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https://www.readbyqxmd.com/read/28923362/human-retinal-endothelial-cells-and-astrocytes-cultured-on-3-d-scaffolds-for-ocular-drug-discovery-and-development
#1
Kay D Beharry, Charles L Cai, Gloria B Valencia, Douglas Lazzaro, Arwin M Valencia, Fabrizio Salomone, Jacob V Aranda
Topical ocular ketorolac improves the outcomes of severe retinopathy of prematurity and when administered with systemic caffeine, decreases the severity of oxygen-induced retinopathy. We tested the hypothesis that co-cultures of human retinal endothelial cells (HRECs) and human retinal astrocytes (HRAs) on 3-dimensional (3-D) hydrogel scaffolds is a more representative biomimetic paradigm of the blood-retinal-barrier (BRB) than 2-D cultures, and should be utilized for preclinical drug discovery and development...
September 15, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28922964/oral-treprostinil-in-the-treatment-of-pulmonary-arterial-hypertension
#2
Jeremy Feldman, Naomi Habib, John Radosevich, Mohan Dutt
Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil - a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH)...
September 19, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28919201/macitentan-for-the-treatment-of-inoperable-chronic-thromboembolic-pulmonary-hypertension-merit-1-results-from-the-multicentre-phase-2-randomised-double-blind-placebo-controlled-study
#3
Hossein-Ardeschir Ghofrani, Gérald Simonneau, Andrea M D'Armini, Peter Fedullo, Luke S Howard, Xavier Jaïs, David P Jenkins, Zhi-Cheng Jing, Michael M Madani, Nicolas Martin, Eckhard Mayer, Kelly Papadakis, Dominik Richard, Nick H Kim
BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm(5) and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo...
September 8, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28918839/prostaglandin-e2-induces-prorenin-dependent-activation-of-pro-renin-receptor-and-upregulation-of-cyclooxygenase-2-in-collecting-duct-cells
#4
Nicolás Salinas-Parra, Cristian Reyes-Martínez, Minolfa C Prieto, Alexis A Gonzalez
BACKGROUND: Prostaglandin E2 (PGE2) regulates renin expression in renal juxtaglomerular cells. PGE2 acts through E-prostanoid (EP) receptors in the renal collecting duct (CD) to regulate sodium and water balance. CD cells express EP1 and EP4, which are linked to protein kinase C (PKC) and PKA downstream pathways, respectively. Previous studies showed that the presence of renin in the CD, and that of PKC and PKA pathways, activate its expression. The (pro)renin receptor (PRR) is also expressed in CD cells, and its activation enhances cyclooxygenase-2 (COX-2) through extracellular signal-regulated kinase (ERK)...
September 2017: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/28912026/influence-of-various-therapeutic-strategies-on-right-ventricular-morphology-function-and-hemodynamics-in-pulmonary-arterial-hypertension
#5
Roberto Badagliacca, Amresh Raina, Stefano Ghio, Michele D'Alto, Marco Confalonieri, Michele Correale, Marco Corda, Giuseppe Paciocco, Carlo Lombardi, Massimiliano Mulè, Roberto Poscia, Laura Scelsi, Paola Argiento, Susanna Sciomer, Raymond L Benza, Carmine Dario Vizza
BACKGROUND: In idiopathic pulmonary arterial hypertension (IPAH) treatment goals include improving right ventricular (RV) function, hemodynamics and symptoms to move patients to a low-risk category for adverse clinical outcomes. No data are available on the effect of upfront combination therapy on RV improvement as compared with monotherapy. The aim of this study was to evaluate echocardiographic RV morphology and function in patients affected by IPAH and treated with different strategies...
August 26, 2017: Journal of Heart and Lung Transplantation
https://www.readbyqxmd.com/read/28904003/preclinical-pharmacology-and-pharmacokinetics-of-inhaled-hexadecyl-treprostinil-c16tr-a-pulmonary-vasodilator-prodrug
#6
Michel R Corboz, Zhili Li, Vladimir Malinin, Adam J Plaunt, Donna M Konicek, Franziska G Leifer, Kuan-Ju Chen, Charles E Laurent, Han Yin, Marzena C Biernat, Dany Salvail, Jianguo Zhuang, Fadi Xu, Aidan Curran, Walter R Perkins, Richard W Chapman
This report describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (> 10 µM) in receptor binding and enzyme inhibition assays including binding to EP2, DP1, IP and EP4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by adenosine diphosphate (ADP) in rat blood...
September 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28904002/assessing-microvascular-function-in-humans-from-a-chronic-disease-perspective
#7
Alfons J H M Houben, Remy J H Martens, Coen D A Stehouwer
Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied...
September 13, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28899749/cyp4a-cyp2c-modulation-of-the-interaction-of-calcium-channel-blockers-with-cyclosporine-on-edhf-mediated-renal-vasodilations-in-rats
#8
Safaa H Hammoud, Amal G Omar, Assaad A Eid, Mahmoud M El-Mas
The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days...
September 9, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28891448/a-special-focus-on-selexipag-treatment-of-pulmonary-arterial-hypertension
#9
Louise Marqvard Sørensen, Markus Wehland, Marcus Krüger, Ulf Simonsen, Mohamed Zakaria Nassef, Manfred Infanger, Daniela Grimm
BACKGROUND: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues. METHODS: We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH. RESULTS: With only few cases per million, PAH is a rare disease, but when untreated it can be life threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2)...
September 7, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28890397/regulated-expression-of-the-tp%C3%AE-isoform-of-the-human-t-prostanoid-receptor-by-the-tumour-suppressors-foxp1-and-nkx3-1-implications-for-the-role-of-thromboxane-in-prostate-cancer
#10
Aine G O'Sullivan, Sarah B Eivers, Eamon P Mulvaney, B Therese Kinsella
The prostanoid thromboxane (TX)A2 signals through the TPα and TPβ isoforms of T Prostanoid receptor (TP) that are transcriptionally regulated by distinct promoters termed Prm1 and Prm3, respectively, within the TBXA2R gene. We recently demonstrated that expression of TPα and TPβ is increased in PCa, differentially correlating with Gleason grade and with altered CpG methylation of the individual Prm1/Prm3 regions within the TBXA2R. The current study sought to localise the sites of CpG methylation within Prm1 and Prm3, and to identify the main transcription factors regulating TPβ expression through Prm3 in the prostate adenocarcinoma PC-3 and LNCaP cell lines...
September 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28890385/reduced-coronary-reactive-hyperemia-in-mice-was-reversed-by-the-soluble-epoxide-hydrolase-inhibitor-t-aucb-role-of-adenosine-a2a-receptor-and-plasma-oxylipins
#11
Ahmad Hanif, Matthew L Edin, Darryl C Zeldin, Christophe Morisseau, John R Falck, Catherine Ledent, Stephen L Tilley, Mohammed A Nayeem
Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR(-/-)) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR(-/-) and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR(-/-) mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition...
September 7, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28887458/increased-15-pgdh-expression-leads-to-dysregulated-resolution-responses-in-stromal-cells-from-patients-with-chronic-tendinopathy
#12
Stephanie G Dakin, Lucy Ly, Romain A Colas, Udo Oppermann, Kim Wheway, Bridget Watkins, Jesmond Dalli, Andrew J Carr
The mechanisms underpinning the failure of inflammation to resolve in diseased musculoskeletal soft tissues are unknown. Herein, we studied bioactive lipid mediator (LM) profiles of tendon-derived stromal cells isolated from healthy donors and patients with chronic tendinopathy. Interleukin(IL)-1β treatment markedly induced prostaglandin biosynthesis in diseased compared to healthy tendon cells, and up regulated the formation of several pro-resolving mediators including 15-epi-LXA4 and MaR1. Incubation of IL-1β stimulated healthy tendon cells with 15-epi-LXA4 or MaR1 down-regulated PGE2 and PGD2 production...
September 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28877347/sex-differences-in-the-role-of-phospholipase-a2-dependent-arachidonic-acid-pathway-in-the-perivascular-adipose-tissue-function-in-pigs
#13
Abdulla A Ahmad, Michael D Randall, Richard E Roberts
Previous studies have demonstrated that perivascular adipose tissue (PVAT) causes vasoconstriction. In this present study, we determined the role of cyclooxygenase-derived prostanoids in this contractile response and determined whether there were any sex differences in the regulation of vascular tone by PVAT. Contractions in isolated segments of coronary arteries were determined using isolated tissue baths and isometric tension recording. Segments were initially cleaned of PVAT, which was then re-added to the tissue bath and changes in tone measured over 1 h...
September 6, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28874611/how-should-aerosols-be-delivered-during-invasive-mechanical-ventilation
#14
Rajiv Dhand
The delivery of aerosols to mechanically ventilated patients presents unique challenges and differs from inhaled drug delivery in spontaneously breathing patients in several respects. Successful aerosol delivery during invasive mechanical ventilation requires careful consideration of a host of factors that influence the amount of drug inhaled by the patient. Pressurized metered-dose inhalers and nebulizers (jet, ultrasonic, and vibrating mesh) are the most commonly used aerosol delivery devices in these patients, although other delivery devices, such as dry powder inhalers, soft mist inhalers, and intratracheal nebulizing catheters, could also be adapted for in-line use...
September 5, 2017: Respiratory Care
https://www.readbyqxmd.com/read/28841455/cardiovascular-dysfunction-in-sepsis-at-the-dawn-of-emerging-mediators
#15
REVIEW
Consolato Sergi, Fan Shen, David W Lim, Weiyong Liu, Mingyong Zhang, Brian Chiu, Vijay Anand, Ziyong Sun
Subcellular dysfunction and impaired metabolism derived from the complex interaction of cytokines and mediators with cellular involvement are on the basis of the cardiovascular response to sepsis. The lethal consequences of an infection are intimately related to its ability to spread to other organ sites and the immune system of the host. About one century ago, William Osler (1849-1919), a Canadian physician, remarkably defined the sequelae of the host response in sepsis: "except on few occasions, the patient appears to die from the body's response to infection rather than from it...
August 22, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28840065/management-of-acute-subdural-hematoma-in-a-patient-with-portopulmonary-hypertension-on-prostanoid-therapy
#16
Richard Rammo, Adam Robin, Jessin John, Aqueel Pabaney, Panayiotis Varelas, Max Kole
BACKGROUND: Treprostinil is a prostacyclin analog used to treat portopulmonary hypertension (PPHTN) and is one of several drugs shown to increase survival, but results in platelet dysfunction. Little is known about the management of patients on treprostinil who present with an acute subdural hematoma (aSDH). We describe such a case and offer our recommendations on management based on our experience and review of the literature. CASE DESCRIPTION: A 63-year-old, right-handed female with a history of PPHTN presented with severe headache and was found to have a large left aSDH with midline shift on imaging...
2017: Surgical Neurology International
https://www.readbyqxmd.com/read/28838229/expression-of-prostaglandin-e2-receptors-in-acquired-middle-ear-cholesteatoma
#17
Sujie Wang, Li Xie, Yanfei Zhang, Pengfei Xu, Aiguo Liu
Objectives.: To investigate the expression of prostaglandin E2 receptor subtypes, E-prostanoid (EP) 1-4 receptors, in acquired cholesteatoma and its possible role in the pathologic process of this disorder. Methods.: Specimens of human acquired cholesteatoma were obtained from 29 patients and 19 skin biopsies of normal external auditory canal were as controls. The mRNA and protein expression of EP receptors was assessed by quantitative real-time polymerase chain reaction, immunohistochemistry and Western blot...
August 26, 2017: Clinical and Experimental Otorhinolaryngology
https://www.readbyqxmd.com/read/28827689/increased-role-of-e-prostanoid-receptor-3-in-prostacyclin-evoked-contractile-activity-of-spontaneously-hypertensive-rat-mesenteric-resistance-arteries
#18
Bin Liu, Mengyi Zhan, Yingzhan Zhang, Hui Li, Xiangzhong Wu, Fengfeng Zhuang, Wenhong Luo, Yingbi Zhou
This study aimed to determine whether E prostanoid receptor-3 (EP3) is involved in prostacyclin (PGI2)-evoked vasoconstrictor activity of resistance arteries and if so, how it changes under hypertensive conditions. Mesenteric resistance arteries from Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were isolated for functional and biochemical studies. Here we show that in vessels from WKYs, PGI2 or the endothelial muscarinic agonist ACh (which stimulates in vitro PGI2 synthesis) evoked vasoconstrictor activity, which increased in SHRs...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28826906/aluminum-exposure-at-human-dietary-levels-promotes-vascular-dysfunction-and-increases-blood-pressure-in-rats-a-concerted-action-of-nad-p-h-oxidase-and-cox-2
#19
Caroline Silveira Martinez, Janaina Trindade Piagette, Alyne Gourlart Escobar, Ángela Martín, Roberto Palacios, Franck Maciel Peçanha, Dalton Valentim Vassallo, Christopher Exley, María Jesús Alonso, Marta Miguel, Mercedes Salaices, Giulia Alessandra Wiggers
Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl3 at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl3 at 100mg/kg bw for 42days, representing a high level of human exposure to Al...
August 19, 2017: Toxicology
https://www.readbyqxmd.com/read/28822852/prostaglandin-d2-is-the-major-cyclooxygenase-1-derived-product-in-prepartum-mouse-uteri-where-it-mediates-an-enhanced-in-vitro-myometrial-contraction
#20
Bin Liu, Jingli Yang, Wenhong Luo, Yingzhan Zhang, Jiarong Li, Hui Li, Lelin Chen, Yingbi Zhou
This study aimed to determine whether prostaglandin D2 (PGD2) is a major uterine cyclooxygenase (COX) product and if so, we wanted to examine the underlying mechanism, its relation to COX-1-mediated metabolism, and how it influences the in vitro myometrial contraction during the late stage of pregnancy. The production of PGD2 or responses evoked by the prostanoid were determined in uteri isolated from prepartum and/or non-pregnant C57Bl/6 wild-type (WT) or COX-1(-/-) mice. Results showed that PGD2, which was not detected in non-pregnant counterparts, appears as the major prostanoid in prepartum (<24h prior to parturition) mouse uteri...
August 16, 2017: European Journal of Pharmacology
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