 3 Wood pulmonary arteries of PAH patients. ET is units.15 one of many important neurohormones that However, due to the rate of disease play arole in the pathophysiology of PAH. progression and the incurability of PAH, the ET-1 is a potent vasoconstrictor produced in goals of therapy still focus upon:1) the endothelium of pulmonary artery smooth preventing clinical worsening; and 2) muscle cells. ETA receptors on the improving exercise capacity, functional endothelial cells stimulate vasoconstriction class, hemodynamics, survival and quality and proliferation while the ETB receptors are of life. The understanding of the thought to stimulate the release of NO and pathogenesisof PAH has increased PGI2, leading to vasodilation and substantially over the last few years,16 as counteracting the effects of ETA and have treatment options, including ultimately ET-1. In PAH, lessET-1 is prostaglandins and Potential cleared. Higher levels of ET-1 correspond 26 phosphodiesterase inhibitors17,18 and ET with more severe disease and prognosis. receptor antagonists.19,20 There are several mechanisms through which ET receptor The Endothelins antagonists might improve PAH and/or right ventricular hypertrophy and failure. In In 1985, Hickey et al described an addition to direct reduction of pulmonary endothelium-derived contractile factor that artery tone through blocking ET receptors was subsequently isolated and sequenced by localized on vascular smooth muscle cells, a Yanagisawa et al from porcine aortic endothelial cell cultures in 1988 and named reduction of vascular media hypertrophy and 27 thus a positive effect on vascular remodeling endothelin. The endothelins are a family of has been described in different preclinical naturally occurring peptides that include experiments.21,22 Progression of PAH is endothelin1(ET-1), endothelin-2 (ET-2), and accompanied by impaired endothelial cell endothelin-3 (ET-3). They are encoded by functioning that is characterized by an three different genes located on chromosomes 6, 1 and 20, respectively.28 Endothelins are AJADD[1][4][2013]572-595 Wal et al_______________________________________________________ ISSN 2321-547X mainly produced by vascular endothelial exhibit similar affinities
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