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https://www.readbyqxmd.com/read/28088839/pharmacokinetic-pharmacodynamic-modeling-of-the-pde4-inhibitor-tak-648-in-type-2-diabetes-early-translational-approaches-for-human-dose-prediction
#1
N Plock, S Vollert, M Mayer, G Hanauer, G Lahu
TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK-648 to required exposure in humans. A first-in-human study with single TAK-648 doses of 0...
January 15, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28065587/ffpm-a-pde4-inhibitor-reverses-learning-and-memory-deficits-in-app-ps1-transgenic-mice-via-camp-pka-creb-signaling-and-anti-inflammatory-effects
#2
Haibiao Guo, Yufang Cheng, Canmao Wang, Jingang Wu, Zhengqiang Zou, Bo Niu, Hui Yu, Haitao Wang, Jiangping Xu
Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing...
January 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28054669/comparison-of-the-pharmacological-profiles-of-selective-pde4b-and-pde4d-inhibitors-in-the-central-nervous-system
#3
Chong Zhang, Ying Xu, Han-Ting Zhang, Mark E Gurney, James M O'Donnell
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28054654/aminophylline-suppresses-stress-induced-visceral-hypersensitivity-and-defecation-in-irritable-bowel-syndrome
#4
Teita Asano, Ken-Ichiro Tanaka, Arisa Tada, Hikaru Shimamura, Rikako Tanaka, Hiroki Maruoka, Mitsuko Takenaga, Tohru Mizushima
Pharmacological therapy for irritable bowel syndrome (IBS) has not been established. In order to find candidate drugs for IBS with diarrhea (IBS-D), we screened a compound library of drugs clinically used for their ability to prevent stress-induced defecation and visceral hypersensitivity in rats. We selected the bronchodilator aminophylline from this library. Using a specific inhibitor for each subtype of adenosine receptors (ARs) and phosphodiesterases (PDEs), we found that both A2BARs and PDE4 are probably mediated the inhibitory effect of aminophylline on wrap restraint stress (WRS)-induced defecation...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28025994/the-analgesic-effect-of-rolipram-is-associated-with-the-inhibition-of-the-activation-of-the-spinal-astrocytic-jnk-ccl2-pathway-in-bone-cancer-pain
#5
Chi-Hua Guo, Lu Bai, Huang-Hui Wu, Jing Yang, Guo-Hong Cai, Xin Wang, Sheng-Xi Wu, Wei Ma
Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal 'neuron-astrocytic' activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti-inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL...
November 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27997807/roflumilast-n-oxide-in-combination-with-formoterol-enhances-the-anti-inflammatory-effect-of-dexamethasone-in-asm-cells
#6
Brijeshkumar S Patel, Md Mostafizur Rahman, Gina Baehring, Dikaia Xenaki, Francesca Su-May Tang, Brian G Oliver, Alaina J Ammit
Roflumilast is an orally active phosphodiesterase 4 (PDE4) inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has demonstrated anti-inflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation...
December 20, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27988361/molecular-modifications-by-regulating-camp-signaling-and-oxidant-antioxidant-defence-mechanisms-produce-antidepressant-like-effect-a-possible-mechanism-of-etazolate-aftermaths-of-impact-accelerated-traumatic-brain-injury-in-rat-model
#7
Ankur Jindal, Radhakrishnan Mahesh, Shvetank Bhatt, Dilip Pandey
Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored...
December 14, 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27939420/mesembrine-alkaloids-review-of-their-occurrence-chemistry-and-pharmacology
#8
REVIEW
John L Krstenansky
ETHNOPHARMACOLOGICAL RELEVANCE: Mesembrine alkaloids are considered to be the primary active constituents of the South African medicinal plant Sceletium tortuosum (L.) N.E.Br. (Aizoaceae), and it is used as the dried or fermented aerial material from the plant, which is known as kanna (aka, channa, kougoed). Traditional regional use ranged from relieving thirst, mild analgesia, and alteration of mood. Current interest has focused primarily on the antidepressant action of preparations based on the plant and commercialization is expanding the recognition and availability of these preparations...
January 4, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27933955/biphenyl-pyridazinone-derivatives-as-inhaled-pde4-inhibitors-structural-biology-and-structure-activity-relationships
#9
Jordi Gràcia, Maria Antonia Buil, Jordi Castro, Peter Eichhorn, Manel Ferrer, Amadeu Gavaldà, Begoña Hernández, Victor Segarra, Martin D Lehner, Imma Moreno, Lluís Pagès, Richard S Roberts, Jordi Serrat, Sara Sevilla, Joan Taltavull, Miriam Andrés, Judit Cabedo, Dolors Vilella, Elena Calama, Carla Carcasona, Montserrat Miralpeix
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27927912/gs-5759-a-bifunctional-%C3%AE-2-adrenoceptor-agonist-and-phosphodiesterase-4-inhibitor-for-chronic-obstructive-pulmonary-disease-with-a-unique-mode-of-action-effects-on-gene-expression-in-human-airway-epithelial-cells
#10
Taruna Joshi, Dong Yan, Omar Hamed, Stacey L Tannheimer, Gary B Phillips, Clifford D Wright, Musong Kim, Michael Salmon, Robert Newton, Mark A Giembycz
GS-5759 is a bifunctional ligand composed of a quinolinone-containing pharmacophore (β2A) found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to GSK 256066 by a pent-1-yn-1-ylbenzene spacer. GS-5759 had similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared to the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower...
December 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27917591/the-pde4-inhibitor-roflumilast-reduces-weight-gain-by-increasing-energy-expenditure-and-leads-to-improved-glucose-metabolism
#11
Julia Möllmann, Florian Kahles, Corinna Lebherz, Ben Kappel, Christer Baeck, Frank Tacke, Christian Werner, Massimo Federici, Nikolaus Marx, Michael Lehrke
AIMS: The PDE4 inhibitor roflumilast is a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. In addition, roflumilast was found to reduce body weight and improve glucose metabolism by a yet unknown mechanism. MATERIALS AND METHODS: Metabolic effects of roflumilast were investigated in C57BL/6J mice on high fat western-type diet treated with or without roflumilast for a period of 12 weeks. RESULTS: Roflumilast led to a marked reduction of body weight gain, which became apparent in the second week following treatment initiation and was attributable to a pronounced increase of energy expenditure...
December 5, 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27901486/triple-negative-breast-cancer-development-can-be-selectively-suppressed-by-sustaining-an-elevated-level-of-cellular-cyclic-amp-through-simultaneously-blocking-its-efflux-and-decomposition
#12
Wei Wang, Yue Li, Jessica Y Zhu, Dongdong Fang, Han-Fei Ding, Zheng Dong, Qing Jing, Shi-Bing Su, Shuang Huang
Triple negative breast cancer (TNBC) has the highest mortality among all breast cancer types and lack of targeted therapy is a key factor contributing to its high mortality rate. In this study, we show that 8-bromo-cAMP, a cyclic adenosine monophosphate (cAMP) analog at high concentration (> 1 mM) selectively suppresses TNBC cell growth. However, commonly-used cAMP-elevating agents such as adenylyl cyclase activator forskolin and pan phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) are ineffective...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27890378/design-and-synthesis-of-4-5-6-7-tetrahydro-1h-1-2-diazepin-7-one-derivatives-as-a-new-series-of-phosphodiesterase-4-pde4-inhibitors
#13
Sara Guariento, Anna Karawajczyk, James A Bull, Gessica Marchini, Martyna Bielska, Xenia Iwanowa, Olga Bruno, Paola Fossa, Fabrizio Giordanetto
Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols...
January 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27878061/oral-apremilast-for-the-treatment-of-plaque-psoriasis
#14
REVIEW
James Q Del Rosso, Leon Kircik
This article provides an update on the use of oral apremilast, a phosphodiesterase-4 (PDE4) inhibitor, for the treatment of plaque psoriasis. Emphasis is placed on safety evaluations, although efficacy considerations are also addressed. Both two-year and three -year data analyses support the favorable safety profile reported in pivotal trials with this agent. Although effective in many study subjects despite baseline characteristics, higher response rates were noted in those with a baseline psoriasis area and severity index (PASI) score <20 and in subjects not previously treated with systemic therapy for psoriasis...
September 2016: Journal of Clinical and Aesthetic Dermatology
https://www.readbyqxmd.com/read/27869356/apremilast-an-oral-phosphodiesterase-4-pde4-inhibitor-a-novel-treatment-option-for-nurse-practitioners-treating-patients-with-psoriatic-disease
#15
Melodie Young, Heather L Roebuck
BACKGROUND AND PURPOSE: Apremilast is an oral nonbiologic medication approved for the treatment of adult patients with active psoriatic arthritis and for patients with moderate to severe plaque psoriasis. This article summarizes the efficacy and safety of apremilast and provides characterization of the novel medication with clinical perspectives to successfully incorporate this therapy into practice for appropriate patients. DATA SOURCES: A review and synthesis of the results from the ESTEEM (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis) phase 3 clinical studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis was conducted...
December 2016: Journal of the American Association of Nurse Practitioners
https://www.readbyqxmd.com/read/27859531/increase-of-intracellular-cyclic-amp-by-pde4-inhibitors-affects-hepg2-cell-cycle-progression-and-survival
#16
Mara Massimi, Silvia Cardarelli, Francesca Galli, Maria Federica Giardi, Federica Ragusa, Nadia Panera, Benedetta Cinque, Maria Grazia Cifone, Stefano Biagioni, Mauro Giorgi
Type 4 cyclic nucleotide phosphodiesterases (PDE4) are major members of a superfamily of enzymes (PDE) involved in modulation of intracellular signaling mediated by cAMP. Broadly expressed in most human tissues and present in large amounts in the liver, PDEs have in the last decade been key therapeutic targets for several inflammatory diseases. Recently, a significant body of work has underscored their involvement in different kinds of cancer, but with no attention paid to liver cancer. The present study investigated the effects of two PDE4 inhibitors, rolipram and DC-TA-46, on the growth of human hepatoma HepG2 cells...
November 16, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27844172/xanthines-and-phosphodiesterase-inhibitors
#17
D Spina, C P Page
Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease...
November 15, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27843073/off-target-effect-of-sildenafil-on-postsurgical-erectile-dysfunction-alternate-pathways-and-localized-delivery-system
#18
Amirali Salmasi, Geun Taek Lee, Neal Patel, Ritu Goyal, Michael Dinizo, Young Suk Kwon, Part K Modi, Izak Faiena, Hee-Jin Kim, Nara Lee, Johanna L Hannan, Joachim Kohn, Isaac Yi Kim
INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures...
December 2016: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/27836756/cyclic-nucleotide-phosphodiesterases-in-human-spermatozoa-and-seminal-fluid-presence-of-an-active-pde10a-in-human-spermatozoa
#19
Loïze Maréchal, Christine Guillemette, Serge Goupil, Patrick Blondin, Pierre Leclerc, François J Richard
BACKGROUND: Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for sperm functions such as capacitation, motility and acrosome reaction. It is well known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. The present study was undertaken to characterize cAMP-PDE activity in human semen. METHODS: cAMP-PDE activity was measured in human sperm and seminal plasma using family specific PDE inhibitors...
February 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27813474/-cyclic-nucleotide-phosphodiesterases-role-in-the-heart-and-therapeutic-perspectives
#20
Ibrahim Bedioune, Pierre Bobin, Sarah Karam, Marta Lindner, Delphine Mika, Patrick Lechêne, Jérôme Leroy, Rodolphe Fischmeister, Grégoire Vandecasteele
Cyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families that are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP, controlling specific cell functions in response to various neurohormonal stimuli...
2016: Biologie Aujourd'hui
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