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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
3.
J Cancer Res Clin Oncol ; 145(6): 1495-1507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028540

RESUMO

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Aprepitanto/administração & dosagem , Aprepitanto/farmacologia , Auranofina/administração & dosagem , Auranofina/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Captopril/administração & dosagem , Captopril/farmacologia , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Camundongos , Camundongos SCID , Minociclina/administração & dosagem , Minociclina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Sertralina/administração & dosagem , Sertralina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Biomolecules ; 9(4)2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934759

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect of combined intake of a high dose of aspirin, atorvastatin, captopril and metformin on oxidative stress in the brain cortex and hippocampus of streptozotocin (STZ)-induced diabetic rats. MATERIAL AND METHODS: Rats were randomly divided into the following 11 groups: control and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg) and/or atorvastatin (AT, 40 mg/kg) as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA) and (D + M + C + AT + ASA). The rats in treatment groups received drugs by gavage daily for six weeks. Serum lipid profile and levels of oxidative markers in the brain cortex and hippocampus tissues were evaluated. RESULTS: The levels of malondialdehyde in the brain cortex and hippocampus in all the treated groups decreased significantly (p < 0.05). There was a significant increase in the total thiol concentration as well as catalase activity in treated rats in (M + AT), (M + C + ASA), (M + C + AT), (M + AT + ASA) and (M + C + AT + ASA) groups in cortex and hippocampus in comparison with the diabetic rats (p < 0.05). Also, the superoxide dismutase activity in all treated rats with medications was significantly increased compared to the diabetic rats (p < 0.05⁻0.01). CONCLUSION: Our findings showed that the combined use of high-dose aspirin, metformin, captopril and atorvastatin potentiated their antioxidant effects on the brain, and hence could potentially improve cognitive function with their neuroprotective effects on hippocampus.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Atorvastatina/administração & dosagem , Atorvastatina/uso terapêutico , Captopril/administração & dosagem , Captopril/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar , Estreptozocina
5.
Vet J ; 245: 7-11, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819428

RESUMO

The purpose of this study was to clarify how alacepril in amounts greater than those recommended on the product labeling approved by drug regulatory agencies affects left atrial pressure (LAP) and central aortic pressure in dogs with experimentally induced mitral valve regurgitation (MR). Six healthy Beagle dogs were surgically induced for MR and received alacepril at either 1.5mg/kg/12-h (3.0mg/kg/day) or 3.0mg/kg/12-h (6.0mg/kg/day) per one administration for seven days. After a four-week washout period, another dosage was administrated as a crossover study. Dogs were randomised to receive 3.0mg/kg/day or 6.0mg/kg/day first. LAP and central systolic (SAP), mean (MAP), and diastolic (DAP) aortic pressure were measured for 24-h before and during the administration of alacepril. The earliest decreases in SAP, MAP, and DAP with 6.0mg/kg/day were observed on days 4, 4, and 5, respectively. With 3.0mg/kg/day, the earliest decrease in DAP was observed on day 7. The maximum LAP was decreased on days 5 and 7 with 6.0mg/kg/day. The mean LAP was decreased on day 7 with 6.0mg/kg/day. In conclusion, the administration of alacepril at 6.0mg/kg/day reduced the LAP and central aortic pressure within several days.


Assuntos
Pressão Arterial/efeitos dos fármacos , Pressão Atrial/efeitos dos fármacos , Captopril/análogos & derivados , Doenças do Cão/tratamento farmacológico , Insuficiência da Valva Mitral/tratamento farmacológico , Insuficiência da Valva Mitral/veterinária , Inibidores da Enzima Conversora de Angiotensina , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Estudos Cross-Over , Doenças do Cão/fisiopatologia , Cães , Feminino , Masculino , Insuficiência da Valva Mitral/fisiopatologia
6.
Eur J Pharm Sci ; 130: 215-224, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30716381

RESUMO

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.


Assuntos
Captopril/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/farmacocinética , Mucosa Bucal/efeitos dos fármacos , Absorção pela Mucosa Oral/efeitos dos fármacos , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Animais , Captopril/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsificantes/administração & dosagem , Mucosa Bucal/metabolismo , Análise Multivariada , Absorção pela Mucosa Oral/fisiologia , Suínos
7.
Eur J Pharm Sci ; 132: 163-173, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30695689

RESUMO

The present study aimed to investigate the potential of zein (a protein obtained from corn) for development of gastroretentive floating tablets for the first time. A compression coated tablet design with outer floating layer and inner drug containing layer was followed to achieve floating over gastric fluid with sustained release of drug. Captopril was used as a model drug for this purpose. Eight formulations were developed and the influence of different components on drug release and floating behavior was evaluated. The drug in coating layer was found to be released at faster rate while sustained release behavior was observed from core layer. In vivo pharmacokinetic studies on rabbits showed significant increase in bioavailability and mean residence time (MRT). Moreover, radiographic study exhibited gastric retention of prepared tablets >12 h. In conclusion, zein can be used for development of gastroretentive floating tablets and by adjusting amount of different formulation factors, desired drug release rate can be achieved.


Assuntos
Captopril/química , Captopril/farmacocinética , Desenho de Drogas , Mucosa Gástrica/metabolismo , Zeína/química , Administração Oral , Animais , Disponibilidade Biológica , Captopril/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Absorção Gástrica , Coelhos , Solubilidade , Propriedades de Superfície , Comprimidos
8.
Biol Pharm Bull ; 42(1): 116-122, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30369530

RESUMO

The emulsion prepared with ß-cyclodextrin as an emulsifier (ßCDE) is considered to be a Pickering emulsion. We examined the characteristics of ßCDEs using captopril (CP) as a model drug, and studied the in vitro skin permeation of CP from ßCDEs through hairless mouse skin. The stability of ßCDE was increased with increasing ßCD concentration and conversely decreased with increasing CP concentration. The yield stress value from the rheological measurement results was suggested to be one of the factors determining the stability of the ßCDE, and ßCDEs with higher yield stress values were more stable. We found that the skin permeability of CP could be improved by using ßCDE with isopropyl myristate as the oil phase and that the flux of CP depended on the free CP concentration in the water phase of ßCDE.


Assuntos
Ciclodextrinas/administração & dosagem , Ciclodextrinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/administração & dosagem , Emulsificantes/metabolismo , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Captopril/administração & dosagem , Captopril/metabolismo , Camundongos , Camundongos Pelados , Técnicas de Cultura de Órgãos , Absorção Cutânea/fisiologia
9.
Free Radic Biol Med ; 129: 107-115, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30227269

RESUMO

S-nitrosocaptopril (CapNO) possesses dual capacities of both Captopril and an NO donor with enhanced efficacy and reduced side effects. CapNO crystals are difficult to make due to its unstable S-NO bond. Here, we report a novel stable S-nitrosocaptopril monohydrate (CapNO·H2O) that is stabilized by intermolecular five-membered structure, where one H of H2O forms a hydrogen bond with O- of the stable resonance zwitterion Cap-S+=N-O-, and the O in H2O forms the dipole-dipole interaction with S+ through two unpaired electrons. With the chelation and common ion effect, we synthesized and characterized CapNO·H2O that is stable at 4 °C for 180 days and thereafter without significant degradation. Compared to Captopril, CapNO showed direct vasorelaxation and beneficial effect on PAH rats, and could be self-assembled in rat stomach when Captopril and NaNO2 were given separately. This novel CapNO·H2O with low entropy paves an avenue for its clinical trials and commercialization.


Assuntos
Anti-Hipertensivos/farmacologia , Captopril/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/síntese química , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiopatologia , Captopril/administração & dosagem , Captopril/síntese química , Captopril/química , Captopril/metabolismo , Captopril/farmacologia , Cristalização , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Doadores de Óxido Nítrico/síntese química , Ratos , Ratos Sprague-Dawley , Nitrito de Sódio/administração & dosagem , Nitrito de Sódio/química , Nitrito de Sódio/metabolismo , Estômago/química , Técnicas de Cultura de Tecidos , Resistência Vascular/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/síntese química
10.
Biol Pharm Bull ; 41(12): 1837-1842, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30259884

RESUMO

We show that a lectin like protein from the mushroom Agaricus bisporus (LSMT) is capable to permeate the epithelial monolayer barrier of the intestine ex vivo. The protein is not toxic or immunogenic upon prolonged administration and elevated dose in mice. Thus, it could be a candidate as a drug carrier for oral administration. However, its permeability should be tested after the protein has been modified, mimicking the condition in which it is used as a drug carrier. The protein was conjugated to captopril, the selected model of a Biopharmaceutical Classification System (BCS) class III drug, with high solubility but poor permeability. The drug was conjugated to LSMT that had been modified with 4-succinimidyloxycarbonyl-alpha-methyl-2-pyridyldithiotoluene (SMPT) as a linker. The success of LSMT modification was confirmed with TLC and MS; the latter also indicated the amount of captopril molecule linked. The modified LSMT could permeate through the intestinal monolayer barrier, and thus could be absorbed in the intestine after modification. The modified protein appears to remain stable after incubation in simulated gastrointestinal fluids. This pioneering work provides an essential basis for further development of the protein as a drug carrier for oral administration.


Assuntos
Agaricus , Captopril/química , Portadores de Fármacos/química , Monofenol Mono-Oxigenase/química , Administração Oral , Agaricales/metabolismo , Agaricus/metabolismo , Células CACO-2 , Captopril/administração & dosagem , Captopril/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Ácido Gástrico/metabolismo , Humanos , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Monofenol Mono-Oxigenase/administração & dosagem , Monofenol Mono-Oxigenase/metabolismo
11.
Physiol Rep ; 6(17): e13821, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30187692

RESUMO

Premature infants have a high incidence of bronchopulmonary dysplasia (BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end-diastolic compliance. This case series studied the usefulness of angiotensin-converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with "severe" BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23-29 weeks and 505-814 g, respectively. All required mechanical ventilation (including high-frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements. Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen (55 ± 25 to 29 ± 3%, two-tailed P = 0.03) and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness [840 ± 94 to 740 ± 83 µm, P = 0.07] and an increased pulsatile diameter [36 ± 14 to 63 ± 25 µm, P = 0.04]). Improvements were observed for both systolic (increased LV output, 188 ± 13 to 208 ± 13 mL/kg/min, P = 0.046 and mean velocity of circumferential fiber shortening, 1.6 ± 0.2 to 2.5 ± 0.3 [circ/sec], P = 0.0004) and diastolic (decreased isovolumic relaxation time, 69.6 ± 8.2 to 59.4 ± 5 msec, P = 0.044) function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance. These findings suggest that improving respiratory and cardiac indices (especially diastolic function) warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Captopril/uso terapêutico , Coração/fisiopatologia , Hemodinâmica , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Displasia Broncopulmonar/fisiopatologia , Captopril/administração & dosagem , Feminino , Coração/diagnóstico por imagem , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Contração Miocárdica , Veias Pulmonares/fisiopatologia , Túnica Íntima/diagnóstico por imagem
12.
Proc Natl Acad Sci U S A ; 115(41): 10511-10516, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30249662

RESUMO

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized l-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In-labeled unmodified PAMAM, l-threonine modified PAMAM, and l-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.


Assuntos
Captopril/farmacologia , Dendrímeros/administração & dosagem , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nefropatias/tratamento farmacológico , Poliaminas/química , Serina/química , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/administração & dosagem , Captopril/química , Dendrímeros/química , Portadores de Fármacos/química , Camundongos
14.
Nutrients ; 10(8)2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115889

RESUMO

Many studies have shown that flavonoids are effective as antihypertensive drugs in arterial hypertension. In the present work, we have analyzed the effects of some flavonoid extracts in the spontaneous hypertensive rat model (SHR). An important feature of this study is that we have used a low dose, far from those that are usually applied in human therapy or experimental animals, a dose that responded to the criterion of a potential future commercial use in human subjects. Treatments were carried out for 6 and 12 weeks in two groups of SHR rats, which received apigenin, lemon extract, grapefruit + bitter orange (GBO) extracts, and cocoa extract. Captopril was used as a positive control in the SHR group treated for 6 weeks (SHR6) and Diosmin was used as the industry reference in the SHR group treated for 12 weeks (SHR12). Captopril and GBO extracts lowered the high arterial pressure of the SHR6 animals, but none of the extracts were effective in the SHR12 group. Apigenin, lemon extract (LE), GBO, and captopril also improved aortic vascular relaxation and increased plasma and urinary excretion of nitrites, but only in the SHR6 group. Kidney and urinary thiobarbituric acid reactive substances (TBARS) were also significantly reduced by GBO in the SHR6 rats. Apigenin also improved vascular relaxation in the SHR12 group and all the flavonoids studied reduced urinary thiobarbituric acid reactive substances (TBARS) excretion and proteinuria. Vascular abnormalities, such as lumen/wall ratio in heart arteries and thoracic aorta, were moderately improved by these treatments in the SHR6 group. In conclusion, the flavonoid-rich extracts included in this study, especially apigenin, LE and GBO improved vascular vasodilatory function of young adult SHRs but only the GBO-treated rats benefited from a reduction in blood pressure. These extracts may be used as functional food ingredients with a moderate therapeutic benefit, especially in the early phases of arterial hypertension.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Flavonoides/farmacologia , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Captopril/administração & dosagem , Captopril/farmacologia , Flavonoides/administração & dosagem , Flavonoides/química , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
Curr Med Res Opin ; 34(10): 1869-1874, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29972310

RESUMO

OBJECTIVE: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. METHODS: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. RESULTS: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44-0.98; p = .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63-0.97; p = .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61-0.94); p = .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. CONCLUSIONS: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.


Assuntos
Anlodipino , Captopril/análogos & derivados , Infarto do Miocárdio , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Captopril/administração & dosagem , Captopril/efeitos adversos , Análise de Dados , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Prognóstico , Tempo para o Tratamento , Resultado do Tratamento
16.
Mol Med Rep ; 18(2): 2300-2306, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29956776

RESUMO

To explore the effects of captopril on calpain­mediated apoptosis of myocardial cells and cardiac function in diabetic rats, 30 adult male Sprague­Dawley rats were randomly divided into three groups: Negative control (NC group), untreated diabetic rats (DM group) and diabetic rats treated with captopril (Cap group). Diabetes was induced by streptozotocin injection. Captopril was intragastrically administered at a daily dose of 50 mg/kg for 12 weeks; the NC and DM groups received an equivalent volume of saline. After 12 weeks of treatment, left ventricular systolic pressure (LVSP), left ventricular end­diastolic pressure (LVDEP), maximal rate of left ventricular pressure increase (+dp/dtmax), maximal rate of left ventricular pressure decrease (­dp/dtmax) and left ventricular mass index (LVMI) were measured. The levels of calpain­1, calpain­2, B­cell lymphoma (Bcl)­2, Bcl­2 associated protein X (Bax) and total caspase­3 were detected in cardiac tissue by western blot analysis. The apoptotic index (AI) was assessed with a terminal deoxynucleotidyl transferase­mediated dUTP nick­end labeling assay. The ultrastructure of cardiac tissue was determined by transmission electron microscopy. Compared with the NC group, LVDEP and LVMI were increased, whereas LVSP, +dp/dtmax and ­dp/dtmax were decreased in the DM group. In the Cap group, LVDEP and LVMI were decreased, whereas LVSP, +dp/dtmax and ­dp/dtmax were increased compared with the DM group. Bcl­2 protein expression was decreased, whereas the levels of calpain­1, calpain­2, Bax and total caspase­3 protein were increased in the DM group, compared with the NC group. Cap treatment increased Bcl­2 protein expression and decreased calpain­1, calpain­2, Bax and total caspase­3 protein expression compared with the DM group. Additionally, the AI was increased in the DM group compared with the NC group, and decreased in the Cap group compared with the DM group. Furthermore, ultrastructural examination demonstrated that myocardial cell injury was reduced in the Cap group compared with the DM group. Therefore, captopril improved myocardial structure and ventricular function, by inhibiting calpain­1 and calpain­2 activation, increasing Bcl­2 expression, reducing Bax expression and subsequently inhibiting caspase­3­dependent apoptosis.


Assuntos
Captopril/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Coração/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Calpaína/efeitos adversos , Calpaína/genética , Caspase 3/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Proteína X Associada a bcl-2/genética
17.
Sleep Med ; 48: 61-69, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29859479

RESUMO

BACKGROUND: Sympathetic hyperactivity and poor sleep quality are reported in myocardial infarction (MI) patients and angiotensin-converting enzyme inhibitors (ACEI) can improve long-term survival in these patients. We aimed to evaluate ACEI effects on cardiac autonomic activity (CAA) and disordered sleep patterns in ambulatory rats after MI. METHODS: Polysomnographic recording was performed in sham (n = 8) and MI (n = 9) male rats during normal daytime sleep before and after captopril treatment. Spectral analyses of the electroencephalogram and electromyogram were evaluated to define active waking (AW), quiet sleep (QS), and paradoxical sleep (PS). Central sleep apnea (CSA) events were measured by analyzing the electromyogram of the diaphragm. CAA was measured by power spectrum analyses of heart rate variability (HRV). RESULTS: In the MI group, there was a higher low frequency/high frequency ratio during sleep, which reduced significantly after captopril treatment, especially at the QS stage compared to that before captopril treatment. The frequency of sleep interruption was higher in the MI group than the sham group. Increased AW and PS, and decreased QS times were noted in the MI group compared to the sham group. These changes were restored to baseline after captopril treatment in the MI group. CSA events were significantly increased in the MI group, and were restored to the normal level after captopril treatment. CONCLUSIONS: Our results demonstrate significant sleep fragmentation with sympathetic hyperactivity after MI, and that captopril restores the autonomic dysfunction and sleep disorder. These findings suggest that ACEI improved sleep-related respiration disorder after MI by restoring autonomic homeostasis, and provide a hypothesis generating for future studies in humans.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Captopril/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/complicações , Transtornos do Sono-Vigília/fisiopatologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Eletrocardiografia/métodos , Eletroencefalografia , Eletromiografia , Humanos , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Ratos , Sono/fisiologia
18.
AAPS PharmSciTech ; 19(5): 2203-2212, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29728997

RESUMO

This work aimed to using optimization study to formulate a patient-friendly captopril fast-dissolving oral film with satisfactory disintegration time. Films were made with pullulan and hydroxypropyl methyl cellulose (HPMC) by using the solvent-casting method. Cellulose nanofiber (CNF) was used as a compatibilizer and glycerine was used as a plasticizer. In order to find an optimum formulation, a response surface methodology and a central composite design were employed. The concentration percentages of pullulan and glycerine were considered to be the design factors. Disintegration time, tensile strength, percent elongation at break, and folding endurance were considered to be the responses. The results showed that CNF improved the compatibility and tensile strength of the pullulan and HPMC blend. Also, the rigid nature of CNF reduced the film elongation but the addition of glycerine improved its flexibility. All formulations showed an acceptable uniformity content and dissolution rate. Complete dissolution for all formulations occurred within 2 min. Films with 26% pullulan, 74% HPMC, 1% CNF, and 5% glycerine were reported to be optimum formulations for captopril fast-dissolving oral films, with 95% confidence levels. The in vivo comparison of optimized formulation with a conventional captopril sublingual tablet exhibited significant increase in AUC (~ 62%) and Cmax (~ 52%) and a major decrease in Tmax (~ 33%). The overall results showed that the captopril FDF is a promising candidate for enhanced in vivo orotransmucosal absorption.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/síntese química , Captopril/administração & dosagem , Captopril/síntese química , Composição de Medicamentos/métodos , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Captopril/metabolismo , Glucanos/administração & dosagem , Glucanos/síntese química , Glucanos/metabolismo , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/síntese química , Derivados da Hipromelose/metabolismo , Nanofibras/administração & dosagem , Nanofibras/química , Coelhos , Distribuição Aleatória , Solubilidade , Resistência à Tração
19.
J Cell Biochem ; 119(1): 926-937, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28681939

RESUMO

Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two-kidney one-clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX-2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.


Assuntos
Anti-Hipertensivos/administração & dosagem , Captopril/administração & dosagem , Flavonoides/administração & dosagem , Glicosídeos/administração & dosagem , Hipertensão/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Angiotensina II/sangue , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Hipertensão/sangue , Hipertensão/metabolismo , Masculino , Norepinefrina/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Renina/sangue
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