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1.
Artigo em Inglês | MEDLINE | ID: mdl-31918307

RESUMO

The aim of this work is to develop an efficient and economical method for the enrichment of total flavonoids from Pteris ensiformis Burm. extracts. Resin screening, adsorption kinetics, adsorption isotherms and thermodynamics were successively researched prior to the dynamic adsorption and desorption tests. NKA-II resin was chosen as the best adsorbent, and the adsorption data were best described by the pseudo-second-order kinetics model and Langmuir isotherm model. The optimum enrichment conditions were as follows: for adsorption the total flavonoids concentration, flow rate and volume of sample were 1.84 mg/mL, 2 BV/h and 5 BV, respectively, and for desorption the flavonoids-loaded NKA-II resin column was desorbed by 7 BV of 50% ethanol at a rate of 2 BV/h. The product had a 6.63-fold higher total flavonoids content than crude extracts, and the recovery yield of total flavonoids was 80.65%. Furthermore, flavonoids-enriched extracts exhibited higher in vitro scavenging activity against superoxide anion radical and hydroxyl radical than crude extracts. In addition, higher antiproliferative activity of flavonoids-enriched extracts against MCF-7 and HepG-2 cell lines was also found as compared to the crude extracts. The developed method is appropriate for large-scale enrichment of total flavonoids from Pteris ensiformis Burm. extracts in the food and pharmaceutical industries.


Assuntos
Antioxidantes , Proliferação de Células/efeitos dos fármacos , Flavonoides , Pteris/química , Adsorção , Antineoplásicos/análise , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antioxidantes/análise , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Flavonoides/análise , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Células Hep G2 , Humanos , Células MCF-7 , Extratos Vegetais/química , Resinas Sintéticas/química
2.
Biomed Chromatogr ; 34(1): e4623, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31215049

RESUMO

Therapeutic drug monitoring (TDM) has shown to benefit patients treated with drugs of many drug classes, among which is oncology. With an increasing demand for drug monitoring, new assays have to be developed and validated. Guidelines for bioanalytical validation issued by the European Medicines Agency and US Food and Drug Administration are applicable for clinical trials and toxicokinetic studies and demand fully validated bioanalytical methods to yield reliable results. However, for TDM assays a limited validation approach is suggested based on the intended use of these methods. This review presents an overview of publications that describe method validation of assays specifically designed for TDM. In addition to evaluating current practice, we provide recommendations that could serve as a guide for future validations of TDM assays.


Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacocinética , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/uso terapêutico , Humanos , Modelos Lineares , Neoplasias/tratamento farmacológico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
Biomed Chromatogr ; 34(1): e4742, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31749152

RESUMO

Quantitation of drugs used for the treatment of chronic lymphocytic leukemia in various biological matrices during both pre-clinical and clinical developments is very important, often in routine therapeutic drug monitoring. The first developed methods for quantitation were traditionally done on LC in combination with either UV or fluorescence detection. However, the emergence of LC with mass spectrometry in tandem in early 1990s has revolutionized the quantitation as it has provided better sensitivity and selectivity within a shorter run time; therefore it has become the choice of method for the analysis of various drugs. In this article, an overview of various bioanalytical methods (HPLC or LC-MS/MS) for the quantification of drugs for the treatment of chronic lymphocytic leukemia, along with applicability of these methods, is given.


Assuntos
Antineoplásicos , Cromatografia Líquida , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Antineoplásicos/análise , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos , Humanos , Espectrometria de Massas em Tandem
4.
Crit Rev Anal Chem ; 50(1): 50-61, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30767558

RESUMO

Determination of intracellular concentration becomes essential for the drugs having target receptors or bioactivation site inside the cells. Majority of the antiviral drugs are nucleoside analogs and their intracellular phosphorylated metabolites are active. The anticancer drugs of the cellular enzyme and nucleoside analog category are also required to be undergone intracellular drug level analysis. In this review, we have sequentially described the cell isolation protocols, cell lysis techniques and sample preparation approach to be followed for quantification of intracellular levels of selected antiviral and anticancer drugs. Major limitations for intracellular analyte quantification and their possible way out has been discussed. Currently, no literature is available summarizing these important aspects including bioanalysis of intracellular quantification of either antiviral or anticancer drugs. This review, thus, can be considered to be first of its kind and will be highly useful in providing guidance for intracellular drug analysis aiming determination of the site-specific bioavailability.


Assuntos
Antineoplásicos/análise , Antivirais/análise , Disponibilidade Biológica , Linhagem Celular Tumoral , Separação Celular , Fracionamento Químico , Cromatografia Líquida , Humanos , Manejo de Espécimes/métodos
5.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117411, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31362187

RESUMO

The present study delves into the interaction of a potent cancer-cell photosensitizer Norharmane (NHM) with non-ionic triblock copolymer P123, followed by the assessment of the stability of the formed complex in the presence of ß-cyclodextrin (ß-CD). Spectroscopic results unveil the modulation of the prototropic equilibrium of NHM within the constrained microheterogeneous medium of the copolymer micelle to be favoured towards the neutral species of NHM over the cationic counterpart; which has been aptly rationalized invoking the key role of hydrophobic interaction in the association process and is further reinforced from steady-state and time-resolved spectroscopic measurements. The micropolarity of the probe-binding site has been evaluated by the archetypal ET(30) analysis revealing that the cationic probe remains in the corona region of the micelle instead of penetrating deeper into the micellar core. Moreover, the effect of ß-CD on the stability of the NHM-bound P123 aggregates has also been investigated, revealing that ß-CD can be used as a potential host for the release of the micelle-encapsulated drug through an inclusion complex formation with the P123 monomers. The result is expected to be of potential interest from medical perspective owing to the context of efficient drug release at their potential sites.


Assuntos
Antineoplásicos , Micelas , Fármacos Fotossensibilizantes , beta-Ciclodextrinas/química , Antineoplásicos/análise , Antineoplásicos/química , Antineoplásicos/farmacocinética , Liberação Controlada de Fármacos , Modelos Moleculares , Fármacos Fotossensibilizantes/análise , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Espectrometria de Fluorescência
6.
J Oncol Pharm Pract ; 26(1): 141-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31132937

RESUMO

INTRODUCTION: All guidelines necessitate wearing personal protective equipment during dispensing of oral anticancer drugs. This study aims to measure the degree of contamination on the press-through-package strips of oral anticancer drugs in Japan. METHOD: Surface contamination of the external packaging of anticancer drugs was examined by performing wipe tests at four hospitals and two community pharmacies. The following commercially available drugs were examined: Xeloda®, TS-1®, and methotrexate tablets and SA-1® and Rheumatrex® capsules. RESULTS: The wipe tests' results revealed that the contamination levels of Xeloda® and TS-1® tablets and SA-1® capsules were within their detection limits. In some facilities, the contamination levels on the press-through-package strips of Rheumatrex® capsules were 3.27 × 10-1, which is close to its detection limit. However, across all facilities, the contamination level of methotrexate tablets was above its detection limit. CONCLUSION: The results of this study suggested that adherence to oral anticancer drugs may not occur during manufacture or transportation. However, it may be due to the presence of pollutants in the facilities. Prevention of pollution in facilities might eliminate the need to wear personal protective equipment during dispensing of oral anticancer drugs.


Assuntos
Antineoplásicos/administração & dosagem , Contaminação de Medicamentos/prevenção & controle , Embalagem de Medicamentos/métodos , Contaminação de Equipamentos/prevenção & controle , Exposição Ocupacional/prevenção & controle , Antineoplásicos/análise , Embalagem de Medicamentos/normas , Monitoramento Ambiental/métodos , Monitoramento Ambiental/normas , Humanos , Japão/epidemiologia , Exposição Ocupacional/normas , Farmácias/normas
7.
J Enzyme Inhib Med Chem ; 35(1): 235-244, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760818

RESUMO

Cyclin-dependent kinase 2 (CDK2) is the family of Ser/Thr protein kinases that has emerged as a highly selective with low toxic cancer therapy target. A multistage virtual screening method combined by SVM, protein-ligand interaction fingerprints (PLIF) pharmacophore and docking was utilised for screening the CDK2 inhibitors. The evaluation of the validation set indicated that this method can be used to screen large chemical databases because it has a high hit-rate and enrichment factor (80.1% and 332.83 respectively). Six compounds were screened out from NCI, Enamine and Pubchem database. After molecular dynamics and binding free energy calculation, two compounds had great potential as novel CDK2 inhibitors and they also showed selective inhibition against CDK2 in the kinase activity assay.


Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacologia , Máquina de Vetores de Suporte , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
8.
Artigo em Inglês | MEDLINE | ID: mdl-31841980

RESUMO

Shikonin, shikonofuran and their derivatives are the main bioactive components of Zicao, a traditional Chinese medicine prepared with the dried roots of Lithospermum erythrorhizon, Arnebia euchroma or Arnebia guttata. To establish an efficient and sensitive method for studying material basis of Zicao, different scan modes of ultra-high performance liquid chromatography quadrupole time of flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) and UHPLC triple quadrupole linear ion trap mass spectrometry (QTRAP-MS/MS) were incorporated to make full use of the sensitivity of multiple reaction monitoring (MRM) and overcome its disadvantages. A total of 73 shikonins and shikonofurans compounds were detected in Zicao utilizing various scanning modes. Thereafter the characteristic chemical profile for shikonins and shikonofurans was established based on UHPLC-QTRAP-MS/MS, which was subsequently used to study the spectrum-effect relationship by correlating the relative quantity of compounds and the anti-tumor activity. As a result, 27 compounds were screened as the main active components inhibiting HeLa cells by othogonal partial least square (OPLS). Among them, shikonin, acetylshikonin have been reported to inhibit HeLa cells previously, and ß, ß-dimethylacrylshikonin has been reported to be active component by other method. Those results showed that chemical characteristic profile combined with chemometric methods was efficient and reliable for discovery of material basis in TCM, especially trace active compounds.


Assuntos
Antineoplásicos , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Naftoquinonas , Espectrometria de Massas em Tandem/métodos , Antineoplásicos/análise , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Furanos/análise , Furanos/farmacologia , Células HeLa , Humanos , Análise dos Mínimos Quadrados , Naftoquinonas/análise , Naftoquinonas/farmacologia
9.
Comput Biol Chem ; 83: 107139, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31751888

RESUMO

Identifying stable gene markers at an individual level can help to understand the genetic mechanisms of each individual patient and accomplish personalized medicine. In this paper, we propose an efficient framework to identify sample-specific markers. Gene expression data first is transformed to a corresponding likelihood matrix to alleviate inherent noise besides adding population information to each sample. Then those significantly differential genes or gene pairs are further mapped to a STRING network for analysis by assuming that the likelihood of each gene or gene pairs in the control group follows a Gaussian distribution. The proposed method is applied to three benchmark datasets including lung adenocarcinoma, kidney renal clear cell carcinoma, and uterine corpus endometrial carcinoma. It is found that disease gene markers identified by the proposed methods outperform the previous sample-specific network (SSN) method in both subtyping and survival analysis. Furthermore, we exploit the application of the subtype markers in following drug selection. The difference of the enriched drug set may reflect some underlying mechanisms of the subtypes and shed light on selecting appropriate drugs for each cancer subtype.


Assuntos
Antineoplásicos/análise , Biomarcadores Tumorais/genética , Descoberta de Drogas , Redes Reguladoras de Genes , Feminino , Humanos , Distribuição Normal
10.
BMC Complement Altern Med ; 19(1): 266, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601198

RESUMO

BACKGROUND: Propolis is a natural bee product with a wide range of biological activities that are related to its chemical composition. The present study investigated the quantification of quercetin (Q) in Ardabil ethanol extract of propolis (AEEP), and then compared its anti-bacterial, anti- biofilm and cytotoxic effects on cancer and normal cell lines. METHOD: In the present study, the chemical composition of AEEP was determined through the high-performance liquid chromatography (HPLC). The AEEP and its main component, quercetin (Q), were evaluated in vitro against 57 oral streptococci by a broth micro-dilution method. The biofilm formation was assessed through the crystal violet staining and MTT assays. The impact of AEEP and Q anti-proliferative effect were evaluated on the fibroblast as normal and cancer cell lines (KB and A431). RESULTS: The Q concentration in the composition of AEEP was 6.9% of all its components. The findings indicated that the AEEP and Q were efficient against the cariogenic bacteria and were able to inhibit the S.mutans biofilm adherence at a sub-MIC concentration. Moreover, electron micrographs indicated the inhibition of biofilms compared to control biofilms. In addition, the AEEP and Q indicated a dose-dependent cytotoxic effect on A431 and KB cell lines. On the contrary, they had no cytotoxic effect on fibroblast cells. CONCLUSION: The results indicated that the synergistic impact of main components of AEEP was related to the inhibition of the cancer cell proliferation, cariogenic bacteria and oral biofilm formation. It may play a promising role in the complementary medicine and, it is suggested to be used as food additives.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Neoplasias/fisiopatologia , Própole/química , Streptococcus/efeitos dos fármacos , Animais , Antibacterianos/análise , Antineoplásicos/análise , Abelhas , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Irã (Geográfico) , Testes de Sensibilidade Microbiana , Boca/microbiologia , Neoplasias/tratamento farmacológico , Quercetina/análise , Quercetina/farmacologia , Streptococcus/crescimento & desenvolvimento
11.
Mar Drugs ; 17(9)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527497

RESUMO

Macroalgae produce a wide range of monoterpenes as secondary metabolites of mevalonate (MVA) and/or methylerythritol phosphate (MEP) pathway (often including haloperoxidase action). Great biodiversity of macroalgal monoterpenes was reported including acyclic, monocyclic, and bicyclic structures. Halogenated monoterpenes exhibited significant biological activity (e.g., anticancer, antiplasmodial, and insecticidal) that is influenced by the number of present halogens (higher halogen content is preferable, especially bromine) and their position within the monoterpene skeleton. In distinction from the existing reviews, the present review provides novelty with respect to: (a) exclusively monoterpenes from red macroalgae are targeted; (b) biosynthesis, isolation, and analysis, as well as bioactivity of monoterpenes are represented; (c) the methods of their isolation, analysis, and structure elucidation are summarized; (d) the bioactivity of macroalgal monoterpenes is systematically presented with emphasis on anticancer activity; (e) the literature references were updated.


Assuntos
Antineoplásicos/farmacologia , Monoterpenos/farmacologia , Rodófitas/química , Alga Marinha/química , Animais , Antineoplásicos/análise , Antineoplásicos/química , Linhagem Celular Tumoral , Eritritol/análogos & derivados , Eritritol/metabolismo , Humanos , Ácido Mevalônico/metabolismo , Estrutura Molecular , Monoterpenos/análise , Monoterpenos/metabolismo , Rodófitas/metabolismo , Alga Marinha/metabolismo , Fosfatos Açúcares/metabolismo
12.
Pesqui. vet. bras ; 39(9): 744-756, Sept. 2019. tab, ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1040747

RESUMO

The objective of this study was to evaluate the hepatoprotective effect of the honey bee Apis mellifera ethanolic extract of the red propolis, obtained in four municipalities of the Rio Grande do Norte semi-arid region, through an in vitro evaluation of the antineoplastic potential in human hepatic carcinoma (HepG2) and normal cell lines (L929), and from the comet assay in hepatic cell lines (ZF-L hepatocytes) to evaluate the genoprotective potential of the extract. The hepatoprotective effect was also evaluated in vivo by the induction of chronic experimental hepatic lesions in rodents (Rattus norvegicus Berkenhout, 1769), Wistar line, by intraperitoneal administration of thioacetamide (TAA) at the dose of 0.2g/kg. The animals were distributed in the following experimental groups: G1 (control), G2 (treated with 500mg/kg ethanolic extract of propolis), G3 (treated with 500mg/kg of ethanolic extract and TAA) and G4 (treated with TAA). All rats were submitted to serum biochemical, macroscopic, histological and stereological biochemical exams of the liver. It was verified the genoprotective effect of red propolis since the mean damages promoted to DNA in cells tested with the extract were significantly lower than the mean of the positive control damage (hydrogen peroxide). The red propolis extract did not present cytotoxic activity to the tumor cells of human liver cancer, as well as to normal ones. The absence of cytotoxicity in normal cells may indicate safety in the use of the propolis extract. The results of the serum biochemical evaluation showed that the serum levels of the aminotransferase enzymes (AST) did not differ significantly between G1, G2 and G3 when compared to each other. G4 showed significant increase in levels compared to the other groups, indicating that the administration of the extract did not cause liver toxicity, as well as exerted hepatoprotective effect against the hepatic damage induced by TAA. The G3 and G4 animals developed cirrhosis, but in G3 the livers were characterized by the presence of small regenerative nodules and level with the surface of the organ, whereas in G4 the livers showed large regenerative nodules. The livers of the G1 and G2 animals presented normal histological appearance, whereas the livers of the G3 animals showed regenerative nodules surrounded by thin septa of connective tissue, and in G4 the regenerative nodules were surrounded by thick septa fibrous connective tissue. The analysis of the hepatic tissues by means of stereology showed that there was no statistical difference between the percentage of hepatocytes, sinusoids, and collagens in G1 and G2. In G3 the percentage of hepatocytes, sinusoids, and collagen did not differ significantly from the other groups. It was concluded that the ethanolic extract of the red propolis exerted a hepatoprotective effect, because it promoted in vitro reduction of the damage to the DNA of liver cells, antineoplastic activity in human hepatocellular carcinoma cell line (HepG2) and did not exert cytotoxic effect in normal cells or was able to reduce liver enzyme activity and the severity of cirrhosis induced by TAA in vivo.(AU)


Este estudo objetivou avaliar o efeito hepatoprotetor do extrato etanólico da própolis vermelha da abelha Apis mellifera, obtido em quatro municípios do semiárido do Rio Grande do Norte, mediante avaliação in vitro do potencial antineoplásico em linhagens de células de carcinoma hepático humano (HepG2) e em linhagens de células normais (L929), além do ensaio cometa em linhagens de células hepáticas (hepatócitos ZF-L) para avaliar o potencial genoprotetor do extrato. O efeito hepatoprotetor também foi avaliado in vivo através da indução de lesões hepática experimental crônica em roedores da espécie Rattus norvegicus (Berkenhout, 1769), linhagem Wistar, pela administração intraperitoneal de tioacetamida (TAA) na dose de 0,2g/kg. Os animais foram distribuídos nos seguintes grupos experimentais: G1 (controle), G2 (tratados com 500mg/kg de extrato etanólico da própolis), G3 (tratados com 500mg/kg de extrato etanólico e TAA) e G4 (tratados com TAA). Todos os ratos foram submetidos aos exames bioquímico sérico, anatomopatológico macroscópico, histológico e esteriológico do fígado. Foi constatado o efeito genoprotetor da própolis vermelha uma vez que as médias dos danos promovidos ao DNA em células testadas com o extrato foram significativamente inferiores à média dos danos do controle positivo (peróxido de hidrogênio). O extrato da própolis vermelha não apresentou atividade citotóxica para células tumorais de câncer de fígado humano, bem como para normais. A ausência de citotoxicidade em células normais, tal como constatado, pode indicar segurança no uso do extrato da própolis. Os resultados da avaliação bioquímica sérica demonstraram que os níveis séricos das enzimas aminotransferase (AST) não diferiram significativamente entre G1, G2 e G3, quando comparadas entre si. No G4 houve aumento significativo dos níveis em relação aos demais grupos, indicando que a administração do extrato não causou toxicidade hepática, bem como exerceu efeito hepatoprotetor frente ao dano hepático induzido pela TAA. Os animais dos G3 e G4 desenvolveram cirrose, porém no G3 os fígados caracterizaram-se pela presença de pequenos nódulos regenerativos e nivelados com a superfície do órgão, enquanto que no G4 os fígados apresentaram grandes nódulos regenerativos. Os fígados dos animais G1 e G2 apresentaram aspecto histológico normal, enquanto que os fígados dos animais do G3 apresentaram nódulos regenerativos circundados por finos septos de tecido conjuntivo, e nos do G4 os nódulos regenerativos foram circundados por espessos septos de tecido conjuntivo fibroso. A análise dos tecidos hepáticos por meio de estereologia mostrou que não houve diferença estatística entre o percentual de hepatócitos, sinusoides e colágenos nos G1 e G2. No G3 o percentual de hepatócitos, sinusoides e colágeno não diferiu significativamente dos demais grupos. Concluiu-se que o extrato etanólico da própolis vermelha exerceu efeito genoprotetor, por promover in vitro redução do dano ao DNA de células hepáticas, atividade antineoplásica em linhagem celular de carcinoma hepatocelular humano (HepG2) e não exerceu efeito citotóxico em células normais ou efeito hepatoprotetor in vivo com diminuição da gravidade da cirrose induzida por TAA.(AU)


Assuntos
Animais , Própole/uso terapêutico , Abelhas , Citotoxinas , Medicamentos Hepatoprotetores , Antineoplásicos/análise
13.
Chem Pharm Bull (Tokyo) ; 67(10): 1076-1081, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31406093

RESUMO

Histone deacetylases (HDACs) are enzymes that play a key role in structural modification and gene expression. The overexpression of HDAC is associated with cancer, and thus inhibiting the enzyme could be an efficient cancer therapy. To discover new HDAC inhibitors (HDACis), we proposed an improved protocol combining a hierarchical pharmacophore search, molecular docking, and molecular dynamic simulations. The test results showed that the improved screening protocol effectively reduced the false-positive rates of drug-like chemicals. Based on the protocol, we obtained 16 hit compounds as potential HDACis from the Life Chemicals database. Enzyme inhibition experiments showed that two of the hit chemical compounds had HDAC-inhibitory effects. In vitro assays showed that Z165155756 could selectively inhibit the proliferation of cancer cells and specifically promoted apoptosis and induced G1/S phase arrest in A2780 cells. It may have potential therapeutic effects in ovarian cancer and is worthy of further investigation.


Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Histona Desacetilases/análise , Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
14.
J Pharm Biomed Anal ; 174: 734-743, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299454

RESUMO

Riccardin D-N (RD-N) is an aminomethylated derivative of the macrocyclic bisbibenzyl compound riccardin D (RD), which has shown stronger activity against cancer cells than RD. However, there has been no research on the metabolism of RD-N. The present study aimed to characterize the in vitro metabolism and metabolic stability of RD-N after incubation with mouse and human hepatic S9 fractions using high performance liquid chromatography-hybrid triple quadrupole/linear ion trap mass spectrometry (HPLC-Q-LIT-MS). Multiple ion monitoring (MIM) and multiple reaction monitoring (MRM)-information dependent acquisition-enhanced product ion (MIM/MRM-IDA-EPI) scans were used to identify the metabolites formed. MRM scans were also used to quantify the changes in the amount of RD-N and to semi-quantify the main metabolites. Twenty-eight metabolic products were detected and 25 structures were predicted. Hydroxylation, dehydrogenation, glucuronidation, and methylation were proposed to be the principle metabolic pathways in the in vitro incubation with human and mouse hepatic S9 fractions. There were differences in the number and abundance of RD-N metabolites between the human and mouse hepatic S9 fractions. RD-N was shown to have good metabolic stability. After 2 h of incubation, 44% of the original RD-N remained in the human hepatic S9 fraction compared with 22% in the mouse. The major metabolites of RD-N, M4, M8, M20 and M21, were monitored semi-quantitatively using the typical transitions. Finally, HPLC-Q-LIT-MS was used for the identification and quantitation of the metabolites of R D-N, which is a simple and efficient method to rapidly screen potential drug candidates.


Assuntos
Antineoplásicos/análise , Fígado/metabolismo , Éteres Fenílicos/análise , Estilbenos/análise , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Hidrogênio/química , Hidroxilação , Metilação , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Oxigênio/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
15.
Biomed Chromatogr ; 33(11): e4638, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31261446

RESUMO

Monitoring gefitinib and its metabolites may help to explore the underlying mechanisms of gefitinib resistance. The concentration of gefitinib and its metabolites in tumor tissues could influence its anticancer activities more than that in the plasma. In the present study, a rapid and specific HPLC-MS/MS method was developed and validated to simultaneously determine gefitinib, M387783, M523595, M537194 and M608236 in tumor tissues of H1975 human lung cancer xenografts of nude mice. The established HPLC-MS/MS method was validated for specificity, linearity, accuracy and precision, matrix effect and recovery, carryover and dilution integrity, and analyte stability. The standard curves were linear (r2 ≥ 0.99) over the range of 0.5-100 ng/mL for M608236 and 1-200 ng/mL for gefitinib, M523595 and M537194 as well as M387783. The accuracy ranged from -8.35 to 6.03% relative error; and the precision was <15% relative standard deviation. Recoveries (87.74-99.96%) and matrix effects (86.60-106.40%) were satisfactory in the biological matrix examined. Stability studies showed that the analytes were stable during the assay procedure and storage. Finally, the validated method was successfully applied to study the pharmacokinetics profiles for gefitinib and its metabolites in nonsmall cell lung cancer (NSCLC) xenograft mouse tumors. Meanwhile, MTT assay showed that gefitinib had a more powerful inhibitory effect than its four major metabolites in H1975 NSCLC cells. This validated HPLC-MS/MS method may be applied to help understand the mechanisms of gefitinib resistance in EGFR-mutant nonsmall cell lung cancer.


Assuntos
Antineoplásicos/análise , Cromatografia Líquida de Alta Pressão/métodos , Gefitinibe/análise , Neoplasias Pulmonares/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gefitinibe/farmacocinética , Xenoenxertos , Modelos Lineares , Camundongos , Camundongos Nus , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
16.
Dalton Trans ; 48(32): 12257-12271, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31339136

RESUMO

Of late, cancer has become a terrible disease affecting people throughout the world. Keeping this in mind, we tried to design drugs that are more lipophilic, target-specific, water-soluble, cytoselective and fluorescent. In this regard, we reported novel ruthenium(ii)-p-cymene imidazophenanthroline scaffolds as effective DNA targeting agents. The planarity of imidazophenanthroline ligands caused the Ru(ii) complex to be a good intercalator. An extended π-electronic conjugation was introduced in the imidazophenanthroline moieties through the Suzuki and Sonogashira coupling reactions. Here, we synthesized nine Ru(ii) complexes (16a-b, 17a-d, and 19a-c). Among these, [(η6-p-cymene)RuCl(K2-N,N-2-(4'-methyl-[1,1'-BIphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (16b) exhibited the best potency and selectivity with excellent cellular uptake; [(η6-p-cymene)RuCl(K2-N,N-2-(4-(phenylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (17a) acted as a cytoselective probe for live cell imaging.


Assuntos
Antineoplásicos/análise , Complexos de Coordenação/análise , Substâncias Luminescentes/análise , Imagem Óptica , Fenantrolinas/análise , Rutênio/análise , Antineoplásicos/síntese química , Antineoplásicos/química , Sobrevivência Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Ligantes , Substâncias Luminescentes/síntese química , Substâncias Luminescentes/química , Estrutura Molecular , Fenantrolinas/química , Rutênio/química , Relação Estrutura-Atividade
17.
Am J Health Syst Pharm ; 76(9): 591-598, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-31361828

RESUMO

PURPOSE: The surface contamination levels of 5 commonly used hazardous drugs in hospital pharmacies are summarized, identifying practice patterns associated with contamination. METHODS: Contamination testing data were compiled to evaluate surface contaminants of 5 hazardous drugs (docetaxel, paclitaxel, cyclophosphamide, ifosfamide, and 5-fluorourcil). Data from 5,842 wipes over 6 years were collected from 338 hospital pharmacies. The contamination level for each drug was categorized as nondetectable (ND; ≤10 ng/ft2), low (between 10 and ≤100 ng/ft2), medium (between 100 and ≤1,000 ng/ft2) or high (>1,000 ng/ft2). Surface exposures for each drug were summarized based on location, contamination at first and subsequent wipe events, and the use of a closed system transfer device (CSTD). RESULTS: The majority of contamination results corresponded to locations at or near hazardous drug preparation, but also occurred in areas where hazardous drugs were not prepared. There was a higher incidence of contamination levels (high, medium, and low, respectively) at first wipe event (10.2%, 17.4%, and 17.7%) compared to subsequent wipe events (5.8%, 12.2%, and 13.6%) (p < 0.0001). There was a lower incidence of contamination levels at institutions that used CSTDs (6.3%, 12.8%, and 14.4%) compared to institutions that did not use CSTDs (14.2%, 17.9%, and 17.3%) (p < 0.0001). CONCLUSIONS: The majority of highest contamination levels corresponded to locations where hazardous drugs were prepared. While the rate of contamination was lower at subsequent wipe events and at institutions that used CSTDs, contamination was not completely eliminated in either scenario.


Assuntos
Antineoplásicos/análise , Contaminação de Equipamentos/prevenção & controle , Substâncias Perigosas/análise , Serviço de Farmácia Hospitalar/normas , Composição de Medicamentos/métodos , Composição de Medicamentos/normas , Monitoramento Ambiental/métodos , Equipamentos e Provisões Hospitalares/normas , Humanos , Serviço de Farmácia Hospitalar/métodos
18.
Adv Exp Med Biol ; 1140: 251-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347052

RESUMO

ADCs are empowered monoclonal antibodies that are designed to harness their targeting ability by linking them to cell-killing agents. They are made up of three main components, the antibody, linker and the cytotoxic drug. The specificity of the antibody with the antigen on the tumor cell surface helps with its internalization into the cell after which the active drug is released causing cell death. The investigation of ADCs can be done using a variety of MS methods. Here, we talk about the bottom-up approach, the top-down approaches such as ECD and ETD, the ESI/MS method and IM-MS. Further, we also focus on the applications of MALDI/MS such as UV-MALDI, IR-MALDI and IMS-MALDI and provide examples of the mass spectra that provide tremendous amount of information on ADC structures.


Assuntos
Anticorpos Monoclonais/análise , Antineoplásicos/análise , Imunoconjugados/análise , Neoplasias , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Biomed Res Int ; 2019: 1847130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240205

RESUMO

Over years, various biological constituents are isolated from Traditional Chinese Medicine and confirmed to show multifunctional activities. Magnolol, a hydroxylated biphenyl natural compound isolated from Magnolia officinalis, has been extensively documented and shows a range of biological activities. Many signaling pathways include, but are not limited to, NF-κB/MAPK, Nrf2/HO-1, and PI3K/Akt pathways, which are implicated in the biological functions mediated by magnolol. Thus, magnolol is considered as a promising therapeutic agent for clinic research. However, the low water solubility, the low bioavailability, and the rapid metabolism of magnolol dramatically limit its clinical application. In this review, we will comprehensively discuss the last five-year progress of the biological activities of magnolol, including anti-inflammatory, antimicroorganism, antioxidative, anticancer, neuroprotective, cardiovascular protection, metabolism regulation, and ion-mediating activity.


Assuntos
Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Lignanas/metabolismo , Lignanas/farmacologia , Medicina Tradicional Chinesa , Anti-Inflamatórios/análise , Antineoplásicos/análise , Antioxidantes/análise , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Fármacos Cardiovasculares/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Lignanas/química , Lignanas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Magnolia/química , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/análise , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Prostate ; 79(12): 1412-1419, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31231865

RESUMO

BACKGROUND: Statins have anticancer effects on prostate cancer both in vitro and in vivo. It is unclear whether this is due to systemic cholesterol-lowering or direct local growth inhibition in the prostate. It is also unclear whether statins can access the prostate; lipophilic statins could, in theory, pass lipid-enriched cell membranes by passive diffusion. However, statin concentrations in the human prostate have not been measured before. METHODS: The study population was based on a randomized clinical trial where 158 men with prostate cancer were randomized to use 80 mg atorvastatin (ATV) or placebo daily for a median of 27 days before radical prostatectomy. ATV and atorvastatin lactone (ATV-Lactone) concentrations in the plasma and in the prostate were measured with mass spectrometry in men randomized to the ATV arm. Linear trends between intraprostatic concentration and plasma concentration, body mass index, age, and duration of intervention were examined. The relative tissue concentrations of ATV and ATV-Lactone were calculated in prostatic tissue and plasma to evaluate drug homeostasis. Subgroup analyses were stratified by tumor and population characteristics. RESULTS: The analysis involved a total of 55 men. When limited to men whose tissue concentrations of ATV was measurable (n = 28, 50%), median ATV concentration was 212% higher in the tissue (median concentration 17.6 ng/g) compared to the plasma (median concentration 3.6 ng/mL). Also, ATV-L concentration was 590% higher in the tissue as compared to the plasma concentration. No statistically significant linear trends between the plasma and tissue concentrations were observed. When comparing the relative concentration of atorvastatin lactone over ATV, the concentrations were in balance in the plasma, In the prostate, however, the relative concentration of atorvastatin lactone was 57% lower compared to ATV (P = .009 for the difference between prostate tissue and plasma). No effect modification by tumor or population characteristics was observed. CONCLUSIONS: Measurable ATV concentrations in the prostate support ATV's ability to access the prostate from the circulation. ATV may accumulate in the prostate as intraprostatic concentrations are elevated compared to the plasma concentration.


Assuntos
Antineoplásicos/análise , Atorvastatina/análise , Próstata/química , Neoplasias da Próstata/química , Administração Oral , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/análise , Anticolesterolemiantes/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Atorvastatina/administração & dosagem , Atorvastatina/sangue , Humanos , Lactonas/administração & dosagem , Lactonas/análise , Lactonas/sangue , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia
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