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1.
AAPS PharmSciTech ; 21(7): 254, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32888102

RESUMO

Olmesartan medoxomil (OLM) an antihypertensive molecule with poor solubility and poor bioavailability (26% when taken orally) was selected as a model drug. Herein, rationale development of amorphous solid dispersion with hot-melt extrusion of poorly bioavailable OLM was carried out with the aid of quality by design (QbD), in-silico, in-vitro, and in-vivo evaluations. Polymer selection commenced with the selection of thermoplastic water-soluble polymers with the compatible processing temperature window as per the thermal behavior of OLM. Molecular dynamics (MD) simulations as well assisted in the selection of a carrier. Promising dissolution enhancement was observed with the help of Kollidon VA-64 (VA-64) as a carrier. Optimization of the formulation was executed using the QbD approach with design of experiment as a statistical optimization tool. Interactions between VA-64 and OLM on the atomic level were studied with the help of atomistic MD simulations. Characterization of the optimized extrudates were carried out with scanning electron microscopy, atomic force microscopy, differential scanning calorimetry, thermogravimetric analysis, Fourier transforms infrared spectroscopy, powder X-ray diffraction, in-vitro dissolution study, and in-vivo pharmacokinetic studies. Molecular-level mixing of OLM with VA-64 resulted into glass solution formation which rapidly dissolves (28 times in-vitro dissolution enhancement) in GI tract fluids and instantly gets absorbed into blood circulation. In-vivo pharmacokinetic studies performed in Sprague-Dawley rats reflected superior bioavailability (201.60%) with a significant increase in the Cmax with short Tmax through amorphization of OLM. The in-silico results were in agreement with the observed results of in-vitro dissolution studies and in-vivo pharmacokinetic study.


Assuntos
Anti-Hipertensivos/farmacocinética , Tecnologia de Extrusão por Fusão a Quente , Olmesartana Medoxomila/farmacocinética , Administração Oral , Animais , Anti-Hipertensivos/química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Simulação por Computador , Técnicas In Vitro , Olmesartana Medoxomila/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
2.
Mol Pharmacol ; 98(5): 529-539, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938720

RESUMO

The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The crystal structure of CYP2C9*2 in complex with an antihypertensive drug losartan was solved using X-ray crystallography at 3.1-Å resolution. The Arg144Cys variation in the *2 complex disrupts the hydrogen-bonding interactions that were observed between the side chain of arginine and neighboring residues in the losartan complex of CYP2C9 and the wild-type (WT) ligand-free structure. The conformation of several secondary structural elements is affected, thereby altering the binding and orientation of drug and important amino acid side chains in the distal active site cavity. The new structure revealed distinct interactions of losartan in the compact active site of CYP2C9*2 and differed in occupancy at the other binding sites previously identified in the WT-losartan complex. Furthermore, the binding studies in solution using losartan illustrated lower activity of the CYP2C9*2 compared with the WT. Together, the findings yield valuable insights into the decreased hydroxylation activity of losartan in patients carrying CYP2C9*2 allele and provide a useful framework to investigate the effect of a single-nucleotide polymorphism that leads to altered metabolism of diverse drug substrates. SIGNIFICANCE STATEMENT: The *2 allele of the human drug-metabolizing enzyme CYP2C9 is found in different populations and results in significantly reduced activity toward various drug substrates. How the CYP2C9*2 variant induces altered drug metabolism is poorly understood given that the Arg144Cys variation is located far away from the active site. This work yield insight into the effect of distal variation using multitude of techniques that include X-ray crystallography, isothermal titration calorimetry, enzymatic characterization, and computational studies.


Assuntos
Citocromo P-450 CYP2C9/genética , Losartan/química , Polimorfismo de Nucleotídeo Único/genética , Alelos , Anti-Hipertensivos/química , Domínio Catalítico/genética , Humanos
3.
Sci Rep ; 10(1): 11680, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669617

RESUMO

Bioactive plant peptides have received considerable interest as potential antihypertensive agents with potentially fewer side effects than antihypertensive drugs. Here, the blood pressure-lowering effects of the Bowman-Birk protease inhibitor, BTCI, and its derived peptides, PepChy and PepTry, were investigated using normotensive (Wistar-WR) and spontaneously hypertensive rats (SHR). BTCI inhibited the proteases trypsin and chymotrypsin, respectively, at 6 µM and 40 µM, a 10-fold greater inhibition than observed with PepTry (60 µM) and PepChy (400 µM). These molecules also inhibited angiotensin converting enzyme (ACE) with IC50 values of 54.6 ± 2.9; 24.7 ± 1.1; and 24.4 ± 1.1 µM, respectively, occluding its catalytic site, as indicated by molecular docking simulation, mainly for PepChy and PepTry. Gavage administration of BTCI and the peptides promoted a decrease of systolic and diastolic blood pressure and an increase of renal and aortic vascular conductance. These effects were more expressive in SHR than in WR. Additionally, BTCI, PepChy and PepTry promoted coronary vasodilation and negative inotropic effects in isolated perfused hearts. The nitric oxide synthase inhibitor blunted the BTCI and PepChy, with no cardiac effects on PepTry. The findings of this study indicate a therapeutic potential of BTCI and its related peptides in the treatment of hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Peptídeos/farmacologia , Inibidor da Tripsina de Soja de Bowman-Birk/farmacologia , Animais , Anti-Hipertensivos/química , Sítios de Ligação , Quimotripsina/química , Quimotripsina/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Simulação de Acoplamento Molecular , NG-Nitroarginina Metil Éster/química , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/química , Óxido Nítrico Sintase Tipo III/metabolismo , Peptídeos/síntese química , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Tripsina/química , Tripsina/metabolismo , Inibidor da Tripsina de Soja de Bowman-Birk/química , Vasodilatação/efeitos dos fármacos
5.
Handb Exp Pharmacol ; 261: 193-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32458136

RESUMO

Pharmacological treatment of arterial hypertension in children is mainly based on individual experience, but there is evidence that blocking the angiotensin system reduces systolic and diastolic blood when compared to placebo, and these drugs are safe to use for a short duration, also in children under 6 years of age. Blocking the angiotensin system either by angiotensin-converting enzyme inhibitors or by antagonizing the angiotensin 1 receptor is effective, but did not display a consistent dose-response relationship with escalating doses, but the effective doses are known. Calcium channel antagonists are effective antihypertensives in children, but the evidence is limited. Based on small-sized studies, beta-blockers modestly reduce systolic blood pressure, but have no significant effect on diastolic blood pressure compared to placebo. They act in combination to antagonize reflex tachycardia induced by vasodilators. The most commonly used antihypertensive agents are safe to use in short-term studies.


Assuntos
Hipertensão , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/fisiologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Criança , Humanos
6.
J Med Chem ; 63(10): 5488-5500, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32337993

RESUMO

Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Desenho de Fármacos , Mesilatos/metabolismo , Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Piridinas/metabolismo , Tiazepinas/metabolismo , Tirosina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Cristalografia por Raios X/métodos , Mesilatos/química , Neprilisina/química , Peptidil Dipeptidase A/química , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Piridinas/química , Tiazepinas/química , Tirosina/química , Tirosina/metabolismo
8.
Am J Health Syst Pharm ; 77(8): 649-657, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32236454

RESUMO

PURPOSE: To evaluate the physical and chemical compatibilities of treprostinil sodium and dopamine hydrochloride. METHODS: Treprostinil sodium (4,000, 76,000, and 500,000 ng/mL) were mixed with dopamine hydrochloride (0.6, 3.2, 6, and 40 mg/mL). Samples were obtained at hours 0, 1, 2, and 4 for physical compatibility and chemical stability testing. Physical compatibility was assessed by visual examination and measurements of turbidity and pH. Drug concentrations were assessed using stability-indicating liquid chromatography mass spectrophotometry (LCMS) for treprostinil sodium and stability-indicating high-performance liquid chromatography (HPLC) for dopamine hydrochloride. RESULTS: Treprostinil sodium 4,000 and 76,000 ng/mL, when mixed with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL, were stable for 4 hours. Treprostinil sodium 500,000 ng/mL was stable when mixed with dopamine hydrochloride 0.6 mg/mL for 4 hours, but when mixed with dopamine hydrochloride 3.2, 6, and 40 mg/mL, significant precipitation was seen. CONCLUSION: Treprostinil sodium 4,000 and 76,000 ng/mL were stable for 4 hours during simulated Y-site coadministration with dopamine hydrochloride 0.6, 3.2, 6, and 40 mg/mL. Treprostinil sodium 500,000 ng/mL is stable when mixed with dopamine hydrochloride 0.6 mg/mL.


Assuntos
Anti-Hipertensivos/química , Dopaminérgicos/química , Dopamina/química , Incompatibilidade de Medicamentos , Epoprostenol/análogos & derivados , Administração Intravenosa , Epoprostenol/química , Concentração de Íons de Hidrogênio , Fatores de Tempo
9.
J Food Sci ; 85(4): 1328-1337, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32220144

RESUMO

Naked oat globulin was hydrolyzed by alcalase, flavourzyme, pepsin, and trypsin in sequence. The hydrolysates (NOGH) were purified using gel chromatography, reversed-phase high performance liquid chromatography (RP-HPLC). Finally, fraction D7d with the highest ACE-inhibitory was subjected to liquid chromatography-mass spectrometry analysis and 14 peptides were identified. Of which, peptide SSYYPFK (890.4 Da) was chose to synthesize based on in silico analysis. The SSYYPFK demonstrated high ACE-inhibitory activity (IC50 : 91.82 µM) with competitive inhibition mode, and could effectively (P < 0.05) lower the systolic blood pressure and diastolic pressure of spontaneously hypertensive rats at the concentration of 100 to 150 mg/kg body weight. Molecular docking simulation demonstrated that SSYYPFK could bind with the active site S1 of ACE via short hydrogen bonds. It could remain the ACE-inhibitory activity after simulated gastrointestinal hydrolysis. Moreover, SSYYPFK showed acceptable renin and endothelin-1 suppressing capacity (47.59% and 27.88% at 1.5 mg/mL, respectively). These results indicated that SSYYPFK may have similar antihypertensive mechanism with captopril, and could be develop to natural antihypertensive products. PRACTICAL APPLICATION: One novel ACE-inhibitory peptide SSYYPFK (890.4 Da) was identified from naked oat globulin hydrolysates. It exhibited relatively high renin and intracellular endothelin-1 suppressing capacity, and could effectively (P < 0.05) lower the systolic blood pressure and diastolic pressure of spontaneously hypertensive rats. This peptide could be used as natural and safe nutraceuticals and/or functional ingredients.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Avena/química , Globulinas/química , Proteínas de Plantas/farmacologia , Animais , Anti-Hipertensivos/química , Avena/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Cromatografia de Fase Reversa , Simulação por Computador , Endotelina-1 , Masculino , Simulação de Acoplamento Molecular , Pepsina A/farmacologia , Peptídeos/química , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/química , Hidrolisados de Proteína/química , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Renina , Tripsina
10.
J Chromatogr A ; 1620: 461003, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32156458

RESUMO

The enormous growth in drug discovery paradigm has necessitated continuous exploration of new methods for drug-protein interaction analysis. To enhance the role of these methodologies in designing rational drugs, this work extended an immobilized angiotensin II type I receptor (AT1R) based affinity chromatography in antihypertensive compound identification. We fused haloalkane dehalogenase at C-terminus of AT1R and expressed the fusion receptor in E. coli. The expressed receptor was covalently immobilized onto 8.0 µm microspheres by mixing the cell lysate with 6-chlorocaproic acid-modified amino polystyrene microspheres. The immobilized AT1R was utilized for thermodynamic and kinetic interaction analysis between the receptor and four specific ligands. Following confirmation of these interactions by molecular docking, we identified puerarin and rosmarinic acid by determining their binding to the receptor. Azilsartan, candesartan, valsartan and olmesartan displayed two kinds of binding sites to AT1R by injection amount-dependent method. By molecular docking, we recognize the driving forces of the interaction as electrostatic interaction, hydrogen bonds and van der Waals force. The dissociation rate constants (kd) of azilsartan, candesartan, valsartan and olmesartan to AT1R were 0.01138 ± 0.003, 0.05142 ± 0.003, 0.07547 ± 0.004 and 0.01310 ± 0.005 min-1 by peak profiling assay. Comparing with these parameters, puerarin and rosmarinic acid presented lower affinity (KA: 0.12 × 104 and 1.5 × 104/M) and slower kinetics (kd: 0.6864 ± 0.03 and 0.3005 ± 0.01 min-1) to the receptor. These results, taking together, indicated that the immobilized AT1R has the capacity to probe antihypertensive compounds.


Assuntos
Anti-Hipertensivos/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Receptor Tipo 1 de Angiotensina/metabolismo , Anti-Hipertensivos/química , Benzimidazóis/química , Benzimidazóis/metabolismo , Sítios de Ligação , Cromatografia de Afinidade , Cinamatos/metabolismo , Depsídeos/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Isoflavonas/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Oxidiazóis/química , Oxidiazóis/metabolismo , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Tetrazóis/química , Tetrazóis/metabolismo , Termodinâmica , Valsartana/química , Valsartana/metabolismo
11.
Curr Protein Pept Sci ; 21(5): 527-541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31951167

RESUMO

Antimicrobial peptides (AMPs) have been found in all organism taxa and may play an essential role as a host defense system. AMPs are organized in various conformations, such as linear peptides, disulfide bond-linked peptides, backbone-linked peptides and circular peptides. AMPs apparently act primarily on the plasma membrane, although an increasing number of works have shown that they may also target various intracellular sites. Spider venoms are rich sources of biomolecules that show several activities, including modulation or blockage of ion channels, anti-insect, anti-cancer, antihypertensive and antimicrobial activities, among others. In spider venoms from the Lycosidae family there are many linear AMPs with a wide range of activities against several microorganisms. Due to these singular activities, some Lycosidae AMPs have been modified to improve or decrease desirable or undesirable effects, respectively. Such modifications, especially with the aim of increasing their antibiotic activity, have led to the filing of many patent applications. This review explores the abundance of Lycosidae venom AMPs and some of their derivatives, and their use as new drug models.


Assuntos
Anti-Infecciosos/química , Anti-Hipertensivos/química , Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/química , Moduladores de Transporte de Membrana/química , Aranhas/química , Sequência de Aminoácidos , Animais , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Membrana Celular/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Expressão Gênica , Hemólise/efeitos dos fármacos , Humanos , Moduladores de Transporte de Membrana/isolamento & purificação , Moduladores de Transporte de Membrana/farmacologia , Peso Molecular , Patentes como Assunto , Coelhos , Venenos de Aranha/química , Aranhas/fisiologia
12.
J Agric Food Chem ; 68(7): 2082-2090, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31984733

RESUMO

IAVPTGVA (Soy1) and LPYP are two soybean peptides, which display a multifunctional behavior, showing in vitro hypocholesterolemic and hypoglycemic activities. A preliminary screening of their structures using BIOPEP suggested that they might be potential angiotensin-converting enzyme (ACE) inhibitors. Therefore, a bottom-up-aided approach was developed in order to clarify the in vitro hypotensive activity. Soy1 and LPYP dropped the intestinal and renal ACE enzyme activity with IC50 values equal to 14.7 ± 0.28 and 5.0 ± 0.28 µM (Caco-2 cells), and 6.0 ± 0.35 and 6.8 ± 0.20 µM (HK-2 cells), respectively. In parallel, a molecular modeling study suggested their capability to act as competitive inhibitors of this enzyme. Finally, in order to increase both their stability and hypotensive properties, a suitable strategy for the harmless control of their release from a nanomaterial was developed through their encapsulation into the RADA16-assembling peptide.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Peptídeos/química , Extratos Vegetais/química , Soja/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peptidil Dipeptidase A/química , Extratos Vegetais/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Chem Biodivers ; 17(2): e1900473, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31961474

RESUMO

Veratrum plant contains a family of compounds called steroidal alkaloids which have been previously reported to cause DNA damage and blood pressure decrease in vivo. In this study, the antihypertensive effects and DNA damage in brain cells of 12 steroidal alkaloids separated from Veratrum plant were all evaluated to develop a relationship among chemical structure, antihypertensive activity and neurotoxicity by utilization of chemical principal component analysis (PCA) and hierarchical cluster analysis (HCA). Twelve steroidal alkaloids markedly reduced high blood pressure of hypertensive mice and also similarly induced varying degrees of DNA single-strand breaks in mouse cerebellum and cerebral cortex after oral administration. On the basis of the PCA and HCA results, it was suggested that the 3-carboxylic esters and benzene group play a core role in the DNA damage of brain cells, while more hydroxy groups in the A-ring and B-ring structure of jervine-type alkaloid led to stronger antihypertensive activity. The primary structure, activity and neurotoxicity relationship were discussed briefly.


Assuntos
Anti-Hipertensivos/química , Alcaloides de Veratrum/química , Veratrum/química , Administração Oral , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Análise por Conglomerados , Dano ao DNA/efeitos dos fármacos , Camundongos , Extratos Vegetais/química , Análise de Componente Principal , Relação Estrutura-Atividade , Veratrum/metabolismo , Alcaloides de Veratrum/farmacologia
14.
J Agric Food Chem ; 68(7): 1877-1883, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31402656

RESUMO

The antihypertensive activity of two αs1-casein-derived peptides and casein hydrolysate containing these sequences was evaluated in the presence of naloxone. The activity was abolished by this opioid antagonist at 2, 4, and 6 h post-administration. Similarly, the antihypertensive effect of the αs1-casein peptides 90RYLGY94 (-23.8 ± 2.5 mmHg) and 143AYFYPEL149 (-21.1 ± 3.2 mmHg) at 5 mg/kg of body weight was antagonized by the co-administration of naloxone. Because peptide 143AYFYPEL149 had recently shown opioid activity, a molecular dynamic simulation of this peptide with human µ-opioid receptor was performed to demonstrate its favorable structure and interaction energy, despite the presence of Ala at the N terminus. Altogether, these results revealed that the in vivo effect on systolic blood pressure of the studied αs1-casein peptides is mediated by interaction with opioid receptors and the antihypertensive activity of casein hydrolysate can be very likely ascribed to them with the possible contribution of other mechanisms.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Caseínas/administração & dosagem , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores Opioides/metabolismo , Animais , Anti-Hipertensivos/química , Caseínas/química , Bovinos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Simulação de Dinâmica Molecular , Naloxona/administração & dosagem , Peptídeos/química , Ratos , Ratos Endogâmicos SHR , Receptores Opioides/química , Receptores Opioides/genética
15.
Drug Deliv Transl Res ; 10(1): 227-240, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31625026

RESUMO

Poor bioavailability of drugs via oral route is the greatest challenge facing drug formulation. To overcome this obstacle, transdermal route was commonly used as an alternative route to improve bioavailability. Lercanidipine HCl (LER) is a vasoselective calcium-channel blocker that has a poor oral bioavailability of 10% due to its hepatic metabolism and low solubility. The main objective of this study was to develop nanoethosomal LER gel for transdermal delivery to increase its skin permeation and promote bioavailability. Nanoethosomes were prepared and optimized using a Box-Behnken design employing ethanol injection method. The design studied the influence of Phospholipon 90G (PL90G), LER, and ethanol concentrations on entrapment efficiency (EE%); vesicle size; % cumulative LER release (CLERR); and cumulative LER permeated per unit area at 24 h Q24 (µg/cm2). The pharmacokinetic parameters of the optimized formulation were determined in rats. Nanoethosomes showed a mean vesicle size between 210.87 and 400.57 nm and EE% ranging from 49.26 to 97.22%. The developed nanoethosomes enhanced % CLERR and Q24 values compared to drug suspension. The experimental parameters of optimized formulation were very close to those calculated by software. The pharmacokinetics study showed three times statistically significant (p < 0.05) enhancement in LER bioavailability following nanoethosomal LER gel transdermal application compared to that of oral LER suspension. Nanoethosomes can be considered as a promising carrier for LER transdermal delivery, thus will be fruitful therapy in hypertension management. Graphical abstract.


Assuntos
Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Di-Hidropiridinas/administração & dosagem , Di-Hidropiridinas/farmacocinética , Administração Cutânea , Animais , Anti-Hipertensivos/química , Disponibilidade Biológica , Di-Hidropiridinas/química , Etanol/química , Géis , Masculino , Modelos Animais , Nanopartículas , Tamanho da Partícula , Fosfatidilcolinas/química , Ratos
16.
J Ethnopharmacol ; 250: 112461, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31830549

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri have a long history of use in the traditional treatment of various ailments including hypertension. Literature reports have indicated that it is a potent antihypertensive herbal medication used traditionally. AIM OF THE STUDY: This study was carried out to investigate the antihypertensive and vasodilatory activity of four solvents extracts of P. niruri namely; petroleum ether (PEPN), chloroform (CLPN), methanol (MEPN) and water (WEPN), with the aim of elucidating the mechanism of action and identifying the phytochemical constituents. MATERIALS AND METHODS: Male Spontaneous Hypertensive Rats (SHRs) were given oral gavage of P. niruri extract daily for two weeks and the blood pressure was recorded in vivo. We also determine the vasodilation effect of the extracts on rings of isolated thoracic aorta pre-contracted with phenylephrine (PE, 1 µM). Endothelium-intact or endothelium-denuded aorta rings were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM) and Methylene blue (MB 10 µM), sGC inhibitors; Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 µM) a nitric oxide synthase (NOS) inhibitor; atropine (10 µM), a cholinergic receptor blocker; indomethacin (10 µM), a cyclooxygenase inhibitor and various K+ channel blockers such as glibenclamide (10 µM) and tetraethyl ammonium (TEA 10 µM) for mechanism study. RESULTS: SHRs receiving P. niruri extracts showed a significant decrease in their blood pressure (BP) when compared to the baseline value, with PEPN being more potent. The extracts (0.125-4 mg/mL) also induced vasorelaxation on endothelium-intact aorta rings. PEPN elicited the most potent maximum relaxation effect (Rmax). Mechanism assessment of PEPN showed that its relaxation effect is significantly suppressed in endothelium-denuded aorta rings. Pre-incubation of aorta rings with atropine, L-NAME, ODQ, indomethacin, and propranolol also significantly attenuated its relaxation effect. Conversely, incubation with TEA and glibenclamide did not show a significant effect on PEPN-induced relaxation. CONCLUSION: This study indicates that the antihypertensive activity of P. niruri extract is mediated by vasoactive phytoconstituents that dilate the arterial wall via endothelium-dependent pathways and ß-adrenoceptor activity which, in turn, cause vasorelaxation and reduce blood pressure.


Assuntos
Anti-Hipertensivos/farmacologia , Phyllanthus , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/química , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Técnicas In Vitro , Óxido Nítrico/fisiologia , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química
17.
Phytochemistry ; 170: 112222, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31810054

RESUMO

Hypertension has become the leading risk factor for worldwide cardiovascular diseases. Conventional pharmacological treatment, after both dietary and lifestyle changes, is generally proposed. In this review, we present the antihypertensive properties of phytocomplexes from thirteen plants, long ago widely employed in ethnomedicines and, in recent years, increasingly evaluated for their activity in vitro and in vivo, also in humans, in comparison with synthetic drugs acting on the same systems. Here, we focus on the demonstrated or proposed mechanisms of action of such phytocomplexes and of their constituents proven to exert cardiovascular effects. Almost seventy phytochemicals are described and scientifically sound pertinent literature, published up to now, is summarized. The review emphasizes the therapeutic potential of these natural substances in the treatment of the 'high normal blood pressure' or 'stage 1 hypertension', so-named according to the most recent European and U.S. guidelines, and as a supplementation in more advanced stages of hypertension, however needing further validation by clinical trial intensification.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Animais , Anti-Hipertensivos/química , Humanos , Compostos Fitoquímicos/química
18.
Food Chem ; 310: 125909, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31816536

RESUMO

Camu-camu (Myrciaria dubia) seeds are discarded without recovering the bioactive compounds. The main aim of the present work was to optimise the solvent mixture to extract higher total phenolic content and antioxidant capacity of camu-camu seeds. The optimised solvent system increased the extraction of phenolic compounds, in which vescalagin and castalagin were the main compounds. The optimised extract displayed antioxidant capacity measured by different chemical and biological assays, exerted antiproliferative and cytotoxic effects against A549 and HCT8 cancer cells, antimicrobial effects, protected human erythrocytes against hemolysis, inhibited α-amylase and α-glucosidase enzymes and presented in vitro antihypertensive effect. Additionally, the optimized extract inhibited human LDL copper-induced oxidation in vitro and reduced the TNF-α release and NF-κB activation in macrophages cell culture. Thus, the use of camu-camu seed showed to be a sustainable way to recover bioactive compounds with in vitro functional properties.


Assuntos
Myrtaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Hemólise/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/análise , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenóis/análise , Sementes/química , alfa-Amilases/antagonistas & inibidores
19.
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 , Ligação 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
20.
J Agric Food Chem ; 68(3): 759-768, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31841328

RESUMO

In this study, we investigated the antihypertensive effects in vitro and in vivo of novel angiotensin-converting enzyme inhibitory (ACEI) peptides purified and identified from bovine bone gelatin hydrolysate (BGH). Thirteen ACEI peptides were identified from BGH, and among which, RGL-(Hyp)-GL and RGM-(Hyp)-GF exhibited high ACE inhibition with IC50 values of 1.44 and 10.23 µM. Molecular docking predicted that RGM-(Hyp)-GF and ACE residues of Glu384, His513, and Lys511 formed hydrogen-bonding interactions at distances of 2.57, 2.99, and 2.42 + 3.0 Å. RGL-(Hyp)-GL formed hydrogen bonds with Lys511 and Tyr523 and generated hydrogen-bonding interactions with His387 and Glu411 in the zinc(II) complexation motif at distances of 2.74 and 3.03 + 1.93 Å. The maximal decrements in systolic blood pressure in spontaneously hypertensive rats induced by one-time gavage of RGL-(Hyp)-GL and RGM-(Hyp)-GF at 30 mg/kg were 31.3 and 38.6 mmHg. RGL-(Hyp)-GL had higher enzyme degradation resistance than that of RGM-(Hyp)-GF in vitro incubation in rat plasma, and they were sequentially degraded into pentapeptides and tetrapeptides within 2 h. Our results indicate that BGH can serve as a nutritional candidate to control blood pressure.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Osso e Ossos/química , Gelatina/química , Peptídeos/química , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Bovinos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
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