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Sven Persoon, Michael Paulus, Stephan Hirt, Carsten Jungbauer, Alexander Dietl, Andreas Luchner, Christof Schmid, Lars S Maier, Christoph Birner
Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively...
March 15, 2018: Heart and Vessels
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
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
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
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
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
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
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
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)
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
Michael F Santillo, Mapa S T Mapa
Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based upon measuring inhibition of PDE5 activity, which is the pharmacological mechanism shared among the adulterants...
February 28, 2018: Drug Testing and Analysis
Luca De Toni, Maurizio De Rocco Ponce, Erica Franceschinis, Stefano Dall'Acqua, Roberto Padrini, Nicola Realdon, Andrea Garolla, Carlo Foresta
Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original per os formulation. Methods: In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption...
2018: Frontiers in Pharmacology
Rune Kleppe, Inge Jonassen, Stein Ove Døskeland, Frode Selheim
Platelet activation contributes to normal haemostasis but also to pathologic conditions like stroke and cardiac infarction. Signalling by cGMP and cAMP inhibit platelet activation and are therefore attractive targets for thrombosis prevention. However, extensive cross-talk between the cGMP and cAMP signalling pathways in multiple tissues complicates the selective targeting of their activities. We have used mathematical modelling based on experimental data from the literature to quantify the steady state behaviour of nitric oxide (NO)/cGMP/cAMP signalling in platelets...
February 19, 2018: International Journal of Molecular Sciences
Sandra Frankenreiter, Dieter Groneberg, Anna Kuret, Thomas Krieg, Peter Ruth, Andreas Friebe, Robert Lukowski
Aims: It has been suggested that the nitric oxide-sensitive guanylyl cyclase (NO-GC)/cGMP-dependent signaling pathway affords protection against cardiac damage during acute myocardial infarction (AMI). It is, however, not clear whether the NO-GC/cGMP system confers its favorable effects through a mechanism located in cardiomyocytes (CMs). The aim of this study was to evaluate the infarct-limiting effects of the endogenous NO-GC in CMs in vivo. Methods and Results: Ischemia/reperfusion (I/R) injury was evaluated in mice with a cardiomyocyte-specific deletion of NO-GC (CM NO-GC KO) and in control siblings (CM NO-GC CTR) subjected to an in vivo model of AMI...
February 9, 2018: Cardiovascular Research
Shariq Abid, Kanny Kebe, Amal Houssaïni, Françoise Tomberli, Elisabeth Marcos, Emilie Bizard, Marielle Breau, Aurelien Parpaleix, Claire-Marie Tissot, Bernard Maitre, Larissa Lipskaia, Genevieve Derumeaux, Elena Bastia, Armand Mekontso-Dessap, Serge Adnot
Nitric oxide (NO) donors may be useful for treating pulmonary hypertension (PH) complicating sickle cell disease (SCD), as endogenous NO is inactivated by hemoglobin released by intravascular hemolysis. Here, we investigated the effects of the new NO donor NCX1443 on PH in transgenic SAD mice, which exhibit mild SCD without severe hemolytic anemia. In SAD and wild-type (WT) mice, the pulmonary pressure response to acute hypoxia was similar and was abolished by 100 mg/kg NCX1443. The level of PH was also similar in SAD and WT mice exposed to chronic hypoxia (9% O2) alone or with SU5416, and was similarly reduced by daily NCX1443 gavage...
February 8, 2018: Journal of Cardiovascular Pharmacology
Takashi Onoe, Asuka Tanaka, Kohei Ishiyama, Kentaro Ide, Hirotaka Tashiro, Hideki Ohdan
BACKGROUND: Portopulmonary hypertension (PPH) is a relatively rare but well-recognized complication of end-stage liver disease. Moderate or severe PPH (mean pulmonary artery pressure [mPAP] ≥ 35 mmHg) is usually a contraindication for liver transplantation due to high operation-related mortality. Here, we report on a patient with moderate PPH whose condition was successfully managed with a phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) and prostaglandin E1, who experienced rapid improvement of PPH after living-donor liver transplantation (LDLT)...
February 7, 2018: Surgical Case Reports
Saskia Klutzny, Anna Anurin, Barbara Nicke, Joseph L Regan, Martin Lange, Luise Schulze, Karsten Parczyk, Patrick Steigemann
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population...
February 7, 2018: Cell Death & Disease
Fei-Peng Lee, Pin-Zhir Chao, Hsing-Won Wang
BACKGROUND: Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. METHODS: This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10 -6 M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions...
January 27, 2018: Journal of the Chinese Medical Association: JCMA
Tsuyoshi Tajima, Tamami Shinoda, Norimoto Urakawa, Kazumasa Shimizu, Takeharu Kaneda
The present study was designed to clarify phosphodiesterase 9 (PDE9) expression in bovine tracheal smooth muscle tissue, and to elucidate that PDE9 may contribute to the regulation of airway relaxation. PDE9 mRNA expression was detected in bovine tracheal smooth muscle. Sodium nitroprusside (an NO donor) and BAY 73-6691 (a selective PDE9 inhibitor) reduced high K+- and carbachol-induced contraction. BAY 73-6691 relaxed tracheal tissue on the same level with vardenafil (a selective PDE5 inhibitor). These results support our hypothesis that PDE9 plays functional role in the tracheal smooth muscle relaxation...
January 30, 2018: Journal of Veterinary Medical Science
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
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