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https://www.readbyqxmd.com/read/28807677/phosphodiesterase-4b-expression-plays-a-major-role-in-alcohol-induced-neuro-inflammation
#1
Diana V Avila, Scott A Myers, JingWen Zhang, Giorgi Kharebava, Craig J McClain, Hee-Yong Kim, Scott R Whittemore, Leila Gobejishvili, Shirish Barve
It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28799255/synergy-between-5-ht4-receptor-stimulation-and-phosphodiesterase-4-inhibition-in-facilitating-acetylcholine-release-in-human-large-intestinal-circular-muscle
#2
V Pauwelyn, W Ceelen, R A Lefebvre
BACKGROUND: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine...
August 10, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/28798156/phosphodiesterase-4-inhibitor-and-phosphodiesterase-5-inhibitor-combination-therapy-has-antifibrotic-and-anti-inflammatory-effects-in-mdx-mice-with-duchenne-muscular-dystrophy
#3
Yasunori Nio, Masayuki Tanaka, Yoshihiko Hirozane, Yo Muraki, Mitsugi Okawara, Masatoshi Hazama, Takanori Matsuo
Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase (PDE)-4 inhibitors have exhibited antifibrotic effects in human and animal models...
August 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28772081/investigational-phosphodiesterase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-alzheimer-s-disease
#4
Jos Prickaerts, Pim R A Heckman, Arjan Blokland
Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD...
August 9, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28768120/investigation-of-lung-pharmacokinetic-of-the-novel-pde4-inhibitor-chf6001-in-preclinical-models-evaluation-of-the-preciseinhale-technology
#5
Alessandro Fioni, Ewa Selg, Valentina Cenacchi, Fernando Acevedo, Giandomenico Brogin, Per Gerde, Paola Puccini
BACKGROUND: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available. METHODS: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage...
August 2, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/28763109/synthesis-of-14-c-and-2-h-labelled-chf6001-a-new-potent-pde4-inhibitor
#6
E Fontana, V Cenacchi, F Pivetti, A Pignatti, T Pazzi, L Bondanza, M Pazzi
A eight steps preparation of (14) C-labelled CHF6001, a potent PDE4 inhibitor in the treatment of respiratory diseases, is described. An overall yield of approximately 9% was obtained starting from copper[(14) C]cyanide. The synthesis of a stable labelled version of CHF6001 is also reported using the commercially available trideuterated bromomethylcyclopropane as starting material.
August 1, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28748375/attenuation-of-ethanol-abstinence-induced-anxiety-and-depressive-like-behavior-by-the-phosphodiesterase-4-inhibitor-rolipram-in-rodents
#7
Mei-Fang Gong, Rui-Ting Wen, Ying Xu, Jian-Chun Pan, Ning Fei, Yan-Meng Zhou, Jiang-Ping Xu, Jian-Hui Liang, Han-Ting Zhang
RATIONALE: Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior. OBJECTIVE: The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models...
July 27, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28737056/quantification-of-human-brain-pde4-occupancy-by-gsk356278-a-11-c-r-rolipram-pet-study
#8
Jasper van der Aart, Cristian Salinas, Rahul Dimber, Sabina Pampols-Maso, Ashley A Weekes, John Tonkyn, Frank A Gray, Jan Passchier, Roger N Gunn, Eugenii A Rabiner
We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [(11)C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28704396/phenotypic-chemical-and-functional-characterization-of-cyclic-nucleotide-phosphodiesterase-4-pde4-as-a-potential-anthelmintic-drug-target
#9
Thavy Long, Liliana Rojo-Arreola, Da Shi, Nelly El-Sakkary, Kurt Jarnagin, Fernando Rock, Maliwan Meewan, Alberto A Rascón, Lin Lin, Katherine A Cunningham, George A Lemieux, Larissa Podust, Ruben Abagyan, Kaveh Ashrafi, James H McKerrow, Conor R Caffrey
BACKGROUND: Reliance on just one drug to treat the prevalent tropical disease, schistosomiasis, spurs the search for new drugs and drug targets. Inhibitors of human cyclic nucleotide phosphodiesterases (huPDEs), including PDE4, are under development as novel drugs to treat a range of chronic indications including asthma, chronic obstructive pulmonary disease and Alzheimer's disease. One class of huPDE4 inhibitors that has yielded marketed drugs is the benzoxaboroles (Anacor Pharmaceuticals)...
July 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28698053/stable-c-n-axial-chirality-in-1-aryluracil-scaffold-and-differences-in-in-vitro-metabolic-clearance-between-atropisomers-of-pde4-inhibitor
#10
Futoshi Hasegawa, Kazushi Kawamura, Hiroshi Tsuchikawa, Michio Murata
We report herein the stable C-N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C-N axially chiral biaryls...
August 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28684234/roflumilast-treatment-inhibits-lung-carcinogenesis-in-benzo-a-pyrene-induced-murine-lung-cancer-model
#11
Chang Dong Yeo, Young Ae Kim, Hwa Young Lee, Jin Woo Kim, Seung Joon Kim, Sang Haak Lee, Young Kyoon Kim
Roflumilast, a potent and selective inhibitor of phosphodiesterase-4 (PDE4), has been used in treatment of COPD. PDE4 inhibitor is associated with inhibition of chronic airway inflammation, oxidative stress, and mesenchymal markers in B(a)P-induced lung tumors. The aim of this study was to assess whether roflumilast alone or added to inhaled budesonide might have dose-dependent inhibition on lung carcinogenesis induced by carcinogen B(a)P in mice. Female A/J mice were given a single dose of benzo(a)pyrene. Administration of roflumilast (1mg/kg or 5mg/kg) via oral gavage and aerosolized budesonide (2...
July 3, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28681318/phosphodiesterase-4-inhibitor-therapies-for-atopic-dermatitis-progress-and-outlook
#12
Jusleen Ahluwalia, Jeremy Udkoff, Andrea Waldman, Jenna Borok, Lawrence F Eichenfield
Phosphodiesterase 4 (PDE4) is a cyclic AMP degrading enzyme in leukocytes. Several decades ago, increased PDE activity was demonstrated in patients with atopic dermatitis (AD). Currently, several PDE4 inhibitors in both topical and oral formulation have been developed to target the inflammatory cascade of AD. This review shows the pathogenic rationale behind these inhibitors, and discusses multiple PDE4 inhibitors that are under evaluation or in the market. PDE4 inhibitors may be considered as favorable agents in the repertoire of current interventions for AD...
July 5, 2017: Drugs
https://www.readbyqxmd.com/read/28677201/everyday-memory-towards-a-translationally-effective-method-of-modelling-the-encoding-forgetting-and-enhancement-of-memory
#13
Mio Nonaka, Richard Fitzpatrick, Jennifer Lapira, Damian Wheeler, Patrick A Spooner, Marta Corcoles-Parada, Mónica Muñoz-López, Tim Tully, Marco Peters, Richard G M Morris
The testing of cognitive enhancers could benefit from the development of novel behavioural tasks that display better translational relevance for daily memory and permit the examination of potential targets in a within-subjects manner with less variability. We here outline an optimized spatial 'everyday memory' task. We calibrate it systematically by interrogating certain well-established determinants of memory and consider its potential for revealing novel features of encoding-related gene activation. Rats were trained in an event arena in which food was hidden in sandwells in a different location everyday...
July 5, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28668883/apremilast-induces-apoptosis-of-human-colorectal-cancer-cells-with-mutant-kras
#14
Kensuke Nishi, Hao Luo, Shuhei Ishikura, Keiko Doi, Yuri Iwaihara, Lauren Wills, George S Baillie, Toshifumi Sakata, Senji Shirasawa, Toshiyuki Tsunoda
BACKGROUND/AIM: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS)...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28655761/the-resolution-of-acute-inflammation-induced-by-cyclic-amp-is-dependent-on-annexin-a1
#15
Kátia M Lima, Juliana P Vago, Thaís R Caux, Graziele Letícia Negreiros-Lima, Michelle A Sugimoto, Luciana P Tavares, Raquel G Arribada, Aline Alves F Carmo, Izabela Galvão, Bruno Rocha C Costa, Frederico M Soriani, Vanessa Pinho, Egle Solito, Mauro Perretti, Mauro M Teixeira, Lirlândia P Sousa
Annexin A1 (AnxA1) is a glucocorticoidregulated protein known for its antiinflammatory and proresolving effects. We have previously shown that cAMP enhancing compounds rolipram (ROL - a PDE4 inhibitor) and db-cAMP (cAMP mimetic) drive caspasedependent resolution of neutrophilic inflammation. In this follow up study, we investigated whether AnxA1 could be involved in the proresolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or db-cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices and increased AnxA1 expression...
June 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28650427/roflumilast-reverses-polymicrobial-sepsis-induced-liver-damage-by-inhibiting-inflammation-in-mice
#16
Hongfang Feng, Jiajia Chen, Haitao Wang, Yufang Cheng, Zhengqiang Zou, Qiuping Zhong, Jiangping Xu
Sepsis is a life-threatening syndrome accompanied by an overwhelming inflammatory response and organ dysfunction. Selective targeting of phosphodiesterase 4 (PDE4) is currently being investigated as an effective therapeutic approach for inflammation-associated diseases. Roflumilast is a selective PDE4 inhibitor, used for the treatment of severe chronic obstructive pulmonary disease in clinic. However, its role in the treatment of sepsis-induced liver damage remains unclear. In the present study, we evaluated the effects of roflumilast in mice with cecal ligation and puncture-induced sepsis, and investigated the underlying mechanism...
June 26, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28646393/the-changing-landscape-of-alopecia-areata-the-therapeutic-paradigm
#17
REVIEW
Yael Renert-Yuval, Emma Guttman-Yassky
Alopecia areata (AA), a prevalent inflammatory cause of hair loss, lacks FDA-approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress. Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination. As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use...
July 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28638635/crystal-structure-of-an-apremilast-ethanol-hemisolvate-hemihydrate-solvatomorph
#18
Yun-Deng Wu, Xiao-Hong Liu, Jian Xu, Si-Han Zhang, Kun Shen, Ling Sun, Yong-Mei He, Yan Ma, Ai-Hua Zhang
The title compound, C22H24N2O7S·0.5C2H5OH·0.5H2O {systematic name: (S)-4-acetamido-2-[1-(3-eth-oxy-4-meth-oxy-phen-yl)-2-(methyl-sulfon-yl)eth-yl]iso-indo-line-1,3-dione ethanol hemisolvate hemihydrate}, is a novel solvatomorph of apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The asymmetric unit contains one mol-ecule of AP and disordered mol-ecules of ethanol and water, both with half occupancy. The dihedral angle between the planes of the phenyl ring and the iso-indole ring is 67...
June 1, 2017: Acta Crystallographica. Section E, Crystallographic Communications
https://www.readbyqxmd.com/read/28618988/synthesis-docking-and-anti-inflammatory-activity-of-triazole-amine-derivatives-as-potential-phosphodiesterase-4-inhibitors
#19
Ajmer Singh Grewal, Viney Lather, Deepti Pandita, Ruchi Dalal
BACKGROUND: Phosphodiesterase 4 (PDE4), one of the member of PDE superfamily catalyzes, the hydrolysis of cyclic adenosine monophosphate to adenosine monophosphate in pro-inflammatory and immunomodulatory cells leading to increased inflammatory processes. PDE4 has been reported as an attractive therapeutic target involved in various inflammatory disorders. OBJECTIVE: The present work was designed to synthesize and evaluate the anti-inflammatory activity of some new triazole amine derivatives as potential PDE4 inhibitors...
June 16, 2017: Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28617319/pde4-inhibition-and-inflammatory-bowel-disease-a-novel-therapeutic-avenue
#20
REVIEW
Marco Spadaccini, Silvia D'Alessio, Laurent Peyrin-Biroulet, Silvio Danese
BACKGROUND: In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets...
June 15, 2017: International Journal of Molecular Sciences
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