Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.199
Filtrar
1.
Curr Top Med Chem ; 19(31): 2919-2936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31763974

RESUMO

Cilostazol is a unique platelet inhibitor that has been used clinically for more than 20 years. As a phosphodiesterase type III inhibitor, cilostazol is capable of reversible inhibition of platelet aggregation and vasodilation, has antiproliferative effects, and is widely used in the treatment of peripheral arterial disease, cerebrovascular disease, percutaneous coronary intervention, etc. This article briefly reviews the pharmacological mechanisms and clinical application of cilostazol.


Assuntos
Cilostazol/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cilostazol/química , Humanos , Estrutura Molecular , Inibidores da Agregação de Plaquetas/química
2.
Cardiovasc Hematol Agents Med Chem ; 17(2): 115-124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622211

RESUMO

AIM: This study aims to find out the components responsible for the antithrombotic activity of Nelumbo nucifera. MATERIAL AND METHODS: Petroleum ether, chloroform and hydroalcoholic extracts of whole plant of Nelumbo nucifera (Lotus) were prepared and assessed for its thrombolytic, anti-platelet aggregation activity and bleeding time. The extracts were further analyzed through HPTLC and GC-MS. Statistical analysis was conducted through ANOVA trailed by Tukey's multiple comparison test test. RESULTS: Hydroalcoholic extract showed the highest activity at the concentration of 400µg/ml in thrombolytic assay (42.03 ± 5.76), anti-platelet aggregation assay (57.93 ± 1.68) and bleeding time (70.17 ± 2.16) in comparison to clopodigrel (33.76 ± 3.43), aspirin (66.55 ± 1.86) and aspirin (93.85 ± 2.75) at the concentration of 100 µg/ml respectively. 25 peaks were identified through GC-MS, out of which, ferulic acid (14.2µ/g) and quercetin (5.4 µ/g) are active chemical compounds. HPTLC showed different chromatograms in hydroalcoholic extracts like (1) chlorogenic, (2) quercetin, (3) benzoic acid, (4) caffeic acid, (5) ferulic acid, (6) kaempferol, and (7) gallic acid. CONCLUSION: Based on these findings, flavonoids present in hydroalcoholic extract may be developed into a drug for clinical application for the treatment of thrombosis in patients.


Assuntos
Fibrinolíticos/uso terapêutico , Flavonoides/uso terapêutico , Nelumbo/química , Extratos Vegetais/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Trombose/tratamento farmacológico , Animais , Tempo de Lise do Coágulo de Fibrina , Fibrinolíticos/química , Flavonoides/química , Masculino , Extratos Vegetais/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Ratos Wistar , Terapia Trombolítica
3.
Molecules ; 24(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597284

RESUMO

Sea buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) is a small tree or bush. It belongs to the Elaeagnaceae family, and has been used for many years in traditional medicine in both Europe and Asia. However, there is no data on the effect of sea buckthorn leaves and twigs on the properties of blood platelets. The aim of the study was to analyze the biological activity of phenolic extracts from leaves and twigs of sea buckthorn in blood platelets in vitro. Two sets of extracts were used: (1) phenolic compounds from twigs and (2) phenolic compounds from leaves. Their biological effects on human blood platelets were studied by blood platelet adhesion, platelet aggregation, arachidonic acid metabolism and the generation of superoxide anion. Cytotoxicity was also evaluated against platelets. The action of extracts from sea buckthorn twigs and leaves was compared to activities of the phenolic extract (a commercial product from the berries of Aronia melanocarpa (Aronox®) with antioxidative and antiplatelet properties. This study is the first to demonstrate that extracts from sea buckthorn leaves and twigs are a source of bioactive compounds which may be used for the prophylaxis and treatment of cardiovascular pathologies associated with blood platelet hyperactivity. Both leaf and twig extracts were found to display anti-platelet activity in vitro. Moreover, the twig extract (rich in proanthocyanidins) displayed better anti-platelet potential than the leaf extract or aronia extract.


Assuntos
Elaeagnaceae/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Inibidores da Agregação de Plaquetas/farmacologia , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação
4.
Eur J Med Chem ; 183: 111722, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563807

RESUMO

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 µM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Trombose/tratamento farmacológico , Animais , Descoberta de Drogas , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombina/metabolismo
5.
BMC Complement Altern Med ; 19(1): 236, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481052

RESUMO

BACKGROUND: Syzygium cumini (L.) Skeels. is one of the very popular traditionally used medicinal plants with numerous pharmacological activities including antioxidant, hypoglycemic and anti-inflammatory. However, actions of S. cumini on blood coagulation and other parameters of blood were poorly pharmacologically studied. Therefore, aim of this present investigation is to examine the effects of methanolic extract of S. cumini on blood coagulation and anticoagulation factors in healthy white albino rabbits at different doses. METHODS: Blood samples were drawn twice during this study and biochemical assays were performed to determine the effect on different parameters such as coagulation, anticoagulation, hematological, Protein C (PC) and thrombin antithrombin (TAT) complex and platelet aggregation. RESULTS: The results showed significant increase in RBCs, hemoglobin, hematocrit and platelets counts up to 1.4 × 103/cm, 2.2 g/dl, 6%, 248.2 × 103/cm respectively. While, thrombin and bleeding time were also prolonged in dose dependent manner which is highly significant (p ≤ 0.005) as compared to control. Similarly, highly significantly increased (p ≤ 0.005) in levels of protein C, thrombin antithrombin complex at dose of 500 mg/kg were observed. Whereas, levels of platelets aggregation and fibrinogen were decreased at high doses. CONCLUSION: The obtained findings of hematological and coagulation tests concludes possibly S. cumini possess anticoagulant and antiplatelet effects.


Assuntos
Anticoagulantes/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Syzygium/química , Animais , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Folhas de Planta/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Coelhos
6.
Arch Pharm Res ; 42(10): 862-878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31493264

RESUMO

Ginseng is the most frequently used herbal medicine for immune system stimulation and as an adjuvant with prescribed drugs owing to its numerous pharmacologic activities. It is important to investigate the beneficial effects and interaction of ginseng with therapeutic drugs. This review comprehensively discusses drug metabolizing enzyme- and transporter-mediated ginseng-drug interaction by analyzing in vitro and clinical results with a focus on ginsenoside, a pharmacologically active marker of ginseng. Impact of ginseng therapy or ginseng combination therapy on diabetic patients and of ginseng interaction with antiplatelets and anticoagulants were evaluated based on ginseng origin and ginsenoside content. Daily administration of Korean red ginseng (0.5-3 g extract; dried ginseng > 60%) did not cause significant herb-drug interaction with drug metabolizing enzymes and transporters. Among various therapeutic drugs administered in combination with ginseng, adjuvant chemotherapy, comprising ginseng (1-3 g extract) and anticancer drugs, was effective for reducing cancer-related fatigue and improving the quality of life and emotional scores. Limited information regarding ginsenoside content in each ginseng product and plasma ginsenoside concentration among patients necessitates standardization of ginseng product and establishment of pharmacokinetic-pharmacodynamic correlation to further understand beneficial effects of ginseng-therapeutic drug interactions in future clinical studies.


Assuntos
Anticoagulantes/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Hipoglicemiantes/farmacologia , Neoplasias/tratamento farmacológico , Panax/química , Inibidores da Agregação de Plaquetas/farmacologia , Anticoagulantes/química , Antineoplásicos Fitogênicos/química , Diabetes Mellitus/tratamento farmacológico , Ginsenosídeos/química , Interações Ervas-Drogas , Humanos , Hipoglicemiantes/química , Inibidores da Agregação de Plaquetas/química
7.
Chin J Nat Med ; 17(8): 591-599, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472896

RESUMO

Whitmania pigra has been used as a traditional Chinese medicine (TCM) for promoting blood circulation, alleviating blood coagulation, activating meridians and relieving stasis for several hundred years. However, the therapeutic components of this species, especially proteins and peptides were poorly exploited. Until now only a few of them were obtained by using chromatographic isolation and purification. In recent decade, transcriptome techniques were rapidly developed, and have been used to fully reveal the functional components of many animal venoms. In the present study, the cDNA of the salivary gland of Whitmania pigra was sequenced by illumina and the transcriptome was assembled by using Trinity. The proteome were analysed by LC-MS/MS. Based on the data of the transcriptome and the proteome, a potential antiplatelet protein named pigrin was found. Pigrin was cloned and expressed using P. pastoris GS115. The antiplatelet andantithrombotic bioactivities of pigrin were tested by using aggregometer and the rat arterio-venous shunt thrombosis model, respectively. Thebleeding time of pigrin was measured by a mice tail cutting method. The docking of pigrin and protease-activated receptor 1 (PAR1) or collagen were conducted using the ZDOCK Server. Pigrin was able to selectively inhibit platelet aggregation stimulated by PAR1 agonist and collagen. Pigrin attenuated thrombotic formation in vivo in rat, while did not prolong bleeding time at its effective dosage. There are significant differences in the key residues participating in binding of Pigrin-Collagen complex from Pigrin-PAR1 complex. In conclusion,a novel PAR1 inhibitor pigrin was found from the leech Whitmania pigra. This study helped to elucidate the mechanism of the leech for the treatment of cardiovascular disorder.


Assuntos
Sanguessugas/química , Receptor PAR-1/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Perfilação da Expressão Gênica , Sanguessugas/genética , Sanguessugas/metabolismo , Camundongos Endogâmicos ICR , Modelos Moleculares , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Proteômica , Ratos Sprague-Dawley , Glândulas Salivares/química , Glândulas Salivares/metabolismo , Trombose/prevenção & controle
8.
Drug Dev Ind Pharm ; 45(9): 1515-1522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267803

RESUMO

Optimization of electrospray ionization (ESI) parameters is routinely carried out by one factor at a time (OFAT) or auto-tune software (ATS). Design of experiments (DOE) approach has been reported to be an excellent alternative to OFAT or ATS. Box-Behnken Design (BBD) was successfully used to optimize ESI parameters like nebulizing gas flow rate, desolvation line temperature, heat block temperature, and drying gas flow rate for [M + H]+ intensity of Clopidogrel bisulfate (CLP) and Ticlopidine (TLP). BBD model was found to be significant with p < .0001 for both CLP and TLP. The predicted and optimized (OL) ESI parameters were used for chromatographic analysis and were compared against three levels of ESI parameters, i.e. low level (LL), medium level (ML), and high level (HL). The OL ESI parameters were subjected to chromatographic analysis and its mean peak area was significantly higher than mean peak area for LL, ML, and HL ESI in case of CLP and TLP (p < .001). However, no significant difference was observed between the mean peak area for ML and OL of TLP. Thus, BBD can be considered with 29 trials to optimize four mass spectrometric parameters. The liquid chromatographic parameters percentage of methanol, percentage of formic acid and flow rate were also optimized using BBD. However, the optimized method did not significantly influence the peak response over the non-optimized method.


Assuntos
Inibidores da Agregação de Plaquetas/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/métodos , Clopidogrel/análise , Clopidogrel/química , Modelos Químicos , Inibidores da Agregação de Plaquetas/química , Sensibilidade e Especificidade , Ticlopidina/análise , Ticlopidina/química
9.
Int J Mol Sci ; 20(11)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163690

RESUMO

Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10-80 µM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2-PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.


Assuntos
Plaquetas/metabolismo , Trombose/etiologia , Trombose/prevenção & controle , Umbeliferonas/uso terapêutico , Biomarcadores , Plaquetas/efeitos dos fármacos , Humanos , Fosfolipase C gama/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/química , Umbeliferonas/farmacologia
10.
J Enzyme Inhib Med Chem ; 34(1): 999-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072143

RESUMO

This study explored the possible bioactive ingredients and target protein of Rostellularia procumbens (L.) Nees. The results of optical turbidimetry revealed that the ethyl acetate extraction obtained from R. procumbens (L.) Nees could inhibit platelet aggregation. Gene chip was used to investigate differentially expressed genes. According to the results of the gene chip, the targets of compounds isolated from the ethyl acetate extraction were predicted by network pharmacology. Computational studies revealed that chinensinaphthol methyl ether and neojusticin B may target the integrin αIIbß3 protein. The results of Prometheus NT.48 and microscale thermophoresis suggested that the molecular interactions between the two compounds with purified integrin αIIbß3 protein in the optimal test conditions were coherent with the docking results. To our best knowledge, this is the first report to state that chinensinaphthol methyl ether and neojusticin B target the integrin αIIbß3 protein.


Assuntos
Acanthaceae/química , Derivados de Benzeno/farmacologia , Dioxolanos/farmacologia , Éteres/farmacologia , Lignanas/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/isolamento & purificação , Dioxolanos/química , Dioxolanos/isolamento & purificação , Relação Dose-Resposta a Droga , Éteres/química , Éteres/isolamento & purificação , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Testes de Função Plaquetária , Relação Estrutura-Atividade
11.
Molecules ; 24(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013947

RESUMO

Many Premna species have been used in traditional medicine to treat hypertension and cardiac insufficiency, and as a tonic for cardiac-related problems. Some have been reported to possess cardiovascular protective activity through several possible mechanisms, but not Premna foetida. In the present study, the methanol extract of P. foetida leaves (PFM) and its isolated compounds were evaluated for their ability to inhibit copper-mediated human low-density lipoprotein (LDL) oxidation and arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation. Six flavonoids, three triterpenoids, vanillic acid and stigmasterol were successfully isolated from PFM. Of the isolated compounds, quercetin was the most active against LDL oxidation (IC50 4.25 µM). The flavonols were more active than the flavones against LDL oxidation, suggesting that hydroxyl group at C-3 and the catechol moiety at B-ring may play important roles in protecting LDL from oxidation. Most tested flavonoids showed stronger inhibition towards AA-induced than the ADP-induced platelet aggregation with apigenin exhibiting the strongest effect (IC50 52.3 and 127.4 µM, respectively) while quercetin and kaempferol showed moderate activity. The results suggested that flavonoids, especially quercetin, apigenin and kaempferol were among the major constituents of P. foetida responsible for anti-LDL oxidation and anti-platelet aggregation.


Assuntos
Plaquetas/metabolismo , Flavonoides , Lamiaceae/química , Lipoproteínas LDL/metabolismo , Extratos Vegetais , Folhas de Planta/química , Inibidores da Agregação de Plaquetas , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Ácido Araquidônico/farmacologia , Plaquetas/citologia , Flavonoides/química , Flavonoides/farmacologia , Humanos , Lipoproteínas LDL/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia
12.
Int J Biol Macromol ; 133: 674-682, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31022485

RESUMO

In the current study, a carboxyl-rich polysaccharide purified from Lycium barbarum L. leaves (hereafter, LP) and its degradation with ascorbic acid and hydrogen peroxide were characterized. Degradation decreased the molecular weight of LP from 4.63 × 104 to 3.45 × 104 Da, and increased its zeta potential from -8.01 to -5.35 mV. In vitro experiments showed that degradation significantly increased the anticoagulant activity and, in particular, antiplatelet activity of LP (p < 0.05). The polysaccharide with the highest degree of degradation had higher inhibitory activity than aspirin against arachidonic acid- and thrombin-induced platelet aggregation at 0.5 g/mL. A reduction in uronic acids between LP and its degradation products significantly decreased their antiplatelet activity (p < 0.05). Further analysis confirmed that polysaccharides changed from a compact spherical structure to a random coil in aqueous solution following degradation, which facilitated the interaction of polysaccharides and platelets.


Assuntos
Lycium/química , Folhas de Planta/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Ácido Ascórbico/química , Configuração de Carboidratos , Frutas/química , Humanos , Peróxido de Hidrogênio/química , Peso Molecular , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia
13.
Int J Biol Macromol ; 131: 787-797, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876901

RESUMO

The recent study deals with the synthesis and characterization of silver nanoparticles bounded to Selaginella bryopteris (Sanjeevini) Plant extract (SPE) as reducing and capping agents. Selaginella bryopteris plant extract silver nanoparticles (SPE@Ag-NPs) was characterized by PXRD, UV-Vis., FESEM, TEM and EDX. The highly stable SPE@Ag-NPs was found promising as antibacterial and antifungal agents when tested against human pathogens S. aureus, E. coli, and A. niger respectively. Furthermore, SPE@Ag-NPs found to show anticoagulant property by enhancing the clotting time of citrated human PRP as well as PPP from the control 160 s to 220 s and 160 s to 284 s respectively. However, SPE@Ag-NPs exhibited mild antiplatelet activity by inhibiting specifically agonist ADP induced platelet aggregation of about 23% at the concentration of 30 µg. Fascinating, SPE@Ag-NPs did not alter the agonist epinephrine-induced platelet function even at the increased dose. Interestingly, SPE@Ag-NPs did not induce edema and hemorrhage in the experimental mice and also did not hydrolyze RBC cells suggesting its nontoxic property. In conclusion, SPE@Ag-NPs was non-toxic and found to exhibit antibacterial, antifungal, anticoagulant and antiplatelet properties. Thus, SPE@Ag-NPs would be a better candidate in the biomedical field especially to treat thrombotic disorders.


Assuntos
Anti-Infecciosos/farmacologia , Anticoagulantes/farmacologia , Nanopartículas Metálicas/química , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Selaginellaceae/química , Prata/química , Anti-Infecciosos/química , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Fenômenos Químicos , Técnicas de Química Sintética , Química Verde , Humanos , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Inibidores da Agregação de Plaquetas/química , Prata/farmacologia , Análise Espectral
14.
Nutrients ; 11(2)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813256

RESUMO

We examined the ability of tomato pomace extract (by-product) to affect platelet aggregation in healthy humans (clinical pilot study). In phase 1 the tolerance of participants (n = 15; 5 per dose level) ingesting tomato pomace extract across three dose levels (1, 2.5, and 10 g) was evaluated. Phase 2 was a single-blind, placebo-controlled, parallel design human (male, n = 99; 33 per group) pilot intervention trial investigating the acute and repeated dose effects (5 days) of different doses of tomato pomace extract (1 g, 2.5 g or placebo) on platelet aggregation ex vivo. Various flavonoids (coumaric acid, floridzin, floretin, procyanidin B2, luteolin-7-O-glucoside, kaempferol, and quercitin) and nucleosides (adenosine, inosine, and guanosine) were identified in the tomato pomace extract. The clinical study showed that the daily consumption of 1 g of aqueous extract of tomato pomace for 5 days exerted an inhibitory activity on platelet aggregation.


Assuntos
Lycopersicon esculentum/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Adolescente , Adulto , Feminino , Manipulação de Alimentos , Humanos , Masculino , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/química , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Inibidores da Agregação de Plaquetas/química , Adulto Jovem
15.
Med Chem ; 15(8): 850-862, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799791

RESUMO

BACKGROUND: Ischemic heart disease, cerebrovascular accident, and venous thromboembolism have the presence of a thrombotic event in common and represent the most common causes of death within the population. OBJECTIVE: Since Schiff base copper(II) complexes are able to interact with polyphosphates (PolyP), a procoagulant and potentially prothrombotic platelet agent, we investigated the antiplatelet aggregating properties of two novel tridentate Schiff base ligands and their corresponding copper( II) complexes. METHODS: The Schiff base ligands (L1) and (L2), as well as their corresponding copper(II) complexes (C1) and (C2), were synthesized and characterized by chemical analysis, X-ray diffraction, mass spectrometry, and UV-Visible, IR and far IR spectroscopy. In addition, EPR studies were carried out for (C1) and (C2), while (L1) and (L2) were further analyzed by 1H and 13C NMR. Tests for antiplatelet aggregation activities of all of the four compounds were conducted. RESULTS: X-ray diffraction studies show that (L1) and (L2) exist in the enol-imine tautomeric form with a strong intramolecular hydrogen bond. NMR studies show that both ligands are found as enol-imine tautomers in CDCl3 solution. In the solid state, the geometry around the copper(II) ion in both (C1) and (C2) is square planar. EPR spectra suggest that the geometry of the complexes is similar to that observed in the solid state by X-ray crystallography. Compound (C2) exhibited the strongest antiplatelet aggregation activity. CONCLUSION: Schiff base copper(II) complexes, which are attracting increasing interest, could represent a new approach to treat thrombosis by blocking the activity of PolyP with a potential anticoagulant activity and, most importantly, demonstrating no adverse bleeding events.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Bases de Schiff/química , Adulto Jovem
16.
Med Chem ; 15(8): 863-872, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30734681

RESUMO

BACKGROUND: Platelet aggregation plays a pathogenic role in the development of arterial thrombi, which are responsible for common diseases caused by thrombotic arterial occlusion, such as myocardial infarction and stroke. Much efforts are directed toward developing platelet aggregation inhibitors that act through several mechanisms: The main antiplatelet family of COXinhibitors, phosphodiesterase inhibitors, and thrombin inhibitors. Recently, the important role in the platelet aggregation of adenosine diphosphate (ADP)-activated P2Y12 and P2Y1 receptors, Gprotein coupled receptors of the P2 purinergic family, has emerged, and their inhibitors are explored as potential therapeutic antithrombotics. P2Y12 inhibitors, i.e. clopidogrel, prasugrel, ticagrelor, and cangrelor, are already used clinically to reduce coronary artery thrombosis risk and prevent acute coronary syndromes. The search for new P2Y12 inhibitors, with better risk-to-benefit profiles is still ongoing. METHODS: Several years ago, our group prepared a series of 6-amino-2-thio-3H-pyrimidin-4-one derivatives that displayed an interesting platelet aggregation inhibiting activity. In order to probe the structure-activity relationships and improve their inhibitory effects of these compounds, we synthesized variously substituted 6-amino-2-thio-3H-pyrimidin-4-one derivatives and substituted 4-amino-2-thiopyrimidine-5-carboxylic acid analogues. All the synthesized compounds were tested by light trasmission aggregometry (LTA) as inducers or inhibitors of platelet aggregation in citrated platelet-rich plasma (PRP). RESULTS: Among the 6-amino-2-thio-3H-pyrimidin-4-one derivatives, compounds 2c and 2h displayed marked inhibitory activity, with a capability to inhibit the ADP(10-6M)-induced platelet aggregation by 91% and 87% at 10-4M concentration, respectively. Selected 4-amino-2- thiopyrimidine-5-carboxylic acid derivatives were tested as P2Y12 and P2Y1 antagonists and found to display negligible activity. CONCLUSION: These negative findings demonstrated that this heterocyclic nucleus is not a useful common pharmacophore for developing P2Y-dependent inhibitors of platelet aggregation. Nevertheless, compounds 2c and 2h could represent a new chemotype to further develop inhibitors of platelet aggregation.


Assuntos
Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
17.
Drug Dev Ind Pharm ; 45(6): 959-967, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30767579

RESUMO

In this work, aspirin (ASP) sustained granules were prepared using micro-crystal coating and hot-melt granulation, respectively. In the process of micro-crystal coating, PVP was used to form the isolation layer and then coated with either Eudragit RS/RL30D or ethyl cellulose (EC) as sustained-release layers to prepare sustained granules (the granules from this method were denoted m-cG). And in the process of hot-melt granulation, the granules were obtained with stearyl alcohol as a binder and EC as matrix material to prepare sustained granules (the granules were denoted h-mG). The in vitro release of ASP sustained-release granules was investigated by dissolution apparatus and the stability of the granules was studied. Since both methods effectively prevented the hydrolysis of ASP, the sustained granules by micro-crystal coating and hot-melt granulation were stable. However, there was a clear difference in the in vitro release of h-mG and m-cG. The h-mG was completely released in 4 h, while the m-cG with EC as sustained-release layer released 80% in 24 h and the m-cG with the Eudragit RS/RL 30 D as sustained-release layer released completely in 5 h. The results showed that micro-crystal coating was more suitable for the preparation of ASP sustained granules, and the granules with EC as sustained layer could achieve a better sustained-release effect.


Assuntos
Aspirina/farmacocinética , Composição de Medicamentos/métodos , Excipientes/química , Inibidores da Agregação de Plaquetas/farmacocinética , Aspirina/administração & dosagem , Aspirina/química , Celulose/análogos & derivados , Celulose/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/química , Solubilidade , Acidente Vascular Cerebral/prevenção & controle
18.
Int J Pharm ; 558: 284-290, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30641181

RESUMO

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol-gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol-gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.


Assuntos
Cilostazol/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Disponibilidade Biológica , Cilostazol/química , Cilostazol/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Cães , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacocinética , Dodecilsulfato de Sódio/administração & dosagem , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/farmacocinética , Vasodilatadores/química , Vasodilatadores/farmacocinética
19.
Molecules ; 24(2)2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669612

RESUMO

The population is now living longer during the period classified as "elderly" (60 years and older), exhibiting multimorbidity associated to the lengthening of the average life span. The dietary intake of phenolic compounds (PC) may affect the physiology, disease development and progression during the aging process, reducing risk factors of age related diseases. The aim of this review is to briefly describe some of the possible effects of a series of PC on the reduction of risk factors of the onset of cardiovascular diseases, considering their potential mechanisms of action. The main actions described for PC are associated with reduced platelet activity, anti-inflammatory effects, and the protection from oxidation to reduce LDL and the generation of advanced glycation end products. Preclinical and clinical evidence of the physiological effects of various PC is presented, as well as the health claims approved by regulatory agencies.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Fenóis/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Disponibilidade Biológica , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Benefícios do Seguro , Fenóis/química , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Fatores de Risco
20.
ACS Appl Mater Interfaces ; 11(4): 4523-4530, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30607929

RESUMO

Two major challenges faced by medical devices are thrombus formation and infection. In this work, surface-tethered nitric oxide (NO)-releasing molecules are presented as a solution to combat infection and thrombosis. These materials possess a robust NO release capacity lasting ca. 1 month while simultaneously improving the nonfouling nature of the material by preventing platelet, protein, and bacteria adhesion. NO's potent bactericidal function has been implemented by a facile surface covalent attachment method to fabricate a triple-action coating-surface-immobilized S-nitroso- N-acetylpenicillamine (SIM-S). Comparison of NO loading amongst the various branching configurations is shown through the NO release kinetics over time and the cumulative NO release. Biological characterization is performed using in vitro fibrinogen and Staphylococcus aureus assays. The material with the highest NO release, SIM-S2, is also able to reduce protein adhesion by 65.8 ± 8.9% when compared to unmodified silicone. SIM-S2 demonstrates a 99.99% (i.e., ∼4 log) reduction for S. aureus over 24 h. The various functionalized surfaces significantly reduce platelet adhesion in vitro, for both NO-releasing and non-NO-releasing surfaces (up to 89.1 ± 0.9%), demonstrating the nonfouling nature of the surface-immobilized functionalities. The ability of the SIM-S surfaces to retain antifouling properties despite gradual depletion of the bactericidal source, NO, demonstrates its potential use in long-term medical implants.


Assuntos
Antibacterianos/química , Anti-Infecciosos/química , Inibidores da Agregação de Plaquetas/química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Humanos , Óxido Nítrico/química , Inibidores da Agregação de Plaquetas/farmacologia , S-Nitroso-N-Acetilpenicilamina/química , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA