scholarly journals Survival of patients with pulmonary arterial hypertension during therapy PAH-specific drugs

2017 ◽  
Vol 14 (3) ◽  
pp. 58-64
Author(s):  
D Yu Platonov ◽  
N A Tsareva ◽  
S N Avdeev
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Patient Survival ◽  
Morphological Changes ◽  
Pulmonary Arteries ◽  
Progressive Increase ◽  
Functional Disorders ◽  
Life Threatening ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a life threatening syndrome, which is characterized by a progressive increase in pulmonary vascular resistance (PVR), medium pulmonary artery pressure and functional disorders and morphological changes of pulmonary arteries. Despite the relative abundance of PAH-specific drugs, the choice of a suitable agent for the treatment of a particular patient remains challenging. One of the most important parameters measured in clinical studies is patient survival or, in some cases, mortality. Survival or mortality as secondary or components of the primary endpoint one way or another has been studied in clinical trials of drugs for the treatment of PAH. For tablets drugs for the treatment of some forms of PAH (sildenafil, riociguat, bosentan, macitentan, ambrisentan) currently available data studies, which studied the survival.

scholarly journals Echocardiography and Pulmonary Arterial Hypertension

2016 ◽  
Vol 68 (4) ◽  
Author(s):  
Eduardo Bossone ◽  
Rodolfo Citro ◽  
Alberto Ruggiero ◽  
Bettina Kuersten ◽  
Giovanni Gregorio ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Progressive Increase ◽  
Accurate Estimate ◽  
Therapeutic Interventions ◽  
Wide Range ◽  
Advanced Stages ◽  
Pulmonary Arterial

Pulmonary Arterial Hypertension (PAH) is an heterogeneous condition brought on by a wide range of causes. It is characterized by structural changes in small pulmonary arteries, that produce a progressive increase in pulmonary artery pressure and pulmonary vascular resistance, ultimately leading to right ventricle failure and death. Given the non-specific nature of its early symptoms and signs, PAH is often diagnosed in its advanced stages. Along with a careful clinical assessment and an accurate electrocardiogram/Chest X-ray interpretation, echocardiography is an essential test in the evaluation of patient with PAH. In fact it not only provides an accurate estimate of pulmonary pressure at rest and during exercise, but may also help to exclude any secondary causes, predict the prognosis, monitor the efficacy of specific therapeutic interventions and detect the preclinical stage of the disease.

scholarly journals Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Yahan Liu ◽  
Xiao Yu Tian ◽  
Yu Huang ◽  
Nanping Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Progressive Increase ◽  
Differential Regulation ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptorγ(PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγagonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence ofL-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increasedETBRbut decreasedETARlevel in pulmonary arteries from PAH rats.ETBRantagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγagonists in PAH.

scholarly journals Present and Prospective Pharmacotherapies in Pulmonary Arterial Hypertension

2009 ◽  
Vol 1 ◽  
pp. CMT.S2108
Author(s):  
Jennifer A. Johnson ◽  
Anna R. Hemnes
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Patient Preference ◽  
Progressive Disease ◽  
Pulmonary Arteries ◽  
Review Article ◽  
Efficacy And Safety ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease leading to obstruction of the small pulmonary arteries. Currently, there are eight approved medications for PAH. This review article focuses on the mechanisms, clinical trials, efficacy, and safety profiles of each of the PAH medications. In addition, this review addresses combination PAH therapy, patient preference, and future therapies.

scholarly journals A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension

2018 ◽  
Vol 51 (6) ◽  
pp. 1702638 ◽  
Author(s):  
Anna R. Hemnes ◽  
Anandharajan Rathinasabapathy ◽  
Eric A. Austin ◽  
Evan L. Brittain ◽  
Erica J. Carrier ◽  
...  
Keyword(s):  
Pilot Study ◽  
Pulmonary Arterial Hypertension ◽  
Angiotensin Converting Enzyme ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Converting Enzyme ◽  
Open Label ◽  
Angiotensin Converting Enzyme 2 ◽  
Markers Of Inflammation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Abstract 3570: A Critical and Novel Role of Nogo (Neurite Outgrowth Inhibitor) in Pulmonary Arterial Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Gopinath Sutendra ◽  
Sebastien Bonnet ◽  
Paulette Wright ◽  
Peter Dromparis ◽  
Alois Haromy ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Nuclear Translocation ◽  
Pulmonary Arteries ◽  
Over Expression ◽  
Nfat Activation ◽  
Pulmonary Arterial ◽  
Systemic Arteries

Nogo was first identified as an inhibitor of neuronal axonal regeneration. Recently, Nogo-B was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced Nogo-B expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels, Nogo-B expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that Nogo is involved in the pathogenesis of PAH . Nogo −/− mice (n=7) had a normal phenotype and, in contrast to Nogo +/+ , did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table ). CH- Nogo +/+ PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca ++ ] i (FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH- Nogo −/− PASMC while all were induced in normoxic Nogo +/+ PASMC by adenoviral over-expression of Nogo-B . Heterozygote CH- Nogo +/− (n=7) values were between Nogo −/− and Nogo +/+ suggesting a gene dose-dependent effect. Nogo is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype. Nogo targeting might represent a novel and selective therapeutic strategy for PAH. Table

Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kenzo Ichimura ◽  
Tetsuya Matoba ◽  
Ryoji Nagahama ◽  
Kaku Nakano ◽  
Kenji Sunagawa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Intravenous Administration ◽  
Pulmonary Arteries ◽  
Intratracheal Instillation ◽  
Poly Lactic Acid ◽  
Bolus Administration ◽  
Sprague Dawley ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT). Methods and Results: Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier). Conclusion: A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.

A Semi-Automated Term Harmonization Pipeline Applied to Pulmonary Arterial Hypertension Clinical Trials

2021 ◽  
Author(s):  
Ryan J. Urbanowicz ◽  
John H. Holmes ◽  
Dina Appleby ◽  
Vanamala Narasimhan ◽  
Stephen Durborow ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
System Organ Class ◽  
High Level Group ◽  
Fuzzy Matching ◽  
Pulmonary Arterial ◽  
High Level ◽  
Level Group ◽  
System Organ

Abstract Objective Data harmonization is essential to integrate individual participant data from multiple sites, time periods, and trials for meta-analysis. The process of mapping terms and phrases to an ontology is complicated by typographic errors, abbreviations, truncation, and plurality. We sought to harmonize medical history (MH) and adverse events (AE) term records across 21 randomized clinical trials in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Methods We developed and applied a semi-automated harmonization pipeline for use with domain-expert annotators to resolve ambiguous term mappings using exact and fuzzy matching. We summarized MH and AE term mapping success, including map quality measures, and imputation of a generalizing term hierarchy as defined by the applied Medical Dictionary for Regulatory Activities (MedDRA) ontology standard. Results Over 99.6% of both MH (N = 37,105) and AE (N = 58,170) records were successfully mapped to MedDRA low-level terms. Automated exact matching accounted for 74.9% of MH and 85.5% of AE mappings. Term recommendations from fuzzy matching in the pipeline facilitated annotator mapping of the remaining 24.9% of MH and 13.8% of AE records. Imputation of the generalized MedDRA term hierarchy was unambiguous in 85.2% of high-level terms, 99.4% of high-level group terms, and 99.5% of system organ class in MH, and 75% of high-level terms, 98.3% of high-level group terms, and 98.4% of system organ class in AE. Conclusion This pipeline dramatically reduced the burden of manual annotation for MH and AE term harmonization and could be adapted to other data integration efforts.

scholarly journals Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

2020 ◽  
Vol 29 (155) ◽  
pp. 190089 ◽  
Author(s):  
Daniela Knafl ◽  
Christian Gerges ◽  
Charles H. King ◽  
Marc Humbert ◽  
Amaya L. Bustinduy
Keyword(s):  
Systematic Review ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Signalling Pathway ◽  
Pathophysiological Mechanisms ◽  
Clinical Registries ◽  
Life Threatening ◽  
Pulmonary Arterial

Schistosomiasis-associated pulmonary arterial hypertension (Sch-PAH) is a life-threatening complication of chronic hepatosplenic schistosomiasis. It is suggested to be the leading cause of pulmonary arterial hypertension (PAH) worldwide. However, pathophysiological data on Sch-PAH are scarce. We examined the hypothesis that there are pronounced similarities in pathophysiology, haemodynamics, and survival of Sch-PAH and idiopathic PAH (iPAH).This systematic review and meta-analysis was registered in the PROSPERO database (identifier CRD42018104066). A systematic search and review of the literature was performed according to PRISMA guidelines for studies published between 01 January 1990 and 29 June 2018.For Sch-PAH, 18 studies evaluating pathophysiological mechanisms, eight studies on haemodynamics (n=277), and three studies on survival (n=191) were identified. 16 clinical registries reporting data on haemodynamics and survival including a total of 5792 patients with iPAH were included for comparison. Proinflammatory molecular pathways are involved in both Sch-PAH and iPAH. The transforming growth factor (TGF)-β signalling pathway is upregulated in Sch-PAH and iPAH. While there was no difference in mean pulmonary artery pressure (54±17 mmHg versus 55±15 mmHg, p=0.29), cardiac output (4.4±1.3 L·min−1versus 4.1±1.4 L·min−1, p=0.046), and cardiac index (2.6±0.7 L·min−1·m−2versus 2.3±0.8 L·min−1·m−2, p<0.001) were significantly higher in Sch-PAH compared to iPAH, resulting in a lower pulmonary vascular resistance in Sch-PAH (10±6 Woods units versus 13±7 Woods units, p<0.001). 1- and 3-year survival were significantly better in the Sch-PAH group (p<0.001).Sch-PAH and iPAH share common pathophysiological mechanisms related to inflammation and the TGF-β signalling pathway. Patients with Sch-PAH show a significantly better haemodynamic profile and survival than patients with iPAH.

Enrichment Benefits of Risk Algorithms for Pulmonary Arterial Hypertension Clinical Trials

2020 ◽  
Author(s):  
Jacqueline V. Scott ◽  
Christine E. Garnett ◽  
Manreet K. Kanwar ◽  
Norman L. Stockbridge ◽  
Raymond L. Benza
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arterial
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