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PDE 5 Inhibitors

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https://www.readbyqxmd.com/read/29029361/the-mechanism-of-attenuation-of-epithelial-mesenchymal-transition-by-a-phosphodiesterase-5-inhibitor-via-renal-klotho-expression
#1
Seung Tae Han, Jae Seok Kim, Jun Young Lee, Min Keun Kim, Jin Sae Yoo, Byoung Geun Han, Seung Ok Choi, Jae Won Yang
OBJECTIVES: Phosphodiesterase-5 (PDE-5) inhibitors induces vasodilation in several organs by blocking cyclic GMP (guanosine monophosphate) degradation. However, the existence of alternative mechanism of action in case of an impaired nitric oxide (NO) system remains controversial. Previous studies suggested that decreased NO bioavailability may result in the down-regulation of klotho expression, but the relationship between klotho and NO remains obscure. Therefore, we investigated whether a PDE-5 inhibitor could preserve epithelial mesenchymal transition (EMT) and relationship exists between the NO and renal klotho expression...
October 13, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28959341/expression-of-recombinant-phosphodiesterases-3a-and-3b-using-baculovirus-expression-system
#2
Yongmin Yan, Wenqian Jiang, Jingwen Liu, Wenrong Xu, Hui Qian
BACKGROUND: Phosphodiesterase 3A (PDE3A) and phosphodiesterase 3B (PDE3B) play a critical role in the regulation of intracellular level of adenosine 3´,5´-cyclic monophosphate (cyclic AMP, cAMP) and guanosine 3´,5´-cyclic monophosphate (cyclic GMP, cGMP). Subsequently PDE3 inhibitors have shown to relax vascular and inhibit platelet aggregation in cardiovascular disease. OBJECTIVES: In this study, our aim was to establish a method of expression for the recombinant human PDE3A and PDE3B proteins in insect cells using baculovirus expression system in order to investigate the activity of the expressed PDE3A and PDE3B proteins...
December 2016: Iranian journal of biotechnology
https://www.readbyqxmd.com/read/28956337/role-of-phosphodiesterases-in-huntington-s-disease
#3
Francesca R Fusco, Emanuela Paldino
Huntington's disease (HD) is an autosomal-dominant rare inherited neurodegenerative disease characterized by a wide variety of symptoms encompassing movement, cognition and behaviour. The cause of the disease is a genetic mutation in the huntingtin protein. The mutation leads to an unstable CAG expansion, translated into a polyglutamine domain within the disease protein. Indeed, huntingtin has a CAG/polyglutamine expansion in the range of 6-39 units in normal individuals, whereas it reaches 39-180 units in HD patients...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28932631/tadalafil-has-biologic-activity-in-human-melanoma-results-of-a-pilot-trial-with-tadalafil-in-patients-with-metastatic-melanoma-tame
#4
Jessica C Hassel, Huanhuan Jiang, Carolin Bender, Julia Winkler, Alexandra Sevko, Ivan Shevchenko, Niels Halama, Antonia Dimitrakopoulou-Strauss, Walter E Haefeli, Dirk Jäger, Alexander Enk, Jochen Utikal, Viktor Umansky
Myeloid-derived suppressor cells (MDSCs) are known to play a critical role in the suppression of T cell antitumor responses. Our preclinical data showed that the phosphodiesterase (PDE)-5 inhibitor sildenafil impaired MDSC functions, enhanced intratumoral T cell activity and prolonged survival of melanoma-bearing mice. In this study, we evaluated biologic effects, safety and efficacy of palliative treatment with the PDE-5 inhibitor tadalafil in metastatic melanoma patients. We conducted an open-label, dose de-escalation trial with tadalafil in pretreated metastatic melanoma patients...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28903860/a-review-of-synthetic-phosphodiesterase-type-5-inhibitors-pde-5i-found-as-adulterants-in-dietary-supplements
#5
REVIEW
Chee-Leong Kee, Xiaowei Ge, Véronique Gilard, Myriam Malet-Martino, Min-Yong Low
To date, there are 80 synthetic PDE-5i found as adulterants in dietary supplements. Analogues of sildenafil remain as the top list with 50 (62%) and are followed by analogues of tadalafil, 21 (26%), analogues of vardenafil, 7 (9%) and others, 2 (3%). The sildenafil group can be sub-categorized into sulphonamide-bonded (24, 48%), acetyl-bonded (11, 22%), carbonyl or thiocarbonyl-bonded (8, 16%) and other types (7, 14%) based on the functional group linked to pyrazolopyrimidine-one moieties. Meanwhile, analogues of tadalafil have become popularly found as adulterants in dietary supplements like beverages and herbal extracts from 2015 to 2016...
August 9, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28891448/a-special-focus-on-selexipag-treatment-of-pulmonary-arterial-hypertension
#6
Louise Marqvard Sørensen, Markus Wehland, Marcus Krüger, Ulf Simonsen, Mohamed Zakaria Nassef, Manfred Infanger, Daniela Grimm
BACKGROUND: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues. METHODS: We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH. RESULTS: With only few cases per million, PAH is a rare disease, but when untreated it can be life threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2)...
September 7, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28888986/pde-5-inhibitor-improves-insulin-sensitivity-by-enhancing-mitochondrial-function-in-adipocytes
#7
Hea Min Yu, Hyo Kyun Chung, Koon Soon Kim, Jae Min Lee, Jun Hwa Hong, Kang Seo Park
Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function...
November 4, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28870522/poly-i-c-impairs-no-donor-induced-relaxation-by-overexposure-to-no-via-the-nf-kappa-b-inos-pathway-in-rat-superior-mesenteric-arteries
#8
Makoto Ando, Takayuki Matsumoto, Kumiko Taguchi, Tsuneo Kobayashi
Recent studies have suggested a link between vascular dysfunction and innate immune activation including toll-like receptors (TLRs), but the detailed mechanism remains unclear. Here we investigated whether poly (I:C) [a synthetic double-strand RNA recognized by TLR3, melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene I (RIG-I)] affected nitric oxide (NO)/cGMP-related vascular relaxation, one of the major cascades of relaxation, in rat superior mesenteric arteries. Using organ-cultured arteries, we found that poly (I:C) (30μg/mL for approximately 1 day) markedly reduced sodium nitroprusside (SNP)-induced relaxation (vs...
September 1, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28845950/-pde-5-inhibitors-patients-preferences
#9
E A Efremov, E V Kasatonova, Ya I Melnik, A A Nikushina
To date, multidisciplinary approach is commonly used to treat erectile dysfunction (ED), and the first line of ED pharmacotherapy, despite its multiple causes, is phosphodiesterase inhibitors of type 5 (PDE-5). They are considered an effective and well tolerated treatment option [1-4]. Concurrently, sildenafil has the largest evidence base for efficacy and safety [5]. The satisfaction of patients with ED therapy is a complex and personal matter, and there are no clearly established and reliable criteria for showing preferences when choosing a PDE-5...
July 2017: Urologii︠a︡
https://www.readbyqxmd.com/read/28836189/evaluation-and-management-of-erectile-dysfunction-in-the-hypertensive-patient
#10
REVIEW
Jay Pravin Patel, Eric Hweegeun Lee, Carlos Ignacio Mena-Hurtado, Charles N Walker
PURPOSE OF REVIEW: The prevalence of hypertension and erectile dysfunction has steadily increased, and greater than 40% of men with erectile dysfunction concurrently share a diagnosis of hypertension. The treatment of the patient with both diseases poses a clinical challenge as both are closely correlated and share multiple overlapping risk factors.To address the recognized knowledge gap among clinicians who care for these patients, we will review the current literature on the diagnosis and treatment of erectile dysfunction in the hypertensive patient and will provide recommendations for the management of this challenging patient population...
August 24, 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/28830281/administration-of-daily-5%C3%A2-mg-tadalafil-improves-endothelial-function-in-patients-with-benign-prostatic-hyperplasia
#11
Toshiyasu Amano, Carolyn Earle, Tetsuya Imao, Yuki Matsumoto, Takahiro Kishikage
INTRODUCTION: Tadalafil is a promising phosphodiesterase (PDE) 5 inhibitor prescribed for erectile dysfunction (ED). Daily low dose (5 mg) of tadalafil has also been used for the treatment of male lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). PDE5 inhibitors induce relaxation of smooth muscle cells in the urethra, prostate, bladder neck, and blood vessels. The aim of this study was to investigate the efficacy of tadalafil on vessels endothelial function, in patients with male LUTS symptoms associated with BPH...
August 22, 2017: Aging Male: the Official Journal of the International Society for the Study of the Aging Male
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
#12
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
#13
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/28796496/discovery-of-clinical-candidate-n-1s-1-3-fluoro-4-trifluoromethoxy-phenyl-2-methoxyethyl-7-methoxy-2-oxo-2-3-dihydropyrido-2-3-b-pyrazine-4-1h-carboxamide-tak-915-a-highly-potent-selective-and-brain-penetrating-phosphodiesterase-2a-inhibitor-for-the-treatment
#14
Satoshi Mikami, Shinji Nakamura, Tomoko Ashizawa, Izumi Nomura, Masanori Kawasaki, Shigekazu Sasaki, Hideyuki Oki, Hironori Kokubo, Isaac D Hoffman, Hua Zou, Noriko Uchiyama, Kosuke Nakashima, Naomi Kamiguchi, Haruka Imada, Noriko Suzuki, Hiroki Iwashita, Takahiko Taniguchi
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration...
September 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28791952/novel-strategies-for-treatment-of-pulmonary-arterial-hypertension
#15
REVIEW
Magdalena Jasińska-Stroschein, Daria Orszulak-Michalak
Pulmonary hypertension (PH) is a rare disorder associated with abnormally elevated pulmonary pressures that, if untreated, leads to right heart failure and premature death. Special population include patents with pulmonary arterial hypertension (PAH). A greater understanding of the epidemiology, pathogenesis, and pathophysiology of PAH has led to significant advances over the past few years. Modern drug therapy provides a significant improvement in patient symptomatic status and a slower rate of clinical deterioration...
July 11, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28761827/spectroscopic-and-spectrometric-methods-used-for-the-screening-of-certain-herbal-food-supplements-suspected-of-adulteration
#16
Cristina Mateescu, Anca Mihaela Popescu, Gabriel Lucian Radu, Tatiana Onisei, Adina Elena Raducanu
Purpose: This study was carried out in order to find a reliable method for the fast detection of adulterated herbal food supplements with sexual enhancement claims. As some herbal products are advertised as "all natural", their "efficiency" is often increased by addition of active pharmaceutical ingredients such as PDE-5 inhibitors, which can be a real health threat for the consumer. Methodes: Adulterants, potentially present in 50 herbal food supplements with sexual improvement claims, were detected using 2 spectroscopic methods - Raman and Fourier Transform Infrared - known for reliability, reproductibility, and an easy sample preparation...
June 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28759228/discovery-of-an-orally-bioavailable-brain-penetrating-in-vivo-active-phosphodiesterase-2a-inhibitor-lead-series-for-the-treatment-of-cognitive-disorders
#17
Satoshi Mikami, Shigekazu Sasaki, Yasutomi Asano, Osamu Ujikawa, Shoji Fukumoto, Kosuke Nakashima, Hideyuki Oki, Naomi Kamiguchi, Haruka Imada, Hiroki Iwashita, Takahiko Taniguchi
Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA)...
September 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28747647/delivery-of-intracavernosal-therapies-using-needle-free-injection-devices
#18
D O'Kane, L Gibson, J du Plessis, A Davidson, D Bolton, N Lawrentschuk
ED affects a significant proportion of males worldwide. With an ever-aging population the prevalence of ED is predicted to double in the next decade. Oral PDE-5 inhibitors are the first-line treatment for ED and have revolutionised its management. These agents are however ineffective in some men. Intracavernosal injection (ICI) of vasoactive agents is an effective second-line therapy for ED. Despite proven efficacy, needle phobia and anxiety with self-needling limit the use of intracavernosal (IC) therapies...
July 27, 2017: International Journal of Impotence Research
https://www.readbyqxmd.com/read/28702718/single-center-experience-using-selexipag-in-a-pediatric-population
#19
Roberto Gallotti, Diana E Drogalis-Kim, Gary Satou, Juan Alejos
Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi(®)), was FDA approved in the US. In this case series, we discuss our single-center experience using selexipag in a pediatric population, composed of both patients with idiopathic PAH, and patients with congenital heart disease and PAH...
July 13, 2017: Pediatric Cardiology
https://www.readbyqxmd.com/read/28701798/cognitive-behavioral-therapy-as-an-adjunct-treatment-for-pakistani-men-with-ed
#20
S Khan, A Amjad, D Rowland
The goal of this study was to determine potential positive effects of cognitive behavioral therapy (CBT) on Pakistani men with ED who were undergoing treatment with a PDE-5 inhibitor. We used a pre-post research design comparing men with and without adjunctive CBT. Men in the two groups were compared to determine whether CBT improved sexual function, as measured by the International Index of Erectile Function (IIEF). A total of 60 individuals diagnosed with ED completed the study. Participants were systematically assigned to one of two groups, the CBT group or the control group...
September 2017: International Journal of Impotence Research
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