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1.
Org Biomol Chem ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38695080

RESUMO

Transition-metal-catalyzed aromatic olefination through direct C-H activation represents an atom and step-economic route for versatile pharmaceutical syntheses, and in many cases, different stoichiometric oxidants are frequently employed for achieving a reasonable catalytic efficiency of the transition metal ions. Herein, we report a Lewis acid promoted Pd(II)-catalyzed acetanilide olefination reaction with atmospheric dioxygen as the oxidant source. The linkage of the Lewis acid to the Pd(II) species through a diacetate bridge significantly improved its catalytic efficiency, and independent kinetic studies on the olefination step revealed that adding the Lewis acid significantly accelerated the olefination rate as well as the C-H activation step. A strong basicity of the internal base in the Pd(II) salt also benefited the olefination reaction plausibly through base-assisted ß-hydride elimination.

2.
Org Biomol Chem ; 22(4): 823-830, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38174952

RESUMO

Aniline derivatives are important nitrogen-containing compounds with wide applications in chemicals, pharmaceuticals and agrochemicals. In the work described herein, nickel(II)/Lewis acid (LA) catalysed olefin hydroamination with anilines was explored for use in aniline derivative syntheses. The Ni(II)/LA catalysis proceeded smoothly under mild conditions, whereas using Ni(OAc)2 alone, the catalyst was inactive. Remarkably, the Markovnikov addition type products were obtained when substituted styrenes were used as the olefin source, while the anti-Markovnikov addition type products were obtained when the electron-deficient olefins such as acrylonitrile and acrylates were used. The mechanistic studies revealed that hydroamination of the styrene derivates proceeded via the amino-Ni(II)/LA attacking the carbocation intermediate which was generated by the protonation of the olefin, whereas for acrylonitrile and acrylates, it proceeded by a direct amino-Ni(II)/LA attack on the olefin by nucleophilic addition. In addition, the hydroarylation product was generated by the Hofmann-Martius rearrangement of the hydroamination product.

3.
Infect Drug Resist ; 13: 3153-3161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32982330

RESUMO

OBJECTIVE: An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of selinexor was established to investigate the effects of isavuconazole, itraconazole and fluconazole on the pharmacokinetics of selinexor in rats, respectively. METHODS: Twenty-four healthy male rats were randomly divided into four groups: group A, normal saline; group B, isavuconazole (20 mg/kg); group C, itraconazole (20 mg/kg); and group D, fluconazole (20 mg/kg). After 30 min of oral administration of normal saline, isavuconazole, itraconazole, and fluconazole, all the rats were given selinexor (8 mg/kg). The plasma concentration of selinexor was estimated by UPLC-MS/MS, and the pharmacokinetic parameters of selinexor were calculated by Drug and Statistics (DAS) 2.0 software. RESULTS: Under these experimental conditions, the method showed good linearity and stability. Intraday and interday accuracy and sample recovery were acceptable. Compared with group A, the Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group B increased by 59.05%, 31.69%, and 31.45%; the Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group C increased by 56.14%, 25.34%, and 25.08%; the Cmax, AUC(0-t) and AUC(0-∞) of selinexor in group D increased by 43.44%, 29.16%, and 31.96%, respectively. The Tmax of the experimental groups were extended, and CLz/F was also significantly reduced. CONCLUSION: These results indicated that isavuconazole, itraconazole, and fluconazole have significant inhibitory effects on selinexor pharmacokinetics and increased selinexor plasma exposure in rats. Therefore, when these drugs were used in combination, clinicians should pay attention to the changes in treatment effects and the occurrence of adverse reactions caused by the drug-drug interactions.

4.
Drug Des Devel Ther ; 14: 2595-2605, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753841

RESUMO

OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Dexmedetomidina/sangue , Midazolam/análogos & derivados , Midazolam/sangue , Tetra-Hidronaftalenos/sangue , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacocinética , Cães , Feminino , Masculino , Midazolam/metabolismo , Midazolam/farmacocinética , Espectrometria de Massas em Tandem , Tetra-Hidronaftalenos/metabolismo , Tetra-Hidronaftalenos/farmacocinética
5.
J Ethnopharmacol ; 260: 112832, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32387465

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danzhi Xiaoyao Powder (DZXY) is a classical prescription, that has been extensively used in traditional Chinese medicine (TMC) to treat depression for many years. However, the mechanism of DZXY is still unclear. AIM OF THE STUDY: The aim was to investigate the mechanism of the antidepressant effect of DZXY on a rat model of chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: Forty male SD (Sprague-Dawley) rats with similar open field test (OFT) results were randomLy divided into a control group (n = 10) and an experimental group (n = 30). A depression model was established in the experimental group using the CUMS method. After the CUMS model was established successfully, the rats were randomLy divided into a depression model group and a DZXY group. The DZXY group was fed DZXY, while the depression model group and control group were given an equal amount of 0.5% sodium carboxymethyl cellulose suspension. Intragastric administration was performed once daily for 14 consecutive days. Animal weight, the sugar preference test, the open field test and the forced swimming test were used to evaluate the modeling effect and the antidepressant effect of DZXY. After the experiment, the plasma of rats was collected and the changes in plasma metabolites were analyzed by UPLC/Q-TOF-MS. The UPLC/Q-TOF-MS spectra data were evaluated by pattern recognition analysis to determine the changes in endogenous metabolites in the rat plasma samples. RESULTS: The results of the behavioral investigation showed that the rat model of depression was successfully replicated and that DZXY had an antidepressant effect. Using the UPLC-MS/MS metabolomics platform, partial least squares (PLS) and orthogonal partial least squares (OPLS), metabolic profile models (R2 and Q2 ≥ 0.5) of rat plasma were successfully constructed. The model could distinguish among the control group, the depression model group and the DZXY group. Finally, 38 differential metabolites were identified in the plasma. According to KEGG (http://www.kegg.jp) pathway analysis, amino acid metabolism, lipid metabolism, purine metabolism, the prolactin signaling pathway and bile secretion were enriched and represented the main metabolic pathways influenced in the plasma. CONCLUSIONS: This study successfully established a CUMS depression model. A total of 38 differential metabolites associated with depression were identified in the plasma of rats, 24 of which were modulated by DZXY. These results suggest that DZXY can improve excitability and play an antidepressant role by regulating phenylalanine metabolism, arachidonic acid metabolism, porphyrin metabolism, D-arginine and D-ornithine metabolism, steroid hormone biosynthesis, unsaturated fatty acid biosynthesis and steroid biosynthesis.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metabolômica , Estresse Psicológico/tratamento farmacológico , Animais , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Depressão/sangue , Depressão/psicologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Pós , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Estresse Psicológico/sangue , Estresse Psicológico/psicologia , Espectrometria de Massas em Tandem
6.
Int J Anal Chem ; 2020: 5084127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292480

RESUMO

In our research, a straightforward UPLC-MS/MS method, with diazepam as the internal standard (IS), was proposed and acknowledged to determine the concentrations of enasidenib in rat plasma. When preparing the sample, we used acetonitrile for protein precipitation. The gradient elution method was used, and the mobile phase was acetonitrile and 0.1% formic acid. Diazepam was used as the IS. We used the Acquity UPLC BEH C18 column to separate enasidenib and IS. Under the positive ion electrospray ionization (ESI) source conditions, the mass transfer pairs of enasidenib were monitored by multiple reaction monitoring (MRM) to be m/z 474.2 ⟶ 456.1 and m/z 474.2 ⟶ 267.0, and the IS mass transfer pairs were m/z 285.0 ⟶ 154.0. Enasidenib had good linearity (r 2 = 0.9985) in the concentration range of 1.0-1000 ng/mL. Besides, the values of intraday and interday precision were 2.25-8.40% and 3.94-5.46%, respectively, and the range of the accuracy values varied from -1.44 to 2.34%. Matrix effect, extraction recovery, and stability were compliant with FDA approval guidelines in terms of bioanalytical method validation. We had established a new method that had been applied to the pharmacokinetic study of enasidenib in rats.

7.
J Pharm Biomed Anal ; 186: 113269, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32247162

RESUMO

This study was to develop a reliable and simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to detect paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ in beagle plasma and to study pharmacokinetic of paeoniflorin and geniposide after single-dose administration of Danzhi Xiaoyao Pill (DZXY). Chromatographic separation was performed using an Agilent C18 column, and multiple reaction monitoring (MRM) mode was used. A gradient elution procedure was used with solvent A (acetonitrile) and solvent B (0.1 % formic acid-water) as mobile phases. The elution procedure was as follows: 85 % B-30 % B (0-7 min) and 30 % B-30 % B (7.1-8 min). The flow rate was 0.3 mL/min. The column temperature was 40 ℃, and the injection volume was 10 µL. The main analytical parameters of paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ were m/z 525→449, m/z 433→224, m/z 780→617, m/z 417→254, m/z 167→43 and m/z 249→231, respectively. Ethyl acetate was used to extract the analytes in the plasma. Standard calibration curves of six analytes showed satisfactory linearity (r2≥0.99 2) within the determined ranges. The lower limits of quantification were 0.5 ng/mL for paeoniflorin and liquiritin, 2.5 ng/mL for geniposide and saikosaponin b2 and 1.0 ng/mL for atractylenolide Ⅲ and paeonol, respectively. The intra-day and inter-day precision (RSD %) were all below 6.94 %, and the intra-day and inter-day accuracy (RE %) were within ± 6.10 %. The recovery and ME of six analytes were 85.99 %-98.10 % and 95.78%-108.06%, respectively. Additionally, the method we established in this experiment can be successfully used to study the pharmacokinetics of paeoniflorin and geniposide in beagle plasma.


Assuntos
Medicamentos de Ervas Chinesas/análise , Glucosídeos/farmacocinética , Iridoides/farmacocinética , Monoterpenos/farmacocinética , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Cães , Glucosídeos/análise , Iridoides/análise , Limite de Detecção , Masculino , Espectrometria de Massas , Monoterpenos/análise , Controle de Qualidade , Reprodutibilidade dos Testes
8.
Drug Des Devel Ther ; 14: 1117-1125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214797

RESUMO

A method for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagle plasma by UPLC-MS/MS was developed and validated. After the plasma was extracted by acetonitrile precipitation, the analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) using acetonitrile-formic acid as the mobile phase in gradient mode. The analytes were monitored by multiple reaction monitoring (MRM) in electrospray negative ion mode. The mass transfer pairs were m/z 368.97→119.01 for parecoxib, m/z 312.89→118.02 for valdecoxib, and m/z 379.98→316.02 for celecoxib (internal standard, IS). The correlation coefficients of parecoxib and valdecoxib ranged from 5 to 4000 ng/mL were greater than 0.9998. The recovery of parecoxib and valdecoxib was greater than 82.54%. The inter- and intra-day precision RSD values were 1.36~3.65% and 2.28~5.91%, respectively. The accuracy of RE values were -1.38%~1.96%. Finally, the matrix effect (ME) and stability were also within acceptable criteria. This method had been successfully applied to the pharmacokinetics of parecoxib and valdecoxib in beagle plasma after injection of parecoxib (1.33 mg/kg, intramuscular injection).


Assuntos
Isoxazóis/sangue , Isoxazóis/metabolismo , Sulfonamidas/sangue , Sulfonamidas/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Cães , Injeções Intramusculares , Isoxazóis/administração & dosagem , Isoxazóis/farmacocinética , Estrutura Molecular , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem
9.
J Pharm Biomed Anal ; 177: 112850, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499430

RESUMO

In the present study, an accurate and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of plasma talazoparib concentration in rats was developed and established. The purpose of chromatographic separation of talazoparib and the internal standard (bosutinib) was achieved on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column with a flow rate of 0.40 mL/min, using a gradient elution with acetonitrile and 0.1% formic acid in water as the mobile phase. The detection was performed on a XEVO TQ-S triple quadrupole tandem mass spectrometer coupled with electrospray ionization interface under positive-ion multiple reaction monitoring (MRM) mode with the precursor-to-product ion transitions of m/z 381.3 → 285.2 for talazoparib and m/z 530.2 → 141.2 for bosutinib (IS), respectively. The method was linear over the range of 0.5-200 ng/mL for talazoparib. The accuracies and precisions of intra- and inter-day were all within the acceptance limits, and no matrix effect was observed in this method. The validated method was further employed to a pharmacokinetic study of talazoparib after oral treatment with 0.2 mg/kg talazoparib to rats.


Assuntos
Ftalazinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Animais , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Masculino , Modelos Animais , Nitrilas/administração & dosagem , Nitrilas/sangue , Ftalazinas/administração & dosagem , Ftalazinas/sangue , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/sangue , Quinolinas/administração & dosagem , Quinolinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
10.
Drug Des Devel Ther ; 13: 3343-3355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571835

RESUMO

OBJECTIVE: To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: Six beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0. RESULTS: The Cmax of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC(0-∞) of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV Cmax of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC(0-∞) were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV Cmax of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC(0-∞) were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the Cmax and AUC(0-∞) of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of Cmax and AUC(0-∞) of ODV and NDV indicated a rise in plasma exposure. CONCLUSION: Danzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida , Cicloexanóis/sangue , Cicloexanóis/farmacocinética , Succinato de Desvenlafaxina/sangue , Cães , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Masculino , Comprimidos , Espectrometria de Massas em Tandem
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