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https://www.readbyqxmd.com/read/28523172/roles-of-roflumilast-a-selective-phosphodiesterase-4-inhibitor-in-airway-diseases
#1
REVIEW
Theerasuk Kawamatawong
Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases. Both diseases have incompletely distinct pathophysiology, clinical manifestation, and treatment responsiveness. Pulmonary and systemic inflammations are the hallmarks of COPD. Most asthma responds to inhaled corticosteroid (ICS) treatment. In contrast, COPD is a corticosteroid-resistant disease. Bronchodilators are a preferred treatment method of COPD, with the aim of improving symptoms and preventing exacerbation...
April 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28515693/rolipram-improves-outcome-in-a-rat-model-of-infant-sepsis-induced-cardiorenal-syndrome
#2
Clark R Sims, Sharda P Singh, Shengyu Mu, Neriman Gokden, Dala Zakaria, Trung C Nguyen, Philip R Mayeux
While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28499587/the-phosphodiesterase-4-inhibitor-apremilast-inhibits-th1-but-promotes-th17-responses-induced-by-6-sulfo-lacnac-slan-dendritic-cells
#3
Stephanie Oehrl, Hridayesh Prakash, Annette Ebling, Nina Trenkler, Priscila Wölbing, Anja Kunze, Thomas Döbel, Marc Schmitz, Alexander Enk, Knut Schäkel
BACKGROUND: The phosphodiesterase 4 (PDE4) inhibitor apremilast increases cellular cAMP levels and has proven effective in the treatment of psoriasis and psoriasis arthritis. We recently described 6-sulfo LacNAc dendritic cells (slanDCs) as immature DCs in blood and as a subset of inflammatory dermal DCs in psoriasis with a pronounced capacity to produce proinflammatory cytokines and to program Th17/Th1 T cell responses. OBJECTIVE: The aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs...
April 20, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28497801/pde4-inhibition-restores-the-balance-between-excitation-and-inhibition-in-vta-dopamine-neurons-disrupted-by-repeated-in-vivo-cocaine-exposure
#4
Xiaojie Liu, Peng Zhong, Casey Vickstrom, Yan Li, Qing-Song Liu
Phosphodiesterase type 4 (PDE4) is a family of enzymes that selectively degrade intracellular cAMP. PDE4 inhibitors have been shown to regulate the rewarding and reinforcing effects of cocaine, but the underlying mechanisms remain poorly understood. Here we show that pretreatments with the PDE4 inhibitor rolipram attenuated cocaine-induced locomotor sensitization in mice. Repeated cocaine exposure in vivo caused a decrease in inhibitory postsynaptic currents (IPSCs) and an increase in the AMPAR/NMDAR ratio in ventral tegmental area (VTA) dopamine neurons in midbrain slices ex vivo...
May 12, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28492291/crisaborole-phosphodiesterase-inhibitor-for-treatment-of-atopic-dermatitis
#5
D M Paton
Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is pruritus. One of the important aspects of AD is inflammation associated with increased activity of phosphodiesterase 4 (PDE4), resulting in decreased intracellular levels of cyclic adenosine monophosphate, which in turn causes increased production of inflammatory cytokines. Crisaborole was developed as a small-molecule, boron-based, selective PDE4 inhibitor that can be used topically...
April 2017: Drugs of Today
https://www.readbyqxmd.com/read/28485811/the-effects-of-second-messenger-camp-and-its-relative-components-on-the-contraction-of-uterine-smooth-muscle-of-rat
#6
S-J Shu, X-G Lei, J-H Liang, Y-H Song, Q Xu, X-D Chen, L-G Mao, Z-G Li
OBJECTIVE: To investigate the effect of second messenger pathways on the uterine smooth muscle contraction and their associated mechanisms, and compare the evaluation methods. MATERIALS AND METHODS: Preparation of uterine smooth muscle strips from healthy pregnant 18-21 d SD and non-pregnant rats. When the contraction of muscle strips was stable, we conducted gradient administration: PDE4 inhibitors (Z90), prostaglandin PGE2, adenylate cyclase inhibitor (SQ 22,530), cAMP analogs (dbcAMP) and AMPK agonists (AICAR), solvent dimethyl sulfoxide (DMSO) as controlled...
April 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28477089/the-phosphodiesterase-4-inhibitor-roflumilast-decreases-ethanol-consumption-in-c57bl-6j-mice
#7
Xin Liu, Pi-Da Hao, Ming-Feng Yang, Jing-Yi Sun, Lei-Lei Mao, Cun-Dong Fan, Zong-Yong Zhang, Da-Wei Li, Xiao-Yi Yang, Bao-Liang Sun, Han-Ting Zhang
RATIONALE: Alcohol use disorders have become one of the most damaging psychiatric disorders in the world; however, there are no ideal treatments in clinic. Phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), has been involved in alcohol use disorders. Roflumilast is the first PDE4 inhibitor approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of particular interest to researchers to determine whether roflumilast altered ethanol consumption...
May 6, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28451841/roflumilast-reduces-cerebral-inflammation-in-a-rat-model-of-experimental-subarachnoid-hemorrhage
#8
Qingjian Wu, Lifeng Qi, Hanxia Li, Leilei Mao, Mingfeng Yang, Rongxia Xie, Xiaoyi Yang, Jian Wang, Zongyong Zhang, Jiming Kong, Baoliang Sun
Roflumilast, a selective inhibitor for PDE4, is approved by FDA as an anti-inflammation drug for treatment of chronic obstructive pulmonary disease (COPD). This study investigates the effects of roflumilast on cerebral inflammation in the rat SAH model. Here, we show that subcutaneous administration of roflumilast (3 mg/kg) significantly improved the neurological deficits. Measurement of evans blue extravasation and brain water content revealed a significant reduction of blood-brain barrier permeability and brain edema...
April 27, 2017: Inflammation
https://www.readbyqxmd.com/read/28450469/novel-phosphodiesterase-4-inhibitor-fcpr03-alleviates-lipopolysaccharide-induced-neuroinflammation-by-regulation-of-camp-pka-creb-signaling-pathway-and-nf-%C3%AE%C2%BAb-inhibition
#9
Zheng-Qiang Zou, Jia-Jia Chen, Hong-Fang Feng, Yu-Fang Cheng, Hai-Tao Wang, Zhong-Zhen Zhou, Hai-Biao Guo, Wenhua Zheng, Jiang-Ping Xu
Over activation of microglia contributes to the induction of neuroinflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation. However, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency. However, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood...
April 27, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28438557/the-isozyme-selective-phosphodiesterase-4-inhibitor-abi-4-attenuates-the-effects-of-lipopolysaccharide-in-human-cells-and-rodent-models-of-peripheral-and-cns-inflammation
#10
Joseph R Hedde, Ashley N Hanks, Christopher J Schmidt, Zoë A Hughes
Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50 ∼14 nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32 mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in blood and brain of mice...
April 21, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28432317/psiguajadials-a-k-unusual-psidium-meroterpenoids-as-phosphodiesterase-4-inhibitors-from-the-leaves-of-psidium-guajava
#11
Gui-Hua Tang, Zhen Dong, Yan-Qiong Guo, Zhong-Bin Cheng, Chu-Jun Zhou, Sheng Yin
Bioassay-guided fractionation of the ethanolic extract of the leaves of Psidium guajava led to the isolation of 11 new Psidium meroterpenoids, psiguajadials A-K (1-11), along with 17 known ones (12-28). Their structures and absolute configurations were elucidated by spectroscopic methods and comparison of experimental and calculated ECD. Compounds 1 and 2 represent two unprecedented skeletons of 3,5-diformyl-benzyl phloroglucinol-coupled sesquiterpenoid, while 3 is the first example of Psidium meroterpenoids coupling via an oxepane ring...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28416366/2-year-animal-carcinogenicity-results-for-crisaborole-a-novel-phosphodiesterase-4-inhibitor-for-atopic-dermatitis
#12
Vic Ciaravino, Dina Coronado, Cheryl Lanphear, Sanjay Chanda
BACKGROUND: Crisaborole is a novel, topical nonsteroidal, anti-inflammatory, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild to moderate atopic dermatitis. OBJECTIVE: As part of a nonclinical safety testing program, these 2-year studies tested the carcinogenic potential of crisaborole. METHODS: Crisaborole ointment, 2%, 5%, or 7%, was applied once daily topically to mice, and crisaborole was administered orally to rats at doses of 30, 100, or 300mg/kg/day for up to 104 weeks...
March 30, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28402318/memory-enhancing-effects-of-gebr-32a-a-new-pde4d-inhibitor-holding-promise-for-the-treatment-of-alzheimer-s-disease
#13
Roberta Ricciarelli, Chiara Brullo, Jos Prickaerts, Ottavio Arancio, Carla Villa, Claudia Rebosio, Elisa Calcagno, Matilde Balbi, Britt T J van Hagen, Elentina K Argyrousi, Hong Zhang, Maria Adelaide Pronzato, Olga Bruno, Ernesto Fedele
Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28383060/phosphodiesterase-4b-negatively-regulates-endotoxin-activated-interleukin-1-receptor-antagonist-responses-in-macrophages
#14
Jing-Xing Yang, Kou-Chou Hsieh, Yi-Ling Chen, Chien-Kuo Lee, Marco Conti, Tsung-Hsien Chuang, Chin-Pyng Wu, S-L Catherine Jin
Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28378713/the-preparation-characterization-structure-and-dissolution-analysis-of-apremilast-solvatomorphs
#15
Yun Deng Wu, Xiao Lei Zhang, Xiao Hong Liu, Jian Xu, Mei Zhang, Kun Shen, Si Han Zhang, Yong Mei He, Yan Ma, Ai Hua Zhang
Apremilast (AP) {systematic name: (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-acetamidoisoindoline-1,3-dione} is an inhibitor of phosphodieasterase-4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The ability of AP to form solvates has been investigated and three solvatomorphs of AP, namely, the AP ethyl acetate hemisolvate, C22H24N2O7S·0.5C4H8O2, the AP toluene hemisolvate, C22H24N2O7S·0.5C7H8, and the AP dichloromethane monosolvate, C22H24N2O7S·CH2Cl2, were obtained...
April 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
https://www.readbyqxmd.com/read/28366471/phosphodiesterase-4-inhibition-restored-hippocampal-long-term-potentiation-after-primary-blast
#16
Edward W Vogel, Fatima N Morales, David F Meaney, Cameron R Bass, Barclay Morrison
Due to recent military conflicts and terrorist attacks, blast-induced traumatic brain injury (bTBI) presents a health concern for military and civilian personnel alike. Although secondary blast (penetrating injury) and tertiary blast (inertia-driven brain deformation) are known to be injurious, the effects of primary blast caused by the supersonic shock wave interacting with the skull and brain remain debated. Our group previously reported that in vitro primary blast exposure reduced long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and that primary blast affects key proteins governing LTP...
March 31, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28290219/2-crisaborole-topical-ointment-for-the-treatment-of-mild-to-moderate-atopic-dermatitis
#17
Alice C Cheape, Dedee F Murrell
Crisaborole 2% topical ointment is an anti-inflammatory, non-steroidal phosphodiesterase 4 inhibitor which is currently under investigation for its potential role in the treatment of atopic dermatitis and psoriasis. Areas covered: So far, 7 trials have been completed in atopic dermatitis. The 2% strength appeared to be the superior dosing regimen. Pruritus improved significantly within one week. The improvements in objective efficacy assessments in crisaborole-treated patients were also statistically significant compared to the vehicle...
May 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28281360/bioactive-triterpenoids-from-the-leaves-of-eriobotrya-japonica-as-the-natural-pde4-inhibitors
#18
Bing-Xin Tan, Lu Yang, Yi-You Huang, Yun-Yun Chen, Guang-Tian Peng, Si Yu, Yi-Nuo Wu, Hai-Bin Luo, Xi-Xin He
The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3β,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3β-hydroxyl-21β-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data...
March 10, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28266741/signalling-and-targeted-therapy-of-inflammatory-cells-in-epidermolysis-bullosa-acquisita
#19
REVIEW
Ralf J Ludwig
Pemphigoid diseases (PDs) are chronic and life-threatening autoimmune diseases of the skin and mucous membranes. PDs are characterized and caused by autoantibodies targeting components of the basement membrane. In the PD epidermolysis bullosa acquisita (EBA), the target autoantigen is type VII collagen. Current treatment options of PD, especially EBA, are limited and are mostly based on systemic immunosuppression. Animal models of PD have greatly advanced our understanding of PD pathogenesis. This has led to the identification of several novel therapeutic targets, including signalling molecules...
March 7, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/28263828/6-hydroxy-5-7-dimethoxy-flavone-suppresses-the-neutrophil-respiratory-burst-via-selective-pde4-inhibition-to-ameliorate-acute-lung-injury
#20
Yung-Fong Tsai, Tzu-Chi Chu, Wen-Yi Chang, Yang-Chang Wu, Fang-Rong Chang, Shun-Chin Yang, Tung-Ying Wu, Yu-Ming Hsu, Chun-Yu Chen, Shih-Hsin Chang, Tsong-Long Hwang
Over-activated neutrophils produce enormous oxidative stress and play a key role in the development of acute and chronic inflammatory diseases. 6-Hydroxy-5,7-dimethoxy-flavone (UFM24), a flavone isolated from the Annonaceae Uvaria flexuosa, showed inhibitory effects on human neutrophil activation and salutary effects on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. UFM24 potently inhibited superoxide anion (O2(•-)) generation, reactive oxidants, and CD11b expression, but not elastase release, in N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils...
March 3, 2017: Free Radical Biology & Medicine
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