Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 207
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31877432

RESUMO

Gandou Decoction (GDD), a well-known traditional Chinese medicine prescription, has been widely used for decades in clinical practice to treat Wilson's disease (WD) in China. However, due to lack of in vivo metabolism research, the absorbed components and metabolites of GDD have not been fully elucidated. In this study, a rapid and high-throughput ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MSE) was applied to rapidly identify prototypes and metabolites after oral administration of GDD. On this basis, the possible metabolic pathways of the main prototypes were proposed between normal and copper-laden rats. As a result, a total of 89 GDD-related xenobiotics were detected in normal dosed rats, including 83 (36 prototypes and 47 metabolites) in plasma and 52 (21 prototypes and 31 metabolites) in liver; a total of 77 GDD-related xenobiotics were detected in copper-laden dosed rats, including 68 (31 prototypes and 37 metabolites) in plasma and 42 (19 prototypes and 23 metabolites) in liver. Our findings showed that anthraquinones, alkaloids and protostane triterpenoids as well as a few saponins, flavonoids, tannins and curcuminoids were the main absorbed chemical components of GDD in rat plasma; anthraquinones, protostane triterpenoids and curcuminoids were the major components in rat liver. Glucuronidation and sulfation were deduced to be the predominant metabolic pathways of GDD. Methylation, acetylation, reduction, hydroxylation, demethylation and deglycosylation were often occurred in the metabolic process. Furthermore, the holistic metabolic profile of GDD revealed that copper-laden rats and normal rats had certain differences in drug absorption and metabolism. This study offered a solid basis for ascertaining bioactive components and action mechanism of GDD.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Fígado , Espectrometria de Massas em Tandem/métodos , Alcaloides/análise , Alcaloides/farmacocinética , Animais , Antraquinonas/análise , Antraquinonas/farmacocinética , Cobre/administração & dosagem , Cobre/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica , Ratos , Triterpenos/análise , Triterpenos/farmacocinética
2.
Carbohydr Polym ; 229: 115473, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826443

RESUMO

The development of solubilizers with high efficiency, high safety and simple technology is one of the important fields in modern pharmaceutical industry. Our previous study found that vinegar baked Radix Bupleurum polysaccharides (VBCP) was a potential candidate. This study aimed to clarify which polysaccharide in VBCP had solubility enhancement effect and its solubilizing mechanism. Here, we reported that a novel acidic branched polysaccharide from VBCP, VBCP-3-A, which was non-toxic and had high solubility to baicalin and rhein. It was much better than that of Tween 80. The solubilization mechanism might be that VBCP-3-A self-assembled to form micelle-like aggregates in water, which can encapsulate water-insoluble constituents through the interaction of both hydrogen bonding and hydrophobic forces. in vivo pharmacokinetic study showed that VBCP-3-A increased Cmax and AUC (0-t) of baicalin and rhein. Those results suggested that VBCP-3-A was a potential solubilizer with high efficiency and high safety.


Assuntos
Bupleurum/química , Portadores de Fármacos/química , Polissacarídeos/química , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Sequência de Carboidratos , Linhagem Celular , Portadores de Fármacos/toxicidade , Flavonoides/química , Flavonoides/farmacocinética , Humanos , Masculino , Micelas , Raízes de Plantas/química , Polissacarídeos/toxicidade , Ratos Sprague-Dawley , Solubilidade
3.
J Pharm Pharmacol ; 71(10): 1475-1487, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373015

RESUMO

OBJECTIVE: Chrysophanol is a natural anthraquinone, also known as chrysophanic acid and 1,8-dihydroxy-3-methyl-anthraquinone. It has been widely used in the food and pharmaceutical fields. This review is intended to provide a comprehensive overview of the pharmacology, toxicity and pharmacokinetic researches of chrysophanol. KEY FINDING: Information on chrysophanol was collected from the Internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PM using a combination of keywords including 'pharmacology', 'toxicology' and 'pharmacokinetics'. The literature we collected included from January 2010 to June 2019. Chrysophanol has a wide spectrum of pharmacological effects, including anticancer, antioxidation, neuroprotection, antibacterial and antiviral, and regulating blood lipids. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity, and pharmacokinetics indicate that the use of chrysophanol in combination with other drugs can reduce toxicity and enhance efficacy. SUMMARY: Chrysophanol can be used in many diseases. Future research directions include how the concentration of chrysophanol affects pharmacological effects and toxicity; the mechanism of synergy between chrysophanol and other drugs.


Assuntos
Antraquinonas/efeitos adversos , Antraquinonas/farmacologia , Animais , Antraquinonas/agonistas , Antraquinonas/farmacocinética , Humanos
4.
J Pharm Biomed Anal ; 174: 696-706, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31288192

RESUMO

Semen Cassiae, called Juemingzi in Chinese, is widely used in clinic for alleviating constipation, improving eyesight and preventing hyperlipidemia. It can be used as medicine or food including many application forms, such as traditional pieces and ultrafine granular powder (UGP). In this paper, comparative pharmacokinetics of Semen Cassiae in different forms of traditional pieces and UGP were achieved to research the clinical dosage of UGP. Also, the scientific connotation of brewing way for traditional pieces of Semen Cassiae application in clinic was revealed. To achieve this purpose, a rapid, sensitive and reliable UHPLC-MS/MS method was developed for simultaneous determination of rhein, emodin, aloe-emodin, chrysophanol, physcion, aurantio-obtusin, chryso-obtusin, obtusifolin and obtusin in rat plasma. Multiple reaction monitoring mode via an electrospray ionization was applied for the quantitation of the analytes. The separation was carried out on an Agilent Extend-C18 column (100 mm × 2.1 mm, 1.8 µm) with an 8.0 min gradient elution using ultra-purify water and acetonitrile as mobile phase. The samples were prepared by liquid-liquid extraction with ethyl acetate. The development and validation of bioanalytical method were performed according to the latest "Bioanalytical Method Validation: Guidance for Industry" issued by FDA in 2018. Finally, the clinical dosage of UGP was concluded to be 1/4 of Semen Cassiae traditional pieces in oral administration way by comparing the pharmacokinetic parameters of UGP to that of traditional pieces in the aspect of mathematical statics using plus of AUC values.


Assuntos
Antraquinonas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Área Sob a Curva , Formas de Dosagem , Limite de Detecção , Extração Líquido-Líquido , Masculino , Modelos Teóricos , Pós , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Tecnologia Farmacêutica/métodos
5.
J Sep Sci ; 42(14): 2341-2350, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31037812

RESUMO

In China, Semen Cassiae has long been used to protect liver, brighten eyes, and relieve constipation. Prepared Semen Cassiae is produced from raw Semen Cassiae by processing, the two forms of Semen Cassiae have different clinical applications. Pathological state is an important factor affecting the efficacy of drugs, the pharmacokinetic behavior of drugs could be significantly changed when people or animal were under different pathological state. To clarify the effect of processing mechanism and pathological state for pharmacokinetic behavior, the pharmacokinetics of nine components of raw and prepared Semen Cassiae under normal and acute liver injury rats were examined. The results showed that the bimodal phenomenon appeared on the plasma concentration-time profiles of obtusin, emodin, chrysophanol, aloe emodin and rhein. The Tmax of aurantio-obtusin, obtusin, chrysoobtusin, emodin, chrysophanol, aloe emodin, physcion in normal groups administrated prepared Semen Cassiae were shorter than those administrated raw Semen Cassiae. For the AUC0-t , aurantio-obtusin, obtusin, chrysoobtusin, chrysophanol, aloe emodin and physcione in model groups administrated prepared Semen Cassiae were significantly higher than other groups, unlike above components, rhein had poor absorption in model groups. The study would be useful for further studies on pharmacokinetics and clinical application of raw and prepared Semen Cassiae.


Assuntos
Cassia/química , Doença Hepática Induzida por Substâncias e Drogas/sangue , Medicamentos de Ervas Chinesas/farmacocinética , Administração Oral , Animais , Antraquinonas/administração & dosagem , Antraquinonas/sangue , Antraquinonas/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Emodina/administração & dosagem , Emodina/análogos & derivados , Emodina/sangue , Emodina/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley
6.
Molecules ; 24(10)2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31108858

RESUMO

(1) Background: Rhubarb anthraquinones-a class of components with neuroprotective function-can be used to alleviate cerebral ischemia reperfusion injury. (2) Methods: The three pharmacodynamic indicators are neurological function score, brain water content, and cerebral infarction area; UPLC-MS/MS was used in pharmacokinetic studies to detect plasma concentrations at different time points, and DAS software was used to calculate pharmacokinetic parameters in a noncompartmental model. (3) Results: The results showed that the pharmacodynamics and pharmacokinetics of one of the five anthraquinone aglycones could be modified by the other four anthraquinones, and the degree of interaction between different anthraquinones was different. The chrysophanol group showed the greatest reduction in pharmacodynamic indicators comparing with other four groups where the rats were administered one of the five anthraquinones, and there was no significant difference between the nimodipine group. While the Aloe-emodin + Physcion group showed the most obvious anti-ischemic effect among the groups where the subjects were administered two of the five anthraquinones simultaneously. Emodin, rhein, chrysophanol, and physcion all increase plasma exposure levels of aloe-emodin, while aloe-emodin lower their plasma exposure levels. (4) Conclusions: This experiment provides a certain preclinical basis for the study of anthraquinone aglycones against cerebral ischemia and a theoretical basis for the study of the mechanism of interaction between anthraquinones.


Assuntos
Antraquinonas/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Rheum/química , Aloe/química , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Modelos Animais de Doenças , Quimioterapia Combinada , Emodina/administração & dosagem , Emodina/análogos & derivados , Emodina/química , Emodina/farmacocinética , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Ratos
7.
Nat Commun ; 10(1): 1604, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962431

RESUMO

Self-assembling natural drug hydrogels formed without structural modification and able to act as carriers are of interest for biomedical applications. A lack of knowledge about natural drug gels limits there current application. Here, we report on rhein, a herbal natural product, which is directly self-assembled into hydrogels through noncovalent interactions. This hydrogel shows excellent stability, sustained release and reversible stimuli-responses. The hydrogel consists of a three-dimensional nanofiber network that prevents premature degradation. Moreover, it easily enters cells and binds to toll-like receptor 4. This enables rhein hydrogels to significantly dephosphorylate IκBα, inhibiting the nuclear translocation of p65 at the NFκB signalling pathway in lipopolysaccharide-induced BV2 microglia. Subsequently, rhein hydrogels alleviate neuroinflammation with a long-lasting effect and little cytotoxicity compared to the equivalent free-drug in vitro. This study highlights a direct self-assembly hydrogel from natural small molecule as a promising neuroinflammatory therapy.


Assuntos
Antraquinonas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Portadores de Fármacos/química , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Hidrogéis/administração & dosagem , Hidrogéis/química , Hidrogéis/farmacocinética , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/imunologia , Camundongos , Microglia/imunologia , Microglia/patologia , Microscopia Eletrônica de Varredura , Inibidor de NF-kappaB alfa/imunologia , Inibidor de NF-kappaB alfa/metabolismo , Nanofibras/administração & dosagem , Nanofibras/química , Nanofibras/ultraestrutura , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacocinética , Rheum/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo
8.
Xenobiotica ; 49(7): 762-777, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30207187

RESUMO

Zhi-Zi-Da-Huang decoction (ZZDHD) has been acknowledged with striking therapeutic effects for hepatobiliary disorders in the history of China. As decoctions are usually administrated orally, intestinal absorption, the prerequisite task of exerting therapeutic effects, is of utmost significance for screening potential active compounds and understanding the mechanism of drug action. In this work, an in vitro-in silico-in vivo strategy based on HPLC-DAD-ESI-TOF/MS was adopted for precisely profiling the intestinal absorption of ZZDHD, which integrated information obtained from rat everted gut sac model, octanol-water partition model, in silico prediction and in vivo experimental data. Besides, 34 main absorbed ingredients were selected as chemical markers to investigate the compatible interaction of the decoction on absorption level using rat everted gut sac experiment. In total, 106 compounds of ZZDHD were speculated as potential absorptive. Among them, 90 constituents predicted absorbable in at least two experimental models were finally recognized as intestinal absorbable ingredients. In addition, the absorption level of iridoids, terpenoids and flavonoid glycosides were found improved and the absorption of catechins and anthraquinones were inhibited after prescription compatibility. Taken together, this study presents a reliable strategy for evaluating intestinal absorption of herbal medicines and offers a reference for the rationality of herbal compatibility and the modernization of traditional Chinese medicine (TCM).


Assuntos
Antraquinonas , Medicamentos de Ervas Chinesas , Flavonoides , Iridoides , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Antraquinonas/farmacologia , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/química , Flavonoides/farmacocinética , Flavonoides/farmacologia , Iridoides/química , Iridoides/farmacocinética , Iridoides/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
9.
Drug Dev Ind Pharm ; 45(1): 96-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30196732

RESUMO

OBJECTIVE: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability. SIGNIFICANCE: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability. METHODS: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and 1H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35 mg/kg for pharmacokinetic studies in Sprague Dawley rats. RESULTS: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73 mg/mL, which exhibited a sustained release pattern over 72 h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T1/2 and AUC0-∞, respectively, as compared to RH suspension. CONCLUSION: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.


Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacocinética , Quitosana/síntese química , Quitosana/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Animais , Antraquinonas/administração & dosagem , Disponibilidade Biológica , Quitosana/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Masculino , Peso Molecular , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
10.
Artigo em Inglês | MEDLINE | ID: mdl-30445288

RESUMO

Anthraquinones and anthrones are the main active components of rhubarb. To investigate the metabolism and possible mutual biotransformations pathways of anthraquinones and anthrones by human intestinal flora, 9 representative constituents (aloe-emodin, rhein, emodin, chrysophanol, physcion, sennosides A, B, C and D) were studied. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with mass spectrometryElevated Energy (MSE) technology was employed to separate and identify their metabolites. As a result, a total of 64 metabolites were identified or characterized from 9 components. Among them, 12 of them were identified by compared with the reference substances, 52 of them were tentatively identified. The results indicated that reduction, hydrolysis, acetylation, oxidation, demethylation, methylation, hydroxylation, dehydroxylation and the bond cleavage of CO and CC were likely to be the metabolic pathways involved in the generation of these metabolites. Moreover, mutual biotransformations existed among the nine representative constituents in rhubarb by human intestinal flora. This study will provide evidences that intestinal flora may play an important role in mediating the bioactivities in vivo of anthraquinones and anthrones in rhubarb.


Assuntos
Antracenos/metabolismo , Antracenos/farmacocinética , Antraquinonas/metabolismo , Antraquinonas/farmacocinética , Microbioma Gastrointestinal/fisiologia , Rheum/química , Antracenos/química , Antraquinonas/química , Fenômenos Bioquímicos , Biotransformação , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Espectrometria de Massas em Tandem/métodos
11.
Carbohydr Polym ; 206: 121-131, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30553305

RESUMO

An amphiphilic carboxymethyl chitosan-rhein (CR) conjugate was prepared, characterized, and evaluated as a potential carrier material for oral delivery of paclitaxel (PTX). CR conjugate self-assembled in aqueous environment into CR polymeric micelles (CR PMs). The drug loading capacity and entrapment efficiency of PTX-loaded CR PMs were 35.24 ± 1.58% and 86.99 ± 12.26%, respectively. Pharmacokinetic results indicate that PTX-loaded CR PMs could significantly enhance the oral bioavailability of PTX. Confocal imaging of intestinal sections verified many of CR PMs were absorbed as whole through the intestinal membrane. The cytotoxicity assays in Caco-2 cells and in vivo antitumor efficacy showed that PTX-loaded CR PMs had a stronger antitumor efficacy. A synergistic antitumor effect between CR conjugate and PTX was proven in MCF-7 cells and antitumor efficacy studies. The investigation of CR conjugate developed in this study showed that CR PMs are promising for oral delivery of water-insoluble antitumor drugs.


Assuntos
Antraquinonas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Portadores de Fármacos/química , Micelas , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Administração Oral , Animais , Antraquinonas/administração & dosagem , Antraquinonas/síntese química , Antraquinonas/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Quitosana/administração & dosagem , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos Endogâmicos ICR , Paclitaxel/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacocinética , Verapamil/uso terapêutico
12.
Rev. int. androl. (Internet) ; 16(4): 147-158, oct.-dic. 2018. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-178043

RESUMO

Objective: Prismatomeris memecyloides Craib (Rubiaceae) is a medicinal plant traditionally used by ethnic minorities in Vietnam for the treatment of erectile dysfunction (ED). The aim of this study was to investigate the chemical compositions and screen in silico its possible inhibitory effect against PDE-5 which reduced cyclic guanosine-3′,5′-monophosphate (cGMP) levels and indirectly caused the male ED. Methods: Separation of natural compounds were carried out on chromatographic column with silica gel or reversed phase materials, eluting with different solvent gradients. The structures of all isolated compounds were elucidated on the basis of spectroscopic data (HR-MS, 1D/2D-NMR). Docking simulation study of compound (1-7) was performed by using flexible side chains protocol based on Iterated Local Search Global Optimizer Algorithm of AutoDock/Vina v.1.1.2. Pharmacokinetic parameters and toxicity prediction were also calculated by appropriate softwares. Results: From the methanol extract of roots of P. memecyloides collected in Vietnam, seven compounds including four anthraquinone/one anthraquinone glycoside namely damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3), rubiadin-3-methyl ether (4), and 1-O-methylrubiadin 3-O-primeveroside (5) along with two iridoid glucosides, asperulosidic acid (6) and aitchisonide A (7) were isolated. The molecular modeling results showed that 5 anthraquinone compounds possess the lowest binding energies to PDE-5. The anthraquinone glucoside 1-O-methylrubiadin 3-O-primeveroside (5) potentially inhibited PDE-5 similarly to commercial PDE-5Is sildenafil (SLD) and tadalafil (TLD). Calculated pharmacokinetic results like pIC50,pred; miLogP, TPSA, enzyme inhibitory of anthraquinone glucoside (5) were similar and even higher to those of the commercial PDE-5 inhibitors. Especially the predictive toxicity of 1-O-methylrubiadin 3-O-primeveroside (5) was even lower than those of SLD and TLD. Conclusion: This is the first study to find a scientific-based evidence for the ethnic use of P. memecyloides as medicinal plant for the treatment of ED. The result indicates that the anthraquinones (damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3) and rubiadin-3-methyl ether (4)), especially anthraquinone glycoside (1-O-methylrubiadin 3-O-primeveroside (5)) are compounds of potential novel drug class for the ED treatment


Objetivo: Prismatomeris memecyloides Craib (Rubiaceae) es una planta medicinal utilizada tradicionalmente por las minorías étnicas en Vietnam para el tratamiento de la disfunción eréctil (DE). El objetivo de este estudio fue investigar sus composiciones químicas y realizar un cribado virtual de su posible efecto inhibitorio frente a PDE-5 con niveles reducidos de guanosín-3′,5′-monofosfato cíclico (cGMP) y la causa indirecta de la DE en los varones. Métodos: Se realizó la separación de los componentes naturales en una columna cromatográfica con gel de silicio o materiales de cambio de fase, diluyéndolos con diferentes gradientes de disolventes. Se dilucidaron las estructuras de los componentes aislados sobre la base de los datos espectroscópicos (HR-MS, 1D/2D-NMR). Se realizó el estudio de simulación de acoplamiento del componente (1-7) utilizando el protocolo de cadenas laterales flexibles basado en el algoritmo «Iterated Local Search Global Optimizer» de los parámetros farmacocinéticos AutoDock Vina v.1.1.2., calculándose asímismo la predicción de toxicidad mediante los softwares adecuados. Resultados: A partir de los extractos de metanol de las raíces de P. memecyloides recolectadas en Vietnam se aislaron 7 componentes, incluyendo 4 antraquinonas/un glucósido antraquinona denominado damnacantal (1), lucidín-ω-metil éter (2), 3-metilalizarín (3), rubiadín-3-metil éter (4) y 1-O-metilrubiadín 3-O-primeverosida (5) junto con 2 glucósidos iridoides, ácido asperulosídico (6) andaitquisonida A (7). Los resultados de modelación molecular reflejaron que 5 componentes de antraquinona poseen las menores energías de ligamiento a PDE-5. El glucósido antraquinona 1-O-metilrubiadín 3-O-primeverosida (5) inhibió potencialmente PDE-5 de manera similar a las PDE-5Is comerciales sildenafil (SLD) y tadalafil (TLD). Los resultados farmacocinéticos calculados como pIC50, pred, miLogP, TPSA, enzima inhibidora de antraquinona glucósido, 1-O-metilrubiadín 3-O-primoverosida (5), fueron similares e incluso más altos que los de los inhibidores comerciales de PDE-5. Especialmente, la toxicidad predictiva de (5) fue incluso menor que la de SLD y TLD. Conclusión: Este es el primer estudio que encuentra una evidencia con base científica para el uso étnico de Prismatormeris memecyloides como planta medicinal para el tratamiento de la DE. El resultado indica que las antraquinonas (damnacantal (1), lucidín-ω-metil éter (2), 3-metilalizarín (3) y rubiadín-3-metil éter (4)), y en especial el glucósido antraquinona (1-O-metilrubiadín 3-O-primeverosida (5)) son componentes de clase farmacológica novel potencial para el tratamiento de la DE


Assuntos
Humanos , Masculino , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacocinética , Antraquinonas/farmacocinética , Extratos Vegetais/farmacocinética , Rubiaceae/química , Resultado do Tratamento
13.
Orphanet J Rare Dis ; 13(1): 193, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382914

RESUMO

Generalized severe epidermolysis bullosa simplex (EBS-gen sev) is caused by mutations within either the KRT5 or KRT14 gene, phenotypically resulting in blistering and wounding of the skin and mucous membranes after minor mechanical friction. In a clinical phase 2/3 trial, diacerein has recently been shown to significantly reduce blister numbers upon topical application. In this study we addressed basic pharmacokinetic parameters of locally applied diacerein in vitro and in vivo. Ex vivo experiments using a Franz diffusion cell confirmed the uptake and bio-transformation of diacerein to rhein in a porcine skin model. Rhein, the active metabolite of diacerein, was also detected in both urine and serum samples of two EBS-gen sev patients who topically applied a 1% diacerein ointment over a period of 4 weeks. The accumulated systemic levels of rhein in EBS-gen sev patients were lower than reported levels after oral application. These preliminary findings point towards the uptake and prolonged persistance of diacerein / rhein within the intended target organ - the skin. Further, they imply an acceptable safety profile at the systemic level. TRIAL REGISTRATION: DRKS. DRKS00005412 . Registered 6 November 2013.


Assuntos
Antraquinonas/farmacocinética , Antraquinonas/uso terapêutico , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Epidermólise Bolhosa Simples/tratamento farmacológico , Administração Tópica , Antraquinonas/administração & dosagem , Antraquinonas/química , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Humanos , Masculino , Estrutura Molecular
14.
Molecules ; 23(10)2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30360359

RESUMO

The herbal formula Yin-Chen-Hao-Tang has been reported to have anti-fibrosis properties. The aim of this study was to reveal the pharmacokinetic characteristics of bioactive compounds in this herbal formula. A new high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of scoparone, geniposide and rhein in rat plasma. A pharmaceutical herbal powder was administered to rats at doses of 1 g/kg and 3 g/kg orally. The method showed excellent linearity (r² > 0.999) and validation was successfully conducted for the pharmacokinetic study. The results show that the Cmax values and areas under the curve of scoparone, geniposide and rhein were higher and not proportional to the dose in rat plasma, while the Tmax and half-life values were consistent in the group that received 1 g/kg. The clearance of the higher dose (3 g/kg) did not decrease proportionally to that of the low dose. The results showed the nonlinear pharmacokinetic properties of scoparone, geniposide and rhein in Yin-Chen-Hao-Tang that suggested possible accumulation of bioactive compounds through oral administration. This pharmacokinetic study reveals that an increased dose of this herbal formula would largely increase the maximum concentration and bioavailability of scoparone, geniposide and rhein.


Assuntos
Antraquinonas/farmacocinética , Cromatografia Líquida , Cumarínicos/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Iridoides/farmacocinética , Espectrometria de Massas em Tandem , Animais , Antraquinonas/química , Cumarínicos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Medicina Herbária , Iridoides/química , Masculino , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
AAPS PharmSciTech ; 19(7): 3097-3109, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30109675

RESUMO

This work aimed to enhance the oral bioavailability of diacerein. The drug was incorporated in self-nanoemulsifying drug delivery system. Ternary phase diagrams were constructed using Capryol™90, Miglyol®812 and isopropyl myristate as oils, Tween®80 and Tween®20 as surfactants and PEG 200 and PEG 300 as co-surfactants. Among a total of 432 formulae, 17 formulae were clear. They were assessed for mean droplet size, polydispersity index (PDI), saturation solubility and transmission electron microscopy. Solid granules were obtained by adsorption on Aeroperl®300. Results for DSC, PXRD, and SEM of prepared granules revealed that diacerein was molecularly dispersed within the formula. Desirability factor was adopted to find the granules with maximum solubility, maximum dissolution efficiency, maximum dissolution rate and percentage of drug dissolved at 5 min and minimum dissolution time and Carr's index. The optimized formula consisted of 10% Miglyol®812, 70% Tween®80 and 20% PEG 200 adsorbed to Aeroperl® 300 with a ratio of 2:1 preconcentrate:carrier. It recorded a 3.77-fold increase in bioavailability, compared to the marketed product. Such enhancement means lower doses and less gastrointestinal side effects.


Assuntos
Antraquinonas/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Emulsões , Lipídeos , Masculino , Nanopartículas/administração & dosagem , Coelhos , Solubilidade , Tensoativos/química , Equivalência Terapêutica
16.
Chem Biol Interact ; 289: 57-67, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29698620

RESUMO

Chrysophanol, a major anthraquinone component occurring in many traditional Chinese herbs, is accepted as important active component with various pharmacological actions such as antibacterial and anticancer activity. Previous studies demonstrated that exposure to chrysophanol induced cytotoxicity, but the mechanisms of the toxic effects remain unknown. In the present metabolism study, three oxidative metabolites (M1-M3, aloe-emodine, 7-hydroxychrysophanol, and 2-hydroxychrysophanol) and five GSH conjugates (M4-M8) were detected in rat and human liver microsomal incubations of chrysophanol supplemented with GSH, and the formation of the metabolites was NADPH dependent except M4 and M5. M4 and M5 were directly derived from parent compound chrysophanol, M6 arose from M2, and M7 and M8 resulted from the oxidation of M4 and M5. Metabolites M5 and M6 were also observed in bile of rats after exposure to chrysophanol, M1-M3 and one NAC conjugate (M9) were detected in urine of rats administrated chrysophanol, and urinary metabolite M9 originated from the degradation of biliary GSH conjugation M6. Recombinant P450 enzyme incubation and microsome inhibition studies demonstrated that P450 1A2 was the primary enzyme responsible for the metabolic activation of chrysophanol and that P450 2B6 and P450 3A4 also participated in the generation of the oxidative metabolites. These findings helped us to understand the mechanisms of chrysophanol-induced cytotoxicity.


Assuntos
Antraquinonas/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Ativação Metabólica , Animais , Antraquinonas/química , Antraquinonas/urina , Bile/metabolismo , Glutationa/metabolismo , Humanos , Masculino , Metaboloma , Microssomos Hepáticos/metabolismo , Oxirredução , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Espectrometria de Massas em Tandem
17.
Drug Deliv ; 25(1): 815-826, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29557244

RESUMO

Diacerein (DCN) is a hydrophobic osteoarthritis (OA) drug with short half-life and low oral bioavailability. Furthermore, DCN oral administration is associated with diarrhea which represents obstacle against its oral use. Hence, this article aimed at developing elastosomes (edge activator (EA)-based vesicular nanocarriers) as a novel transdermal system for delivering DCN efficiently and avoiding its oral problems. For achieving this goal, elastosomes were prepared according to 41.21 full factorial design using different EAs in varying amounts. The prepared formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and deformability index (DI). Desirability function was employed using Design-Expert® software to select the optimal elastosomes (E1) which showed EE% of 96.25 ± 2.19%, PS of 506.35 ± 44.61 nm, PDI of 0.46 ± 0.09, ZP of -38.65 ± 0.91 mV, and DI of 12.74 ± 2.63 g. In addition, E1 was compared to DCN-loaded bilosomes and both vesicles exhibited superior skin permeation potential and retention capacity compared to drug suspension. In-vivo histopathological study was performed which ensured the safety of E1 for topical application. Furthermore, the pharmacokinetic study conducted in albino rabbits demonstrated that there was no significant difference in the rate and extent of DCN absorption from topically applied E1 compared to oral suspension. Multiple level C in-vitro in-vivo correlation showed good correlation between in-vitro release and in-vivo drug performance for E1 and DCN oral suspension. Overall, results confirmed the admirable potential of E1 to be utilized as novel carrier for transdermal delivery of DCN and bypassing its oral side effects.


Assuntos
Antraquinonas/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Nanoestruturas/química , Absorção Cutânea , Administração Cutânea , Administração Oral , Animais , Animais Recém-Nascidos , Antraquinonas/efeitos adversos , Antraquinonas/metabolismo , Antraquinonas/farmacocinética , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos/efeitos adversos , Elasticidade , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Lipossomos , Masculino , Microscopia Eletrônica de Transmissão , Nanoestruturas/efeitos adversos , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Coelhos , Distribuição Aleatória , Ratos , Ratos Wistar , Propriedades de Superfície , Suspensões , Distribuição Tecidual
18.
Biochem Biophys Res Commun ; 498(1): 178-185, 2018 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-29317204

RESUMO

Tumor targeting delivery system has been suggested as an attractive strategy against tumor progression. Combination chemotherapy is essential and effective in preventing ovarian cancer. Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is a lipophilic anthraquinone. Emerging evidence indicates that rhein has many pharmacological effects, such as nephroprotective, hepatoprotective, anti-inflammatory, antioxidant, and anticancer activities. In our study, doxorubicin (DOX) and rhein (RHE) co-loaded polymeric micelle (nano-DOX/RHE) were prepared to attenuate drug resistance in ovarian cancer cells while promoting the therapeutic efficiency of DOX. The morphology, particle size (about 25 nm), zeta potential, release profile in vitro, cell proliferation and cytotoxicity effects were calculated. The results suggested that DOX and RHE could be efficiently loaded into micelle nanoparticles, and in vitro study indicated that they could be released from the nanoparticles in an extended period into DOX-resistant SKOV3 cells (SKOV3/DOX). Nano-DOX/RHE exerted an enhanced cytotoxicity and high apoptosis-inducing activities in SKOV3/DOX cells. Importantly, nano-DOX/RHE exhibited better cancer targeting ability, enhancing the anti-tumor efficacy with little toxicity. In conclusion, nano-DOX/RHE promoted the drug target on tumor site with preferable anti-tumor effects, which could be a promising therapeutic strategy against human ovarian cancer.


Assuntos
Antraquinonas/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Micelas , Nanopartículas/química , Neoplasias Ovarianas/patologia , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus
19.
Eur J Drug Metab Pharmacokinet ; 43(3): 291-300, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29134502

RESUMO

BACKGROUND AND OBJECTIVES: Rhubarb-Radix scutellariae is a classic herb pair, which is commonly used to clear away heat and toxin in clinic. The aim of this study was to investigate the influence of compatibility of Rhubarb and Radix scutellariae on the pharmacokinetic behaviors of anthraquinones and flavonoids in rat plasma. METHODS: Eighteen rats were randomly divided into three groups, and were orally administered Rhubarb and/or Radix scutellariae extracts. A sensitive and rapid UPLC-MS/MS method was developed and validated to determine the concentrations of baicalin, baicalein, wogonside, wogonin, rhein, and emodin in rat plasma. The concentrations of phase II conjugates of flavonoid aglycones and anthraquinone aglycones were also determined after hydrolyzing the plasma with sulfatase. RESULTS: Compared with administration of Radix scutellariae alone, co-administration of Rhubarb significantly decreased the first maximum plasma concentration (C max1) of baicalin, wogonside, and the phase II conjugates of baicalein, wogonin to 46.40, 61.27, 41.49, and 20.50%, respectively. The area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) was significantly decreased from 82.60 ± 20.22 to 51.91 ± 7.46 µM·h for rhein and 276.83 ± 98.02 to 175.42 ± 86.82 µM·h for the phase II conjugates of wogonin after compatibility. The time to reach the first maximum plasma concentration (T max1) of anthraquinones was shortened and the second peak of anthraquinones disappeared after compatibility. CONCLUSIONS: Compatibility of Rhubarb and Radix scutellariae can significantly affect the pharmacokinetic behaviors of characteristic constituents of the two herbs. The cause of these pharmacokinetic differences was further discussed combined with the in vivo ADME (absorption, disposition, metabolism, and excretion) processes of anthraquinones and flavonoids.


Assuntos
Antraquinonas/sangue , Antraquinonas/farmacocinética , Medicamentos de Ervas Chinesas/efeitos adversos , Flavonoides/sangue , Flavonoides/farmacocinética , Rheum/efeitos adversos , Scutellaria baicalensis/efeitos adversos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Flavanonas/sangue , Interações Ervas-Drogas , Masculino , Extratos Vegetais/efeitos adversos , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
20.
J Biomed Mater Res B Appl Biomater ; 106(1): 310-319, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28140510

RESUMO

Many polymeric medical device materials contain color additives which could lead to adverse health effects. The potential health risk of color additives may be assessed by comparing the amount of color additive released over time to levels deemed to be safe based on available toxicity data. We propose a conservative model for exposure that requires only the diffusion coefficient of the additive in the polymer matrix, D, to be specified. The model is applied here using a model polymer (poly(ether-block-amide), PEBAX 2533) and color additive (quinizarin blue) system. Sorption experiments performed in an aqueous dispersion of quinizarin blue (QB) into neat PEBAX yielded a diffusivity D = 4.8 × 10-10 cm2  s-1 , and solubility S = 0.32 wt %. On the basis of these measurements, we validated the model by comparing predictions to the leaching profile of QB from a PEBAX matrix into physiologically representative media. Toxicity data are not available to estimate a safe level of exposure to QB, as a result, we used a Threshold of Toxicological Concern (TTC) value for QB of 90 µg/adult/day. Because only 30% of the QB is released in the first day of leaching for our film thickness and calculated D, we demonstrate that a device may contain significantly more color additive than the TTC value without giving rise to a toxicological concern. The findings suggest that an initial screening-level risk assessment of color additives and other potentially toxic compounds found in device polymers can be improved. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 310-319, 2018.


Assuntos
Antraquinonas , Corantes , Modelos Químicos , Nylons/química , Antraquinonas/química , Antraquinonas/farmacocinética , Corantes/química , Corantes/farmacocinética , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA