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PDE 5 Inhibitors

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https://www.readbyqxmd.com/read/28204955/inactivation-of-non-canonical-cyclic-nucleotides-hydrolysis-and-transport
#1
Erich H Schneider, Roland Seifert
This chapter addresses cNMP hydrolysis by phosphodiesterases (PDEs) and export by multidrug resistance associated proteins (MRPs). Both mechanisms are well-established for the canonical cNMPs, cAMP, and cGMP. Increasing evidence shows that non-canonical cNMPs (specifically cCMP, cUMP) are also PDE and MRP substrates. Hydrolysis of cUMP is achieved by PDE 3A, 3B, and 9A, which possibly explains the cUMP-degrading activities previously reported for heart, adipose tissue, and brain. Regarding cCMP, the only known "conventional" (class I) PDE that hydrolyzes cCMP is PDE7A...
February 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28132040/erectile-dysfunction-as-a-predictor-of-cardiovascular-disease
#2
Sh Janjgava, T Doliashvili
Endothelial dysfunction precedes the clinical stage of atherosclerotic disease and is recognized as an additional risk factor when detecting symptomatic patients. Endothelial function is largely mediated by nitric oxide, and this vasodilatory mechanism is also responsible for the venous and arterial dilatation required to obtain and maintain an erection. The physiological effects and clinical aspects of sexual function have been extensively studied and reported in patients who have angina or who have experienced a myocardial infarction and in those who have undergone coronary artery bypass graft surgery or heart transplant...
December 2016: Georgian Medical News
https://www.readbyqxmd.com/read/28124739/the-regulation-of-transient-receptor-potential-canonical-4-trpc4-channel-by-phosphodiesterase-5-inhibitor-via-the-cyclic-guanosine-3-5-monophosphate
#3
Jinhong Wie, SeungJoo Jeong, Misun Kwak, Jongyun Myeong, MeeRee Chae, Jong Kwan Park, Sung Won Lee, Insuk So
The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to the fruit fly Drosophila TRP. The TRP superfamily is distinct from other groups of ion channels in displaying a large diversity in ion selectivity, modes of activation, and physiological functions. Classical TRP (transient receptor potential canonical (TRPC)) channels are activated by stimulation of Gq-PLC-coupled receptors and modulated by phosphorylation. The cyclic guanosine monophosphate (cGMP)-PKG pathway is involved in the regulation of TRPC3 and TRPC6 channels...
January 26, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28123846/phosphodiesterase-5-inhibition-suppresses-colonic-inflammation-induced-tumorigenesis-via-blocking-the-recruitment-of-mdsc
#4
Shiyong Lin, Jing Wang, Lihui Wang, Jing Wen, Yandong Guo, Weiguang Qiao, Jieqiong Zhou, Guoliang Xu, Fachao Zhi
Phosphodiesterase 5 (PDE-5) is a major isoform of cGMP phosphodiesterase in diverse tissues and plays a critical role in regulating intracellular cGMP concentrations. However, the distribution and expression of PDE-5 in colitis-related colon cancer was still unclear, not even the function and mechanism. Western blotting and ELISA were performed to detect colonic PDE-5 expression in AOM/DSS-induced tumorigenesis model. Sildenafil, a specific PDE-5 inhibitor, was used to treat AOM/DSS-induced and AOM-induced colonic tumorigenesis model and DSS-induced colitis model...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28120486/a-phase-i-randomized-proof-of-clinical-mechanism-study-assessing-the-pharmacokinetics-and-pharmacodynamics-of-the-oral-pde9a-inhibitor-bi-409306-in-healthy-male-volunteers
#5
Katja Boland, Viktoria Moschetti, Chantaratsamon Dansirikul, Solen Pichereau, Lien Gheyle, Frank Runge, Heike Zimdahl-Gelling, Michael Sand
OBJECTIVE: Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor. METHODS: In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF)...
January 2017: Human Psychopharmacology
https://www.readbyqxmd.com/read/28097089/selective-inhibition-of-phosphodiesterases-4-5-and-9-induces-hsp20-phosphorylation-and-attenuates-amyloid-beta-1-42-mediated-cytotoxicity
#6
Ryan T Cameron, Ellanor Whiteley, Jon P Day, Anna I Parachikova, George S Baillie
Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1-42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide...
January 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28013386/potentiation-of-the-no-cgmp-pathway-and-blood-flow-responses-during-dynamic-exercise-in-healthy-humans
#7
Jacqueline K Limberg, Katherine R Malterer, J Mikhail Kellawan, William G Schrage, Brad W Wilkins, Wayne T Nicholson, John H Eisenach, Michael J Joyner, Timothy B Curry
PURPOSE: Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor)...
February 2017: European Journal of Applied Physiology
https://www.readbyqxmd.com/read/27979766/nebulized-solid-lipid-nanoparticles-for-the-potential-treatment-of-pulmonary-hypertension-via-targeted-delivery-of-phosphodiesterase-5-inhibitor
#8
Shaimaa Makled, Noha Nafee, Nabila Boraie
Phosphodiesterase type 5 (PDE-5) inhibitors - among which sildenafil citrate (SC) - play a primary role in the treatment of pulmonary hypertension (PH). Yet, SC can be only administered orally or parenterally with lot of risks. Targeted delivery of SC to the lungs via inhalation/nebulization is mandatory. In this study, solid lipid nanoparticles (SLNs) loaded with SC were prepared and characterized in terms of colloidal, morphological and thermal properties. The amount of drug loaded and its release behavior were estimated as a function of formulation variables...
December 12, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27928428/evidence-for-the-efficacy-and-safety-of-tadalafil-and-finasteride-in-combination-for-the-treatment-of-lower-urinary-tract-symptoms-and-erectile-dysfunction-in-men-with-benign-prostatic-hyperplasia
#9
REVIEW
Chris Olesovsky, Anil Kapoor
Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual's quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. The three classes of drugs approved for treating BPH include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors...
August 2016: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/27909693/unfractionated-and-low-molecular-weight-heparin-and-the-phosphodiesterase-inhibitors-ibmx-and-cilostazol-block-ex-vivo-equid-herpesvirus-type-1-induced-platelet-activation
#10
Tracy Stokol, Priscila B D Serpa, Muhammad N Zahid, Marjory B Brooks
Equid herpes virus type-1 (EHV-1) is a major pathogen of horses, causing abortion storms and outbreaks of herpes virus myeloencephalopathy. These clinical syndromes are partly attributed to ischemic injury from thrombosis in placental and spinal vessels. The mechanism of thrombosis in affected horses is unknown. We have previously shown that EHV-1 activates platelets through virus-associated tissue factor-initiated thrombin generation. Activated platelets participate in thrombus formation by providing a surface to localize coagulation factor complexes that amplify and propagate thrombin generation...
2016: Frontiers in Veterinary Science
https://www.readbyqxmd.com/read/27887774/rationale-and-study-design-of-respite-an-open-label-phase-3b-study-of-riociguat-in-patients-with-pulmonary-arterial-hypertension-who-demonstrate-an-insufficient-response-to-treatment-with-phosphodiesterase-5-inhibitors
#11
Marius M Hoeper, James R Klinger, Raymond L Benza, Gerald Simonneau, David Langleben, Robert Naeije, Paul A Corris
Patients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i...
November 5, 2016: Respiratory Medicine
https://www.readbyqxmd.com/read/27879305/partial-segmental-thrombosis-of-the-corpus-cavernosum-presenting-with-perineal-pain
#12
Michelle Christodoulidou, Arie Parnham, Navin Ramachandran, Asif Muneer
We describe the case of a man aged 43 years who presented with a 2-week history of a palpable lump in the right proximal penile shaft. This was preceded by a 6-month history of perineal pain, accompanied by erectile dysfunction. An urgent MRI scan of his penis identified a thrombus within the right crus and corpus of the penis. His thrombophilia screen was normal. The patient was started on oral anticoagulation and a phosphodiesterase inhibitor (PDE-5i) to prevent thrombus progression and maintain erectile function...
November 22, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27871960/useful-implications-of-low-dose-long-term-use-of-pde-5-inhibitors
#13
REVIEW
Taymour Mostafa
INTRODUCTION: Phosphodiesterase type 5 (PDE-5) hydrolyzes cyclic guanylate monophosphate (cGMP) specifically to 5' GMP, promoting successful corporeal vascular relaxation and penile erection during sexual stimulation. Oral PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil have provided noninvasive, effective, well-tolerated treatment for erectile dysfunction (ED) patients and, at the same time, stimulated both academic and clinical interests. Lately, some oral PDE-5 inhibitors were released as low-dose preparations with the concept of potential daily administration and long-term use...
July 2016: Sexual Medicine Reviews
https://www.readbyqxmd.com/read/27869315/aminoalkyl-derivatives-of-8-alkoxypurine-2-6-diones-multifunctional-5-ht1a-5-ht7-receptor-ligands-and-pde-inhibitors-with-antidepressant-activity
#14
Grażyna Chłoń-Rzepa, Agnieszka Zagórska, Paweł Żmudzki, Adam Bucki, Marcin Kołaczkowski, Anna Partyka, Anna Wesołowska, Grzegorz Kazek, Monika Głuch-Lutwin, Agata Siwek, Gabriela Starowicz, Maciej Pawłowski
In the search for potential psychotropic agents, a new series of 3,7-dimethyl- and 1,3-dimethyl-8-alkoxypurine-2,6-dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5-16 and 21-32) were synthesized and evaluated for 5-HT1A /5-HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-3,7-dimethyl-8-propoxypurine-2,6-dione (16) and 7-(2-hydroxyphenyl)piperazinylalkyl-1,3-dimethyl-8-ethoxypurine-2,6-diones (31 and 32) as potent dual 5-HT1A /5-HT7 receptor ligands with antagonistic activity produced an antidepressant-like effect in the forced swim test in mice...
December 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27860455/papaverine-sensitive-phosphodiesterase-activity-is-measured-in-bovine-spermatozoa
#15
A Bergeron, A Hébert, C Guillemette, A Laroche, M-P Poulin, J P Aragon, P Leclerc, R Sullivan, P Blondin, C Vigneault, F J Richard
Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is well-known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. This study was undertaken to characterize cAMP-PDE activity in bovine spermatozoa. Total cAMP-PDE activity in cauda epididymal and ejaculated spermatozoa was 543.2 ± 49.5 and 1252.6 ± 86.5 fmoles/min/10(6) spermatozoa, respectively. Using different family-specific PDE inhibitors, we showed that in cauda epididymal and ejaculated spermatozoa, the major cAMP-PDE activity was papaverine-sensitive (44...
January 2017: Andrology
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/27843073/off-target-effect-of-sildenafil-on-postsurgical-erectile-dysfunction-alternate-pathways-and-localized-delivery-system
#17
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/27832298/-recurrence-free-survival-after-radical-prostatectomy-and-pde-5-inhibitor-intake
#18
L Hofer, J P Radtke, C Rapp, S Pahernik, D Teber, M Hohenfellner, B Hadaschik
BACKGROUND: Phosphodiesterase type 5 (PDE-5) inhibitors are widely used for penile rehabilitation and treatment of erectile dysfunction after radical prostatectomy. Recently, Michl et al. showed in a monocentric, retrospective and non-randomized analysis that PDE-5 inhibitors may cause higher biochemical recurrence rates after radical prostatectomy. This unexpected and serious adverse side effect of PDE-5 inhibitors was scrutinized on the basis of patients in our prospective tumor database...
November 10, 2016: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/27769022/tadalafil-reduces-airway-hyperactivity-and-protects-against-lung-and-respiratory-airways-dysfunction-in-a-rat-model-of-silicosis
#19
Rania R Abdelaziz, Wagdi F Elkashef, Eman Said
Silicosis is a crippling respiratory disorder characterized by massive lung inflammation and fibrosis. The current study provides evidence on the protective potential of tadalafil; a specific phosphodiesterase-5 (PDE-5) inhibitor against experimentally-induced pulmonary silicosis in rats. Silicosis was induced by intranasal instillation of crystalline silica (50mg/rat). Halofuginone hydrobromide; a standard collagen-1 synthesis inhibitor was selected as a reference anti-fibrotic. Daily oral administration of tadalafil (1mg/kg) for 8weeks significantly ameliorated silica-induced pulmonary damage...
November 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27766379/aryl-1-3-5-triazine-ligands-of-histamine-h4-receptor-attenuate-inflammatory-and-nociceptive-response-to-carrageen-zymosan-and-lipopolysaccharide
#20
Szczepan Mogilski, Monika Kubacka, Dorota Łażewska, Małgorzata Więcek, Monika Głuch-Lutwin, Małgorzata Tyszka-Czochara, Karolina Bukowska-Strakova, Barbara Filipek, Katarzyna Kieć-Kononowicz
OBJECTIVE AND DESIGN: Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. MATERIALS AND SUBJECTS: We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test...
January 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
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