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Endothelin inhibitor

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https://www.readbyqxmd.com/read/28628863/simultaneous-quantification-of-endothelin-receptor-antagonists-and-phosphodiesterase-5-inhibitors-currently-used-in-pulmonary-arterial-hypertension
#1
Yeliz Enderle, Lukas Witt, Heinrike Wilkens, Ekkehard Grünig, Walter E Haefeli, Jürgen Burhenne
Combination treatment with endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) improved efficacy of pulmonary arterial hypertension (PAH) therapy. However, drug-drug interactions, variable exposure, non-adherence can influence plasma levels. For these reasons, drug quantification may be advantageous particularly in patients with poor treatment responses. We developed, validated, and applied an assay for the simultaneous quantification of ambrisentan, bosentan, macitentan, sildenafil, and tadalafil as well as their main (and partly active) metabolites in human plasma...
June 10, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28619112/docosahexaenoic-acid-regulates-vascular-endothelial-cell-function-and-prevents-cardiovascular-disease
#2
REVIEW
Kazuo Yamagata
Docosahexaenoic acid (DHA) is present in high concentrations in salmon, herring, and trout. Epidemiologic studies have shown that high dietary consumption of these and other oily fish is associated with reduced rates of myocardial infarction, atherosclerosis, and other ischemic pathologies. Atherosclerosis is induced by inflammation and can lead to acute cardiovascular events and extensive plaque. DHA inhibits the development of inflammation in endothelial cells, alters the function and regulation of vascular biomarkers, and reduces cardiovascular risk...
June 15, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28611287/vorinostat-suppresses-hypoxia-signaling-by-modulating-nuclear-translocation-of-hypoxia-inducible-factor-1-alpha
#3
Chao Zhang, Chunzhang Yang, Michael J Feldman, Herui Wang, Ying Pang, Dominic M Maggio, Dongwang Zhu, Cody L Nesvick, Pauline Dmitriev, Petra Bullova, Prashant Chittiboina, Roscoe O Brady, Karel Pacak, Zhengping Zhuang
Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28606996/targeting-endothelin-receptor-signalling-overcomes-heterogeneity-driven-therapy-failure
#4
Michael P Smith, Emily J Rowling, Zsofia Miskolczi, Jennifer Ferguson, Loredana Spoerri, Nikolas K Haass, Olivia Sloss, Sophie McEntegart, Imanol Arozarena, Alex von Kriegsheim, Javier Rodriguez, Holly Brunton, Jivko Kmarashev, Mitchell P Levesque, Reinhard Dummer, Dennie T Frederick, Miles C Andrews, Zachary A Cooper, Keith T Flaherty, Jennifer A Wargo, Claudia Wellbrock
Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a "MITF-high" phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance "AXL-high" phenotype. > 50% of melanomas progress with enriched "AXL-high" populations, and because AXL is linked to de-differentiation and invasiveness avoiding an "AXL-high relapse" is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF-induced expression of endothelin 1 (EDN1)...
June 12, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28605810/a-compact-whole-eye-perfusion-system-to-evaluate-pharmacologic-responses-of-outflow-facility
#5
Enhua H Zhou, Michael Paolucci, Thaddeus P Dryja, Ted Manley, Chuanxi Xiang, Dennis S Rice, Ganesh Prasanna, Amy Chen
Purpose: To discover novel therapies that lower IOP by increasing aqueous humor outflow facility, ex vivo ocular perfusion systems provide a valuable tool. However, currently available designs are limited by their throughput. Here we report the development of a compact, scalable perfusion system with improved throughput and its validation using bovine and porcine eyes. Methods: At a fixed IOP of 6 mm Hg, flow rate was measured by flow sensors. We validated the system by measuring the outflow responses to Y-39983 (a Rho kinase inhibitor), endothelin-1 (ET-1), ambrisentan (an antagonist for endothelin receptor A [ETA]), sphigosine-1-phosphate (S1P), JTE-013 (antagonist for S1P receptor 2 [S1P2]), S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide [NO] donor), and 3-Morpholino-sydnonimine (SIN-1, another NO donor)...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28597774/combination-therapy-in-pulmonary-arterial-hypertension-recent-accomplishments-and-future-challenges
#6
Annie-Christine Lajoie, Sebastien Bonnet, Steeve Provencher
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Throughout the past 20 years, numerous specific pharmacologic agents, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostaglandins, and more recently, soluble guanylate cyclase stimulators and selective IP prostacyclin receptor agonist, have emerged for the treatment of PAH. Early clinical trials were typically of short-term duration, comparing the effects of PAH-targeted therapies versus placebo and using exercise tolerance as the primary endpoint in most trials...
April 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28597771/first-in-child-use-of-the-oral-selective-prostacyclin-ip-receptor-agonist-selexipag-in-pulmonary-arterial-hypertension
#7
Lianne M Geerdink, Harald Bertram, Georg Hansmann
Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. Selexipag is a selective prostacyclin receptor agonist with vasodilatory, anti-proliferative, anti-inflammatory, and pro-angiogenic properties. However, no clinical data on its therapeutic use in children with PAH are currently available. Here, we report the case of a 12-year-old girl who presented in World Health Organization (WHO) functional class III and right ventricular (RV) failure with recurrent syncope, dizziness, and progressive fatigue for two years...
April 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28597766/identifying-super-responders-in-pulmonary-arterial-hypertension
#8
Stephen J Halliday, Anna R Hemnes
Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called "super responders...
April 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28597753/circulatory-power-and-ventilatory-power-over-time-under-goal-oriented-sequential-combination-therapy-for-pulmonary-arterial-hypertension
#9
Akihiro Hirashiki, Shiro Adachi, Yoshihisa Nakano, Yoshihiro Kamimura, Shigetake Shimokata, Kyosuke Takeshita, Atsuya Shimizu, Kenji Toba, Toyoaki Murohara, Takahisa Kondo
Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2 cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner...
April 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28597546/endothelin-1-receptor-blockade-as-new-possible-therapeutic-approach-in-multiple-myeloma
#10
Anna Russignan, Cecilia Spina, Nicola Tamassia, Adriana Cassaro, Antonella Rigo, Anna Bagnato, Laura Rosanò, Angela Bonalumi, Michele Gottardi, Lucia Zanatta, Alice Giacomazzi, Maria Teresa Scupoli, Martina Tinelli, Ugo Salvadori, Federico Mosna, Alberto Zamò, Marco A Cassatella, Fabrizio Vinante, Cristina Tecchio
New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1...
June 9, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28586781/house-dust-mites-induce-production-of-endothelin-1-and-matrix-metalloproteinase-9-in-keratinocytes-via-proteinase-activated-receptor-2-activation
#11
Yoshihito Yamada, Tatsumi Matsumoto
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and abnormal immune response. House dust mites (HDM) are a major source of allergens, some of which have cysteine and serine protease activities. Keratinocytes stimulated by HDM-derived proteases have been suggested to contribute to the pathogenesis of AD by producing various cytokines. However, whether keratinocytes contribute to the induction of pruritus in AD, especially by producing pruritus-related mediators upon stimulation with HDM-derived proteases, has not been fully elucidated...
June 7, 2017: International Archives of Allergy and Immunology
https://www.readbyqxmd.com/read/28584116/high-mobility-group-box-1-as-an-autocrine-trophic-factor-in-white-matter-stroke
#12
Jun Young Choi, Yuexian Cui, Samma Tasneem Chowdhury, Byung Gon Kim
Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28579512/homocysteine-up-regulates-endothelin-type-a-receptor-in-vascular-smooth-muscle-cells-through-sirt1-erk1-2-signaling-pathway
#13
Yulong Chen, Huanhuan Liu, Xinhong Wang, Hongmei Zhang, Enqi Liu, Xingli Su
Sirtuin 1 (Sirt1) is a longevity gene that has protective effects in cardiovascular diseases (CVDs). The endothelin type A (ETA) receptor is involved in pathogenesis of CVDs. The extracellular signal related kinases 1 and 2 (ERK1/2) signaling pathway is involved in regulation of the ETA receptor induced by some CVD risk factors in vascular smooth muscle cells (VSMCs). Hyperhomocysteinemia (HHcy) is an independent risk factor for CVDs. The present study was designed to investigate the hypothesis that homocysteine up-regulates ETA receptor through the Sirt1/ERK1/2 signaling pathway...
June 1, 2017: Microvascular Research
https://www.readbyqxmd.com/read/28566491/chronic-hypoxia-alters-fetal-cerebrovascular-responses-to-endothelin%C3%A2-1
#14
Jinjutha Silpanisong, Dahlim Kim, James M Williams, Olayemi Adeoye, Richard Thorpe, William J Pearce
In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin‑1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3820 m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner...
May 31, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28554252/efficient-isolation-and-culture-of-endothelial-cells-from-venous-malformation-using-the-rho-associated-protein-kinase-inhibitor-y27632
#15
Takashi Satoh, Masakazu Kurita, Hirotaka Suga, Hitomi Eto, Mine Ozaki, Akihiko Takushima, Kiyonori Harii
BACKGROUND: The investigation of primary cells from a pathological lesion can elucidate the pathogenesis of diseases, but, for vascular malformations in humans, such basic research is still stagnant, because the isolation and culture of vascular endothelial cells (ECs) is very difficult. To obtain a sufficient amount of ECs from venous malformation (VM) this study took advantage of a Rho-associated protein kinase inhibitor, Y27632, which had been used for the efficient procurement of primary keratinocytes...
May 30, 2017: Journal of Plastic Surgery and Hand Surgery
https://www.readbyqxmd.com/read/28532389/the-use-of-macitentan-in-fontan-circulation-a-case-report
#16
Polyvios Demetriades, Amir Aziz, Robin Condliffe, Sarah E Bowater, Paul F Clift
BACKGROUND: The Fontan circulation, a result of a palliative procedure in patients with single systemic ventricles, is defined by chronically elevated pulmonary vascular resistance. When traditional heart failure therapies fail, pharmacological agents that reduce pulmonary artery pressures may be used. These include endothelial-receptor antagonists, prostanoids and phosphodiesterase type 5 inhibitors. We report the first use of macitentan, an endothelin-receptor antagonist, in a patient with a Fontan circulation...
May 22, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28514291/role-of-microrna-130a-in-the-pathogeneses-of-obstructive-sleep-apnea-hypopnea-syndrome-associated-pulmonary-hypertension-by-targeting-the-gax-gene
#17
Zhe An, Dan Wang, Guang Yang, Wen-Qi Zhang, Jin Ren, Jin-Ling Fu
OBJECTIVE: The purpose of this study was to elucidate the role of microRNA-130a (miR-130a) in obstructive sleep apnea hypopnea syndrome (OSAHS)-associated pulmonary hypertension (PHT) by targeting the growth arrest-specific homeobox (GAX) gene. METHODS: A total of 108 patients with OSAHS-associated PHT were recruited as the OSAHS-associated PHT group and 110 healthy individuals were randomly selected as the normal control group. Human umbilical vein endothelial cells (HUVECs) were selected and divided into the control, miR-130a mimic, mimic negative control (NC), miR-130a inhibitor, and inhibitor-NC groups...
May 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28513772/etanercept-protects-rat-cardiomyocytes-against-hypertrophy-by-regulating-inflammatory-cytokines-secretion-and-cell-apoptosis
#18
Q Li, Q Yu, R Na, B Liu
We aimed to investigate the effect of etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, on rat cardiomyocyte hypertrophy and its underlying mechanism. Primary neonatal rat cardiomyocytes were isolated from Sprague-Dawley rats. The model of rat cardiomyocyte hypertrophy was induced by endothelin, and then treated with different concentrations of etanercept (1, 10, and 50 μM). After treatment, cell counts, viability and cell apoptosis were evaluated. The mRNA levels of myocardial hypertrophy marker genes, including atrial natriuretic factor (ANF), matrix metalloproteinase (MMP)-9 and MMP-13, were detected by qRT-PCR, and the expressions of apoptosis-related proteins (Bcl-2 and Bax) were measured by western blotting...
May 15, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28507431/targeted-drugs-for-pulmonary-arterial-hypertension-a-network-meta-analysis-of-32-randomized-clinical-trials
#19
Xiao-Fei Gao, Jun-Jie Zhang, Xiao-Min Jiang, Zhen Ge, Zhi-Mei Wang, Bing Li, Wen-Xing Mao, Shao-Liang Chen
BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH...
2017: Patient Preference and Adherence
https://www.readbyqxmd.com/read/28494463/plasma-drug-concentrations-in-patients-with-pulmonary-arterial-hypertension-on-combination-treatment
#20
Ekkehard Grünig, Johanna Ohnesorge, Nicola Benjamin, Jürgen Burhenne, Yeliz Enderle, Benjamin Egenlauf, Christine Fischer, Satenik Harutyunova, Andrea Huppertz, Hans Klose, Walter E Haefeli
BACKGROUND: Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH). OBJECTIVE: The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments. METHODS: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations...
2017: Respiration; International Review of Thoracic Diseases
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