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PDE 5 Inhibitors

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https://www.readbyqxmd.com/read/29672041/targeting-a-subpocket-in-trypanosoma-brucei-phosphodiesterase-b1-tbrpdeb1-enables-the-structure-based-discovery-of-selective-inhibitors-with-trypanocidal-activity
#1
Antoni R Blaazer, Abhimanyu Kumar Singh, Erik de Heuvel, Ewald Edink, Kristina M Orrling, Johan J N Veerman, Toine van den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J Mooij, Hans Custers, Maarten Sijm, Daniel N A Tagoe, Titilola D Kalejaiye, Jane C Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris de Graaf, Louis Maes, Harry P de Koning, David S Bailey, Geert Jan Sterk, Iwan J P De Esch, David G Brown, Rob Leurs
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, pharmacological evaluation, and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29568269/camp-catalyzing-phosphodiesterases-control-cholinergic-muscular-activity-but-their-inhibition-does-not-enhance-5-ht-4-receptor-mediated-facilitation-of-cholinergic-contractions-in-the-murine-gastrointestinal-tract
#2
Vicky Pauwelyn, Romain A Lefebvre
Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29557941/effects-of-the-phosphodiesterase-5-pde-5-inhibitors-avanafil-and-zaprinast-on-bone-remodeling-and-oxidative-damage-in-a-rat-model-of-glucocorticoid-induced-osteoporosis
#3
Zübeyir Huyut, Nuri Bakan, Serkan Yıldırım, Hamit Hakan Alp
No abstract text is available yet for this article.
March 13, 2018: Medical Science Monitor Basic Research
https://www.readbyqxmd.com/read/29549244/effects-of-sildenafil-treatment-on-thermogenesis-and-glucose-homeostasis-in-diet-induced-obese-mice
#4
Kornelia Johann, Marlen Colleen Reis, Lisbeth Harder, Beate Herrmann, Sogol Gachkar, Jens Mittag, Rebecca Oelkrug
Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days...
March 13, 2018: Nutrition & Diabetes
https://www.readbyqxmd.com/read/29501590/modeling-of-pharmacokinetics-efficacy-and-hemodynamic-effects-of-macitentan-in-patients-with-pulmonary-arterial-hypertension
#5
Andreas Krause, Jochen Zisowsky, Jasper Dingemanse
BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent...
February 28, 2018: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29484221/peyronie-s-disease-surgery-surgical-outcomes-of-268-cases
#6
Ateş Kadıoğlu, Emre Salabaş, Abdulkadir Özmez, Abdullah Feyyaz Ural, Ömer Barış Yücel, Mazhar Ortaç, Yaşar Pazır, Bahadır Ermeç
Objective: To assess the outcomes of the surgical techniques used in Peyronie's disease (PD) surgery. Material and methods: Two hundred and sixty-eight patients received surgical treatment for PD. Fifty four and 144 patients underwent simple corporoplasties (shortening procedure, SP, group 1) or plaque incision and grafting surgery (lengthening surgery, LP, group 2), respectively, whereas 70 patients with erectile dysfunction underwent penile prosthesis implantation...
January 2018: Turkish Journal of Urology
https://www.readbyqxmd.com/read/29477888/synthesis-and-molecular-docking-of-new-roflumilast-analogues-as-preferential-selective-potent-pde-4b-inhibitors-with-improved-pharmacokinetic-profile
#7
Bahia A Moussa, Asmaa A El-Zaher, Mohamed K El-Ashrey, Marwa A Fouad
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5...
March 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29458418/amyloid-%C3%AE-induced-impairments-on-mitochondrial-dynamics-hippocampal-neurogenesis-and-memory-are-restored-by-phosphodiesterase-7-inhibition
#8
Fernando Bartolome, Macarena de la Cueva, Consuelo Pascual, Desiree Antequera, Tamara Fernandez, Carmen Gil, Ana Martinez, Eva Carro
BACKGROUND: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. METHODS: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice...
February 20, 2018: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29436260/treatment-patterns-and-associated-health-care-costs-before-and-after-treatment-initiation-among-pulmonary-arterial-hypertension-patients-in-the-united-states
#9
Charles D Burger, A Burak Ozbay, Howard M Lazarus, Ellen Riehle, Leslie B Montejano, Gregory Lenhart, R James White
BACKGROUND: Despite multiple treatment options, the prognosis of pulmonary arterial hypertension (PAH) remains poor. PAH patients experience a high economic burden due to comorbidities, hospitalizations, and medication costs. Although combination therapy has been shown to reduce hospitalizations, the relationship between treatment, health care utilization, and costs remains unclear. OBJECTIVE: To provide a characterization of health care utilization and costs in real-world settings by comparing periods before and after initiating PAH-specific treatment...
February 13, 2018: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/29391766/beneficial-long-term-effect-of-a-phosphodiesterase-5-inhibitor-in-cirrhotic-portal-hypertension-a-case-report-with-8-years-follow-up
#10
Peter Deibert, Adhara Lazaro, Zoran Stankovic, Denise Schaffner, Martin Rössle, Wolfgang Kreisel
Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored...
January 21, 2018: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29380385/role-of-l-arginine-snap-no-cgmp-katp-channel-signalling-pathway-in-antinociceptive-effect-of-%C3%AE-terpineol-in-mice
#11
Sara Safaripour, Yasaman Nemati, Siavash Parvardeh, Shiva Ghafghazi, Anahita Fouladzadeh, Mahsa Moghimi
OBJECTIVES: The main purpose of this study was to assess the role of l-arginine/SNAP/NO/cGMP/KATP channel pathway in analgesic effects of α-terpineol in mice. METHODS: Male NMRI mice were pretreated intraperitoneally with NO precursor (l-arginine, 100 mg/kg), NO synthase inhibitor (l-NAME, 30 mg/kg), NO donor (SNAP, 1 mg/kg), guanylyl cyclase inhibitor (methylene blue, 20 mg/kg), PDE inhibitor (sildenafil, 0.5 mg/kg), KATP channel blocker (glibenclamide, 10 mg/kg) and naloxone (2 mg/kg) 20 min before the administration of α-terpineol...
January 30, 2018: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29376615/-current-approaches-to-conservative-treatment-of-men-with-concomitant-benign-prostatic-hyperplasia-and-erectile-dysfunction
#12
A A Kamalov, A M Takhirzade
The article reviews the results of various conservative treatments for concomitant benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). Phosphodiesterase type 5 (PDE5) inhibitors remain the first-line therapy for this category of patients taking into account their positive effect on both ED and BPH. The preferred treatment scheme includes PDE-5 inhibitor co-administered with 1-adrenoblocker. However, other combination treatments are considered promising, for example, a PDE-5 inhibitor with a 5-reductase inhibitor or a three-component treatment regimen: 1-adrenoblocker + 5-reductase inhibitor + PDE-5 inhibitor...
December 2017: Urologii︠a︡
https://www.readbyqxmd.com/read/29375047/effects-of-tadalafil-pde5-inhibitor-and-roflumilast-pde4-inhibitor-on-airway-reactivity-and-markers-of-inflammation-in-ovalbumin-induced-airway-hyperresponsiveness-in-guinea-pigs
#13
J Mokry, A Urbanova, I Medvedova, M Kertys, P Mikolka, P Kosutova, D Mokra
Selective phosphodiesterase (PDE) 4 inhibitors have recently been introduced into the therapy of chronic obstructive pulmonary disease. However, suppression of airway reactivity and eosinophilic inflammation by increased intracellular cAMP could be beneficial in bronchial asthma as well. PDE5 inhibitors are used for the therapy of erectile dysfunction, pulmonary hypertension, and other cardiovascular diseases, but an expression of PDE5 in several immune cells suggests its perspectives in inflammation, as well...
October 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/29307087/targeting-the-prostacyclin-pathway-with-selexipag-in-patients-with-pulmonary-arterial-hypertension-receiving-double-combination-therapy-insights-from-the-randomized-controlled-griphon-study
#14
J Gerry Coghlan, Richard Channick, Kelly Chin, Lilla Di Scala, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Irene M Lang, Vallerie McLaughlin, Ralph Preiss, Lewis J Rubin, Gérald Simonneau, Olivier Sitbon, Victor F Tapson, Sean Gaine
BACKGROUND: In pulmonary arterial hypertension (PAH), combination therapy is an important treatment strategy. Although randomized controlled trial data are available to support the combination of two therapies, data regarding triple combination therapy are few. OBJECTIVE: The phase III GRIPHON trial enrolled 1156 patients with PAH, including 376 receiving background double combination therapy. We evaluated the efficacy and safety of selexipag as a third agent in these patients and further analyzed this subgroup according to symptom burden at baseline as indicated by World Health Organization (WHO) functional class (FC)...
February 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/29291443/prenylated-flavonoids-as-potent-phosphodiesterase-4-inhibitors-from-morus-alba-isolation-modification-and-structure-activity-relationship-study
#15
Yan-Qiong Guo, Gui-Hua Tang, Lan-Lan Lou, Wei Li, Bei Zhang, Bo Liu, Sheng Yin
The bioassay-guided phytochemical study of a traditional Chinese medicine Morus alba led to the isolation of 18 prenylated flavonoids (1-18), of which (±)-cyclomorusin (1/2), a pair of enantiomers, and 14-methoxy-dihydromorusin (3) are the new ones. Subsequent structural modification of the selected components by methylation, esterification, hydrogenation, and oxidative cyclization led to 14 more derivatives (19-32). The small library was screened for its inhibition against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease (COPD)...
January 20, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29280064/macitentan-in-pulmonary-arterial-hypertension-a-focus-on-combination-therapy-in-the-seraphin-trial
#16
REVIEW
Pavel Jansa, Tomás Pulido
SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0...
February 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/29237389/venlafaxine-attenuates-the-development-of-morphine-tolerance-and-dependence-role-of-l-arginine-nitric-oxide-cgmp-pathway
#17
Mohammad Taghi Mansouri, Bahareh Naghizadeh, Behnam Ghorbanzadeh, Soheila Alboghobeish, Gholamreza Houshmand, Neda Amirgholami
BACKGROUND: Severe pain reduce quality of life in patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) play a role in morphine tolerance and dependence. OBJECTIVE: Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice...
December 13, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/29233027/effects-of-phosphodiestrase-type-5-inhibitors-in-epinephrine-induced-arrhythmia-in-rats-involvement-of-lactate-dehydrogenase-and-creatine-kinase-downregulation-and-adiponectin-expression
#18
Aaa Salama, R E Mostafa, E A Omara
Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals...
March 2018: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/29220595/dose-dependent-effects-of-tadalafil-and-roflumilast-on-ovalbumin-induced-airway-hyperresponsiveness-in-guinea-pigs
#19
Anna Urbanova, Ivana Medvedova, Martin Kertys, Pavol Mikolka, Petra Kosutova, Daniela Mokra, Juraj Mokrý
INTRODUCTION: Chronic obstructive diseases of airways associated with cough and/or airway smooth muscle hyperresponsiveness are usually treated with bronchodilating and anti-inflammatory drugs. Recently, selective phosphodiesterase (PDE) 4 inhibitors have been introduced into the therapy of chronic obstructive pulmonary disease. Several studies have demonstrated their ability to influence the airway reactivity and eosinophilic inflammation by increasing the intracellular cAMP concentrations also in bronchial asthma...
November 2017: Experimental Lung Research
https://www.readbyqxmd.com/read/29201504/effect-of-sildenafil-citrate-in-testosterone-induced-benign-prostate-hyperplasia-rat-model
#20
Selahattin Çalışkan, Muzaffer Oğuz Keleş, Metin İshak Öztürk, Musab Ali Kutluhan, Olgu Enis Tok, Feriha Ercan, Muhammet İhsan Karaman
Objective: Efficacy of treatments for benign prostate hyperplasia (BPH) is limited because the disease has complex etiopathogenesis. Recent studies have demonstrated the presence of phosphodiesterase-5 (PDE-5) receptors in prostate tissue. We investigated efficacy of sildenafil citrate in testosteron - induced BPH in rats. Material and methods: The rats were divided into three groups. Each groups had 7 rats. Group 1 was control group. Testosteron propionate 3 mg/kg/day was injected subcutaneously for two weeks in Group 2...
December 2017: Turkish Journal of Urology
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