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Phosphodiesterase 5 inhibitors

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https://www.readbyqxmd.com/read/29672270/role-of-atrial-natriuretic-peptide-in-controlling-diabetic-nephropathy-in-rats
#1
Lakhwinder Singh, Atul Arya, Sumeet Gupta
BACKGROUND: Diabetes is a downregulator of atrial natriuretic peptide (ANP), resulting in reduced nitric oxide level and low expression of endothelial nitric oxide synthase by which nitric oxide level get reduced. In the present study, we examined the role of ANP in reduced nitric oxide level, which may be responsible in controlling diabetic nephropathy in rats. METHODS: Serum nitrite/nitrate ratio, blood urea nitrogen, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney hypertrophy, renal cortical collagen content, thiobarbituric acid level, and antioxidant enzymatic activities were assessed...
April 19, 2018: Journal of Basic and Clinical Physiology and Pharmacology
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
#2
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/29667617/combination-of-stromal-vascular-fraction-and-ad-comp-ang1-gene-therapy-improves-long-term-therapeutic-efficacy-for-diabetes-induced-erectile-dysfunction
#3
Guo-Nan Yin, Lin Wang, Xiang-Nan Lin, Lei Shi, Zhen-Lin Gao, Feng-Chan Han, Ping Li, Yin-Chuan Jin, Jun-Kyu Suh, Ji-Kan Ryu, Xiong Wang, Hai-Rong Jin
Men with diabetic erectile dysfunction (ED) respond poorly to the currently available oral phosphodiesterase-5 inhibitors. Therefore, functional therapies for diabetic ED are needed. Stromal vascular fraction (SVF) and the adenovirus-mediated cartilage oligomeric matrix angiopoietin-1 (Ad-COMP-Ang1) gene are known to play critical roles in penile erection. We previously reported that SVF and Ad-COMP-Ang1 have only a short-term effect in restoring erectile function. Further improvements to ED therapy are needed for long-lasting effects...
April 17, 2018: Asian Journal of Andrology
https://www.readbyqxmd.com/read/29667180/pde5-inhibitors-pharmacology-and-clinical-applications-20-years-after-sildenafil-discovery
#4
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/29665997/lower-urinary-tract-symptoms-what-s-new-in-medical-treatment
#5
REVIEW
Benoit Peyronnet, Benjamin M Brucker, Martin C Michel
CONTEXT: Pharmacological treatment is a cornerstone in the management of patients with lower urinary tract symptoms (LUTS). OBJECTIVE: To review emerging evidence in the medical treatment of LUTS. EVIDENCE ACQUISITION: An Embase/Pubmed-based literature search was conducted in December 2017, screening for randomized controlled trials (RCTs), prospective and retrospective series, animal model studies, and reviews on medical treatment of LUTS...
April 14, 2018: European Urology Focus
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
#6
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/29656983/prophylaxis-and-treatment-of-foetal-growth-restriction
#7
REVIEW
Aamod Nawathe, Anna L David
Foetal growth restriction (FGR) and associated placental pathologies such as pre-eclampsia and stillbirth arise in early pregnancy when inadequate remodelling of maternal spiral arteries leads to persistent high-resistance low-flow uteroplacental circulation. Current interventions concentrate on targeting the placental ischaemia-reperfusion injury and oxidative stress associated with an imbalance in angiogenic/anti-angiogenic factors. Recent meta-analyses confirm that aspirin modestly reduces the risk for small-for-gestational-age pregnancy in high-risk women...
February 23, 2018: Best Practice & Research. Clinical Obstetrics & Gynaecology
https://www.readbyqxmd.com/read/29656464/design-and-synthesis-of-novel-annulated-thienopyrimidines-as-phosphodiesterase-5-pde5-inhibitors
#8
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/29653137/hyperactivity-and-memory-learning-deficits-evoked-by-developmental-exposure-to-nicotine-and-or-ethanol-are-mitigated-by-camp-and-cgmp-signaling-cascades-activation
#9
Yael Abreu-Villaça, Anna C Carvalho-Graça, Gabriela Skinner, Bruna M Lotufo, Vitor H S Duarte-Pinheiro, Anderson Ribeiro-Carvalho, Alex C Manhães, Claudio C Filgueiras
Pregnant smoking women are frequently episodic drinkers. Here, we investigated whether ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to nicotine aggravates memory/learning deficits and hyperactivity, and associated cAMP and cGMP signaling disruption. To further investigate the role of these signaling cascades, we verified whether vinpocetine (a phosphodiesterase inhibitor) ameliorates the neurochemical and behavioral outcomes. Swiss mice had free access to nicotine (NIC, 50 μg/ml) or water to drink during gestation and until the 8th postnatal day (PN8)...
April 10, 2018: Neurotoxicology
https://www.readbyqxmd.com/read/29621314/sildenafil-ameliorates-right-ventricular-early-molecular-derangement-during-left-ventricular-pressure-overload
#10
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/29619016/cyclic-amp-pathway-activation-and-extracellular-zinc-induce-rapid-intracellular-zinc-mobilization-in-candida-albicans
#11
Lasse Kjellerup, Anne-Marie L Winther, Duncan Wilson, Anja T Fuglsang
Zinc is an essential micronutrient, required for a range of zinc-dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo-5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans . We provide evidence for a link between cyclic AMP/PKA- and zinc-signaling in this major human fungal pathogen...
2018: Frontiers in Microbiology
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
#12
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/29608499/diagnosis-treatment-and-management-of-orthotopic-liver-transplant-candidates-with-portopulmonary-hypertension
#13
Anna Koulava, Abdallah Sannani, Avi Levine, Chhaya Aggarwal Gupta, Sarina Khanal, William Frishman, Roxana Bodin, David C Wolf, William Aronow, Gregg M Lanier
Portopulmonary hypertension (POPH) is seen in 5-8% of orthotopic liver transplantation (OLT) candidates and has significant implications for clinical outcomes. POPH is characterized by vasoconstriction and remodeling of the pulmonary vasculature. It is exacerbated by the hyperdynamic circulation that is common in advanced liver disease. Screening all OLT candidates with transthoracic echocardiography to assess pulmonary pressures and right ventricular function is crucial, as clinical symptoms alone are not reliable...
March 30, 2018: Cardiology in Review
https://www.readbyqxmd.com/read/29603785/alpha-1-adrenergic-antagonists-5-alpha-reductase-inhibitors-phosphodiesterase-type-5-inhibitors-and-phytotherapic-compounds-in-men-with-lower-urinary-tract-symptoms-suggestive-of-benign-prostatic-obstruction-a-systematic-review-and-meta-analysis-of-urodynamic
#14
REVIEW
Ferdinando Fusco, Massimiliano Creta, Cosimo De Nunzio, Mauro Gacci, Vincenzo Li Marzi, Enrico Finazzi Agrò
AIMS: To perform a systematic review and meta-analysis of studies evaluating the urodynamic outcomes of alpha-1 adrenergic antagonists (ABs), 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitors (PDE5is), and phytotherapic compounds in patients with lower urinary tract symptoms related to benign prostatic obstruction (LUTS/BPO). METHODS: A systematic review of PubMed/Medline, ISI Web of Knowledge, and Scopus databases was performed in June 2017...
March 31, 2018: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/29594552/determination-of-protein-kinase-a-activity-and-inhibition-by-using-hydroxyapatite-nanoparticles-as-a-fluorescent-probe
#15
Kaina Zhang, Ke Zeng, Congcong Shen, Shiyu Tian, Minghui Yang
The authors describe a fluorometric method for the determination of the activity and inhibition of protein kinase A (PKA). In the presence of ATP, PKA catalyzes the transfer of phosphate groups from ATP to a peptide, and the generated phosphorylated peptide quenches the fluorescence (measured at excitation/emission peaks of 340/440 nm) of the hydroxyapatite nanoparticles (HAP-NPs). A linear logarithmic relationship of PKA concentrations with fluorescence intensity in the range from 1 to 50 U·L-1 was obtained, and the lower limit of detection (LOD) is 0...
March 16, 2018: Mikrochimica Acta
https://www.readbyqxmd.com/read/29589656/-what-s-new-in-the-management-of-atopic-dermatitis-in-children-and-adolescents
#16
Justine Czernielewski, Émilie Comte Krieger, Stéphanie Christen-Zaech
A better understanding of the atopic dermatitis (AD) pathogenesis and the need for more efficient and safer treatments in severe AD promoted the development of new therapies. Several underwent and are still undergoing clinical trials, but due to safety reasons, they include mainly adults for now. AD is however predominant in childhood with a prevalence 20 % in children compared to only 5 % in adults. Regarding the pediatric population, the new pipeline relies on two selective immunosuppressive agents, notably crisaborole (phosphodiesterase-4 inhibitor) and dupilumab (IL-4 and IL-13 inhibitor)...
March 28, 2018: Revue Médicale Suisse
https://www.readbyqxmd.com/read/29577043/multidimensional-fatigue-in-pulmonary-hypertension-prevalence-severity-and-predictors
#17
Todd M Tartavoulle, Aryn C Karpinski, Andrew Aubin, Benzi M Kluger, Oliver Distler, Lesley Ann Saketkoo
Pulmonary hypertension is a potentially fatal disease. Despite pharmacological advances in pulmonary hypertension, fatigue remains common in patients with pulmonary hypertension. A convenience sample of 120 participants at an international patient conference completed the Multidimensional Fatigue Inventory (MFI)-20 scale. Data on New York Heart Association Functional Class, body mass index, oxygen use and medication type/use were also collected. There was a high prevalence of "severe" to "very severe" fatigue for each dimension: General Fatigue (60%), Physical Fatigue (55...
January 2018: ERJ Open Research
https://www.readbyqxmd.com/read/29576441/low-intensity-shockwave-therapy-for-erectile-dysfunction
#18
REVIEW
Paul J Rizk, Jordan R Krieger, Taylor P Kohn, Alexander W Pastuszak
BACKGROUND: Vasculogenic erectile dysfunction (ED) is one of the leading causes of male sexual dysfunction. In the past decade, multiple studies have examined the use of low-intensity extracorporeal shockwave therapy (Li-ESWT) for the treatment of ED. AIM: Investigate the efficacy of Li-ESWT for the treatment of ED. METHODS: We reviewed the published literature, including randomized controlled trials (RCTs), meta-analyses, and select single-arm studies on the use of Li-ESWT for the treatment of ED...
March 22, 2018: Sexual Medicine Reviews
https://www.readbyqxmd.com/read/29574615/enhancement-of-hiv-1-vlp-production-using-gene-inhibition-strategies
#19
Javier Fuenmayor, Laura Cervera, Cristina Rigau, Francesc Gòdia
Gag polyprotein from HIV-1 is able to generate virus-like particles (VLPs) when recombinantly expressed in animal cell platforms. HIV-1 VLP production in HEK293 cells can be improved by the use of different strategies for increasing product titers. One of them is the so-called extended gene expression (EGE), based on repeated medium exchanges and retransfections of the cell culture to prolong the production phase. Another approach is the media supplementation with gene expression enhancers such as valproic acid and caffeine, despite their detrimental effect on cell viability...
March 24, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29572341/in-vitro-assessment-of-pharmacokinetic-drug-drug-interactions-of-direct-oral-anticoagulants-type-5-phosphodiesterase-inhibitors-are-inhibitors-of-rivaroxaban-and-apixaban-efflux-by-p-glycoprotein
#20
Victor Margelidon-Cozzolino, Sophie Hodin, Elodie Jacqueroux, Olivier Delezay, Laurent Bertoletti, Xavier Delavenne
Direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists in pulmonary arterial hypertension (PAH) patients because of lower bleeding risk and their simplicity of use. P-glycoprotein (P-gp) plays a key role in DOACs pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5i), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp mediated-drug-drug interactions between PDE5i and DOACs using in vitro methods...
March 23, 2018: Journal of Pharmacology and Experimental Therapeutics
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