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Phosphodiesterase 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/29025574/genetics-of-no-deficiency
#2
Kirsten Leineweber, Sven Moosmang, Dan Paulson
The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a key role in regulating cardiovascular homeostasis, and genetic variants allocated to NO-cGMP pathway genes, leading to NO-cGMP deficiency, may influence the prevalence or course of cardiovascular disease. NO-cGMP deficiency can be caused by nitric oxide synthase substrate deficiency, substrate competition, defects, or uncoupling; endogenous inhibitors of nitric oxide synthase; decreased cGMP production; or increased cGMP degradation. This review presents evidence supporting the role of NO-cGMP deficiency in cardiovascular disease, including findings from genetic association studies for particular polymorphisms, haplotypes, and racial disparities...
October 15, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/28994773/improved-method-for-the-establishment-of-an-in-vitro-blood-brain-barrier-model-based-on-porcine-brain-endothelial-cells
#3
Simone S E Nielsen, Piotr Siupka, Ana Georgian, Jane E Preston, Andrea E Tóth, Siti R Yusof, N Joan Abbott, Morten S Nielsen
The aim of this protocol presents an optimized procedure for the purification and cultivation of pBECs and to establish in vitro blood-brain barrier (BBB) models based on pBECs in mono-culture (MC), MC with astrocyte-conditioned medium (ACM), and non-contact co-culture (NCC) with astrocytes of porcine or rat origin. pBECs were isolated and cultured from fragments of capillaries from the brain cortices of domestic pigs 5-6 months old. These fragments were purified by careful removal of meninges, isolation and homogenization of grey matter, filtration, enzymatic digestion, and centrifugation...
September 24, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28994364/comparison-of-the-therapeutic-effects-and-side-effects-of-tadalafil-and-sildenafil-after-surgery-in-young-infants-with-pulmonary-arterial-hypertension-due-to-systemic-to-pulmonary-shunts
#4
Mohammad Reza Sabri, Hamid Bigdelian, Mohsen Hosseinzadeh, Alireza Ahmadi, Mehdi Ghaderian, Mohammad Shoja
Young children with CHD and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension. At present, phosphodiesterase type-5 inhibitors such as sildenafil have been used to control pulmonary pressure before and after cardiac surgery. Recently, tadalafil has been utilised in older children with similar efficacy, but it has been used to a lesser extent in young infants. From April, 2015 to June, 2016, 42 patients aged 3-24 months with a large septal defect and pulmonary arterial hypertension were randomly divided into two equal groups: one group received oral sildenafil (1-3 mg/kg/day every 8 hours), whereas the other group received oral tadalafil (1 mg/kg once a day) from 7-10 days before surgery to 3-4 weeks after surgery...
November 2017: Cardiology in the Young
https://www.readbyqxmd.com/read/28992178/tadalafil-improves-l-ng-nitroarginine-methyl-ester-induced-preeclampsia-with-fetal-growth-restriction-like-symptoms-in-pregnant-mice
#5
Kento Yoshikawa, Takashi Umekawa, Shintaro Maki, Michiko Kubo, Masafumi Nii, Kayo Tanaka, Hiroaki Tanaka, Kazuhiro Osato, Yuki Kamimoto, Eiji Kondo, Kenji Ikemura, Masahiro Okuda, Kan Katayama, Takekazu Miyoshi, Hiroshi Hosoda, Ning Ma, Toshimichi Yoshida, Tomoaki Ikeda
BACKGROUND: We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model. METHODS: C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC...
August 3, 2017: American Journal of Hypertension
https://www.readbyqxmd.com/read/28986358/pulmonary-vasodilation-by-phosphodiesterase-5-inhibition-is-enhanced-and-nitric-oxide-independent-in-early-pulmonary-hypertension-after-myocardial-infarction
#6
Richard W B van Duin, Birgit Houweling, Andre Uitterdijk, Dirk J Duncker, Daphne Merkus
Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be of benefit in PH secondary to MI. Nitric oxide (NO) is an important source of cGMP and can be enhanced in early PH and decreased in severe PH. In the present study we investigated if PDE5-inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential...
October 6, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28985058/identification-of-a-novel-1-2-3-4-tetrahydrobenzo-b-1-6-naphthyridine-analog-as-a-potent-phosphodiesterase-5-inhibitor-with-improved-aqueous-solubility-for-the-treatment-of-alzheimer-s-disease
#7
Jole Fiorito, Jeremie Vendome, Faisal Saeed, Agnieszka Staniszewski, Hong Zhang, Shijun Yan, Shi-Xian Deng, Ottavio Arancio, Donald W Landry
Phosphodiesterase 5 (PDE5) hydrolyzes cyclic guanosine monophosphate (cGMP) leading to increased levels of cAMP response element binding protein (CREB), a transcriptional factor involved with learning and memory processes. We previously reported potent quinoline-based PDE5 inhibitors (PDE5Is) for the treatment of Alzheimer's disease (AD). However, the low aqueous solubility rendered them undesirable drug candidates. Here we report a series of novel PDE5Is with two new scaffolds, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine and 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one...
October 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28977204/tadalafil-protective-action-against-the-development-of-multiple-organ-failure-syndrome
#8
Granville G de Oliveira, Samer A H de Oliveira, Paulo Henrique H Botelho, Marcos Aurelio Barboza de Oliveira, Ka Bian, Ferid Murad
INTRODUCTION: Multiple organ failure syndrome (MOFS) is a pathology associated to unspecified and severe trauma, characterized by elevated morbidity and mortality. The complex inflammatory MOFS-related reactions generate important ischemia-reperfusion responses in the induction of this syndrome. Nitric oxide elevation, through the activation of cyclic guanosine monophosphate (cGMP), has the potential of counteracting the typical systemic vasoconstriction, and platelet-induced hypercoagulation...
July 2017: Brazilian Journal of Cardiovascular Surgery
https://www.readbyqxmd.com/read/28977106/daily-use-of-phosphodiesterase-type-5-inhibitors-as-prevention-for-recurrent-priapism
#9
Archimedes Nardozza, Marcelo Rodrigues Cabrini
OBJECTIVE: The pathogenesis of recurrent priapism is currently being investigated based on the regulation of the phosphodiesterase 5 (PDE5) enzyme. We explored the daily use of PDE5 inhibitors to treat and prevent priapism recurrences. METHOD: We administered PDE5 inhibitors using a long-term therapeutic regimen in seven men with recurrent priapism, with a mean age of 29.2 years (range 21 to 35 years). Six men (85.7%) had idiopathic priapism recurrences and one man (24...
August 2017: Revista da Associação Médica Brasileira
https://www.readbyqxmd.com/read/28964952/preparation-and-characterization-of-intravaginal-vardenafil-suppositories-targeting-a-complementary-treatment-to-boost-in-vitro-fertilization-process
#10
Eman Gomaa, Amr S Abu Lila, Azza A Hasan, Fakhr-Eldin S Ghazy
Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases...
September 28, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28964803/cyclic-guanosine-monophosphate-modulates-accumulation-of-phosphodiesterase-5-inhibitors-in-human-platelets
#11
Gzona Bajraktari, Jürgen Burhenne, Peter Bugert, Walter Emil Haefeli, Johanna Weiss
Sildenafil and tadalafil are widely-used phosphodiesterase 5 (PDE5) inhibitors for which no clear dose-response relationship could be established. Using isolated and/or recombinant PDE5, it has been demonstrated that cGMP can increase the affinity of this enzyme for sildenafil and tadalafil. We thus hypothesized that in cells expressing the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate - PDE5 (NO-sGC-cGMP-PDE5) pathway such as platelets, the presence of NO increases the intracellular cGMP content and thus promotes the intracellular accumulation of sildenafil or tadalafil...
September 27, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28959341/expression-of-recombinant-phosphodiesterases-3a-and-3b-using-baculovirus-expression-system
#12
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/28956417/potential-risk-of-developing-herpes-simplex-encephalitis-in-patients-treated-with-sildenafil-following-primary-exposure-to-genital-herpes
#13
A Goren, J Mccoy, M Kovacevic, M Situm, N Lonky
Herpes simplex encephalitis (HSE) is associated with significant mortality and morbidity. As a consequence of HSE, up to 75% of infected individuals die or experience irreversible neurological damage. While the pathogenesis of the disease is unknown, it is traditionally hypothesized that the viral infection occurs by neuronal transmission directly from peripheral sites. Non-neuronal modes of infection have generally been overlooked as the brain is protected by the blood-brain-barrier (BBB). The BBB poses an effective barrier to pathogens as well as to drugs such as chemotherapies...
July 2017: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/28956337/role-of-phosphodiesterases-in-huntington-s-disease
#14
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/28955799/liposomal-delivery-of-phosphodiesterase-5-inhibitors-augments-ut-15c-stimulated-atp-release-from-human-erythrocytes
#15
Elizabeth A Bowles, Dimitri Feys, Nuran Ercal, Randy S Sprague
The use of liposomes to affect targeted delivery of pharmaceutical agents to specific sites may result in the reduction of side effects and an increase in drug efficacy. Since liposomes are delivered intravascularly, erythrocytes, which constitute almost half of the volume of blood, are ideal targets for liposomal drug delivery. In vivo, erythrocytes serve not only in the role of oxygen transport but also as participants in the regulation of vascular diameter through the regulated release of the potent vasodilator, adenosine triphosphate (ATP)...
December 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28952072/role-of-the-unfolded-protein-response-in-determining-the-fate-of-tumor-cells-and-the-promise-of-multi-targeted-therapies
#16
REVIEW
Kunyu Shen, David W Johnson, David A Vesey, Michael A McGuckin, Glenda C Gobe
Although there have been advances in our understanding of carcinogenesis and development of new treatments, cancer remains a common cause of death. Many regulatory pathways are incompletely understood in cancer development and progression, with a prime example being those related to the endoplasmic reticulum (ER). The pathological sequelae that arise from disruption of ER homeostasis are not well defined. The ER is an organelle that is responsible for secretory protein biosynthesis and the quality control of protein folding...
September 27, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28939768/plasma-membrane-phosphatidylinositol-4-phosphate-and-4-5-bisphosphate-determine-the-distribution-and-function-of-k-ras4b-but-not-h-ras-proteins
#17
Gergö Gulyás, Glória Radvánszki, Rita Matuska, András Balla, László Hunyady, Tamas Balla, Péter Várnai
Plasma membrane (PM) localization of Ras proteins is crucial for transmitting signals upon mitogen stimulation. Posttranslational lipid modification of Ras proteins plays an important role in their recruitment to the PM. Electrostatic interactions between negatively charged PM phospholipids and basic amino acids found in K-Ras4B (K-Ras) but not in H-Ras are important for permanent K-Ras localization to the PM. Here, we investigated how acute depletion of negatively charged PM polyphosphoinositides (PPIns) from the PM alters the intracellular distribution and activity of K- and H-Ras proteins...
September 22, 2017: Journal of Biological Chemistry
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
#18
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/28926093/pulmonary-hypertension-molecular-aspects-of-current-therapeutic-intervention-and-future-direction
#19
Taruna Katyal Arora, Amit KumarArora, Monika Katyal Sachdeva, Satyendra Kumar Rajput, Arun Kumar Sharma
Pulmonary hypertension (PH) is a life-threatening lung disorder with towering prevalence and risk for future has been gradually rising worldwide. Even, no specific medications are available for pulmonary hypertension; various classes of treatment based upon the origin and magnitude of hypertension are still used for the treatment of PH. Consideration of molecular or signaling modulation is the imperative approach that can offer a new notion for prevalent pharmacotherapeutic agents. Instead of concurrent targets, including endothelin receptor antagonists (ETA/ETB), phosphodiesterase 5 inhibitor (PDF-5), calcium channel blockers, anticoagulants, diuretics and long acting prostacyclin analogue, recent scientific reports revealed the numerous potential alternative therapeutic approaches that can significantly target the pathological signaling alteration associated with PH...
September 19, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28925560/apremilast-in-psoriasis-a-prospective-real-world-study
#20
I Vujic, R Herman, M Sanlorenzo, C Posch, B Monshi, K Rappersberger, L Richter
BACKGROUND: Apremilast is a novel oral phosphodiesterase-4 inhibitor approved for psoriasis treatment. Randomized trials have documented its efficacy and safety, but data on real-world patients are scarce. OBJECTIVES: We aim to characterize psoriasis patients treated with apremilast in a real-world setting and calculate drug survival as an important measure of efficacy and compliance. METHODS: All patients with psoriasis who received apremilast between 1 April 2015 and 19 January 2017 were evaluated every 4 weeks, and we documented: age, weight, height, smoking status, family history of psoriasis, joint involvement, previous treatments, psoriasis area severity index (PASI) scores, and the onset and duration of adverse events (AE)...
September 19, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
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