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https://www.readbyqxmd.com/read/29241652/acute-administration-of-roflumilast-enhances-immediate-recall-of-verbal-word-memory-in-healthy-young-adults
#1
M A Van Duinen, A Sambeth, P R A Heckman, S Smit, M Tsai, G Lahu, T Uz, A Blokland, J Prickaerts
The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording...
December 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29240859/real-world-clinical-experience-with-apremilast-in-a-large-us-retrospective-cohort-study-of-patients-with-moderate-to-severe-plaque-psoriasis
#2
April Armstrong, Eugenia Levi
<p>OBJECTIVE: To examine real-world use and patient outcomes with apremilast, an oral PDE4 inhibitor, in the dermatology practice set-ting for treatment of patients with moderate to severe plaque psoriasis.</p> <p>METHODS: This retrospective, multicenter, longitudinal, observational cohort study used Modernizing Medicine's electronic medi-cal record (EMR) database of >5000 US dermatology providers. There were 7517 adults aged ≥18 years with a psoriasis diagnosis (ICD-9, ICD-10) who received apremilast therapy from October 1, 2015, to January 31, 2016, and were included in effcacy and safety analyses...
December 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/29226622/pde4-inhibitor-rolipram-inhibits-the-expression-of-microsomal-prostaglandin-e-synthase-1-by-a-mechanism-dependent-on-map-kinase-phosphatase-1
#3
Lauri Tuure, Mari Hämäläinen, Eeva Moilanen
Phosphodiesterase-4 (PDE4) inhibitors have recently been introduced to the treatment of COPD and psoriatic arthritis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme synthesizing PGE2 , the most abundant prostanoid related to inflammation and inflammatory pain. mPGES-1 is a potential drug target for novel anti-inflammatory treatments aiming at an improved safety profile as compared to NSAIDs. Here we investigated the effect of the PDE4 inhibitor rolipram on the expression of mPGES-1 in macrophages; and a potential mediator role in the process for MAP kinase phosphatase-1 (MKP-1) which is an endogenous factor limiting the activity of the proinflammatory MAP kinases p38 and JNK...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29220595/dose-dependent-effects-of-tadalafil-and-roflumilast-on-ovalbumin-induced-airway-hyperresponsiveness-in-guinea-pigs
#4
Anna Urbanova, Ivana Medvedova, Martin Kertys, Pavol Mikolka, Petra Kosutova, Daniela Mokra, Juraj Mokrý
INTRODUCTION: Chronic obstructive diseases of airways associated with cough and/or airway smooth muscle hyperresponsiveness are usually treated with bronchodilating and anti-inflammatory drugs. Recently, selective phosphodiesterase (PDE) 4 inhibitors have been introduced into the therapy of chronic obstructive pulmonary disease. Several studies have demonstrated their ability to influence the airway reactivity and eosinophilic inflammation by increasing the intracellular cAMP concentrations also in bronchial asthma...
December 8, 2017: Experimental Lung Research
https://www.readbyqxmd.com/read/29216750/pde-camp-epac-c-ebp-%C3%AE-signaling-cascade-regulates-mitochondria-biogenesis-of-tubular-epithelial-cells-in-renal-fibrosis
#5
Hao Ding, Feng Bai, Hongdi Cao, Jing Xu, Li Fang, JiNing Wu, Qi Yuan, Yang Zhou, Qi Sun, WeiChun He, ChunSun Dai, Ke Zen, Lei Jiang, Junwei Yang
AIM: cAMP is a universal second messenger that plays an important role in intracellular signal transduction. cAMP is synthesized by adenylate cyclases (ACs) from adenosine triphosphate (ATP), and terminated by the phosphodiesterases (PDEs). In the present study, we investigated the role of the cAMP pathway in tubular epithelial cells mitochondrial biogenesis in the pathogenesis of renal fibrosis. RESULTS: We found that the cAMP levels were decreased in fibrotic kidney tissues, and replenishing cAMP could ameliorate tubular atrophy and extracellular matrix deposition...
December 7, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29201082/pharmacophore-based-virtual-screening-approach-to-identify-selective-pde4b-inhibitors
#6
Anand Gaurav, Vertika Gautam
Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton...
2017: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/29200281/discovery-and-optimization-of-thiazolidinyl-and-pyrrolidinyl-derivatives-as-inhaled-pde4-inhibitors-for-respiratory-diseases
#7
Laura Carzaniga, Gabriele Amari, Andrea Rizzi, Carmelida Capaldi, Renato De Fanti, Eleonora Ghidini, Gino Villetti, Chiara Carnini, Nadia Moretto, Fabrizio Facchinetti, Paola Caruso, Gessica Marchini, Loredana Battipaglia, Riccardo Patacchini, Valentina Cenacchi, Roberta Volta, Francesco Amadei, Alice Pappani, Silvia Capacchi, Valentina Bagnacani, Maurizio Delcanale, Paola Puccini, Silvia Catinella, Maurizio Civelli, Elisabetta Armani
Phosphodiesterase 4 (PDE4) is a key cAMP-metabolising enzyme involved in the pathogenesis of inflammatory disease and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket...
December 4, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29197324/altered-phosphorylation-electrophysiology-and-behavior-on-attenuation-of-pde4b-action-in-hippocampus
#8
Susan L Campbell, Thomas van Groen, Inga Kadish, Lisa High Mitchell Smoot, Graeme B Bolger
BACKGROUND: PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored...
December 2, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/29183759/phosphodiesterase-4b-plays-a-role-in-benzophenone-3-induced-phototoxicity-in-normal-human-keratinocytes
#9
Hyoung-June Kim, Eunyoung Lee, Moonyoung Lee, Sungjin Ahn, Jungmin Kim, Jingjing Liu, Sun Hee Jin, Jaehyoun Ha, Il Hong Bae, Tae Ryong Lee, Minsoo Noh
Benzophenone-3 (BP-3), which is extensively used in organic sunscreen, has phototoxic potential in human skin. Phosphodiesterase 4B (PDE4B) has a well-established role in inflammatory responses in immune cells. Currently, it is unknown if PDE4B is associated with BP-3-induced phototoxicity in normal human keratinocytes (NHKs). We found that BP-3 significantly increased PDE4B expression in ultraviolet B (UVB)-irradiated NHKs. Notably, BP-8, a sunscreen agent that shares the 2-hydroxy-4-methoxyphenyl methanone moiety with BP-3, also upregulated PDE4B expression in NHKs...
November 25, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29175000/cyclic-nucleotide-signaling-changes-associated-with-normal-aging-and-age-related-diseases-of-the-brain
#10
REVIEW
Michy P Kelly
Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break down in cyclic nucleotide signaling at the level of synthesis, execution, and/or degradation may contribute to these deficits. A number of findings have been reported in both the human and animal model literature that point to brain region-specific changes in Galphas (a...
November 23, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29162108/reduced-suppressive-effect-of-%C3%AE-2-adrenoceptor-agonist-on-fibrocyte-function-in-severe-asthma
#11
Chun-Yu Lo, Charalambos Michaeloudes, Pankaj K Bhavsar, Chien-Da Huang, Po-Jui Chang, Chun-Hua Wang, Han-Pin Kuo, Kian Fan Chung
BACKGROUND: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function. METHODS: Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone...
November 21, 2017: Respiratory Research
https://www.readbyqxmd.com/read/29158883/the-role-of-protein-kinase-b-signaling-pathway-in-anti-cancer-effect-of-rolipram-on-glioblastoma-multiforme-an-in-vitro-study
#12
Sara Ramezani, Mahmoudreza Hadjighassem, Nasim Vousooghi, Mansour Parvaresh, Farshid Arbabi, Naser Amini, Mohammad Taghi Joghataei
Introduction: The mechanism of putative cytotoxicity of 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone (rolipram), a specific phosphodiesterase-4 (PDE4) inhibitor, on glioblastoma multiforme (GBM) is almost unknown. This study aimed to investigate the role of protein kinase B (Akt) pathway in the cytotoxic effect of rolipram on human GBM U87 MG cell line and Tumor-Initiating Cells (TICs) isolated from patient's GBM specimen. Methods: TICs were characterized by using flow cytometry and quantitative real-time PCR...
July 2017: Basic and Clinical Neuroscience
https://www.readbyqxmd.com/read/29155261/the-phosphodiesterase-4-inhibitor-fcpr16-attenuates-ischemia-reperfusion-injury-in-rats-subjected-to-middle-cerebral-artery-occlusion-and-reperfusion
#13
Jiajia Chen, Hui Yu, Jiahong Zhong, Hongfang Feng, Haitao Wang, Yufang Cheng, Zhengqiang Zou, Chang Huang, Zhongzhen Zhou, Wenhua Zheng, Jiangping Xu
Current phosphodiesterase-4 (PDE4) inhibitors exert beneficial effects in central nervous system diseases via anti-inflammatory and anti-apoptotic properties, but many of them are plagued by side effects like nausea and emesis. FCPR16, a novel PDE4 inhibitor synthesized in our lab, has potential anti-inflammatory property. In the present study, we aimed to investigate the effects of FCPR16 in a rat model of ischemic stroke and evaluate its emetogenic potential. Our results showed that FCPR16 treatment improved neurological function, reduced cerebral infarct volume, and attenuated brain histological changes in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R)...
November 16, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/29151951/potential-synergistic-effect-of-phosphodiesterase-inhibitors-with-chemotherapy-in-lung-cancer
#14
Kalliopi Domvri, Konstantinos Zarogoulidis, Nikolaos Zogas, Paul Zarogoulidis, Savvas Petanidis, Konstantinos Porpodis, Efrosini Kioseoglou, Wolfgang Hohenforst-Schmidt
Purpose: Lung cancer remains the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Differentiation-based therapeutics (Methylxanthines) and phosphodiesterase inhibitors (type 4 and 5), have been implicated in cancer treatment. Our objectives were to capture any potential anti-tumor effect of these drug combinations with chemotherapeutic agents in vitro. Methods: Theophylline as Methylxanthines, Roflumilast as phosphodiesterase type 4 (PDE4) inhibitor and Sildenafil as phosphodiesterase type 5 (PDE5) inhibitor are the drugs that we combined with the chemotherapeutic agents (Docetaxel, Cisplatin and Carboplatin) in vitro...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29123207/atropine-augments-cardiac-contractility-by-inhibiting-camp-specific-phosphodiesterase-type-4
#15
Ruwan K Perera, Thomas H Fischer, Michael Wagner, Matthias Dewenter, Christiane Vettel, Nadja I Bork, Lars S Maier, Marco Conti, Juergen Wess, Ali El-Armouche, Gerd Hasenfuß, Viacheslav O Nikolaev
Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Förster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that atropine inhibited acetylcholine-induced decreases in cAMP. Unexpectedly, even in the absence of acetylcholine, after G-protein inactivation with pertussis toxin or in myocytes from M2- or M1/3-muscarinic receptor knockout mice, atropine increased cAMP levels that were pre-elevated with the β-adrenergic agonist isoproterenol...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29098911/targeted-treatments-for-hidradenitis-suppurativa-a-review-of-the-current-literature-and-ongoing-clinical-trials
#16
Melody Maarouf, Ashley K Clark, Dylan E Lee, Vivian Y Shi
PURPOSE: Targeted, immune-modulating drugs are at the forefront of therapy for HS, and a comprehensive clinical trial registry is needed to facilitate data pooling and clinical efficacy comparison. MATERIALS AND METHODS: A systematic review of the ClinicalTrials.gov database was searched for planned, in-progress, completed, or terminated trials investigating the effect of targeted biologic therapies for hidradenitis suppurativa (HS). When results of RCTs were not available, case reports or series were included...
November 10, 2017: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/29098341/acute-administration-of-roflumilast-enhances-sensory-gating-in-healthy-young-humans-in-a-randomized-trial
#17
Pim R A Heckman, Marlies A Van Duinen, Arjan Blokland, Tolga Uz, Jos Prickaerts, Anke Sambeth
INTRODUCTION: Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating...
November 3, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/29076116/crisaborole-ointment-2-a-review-in-mild-to-moderate-atopic-dermatitis
#18
Sheridan M Hoy
Crisaborole ointment 2% (Eucrisa™) is a novel, anti-inflammatory inhibitor of phosphodiesterase 4 (PDE4) that is available in the USA for the topical treatment of mild to moderate atopic dermatitis in patients aged ≥ 2 years. In two short-term (28 days), identically designed, multicentre, phase III studies in this patient population, topical therapy with crisaborole ointment 2% reduced disease severity and pruritus severity compared with vehicle, with the effect established early and sustained over the course of treatment...
October 26, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29068290/otezla-warts-and-all-racks-up-sales-and-eyes-blockbuster-status
#19
Thomas Reinke
Otezla-the generic name is apremilast-also exploited a new mechanism of action as the first inhibitor of phosphodiesterase 4 (PDE4) that results in increased expression of both anti-inflammatory proteins and reduced expression of their pro-inflammatory counterparts.
October 2017: Managed Care
https://www.readbyqxmd.com/read/29065765/rolipram-loaded-polymeric-micelle-nanoparticle-reduces-secondary-injury-after-rat-compression-spinal-cord-injury
#20
Christian Macks, So-Jung Gwak, Michael Lynn, Jeoung Soo Lee
Among the complex pathophysiological events following spinal cord injury, one of the most important molecular level consequences is a dramatic reduction in neuronal cyclic adenosine monophosphate (cAMP) levels. Many studies shown that rolipram (Rm), a phosphodiesterase IV (PDE4) inhibitor, can protect against secondary cell death, reduce inflammatory cytokine levels and immune cell infiltration, and increase white matter sparing and functional improvement. Previously, we developed a polymeric micelle nanoparticle, (poly (lactide-co-glycolide)-g-polyethylenimine, PgP) for combinatorial delivery of therapeutic nucleic acids (TNAs) and drugs for SCI repair...
October 25, 2017: Journal of Neurotrauma
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