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‣ Stimulation of Neural Stem Cell Proliferation by Inhibition of Phosphodiesterase 5

Santos, Ana I.; Carreira, Bruno P.; Nobre, Rui J.; Carvalho, Caetana M.; Araujo, Ines M.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.838193%
The involvement of nitric oxide (NO) and cyclic GMP (cGMP) in neurogenesis has been progressively unmasked over the last decade. Phosphodiesterase 5 (PDE5) specifically degrades cGMP and is highly abundant in the mammalian brain. Inhibition of cGMP hydrolysis by blocking PDE5 is a possible strategy to enhance the first step of neurogenesis, proliferation of neural stem cells (NSC). In this work, we have studied the effect on cell proliferation of 3 inhibitors with different selectivity and potency for PDE5, T0156, sildenafil, and zaprinast, using subventricular zone-(SVZ-) derived NSC cultures.We observed that a short- (6 h) or a long-term (24 h) treatment with PDE5 inhibitors increased SVZ-derived NSC proliferation. Cell proliferation induced by PDE5 inhibitors was dependent on the activation of the mitogen-activated protein kinase (MAPK) and was abolished by inhibitors of MAPK signaling, soluble guanylyl cyclase, and protein kinase G. Moreover, sildenafil neither activated ERK1/2 nor altered p27Kip1 levels, suggesting the involvement of pathways different from those activated by T0156 or zaprinast. In agreement with the present results, PDE5 inhibitors may be an interesting therapeutic approach for enhancing the proliferation stage of adult neurogenesis.; This work was supported by FEDER funds via Programa Operacional Factores de Competitividade (COMPETE) and by national funds by the Foundation for Science and Technology (FCT...

‣ Sildenafil preserves diastolic relaxation after reduction by L-NAME and increases phosphodiesterase-5 in the intercalated discs of cardiac myocytes and arterioles

FERREIRA-MELO, Silvia Elaine; DEMACQ, Caroline; LACCHINI, Silvia; KRIEGER, José Eduardo; IRIGOYEN, Maria Cláudia; MORENO, Heitor
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.039946%
OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.; (FAPESP) São Paulo Research Foundation; Coordination for Higher Level Graduates Improvement (CAPES); (CNPq) National Council for Scientific and Technological Development

‣ PHOSPHODIESTERASE-4 INHIBITION REDUCES PROTEOLYSIS AND ATROGENES EXPRESSION IN RAT SKELETAL MUSCLES

LIRA, Eduardo C.; GONCALVES, Dawit A. P.; PARREIRAS-E-SILVA, Lucas T.; ZANON, Neusa M.; KETTELHUT, Isis C.; NAVEGANTES, Luiz C. C.
Fonte: WILEY-BLACKWELL Publicador: WILEY-BLACKWELL
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.706895%
Phosphodiesterase (PDE) inhibition reduces skeletal muscle atrophy, but the underlying molecular mechanism remains unclear. We used microdialysis to investigate the effects of different PDE inhibitors on interstitial tyrosine concentration as well as proteolytic activity and atrogenes expression in isolated rat muscle. Rolipram, a PDE-4-selective inhibitor, reduced the interstitial tyrosine concentration and rates of muscle protein degradation. The rolipram-induced muscle cAMP increase was accompanied by a decrease in ubiquitin proteasome system (UPS) activity and atrogin-1 mRNA, a ubiquitin-ligase involved in muscle atrophy. This effect was not associated with Akt phosphorylation but was partially blocked by a protein kinase A inhibitor. Fasting increased atrogin-1, MuRF-1 and LC3b expression, and these effects were markedly suppressed by rolipram. Our data suggest that activation of cAMP signaling by PDE-4 blockade leads to inhibition of UPS activity and atrogenes expression independently of Akt. These findings are important for identifying novel approaches to attenuate muscle atrophy. Muscle Nerve 44: 371-381, 2011; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[FAPESP 08/06694-6]; FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[09/07584-2]; Conselho Nacional de Pesquisa[CNPq 140094/07-5]; CNPq Conselho Nacional de Pesquisa[306101/09-2]; CNPq Conselho Nacional de Pesquisa[303786/08-6]

‣ Decreased cGMP Level Contributes to Increased Contraction in Arteries From Hypertensive Rats Role of Phosphodiesterase 1

GIACHINI, Fernanda R.; LIMA, Victor V.; CARNEIRO, Fernando S.; TOSTES, Rita C.; WEBB, R. Clinton
Fonte: LIPPINCOTT WILLIAMS & WILKINS Publicador: LIPPINCOTT WILLIAMS & WILKINS
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.706895%
Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3` 5`-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng.min(-1)) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (E(max)168%+/- 8% vs 136%+/- 4%) and small mesenteric arteries (SMA; E(max)170%+/- 6% vs 143%+/- 3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 mu mol/L) reduced PE-induced contraction in aortas from Ang II rats (E(max)94%+/- 12%) but not in controls (154%+/- 7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1 +/- 0.1 vs 5.9 +/- 0.06), but not in controls (6.0 +/- 0.03 vs 6.1 +/- 0.04). Sildenafil (10 mu mol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 mu mol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (E(max)82%+/- 12% vs 445 +/- 5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1 +/- 0.3 vs 5.3 +/- 0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production...

‣ A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers

Mendes, Gustavo D.; dos Santos Filho, Hilton Oliveira; Pereira, Alberto dos Santos; Mendes, Fabiana D.; Ilha, Jaime O.; Alkharfy, Khalid M.; Nucci, Gilberto de
Fonte: DUSTRI-VERLAG DR KARL FEISTLE; DEISENHOFEN-MUENCHEN Publicador: DUSTRI-VERLAG DR KARL FEISTLE; DEISENHOFEN-MUENCHEN
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.706895%
Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. Objective: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). Methods: The study was an open-label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. Results: No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements...

‣ Estudo da ação do inibidor de fosfodiesterase (sildenafil) no diabetes insipidus induzido pelo lítio; Role of phosphodiesterase inhibitor(sildenafil) in lithium-induced diabetes insipidus

Sanches, Talita Rojas Cunha
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 26/11/2008 Português
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Os pacientes que usam lítio (Li) para tratamento do transtorno bipolar freqüentemente apresentam poliúria e deficiência de concentração urinária, sintomas do Diabetes Insipidus nefrogênico (DIN). Animais tratados com Li apresentam baixos níveis de produção de adenosina monofosfato cíclico (AMPc) em resposta ao hormônio antidiurético (HAD). O Sildenafil (Sil), um inibidor da fosfodiesterase 5 (PDE5), eleva os níveis intracelulares de guanosina monofosfato cíclico (GMPc), levando a inserção de aquaporina 2 (AQP2) na membrana plasmática das células do ducto coletor. Portanto, inibidores de PDE podem promover a inserção de AQP2 na membrana plasmática mesmo sem a ativação do receptor de HAD, indicando a participação de uma via alternativa mediada pelo GMPc. Nós investigamos o efeito do Sil na expressão renal das proteínas de membrana AQP2, UT-A1, NKCC2, NHE3, P-ENaC em ratos com DIN induzido pelo Li. Ratos Wistar foram divididos nos seguintes grupos: grupo controle, recebendo dieta alimentar normal durante quatro semanas; grupo Li, recebendo dieta alimentar normal com 40 mmol Li por quilo de dieta durante quatro semanas; grupo Li + Sil, recebendo dieta alimentar normal com 40 mmol Li por quilo de dieta durante quatro semanas e 200 mg por quilo de dieta de Sil a partir da segunda semana; grupo Sil...

‣ Benefícios e riscos da testosterona para tratamento de desejo sexual hipoativo de mulheres: uma revisão crítica da literatura referente às décadas pré e após o advento dos inibidores da fosfodiesterase tipo 5; Benefits and risks of testosterone treatment for hypoactive sexual desire in women: a critical review of the literature related to the decades before and after the advent of Phosphodiesterase type 5 inhibitors

Reis, Sandra Léa Bonfim
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 16/09/2013 Português
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Introdução: Vários são os fatores que alteram a atividade sexual de homens e mulheres. Com o envelhecimento observa-se aumento das queixas de desejo hipoativo feminino e de disfunção erétil. Visto que o homem e sua parceira constituem um sistema dinâmico, antes do advento dos inibidores da fosfodiesterase eles se adaptavam às condições disfuncionais do casal. A eficácia aliada a poucos efeitos colaterais e à facilidade de administração da sildenafila e, posteriormente, da vardenafila e tadalafila, revolucionou o tratamento da disfunção erétil. Por outro lado, até a presente data, a terapêutica medicamentosa com testosterona para o desejo sexual hipoativo de mulheres, ainda gera controvérsias. Objetivo: Avaliar o uso de androgênio, utilizado para tratamento das queixas de desejo sexual hipoativo em mulheres, comparando dois períodos, ou seja, pré e após o aparecimento iPDE 5. Os efeitos colaterais e as divergências em relação a este tratamento também serão analisados. Método: Foram selecionados estudos em inglês, português e espanhol, publicados entre 1988 e os dias atuais, ou seja, na década pré-advento dos inibidores da fosfodiesterase 5 e após. A busca dos artigos foi feita em periódicos indexados nas bases Lilacs...

‣ Metodo de quantificação de nucleotideos por HPLC-MS/MS e avaliação da atividade de analogos de sildenafil sobre fosfodiesterase; Metho of quantification of nucleotides by HPLC-MS/MS and evaluation of the activity of sildenafil analoges in phosphodiesterase

Raquel Lorenzetti
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 28/08/2007 Português
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No presente trabalho foi padronizado um novo método para a dosagem da atividade de fosfodiesterase in vitro, por HPLC-MS/MS. Este novo método conseguiu apresentar exatidão, precisão, sensibilidade e rapidez nas análises; monitorando os nucleotídeos (AMP, GMP, AMPc e GMPc). O desenvolvimento de novos fármacos derivados de um protótipo aponta para a obtenção de moléculas com um melhor perfil farmacocinético ou uma melhor relação estrutura-atividade. Atualmente o sildenafil é considerado o principal fármaco para o tratamento de disfunção erétil. Neste trabalho, avaliaram-se novos compostos denominados análogos de sildenafil (carbonato de lodenafil, dímero uréia e dímero uretana). Os análogos foram analisados quanto à atividade em PDE5 e agregação plaquetária humana, in vitro. Foi determinada a estabilidade destes compostos, em meio ácido e plasma humano, in vitro, além de seus possíveis metabólitos em microssomas e hepatócitos de rato in vitro, e os seus parâmetros farmacocinéticos via intravenosa e oral, em cão, in vivo. Os resultados mostraram que os análogos de sildenafil inibem a atividade de PDE e não inibem a agregação plaquetária do mesmo modo que o sildenafil in vitro, no entanto potencializam a ação do doador de NO (SNP). Os análogos de sildenafil foram estáveis em meio ácido e em plasma humano. No ensaio de metabolização...

‣ Estudo clínico fase I de carbonato de lodenafila, um novo tipo de inibidor de fosfodiesterase 5 (PDE5), em voluntários saudáveis do sexo masculino = : A phase I clinical trial of lodenafil carbonate, a new phosphodiesterase type 5 (PDE5) inhibitor, in healthy male volunteers; A phase I clinical trial of lodenafil carbonate, a new phosphodiesterase type 5 (PDE5) inhibitor, in healthy male volunteers

Hilton Oliveira dos Santos Filho
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 13/05/2013 Português
Relevância na Pesquisa
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Carbonato de Lodenafila é um novo tipo de inibidor de fosfodiesterase 5 (PDE5) utilizado no tratamento da disfunção erétil. O presente estudo foi realizado para avaliar a segurança, tolerabilidade e farmacocinética do carbonato de lodenafila após a administração de doses orais únicas ascendentes (de 1 a 100 mg) a voluntários saudáveis do sexo masculino (n = 33). O estudo foi um estudo clínico fase I, aberto, de escalonamento de dose, utilizando a administração de doses orais únicas de carbonato de lodenafila. Carbonato de Lodenafila foi administrado sequencialmente escalonado em doses únicas de 1 mg a 100 mg com um período sem uso do medicamento (washout) de pelo menos 1 semana, entre cada dose. A progressão para a próxima dose foi permitida se após a avaliação dos exames clínicos, laboratoriais e Monitorização Ambulatorial da Pressão Arterial (MAPA), não demonstrassem alterações e eventos adversos sem relevância clínica. As amostras de sangue foram coletadas na pré-dose e em intervalos determinados e 24 horas após a administração. As amostras de plasma para a mensuração de carbonato lodenafila e lodenafila foram analisadas por cromatografia líquida acoplada à espectrometria de massa. Não foram observados eventos adversos graves...

‣ Sildenafil preserves diastolic relaxation after reduction by L-NAME and increases phosphodiesterase-5 in the intercalated discs of cardiac myocytes and arterioles

FERREIRA-MELO, Silvia Elaine; DEMACQ, Caroline; LACCHINI, Silvia; KRIEGER, José Eduardo; IRIGOYEN, Maria Cláudia; MORENO, Heitor
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.039946%
OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

‣ A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers

Mendes, Gustavo D.; dos Santos Filho, Hilton Oliveira; Pereira, Alberto dos Santos; Mendes, Fabiana D.; Ilha, Jaime O.; Alkharfy, Khalid M.; De Nucci, Gilberto
Fonte: Dustri-Verlag Dr Karl Feistle; Deisenhofen-Muenchen Publicador: Dustri-Verlag Dr Karl Feistle; Deisenhofen-Muenchen
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
36.706895%
Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. Objective: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). Methods: The study was an open-label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. Results: No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements...

‣ Protective effects of phosphodiesterase inhibitors on lung function and remodeling in a murine model of chronic asthma

Campos,H.S.; Xisto,D.G.; Oliveira,M.B.G.; Teixeira,I.; Negri,E.M.; Mauad,T.; Carnielli,D.; Lima,L.M.; Barreiro,E.J.; Faffe,D.S.; Zin,W.A.; Lapa e Silva,J.R.; Rocco,P.R.M.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2006 Português
Relevância na Pesquisa
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The aim of the present study was to compare the efficacy of a novel phosphodiesterase 4 and 5 inhibitor, LASSBio596, with that of dexamethasone in a murine model of chronic asthma. Lung mechanics (airway resistance, viscoelastic pressure, and static elastance), histology, and airway and lung parenchyma remodeling (quantitative analysis of collagen and elastic fiber) were analyzed. Thirty-three BALB/c mice were randomly assigned to four groups. In the asthma group (N = 9), mice were immunized with 10 µg ovalbumin (OVA, ip) on 7 alternate days, and after day 40 they were challenged with three intratracheal instillations of 20 µg OVA at 3-day intervals. Control mice (N = 8) received saline under the same protocol. In the dexamethasone (N = 8) and LASSBio596 (N = 8) groups, the animals of the asthma group were treated with 1 mg/kg dexamethasone disodium phosphate (0.1 mL, ip) or 10 mg/kg LASSBio596 dissolved in dimethyl sulfoxide (0.2 mL, ip) 24 h before the first intratracheal instillation of OVA, for 8 days. Airway resistance, viscoelastic pressure and static elastance increased significantly in the asthma group (77, 56, and 76%, respectively) compared to the control group. The asthma group presented more intense alveolar collapse...

‣ Acute effect of phosphodiesterase type 5 inhibitor on serum oxidative status and prolidase activities in men with erectile dysfunction

Savas,Murat; Yeni,Ercan; Verit,Ayhan; Gulum,Mehmet; Aksoy,Nurten; Ciftci,Halil; Celik,Hakim; Altunkol,Adem; Oncel,Halil
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2010 Português
Relevância na Pesquisa
36.706895%
OBJECTIVES: To investigate the acute effect of phosphodiesterase type 5 (PDE5) inhibitor on erectile dysfunction by evaluating serum oxidative status and prolidase activity. METHODS: Serum samples of 36 patients with erectile dysfunction and 30 control cases were analyzed for total antioxidant status, total oxidant status, and prolidase activity, before and after the administration of tadalafil citrate. RESULTS: Before and after tadalafil citrate administration, serum total antioxidant status, total oxidant status, and prolidase were 1.1+0.0 vs. 1.6 + 0.0 umol H2O2 Eq/L, 10.3+1.1 vs. 6.9 + 1.2 umol H2O2 Eq/L, and 236.4+19.5 vs. 228.2 + 19.2 U/L, respectively (p<0.0001 for all). CONCLUSIONS: Evaluation of serum oxidative status and prolidase activity confirmed the beneficial acute effects of PDE5 inhibitor in patients with erectile dysfunction.

‣ Sildenafil preserves diastolic relaxation after reduction by L-NAME and increases phosphodiesterase-5 in the intercalated discs of cardiac myocytes and arterioles

Ferreira-Melo,Silvia Elaine; Demacq,Caroline; Lacchini,Silvia; Krieger,José Eduardo; Irigoyen,Maria Cláudia; Moreno,Heitor
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2011 Português
Relevância na Pesquisa
37.039946%
OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.

‣ A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

Codevilla,Cristiane Franco; Castilhos,Tamara dos Santos; Bergold,Ana Maria
Fonte: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2013 Português
Relevância na Pesquisa
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The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs.

‣ Vergleichende Untersuchungen zur Steigerung der Kontraktilität und der mechanischen Effizienz von Ferkel-Herzen nach kardioplegem Herzstillstand durch Kalziumsensitizer, Beta-Adrenozeptor-Agonisten und Phosphodiesterase-III-Hemmern im ex-situ ...; Analysis to compare the contractility increase and the mechanical efficiency of young pig hearts after cardioplegia using calcium sensitizer, beta-adrenergic agonist and phosphodiesterase type 3 inhibitor within the ex-situ working heart model

Löhle, Thomas
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
Relevância na Pesquisa
37.108516%
Vergleichende Untersuchungen zur Steigerung der Kontraktilität und der mechanischen Effizienz von Ferkel-Herzen nach kardioplegem Herzstillstand durch Kalziumsensitizer, Beta-Adrenozeptor-Agonisten und Phosphodiesterase-III-Hemmern im ex-situ Working Heart Modell Die vorliegende Studie untersucht den Einfluß des reinen (+) - Enantiomers des Kalziumsensitizers EMD 57033 auf die Myokardfunktion nach kardioplegem Herzstillstand. Die Wirkung wird im ex-situ Working Heart Modell mit der des Beta-Adrenozeptor-Agonisten Adrenalin und der des Phosphodiesterase-III-Hemmers Milrinon, die beide bereits klinisch angewendet werden, verglichen. Es wurden für Adrenalin 8, für Milrinon 10 und für den Kalziumsensitizer EMD 57033 6 Herzen nach Induktion des kardioplegen Herzstillstandes explantiert und in das Perfusionsmodell integriert. Nach einer einstündigen Ischämie wurden alle 24 Herzen über 20 Minuten mit physiologisch konditioniertem Schweineblut reperfundiert und wiedererwärmt. Unmittelbar nach der Reperfusionsphase wurde in den Working Heart Modus übergegangen. Bei stabilen hämodynamischen Verhältnissen wurden die funktionellen Zielparameter (Stroke-Work-Index, enddiastolischer linksventrikulärer Druck, mittlerer Aortenfluß...

‣ Biochemische Charakterisierung der Funktion der GAF-Domänen der Phosphodiesterase 11A4; Biochemical characterization of the function of the GAF-domains of phosphodiesterase 11A4

Groß-Langenhoff, Marco
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
Relevância na Pesquisa
36.927139%
Hier wurde die Funktion des Tandem-GAF-Ensembles der PDE11A4 untersucht. Als Ligand an die GAF-Domänen wurde das cyclische Nukleotid cGMP gefunden. Dies war möglich, da sich durch die Schaffung eines speziellen Testsystems im Gegensatz zum Holoenzym Ligand und Substrat voneinander unterschieden. Der Einbau des N-terminalen Bereichs der PDE11A4 in die cyanobakterielle Adenylatcyclase CyaB1 erzeugte ein hochempfindliches Testsystem, das die Charakterisierung der PDE11A4 GAF-Domänen und seines N-Terminus durch Messung der enzymatischen Aktivität der Adenylatcyclase ermöglichte. Die Bindung des Liganden erfolgte mit geringer Affinität und sorgte für eine bis zu vierfache Stimulation des katalytischen Zentrums. Die nähere Charakterisierung der GAF-Domänen zeigte, dass GAF-A cGMP bindet und für die Dimerisierung notwendig ist, während für die GAF-B nachgewiesen werden konnte, dass diese keine cGMP bindet, aber für die Ausbildung einer Struktur, die die Signalweiterleitung ermöglicht, essentiell ist. Durch Modifikationen ließ sich die Affinität der GAF-Domänen für cGMP erhöhen. Zum einen durch eine Phosphorylierung eines Serinrestes durch PKG (Ser-162), zum anderen durch eine Proteolyse im Bereich des N-Terminus. Die Phosphorylierung an Ser-162 führte zu einer bis zu vierfachen Affinität der GAF-Domänen für cGMP...

‣ Sildenafil preserves diastolic relaxation after reduction by L-NAME and increases phosphodiesterase-5 in the intercalated discs of cardiac myocytes and arterioles

Ferreira-Melo, Silvia Elaine; Demacq, Caroline; Lacchini, Silvia; Krieger, José Eduardo; Irigoyen, Maria Cláudia; Moreno, Heitor
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2011 Português
Relevância na Pesquisa
37.039946%
OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.

‣ A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

Codevilla, Cristiane Franco; Castilhos, Tamara dos Santos; Bergold, Ana Maria
Fonte: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; Formato: application/pdf
Publicado em 01/03/2013 Português
Relevância na Pesquisa
36.991377%
A introdução da terapia oral com inibidores da fosfodiesterase tipo 5, em 1998, revolucionou o tratamento da disfunção erétil. A disfunção erétil é o problema sexual mais comum em homens. Muitas vezes tem um efeito profundo nas relações íntimas e na qualidade de vida. A análise de produtos farmacêuticos é uma parte importante do processo de desenvolvimento de fármacos, bem como para a análise de rotina e controle de qualidade das formulações comerciais. Enquanto a determinação do citrato de sildenafila, vardenafila e tadalafila está bem documentada por uma variedade de métodos, existem poucas publicações sobre a determinação de udenafila, carbonato de lodenafila, mirodenafila e avanafila. O artigo apresenta uma breve revisão do mecanismo de ação, efeitos adversos, farmacocinética e os mais recentes métodos analíticos, que podem determinar a concentração do fármaco em matrizes biológicas e formulações farmacêuticas destes quatro fármacos.; The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate...

‣ Freqüência de uso de inibidores de fosfodiesterase-5 por estudantes universitários; Uso de inhibidores de fosfodiesterasa-5 por estudiantes universitários; Use of phosphodiesterase-5 inhibitors by college students

Freitas, Vanessa Mello de; Menezes, Fabiana Gatti de; Antonialli, Michele Melo Silva; Nascimento, Jorge Willian Leandro
Fonte: Universidade de São Paulo. Faculdade de Saúde Pública Publicador: Universidade de São Paulo. Faculdade de Saúde Pública
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf; application/pdf
Publicado em 01/10/2008 Português
Relevância na Pesquisa
36.838193%
The objective of this study was to identify the use of phosphodiesterase type 5 inhibitors among university students from the city of Sao Paulo (SP) in Brazil. Male students (n=350) replied to a questionnaire about diagnosis of erectile dysfunction, the frequency and reason for the use of phosphodiesterase type 5 inhibitors, the specific medication used, whether their use was accompanied by a medical prescription and any reported side-effects. The results shows that a total of 53 (14.7%) students had already used this kind of medication without a prescription or medical diagnosis for erectile dysfunction, of which 53% reported using sildenafil, 37% tadalafil and 10% vardenafil. The main adverse side-effects reported were headache (23%) and flushing (10%) and the main reasons for using the inhibitor were curiosity (70%) and erectile improvement (12%).; O objetivo do estudo foi identificar o uso de inibidores da fosfodiesterase-5 por estudantes universitários da cidade de São Paulo (SP), em 2006. Alunos do sexo masculino (n=360) responderam questionário sobre diagnóstico de disfunção erétil, freqüência e motivo do uso, medicamento utilizado, existência de prescrição médica e relato de efeitos adversos. Os resultados mostraram que 53 (14...