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1.
Biomed Chromatogr ; 37(4): e5573, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36529812

RESUMO

Moscatilin, a bibenzyl derivative from the stem of Dendrobium loddigesii, has been shown to have anticancer activity. The aim of this study was to identify and characterize the possible in vitro metabolites of moscatilin generated from hepatocytes. The metabolites generated in the hepatocytes of mouse, rat, dog, monkey and human were identified and characterized employing ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap tandem mass spectrometry (LC-Orbitrap-MS/MS) based on diagnostic fragment ions and accurate mass measurements. A total of 18 metabolites were identified, among which seven were phase I and 11 were phase II metabolites. The plausible structures of the metabolites and the probable biotransformation pathways were proposed based on the diagnostic fragment ions, chemical formula and mass fragmentation pattern, as well as the accurate masses. The majority of phase I metabolites were generated by demethylation and hydroxylation, while phase II metabolites were mainly generated by glucuronidation, glutathione conjugation and sulfation. Our study first expounded the metabolites of moscatilin in mouse, rat, dog, monkey and human hepatocytes and provided a foundation for a further pharmacokinetic and toxicity study. More importantly, LC-Orbitrap-MS/MS combined with diagnostic fragment ions and accurate mass measurements has been proved to be an effective method for the rapid identification of bibenzyl derivatives and their metabolites.


Assuntos
Bibenzilas , Espectrometria de Massas em Tandem , Ratos , Humanos , Cães , Camundongos , Animais , Espectrometria de Massas em Tandem/métodos , Haplorrinos , Hepatócitos/metabolismo
2.
Molecules ; 28(16)2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37630333

RESUMO

In this study, we have successfully constructed Ag3PO4/Ag/g-C3N4 heterojunctions via the hydrothermal method, which displays a wide photo-absorption range. The higher photocurrent intensity of Ag3PO4/Ag/g-C3N4 indicates that the separation efficiency of the photogenerated electron-hole pairs is higher than that of both Ag3PO4 and Ag/g-C3N4 pure substances. It is confirmed that the efficient separation of photogenerated electron-hole pairs is attributed to the heterojunction of the material. Under visible light irradiation, Ag3PO4/Ag/g-C3N4-1.6 can remove MO (~90%) at a higher rate than Ag3PO4 or Ag/g-C3N4. Its degradation rate is 0.04126 min-1, which is 4.23 and 6.53 times that of Ag/g-C3N4 and Ag3PO4, respectively. After five cycles of testing, the Ag3PO4/Ag/g-C3N4 photocatalyst still maintained high photocatalytic activity. The excellent photocatalysis of Ag3PO4/Ag/g-C3N4-1.6 under ultraviolet-visible light is due to the efficient separation of photogenerated carriers brought about by the construction of the Ag3PO4/Ag/g-C3N4 heterostructure. Additionally, Ag3PO4/Ag/g-C3N4 specimens can be easily recycled with high stability. The effects of hydroxyl and superoxide radicals on the degradation process of organic compounds were studied using electron paramagnetic resonance spectroscopy and radical quenching experiments. Therefore, the Ag3PO4/Ag/g-C3N4 composite can be used as an efficient and recyclable UV-vis spectrum-driven photocatalyst for the purification of organic pollutants.

3.
Molecules ; 28(22)2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-38005200

RESUMO

Nanofluid-enhanced oil recovery (EOR) technology is an innovative approach to enhancing oil production in oilfields. It entails the dispersion of nanoparticles within a fluid, strategically utilizing the distinctive properties of these nanoparticles (NPs) to engage with reservoir rocks or crude oil, resulting in a significant enhancement of the oil recovery rate. Despite the notable advantages of nanofluid EOR technology over conventional oil recovery methods such as binary and ternary flooding, practical implementations continue to grapple with a range of pressing challenges. These challenges encompass concerns regarding the economic viability, stability, and adaptability of nanomaterials, which pose significant barriers to the widespread adoption of nanofluid EOR technology in the oil field. To tackle these challenges, addressing the current issues may involve selecting simpler and more readily available materials coupled with straightforward material modification techniques. This approach aims to more effectively meet the requirements of large-scale on-site applications. Within this framework, this review systematically explores commonly employed nanofluids in recent years, including inorganic nanofluids, organic nanofluids, and composite nanofluids. It categorizes the research advancements in optimizing modification techniques and provides a comprehensive overview of the mechanisms that underpin nanofluid EOR technology and its practical applications in oilfields. This comprehensive review aims to offer valuable references and serve as a solid foundation for subsequent research endeavors.

4.
Acta Pharmacol Sin ; 43(10): 2678-2686, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35228653

RESUMO

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cisteína , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Biomed Chromatogr ; 36(3): e5282, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34806205

RESUMO

Kansuinine A is a macrocyclic jatrophane diterpene isolated from the plant Euphorbia kansui Liou. It exhibits many pharmacological activities including cytoxic, antitumor, antiallergic and proinflammatory effects. In the present study, a simple and sensitive LC-MS/MS method was established and validated for the determination of kansuinine A in rat plasma. After methanol-mediated protein precipitation, chromatographic separation was achieved on an Acquity BEH C18 column (2.1 × 100 mm, 1.7 µm) using acetonitrile and 0.1% formic acid in water as mobile phase by gradient elution. Kansuinine A and IS were quantified in negative multiple reaction monitoring mode with ion transitions at m/z 731.1-693.2 for kansuinine A and m/z 723.2-623.1 for IS. The method showed excellent linearity over the range 1-500 ng/ml. The intra- and inter-day precisions (relative standard deviation) were 2.13-4.28 and 3.83-7.67%, respectively, whereas accuracy (relative error) ranged from -4.17 to 3.73%. The extraction recovery, stability and matrix effect met the requirement of the regulations issued by the US Food and Drug Administration. The validated method was successfully applied to the pre-clinical pharmacokinetic study of kansuinine A in rats after oral administration (20 mg/kg) and intravenous administration (2 mg/kg). This study provides valuable reference for the further study of E. kansui liou, especially for the drug development and clinical application of kansuinine A.


Assuntos
Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Modelos Lineares , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
6.
Chem Res Toxicol ; 34(9): 2157-2165, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34431289

RESUMO

Marrubiin, a furanoid compound, is a well-known diterpenoid lactone isolated from Marrubium vulgare, which displays a wide spectrum of pharmacological effects and potential hepatotoxicity. Considering that marrubiin contains a structural alert, furan ring, metabolic activation may be one of the major metabolic pathways, and the reactive metabolite may be involved in the hepatotoxicity. The present study was carried out to investigate the bioactivation mechanism of marrubiin in rats and humans. Marrubiin was initially metabolized into cis-butene-1,4-dial intermediate, which was readily trapped by glutathione (GSH) and N-acetyl-lysine (NAL) in the microsomal incubations supplemented with NADPH. A total of nine conjugates were detected and identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. M1-M3 and M6 and M7 were characterized as mono-GSH conjugates, and M4 and M5 were identified as bis-GSH conjugates. M8 and M9 were identified as NAL conjugates. In rat bile, five GSH conjugates (M1-M3; M6 and M7) were detected. M1, M8, and M9 were chemically synthesized, and their structures were characterized by 13C NMR. Sulfaphenazole, ticlopidine, and ketoconazole displayed significant inhibitory effect on the bioactivation of marrubiin. Further phenotyping revealed that CYP2C9, CYP2C19, and CYP3A4 were the primary enzymes catalyzing the bioactivation of marrubiin. The current study provides evidence for the CYP-dominated bioactivation of marrubiin to the corresponding cis-butene-1,4-dial intermediate, which enables us to better understand the potential side effects caused by marrubiin.


Assuntos
Diterpenos/metabolismo , Marrubium/química , Ativação Metabólica , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley
7.
Invest New Drugs ; 38(5): 1272-1281, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31872348

RESUMO

Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
8.
Chem Res Toxicol ; 33(8): 2208-2217, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32633501

RESUMO

Nomilin is a furan-containing triterpenoid isolated from the medicinal plants of citrus. The aim of this study was to investigate the in vitro and in vivo bioactivation of nomilin and the role in nomilin-induced hepatotoxicity. Microsomal incubations of nomilin supplemented with NADPH and GSH or NAL resulted in the detection of six conjugates (M1-M6). The structures of the metabolites were characterized based on LC-HRMS and NMR. Nomilin was bioactivated to a reactive cis-butene-dial (BDA) intermediate dependent on NADPH, and this intermediate suffered from the reaction with the nucleophiles (GSH and NAL) to form stable adducts. M1-M4 were identified as pyrrole derivatives, and M5 and M6 were pyrrolinone derivatives. M1 was further chemically synthesized and characterized by 13C NMR spectroscopy. M1 was the major metabolite detected in mice bile. Pretreatment with ketoconazole significantly reduced the formation of M1 in mice bile, while pretreatment with rifampicin significantly increased the formation of M1. Chemical inhibition together with recombinant human CYP450 phenotyping demonstrated that CYP3A4 was the major enzyme contributing to the bioactivation of nomilin. Toxicity study suggested that nomilin displayed dose-dependent liver injury in mice, while tetrahydro-nomilin was found to be nonhepatotoxic. Pretreatment with ketoconazole prevented mice from nomilin-induced liver injury. The liver injury induced by nomilin was deteriorated when the mice were pretreated with rifampicin. These findings provide evidence that CYP3A4-mediated bioactivation was indispensable in nomilin-induced hepatotoxicity.


Assuntos
Benzoxepinas/toxicidade , Citocromo P-450 CYP3A/metabolismo , Limoninas/toxicidade , Fígado/efeitos dos fármacos , Administração Oral , Animais , Benzoxepinas/administração & dosagem , Feminino , Humanos , Limoninas/administração & dosagem , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo
9.
Chem Res Toxicol ; 33(7): 1960-1968, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32484342

RESUMO

Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Dictamnus dasycarpus Turcz, which is extensively spread throughout Asian countries. This herb was reported to cause liver injury in clinical application. However, the mechanism behind is still not fully understood. This study mainly focused on the hepatotoxicity of fraxinellone and the underlying mechanism. The current study demonstrated that fraxinellone resulted in a significant elevation of serum alanine aminotransferase and aspartate aminotransferase in a dose-dependent manner in mice after oral administration. Pretreatment with ketoconazole for three successive days could significantly alleviate the hepatotoxicity of fraxinellone. Considering that fraxinellone has a structural alert of furan ring, it is believed that the hepatotoxicity caused by fraxinellone required cytochrome P450-mediated bioactivation. Bioactivation studies were subsequently carried out in vitro and in vivo. Fraxinellone was metabolized into cis-enedial intermediate, an electrophile that was prone to react with glutathione or N-acetyl-lysine through 1,2- or 1,4-addition to form stable conjugates. Ketoconazole significantly inhibited the formation of the glutathione conjugates (M1 and M2) in microsomal incubation and similar finding was obtained in vivo. Phenotyping study indicated that CYP3A4 was the principal enzyme responsible for the bioactivation of fraxinellone. This study suggested that CYP3A4-mediated bioactivation plays an indispensable role in fraxinellone-induced hepatotoxicity. The work performed herein enables us to better understand the hepatotoxicity of fraxinellone as well as the mechanism behind.


Assuntos
Benzofuranos/farmacocinética , Benzofuranos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ativação Metabólica , Administração Oral , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dictamnus , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Proteínas Recombinantes/metabolismo
10.
Pharm Res ; 37(9): 167, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778962

RESUMO

The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be life-threatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dual-purpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , COVID-19 , Humanos , Pandemias
11.
Nanomedicine ; 29: 102283, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32777451

RESUMO

Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117 h (>20-fold). In the 150 days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8 days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML.


Assuntos
Genes abl/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nanopartículas/química , Inibidores de Proteínas Quinases/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Genes abl/genética , Humanos , Mesilato de Imatinib/química , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia
12.
Biomed Chromatogr ; 33(11): e4645, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31306503

RESUMO

AdipoRon is an orally active adiponectin receptor agonist. The aim of this study was to characterize the metabolites of AdipoRon in rat and human liver microsomes using ultra-high performance liquid chromatography combined with Q-Exactive Orbitrap tandem mass spectrometry (UPLC-Q-Exactive-Orbitrap-MS) together with data processing techniques including extracted ion chromatograms and a mass defect filter. AdipoRon (10 µm) was incubated with liver microsomes in the presence of NADPH and this resulted in a total of 11 metabolites being detected. The identities of these metabolites were characterized by comparing their accurate masses and fragment ions as well as their retention times with those of AdipoRon using MetWorks software. Metabolites M1-M3, M6, and M8-M11 were identified for the first time. Metabolite M4, the major metabolite both in rat and human liver microsomes, was further confirmed using the reference standard. Our results revealed that the metabolic pathways of AdipoRon in liver microsomes were N-dealkylation (M2), hydroxylation (M, M5-M9), carbonyl reduction (M4) and the formation of amide (M10 and M11). Our results provide valuable information about the in vitro metabolism of AdipoRon, which would be helpful for us to understand the mechanism of the elimination of AdipoRon and, in turn, its effectiveness and toxicity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Piperidinas/análise , Piperidinas/farmacocinética , Ratos
13.
Biomed Chromatogr ; 33(9): e4580, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31077415

RESUMO

Ginsenoside Rk1 (Rk1) exhibited various potent biological activities. However, its pharmacokinetic profile in vivo remains unclear. In the present study, a simple and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for determination of Rk1 in rat plasma and applied in a pharmacokinetic study. The sample was precipitated with acetonitrile and separated on a Zorbax Eclipse XDB C18 column (50 × 2.1 mm, 1.8 µm). The mobile phase was composed of 0.1% formic acid in water and acetonitrile at a flow rate of 0.4 mL/min. Rk1 and internal standard (ginsenoside Rg3) were quantitatively monitored with precursor-to-product ion transitions of m/z 765.4 → 441.5 and m/z 783.5 → 621.4, respectively. The assay was linear over the concentration range of 5-1000 ng/mL (r > 0.99) with the LLOQ of 5 ng/mL. Other parameters including intra- and inter-day precision and accuracy, extraction recovery and matrix effect were within the acceptable limits. The analyte was stable under the tested storage conditions. The validated method has been successfully applied to a pharmacokinetic study of Rk1 in rat plasma after intravenous (5 mg/kg) and oral (25 mg/kg, 50 mg/kg) administration. After oral administration, Rk1 could be detected in blood at 30 min and reached the highest concentration at 4.29~4.57 h. Our results demonstrated that Rk1 showed low clearance, moderate half-life (3.09-3.40 h) and low bioavailability (2.87-4.23%). The study will provide information for the further application of Rk1.


Assuntos
Cromatografia Líquida/métodos , Ginsenosídeos/sangue , Ginsenosídeos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Disponibilidade Biológica , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
15.
Xenobiotica ; 44(8): 757-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24524624

RESUMO

1. DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague-Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method. 2. The area under concentration-time curve AUC0-t and AUC0-∞ for platinum originating from DN604 at 10 mg/kg were 25.15 ± 1.29 and 28.72 ± 1.04 µg/hml, respectively. The mean residence time MRT was 36.59 ± 6.65 h. The volume of distribution Vz was 11.42 ± 2.49 l/kg and clearance CL was 0.18 ± 0.01 l/h/kg. In addition, the elimination half-life T1/2z was 44.83 ± 9.75 h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120 h was 63.5% ± 7.7% for urine, but only 6.94% ± 0.11% for feces. 3. The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.


Assuntos
Antineoplásicos/farmacocinética , Espectrometria de Massas/métodos , Platina/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/urina , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fezes/química , Platina/administração & dosagem , Platina/química , Platina/urina , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual
16.
Xenobiotica ; 44(7): 583-90, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24329500

RESUMO

Triacontanol was confirmed to have a potential anti-cancer effect, the aim was to assess whether the co-administration of triacontanol alters the exposure of docetaxel via inducing hepatic CYP3A1/2 activity. The concentration of docetaxel in rats pretreated with triacontanol for seven successive days was determined, and the expression levels of CYP3A protein and mRNA were analyzed by the western blot and real time polymerase chain reaction (RT-PCR) technique, respectively. 2. The concentrations of docetaxel in rats pretreated with triacontanol were decreased, with 61.5%, 61.9% decrease in AUC0-24h and 65.7%, 54.9% reduction in Cmax (120 and 180 mg kg(-1), respectively) compared with the control. Hepatic clearance of docetaxel was enhanced in vitro and in vivo at dosage of 120 and 180 mg kg(-1), and CYP3A activity was up-regulated by measuring the formation rate of 1-hydroxymidazolam. Triacontanol preferentially induced protein expression level of CYP3A2 in a dose-dependent manner and of CYP 3A1 at dosage of 120 and 180 mg kg(-1). The mRNA expression of CYP3A1 was moderately different with the western blot results, but the trends appeared similar. CYP3A2 mRNA level was not markedly affected by triacontanol. 3. The significant triacontanol-docetaxel interaction was largely due to the induction of CYP3A1/2, which brought useful information in the clinical therapy when the combination is administered in human.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Álcoois Graxos/farmacologia , Taxoides/farmacocinética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Área Sob a Curva , Citocromo P-450 CYP3A/genética , Docetaxel , Indução Enzimática/efeitos dos fármacos , Álcoois Graxos/administração & dosagem , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Midazolam/análogos & derivados , Midazolam/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Taxoides/administração & dosagem
17.
Molecules ; 19(5): 5538-49, 2014 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-24786691

RESUMO

Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague-Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of wogonin in different rat biological samples. After i.v. dosing of wogonin at different levels (10, 20 and 40 mg/kg) the elimination half-life was approximately 14 min, the AUC0-∞ increased in a dose disproportional manner from 112.13 mg/L·min for 10 mg/kg to 758.19 mg/L·min for 40 mg/kg, indicating a non linear pharmacokinetic profile. After i.g. dosing at 100 mg/kg, plasma levels of wogonin peaked at 28 min with a Cmax value of 300 ng/mL and a very low oral bioavailability (1.10%). Following i.v. single dose (20 mg/kg), wogonin was detected in all examined tissues (including testis) with the highest levels in kidney and liver. Approximately 21% of the administered dose was excreted as unchanged drug (mainly via non-biliairy fecal route (16.33%). Equilibrium dialysis was used to evaluate plasma protein binding of wogonin at three concentrations (0.1, 0.5 and 2 µg/mL). Results indicated a very high protein binding degree (over 90%), reducing substantially the free fraction of the compound.


Assuntos
Proteínas Sanguíneas/metabolismo , Flavanonas/sangue , Flavanonas/farmacocinética , Animais , Disponibilidade Biológica , Flavanonas/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ligação Proteica , Ratos , Espectrometria de Massas em Tandem , Distribuição Tecidual
18.
Zhongguo Zhong Yao Za Zhi ; 39(5): 860-6, 2014 Mar.
Artigo em Zh | MEDLINE | ID: mdl-25204180

RESUMO

Persicae Semen (PS), a traditional Chinese medicine, has been widely used for the syndrome of blood stasis in China since the Eastern Han Dynasty. In the present study, we developed an HPLC-UV fingerprint analysis method for the quality control of PS. The HPLC fingerprint was performed on Shimadzu Inertsil C18 column (4.6 mm x 250 mm, 5 microm) at 35 degrees C. The mobile phases were composed of acetonitrile and water using a gradient elution. The flow rate was 1.0 mL x min(-1), and the detection wavelength was set at 210 nm. The fingerprint method was validated according to the Guidelines for Traditional Chinese Medicine Injection Fingerprint, and applied to determine 41 batches representative herbs collected from Xinjiang of China. The chromatographic peaks were characterized by UPLC-Q-TOF-MS, and nine of them were identified by comparison with the literature and/or reference standards. In order to classify and assess the samples, hierarchical clustering analysis and partial least square discriminant analysis were performed based on the common chromatographic peaks, and the samples were geographically classified into two classes, with six chemical compounds as classification markers which were significantly different between the two classes (P < 0.05).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Prunus/química , Sementes/química , China , Cromatografia Líquida de Alta Pressão/instrumentação , Medicamentos de Ervas Chinesas/isolamento & purificação , Controle de Qualidade
19.
J Pharm Biomed Anal ; 248: 116338, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38971092

RESUMO

Tetrahydroxy stilbene glucoside (TSG) is a water-soluble natural product that has shown potential in treating atherosclerosis (AS). However, its underlying mechanisms remain unclear. Here, we demonstrate that an 8-week TSG treatment (100 mg/kg/d) significantly reduces atherosclerotic lesions and alleviates dyslipidemia symptoms in ApoE-/- mice. 1H nuclear magnetic resonance metabolomic analysis reveals differences in both lipid components and water-soluble metabolites in the livers of AS mice compared to control groups, and TSG treatment shifts the metabolic profiles of AS mice towards a normal state. At the transcriptional level, TSG significantly restores the expression of fatty acid metabolism-related genes (Srepb-1c, Fasn, Scd1, Gpat1, Dgat1, Pparα and Cpt1α), and regulates the expression levels of disturbed cholesterol metabolism-related genes (Srebp2, Hmgcr, Ldlr, Acat1, Acat2 and Cyp7a1) associated with lipid metabolism. Furthermore, at the cellular level, TSG remarkably polarizes aortic macrophages to their M2 phenotype. Our data demonstrate that TSG alleviates arthrosclerosis by dual-targeting to hepatic lipid metabolism and aortic M2 macrophage polarization in ApoE-/- mice, with significant implications for translational medicine and the treatment of AS using natural products.

20.
Materials (Basel) ; 16(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37444973

RESUMO

The Ag3PO4/CoFe1.95Y0.05O4 nanocomposite with magnetic properties was simply synthesized by the hydrothermal method. The structure and morphology of the prepared material were characterized, and its photocatalytic activity for degradation of the methylene blue and rhodamine B dyes was also tested. It was revealed that the Ag3PO4 in the nanocomposite exhibited a smaller size and higher efficiency in degrading dyes than the individually synthesized Ag3PO4 when exposed to light. Furthermore, the magnetic properties of CoFe1.95Y0.05O4 enabled the nanocomposite to possess magnetic separation capabilities. The stable crystal structure and effective degradation ability of the nanocomposite were demonstrated through cyclic degradation experiments. It was shown that Ag3PO4/CoFe1.95Y0.05O4-0.2 could deliver the highest activity and stability in degrading the dyes, and 98% of the dyes could be reduced within 30 min. Additionally, the photocatalytic enhancement mechanism and cyclic degradation stability of the magnetic nanocomposites were also proposed.

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