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1.
Drug Metab Dispos ; 48(8): 662-672, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32499339

RESUMO

This work aims to investigate how the bile acid metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary bile acids (BAs). The total unconjugated BA profiles were quantitatively determined by enzyme digestion techniques in urine of 21 newborns born by cesarean section, 29 healthy parturient women, 30 healthy males, and 28 healthy nonpregnant females. As expected, because of a lack of developed gut microbiota, newborns exhibited poor metabolism of secondary BAs. Accordingly, the tertiary BAs contributed limitedly to the urinary excretion of BAs in newborns despite their tertiary-to-secondary ratios significantly increasing. As a result, the primary BAs of newborns underwent extensive oxidative metabolism, resulting in elevated urinary levels of some fetal-specific BAs, including 3-dehydroCA, 3ß,7α,12α-trihydroxy-5ß-cholan-24-oic acid, 3α,12-oxo-hydroxy-5ß-cholan-24-oic acid, and nine tetrahydroxy-cholan-24-oic acids (Tetra-BAs). Parturient women had significantly elevated urinary levels of tertiary BAs and fetal-specific BAs compared with female control, indicating that they may be excreted into amniotic fluid for maternal disposition. An in vitro metabolism assay in infant liver microsomes showed that four Tetra-BAs and 3-dehydroCA were hydroxylated metabolites of cholate, glycocholate, and particularly taurocholate. However, the recombinant cytochrome P450 enzyme assay found that the fetal-specific CYP3A7 did not contribute to these oxidation metabolisms as much as expected compared with CYP3A4. In conclusion, newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of secondary BA metabolism. Translational studies following this finding may bring new ideas and strategies for both pediatric pharmacology and diagnosis and treatment of perinatal cholestasis-associated diseases. SIGNIFICANCE STATEMENT: The prenatal BA disposition is different from adults because of a lack of gut microbiota. However, how the BA metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary BAs remains poorly defined. This work demonstrated that the urinary BA profiles of newborns born by cesarean section are characterized by oxidative metabolism of primary BAs, in which the fetal-specific CYP3A7 plays a limited role in the downstream oxidation metabolism of cholate.

2.
Acta Pharmacol Sin ; 41(1): 73-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31427695

RESUMO

Kaempferol is a natural flavonol that possesses various pharmacological activities, including anti-arthritis effects, yet the underlying mechanisms remain controversial. To evaluate the anti-arthritis efficacy and the underlying mechanisms of kaempferol, collagen-induced arthritis (CIA) mice were treated with kaempferol intragastrically (200 mg · kg-1 · d-1) and intraperitoneally (20 mg · kg-1 · d-1). Pharmacodynamic and pharmacokinetic studies showed that the oral administration of kaempferol produced distinct anti-arthritis effects in model mice with arthritis in terms of the spleen index, arthritis index, paw thickness, and inflammatory factors; the bioavailability (1.5%, relative to that of the intraperitoneal injection) and circulatory exposure of kaempferol (Cmax = 0.23 ± 0.06 ng/mL) and its primary metabolite kaempferol-3-O-glucuronide (Cmax = 233.29 ± 89.64 ng/mL) were rather low. In contrast, the intraperitoneal injection of kaempferol caused marginal anti-arthritis effects, although it achieved a much higher in vivo exposure. The much higher kaempferol content in the gut implicated a potential mechanism involved in the gut. Analysis of 16S ribosomal RNA revealed that CIA caused imbalance of 14 types of bacteria at the family level, whereas kaempferol largely rebalanced the intestinal microbiota in CIA mice. A metabolomics study showed that kaempferol treatment significantly reversed the perturbation of metabolites involved in energy production and the tryptophan, fatty acid and secondary bile acid metabolisms in the gut contents of the CIA mice. In conclusion, we demonstrate for the first time that the high level of kaempferol in the gut regulates the intestinal flora and microbiotic metabolism, which are potentially responsible for the anti-arthritis activities of kaempferol.

3.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3365-3367, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602896

RESUMO

As entering a new era,our country has introduced a series of favorable policies,which may provide the powerful and new momentum for the development of traditional Chinese medicine( TCM). However,more and more attentions have been paid to the safety and effectiveness of TCM. Tripterygium wilfordii Hook.f. is one of Chinese herbs with clinical efficacy and safety risk. In recent years,accumulating groups have carried out a series of exploratory studies on the clinical rational use of T. wilfordii-related preparations. Considering this situation,the goal of this special issue is to bring together a collection of original research and review articles addressing the expanding field of T. wilfordii. The special issue covers the clinical application,pharmacodynamics,toxicology,pharmacodynamics,resource identification and molecular pharmacognosy of T. wilfordii-related preparations. It focuses on the multi-disciplinary collaborative innovation,and may provide a stimulating resource for the fascinating subject of the safe and rational use of TCM,as well as have important practical significance and promotion value for the healthy development of TCM industry.


Assuntos
Medicamentos de Ervas Chinesas/normas , Medicina Tradicional Chinesa , Tripterygium
4.
Drug Metab Dispos ; 47(6): 574-581, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30918015

RESUMO

The primary bile acids (BAs) synthesized from cholesterol in the liver are converted to secondary BAs by gut microbiota. It was recently disclosed that the major secondary BA, deoxycholate (DCA) species, is stereoselectively oxidized to tertiary BAs exclusively by CYP3A enzymes. This work subsequently investigated the in vitro oxidation kinetics of DCA at C-1ß, C-3ß, C-4ß, C-5ß, C-6α, C-6ß, and C-19 in recombinant CYP3A enzymes and naive enzymes in human liver microsomes (HLMs). The stereoselective oxidation of DCA fit well with Hill kinetics at 1-300 µM in both recombinant CYP3A enzymes and pooled HLMs. With no contributions or trace contributions from CYP3A5, CYP3A7 favors oxidation at C-19, C-4ß, C-6α, C-3ß, and C-1ß, whereas CYP3A4 favors the oxidation at C-5ß and C-6ß compared with each other. Correlation between DCA oxidation and testosterone 6ß-hydroxylation in 14 adult single-donor HLMs provided proof-of-concept evidence that DCA 19-hydroxylation is an in vitro marker reaction for CYP3A7 activity, whereas oxidation at other sites represents mixed indicators for CYP3A4 and CYP3A7 activities. Deactivation caused by DCA-induced cytochrome P450-cytochrome P420 conversion, as shown by the spectral titrations of isolated CYP3A proteins, was observed when DCA levels were near or higher than the critical micelle concentration (about 1500 µM). Unlike CYP3A4, CYP3A7 showed abnormally elevated activities at 500 and 750 µM, which might be associated with an altered affinity for DCA multimers. The disclosed kinetic and functional roles of CYP3A isoforms in disposing of the gut bacteria-derived DCA may help in understanding the structural and functional mechanisms of CYP3A.


Assuntos
Biomarcadores/metabolismo , Citocromo P-450 CYP3A/metabolismo , Ácido Desoxicólico/metabolismo , Humanos , Hidroxilação/fisiologia , Cinética , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Oxirredução
5.
Drug Metab Dispos ; 47(3): 283-294, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606729

RESUMO

The gut microbiota modifies endogenous primary bile acids (BAs) to produce exogenous secondary BAs, which may be further metabolized by cytochrome P450 enzymes (P450s). Our primary aim was to examine how the host adapts to the stress of microbe-derived secondary BAs by P450-mediated oxidative modifications on the steroid nucleus. Five unconjugated tri-hydroxyl BAs that were structurally and/or biologically associated with deoxycholate (DCA) were determined in human biologic samples by liquid chromatography-tandem mass spectrometry in combination with enzyme-digestion techniques. They were identified as DCA-19-ol, DCA-6ß-ol, DCA-5ß-ol, DCA-6α-ol, DCA-1ß-ol, and DCA-4ß-ol based on matching in-laboratory synthesized standards. Metabolic inhibition assays in human liver microsomes and recombinant P450 assays revealed that CYP3A4 and CYP3A7 were responsible for the regioselective oxidations of both DCA and its conjugated forms, glycodeoxycholate (GDCA) and taurodeoxycholate (TDCA). The modification of secondary BAs to tertiary BAs defines a host liver (primary BAs)-gut microbiota (secondary BAs)-host liver (tertiary BAs) axis. The regioselective oxidations of DCA, GDCA, and TDCA by CYP3A4 and CYP3A7 may help eliminate host-toxic DCA species. The 19- and 4ß-hydroxylation of DCA species demonstrated outstanding CYP3A7 selectivity and may be useful as indicators of CYP3A7 activity.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Ácido Desoxicólico/metabolismo , Microbioma Gastrointestinal/fisiologia , Adulto , Ácido Desoxicólico/sangue , Ácido Desoxicólico/toxicidade , Ácido Desoxicólico/urina , Feminino , Voluntários Saudáveis , Humanos , Hidroxilação , Fígado/metabolismo , Masculino , Microssomos Hepáticos , Oxirredução , Adulto Jovem
6.
Front Pharmacol ; 9: 1115, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416442

RESUMO

Although hepatoprotective properties of silybin are well documented, the clinical therapeutic efficacy is limited by its low bioavailability due to absorption rates, extensive phase II metabolism, and biliary excretion. As our previous study indicated that metabolic enzymes may have limited effects on the pharmacokinetic (PK) behavior of silymarin, here, we intended to increase the oral bioavailability and bio-efficacy of silybin through the inhibition of active efflux. In Caco-2 and transfected MDCKII cell models, flavone baicalein significantly inhibited the efflux of silybin as a BCRP and MRP2 inhibitor. In addition, baicalein reduced the biliary excretion index (BEI) and biliary clearance of silybin conjugates in the sandwich-cultured rat hepatocyte (SCH) model, indicating the inhibition of baicalein in biliary excretion of conjugated silybin metabolites. PK study demonstrated that baicalein significantly increased the area under the curve (AUC) and Cmax of silybin and its conjugates, suggesting enhanced absorption in vivo. Moreover, coadministration of silybin with baicalein boosted the liver protective, antioxidant, and anti-inflammatory effects of silybin in the carbon tetrachloride (CCl4)-induced liver injury model in comparison with silybin given alone. In summary, efflux transporters play a critical role in the low bioavailability of silybin, while inhibition of breast cancer resistance protein (BCRP) and multi-drug resistance protein 2 (MRP2) by baicalein can significantly increase the absorption and bio-efficacy of silybin, which provides a new combination therapeutic approach for the treatment of chronic liver diseases.

7.
Phytomedicine ; 44: 85-86, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29895496
8.
Phytomedicine ; 45: 49-58, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29691116

RESUMO

BACKGROUND: Radix Wikstroemia indica (RWI), named "Liao Ge Wang" in Chinese, is a kind of toxic Chinese herbal medicine (CHM) commonly used in Miao nationality of South China. "Sweat soaking method" processed RWI could effectively decrease its toxicity and preserve therapeutic effect. However, the underlying mechanism of processing is still not clear, and the Q-markers database for processed RWI has not been established. PURPOSE: Our study is to investigate and establish the quality evaluation system and potential Q-markers based on "effect-toxicity-chemicals" relationship of RWI for quality/safety assessment of "sweat soaking method" processing. METHODS: The variation of RWI in efficacy and toxicity before and after processing was investigated by pharmacological and toxicological studies. Cytotoxicity test was used to screen the cytotoxicity of components in RWI. The material basis in ethanol extract of raw and processed RWI was studied by UPLC-Q-TOF/MS. And the potential Q-markers were analyzed and predicted according to "effect-toxicity-chemical" relationship. RESULTS: RWI was processed by "sweat soaking method", which could preserve efficacy and reduce toxicity. Raw RWI and processed RWI did not show significant difference on the antinociceptive and anti-inflammatory effect, however, the injury of liver and kidney by processed RWI was much weaker than that by raw RWI. The 20 compounds were identified from the ethanol extract of raw product and processed product of RWI using UPLC-Q-TOF/MS, including daphnoretin, emodin, triumbelletin, dibutyl phthalate, Methyl Paraben, YH-10 + OH and matairesinol, arctigenin, kaempferol and physcion. Furthermore, 3 diterpenoids (YH-10, YH-12 and YH-15) were proved to possess the high toxicity and decreased by 48%, 44% and 65%, respectively, which could be regarded as the potential Q-markers for quality/safety assessment of "sweat soaking method" processed RWI. CONCLUSION: A Q-marker database of processed RWI by "sweat soaking method" was established according to the results and relationship of "effect-toxicity-chemicals", which provided a scientific evidence for processing methods, mechanism and the clinical application of RWI, also provided experimental results to explore the application of Q-marker in CHM.


Assuntos
Biomarcadores Farmacológicos/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Wikstroemia/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , China/etnologia , Cromatografia Líquida/métodos , Cumarínicos/análise , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/análise , Emodina/análogos & derivados , Emodina/análise , Furanos/análise , Humanos , Lignanas/análise , Espectrometria de Massas/métodos , Camundongos , Extratos Vegetais/análise , Extratos Vegetais/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-29202359

RESUMO

YiQiFuMai powder injection (YQFM), derived from the classical traditional Chinese medicine (TCM) formula Shengmai San, is a modern preparation widely used to combat cardiovascular diseases, chronic heart failure (CHF) for example, in clinical practice in China. Ginsenosides are the major components of YQFM, which are responsible for its therapeutic effect. In this research, we developed a rapid, sensitive and simple method for simultaneous determination of ten ginsenosides from YQFM in CHF rat plasma with ultra-fast liquid chromatography tandem mass spectrometry (UFLC-MS/MS). After solid phase extraction (SPE), chromatography was done on an Acquity UPLC HSS T3 column (1.8µm, 100mm×2.1mm, i.d.) through an 8.0min gradient elution with acetonitrile and 0.1% formic acid in water, while mass spectrometry was performed in the positive ion electrospray ionization (ESI) mode. A good linearity was achieved for each analyte with correlation coefficient (r) >0.9920. The lower limits of quantification (LLOQ) were 1.25ng/mL for ginsenoside Rg1, Rd, Re and Rh1, 2.5ng/mL for ginsenoside Rf, Rg3, Rb2 and Rb3 and 5.0ng/mL for ginsenoside Rb1 and Rc, respectively. All the precision (RSD) data ranged from 1.7-14.5% and the accuracy (RE) data was within ±13.73%. Moreover, the validated method has been applied to investigate the integrated pharmacokinetic profiles of ginsenosides in CHF rats following intravenous administration of YQFM successfully.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Ginsenosídeos/sangue , Ginsenosídeos/farmacocinética , Insuficiência Cardíaca/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Doença Crônica , Medicamentos de Ervas Chinesas/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Pharmacol Res ; 128: 153-166, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28958806

RESUMO

Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl4-induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Flavonas/farmacologia , Silibina/farmacocinética , Animais , Disponibilidade Biológica , Células CACO-2 , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cães , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Ratos Sprague-Dawley
11.
Yao Xue Xue Bao ; 52(1): 132-8, 2017 01.
Artigo em Chinês | MEDLINE | ID: mdl-29911810

RESUMO

This study was designed to clarify the chemical constituents in Yuanhu Zhitong prescription (YHZT), a rapid high performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (HPLC-QTOF/MS) method was established. Based on the high resolution MS spectra data, fragment ion information, reference standards data and literature reports, 51 peaks including 28 alkaloid compounds and 23 coumarin compounds were identified. The chemical constituents in YHZT were rapidly, accurately, systematically analyzed. The results lay a foundation for the quality control of effective compounds of YHZT.


Assuntos
Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta Pressão , Controle de Qualidade , Espectrometria de Massas por Ionização por Electrospray
12.
Yao Xue Xue Bao ; 51(3): 380-7, 2016 03.
Artigo em Chinês | MEDLINE | ID: mdl-29858896

RESUMO

This study was designed to explore the mechanism of Yuanhu Zhitong Dropping Pills(YHZT) in the treatment of primary dysmenorrhea by pharmacological network technology and establish a research approach of "Compound-Target-Pathway-Disease" network. Twenty-eight compounds absorbed into blood including 22 prototype and 6 metabolites of YHZT were submitted to Pharm Mapper and Kyoto Encyclopedia of Genes and Genomes(KEGG) bioinformatics softwares to predict the target proteins and related pathways respectively. The network of "Compound-Target-Pathway-Disease" was constructed and analyzed using Cytoscape software. The in silico prediction results showed that the 28 constituents of YHZT affected 111 pathways through 109 target proteins. Among them, a total of 52 proteins and 31 pathways were related to the primary dysmenorrhea. The effect of YHZT on primary dysmenorrhea may be dependent on regulation of the proteins and pathways related with hormonal regulation, central analgesia, spasmolysis, inflammation and immunoregulation.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Dismenorreia/tratamento farmacológico , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos , Feminino , Humanos , Software
13.
Yao Xue Xue Bao ; 51(8): 1302-8, 2016 08.
Artigo em Chinês | MEDLINE | ID: mdl-29906033

RESUMO

The chemical constituents of Corydalis Rhizoma were identified in the 60% ethanol extract using high performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (HPLC-QTOF/MS). The stimulation and inhibition effects of Corydalis Rhizoma and its representative compounds (protopine, palmatine, tetrahydropalmatine) on G protein-coupled receptor (GPCR), including 5-hydroxytryptamine 1A receptor(5-HT(1A)), µ opioid receptor (OPRM1), ß(2) adrenergic receptor (ADRB2), dopamine receptor (D(2)), acetylcholine receptor (M(2)) and thromboxane-prostaglandin receptor (TP) were explored using the fluorescence assay of intracellular calcium ion. As a result, 31 compounds were obtained and 28 alkaloid compounds were identified. The results of GPCR experiments showed that Corydalis Rhizoma could activate 5-HT(1A), OPRM1, ADRB2 receptors and block D(2) receptor. Protopine showed antagonism on D2 and M2 receptors, tetrahydropalmatine could agitate ADRB2 receptor and antagonize D(2) and TP receptors, while palmatine showed no significant biological activity on the 6 GPCRs. In conclusion, Corydalis Rhizoma may exert biological activity by multi-components acting on multi-targets.


Assuntos
Benzofenantridinas/farmacologia , Alcaloides de Berberina/farmacologia , Corydalis/química , Receptores Acoplados a Proteínas-G/metabolismo , Alcaloides , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas , Humanos , Espectrometria de Massas , Rizoma/química
14.
Yao Xue Xue Bao ; 51(12): 1864-70, 2016 12.
Artigo em Chinês | MEDLINE | ID: mdl-29908557

RESUMO

Bentysrepinine (Y101), a derivative of phenyalanine dipeptide, has a novel mechanism in the treatment of hepatitis B virus (HBV) infection with a good anti-HBV effect. In the present study, a fluorometric-based high throughput method using cytochrome P450 (CYP) screening kit was adopted to evaluate in vitro inhibition potential of Y101 on CYP isoenzymes by calculating remaining enzyme activities and inhibitory potential (IC(50) values) using the determined values of fluorescence intensity. The result showed that Y101 exhibited little activity in the inhibition of CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6 (IC(50) > 100 µmol·L(-1)). Y101 was used to treat human primary hepotocytes for 72 h, and the enzyme activities of CYP1A2, CYP2B6 and CYP3A4 were determined with a cocktail of probe substrates for the three CYP isoforms. The metabolites were simultaneously determined using a LC-MS/MS method. Y101 had no activity in the induction of CYP1A2, CYP2B6 and CYP3A4 on the basis of the following results: 1 The ratio of enzyme activities between test and control groups were all below than 1 (varied from 0.662 to 0.928); 2 The induction potential of Y101 were lower than forty percent compared with that of positive groups. The above results suggest that Y101 has little activity in the regulation of metabolic drug-drug interactions based on the CYP isoform changes following co-administration of drugs.


Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450 , Dipeptídeos/farmacologia , Células Cultivadas , Cromatografia Líquida , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Interações Medicamentosas , Vírus da Hepatite B , Hepatócitos/efeitos dos fármacos , Humanos , Espectrometria de Massas em Tandem
15.
Yao Xue Xue Bao ; 51(10): 1540-50, 2016 10.
Artigo em Chinês | MEDLINE | ID: mdl-29932598

RESUMO

Pharmacokinetic behavior of orally administrated formulations involves dissolution and absorption in the gastrointestinal tract (GIT), which is required for the systemic effects of a drug. The dissolution and subsequent penetration through the intestinal epithelia is a vital step toward in vivo bioavailability. A lot of effort has been devoted to the study of physiological characteristics of GIT by means of in vitro dissolution methods or in vitro permeation methods. Moreover, drug dissolution/permeation synchronous evaluation technology could be employed to predict the process of drug dissolution and absorption by the combination of dissolution apparatus and permeation apparatus. Better prediction tools are priority in the critical path initiative of US Food and Drug Administration. The studies and applications of the drug dissolution/permeation synchronous evaluation technology are attracting more and more attention each year. However, there is no systematic review on the theoretical basis and the recent development. Therefore, in this review, we will give an overview on the physiological basis and theoretical basis of the drug dissolution/permeation synchronous evaluation technology, as well as their recent advances of this kind of equipments at home and abroad. Moreover, we have also compared their advantages and disadvantages, and the applicable scopes. With hope that the critical path study will promote the development of innovative drug research and development, and improve the druggability.


Assuntos
Liberação Controlada de Fármacos , Trato Gastrointestinal/fisiologia , Preparações Farmacêuticas/química , Administração Oral , Disponibilidade Biológica , Composição de Medicamentos , Humanos , Absorção Intestinal , Permeabilidade , Solubilidade
16.
Zhongguo Zhong Yao Za Zhi ; 41(8): 1367-1375, 2016 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28884525

RESUMO

This paper discusses the research situation of the standard decoction of medicinal slices at home and abroad. Combined with the experimental data, the author proposes that the standard decoction of medicinal slices is made of single herb using standard process which should be guided by the theory of traditional Chinese medicine, based on clinical practice and referred to modern extraction method with a standard process. And the author also proposes the principles of establishing the specification of process parameters and quality standards and established the basis of drug efficacy material and biological reference. As a standard material and standard system, the standard decoction of medicinal slices can provide standards for clinical medication, standardize the use of the new type of medicinal slices especially for dispensing granules, which were widely used in clinical. It can ensure the accuracy of drugs and consistency of dose, and to solve current supervision difficulties. Moreover the study of standard decoction of medicinal slices will provide the research on dispensing granules, traditional Chinese medicine prescription standard decoction and couplet medicines standard decoction a useful reference.


Assuntos
Composição de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Projetos de Pesquisa
17.
Yao Xue Xue Bao ; 51(8): 1233-9, 2016 08.
Artigo em Chinês | MEDLINE | ID: mdl-29897720

RESUMO

Bentysrepinine (Y101), a derivative of phenylalanine dipeptide, is a novel drug candidate for the treatment of hepatitis B virus (HBV) infection. Our previous preclinical pharmacokinetic study showed that its in vivo absorption and distribution characteristics were probably related to transmembrane transport after Y101 was administered intragastically in rats. In this study, Caco-2 and MDCK-MDR1 cell models were used to investigate interactions between Y101 and P-gp through the apparent permeation coefficient (P(app)) and efflux ratio (RE); the results showed that Y101 was a substrate of P-gp. In addition, gene-transfected cell models, HEK293-h OATP1B1, HEK293-h OATP2B1 and CHO-PEPT1 were used to evaluate the affinity to OATP1B1, OATP2B1 and PEPT1. The results suggest that Y101 has a weak inhibitory effect on OATP1B1 and OATP2B1, and Y101 may not be substrates of OATP1B1, OATP2B1 or PEPT1. The above results can be used to explain the in vivo absorption and distribution characteristics, and to provide a scientific basis for the further development of Y101.


Assuntos
Antivirais/farmacocinética , Benzamidas/farmacocinética , Dipeptídeos/farmacocinética , Vírus da Hepatite B/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Células CACO-2 , Cães , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Ratos
18.
Artigo em Inglês | MEDLINE | ID: mdl-26657802

RESUMO

Traditional Chinese herb medicines (TCHMs) have been used in the treatment of a variety of diseases for thousands of years in Asian countries. The active components of TCHMs usually exert combined synergistic therapeutic effects on multiple targets, but with less potential therapeutic effect based on routine indices than Western drugs. These complex effects make the assessment of the efficacy of TCHMs and the clarification of their underlying mechanisms very challenging, and therefore hinder their wider application and acceptance. Metabolomics is a crucial part of systems biology. It allows the quantitative measurement of large numbers of the low-molecular endogenous metabolites involved in metabolic pathways, and thus reflects the fundamental metabolism status of the body. Recently, dozens of metabolomic studies have been devoted to prove the efficacy/safety, explore the underlying mechanisms, and identify the potential biomarkers to access the action targets of TCHMs, with fruitful results. This article presents an overview of these studies, focusing on the progress made in exploring the pharmacology and toxicology of various herbal medicines.


Assuntos
Medicina Tradicional Chinesa , Metabolômica
19.
Anticancer Drugs ; 27(1): 1-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26426520

RESUMO

Temozolomide (TMZ) combination with whole-brain radiotherapy (WBRT) has been tested by many randomized controlled trials in the treatment of brain metastases (BMs) in China and other countries. We performed an up-to-date meta-analysis to determine (i) the log odds ratios (LORs) of objective response (ORR) and adverse effects (AEs) for all-grade, and (ii) the T value of mean overall survival in patients with BMs treated with WBRT combined with TMZ versus WBRT alone. PubMed, Chinese National Knowledge Infrastructure, and WanFang Data were searched for articles published up to 28 January 2015. Eligible studies were selected according to the PRISMA statement. ORR, AEs, and 95% confidence intervals were calculated using random-effects models. Eighteen studies were included in our analysis. A total of 1028 participants were enrolled. Summary LORs of ORR were 1.0239 (P<0.0001) on comparing WBRT plus TMZ with WBRT ORR (n=17). The overall mean difference of mean overall survival (n=17) between TMZ plus WBRT and WBRT was 2.2505 weeks (P=0.02185). There was a significant difference between WBRT plus TMZ and WBRT alone with a LOR of AEs for all-grade of (i) 0.923 for gastrointestinal toxicity and (ii) 0.7978 for myelosuppression. Sensitivity analysis and subgroup analysis were also performed. The 18 eligible randomized controlled trials demonstrated that the combination of WBRT and TMZ significantly improves the ORR and is statistically insignificant in prolonging the survival of patients with BMs. In addition, an increase in the incidence of gastrointestinal toxicity and myelosuppression was significant for all-grade.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Neoplasias Encefálicas/secundário , Terapia Combinada , Dacarbazina/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Temozolomida
20.
Curr Drug Metab ; 16(10): 894-910, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26652257

RESUMO

The liposome delivery system has been intensively explored as novel drug delivery system (DDS) for antitumor drugs, due to its safety, selective cytotoxicity, long circulation and slow elimination in blood, which is favorable for cancer therapy. The liposome-based chemotherapeutics are used to treat a variety of cancers to enhance the therapeutic index of antitumor drugs. Here, the author reviewed the important targets for cancer therapy and the pharmacokinetic behavior of liposomal drugs in vivo, as well as the application of the targeting liposomal system in cancer therapy. Considering further application for clinical use, the great challenges of the liposome-based delivery system were also proposed as follows: 1) prepare stealth liposome with steric stabilization and further enhance the therapeutic effects and safety; 2) explore more safe clinical targets and complementary or different types of targeting liposome; 3) thirdly, more investment is needed on the research of pharmacokinetics of the elements such as the ligands (antibody), PEG and lipids of liposome delivery system as well as safety evaluation. Considering the complex process of the liposomal encapsulation drugs in vivo, the author inferred that there are maybe different forms of the encapsulation drug to be internalized by the tumor tissues at the same time and space, although there are little reports on it.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Humanos , Ligantes , Lipídeos/química , Lipossomos , Polietilenoglicóis/química
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