New Drugs, Therapeutic Strategies, and Future Direction for the Treatment of Pulmonary Arterial Hypertension

Mercurio, Valentina; Bianco, Anna Monica; Campi, Giacomo; Cuomo, Alessandra; Diab, Nermin; Mancini, Angela; Parrella, Paolo; Petretta, Mario; Hassoun, Paul M.; Bonaduce, Domenico

doi:10.2174/0929867325666180201095743

Cited by 23 publications

(19 citation statements)

References 140 publications

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“…Pulmonary hypertension is a syndrome that encompasses several diseases, all of which have in common increased pulmonary artery pressures ( Handler and Coghlan, 2010 ). Currently, prostacyclin, ET antagonists, and phosphodiesterase type 5 inhibitors are the primary drugs to improve the quality of life of PAH patients and alleviate symptoms ( Jasinska-Stroschein and Orszulak-Michalak, 2014 ; Mercurio et al, 2018 ). However, no known agent can cure pulmonary hypertension ( Antel et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…It can be used as a vascular modulator in the development of PAH and provides symptomatic relief, but it fails to fully reverse the progression of the disease and reduce the high mortality rate ( Antel et al, 2010 ; Galie et al, 2016 ). Currently, novel approaches and more effective agents are urgently needed for the treatment of PAH ( Mercurio et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

et al. 2018

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Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a tetracyclic antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

et al. 2018

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“…Bosentan was studied in the Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1) trial, where the magnitude of improvement in 6MWD of SSc–PAH patients was lower than the one of idiopathic PAH patients, but still prevented the worsening of the disease clinically [ 58 ]; moreover, it proved in the Randomized, Double-Blind, Placebo-Controlled Study with Bosentan on the Healing and Prevention of Ischemic Digital Ulcers in Patients with Systemic Sclerosis (RAPIDS-2) study to prevent the formation of digital ulcers, but not their healing rate [ 59 ]. Finally, macitentan, a newer molecule of this class of drugs, demonstrated a safer hepatotoxicity profile [ 60 ] and proved to reduce the mortality of PAH patients in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial, with similar results between CTD–PAH and idiopathic PAH patients [ 61 , 62 ]. A further analysis on the use of macitentan in SSc–PAH was offered from the OPsumit USers (OPUS) prospective registry, which characterized the use and safety profile of this drug in a real-world setting, where patients who has recently started a therapy with macitentan were eligible for enrollment in this registry.…”

Section: Molecular Pathways Targeted By Pah-specific Therapiesmentioning

confidence: 99%

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment

Attanasio

Cuomo

Pirozzi

et al. 2020

IJMS

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Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.

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“…Pulmonary hypertension (PH) is a progressive, incurable disorder that complicates the majority of cardiovascular and respiratory diseases 1 , 2 . According to the 6th World Symposium on Pulmonary Hypertension of 2018, the updated clinical classification includes five types of PH 3 .…”

Section: Introductionmentioning

confidence: 99%

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction

Chen¹,

Lin²,

Liu³

et al. 2020

Int. J. Med. Sci.

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Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

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New Drugs, Therapeutic Strategies, and Future Direction for the Treatment of Pulmonary Arterial Hypertension

Cited by 23 publications

References 140 publications

Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction

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