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PDE5 inhibitor

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https://www.readbyqxmd.com/read/29677206/synergistic-interaction-between-a-pde5-inhibitor-sildenafil-and-a-new-adenosine-a2a-receptor-agonist-lassbio-1359-improves-pulmonary-hypertension-in-rats
#1
Allan K Alencar, Fábio I Carvalho, Ananssa M Silva, Sabrina T Martinez, Jorge A Calasans-Maia, Carlos M Fraga, Eliezer J Barreiro, Gisele Zapata-Sudo, Roberto T Sudo
INTRODUCTION: Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats. METHODS: An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs)...
2018: PloS One
https://www.readbyqxmd.com/read/29667180/pde5-inhibitors-pharmacology-and-clinical-applications-20-years-after-sildenafil-discovery
#2
REVIEW
K-E Andersson
The discovery of the nitric oxide/cyclic cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of phosphodiesterase isoenzymes type 5 (PDE5) have been first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms (LUTS), and pulmonary arterial hypertension, which are now approved indications...
April 17, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29665366/3-7-bis-2-hydroxyethyl-icaritin-a-potent-inhibitor-of-phosphodiesterase-5-prevents-monocrotaline-induced-pulmonary-arterial-hypertension-via-no-cgmp-activation-in-rats
#3
Tao-Hua Lan, Xiao-Ling Chen, Yun-Shan Wu, Hui-Liang Qiu, Jun-Zhe Li, Xin-Min Ruan, Dan-Ping Xu, Dong-Qun Lin
Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40mg/kg/d), Icariin (ICA) (40mg/kg/d) and Sildenafil (25mg/kg/d)...
April 14, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29660387/long-term-inhibition-of-pde5-ameliorates-aging-induced-changes-in-rat-testis
#4
Srdjan J Sokanovic, Ivan Capo, Marija M Medar, Silvana A Andric, Tatjana S Kostic
NO-cGMP signaling pathway has been implicated in reduction of testicular steroidogenesis during aging. Here we analyzed the effect of PDE5 inhibition on old testicular phenotype formation. The old phenotype exhibited low testosterone and increased nitrite levels in circulation, increased cGMP accumulation in testicular interstitial fluid (TIF), progressive atrophy of testicular seminiferous tubules and enlargement of interstitial area followed by rise in blood vessel density and slight increase in the number of Leydig cells and macrophages...
April 13, 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29656464/design-and-synthesis-of-novel-annulated-thienopyrimidines-as-phosphodiesterase-5-pde5-inhibitors
#5
Lina Y El-Sharkawy, Rowaida A El-Sakhawy, Mohammad Abdel-Halim, Kevin Lee, Gary A Piazza, Christian Ducho, Rolf W Hartmann, Ashraf H Abadi
Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by varying the substituents at position 4 through the attachment of different groups including aniline, benzylamine, cyclohexylethylamine, methyl/acetyl/aryl piperazines, and aryl hydrazones. Compound 15Y with a benzylamine substituent and cycloheptene as terminal ring showed the highest PDE5 inhibitory activity with an IC50 value as low as 190 nM and with good selectivity versus PDE7 and PDE9...
April 14, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29621314/sildenafil-ameliorates-right-ventricular-early-molecular-derangement-during-left-ventricular-pressure-overload
#6
Yousuke Imai, Taro Kariya, Masaki Iwakiri, Yoshitsugu Yamada, Eiki Takimoto
Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined...
2018: PloS One
https://www.readbyqxmd.com/read/29616790/novel-tadalafil-derivatives-ameliorates-scopolamine-induced-cognitive-impairment-in-mice-via-inhibition-of-acetylcholinesterase-ache-and-phosphodiesterase-5-pde5
#7
Wei Ni, Huan Wang, Xiaokang Li, Xinyu Zheng, Manjiong Wang, Jian Zhang, Qi Gong, Dazheng Ling, Fei Mao, Haiyan Zhang, Jian Li
Based on the drugs repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5), have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the nineteen analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition, good blood-brain barrier (BBB) permeability...
April 4, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29587411/relationship-between-response-to-pde5-inhibitors-and-penile-duplex-doppler-ultrasound-in-erectile-dysfunction
#8
Ercan Ogreden, Ural Oğuz, Erhan Demirelli, Alptekin Tosun, Orhan Yalçın
The relationship between the results of penile duplex Doppler ultrasound (PDDU) and response to vardenafil was investigated in patients diagnosed with erectile dysfunction (ED). Data from 148 patients with ED were analyzed retrospectively. Patients who did not respond to therapy were classified in to Group I ( n = 32), those who responded partially were classified into Group II ( n = 40), and complete responders were classified into Group III ( n = 76). Age, comorbidities, and vascular and penile pathologies were compared among the three groups...
March 26, 2018: Medical Sciences: Open Access Journal
https://www.readbyqxmd.com/read/29566267/tadalafil-attenuates-hypotonicity-induced-ca-2-influx-via-trpv2-and-trpv4-in-primary-rat-bladder-urothelial-cell-cultures
#9
Xiao Dong, Hiroshi Nakagomi, Tatsuya Miyamoto, Tatsuya Ihara, Satoru Kira, Norifumi Sawada, Takahiko Mitsui, Masayuki Takeda
AIMS: To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. METHODS: PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques...
March 22, 2018: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/29551532/effect-of-ginger-paullinia-cupana-muira-puama-and-l-citrulline-singly-or-in-combination-on-modulation-of-the-inducible-nitric-oxide-no-cgmp-pathway-in-rat-penile-smooth-muscle-cells
#10
Monica G Ferrini, Eduardo Garcia, Andrea Abraham, Jorge N Artaza, Sabine Nguyen, Jacob Rajfer
INTRODUCTION: COMP-4 is a natural compound-based dietary supplement consisting of the combination of ginger, Paullinia cupana, muira puama and l-citrulline, which when given long-term has been shown in the aged rat to a) upregulate iNOS in the penile smooth muscle cells (SMC), b) reverse the corporal SMC apoptosis and fibrosis associated with corporal veno-occlusive dysfunction (CVOD), and c) improve resulting erectile function. To elucidate the mechanism of how COMP-4 and its individual components modulate the iNOS-cGMP pathway, an in vitro study was conducted using a rat corporal primary SMC culture to determine its effect on NOS, soluble guanylate cyclase (sGC), cGMP and the phosphodiesterase 5 enzyme (PDE5)...
March 15, 2018: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/29549837/design-synthesis-biological-evaluation-and-in-vivo-testing-of-dual-phosphodiesterase-5-pde5-and-histone-deacetylase-6-hdac6-selective-inhibitors-for-the-treatment-of-alzheimer-s-disease
#11
Obdulia Rabal, Juan A Sánchez-Arias, Mar Cuadrado-Tejedor, Irene de Miguel, Marta Pérez-González, Carolina García-Barroso, Ana Ugarte, Ander Estella-Hermoso de Mendoza, Elena Sáez, Maria Espelosin, Susana Ursua, Tan Haizhong, Wu Wei, Xu Musheng, Ana Garcia-Osta, Julen Oyarzabal
We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors...
March 14, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29549279/phosphodiesterase-type-4-inhibition-enhances-nitric-oxide-and-hydrogen-sulfide-mediated-bladder-neck-inhibitory-neurotransmission
#12
Ángel Agis-Torres, Paz Recio, María Elvira López-Oliva, María Pilar Martínez, María Victoria Barahona, Sara Benedito, Salvador Bustamante, Miguel Ángel Jiménez-Cidre, Albino García-Sacristán, Dolores Prieto, Vítor S Fernandes, Medardo Hernández
Nitric oxide (NO) and hydrogen sulfide (H2 S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples...
March 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29545395/prevention-of-pkg-1%C3%AE-oxidation-suppresses-antihypertrophic-antifibrotic-effects-from-pde5-inhibition-but-not-sgc-stimulation
#13
Taishi Nakamura, Guangshuo Zhu, Mark J Ranek, Kristen Kokkonen-Simon, Manling Zhang, Grace E Kim, Kenichi Tsujita, David A Kass
BACKGROUND: Stimulation of sGC (soluble guanylate cyclase) or inhibition of PDE5 (phosphodiesterase type 5) activates PKG (protein kinase G)-1α to counteract cardiac hypertrophy and failure. PKG1α acts within localized intracellular domains; however, its oxidation at cysteine 42, linking homomonomers, alters this localization, impairing suppression of pathological cardiac stress. Because PDE5 and sGC reside in separate microdomains, we speculated that PKG1α oxidation might also differentially influence the effects from their pharmacological modulation...
March 2018: Circulation. Heart Failure
https://www.readbyqxmd.com/read/29534582/association-between-phosphodiesterase-type-5-inhibitors-use-and-risk-of-melanoma-a-meta-analysis
#14
T Deng, X Duan, B Liu, Y Lan, C Cai, T Zhang, W Zhu, Z Mai, W Wu, G Zeng
This meta-analysis aimed to clarify the actual association between the phosphodiesterase type 5 inhibitors (PDE5-Is) use and the risk of melanoma in erectile dysfunction (ED) patients. A systematic literature search was conducted in online databases in October, 2016 to identify studies focusing on the association between PDE5-Is use and the risk of melanoma. Summarized multivariate adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to assess the strength of associations. A total of six clinical trials containing more than one million participants were included...
2018: Neoplasma
https://www.readbyqxmd.com/read/29526379/an-immunohistochemical-and-ultrastructural-analysis-of-the-retina-in-tadalafil-cialis-treated-rats
#15
Nahla Reda Sarhan, Nesreen Moustafa Omar
Tadalafil (Cialis) is one of the most commonly used phosphodiesterase type5 (PDE5) inhibitors. This work aimed to analyze the histological and ultrastructural changes provoked by chronic tadalafil administration in the rat retina, correlate between such changes and PDE5 immunoexpression and to evaluate the possible reversibility of these changes. Thirty Sprague Dawley male rats were randomly distributed into 3 groups. Control group; given 1 ml distilled water daily for 6 weeks. Tadalafil group; given tadalafil in a daily dose of 2...
March 8, 2018: Acta Histochemica
https://www.readbyqxmd.com/read/29519873/phosphodiesterase-5-inhibitors-and-the-heart-compound-cardioprotection
#16
REVIEW
David Charles Hutchings, Simon George Anderson, Jessica L Caldwell, Andrew W Trafford
Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias...
March 8, 2018: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/29512263/risk-of-sudden-sensorineural-hearing-loss-in-adults-using-phosphodiesterase-type-5-inhibitors-population-based-cohort-study
#17
Wei Liu, Patrick J Antonelli, Philipp Dahm, Tobias Gerhard, Joseph A C Delaney, Richard Segal, Stephen Crystal, Almut G Winterstein
PURPOSE: The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors. METHODS: We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use)...
March 7, 2018: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/29511676/effect-of-riociguat-and-sildenafil-on-right-heart-remodeling-and-function-in-pressure-overload-induced-model-of-pulmonary-arterial-banding
#18
Nabham Rai, Swathi Veeroju, Yves Schymura, Wiebke Janssen, Astrid Wietelmann, Baktybek Kojonazarov, Norbert Weissmann, Johannes-Peter Stasch, Hossein Ardeschir Ghofrani, Werner Seeger, Ralph Theo Schermuly, Tatyana Novoyatleva
Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload. The increased RV afterload leads to right ventricular failure (RVF) which is the reason for the high morbidity and mortality in PAH patients. The objective was to evaluate the therapeutic efficacy and antiremodeling potential of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil and the soluble guanylate cyclase stimulator riociguat in a model of pressure overload RV hypertrophy induced by pulmonary artery banding (PAB)...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29505934/design-and-synthesis-of-furyl-thineyl-pyrroloquinolones-based-on-natural-alkaloid-perlolyrine-lead-to-the-discovery-of-potent-and-selective-pde5-inhibitors
#19
Hongbo Zheng, Lin Li, Bin Sun, Yun Gao, Wei Song, Xiaoyu Zhao, Yanhui Gao, Zhiyu Xie, Nianzhao Zhang, Jianbo Ji, Huiqing Yuan, Hongxiang Lou
Based on perlolyrine (1), a natural alkaloid with weak PDE5 potency from the traditional Chinese aphrodisiac plant Tribulus terrestris L., a series α-substituted tetrahydro-β-carboline (THβC) derivatives were synthesized via T+ BF4- -mediated oxidative C-H functionalization of N-aryl THβCs with diverse potassium trifluoroborates. Following Winterfeldt oxidation afforded the corresponding furyl/thienyl pyrroloquinolones, of which 5-ethylthiophene/ethylfuran derivatives 20a-b were identified as the most potent and selective PDE5 inhibitors...
February 16, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29504984/are-phosphodiesterase-type-5-inhibitors-associated-with-increased-risk-of-melanoma-a-systematic-review-and-meta-analysis
#20
Shijian Feng, Liang Zhou, Qinyu Liu, Qing He, Banghua Liao, Xin Wei, Hong Li, Kunjie Wang, Yuchun Zhu
Phosphodiesterase type 5 (PDE5) inhibitors are recommended for patients with erectile dysfunction by American Urological Association and European Association Urology guidelines. However, recent researches have shown that PDE5 inhibitors may lead to increased melanoma risk. Thus, we aimed to explore whether PDE5 inhibitors are associated with increased melanoma risk based on published literatures.We conducted a systematic online search on PubMed, EMBASE, Cochrane Library, Chinese Biochemical Literature, China National Knowledge Infrastructure, and Chinese Science and Technology Periodical databases to identify the related studies...
January 2018: Medicine (Baltimore)
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