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1.
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
2.
J Enzyme Inhib Med Chem ; 35(1): 383-390, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31865756

RESUMO

A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call 'sugar-tail' approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay.


Assuntos
Anti-Hipertensivos/farmacologia , Carboidratos/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Drogas , Sulfonamidas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Carboidratos/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Epiteliais , Humanos , Concentração de Íons de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
3.
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
4.
Int J Pharm Compd ; 23(6): 519-527, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31751949

RESUMO

Amlodipine besylate is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available 2.5-mg, 5-mg, and 10-mg amlodipine besylate tablets do not provide the necessary flexibility in dosing needed for treating children. This flexibility is readily achieved using an oral, liquid dosage form. However, no commercial liquid dosage form of amlodipine currently exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide a convenient option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of extemporaneously compounded amlodipine besylate suspensions in the PCCA Base, SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. The study design included two amlodipine besylate concentrations to provide stability documentation over a bracketed concentration range for eventual use by compounding pharmacists. A robust stabilityindicating high-performance liquid chromatographic assay for the determination of the chemical stability of amlodipine besylate in SuspendIt was developed and validated. Suspensions of amlodipine were prepared in SuspendIt at 0.5-mg/mL and 10.0-mg/mL concentrations, selected to represent a range within which the drug is commonly dosed. Samples were stored in plastic amber prescription bottles at two temperature conditions (5°C and 25°C). Samples were assayed initially, and at the following time points: 7 days, 14 days, 29 days, 46 days, 60 days, 90 days, 120 days, and 180 days. Physical data such as pH, viscosity, and appearance were also noted. All measurements were obtained in triplicate. A stable extemporaneous product is defined as one that retains at least 90% of the initial drug concentration throughout the sampling period. This study demonstrates that amlodipine besylate is physically and chemically stable in SuspendIt for 90 days in the refrigerator and 7 days at room temperature, retaining 90% of the label claim (initial drug concentration) at both concentrations. The pH values did not change significantly. The viscosity of the refrigerated samples at both concentrations decreased slightly, while that of the room temperature samples showed a marked increase in viscosity. This study provides a viable, compounded alternative for amlodipine in a liquid dosage form, with an adequate beyond-use-date to meet patient needs. The study further provides stability documentation over a bracketed amlodipine concentration range of 0.5 mg/mL to 10.0 mg/mL, allowing compounding pharmacists more flexibility in customizing their formulations.


Assuntos
Anlodipino , Anti-Hipertensivos , Cromonas , Composição de Medicamentos , Administração Oral , Adolescente , Anlodipino/química , Anti-Hipertensivos/química , Criança , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Suspensões
5.
Mini Rev Med Chem ; 19(15): 1219-1254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31735158

RESUMO

Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet's published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.


Assuntos
Di-Hidropiridinas/farmacologia , Compostos Heterocíclicos/farmacologia , Neoplasias/tratamento farmacológico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/química , Antiulcerosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Di-Hidropiridinas/química , Compostos Heterocíclicos/química , Úlcera/tratamento farmacológico
6.
Cardiovasc Hematol Agents Med Chem ; 17(2): 135-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31589128

RESUMO

BACKGROUND: Matricaria pubescens is a medicinal plant from North Africa. This plant is widely used in alternative medicine as a remedy against rheumatism, inflammation, diabetes and hypertension. AIM: The aim of the study was to evaluate the possible antihypertensive and vasodilator activity of the aqueous extract of Matricaria pubescens (M. pubescens). MATERIAL AND METHODS: In the current study, the aqueous extract of the aerial parts of M. pubescens (AEMP) was prepared and its antihypertensive activity was examined in N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. RESULTS: The results indicated that AEMP reduced the systolic, diastolic, mean arterial blood pressure in hypertensive rats but not in normotensive rats. The data revealed that AEMP exhibits its antihypertensive effect through vasorelaxant activity. More interestingly, this study approved that the vasorelaxant capacity of AEMP seems to be mediated through vascular cyclooxygenase pathway, the opening of K+ channels and sGC-cGMP induction pathway. CONCLUSION: The study illustrates the beneficial action of M. pubescens as an antihypertensive agent.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Matricaria/química , Extratos Vegetais/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/efeitos adversos , Extratos Vegetais/química , Ratos Wistar , Vasodilatadores/química
7.
J Agric Food Chem ; 67(37): 10313-10320, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31502448

RESUMO

A peptide fraction with molecular masses below 3 kDa (PSH-3 kDa) from a peach seed hydrolysate demonstrated high angiotensin converting enzyme (ACE) inhibitory activity (concentration to inhibit 50% ACE (IC50) = 16.4 µg/mL) in our previous work. This work proposes a further study of this highly active fraction. RP-HPLC enabled two fractions (F3 and F4) with high inhibitory activity (IC50 = 2.0 ± 0.5 and 1.2 ± 0.2 µg/mL, respectively) to be isolated. Peptide analysis by LC-Q-TOF-MS/MS using reverse-phase and hydrophilic interaction chromatography enabled 33 peptides within both fractions to be identified. Among them, peptide isoleucine-tyrosine-serine-proline-histidine (IYSPH) showed the highest capacity. The lack of cytotoxicity of peptides was demonstrated in three different cell lines (HeLa, HT-29, and HK-2). Oral administration of PSH-3 kDa fraction or peptide IYSPH caused a significant systolic blood pressure reduction (-30 mmHg) on spontaneously hypertensive rats after 3-6 h treatment.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Hipertensão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Prunus persica/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/isolamento & purificação , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR , Sementes/química
8.
Mar Drugs ; 17(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398788

RESUMO

Angiotensin-I-converting enzyme (ACE) inhibitory peptides derived from natural products have shown a blood pressure lowering effect with no side effects. In this study, two novel ACE inhibitory peptides (His-Leu-His-Thr, HLHT and Gly-Trp-Ala, GWA) were purified from pearl oyster (Pinctada fucata martensii) meat protein hydrolysate with alkaline protease by ultrafiltration, polyethylene glycol methyl ether modified immobilized metal ion affinity medium, and reverse-phase high performance liquid chromatography. Both peptides exhibited high ACE inhibitory activity with IC50 values of 458.06 ± 3.24 µM and 109.25 ± 1.45 µM, respectively. Based on the results of a Lineweaver-Burk plot, HLHT and GWA were found to be non-competitive inhibitor and competitive inhibitor respectively, which were confirmed by molecular docking. Furthermore, the pearl oyster meat protein hydrolysate exhibited an effective antihypertensive effect on SD rats. These results conclude that pearl oyster meat protein is a potential resource of ACE inhibitory peptides and the purified peptides, HLHT and GWA, can be exploited as functional food ingredients against hypertension.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Pinctada/química , Hidrolisados de Proteína/química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Hipertensão/tratamento farmacológico , Masculino , Carne , Simulação de Acoplamento Molecular , Pinctada/metabolismo , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Sprague-Dawley , Ultrafiltração/métodos
9.
AAPS PharmSciTech ; 20(7): 282, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407104

RESUMO

The antihypertensive drug felodipine (FD) is a typical biopharmaceutics classification system (BCS) II drug; thus, improving the dissolution rate of FD is very important to enhance its bioavailability. Besides, according to the in situ "close loop" perfusion assay, we found that the jejunum is the main absorptive site, then the duodenum and ileum. Consequently, a novel micron-size particulate of FD in a core-shell structure was fabricated by a coaxial electrospray technique; within the drug delivery system, Hypromellose K4M (HPMC K4M) was selected as a sheath material to prolong the retention time in the upper GI tract, while povidone K30 (PVP K30) was mixed with FD in the inner layer. The dissolution study in three different media (0.02% Tween-80 solution; phosphate buffer containing 0.02% Tween-80, pH 6.8; and HCl solution containing 0.02% Tween-80, pH 1.2) demonstrated that FD-loaded coaxial electrospray particles (F-COES) could greatly improve the dissolution of FD. Furthermore, in vivo pharmacokinetics revealed that F-COES emerged no changes in the half-life but significantly prolonged the tmax and increased the oral bioavailability. Collectively, this work supplies a promising drug release system that will improve the dissolution and enhance the bioavailability simultaneously for those poorly water-soluble drugs mainly absorbed in the upper GI tract.


Assuntos
Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Felodipino/administração & dosagem , Felodipino/farmacocinética , Administração Oral , Animais , Anti-Hipertensivos/química , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Felodipino/química , Técnicas In Vitro , Intestino Delgado/metabolismo , Masculino , Tamanho da Partícula , Polissorbatos , Ratos Sprague-Dawley , Solubilidade
10.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370142

RESUMO

Hypertension is considered a major public health issue due to its high prevalence and subsequent risk of cardiovascular and kidney diseases. Thus, the search for new antihypertensive compounds remains of great interest. Snake venoms provide an abundant source of lead molecules that affect the cardiovascular system, which makes them prominent from a pharmaceutical perspective. Such snake venom components include bradykinin potentiating peptides (proline-rich oligopeptides), natriuretic peptides, phospholipases A2, serine-proteases and vascular endothelial growth factors. Some heparin binding hypotensive factors, three-finger toxins and 5' nucleotidases can also exert blood pressure lowering activity. Great advances have been made during the last decade regarding the understanding of the mechanism of action of these hypotensive proteins. Bradykinin potentiating peptides exert their action primarily by inhibiting the angiotensin-converting enzyme and increasing the effect of endogenous bradykinin. Snake venom phospholipases A2 are capable of reducing blood pressure through the production of arachidonic acid, a precursor of cyclooxygenase metabolites (prostaglandins or prostacyclin). Other snake venom proteins mimic the effects of endogenous kallikrein, natriuretic peptides or vascular endothelial growth factors. The aim of this work was to review the current state of knowledge regarding snake venom components with potential antihypertensive activity and their mechanisms of action.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipotensão/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Anti-Hipertensivos/química , Bradicinina/química , Bradicinina/uso terapêutico , Humanos , Peptídeos/química , Peptídeos/uso terapêutico , Venenos de Serpentes/química
11.
Life Sci ; 234: 116753, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419445

RESUMO

AIMS: Hypertension is a global disease that has been combating the world health for ages. Peristrophe roxburghiana (PR) is used in traditional medicine to treat hypertension and other ailments. The present study examined phytochemical constituents, antioxidant activities and GC-MS analysis of extracts of PR leaf and also evaluated their anti-hypertensive and anti-lipidemic effects in NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. METHODS: Wistar rats were grouped into two groups: control and hypertensive. Hypertension was induced in the hypertensive group by oral gavage of 60 mg/kg b.w of L-NAME for 3 weeks. After induction, the hypertensive group was randomly sub-grouped into hypertensive, hypertensive treated and hypertensive untreated groups. These were orally gavaged respectively with 60 mg/kg b.w of L-NAME, 60 mg/kg b.w/day of L-NAME +200 mg/kg b.w of different extracts of PR (aqueous, ethanolic and methanolic extracts) and 60 mg/kg b.w of L-NAME +20 mg/kg b.w ramipril for 3 weeks. The blood pressure was measured by tail-cuff method at the third and sixth weeks. KEY FINDINGS: The results showed that the extracts of PR significantly decrease blood pressure, pro-atherogenic lipids and atherogenic ratios in L-NAME hypertensive rats. White blood cells count, neutrophil count and creatinine level were also effectively decreased by the extracts. Furthermore, the extracts increase serum nitric oxide (NO) level, anti-atherogenic lipid, glutathione level, lymphocyte and platelet count in the rats. SIGNIFICANCE: Extracts of PR leaf decrease blood pressure and increase NO level in L-NAME hypertensive rats and also corrected the hyperlipidemia and inflammatory response arising from the reduction in NO bioavailability.


Assuntos
Acanthaceae/química , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Hipertensivos/química , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipolipemiantes/química , Lipídeos/sangue , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico/sangue , Extratos Vegetais/química , Folhas de Planta/química , Ratos Wistar
12.
ACS Appl Mater Interfaces ; 11(34): 30575-30584, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31382742

RESUMO

A hypertensive emergency causes severe cardiovascular diseases accompanied by acute target organ damage, requiring rapid and smooth blood pressure (BP) reduction. Current medicines for treating hypertensive emergencies, such as sodium nitroprusside (SNP), require careful dose control to avoid side effects (e.g., cyanide poisoning). The clinical administration of SNP using intravenous injection or drip further restrict its usage for first aid or self-aid in emergencies. Here, we developed an antihypertensive microneedle (aH-MN) technique to transdermally deliver SNP in combination with sodium thiosulfate (ST) as a cyanide antidote in a painless way. Dissolvable microneedles loaded with SNP and ST were fabricated via the centrifugation casting method, where the SNPs were stably packaged in microneedles and would be immediately released into the systemic circulation via subcutaneous capillaries when aH-MNs penetrated the skin. The antihypertensive effects were demonstrated on spontaneously hypertensive rat models. Rapid and potent BP reduction was achieved via aH-MN treatment, fulfilling clinical BP-control requirements for hypertensive emergencies. The side effects including skin irritation and target organ damage of aH-MN therapies were evaluated; the combinative delivery of ST effectively suppressed these side effects induced by the consecutive intake of SNP. This study introduces an efficient and patient-friendly antihypertensive therapy with a favorable side-effect profile, particularly a controllable and self-administrable approach to treat hypertensive emergencies.


Assuntos
Anti-Hipertensivos , Hipertensão/tratamento farmacológico , Agulhas , Pele/metabolismo , Administração Cutânea , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Ratos
13.
Ultrason Sonochem ; 58: 104635, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31450293

RESUMO

This work compares the sonochemical degradation of losartan and valsartan (antihypertensives) in water. Initially, the suitable operational conditions of ultrasonic power density and frequency were established. Under such conditions, losartan was eliminated in a higher percentage than valsartan, which was associated to differences in their hydrophobicities. Additionally, degradations in presence of isopropanol and ferrous ions confirmed that losartan was closer to cavitation bubble than valsartan. The structures of primary products indicated that sonogenerated hydroxyl radical attacked biphenyl tetrazole moiety (common nucleus of both pharmaceuticals). Then, theoretical calculations were applied to the products to estimate the toxicity, degree of oxidation and probable routes of aerobic biodegradation suggesting a beneficial action of sonodegradation. Finally, the sonochemical degradation of the antihypertensives was carried out in two simulated complex matrices (i.e., seawater and hospital wastewater) and an actual wastewater. Interestingly, the losartan and valsartan eliminations in such waters were similar to the observed in distilled water. This fact indicates the high potentiality of ultrasound to degrade losartan or valsartan in waters containing other substances, even at higher concentrations than these pollutants.


Assuntos
Anti-Hipertensivos/química , Modelos Químicos , Sonicação , Águas Residuárias/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Losartan/química , Oxirredução , Valsartana/química
14.
Curr Protein Pept Sci ; 20(10): 984-995, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389312

RESUMO

Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis. But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflammation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention. Hypertension is a disease with high incidence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vascular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with increased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly raise BP and promote target organ damage. Due to the high correlation between vitamin D and hypertension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage.


Assuntos
Anti-Hipertensivos , Hipertensão/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos
15.
Adv Food Nutr Res ; 89: 165-207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31351525

RESUMO

Non-communicable diseases including cardiovascular diseases (CVDs) and associated metabolic disorders are responsible for nearly 40 million deaths globally per year. Hypertension or high blood pressure (BP) is one of the primary reasons for the development of CVDs. A healthy nutritional strategy complementing with physical activity can substantially reduce high BP and prevent the occurrence of CVD-associated morbidity and mortality. Bioactive peptides currently are the next wave of the promising bench to clinic options for potential targeting chronic and acute health issues including hypertension. Peptides demonstrating anti-inflammatory, anti-oxidant, and angiotensin-converting enzyme-I inhibitory activity are widely studied for the amelioration of hypertension and associated CVDs. Isolating these potent bioactive peptides from different food sources is a promising endeavor toward nutraceutical based dietary management and prevention of hypertension. Understanding the pathophysiology of hypertension and the action mechanisms of the bioactive peptides would complement in designing and characterizing more potent peptides and suitable comprehensive dietary plans for the prevention of hypertension and associated CVDs.


Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Hipertensão/dietoterapia , Hipertensão/fisiopatologia , Peptídeos/farmacologia , Proteínas na Dieta/farmacologia , Suplementos Nutricionais , Humanos , Peptídeos/química
16.
Eur J Med Chem ; 180: 562-612, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344615

RESUMO

Heterocycles occupy a salient place in chemistry due to their wide range of activity in the fields of drug design, photochemistry, agrochemicals, dyes, and so on. Amongst all, indole scaffold is considered as one of the most promising heterocycles found in natural and synthetic sources and has been shown to possess various biological activity, including anti-inflammatory, anti-HIV, antitubercular, antimalarial, anticonvulsant, antidiabetic, antihypertensive, analgesics, antidepressant, anticancer, antioxidant, antifungal, and antimicrobial, etc. All the reported indole molecules bind to multiple receptors with high affinity, thus expedite the research on the development of novel biologically active compounds through the various approach. In this review, we aimed to highlight synthetic and medicinal perspective on the development of indole-based analogs. In addition, structural activity relationship (SAR) study to correlate for their biological activity also discussed.


Assuntos
Indóis/síntese química , Indóis/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade
17.
Curr Med Chem ; 26(22): 4241-4252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31345142

RESUMO

Glaucoma is the second leading cause of blindness in the world, affecting more than 60 million people globally. In order to reduce the progression of the disease, both medical and surgical treatments are used. Frequent side effects of both treatments include a range of modifications of the ocular surface grouped as the Ocular Surface Disease (OSD), which include Dry Eye Disease (DED). DED and other OSD negatively impact on the success of anti-glaucoma treatments and reduce the adherence to medical therapies. Tear film osmolarity (TFO) is a relatively novel test which has become a hallmark of DED. The aim of this paper was to review the association between OSD, DED and glaucoma in view of published TFO data, and to discuss future fields of research and treatments on the topic of glaucoma iatrogenic damage.


Assuntos
Anti-Hipertensivos/farmacologia , Doenças da Córnea/tratamento farmacológico , Glaucoma/tratamento farmacológico , Conservantes Farmacêuticos/farmacologia , Lágrimas/efeitos dos fármacos , Animais , Anti-Hipertensivos/química , Humanos , Concentração Osmolar , Conservantes Farmacêuticos/química , Propriedades de Superfície
18.
Eur J Med Chem ; 180: 486-508, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330449

RESUMO

From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.


Assuntos
Compostos Heterocíclicos/farmacologia , Enxofre/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Farmacêutica , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Enxofre/química
19.
Mater Sci Eng C Mater Biol Appl ; 103: 109800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349458

RESUMO

Azelnidipine, dihydropyridine based calcium channel blocker has been used for treating ischemic heart disease and cardiac remodeling after myocardial infarction but it is having a low bioavailability due to its poor solubility. The present study is to investigate the formulation and evaluation of floating tablets of Azelnidipine for controlled release and to increase bioavailability by increasing the gastrointestinal transit time and mucoadhesion of drug. The gastro retentive tablets were prepared by direct compression method using different concentrations of combination of Polyoxyethylene oxide WSR 303 as hydrophilic polymer and Potassium bicarbonate as gas generating agent. Main effects of the formulation variables were evaluated quantitatively using design approach showing that both independent variables have significant effects on floating lag time, % drug release at 1 h (D1 h) and time required to release 90% of the drug (t90). The statistically optimized formulation (F3) released 95.11 ±â€¯1.43% drug for 12 h followed K-Peppas drug release kinetics indicating release of drug by diffusion and erosion mechanism. Evaluation of the optimized formulation in vivo in human volunteers showed that the GFT was buoyant in gastric fluid and that its gastric residence time was enhanced. Pharmacokinetics studies carried out revealed significant (P < 0.05) equivalent Cmax, longer Tmax and higher AUC values for the optimized formula compared to the marketed oral product. From the results obtained it can be concluded that Azelnidipine Gastro retentive tablets with enhanced bioavailability and better release pattern is suitable for more effective treatment compared to marketed conventional tablets.


Assuntos
Anti-Hipertensivos/farmacocinética , Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas/química , Portadores de Fármacos/química , Mucosa Gástrica/metabolismo , Comprimidos/química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Ácido Azetidinocarboxílico/farmacologia , Bicarbonatos/química , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ácido Gástrico/química , Meia-Vida , Humanos , Polietilenoglicóis/química , Compostos de Potássio/química , Coelhos
20.
Int J Pharm ; 568: 118509, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301463

RESUMO

The objectives of this study were to evaluate the impact of formulation variables on the drying of nanocrystalline suspensions either via bead layering or spray granulation and develop mini-tablets from the dried nanocrystalline powders. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound. An optimized irbesartan nanocrystalline suspension with a mean particle size of 300 nm was utilized for the downstream processing. Irbesartan nanocrystalline suspension was dried either by layering onto the microcrystalline cellulose beads (i.e. 200 or 500 µm) or by granulation (mannitol or microcrystalline cellulose as substrates) at two different drug loadings (i.e. 10% or 30% w/w). Smaller size beads layered with nanocrystals resulted in faster dissolution profiles compared to larger size beads at both the studied drug loadings (i.e. 10 and 30% w/w). Mannitol granules containing irbesartan nanocrystals resulted in faster dissolution profiles compared to microcrystalline cellulose granules. Microcrystalline cellulose beads and mannitol granules containing irbesartan nanocrystals (i.e. 30% w/w drug loading) were further compressed into mini-tablets. Mini-tablets retained fast drug dissolution characteristics of the dried powders. The results from this study indicated that the spray granulation is a superior drying approach compared to bead layering for drying of irbesartan nanocrystalline suspension and mini-tablet development.


Assuntos
Anti-Hipertensivos/química , Composição de Medicamentos/métodos , Irbesartana/química , Nanopartículas/química , Celulose/química , Dessecação , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Manitol/química , Suspensões , Comprimidos
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