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1.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670094

RESUMO

Unapproved ingredients included in herbal medicines and dietary supplements have been detected as adulterated synthetic drugs used for erectile dysfunction. Extraction from a dietary supplement was performed to isolate the compounds by HPLC analysis. The structural characterization was confirmed using mass spectrometry (ESI-TOF/MS and LC-MS/MS), 1H NMR, and 13C NMR spectroscopy techniques. Results identified the thus-obtained compound to be sulfoaildenafil, a thioketone analogue of sildenafil. The biological activities of this active compound have been focused for the first time by the experimental point of view performance in vitro. The results revealed that sulfoaildenafil can affect the therapeutic level of nitric oxide through the upregulation of nitric oxide synthase and phosphodiesterase type 5 (PDE5) gene expressions. This bulk material, which displays structural similarity to sildenafil, was analyzed for the presence of a PDE5 inhibitor using a theoretical calculation. These unique features of the potential activity of PDE5 protein and its inhibitors, sildenafil and sulfoaildenafil, may play a key consideration for understanding the mode of actions and predicting the biological activities of PDE5 inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Suplementos Nutricionais , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/química , Cromatografia Líquida de Alta Pressão , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/efeitos dos fármacos , Disfunção Erétil/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Medicina Herbária , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/química , Piperazinas/uso terapêutico , Citrato de Sildenafila/química , Citrato de Sildenafila/uso terapêutico , Sulfonas/química , Sulfonas/uso terapêutico
2.
Cochrane Database Syst Rev ; 3: CD004434, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33765691

RESUMO

BACKGROUND: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020. SELECTION CRITERIA: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality. MAIN RESULTS: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA.   We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide.  As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome. AUTHORS' CONCLUSIONS: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.


Assuntos
Anti-Hipertensivos/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Viés , Humanos , Hipertensão Pulmonar/mortalidade , Inibidores da Fosfodiesterase 5/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Teste de Caminhada
3.
Medicine (Baltimore) ; 100(8): e23778, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663041

RESUMO

BACKGROUND: To verify which phosphodiesterase type 5 inhibitors (PDE5is) strategy is better for erectile dysfunction (ED) following nerve-sparing radical prostatectomy (NSRP). METHODS: This systematic literature search was conducted in MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials database to identify eligible studies from the startup of these databases to 1 November, 2019. The ED recovery rate was the main outcome. Traditional pair-wise meta-analysis and multivariate random-effects network meta-analysis (NMA) were performed to explore direct and indirect comparisons, respectively. The surface under the cumulative ranking (SUCRA) probabilities was used to evaluate the efficacy of treatments. RESULTS: A total of 14 randomized controlled trials with four kinds of PDE5is were included. Further pooled evidence suggested that PDE5is followed by NSRP had a benefit for penile rehabilitation compared to placebo using traditional pair-wise meta-analyses. Our NMA showed that Avanafil 200 mg on demand might be most likely to be the best treatment option according to the first rank of SUCRA both in NMA (SUCRA 83.5) and sensitivity analysis (SUCRA 90.2). CONCLUSION: Avanafil 200 mg on demand has the highest probability of being the best intervention among PDE5is in treating ED following NSRP. However, more randomized controlled trials are needed to validate this in consideration of the published data regarding Avanafil is relatively small scale.


Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostatectomia/efeitos adversos , Neoplasias da Próstata/cirurgia , Humanos , Masculino , Metanálise em Rede , Ereção Peniana , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica
4.
JAMA Netw Open ; 4(2): e2036337, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33599772

RESUMO

Importance: Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. Objective: To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Data Sources: Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Study Selection: Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data Extraction and Synthesis: Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. Results: A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. Conclusions and Relevance: This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.


Assuntos
Antioxidantes/uso terapêutico , Equipamentos e Provisões , Disfunção Erétil/terapia , Tratamento por Ondas de Choque Extracorpóreas , Inibidores da Fosfodiesterase 5/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Terapia Combinada , Quimioterapia Combinada , Ácido Fólico/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Tadalafila/uso terapêutico , Resultado do Tratamento , Complexo Vitamínico B/uso terapêutico
5.
Pneumologie ; 75(5): 369-376, 2021 May.
Artigo em Alemão | MEDLINE | ID: mdl-33472251

RESUMO

Various vasodilator medications are used in the treatment of pulmonary arterial hypertension (PAH), such as endothelin receptor antagonists (ERA) or phosphodiesterase-5-(PDE-5-)inhibitors. In a human ex vivo model, we investigated whether the combination of two substance classes could achieve a higher effect or - without loss of vasodilatation - a lower dosage of the individual substances might be sufficient. We established an ex vivo organ bath model to evaluate the dose-dependent effects of ERA and PDE-5-inhibitors on pulmonary vessels harvested from patients who underwent surgery (lung resection/transplantation). We compared the combined use of both substance classes with administration of one class of drugs alone. Due to the limitations of the experimental design, it is not possible to extrapolate our results to the conditions in vivo. Nevertheless, organ bath proved to be helpful in evaluating the dose-dependent effects of ERA and PDE-5 inhibitors, which is not practical in everyday clinical practice. In this setting, the effectiveness of the combination therapy and the potential for dose reduction depended on the concentrations used and on the influence of previous illnesses on blood vessel function. This article describes the most important results of our experimental investigations and suggestions for future projects.


Assuntos
Hipertensão Pulmonar , Preparações Farmacêuticas , Hipertensão Arterial Pulmonar , Anti-Hipertensivos , Quimioterapia Combinada , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico
6.
Biomed Pharmacother ; 134: 111128, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33348311

RESUMO

Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiologically processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing for a wider range of clinical applications.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Domínio Catalítico , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Humanos , Isoenzimas , Inibidores da Fosfodiesterase 5/química , Fosforilação , Conformação Proteica , Relação Estrutura-Atividade
7.
J Med Chem ; 63(24): 15153-15186, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33314936

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating disease that can lead to right ventricular failure and premature death. Although approved drugs have been shown to be safe and effective, PAH remains a severe clinical condition, and the long-term survival of patients with PAH is still suboptimal. Thus, potential therapeutic targets and new agents to treat PAH are urgently needed. In recent years, a variety of related pathways and potential therapeutic targets have been found, which brings new hope for PAH therapy. In this perspective, not only are the marketed drugs used to treat PAH summarized but also the recently developed novel pharmaceutical therapies currently in clinical trials are discussed. Furthermore, the advances in natural products as potential treatment for PAH are also updated.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Hipertensão Arterial Pulmonar/patologia , Receptores de Endotelina/química , Receptores de Endotelina/metabolismo , Receptores de Epoprostenol/agonistas , Receptores de Epoprostenol/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 234-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093789

RESUMO

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Piridazinas/uso terapêutico , Sarcoidose Pulmonar/complicações , Tadalafila/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose Pulmonar/diagnóstico , Resultado do Tratamento
10.
Medicine (Baltimore) ; 99(34): e21866, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846840

RESUMO

INTRODUCTION: Premature ejaculation (PE) affects 8% to 30% of adult men worldwide. Recently, the incidence of PE is on the rise. A series of prior studies suggested that the incidence of PE is related to various biological factors as low testosterone, low serum vitamin D, diabetes, lower urinary tract symptoms, and other psychological factors. At present, the major treatments include selective serotonin reuptake inhibitors antidepressants (dapoxetine, paroxetine), topical anesthetics, phosphodiesterase-5 inhibitor, circumcision, and selective dorsal neurotomy (SDN). The previous study found that SDN is effective for PE. METHODS AND ANALYSIS: The electronic databases of MEDLINE, PubMed, Web of Science, EMBASE, Cochrane Library, Clinicaltrials. org, China National Knowledge Infrastructure Database (CNKI), Wan fang Database, China Biology Medicine Database (CBM), VIP Science Technology Periodical Database, Chinese Clinical Trial Registry will be retrieved. All the randomized controlled trials of selective dorsal penile neurotomy for patients with PE will be included. The outcome includes intravaginal ejaculation latency time and Chinese Index of Sexual Function for Premature Ejaculation-5. We will conduct this study strictly according to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: The present study is a protocol for systematic review and meta-analysis without results, and data analysis will be carried out after the protocol. We will share our findings on June 30th of 2021. CONCLUSION: SDN can effectively prolong IELT, but its efficacy has not been assessed scientifically and systematically. To address this limitation, this study will inspect the efficacy and safety of the SDN treatment in patients with PE. ETHICS AND DISSEMINATION: Formal ethical approval is not required in this protocol. We will collect and analyze data based on published studies, and since there are no patients involved in this study, individual privacy will not be under concerns. The results of this review will be disseminated to peer-reviewed journals or submit to related conferences. PROTOCOL REGISTRATION NUMBER: INPLASY202070084.


Assuntos
Pênis/inervação , Ejaculação Precoce/terapia , Nervo Pudendo/cirurgia , Adulto , Anestésicos Locais/uso terapêutico , Benzilaminas/uso terapêutico , Circuncisão Masculina/métodos , Ejaculação/fisiologia , Humanos , Incidência , Masculino , Naftalenos/uso terapêutico , Paroxetina/uso terapêutico , Pênis/fisiopatologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Ejaculação Precoce/epidemiologia , Ejaculação Precoce/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Captação de Serotonina/uso terapêutico
11.
Vasc Health Risk Manag ; 16: 231-239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606719

RESUMO

Erectile dysfunction (ED) is defined as a man's consistent or recurrent inability to attain and/or maintain penile erection enough for successful vaginal intercourse. ED affects a large part of the population, increasing its incidence with age and comorbidities. It is estimated by the year 2025, 322 million men will suffer from ED. Incidence of ED has been related not only to chronic diseases such as diabetes mellitus, metabolic syndrome, hyperlipidemia, psychiatric diseases or urinary tract diseases, but also to hypertension and especially to antihypertensive treatments. This review summarizes current knowledge about the management of ED in hypertensive men and its role as cardiovascular disease predictor.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Disfunção Erétil/terapia , Hipertensão/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Tomada de Decisão Clínica , Disfunção Erétil/diagnóstico , Disfunção Erétil/epidemiologia , Disfunção Erétil/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Masculino , Inibidores da Fosfodiesterase 5/efeitos adversos , Fatores de Risco , Resultado do Tratamento
12.
Med Hypotheses ; 143: 110129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721814

RESUMO

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Estrogênios/fisiologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação , Interleucinas/fisiologia , Modelos Animais , Modelos Biológicos , Óxido Nítrico/uso terapêutico , Obesidade/complicações , Obesidade/fisiopatologia , Uso Off-Label , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/fisiologia , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pneumonia Viral/complicações , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Tadalafila/farmacologia , Tadalafila/uso terapêutico
13.
Int Heart J ; 61(4): 799-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728000

RESUMO

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Fenilpropionatos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Bosentana/administração & dosagem , Estudos de Casos e Controles , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Placebos/administração & dosagem , Prostaglandinas I/uso terapêutico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
14.
Urologiia ; (3): 50-55, 2020 Jun.
Artigo em Russo | MEDLINE | ID: mdl-32597586

RESUMO

AIM: To evaluate the efficacy and safety of combination therapy with 1-blocker and phosphodiesterase type 5 inhibitor (PDE5) in patients with benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). MATERIALS AND METHODS: The observational multicenter program involving 18 medical institutions in Moscow included 315 men aged 40-65 years with BPH and ED. The inclusion criteria were a total IPSS score more than 8 points, QoL score of more than 3 points and clinical manifestations of ED ( less or equal 20 points on the IIEF-5 score). All patients received combined pharmacotherapy with Alfuprost MP 10 mg/day and Viatail 50 mg/day (if necessary, the dose was increased to 100 mg/day) for 3 months. RESULTS: The combination therapy showed a high clinical efficiency and a favorable safety profile. Lower urinary tract symptoms improved by more than 60%, QoL increased by 64% and erectile function improved in more than 80% of patients. At the end of treatment, the average patient satisfaction score on the Likert scale was 4.2 (high and very high satisfaction), while doctors satisfaction with the clinical response of patients to the treatment was 4.35 points, which also corresponds to high and very high efficacy of therapy. CONCLUSION: Combination of Alfuprost MP 10 mg/day and Viatail 50 mg/day (100 mg, if necessary) can be considered as one of the best options for non-surgical treatment of patients with BPH and ED.


Assuntos
Disfunção Erétil , Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Adulto , Idoso , Carbolinas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Moscou , Inibidores da Fosfodiesterase 5/uso terapêutico , Estudos Prospectivos , Tadalafila , Resultado do Tratamento
15.
Nat Commun ; 11(1): 3191, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581298

RESUMO

Phosphodiesterase-5 (PDE5) inhibitors are suggested to have anti-tumor effects and to inhibit surgery-induced immunosuppression. We aimed to explore whether post-diagnostic use of PDE5 inhibitors was associated with a better prognosis among male patients with colorectal cancer (CRC) and the role of open surgery in the association. Here we show that post-diagnostic use of PDE5 inhibitors is associated with a decreased risk of CRC-specific mortality (adjusted HR = 0.82, 95% CI 0.67-0.99) as well as a decreased risk of metastasis (adjusted HR = 0.85, 95% CI 0.74-0.98). Specifically, post-operative use of PDE5 inhibitors has a strong anti-cancer effect. The reduced risk of metastasis is mainly due to distant metastasis but not regional lymphatic metastasis. PDE5 inhibitors have the potential to be an adjuvant drug for patients with CRC to improve prognosis, especially those who have undergone open surgery.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Causas de Morte , Quimioterapia Adjuvante , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Bases de Dados Genéticas , Relação Dose-Resposta a Droga , Humanos , Masculino , Metástase Neoplásica , Prognóstico , Sistema de Registros , Suécia/epidemiologia
16.
Rev Col Bras Cir ; 47: e20202469, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32491031

RESUMO

PURPOSE: The aim of this study was to evaluate the impact of penile rehabilitation in restoring erectile function in patients submitted to anterior resection of the rectum (ARR) or radical prostatectomy (RP), comparing the results between these two groups. MATERIALS AND METHODS: We performed a unicenter retrospective cohort study, on patients evaluated in our multidisciplinary oncosexology consultation, between January 2015 and January 2018, submitted to RP or ARR (males) and presenting sexual dysfunction. We evaluate the patient and oncologic characteristics, the type of sexual dysfunction, marital status, assessed the International Index of Erectile Function (IIEF-5) on the first and last consultation and the therapeutic approach. A statistical analysis was performed. RESULTS: A total of 55 patients were included, 60% (33) performed ARR and 40% (22) RP. Regarding the sexual dysfunction after surgery, erectile dysfunction (ED) was found in the majority of patients (>95%). On the initial IIEF-5 scoring, ARR and RP patients had, most frequently, severe or moderate ED (score 5-11), 78.8% and 59.1% respectively. When reassessed the IIEF-5 scoring of each patient during follow-up, there was an improvement in 69.7% of ARR patients and 72.7% of RP patients (p=0.81). Regarding the therapeutic approach, 84.8% of ARR patients used phosphodiesterase-5 inhibitors (PDE5I) exclusively, 3% used Alprostadil injection, while RP patients used 63.6% and 31.8%, respectively (p<0.05). CONCLUSIONS: Despite the technical differences of these surgeries, from the sexual point of view these patients benefit with a penile rehabilitation.


Assuntos
Alprostadil/uso terapêutico , Disfunção Erétil/reabilitação , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Disfunção Erétil/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ereção Peniana/efeitos dos fármacos , Prostatectomia/efeitos adversos , Reto , Estudos Retrospectivos
17.
JAMA Netw Open ; 3(6): e205323, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585017

RESUMO

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.


Assuntos
Peso ao Nascer , Término Precoce de Ensaios Clínicos , Retardo do Crescimento Fetal/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Doenças Placentárias/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Retardo do Crescimento Fetal/etiologia , Idade Gestacional , Humanos , Hipertensão Pulmonar/induzido quimicamente , Recém-Nascido , Doenças do Recém-Nascido/induzido quimicamente , Doenças do Recém-Nascido/prevenção & controle , Análise de Intenção de Tratamento , Masculino , Artéria Cerebral Média/fisiologia , Mortalidade Perinatal , Inibidores da Fosfodiesterase 5/efeitos adversos , Doenças Placentárias/fisiopatologia , Pré-Eclâmpsia/etiologia , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Fluxo Pulsátil , Citrato de Sildenafila/efeitos adversos , Artérias Umbilicais/fisiologia
19.
Proc Natl Acad Sci U S A ; 117(25): 14386-14394, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513693

RESUMO

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine ß-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.


Assuntos
Disfunção Erétil/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Envelhecimento/fisiologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Reposicionamento de Medicamentos , Disfunção Erétil/complicações , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Modelos Moleculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteoporose/complicações , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/uso terapêutico , Cultura Primária de Células , Tadalafila/química , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Dicloridrato de Vardenafila/química , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/uso terapêutico
20.
Am J Otolaryngol ; 41(4): 102561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32504853

RESUMO

OBJECTIVE: Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. It is applied to treatment of erectile dysfunction. PDE5 inhibitors dilate the penile blood vessels and cause prolonged erections. However, the effects of Levitra on human nasal mucosa are not yet fully explored. MATERIALS AND METHODS: We examined the effectiveness of Levitra on human nasal mucosa directly in vitro by testing: 1) effect on human nasal mucosa resting tension; 2) effect on contraction caused by 10-6 M methoxamine as a sympathetic mimetic; 3) effect of the drugs on electrically induced human nasal mucosa contractions. RESULTS: The results showed that addition of methoxamine to the incubation medium caused the nasal mucosa to contract in a dose-dependent manner. Addition of Levitra at doses of 10-4 M elicited a significant relaxation response to 10-6 M methoxamine-induced mucosa strip contraction. Levitra could not inhibit electrical field stimulation-induced spike contraction and had a minimal effect on the basal tension of nasal mucosa as the concentration increased. CONCLUSION: This study indicated that high concentrations of Levitra had a significant spasmolytic effect by antagonizing α-adrenoceptors. Moreover, nasal obstruction might not be relieved in patients suffering from erectile dysfunction and stuffy noses who were concomitant using α-adrenergic agonist and Levitra.


Assuntos
Reposicionamento de Medicamentos , Contração Isométrica/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Parassimpatolíticos , Inibidores da Fosfodiesterase 5/farmacologia , Dicloridrato de Vardenafila/farmacologia , Relação Dose-Resposta a Droga , Disfunção Erétil/tratamento farmacológico , Humanos , Técnicas In Vitro , Masculino , Metoxamina/farmacologia , Obstrução Nasal/diagnóstico por imagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Simpatomiméticos/farmacologia , Dicloridrato de Vardenafila/uso terapêutico
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