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1.
J Sci Food Agric ; 100(1): 315-324, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525262

RESUMO

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Captopril/química , Hipertensão/tratamento farmacológico , Peptídeos/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Ciclídeos , Digestão , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Endogâmicos SHR
2.
AAPS PharmSciTech ; 20(8): 321, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650430

RESUMO

Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIFmod of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.


Assuntos
Liberação Controlada de Fármacos , Indapamida/administração & dosagem , Indapamida/metabolismo , Absorção Intestinal/efeitos dos fármacos , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Cães , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Absorção Intestinal/fisiologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade , Comprimidos/administração & dosagem , Comprimidos/química , Comprimidos/farmacocinética
3.
Clin Drug Investig ; 39(11): 1031-1044, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31420854

RESUMO

BACKGROUND: The combination of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor having different biological targets has become an integral part of the treatment of pulmonary arterial hypertension; however, several clinical studies have reported conflicting results. OBJECTIVE: The objective of this meta-analysis was to evaluate the effect of an endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination in pulmonary arterial hypertension. METHODS: After performing a comprehensive literature search in MEDLINE, Cochrane and the International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from seven relevant articles (publications till December 2018). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed in the selection, analysis and reporting of findings. The odds ratio and mean difference were calculated to estimate the difference in clinical worsening, 6-minute walking distance, pulmonary vascular resistance and N-terminal pro-brain natriuretic peptide between the groups. Quality assessment was performed using the risk of bias assessment tool and a meta-regression for probable variables affecting effect size. RESULTS: The random-effect model analysis revealed an odds ratio of 0.56 [95% confidence interval (CI) 0.41-0.76; p = 0.0002] for clinical worsening, mean difference of 15.64 (95% CI 2.67-28.61; p = 0.02) for 6-minute walking distance, - 1.66 (95% CI - 3.82 to 0.50; p = 0.13) for pulmonary vascular resistance and - 21.04 (95% CI - 26.87 to - 15.22; p < 0.00001) for N-terminal pro-brain natriuretic peptide. The meta-regression showed no statistically significant association between the dose and duration of treatment and outcomes (odds ratio of clinical worsening and mean difference of 6-minute walking distance). CONCLUSIONS: In pulmonary arterial hypertension, endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination therapy significantly improved 6-minute walking distance, clinical worsening and N-terminal pro-brain natriuretic peptide compared with the monotherapy but did not offer any advantage in improving pulmonary vascular resistance. PROSPERO REGISTRATION NO: CRD42018091133.


Assuntos
Antagonistas dos Receptores de Endotelina/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , /tratamento farmacológico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Ensaios Clínicos como Assunto/métodos , Quimioterapia Combinada , Antagonistas dos Receptores de Endotelina/metabolismo , Humanos , Pulmão/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , /metabolismo , Resultado do Tratamento
4.
Toxicol Lett ; 315: 9-13, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408697

RESUMO

Cytochrome P450 mediated metabolism is the rate-limiting step of elimination for many drugs. CYP3A4 is the most abundant hepatic isoform and CYP3A4/5 metabolize the largest fraction of drugs. Pharmacogenetic studies have not been able to characterize population variability in CYP3A4 activity because few variant alleles associated with aberrant enzyme activity have been found. Substrate probes such as midazolam and testosterone have been utilized in-vivo and in-vitro to determine catalytic activity of these enzymes, but they suffer from several limitations. Eplerenone, an aldosterone antagonist, is also metabolized by CYP3A enzymes, and it has the potential to be an excellent substrate probe for CYP3A4/5. Eplerenone's primary metabolite, 6 beta-hydroxyeplerenone is formed preferentially via CYP3A4, however, the relative contribution of CYP3A5 to the 21-hydroxyeplerenone metabolite formation is unknown. Through in-vitro microsomal incubations with recombinant CYP3A4 and CYP3A5 enzymes, we identified their relative contributions to 21-hydroxyeplerenone metabolism. The 21-hydroxy metabolite is formed preferentially via CYP3A5 Vmax/KM (3.3) versus CYP3A4 Vmax/KM (1.9). Based on these findings, eplerenone has the potential to serve as an in-vivo substrate probe for CYP3A4 by monitoring 6-beta-hydroxy metabolite formation as well as CYP3A4/5 by monitoring 21-hydroxy metabolite formation.


Assuntos
Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/farmacologia , Eplerenona/metabolismo , Eplerenona/farmacologia , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Humanos , Microssomos/metabolismo
5.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336853

RESUMO

Angiotensin I-converting enzyme (ACE) is a paramount therapeutic target to treat hypertension. ACE inhibitory peptides derived from food protein sources are regarded as safer alternatives to synthetic antihypertensive drugs for treating hypertension. Recently, marine organisms have started being pursued as sources of potential ACE inhibitory peptides. Marine organisms such as fish, shellfish, seaweed, microalgae, molluscs, crustaceans, and cephalopods are rich sources of bioactive compounds because of their high-value metabolites with specific activities and promising health benefits. This review aims to summarize the studies on peptides from different marine organisms and focus on the potential ability of these peptides to inhibit ACE activity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Organismos Aquáticos/metabolismo , Biossíntese Peptídica , Peptídeos/metabolismo , Peptídeos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Biomarcadores , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Peptídeos/química
6.
Anal Bioanal Chem ; 411(22): 5867-5876, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286177

RESUMO

It has been reported that antidepressant, anxiolytic and antihypertensive drugs alter the behavior and reproduction of the microcrustacean Daphnia magna at very low concentrations. However, there is little evidence for how these drugs act on their neurotransmitter targets. A method based on hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry has been developed and applied for the first time using D. magna extracts and validated by studying the changes in the levels of a suite of neurotransmitters caused by five different neuroactive pharmaceuticals (fluoxetine, venlafaxine, carbamazepine, propranolol, and diazepam) dosed at 100 ng/L. Sample extraction and chromatographic and detection conditions were optimized for accurate detection of the selected neurotransmitters in whole D. magna organisms. The method allowed the simultaneous quantification of eight neurotransmitters belonging to six neuroendocrine systems: the dopaminergic, adrenergic, GABAergic, serotoninergic, histaminergic, and cholinergic systems. Neurotransmitters were eluted with a ZIC-HILIC column and quantified by tandem mass spectrometry in positive electrospray ionization mode performed in multiple reaction monitoring mode. All method validation assays (i.e., quality controls for linearity, sensitivity, accuracy, precision, stability, recovery, matrix effect, and carryover) were compliant with the standard requirements for similar analysis. Exposure to fluoxetine enhanced serotonin concentrations, whereas exposure to diazepam decreased the levels of dopamine, and exposure to propranolol increased the levels of norepinephrine. Exposure to both propranolol and diazepam decreased the levels of histamine. The results show the usefulness of this approach for environmental neurotoxicity studies. Graphical abstract.


Assuntos
Ansiolíticos/metabolismo , Antidepressivos/metabolismo , Anti-Hipertensivos/metabolismo , Cromatografia Líquida/métodos , Daphnia/metabolismo , Neurotransmissores/metabolismo , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/metabolismo , Animais , Daphnia/crescimento & desenvolvimento , Padrões de Referência , Reprodutibilidade dos Testes
7.
Eur J Pharmacol ; 858: 172482, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31233749

RESUMO

In the present study, we report that neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) relaxes the superior mesenteric artery in a concentration dependent manner (pD2 value 5.392 ±â€¯0.04; n = 8 for endothelium intact and 5.204 ±â€¯0.03; n = 8 for endothelium denuded mesenteric rings, respectively). The relaxation response of neolignan1 was found to be endothelium independent and sensitive to 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-on (ODQ; 1 µM) and tetraethyl ammonium (TEA; 1 mM). In-silico studies showed good LibDock score (92.66) of neolignan1 with BKCa channel and are in well corroboration with ex-vivo study. Further, neolignan1 significantly decreased the systolic blood pressure, diastolic blood pressure and mean arterial pressure in the Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 50 mg/kg) treated Wistar rats at the dose of 30 and 100 mg/kg given once orally for 15 days. In addition, neolignan1 is well tolerated up to 100 mg/kg when given as a repeated dose, once orally for 28 days in Swiss albino mice. Neolignan1 was well absorbed from oral route, reached peak at 4 h and eliminated below detection level by 12 h after administration. Our present study concludes that neolignan1 produced relaxation in superior mesenteric artery by opening of BKCa channel and produced significant antihypertensive activity in L-NAME treated Wistar rats and was well tolerated by the experimental animal.


Assuntos
Anti-Hipertensivos/farmacologia , Ácidos Cumáricos/farmacologia , Lignanas/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacocinética , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/farmacocinética , Feminino , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Lignanas/metabolismo , Lignanas/farmacocinética , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
8.
Clin Lab ; 65(5)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115220

RESUMO

BACKGROUND: CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Asian patients. Utilizing an efficient method for identifying the CYP2D6*10 genotypes is clinically important for evaluating the pharmacokinetic effect of administration of metoprolol. This study attempted to evaluate the effectiveness of the two methods used to detect the rs1065852 and rs1135840 SNPs of the CYP2D6*10 gene. METHODS: Blood samples were processed for the collection of genomic DNA from 198 subjects across Chinese population, and detection of CYP2D6*10 (rs1065852 and rs1135840) was performed using the PyroMark Q24 pyrose-quencing and matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF MS). The discordant results were further validated with Sanger sequencing. We eventually attempted to assess some features of these two methods including reliability, rapidness, being appropriate, and cost-effectiveness. RESULTS: Genotyping of rs1065852 and rs1135840 detected by MALDI-TOF MS were concordant with those identified by PyroMark Q24 pyrosequencing in all 198 (100%) individuals. The hands-on-time and the turnaround time were shorter in the PyroMark Q24 pyrosequencing method than in the MALDI-TOF MS method for SNP of CYP2D6*10. In terms of being cost-effective and high-throughput, the MALDI-TOF MS method outperformed the PyroMark Q24 pyrosequencing method. CONCLUSIONS: CYP2D6*10 genotypes detected by PyroMark Q24 pyrosequencing and MALDI-TOF-MS showed that both methods were reliable, rapid, appropriate, and cost-effective methods. These methods are valuable for clinical applications.


Assuntos
Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Idoso , Anti-Hipertensivos/sangue , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , China , Análise Custo-Benefício , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Técnicas de Genotipagem/economia , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Metoprolol/sangue , Metoprolol/metabolismo , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
9.
J Food Sci ; 84(5): 1170-1179, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30997940

RESUMO

High blood pressure can lead to cardiovascular diseases. The objective of this work was to obtain protein hydrolysates with antihypertensive potential from chia oil industry meal byproduct. Chia seed protein isolates (CPIs) were obtained from chia seed meal byproduct. CPI was hydrolyzed using different proteases (alcalase, pepsin, trypsin, and α-chymotrypsin) and their biological potential was evaluated using in vitro and in silico approaches. Chia seed pepsin protein hydrolysate showed the highest angiotensin-converting enzyme inhibition potential IC50 of 0.128 mg/mL (P < 0.05) compared to the rest of hydrolysates. Peptide sequence LIVSPLAGRL presented the lowest predicted binding energy and highest inhibition potential (-9.5 kcal/mol) compared to other sequenced peptides and positive controls (captopril and lisinopril). Chia peptides showed potential to block angiotensin-converting enzyme by interacting with its catalytic site. Chia seed oil industry meal byproduct could be used as an inexpensive source of protein and bioactive peptides with antihypertensive potential. PRACTICAL APPLICATION: This research shows an upcycling alternative for chia oil industry byproduct. Chia meal is a rich source of protein and can be used to generate bioactive peptides with antihypertensive potential. Chia protein isolate was obtained from chia meal and hydrolyzed using different enzymes, pepsin showed the highest antihypertensive potential. Chia meal waste could be a low-cost source of protein and protein hydrolysates that could be used as a food ingredient with antihypertensive potential.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Pepsina A , Peptidil Dipeptidase A , Proteínas de Plantas , Salvia/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Domínio Catalítico , Pepsina A/química , Pepsina A/metabolismo , Pepsina A/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/farmacologia , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Hidrolisados de Proteína/farmacologia
10.
Drug Deliv ; 26(1): 147-157, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30822171

RESUMO

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Fluorcarbonetos/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Água/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/metabolismo , Fluorcarbonetos/metabolismo , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/metabolismo , Masculino , Fenilpropionatos/administração & dosagem , Fenilpropionatos/metabolismo , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/metabolismo , Piridazinas/administração & dosagem , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Água/metabolismo
11.
Food Chem ; 282: 109-119, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711094

RESUMO

Kefir, a probiotic beverage prepared from fermented milk, has been associated with antihypertensive activity. However, the bioactive molecules responsible for this activity still remain unclear. Therefore, in this study we aim to evaluate the mechanisms of the antihypertensive effects of Kefir in the two-kidney one-clip hypertension model, and to bioprospect for bioactive peptides identified by proteomic methodologies. Treatment with Kefir was performed via gavage, and resulted in a 37 mmHg reduction in systolic arterial pressure and 19% inhibition of angiotensin converting enzyme (ACE) activity. For the proteopeptidomic study, the protein extract of Kefir beverage and non-fermented bovine milk were analysed by MALDI-TOF mass spectrometry, and their tryptic digestion products sequenced via Shotgun proteomics (Q-Exactive mass spectrometer). A list of 35 peptides with potential hypertensive activity due to ACE inhibition were identified. These results demonstrate the benefits of Kefir products, and may guide the design of new antihypertensive drugs.


Assuntos
Anti-Hipertensivos/análise , Kefir/análise , Peptídeos/análise , Proteômica/métodos , Animais , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/metabolismo , Sítios de Ligação , Bovinos , Leite/química , Modelos Biológicos , Simulação de Acoplamento Molecular , Peptídeos/isolamento & purificação , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pletismografia , Estrutura Terciária de Proteína , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
Recent Pat Biotechnol ; 13(3): 239-248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747089

RESUMO

BACKGROUND: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. OBJECTIVE: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. METHODS: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. RESULTS: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. CONCLUSION: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Moringa oleifera/química , Peptidil Dipeptidase A/química , Tiocarbamatos/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/metabolismo , Captopril/química , Captopril/metabolismo , Domínio Catalítico , Enalapril/química , Enalapril/metabolismo , Expressão Gênica , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Cinética , Simulação de Acoplamento Molecular , Patentes como Assunto , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Especificidade por Substrato , Termodinâmica , Tiocarbamatos/isolamento & purificação , Tiocarbamatos/metabolismo
13.
Drug Dev Ind Pharm ; 45(1): 63-66, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30230390

RESUMO

OBJECTIVE: To evaluate, for the first time, the use of SCC4 cell monolayers as an alternative sublingual barrier model and study the influence of nanoencapsulation on carvedilol transport across SCC4 cell monolayers. SIGNIFICANCE: The sublingual cavity is an interesting route for administration of drugs with limited oral bioavailability due to hepatic first pass metabolism. By this route, the drug is directly absorbed into blood circulation. In this sense, mucoadhesive carvedilol-loaded nanocapsules (CAR-NC) were previously proposed for the administration of this drug by sublingual route. Carvedilol is used for cardiovascular diseases and suffers metabolism in liver when orally administrated. Nanoencapsulation of carvedilol controlled its permeation across porcine sublingual mucosa. METHODS: Carvedilol-loaded cationic nanocapsules were prepared by interfacial deposition of a preformed polymer. Drug permeation studies were carried out in Transwell® inserts. The integrity of cell monolayers after the drug transport was assessed by transepithelial electric resistance. Compatibility of the CAR-NC with the SCC4 cells was evaluated by the Sulforhodamine B assay. RESULTS: The drug permeated the cell monolayer by a controlled way when nanoencapsulated and this profile had a linear relation with those observed in porcine sublingual mucosa. The integrity of the cell monolayer was maintained after drug permeation and CAR-NC was no cytotoxic to SCC4 cells. CONCLUSION: Nanoencapsulated carvedilol permeated by a controlled and safe way by SCC4 cell monolayer. SCC4 cells monolayers may be used as in vitro model for sublingual drug transport studies in the development of novel formulations.


Assuntos
Anti-Hipertensivos/síntese química , Anti-Hipertensivos/metabolismo , Carvedilol/síntese química , Carvedilol/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Nanocápsulas/química , Administração Sublingual , Anti-Hipertensivos/administração & dosagem , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Carvedilol/administração & dosagem , Humanos , Nanocápsulas/administração & dosagem , Células Tumorais Cultivadas
14.
J Pharm Biomed Anal ; 164: 326-336, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30412806

RESUMO

Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literature review indicates lack of comprehensive reports on its metabolic fate. The present study reports the in vivo and in vitro identification and characterization of metabolites of riociguat, using high-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. In vitro studies were conducted by incubating the drug in human and rat liver microsomes in presence of respective cofactors. In vivo studies were undertaken by oral administration of suspension of drug to male Sprague-Dawley rats followed by collection of urine, feces and blood at specific intervals. A total of 18 metabolites were observed in in vivo and in vitro matrices which includes hydroxyl, N-oxide, desmethyl, defluorinated hydroxyl, glucuronides and N-acetyl cysteine conjugates. Presence of N-acetyl cysteine conjugates strongly points towards the formation of a reactive metabolite intermediate trapped through N-acetyl cysteine and can be considered a matter of concern as the reactive metabolites have been known to manifest toxicities. Their presence was mimicked in in vitro samples as well. The toxicological properties of drug and metabolites were evaluated by using ADMET Predictor ™ software.


Assuntos
Anti-Hipertensivos/análise , Guanilato Ciclase/antagonistas & inibidores , Pirazóis/análise , Pirimidinas/análise , Software , Acetilcisteína/química , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/toxicidade , Biotransformação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Simulação por Computador , Mineração de Dados , Humanos , Masculino , Microssomos Hepáticos , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/toxicidade , Pirimidinas/administração & dosagem , Pirimidinas/metabolismo , Pirimidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
15.
Drug Metab Pharmacokinet ; 34(1): 108-110, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30415897

RESUMO

Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats. The rats were orally administered 0.08 mg/kg of AML, with or without 33 mg/kg of activated charcoal, under the fasted or fed condition and the plasma concentration profiles of AML were monitored. For the fed group, the standard breakfast used in clinical studies was smashed and administered at a dose of 11 g/kg. The AUC value of AML under the fasted condition was significantly decreased to 24.8% by coadministration of activated charcoal. On the other hand, activated charcoal moderately decreased the AUC value of AML to 74.8% under the fed condition. These results suggest that the extent of drug interactions caused by activated charcoal is attenuated by food intake.


Assuntos
Anlodipino/metabolismo , Carvão Vegetal/metabolismo , Interações de Medicamentos/fisiologia , Ingestão de Alimentos/fisiologia , Interações Alimento-Droga/fisiologia , Absorção Gastrointestinal/fisiologia , Anlodipino/farmacologia , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Carvão Vegetal/farmacologia , Absorção Gastrointestinal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
16.
Environ Sci Pollut Res Int ; 26(5): 4426-4437, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29971747

RESUMO

In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED)-type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42 mA/cm2 after 90 min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90 min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (•OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to-metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system.


Assuntos
Eletrodos , Losartan/química , Valsartana/química , Poluentes Químicos da Água/química , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Biodegradação Ambiental , Ácido Cítrico/química , Difusão , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Radical Hidroxila/química , Ferro/química , Iluminação/instrumentação , Iluminação/métodos , Losartan/metabolismo , Oxirredução , Tartaratos/química , Valsartana/metabolismo , Poluentes Químicos da Água/metabolismo
17.
J Agric Food Chem ; 66(51): 13414-13422, 2018 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-30511571

RESUMO

Angiotensin-converting enzyme (ACE) inhibitory peptides derived from food protein exhibited antihypertensive effects by inhibiting ACE activity. In this work, the interaction between ACE inhibitory peptide GMKCAF (GF-6) and ACE was studied by isothermal titration calorimetry (ITC), molecular docking, ultraviolet absorption spectroscopy, fluorescence spectroscopy, and circular dichroism spectroscopy. Experimental results revealed that the binding of GF-6 to ACE was a spontaneous exothermic process driven by both enthalpy and entropy. The interaction occurred via a static quenching mechanism and involved the alteration of the conformation of ACE. In addition, ITC and molecular docking results indicated binding of GF-6 to ACE via multiple binding sites on the protein surface. This study could be deemed helpful for the better understanding of the inhibitory mechanism of ACE inhibitory peptides.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Proteínas de Peixes/química , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Sítios de Ligação , Proteínas de Peixes/metabolismo , Peixes , Cinética , Simulação de Acoplamento Molecular , Peptídeos/química , Peptidil Dipeptidase A/metabolismo , Espectrometria de Fluorescência , Suínos , Termodinâmica
18.
Mar Drugs ; 16(10)2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279337

RESUMO

Antihypertensive peptides (AHTPs) are a group of small peptides with the main role to block key enzymes or receptors in the angiotensin genesis pathway. A great number of AHTPs have been isolated or digested from natural food resources; however, comprehensive studies on comparisons of AHTPs in various species from the perspective of big data are rare. Here, we established a simplified local AHTP database, and performed in situ mapping for high throughput identification of AHTPs with high antihypertensive activity from high-quality whole proteome datasets of 18 fish species. In the 35 identified AHTPs with reported high activity, we observed that Gly-Leu-Pro, Leu-Pro-Gly, and Val-Ser-Val are the major components of fish proteins, and AHTP hit numbers in various species demonstrated a similar distributing pattern. Interestingly, Atlantic salmon (Salmo salar) is in possession of far more abundant AHTPs compared with other fish species. In addition, collagen subunit protein is the largest group with more matching AHTPs. Further exploration of two collagen subunits (col4a5 and col8a1) in more fish species suggested that the hit pattern of these conserved proteins among teleost is almost the same, and their phylogeny is consistent with the evolution of these fish species. In summary, our present study provides basic information for the relationship of AHTPs with fish proteins, which sheds light on rapid discovery of marine drugs or food additives from fish protein hydrolysates to alleviate hypertension.


Assuntos
Anti-Hipertensivos/metabolismo , Proteínas de Peixes/metabolismo , Peixes/metabolismo , Peptídeos/metabolismo , Proteoma/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Filogenia , Hidrolisados de Proteína/metabolismo , Salmo salar/metabolismo , Alimentos Marinhos
19.
BMC Geriatr ; 18(1): 238, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30290768

RESUMO

BACKGROUND: Inappropriate use of medications, particularly among minority older adults with co-morbidity, remains a major public health concern. The American Geriatrics Society (AGS) reports that Potentially Inappropriate Medication (PIM) continues to be prescribed for older adults, despite evidence of poor outcomes. The main objective of this study was to examine the prevalence of PIM use among underserved non-institutionalized hypertensive older African-American adults. Furthermore, this study examines potential correlations between PIM use and the number and type of chronic conditions. METHODS: This cross-sectional study is comprised of a convenience sample of 193 hypertensive non-institutionalized African-American adults, aged 65 years and older recruited from several senior housing units located in underserved areas of South Los Angeles. The updated 2015 AGS Beers Criteria was used to identify participants using PIMs. RESULTS: Almost one out of two participants had inappropriate medication use. While the average number of PIMs taken was 0.87 drugs, the range was from one to seven medications. Almost 23% of PIMs were due to drugs with potential drug-drug interactions. The most common PIM was the use of proton pump inhibitors (PPI) and Central Nervous System (CNS) active agents. Nearly 56% of PIMs potentially increased the risk of falls and fall-associated bone fractures. The use of PIMs was significantly higher among participants who reported a higher number of chronic conditions. Nearly 70% of participants with PIM use reported suffering from chronic pain. CONCLUSIONS: The major reason for high levels of polypharmacy, PIMs, and drug interactions is that patients suffer from multiple chronic conditions. But it may not be possible or necessary to treat all chronic conditions. Therefore, the goals of care should be explicitly reviewed with the patient in order to determine which of the many chronic conditions has the greatest impact on the life goals and/or functional priorities of the patient. Those drugs that have a limited impact on the patient's functional priorities and that may cause harmful drug-drug interactions can be reduced or eliminated, while the remaining medications can focus on the most important functional priorities of the patient.


Assuntos
Afro-Americanos , Anti-Hipertensivos/efeitos adversos , Interações de Medicamentos/fisiologia , Hipertensão/tratamento farmacológico , Prescrição Inadequada/tendências , Lista de Medicamentos Potencialmente Inapropriados/tendências , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/metabolismo , Doença Crônica , Comorbidade , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Prescrição Inadequada/prevenção & controle , Masculino , Polimedicação , Prevalência
20.
Food Funct ; 9(10): 5230-5237, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30206615

RESUMO

Hypertension is known as an important factor in cardiovascular disease. An angiotensin-I-converting enzyme (ACE) inhibitor is one of the synthetic drugs that is widely used to control hypertension. Here, we have prepared and investigated the ACE inhibitory peptide from Ruditapes philippinarum fermented with Bacillus natto. The fermented product obtained under optimized fermentation conditions exhibited ACE inhibitory activity. The ACE inhibitory peptides were purified by ultrafiltration, gel filtration chromatography and RP-HPLC, sequentially. A novel peptide with high ACE inhibitory activity (IC50 of 8.16 µM) was isolated and the amino acid sequence was identified to be Val-Ile-Ser-Asp-Glu-Asp-Gly-Val-Thr-His (VISDEDGVTH) by LC-MS/MS. The Lineweaver-Burk plots suggested that VISDEDGVTH acts as a competitive inhibitor against ACE. Our in vitro study indicated the stability of VISDEDGVTH against gastrointestinal proteases. An in vivo study in rats proved the significant anti-hypertension effect of the peptide. Furthermore, the cellular mechanism of VISDEDGVTH moderating hypertension was investigated. We found that VISDEDGVTH enhanced the release of NO, inhibited the secretion of EF-1, and scavenged ROS in human vascular endothelial cells. Our study suggests that VISDEDGVTH serves as an anti-hypertension and anti-inflammatory drug and as a beneficial ingredient in functional foods and pharmaceuticals.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Bacillus/metabolismo , Bivalves/microbiologia , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/metabolismo , Bivalves/química , Bivalves/metabolismo , Fermentação , Humanos , Hipertensão/enzimologia , Masculino , Mapeamento de Peptídeos , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley
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