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https://www.readbyqxmd.com/read/29348829/roflumilast-restores-camp-pka-creb-signaling-axis-for-ftmt-mediated-tumor-inhibition-of-ovarian-cancer
#1
Shipeng Gong, Yongning Chen, Fanliang Meng, Yadi Zhang, Huan Wu, Fei Wu
The abrogation of cAMP generation by overexpression of PDE isoforms promotes the inflammatory pathology, and the PDE inhibitors have showed the potential anti-inflammation effects in clinical. However, the function of PDE inhibitors in cancer treatment remains unclear. We here investigated the role of PDE4 inhibitor Roflumilast in the treatment of ovarian cancer. We found that Roflumilast could effectively inhibit the proliferation, and induce apoptosis and cell cycle arrest in two ovarian cancer cell lines OVCAR3 and SKOV3...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29337269/inhibitors-of-phosphodiesterases-in-the-treatment-of-cough
#2
REVIEW
Juraj Mokry, Anna Urbanova, Martin Kertys, Daniela Mokra
A group of 11 enzyme families of metalophosphohydrolases called phosphodiesterases (PDEs) is responsible for a hydrolysis of intracellular cAMP and cGMP. Xanthine derivatives (methylxanthines) inhibit PDEs without selective action on their single isoforms and lead to many pharmacological effects, e.g. bronchodilation, anti-inflammatory and immunomodulating effects, and thus they can modulate the cough reflex. Contrary, selective PDE inhibitors have been developed to inhibit PDE isoforms with different pharmacological effects based on their tissue expression...
January 11, 2018: Respiratory Physiology & Neurobiology
https://www.readbyqxmd.com/read/29307087/targeting-the-prostacyclin-pathway-with-selexipag-in-patients-with-pulmonary-arterial-hypertension-receiving-double-combination-therapy-insights-from-the-randomized-controlled-griphon-study
#3
J Gerry Coghlan, Richard Channick, Kelly Chin, Lilla Di Scala, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Irene M Lang, Vallerie McLaughlin, Ralph Preiss, Lewis J Rubin, Gérald Simonneau, Olivier Sitbon, Victor F Tapson, Sean Gaine
BACKGROUND: In pulmonary arterial hypertension (PAH), combination therapy is an important treatment strategy. Although randomized controlled trial data are available to support the combination of two therapies, data regarding triple combination therapy are few. OBJECTIVE: The phase III GRIPHON trial enrolled 1156 patients with PAH, including 376 receiving background double combination therapy. We evaluated the efficacy and safety of selexipag as a third agent in these patients and further analyzed this subgroup according to symptom burden at baseline as indicated by World Health Organization (WHO) functional class (FC)...
January 6, 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/29301136/assessment-of-the-airway-smooth-muscle-relaxant-effect-of-drotaverine
#4
Zoltán Patai, András Guttman, Endre G Mikus
BACKGROUND: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3',5'-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. SUMMARY: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations...
January 4, 2018: Pharmacology
https://www.readbyqxmd.com/read/29291443/prenylated-flavonoids-as-potent-phosphodiesterase-4-inhibitors-from-morus-alba-isolation-modification-and-structure-activity-relationship-study
#5
Yan-Qiong Guo, Gui-Hua Tang, Lan-Lan Lou, Wei Li, Bei Zhang, Bo Liu, Sheng Yin
The bioassay-guided phytochemical study of a traditional Chinese medicine Morus alba led to the isolation of 18 prenylated flavonoids (1-18), of which (±)-cyclomorusin (1/2), a pair of enantiomers, and 14-methoxy-dihydromorusin (3) are the new ones. Subsequent structural modification of the selected components by methylation, esterification, hydrogenation, and oxidative cyclization led to 14 more derivatives (19-32). The small library was screened for its inhibition against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease (COPD)...
December 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29280064/macitentan-in-pulmonary-arterial-hypertension-a-focus-on-combination-therapy-in-the-seraphin-trial
#6
REVIEW
Pavel Jansa, Tomás Pulido
SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0...
December 26, 2017: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/29277372/effects-of-chlorogenic-acid-on-carbachol-induced-contraction-of-mouse-urinary-bladder
#7
Takeharu Kaneda, Noriyasu Sasaki, Norimoto Urakawa, Kazumasa Shimizu
Chlorogenic acid (CGA) is a polyphenol found in coffee and medicinal herbs such as Lonicera japonica. In this study, the effect of CGA-induced relaxation on carbachol (CCh)-induced contraction of mouse urinary bladder was investigated. CGA (30-300 μg/ml) inhibited CCh- or U46619-induced contraction in a concentration-dependent manner. SQ22536 (adenylyl cyclase inhibitor) recovered CGA-induced relaxation of CCh-induced contraction; however, ODQ (guanylyl cyclase inhibitor) did not have the same effect. In addition, 3-isobutyl-1-methylxanthine (IBMX) enhanced CGA-induced relaxation; however, forskolin or sodium nitroprusside did not have the same effect...
December 15, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29262264/pde8-is-expressed-in-human-airway-smooth-muscle-and-selectively-regulates-camp-signaling-by-%C3%AE-2ar-ac6
#8
Timothy B Johnstone, Kaitlyn H Smith, Cynthia J Koziol-White, Fengying Li, Austin G Kazarian, Maia L Corpuz, Maya Shumyatcher, Frederick J Ehlert, Blanca E Himes, Reynold A Panettieri, Rennolds S Ostrom
Two cAMP signaling compartments centering around adenylyl cyclase (AC) exist in human airway smooth muscle (HASM) cells, one containing ß2AR-AC6 and another containing E prostanoid receptors (EPR)-AC2. We hypothesized that different phosphodiesterase (PDE) isozymes selectively regulate cAMP signaling in each compartment. According to RNA-seq data, 18 of 24 PDE genes were expressed in primary HASM cells derived from age- and gender-matched donors with and without asthma. PDE8A was the third most abundant of the cAMP-degrading PDE genes, after PDE4A and PDE1A...
December 20, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29241652/acute-administration-of-roflumilast-enhances-immediate-recall-of-verbal-word-memory-in-healthy-young-adults
#9
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/29237389/venlafaxine-attenuates-the-development-of-morphine-tolerance-and-dependence-role-of-l-arginine-nitric-oxide-cgmp-pathway
#10
Mohammad Taghi Mansouri, Bahareh Naghizadeh, Behnam Ghorbanzadeh, Soheila Alboghobeish, Gholamreza Houshmand, Neda Amirgholami
BACKGROUND: Severe pain reduce quality of life in patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) play a role in morphine tolerance and dependence. OBJECTIVE: Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice...
December 13, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/29233753/targeting-the-26s-proteasome-to-protect-against-proteotoxic-diseases
#11
REVIEW
Natura Myeku, Karen E Duff
Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction...
December 9, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29233660/negative-inotropic-effects-of-diadenosine-tetraphosphate-are-mediated-by-protein-kinase-c-and-phosphodiesterases-stimulation-in-the-rat-heart
#12
Nikolai Pakhomov, Ksenia Pustovit, Victoria Potekhina, Tatiana Filatova, Vladislav Kuzmin, Denis Abramochkin
Extracellular diadenosine polyphosphates (ApnA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular ApnA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie ApnA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap4A) effects in the rat heart has been investigated for the first time...
December 9, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29233027/effects-of-phosphodiestrase-type-5-inhibitors-in-epinephrine-induced-arrhythmia-in-rats-involvement-of-lactate-dehydrogenase-and-creatine-kinase-downregulation-and-adiponectin-expression
#13
Aaa Salama, R E Mostafa, E A Omara
Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/29220595/dose-dependent-effects-of-tadalafil-and-roflumilast-on-ovalbumin-induced-airway-hyperresponsiveness-in-guinea-pigs
#14
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
#15
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/29201504/effect-of-sildenafil-citrate-in-testosterone-induced-benign-prostate-hyperplasia-rat-model
#16
Selahattin Çalışkan, Muzaffer Oğuz Keleş, Metin İshak Öztürk, Musab Ali Kutluhan, Olgu Enis Tok, Feriha Ercan, Muhammet İhsan Karaman
Objective: Efficacy of treatments for benign prostate hyperplasia (BPH) is limited because the disease has complex etiopathogenesis. Recent studies have demonstrated the presence of phosphodiesterase-5 (PDE-5) receptors in prostate tissue. We investigated efficacy of sildenafil citrate in testosteron - induced BPH in rats. Material and methods: The rats were divided into three groups. Each groups had 7 rats. Group 1 was control group. Testosteron propionate 3 mg/kg/day was injected subcutaneously for two weeks in Group 2...
December 2017: Turkish Journal of Urology
https://www.readbyqxmd.com/read/29175000/cyclic-nucleotide-signaling-changes-associated-with-normal-aging-and-age-related-diseases-of-the-brain
#17
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...
January 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29159668/new-pulmonary-hypertension-model-in-conscious-dogs-to-investigate-pulmonary-selectivity-of-acute-pharmacological-interventions
#18
Thomas Mondritzki, Philip Boehme, Lena Schramm, Julia Vogel, Ilka Mathar, Peter Ellinghaus, Peter Kolkhof, Erwin Bischoff, Jörg Hüser, Wilfried Dinh, Peter Sandner, Hubert Truebel
PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs...
November 20, 2017: European Journal of Applied Physiology
https://www.readbyqxmd.com/read/29152042/selective-inhibitors-of-phosphodiesterase-4b-pde-4b-may-provide-a-better-treatment-for-cns-metabolic-autoimmune-and-inflammatory-diseases
#19
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29151951/potential-synergistic-effect-of-phosphodiesterase-inhibitors-with-chemotherapy-in-lung-cancer
#20
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
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