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  1 / 11895 MEDLINE  
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[PMID]:29334287
[Au] Autor:Sridharan K; Sivaramakrishnan G
[Ad] Endereço:a Associate Professor, Department of Pharmacology and Therapeutics , College of Medicine and Medical Sciences, Arabian Gulf University , Manama , Bahrain.
[Ti] Título:Efficacy and safety of alpha blockers in medical expulsive therapy for ureteral stones: a mixed treatment network meta-analysis and trial sequential analysis of randomized controlled clinical trials.
[So] Source:Expert Rev Clin Pharmacol;11(3):291-307, 2018 Mar.
[Is] ISSN:1751-2441
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Alpha blockers (AB) are the main group of drugs used for medical expulsive therapy (MET) in patients with ureteral stones. However, there is no consensus on the relative efficacy and safety of individual AB in MET. Areas covered: The present work is a network meta-analysis of randomized controlled trials comparing AB with either placebo or standard of care in patients with ureteral stones. Electronic databases of Medline, Cochrane CENTRAL and Google Scholar were searched for eligible clinical studies. Inverse variance heterogeneity model was used for mixed treatment comparisons. Stone expulsion rate (SER) and stone expulsion time (SET) were the primary outcomes. Sub-group analyses for the following sub-groups were carried out: children; after shockwave lithotripsy; stone size of ≤5 mm; >5 mm; proximal and distal ureteral stones. Expert review: AB, phosphodiesterase inhibitors and combined AB with corticosteroids were observed with significant stone expulsion rate compared to control group in a recent network meta-analysis. Due to lack of head-to-head clinical trials within AB, only tamsulosin has been widely recommended by various urological guidelines. The results of this network meta-analysis will guide the future researchers in evaluating other promising ABs as agents for MET.
[Mh] Termos MeSH primário: Antagonistas Adrenérgicos alfa/administração & dosagem
Sulfonamidas/administração & dosagem
Cálculos Ureterais/tratamento farmacológico
[Mh] Termos MeSH secundário: Corticosteroides/administração & dosagem
Antagonistas Adrenérgicos alfa/efeitos adversos
Adulto
Criança
Quimioterapia Combinada
Seres Humanos
Inibidores de Fosfodiesterase/administração & dosagem
Guias de Prática Clínica como Assunto
Ensaios Clínicos Controlados Aleatórios como Assunto
Sulfonamidas/efeitos adversos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Adrenal Cortex Hormones); 0 (Adrenergic alpha-Antagonists); 0 (Phosphodiesterase Inhibitors); 0 (Sulfonamides); G3P28OML5I (tamsulosin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180116
[St] Status:MEDLINE
[do] DOI:10.1080/17512433.2018.1424537


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[PMID]:28458366
[Au] Autor:Badr MH; Rostom SAF; Radwan MF
[Ad] Endereço:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University.
[Ti] Título:Novel Polyfunctional Pyridines as Anticancer and Antioxidant Agents. Synthesis, Biological Evaluation and in Silico ADME-T Study.
[So] Source:Chem Pharm Bull (Tokyo);65(5):442-454, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Two series of novel alkoxylated 2-oxo(imino)-3-pyridinecarbonitriles (structurally-relevant to some reported anticancer pyridines with phosphodiesterase 3A (PDE3A) inhibitory activity) were synthesized and evaluated for their in vitro differential tumor cell growth inhibitory potential against the breast MCF7, hepatocellular Hep-G2, colon CACO-2 cell lines, and a normal human foreskin fibroblast Hs27 cell line. Compounds 8, 16 and 19 displayed recognizable growth inhibitory ability and selectivity towards the breast MCF7 (LC 19.15, 17.34 and 14.70 µM, respectively) as compared with doxorubicin (LC 3.94 µM). Meanwhile, compounds 8, 15, 16, and 19 revealed a marginal inhibitory effect on the growth of the normal human foreskin fibroblast Hs27 cell line, beside a distinctive antioxidant potential in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. These four compounds were further assessed for their in vitro inhibition of PDE3A (a current antitumor therapeutic target), where 16 and 19 showed moderate to weak PDE3A inhibitory as compared with milrinone, the positive control. No clear straightforward liaison between the anticancer potential and PDE3A inhibitory activity could be deduced. Computations of the predicted pharmacokinetic properties, toxicity effects (ADME-T), drug-likeness and drug scores for the newly developed compounds showed non-violations of Lipinski's RO5 and Veber's criteria for good bioavailability, with a predicted high safety profile.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antioxidantes/farmacologia
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo
Inibidores de Fosfodiesterase/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Antioxidantes/síntese química
Antioxidantes/química
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Inibidores de Fosfodiesterase/síntese química
Inibidores de Fosfodiesterase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Antioxidants); 0 (Phosphodiesterase Inhibitors); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3); EC 3.1.4.17 (PDE3A protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c16-00761


  3 / 11895 MEDLINE  
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[PMID]:28458351
[Au] Autor:Yamaguchi M; Saito SY; Nishiyama R; Nakamura M; Todoroki K; Toyo'oka T; Ishikawa T
[Ad] Endereço:Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka.
[Ti] Título:Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors.
[So] Source:Biol Pharm Bull;40(5):658-664, 2017.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.
[Mh] Termos MeSH primário: Cafeína/farmacologia
AMP Cíclico/metabolismo
Células Estreladas do Fígado/efeitos dos fármacos
Inibidores de Fosfodiesterase/farmacologia
Receptores Purinérgicos P1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Quelantes/farmacologia
Relação Dose-Resposta a Droga
Ácido Egtázico/análogos & derivados
Ácido Egtázico/farmacologia
Cirrose Hepática/tratamento farmacológico
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Masculino
Camundongos
Fosforilação
Quinazolinas/farmacologia
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chelating Agents); 0 (Phosphodiesterase Inhibitors); 0 (Quinazolines); 0 (Receptors, Purinergic P1); 0 (Triazoles); 104615-18-1 (9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine); 139890-68-9 (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester); 3G6A5W338E (Caffeine); 526U7A2651 (Egtazic Acid); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1248/bpb.b16-00947


  4 / 11895 MEDLINE  
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[PMID]:29174506
[Au] Autor:Qiu X; Huang Y; Wu D; Mao F; Zhu J; Yan W; Luo HB; Li J
[Ad] Endereço:Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
[Ti] Título:Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: Structure-based virtual screening, optimization and biological evaluation.
[So] Source:Bioorg Med Chem;26(1):119-133, 2018 01 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC = 3.12 ±â€¯0.67 µM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC = 0.32 ±â€¯0.04 µM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5'-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
[Mh] Termos MeSH primário: Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores
Descoberta de Drogas
Nucleosídeos/farmacologia
Inibidores de Fosfodiesterase/farmacologia
Purinas/farmacologia
[Mh] Termos MeSH secundário: Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo
Relação Dose-Resposta a Droga
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Nucleosídeos/síntese química
Nucleosídeos/química
Inibidores de Fosfodiesterase/síntese química
Inibidores de Fosfodiesterase/química
Purinas/síntese química
Purinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nucleosides); 0 (Phosphodiesterase Inhibitors); 0 (Purines); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2); EC 3.1.4.17 (PDE2A protein, human); W60KTZ3IZY (purine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180106
[Lr] Data última revisão:
180106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  5 / 11895 MEDLINE  
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[PMID]:29271265
[Au] Autor:Zhang C; Zhou Q; Wu XN; Huang YS; Zhou J; Lai Z; Wu Y; Luo HB
[Ad] Endereço:a School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou , PR China.
[Ti] Título:Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.
[So] Source:J Enzyme Inhib Med Chem;33(1):260-270, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.
[Mh] Termos MeSH primário: 3´,5´-AMP Cíclico Fosfodiesterases/antagonistas & inibidores
Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/enzimologia
Antioxidantes/farmacologia
Descoberta de Drogas
Inibidores de Fosfodiesterase/farmacologia
[Mh] Termos MeSH secundário: 3',5'-AMP Cíclico Fosfodiesterases/metabolismo
Antioxidantes/síntese química
Antioxidantes/química
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Inibidores de Fosfodiesterase/síntese química
Inibidores de Fosfodiesterase/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Phosphodiesterase Inhibitors); EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases); EC 3.1.4.17 (PDE9A protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1412315


  6 / 11895 MEDLINE  
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[PMID]:28451983
[Au] Autor:Sala V; Margaria JP; Murabito A; Morello F; Ghigo A; Hirsch E
[Ad] Endereço:Department of Molecular Biotechnology, Molecular Biotechnology Center, University of Torino, Torino, Italy.
[Ti] Título:Therapeutic Targeting of PDEs and PI3K in Heart Failure with Preserved Ejection Fraction (HFpEF).
[So] Source:Curr Heart Fail Rep;14(3):187-196, 2017 Jun.
[Is] ISSN:1546-9549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF REVIEW: Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms. RECENT FINDINGS: The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.
[Mh] Termos MeSH primário: Insuficiência Cardíaca/tratamento farmacológico
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Inibidores de Fosfodiesterase/uso terapêutico
Volume Sistólico/fisiologia
[Mh] Termos MeSH secundário: Endotélio Vascular/fisiopatologia
Insuficiência Cardíaca/mortalidade
Insuficiência Cardíaca/fisiopatologia
Seres Humanos
Hipertensão Pulmonar/complicações
Inflamação/complicações
Doença Pulmonar Obstrutiva Crônica/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Phosphodiesterase Inhibitors); EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1007/s11897-017-0331-2


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[PMID]:28938466
[Au] Autor:Chimerel C; Riccio C; Murison K; Gribble FM; Reimann F
[Ad] Endereço:Metabolic Research Laboratories and Medical Research Council (MRC) Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
[Ti] Título:Optogenetic Analysis of Depolarization-Dependent Glucagonlike Peptide-1 Release.
[So] Source:Endocrinology;158(10):3426-3434, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Incretin hormones play an important role in the regulation of food intake and glucose homeostasis. Glucagonlike peptide-1 (GLP-1)-secreting cells have been demonstrated to be electrically excitable and to fire action potentials (APs) with increased frequency in response to nutrient exposure. However, nutrients can also be metabolized or activate G-protein-coupled receptors, thus potentially stimulating GLP-1 secretion independent of their effects on the plasma membrane potential. Here we used channelrhodopsins to manipulate the membrane potential of GLUTag cells, a well-established model of GLP-1-secreting enteroendocrine L cells. Using channelrhodopsins with fast or slow on/off kinetics (CheTA and SSFO, respectively), we found that trains of light pulses could trigger APs and calcium elevation in GLUTag cells stably expressing either CheTA or SSFO. Tetrodotoxin reduced light-triggered AP frequency but did not impair calcium responses, whereas further addition of the calcium-channel blockers nifedipine and ω-conotoxin GVIA abolished both APs and calcium transients. Light pulse trains did not trigger GLP-1 secretion from CheTA-expressing cells under basal conditions but were an effective stimulus when cyclic adenosine monophosphate (cAMP) concentrations were elevated by forskolin plus 3-isobutyl 1-methylxanthine. In SSFO-expressing cells, light-stimulated GLP-1 release was observed at resting and elevated cAMP concentrations and was blocked by nifedipine plus ω-conotoxin GVIA but not tetrodotoxin. We conclude that cAMP elevation or cumulative membrane depolarization triggered by SSFO enhances the efficiency of light-triggered action potential firing, voltage-gated calcium entry, and GLP-1 secretion.
[Mh] Termos MeSH primário: Potenciais de Ação/efeitos dos fármacos
Bloqueadores dos Canais de Cálcio/farmacologia
Células Enteroendócrinas/efeitos dos fármacos
Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos
Potenciais da Membrana/efeitos dos fármacos
[Mh] Termos MeSH secundário: 1-Metil-3-Isobutilxantina/farmacologia
Animais
Cálcio/metabolismo
Colforsina/farmacologia
Células Enteroendócrinas/metabolismo
Células Enteroendócrinas/secreção
Peptídeo 1 Semelhante ao Glucagon/secreção
Camundongos
Nifedipino/farmacologia
Optogenética
Técnicas de Patch-Clamp
Inibidores de Fosfodiesterase/farmacologia
Rodopsina
Bloqueadores dos Canais de Sódio/farmacologia
Tetrodotoxina/farmacologia
Vasodilatadores/farmacologia
ômega-Conotoxina GVIA/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Phosphodiesterase Inhibitors); 0 (Sodium Channel Blockers); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); 4368-28-9 (Tetrodotoxin); 89750-14-1 (Glucagon-Like Peptide 1); 9009-81-8 (Rhodopsin); 92078-76-7 (omega-Conotoxin GVIA); I9ZF7L6G2L (Nifedipine); SY7Q814VUP (Calcium); TBT296U68M (1-Methyl-3-isobutylxanthine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00434


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[PMID]:28915270
[Au] Autor:Kunz S; Balmer V; Sterk GJ; Pollastri MP; Leurs R; Müller N; Hemphill A; Spycher C
[Ad] Endereço:Institute of Parasitology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
[Ti] Título:The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target.
[So] Source:PLoS Negl Trop Dis;11(9):e0005891, 2017 Sep.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Giardiasis is an intestinal infection correlated with poverty and poor drinking water quality, and treatment options are limited. According to the Center for Disease Control and Prevention, Giardia infections afflict nearly 33% of people in developing countries, and 2% of the adult population in the developed world. This study describes the single cyclic nucleotide-specific phosphodiesterase (PDE) of G. lamblia and assesses PDE inhibitors as a new generation of anti-giardial drugs. METHODS: An extensive search of the Giardia genome database identified a single gene coding for a class I PDE, GlPDE. The predicted protein sequence was analyzed in-silico to characterize its domain structure and catalytic domain. Enzymatic activity of GlPDE was established by complementation of a PDE-deficient Saccharomyces cerevisiae strain, and enzyme kinetics were characterized in soluble yeast lysates. The potency of known PDE inhibitors was tested against the activity of recombinant GlPDE expressed in yeast and against proliferating Giardia trophozoites. Finally, the localization of epitope-tagged and ectopically expressed GlPDE in Giardia cells was investigated. RESULTS: Giardia encodes a class I PDE. Catalytically important residues are fully conserved between GlPDE and human PDEs, but sequence differences between their catalytic domains suggest that designing Giardia-specific inhibitors is feasible. Recombinant GlPDE hydrolyzes cAMP with a Km of 408 µM, and cGMP is not accepted as a substrate. A number of drugs exhibit a high degree of correlation between their potency against the recombinant enzyme and their inhibition of trophozoite proliferation in culture. Epitope-tagged GlPDE localizes as dots in a pattern reminiscent of mitosomes and to the perinuclear region in Giardia. CONCLUSIONS: Our data strongly suggest that inhibition of G. lamblia PDE activity leads to a profound inhibition of parasite proliferation and that GlPDE is a promising target for developing novel anti-giardial drugs.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Descoberta de Drogas
Giardia lamblia/enzimologia
Giardia lamblia/genética
Inibidores de Fosfodiesterase/farmacologia
Diester Fosfórico Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
Giardia lamblia/efeitos dos fármacos
Giardia lamblia/crescimento & desenvolvimento
Giardíase/tratamento farmacológico
Giardíase/parasitologia
Seres Humanos
Enteropatias Parasitárias/tratamento farmacológico
Enteropatias Parasitárias/parasitologia
Inibidores de Fosfodiesterase/isolamento & purificação
Diester Fosfórico Hidrolases/genética
Diester Fosfórico Hidrolases/isolamento & purificação
Saccharomyces cerevisiae/genética
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Phosphodiesterase Inhibitors); EC 3.1.4.- (Phosphoric Diester Hydrolases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005891


  9 / 11895 MEDLINE  
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[PMID]:28817686
[Au] Autor:Chen SP; Singh K; Lin SC
[Ad] Endereço:Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, United States of America.
[Ti] Título:Use of phosphodiesterase inhibitors and prevalence of self-reported glaucoma in the United States.
[So] Source:PLoS One;12(8):e0183388, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: While decreased ocular blood flow is thought to be a possible contributor to glaucoma pathogenesis, it is unclear what role systemic phosphodiesterase inhibitors (PDEi) play. We performed a cross-sectional study of a nationally representative sample of the U.S. population to investigate the relationship between the most commonly used PDEi, sildenafil and theophylline, and self-reported glaucoma. METHODS: We used the National Health and Nutrition Examination Survey 2005-2008 cycles for this observational study. 7,042 participants, aged 40 years and over, responded to a survey item on glaucoma status and were included in the analysis. Multivariable logistic regression models were constructed to evaluate the association between at least 1 year of self-reported PDEi use and prevalent glaucoma. Regressions were adjusted for potential confounding variables, including demographics, socioeconomic status, and general health conditions, and accounted for the complex design of the survey. Sample weights were constructed and used to ensure the generalizability of results. RESULTS: 482 respondents self-reported a diagnosis of glaucoma, of which 11 used sildenafil and 20 used theophylline for at least 1 year. Covariates significantly associated with higher odds of glaucoma prevalence in univariable analyses included older age, black race, former smoking status, diabetes, hyperlipidemia, myocardial infarction, and stroke. Conversely, higher education and income were significantly associated with lower odds of glaucoma prevalence. In regression analyses adjusted for demographic and socioeconomic variables, sildenafil (OR = 4.90, CI: 1.24-19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46-6.80, p = 0.005) were significantly associated with higher odds of self-reported glaucoma. These associations held after further adjustment with general health behaviors and conditions for both sildenafil and theophylline. CONCLUSIONS: Use of sildenafil and theophylline for one or more years was associated with greater prevalence of self-reported glaucoma, a finding which requires further prospective study to assess causality and possible mechanisms of action.
[Mh] Termos MeSH primário: Glaucoma/induzido quimicamente
Inibidores de Fosfodiesterase/efeitos adversos
[Mh] Termos MeSH secundário: Idoso
Estudos Transversais
Feminino
Seres Humanos
Masculino
Meia-Idade
Citrato de Sildenafila/efeitos adversos
Teofilina/efeitos adversos
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphodiesterase Inhibitors); BW9B0ZE037 (Sildenafil Citrate); C137DTR5RG (Theophylline)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183388


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[PMID]:28797798
[Au] Autor:Tian LW; Feng Y; Tran TD; Shimizu Y; Pfeifer T; Vu HT; Quinn RJ
[Ad] Endereço:Griffith Institute for Drug Discovery, Griffith University, Brisbane QLD 4111, Australia.
[Ti] Título:Achyrodimer F, a tyrosyl-DNA phosphodiesterase I inhibitor from an Australian fungus of the family Cortinariaceae.
[So] Source:Bioorg Med Chem Lett;27(17):4007-4010, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mass-guided isolation of the dichloromethane/methanol extracts from a specimen of teleomorphic fungus of the family Cortinariaceae resulted in the identification of a new dimeric cyclobutane metabolite, achyrodimer F (1), along with the monomers hispidin (2) and bisnoryangonin (3). Their structures were determined by NMR and MS data analyses. Density Function Theory (DFT) NMR calculations was employed to confirm the chemical structure of achyrodimer F. Compound 1 inhibited tyrosyl-DNA phosphodiesterase I with an IC value of 1µM.
[Mh] Termos MeSH primário: Agaricales/química
Ciclobutanos/farmacologia
Inibidores de Fosfodiesterase/farmacologia
Diester Fosfórico Hidrolases/metabolismo
Pironas/farmacologia
[Mh] Termos MeSH secundário: Austrália
Ciclobutanos/química
Ciclobutanos/isolamento & purificação
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Inibidores de Fosfodiesterase/química
Inibidores de Fosfodiesterase/isolamento & purificação
Pironas/química
Pironas/isolamento & purificação
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclobutanes); 0 (Phosphodiesterase Inhibitors); 0 (Pyrones); 0 (achyrodimer F); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.- (TDP1 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE



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