RESUMO
Approximately 12-18% of hypertensive patients are diagnosed with resistant hypertension (RH). The risk of having worse cardiovascular outcomes is twice higher in those patients. The low effectiveness of conventional antihypertensive drugs in RH emphasizes the need to evaluate complementary drug therapies to achieve blood pressure (BP) control. Previous studies have demonstrated that phosphodiesterase 5 (PDE-5) inhibitors improve hemodynamics and reduce BP on essential hypertension. So, the authors aimed to summarize current clinical trials-based evidence published concerning the use of PDE-5 inhibitors on BP, cardiovascular function, and hemodynamics of patients with RH. We searched MEDLINE, EMBASE, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry databases on May 15th, 2020 using pre-defined search terms. Two independent reviewers assessed and extracted data from clinical trials that evaluated the effect of PDE-5 inhibitors on BP. We have included five articles in this systematic review. Four of them developed a single-day protocol, while one has developed a 14-day study. The main findings indicate that PDE-5 inhibitors ameliorate BP, vascular hemodynamics, and diastolic function parameters. Some data demonstrated improvement of endothelial function, but it was not a consensus. The side effects seemed to be limited and well-tolerated. In brief, our systematic review highlights the potential of PDE-5 inhibitors as a therapeutic alternative in addition to the multiple-drug regime for RH. Larger studies are still needed to determine whether the beneficial effects of PDE-5 inhibitors on RH would be maintained with chronic administration.
Assuntos
Hipertensão/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Diástole/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Inibidores da Fosfodiesterase 5/metabolismoRESUMO
The crude drug ysypó hû (Adenocalymma marginatum DC., Bignoniaceae) is used traditionally by the Guarani of Eastern Paraguayan as a male sexual enhancer. The aim of the present study was to identify the main constituents of the crude drug and to evaluate the in vitro inhibitory activity towards the enzyme phosphodiesterase-5 (PDE-5). The main compounds were isolated by counter-current chromatography (CCC). The metabolites were identified by spectroscopic and spectrometric means. The chemical profiling of the extracts was assessed by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). The crude extract and main isolated compounds were tested for their PDE-5 inhibitory activity using commercial kits. The iridoid theviridoside and 4-hydroxy-1-methylproline were isolated as the main constituent of the crude drug. Four chlortheviridoside hexoside derivatives were detected for the first time as natural products. Chemical profiling by HPLC-MS/MS led to the tentative identification of nine iridoids, six phenolics, and five amino acids. The crude extracts and main compounds were inactive towards PDE-5 at concentrations up to 500 µg/mL. Iridoids and amino acid derivatives were the main compounds occurring in the Paraguayan crude drug. The potential of ysypó hû as a male sexual enhancer cannot be discarded, since other mechanisms may be involved.
Assuntos
Bignoniaceae/química , Iridoides/química , Inibidores da Fosfodiesterase 5/química , Extratos Vegetais/química , Aminoácidos/análise , Aminoácidos/química , Aminoácidos/isolamento & purificação , Bignoniaceae/metabolismo , Cromatografia Líquida de Alta Pressão , Misturas Complexas , Distribuição Contracorrente , Glicosídeos Iridoides , Iridoides/análise , Iridoides/isolamento & purificação , Paraguai , Fenóis/análise , Fenóis/química , Fenóis/isolamento & purificação , Inibidores da Fosfodiesterase 5/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Espectrometria de Massas em TandemRESUMO
Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells with various biological and therapeutic effects. Several PDE-5 inhibitors exist, with Tadalafil being one of the most commonly studied and used in clinical therapy. In this study, we applied Molecular Dynamics simulations coupled to the ABF (Adaptive Biasing Force) method to study the effect of the mutation on the Gln817 residue (Q817G). The results of the free energy profiles made clear that the affinity of the inhibitor for PDE-5 is dependent on the amino acid residue Gln817. The hydrogen bond made between the side chain of glutamine and the indole ring of Tadalafil results in the stabilization of the ligand in the catalytic site. Despite the prominent role of this interaction, it is important to highlight the contribution of other residues of the catalytic domain for the stabilization of the compound, due to the set of polar, hydrophobic and electrostatic interactions performed by specific amino acid residues.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/química , Tadalafila/química , Sítios de Ligação , Domínio Catalítico , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Inibidores da Fosfodiesterase 5/metabolismo , Tadalafila/metabolismo , TermodinâmicaRESUMO
The aim of the present study is to contribute to the scientific characterization of sildenafil citrate according to the Biopharmaceutics Classification System, following the World Health Organization (WHO) guidelines for biowaivers. The solubility and intestinal permeability data of sildenafil citrate were collected from literature; however, the experimental solubility studies are inconclusive and its "high permeability" suggests an API in the borderline of BCS Class I and Class II. The pH-solubility profile was determined using the saturation shake-flask method over the pH range of 1.2-6.8 at a temperature of 37 °C in aqueous media. The intestinal permeability was determined in rat by a closed-loop in situ perfusion method (the Doluisio technique). The solubility of sildenafil citrate is pH-dependent and at pH 6.8 the dose/solubility ratio obtained does not meet the WHO criteria for "high solubility." The high permeability values obtained by in situ intestinal perfusion in rat reinforce the published permeability data for sildenafil citrate. The experimental results obtained and the data available in the literature suggest that sildenafil citrate is clearly a Class II of BCS, according to the current biopharmaceutics classification system and WHO guidance.
Assuntos
Absorção Intestinal/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/classificação , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/classificação , Citrato de Sildenafila/farmacologia , Animais , Biofarmácia/métodos , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Permeabilidade , Inibidores da Fosfodiesterase 5/metabolismo , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/metabolismo , Solubilidade , Equivalência TerapêuticaRESUMO
We have previously demonstrated an impairment of intraplatelet L-arginine-nitric oxide-cGMP pathway in major depression (MD) associated to platelet dysfunction. Here, we evaluated arginase pathway and phosphodiesterase 5 (PDE5) expression in platelets, systemic and intraplatelet oxidative status in untreated MD patients, and their effects on platelet aggregation. Blood samples were collected from 22 treatment naive MD patients (31 ± 2 yr) and 27 healthy subjects (33 ± 2 yr). MD patients presented with an activation of platelet arginase II, which competes with L-arginine for the production of nitric oxide (NO). An increase in protein carbonylation, overexpression of NADPH oxidase and PDE5, an enzyme that inactivates cGMP, was observed in platelets from MD patients compared to controls. In this context, platelet hyperaggregability was found in MD patients. On the other hand, antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase activities in serum and in platelets did not differ between groups. The increased activation of intraplatelet arginase and platelet aggregability, in addition to an overexpression of PDE5 and oxidative stress may contribute to alterations in L-arginine-NO-cGMP pathway and in platelet function, and consequently to the increased thrombotic risk in MD.