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1.
J Immunol ; 207(8): 2118-2128, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34507947

RESUMO

Sepsis is a life-threatening organ dysfunction caused by a dysfunctional host response to infection. Neutrophils play a protective role by releasing antibacterial proteins or by phagocytizing bacteria. However, excess neutrophils can induce tissue damage. Recently, a novel intercellular communication pathway involving extracellular vesicles (EVs) has garnered considerable attention. However, whether EVs secreted by macrophages mediate neutrophil recruitment to infected sites has yet to be studied. In this study, we assessed the chemotactic effect of EVs isolated from mouse Raw264.7 macrophages on mouse neutrophils and found that CXCL2 was highly expressed in these EVs. By regulating CXCL2 in Raw264.7 macrophages, we found that CXCL2 on macrophage EVs recruited neutrophils in vitro and in vivo. The CXCL2 EVs activated the CXCR2/PKC/NOX4 pathway and induced tissue damage. This study provides information regarding the mechanisms underlying neutrophil recruitment to tissues and proposes innovative strategies and targets for the treatment of sepsis.

2.
Nano Lett ; 21(19): 8086-8094, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34559543

RESUMO

Inspired by the tactic organisms in Nature that can self-direct their movement following environmental stimulus gradient, we proposed a DNase functionalized Janus nanoparticle (JNP) nanomotor system for the first time, which can be powered by ultralow nM to µM levels of DNA. The system exhibited interesting chemotactic behavior toward a DNA richer area, which is physiologically related with many diseases including tumors. In the presence of the subtle DNA gradient generated by apoptotic tumor cells, the cargo loaded nanomotors were able to sense the DNA signal released by the cells and demonstrate directional motion toward tumor cells. For our system, the subtle DNA gradient by a small amount (10 µL) of tumor cells is sufficient to induce the chemotaxis behavior of self-navigating and self-targeting ability of our nanomotor system, which promises to shed new light for tumor diagnosis and therapy.


Assuntos
Quimiotaxia , Neoplasias , DNA , Humanos , Movimento (Física) , Neoplasias/tratamento farmacológico
3.
Hum Cell ; 34(6): 1717-1726, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34435315

RESUMO

Acute myocardial infarction (AMI) is a severe cardiovascular disease with high mortality. It is reported to be closely related to the mitochondrial dysfunction and metabolic disturbance on endothelial cells under a chronic hypoxic state. Significant declined mitochondrial respiration, ATP production, and metabolic changes are the main characteristics of endothelial injury in the disease. Trelagliptin is a DPP-4 inhibitor applied for the treatment of type II diabetes and has been recently reported to exert various pharmacological properties. In this investigation, we examined whether Trelagliptin possessed a protective effect against mitochondrial dysfunction and metabolic disturbance in human aortic valvular endothelial cells (HAVECs) under oxygen-glucose deprivation/reperfusion (OGD/R) conditions. We found that both the cytotoxicity and mitochondrial oxidative stress in HAVECs induced by OGD/R stimulation were greatly alleviated by Trelagliptin. In addition, the declined mitochondrial respiration and ATP production decreased secretion of cystathionine and creatine, and the increased production of triglyceride and adiponectin in OGD/R-challenged HAVECs was dramatically reversed by Trelagliptin, accompanied by the upregulated expression level of PGC-1α and CPT-1. Lastly, the AMPK pathway was observed to be significantly activated in OGD/R-challenged HAVECs by Trelagliptin treatment. After co-administration of the inhibitor of the AMPK pathway, the effects of Trelagliptin on mitochondrial function and metabolic alterations were significantly abolished. Taken together, our data indicate that Trelagliptin ameliorated OGD/R-induced mitochondrial disturbance and metabolic changes by activating the AMPK pathway.

4.
Drug Des Devel Ther ; 15: 3661-3673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456561

RESUMO

Purpose: Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of avitinib on cytochrome CYP450 enzymes metabolic activity. Methods: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC50 values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program. Results: In vitro experiments revealed different inhibitory effects of avitinib on the six probe substrates with various IC50 values (bupropion, 6.39/22.64 µM; phenacetin, 15.79/48.36 µM; chlorzoxazone, 23.15/57.09 µM; midazolam, 27.64/59.6 µM; tolbutamide, 42.18/6.91 µM; dextromethorphan, 44.39/56.57 µM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences (P <0.05) in distinct pharmacokinetic parameters (AUC(0-t), AUC (0-∞), Cmax, MRT(0-t), MRT (0-∞), and CLz/F) for the six probe substrates after avitinib pretreatment. Conclusion: A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.

5.
ACS Appl Mater Interfaces ; 13(32): 38050-38060, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34369138

RESUMO

Chemodynamic therapy (CDT) is an emerging strategy for cancer treatment based on Fenton chemistry, which can convert endogenous H2O2 into toxic ·OH. However, the limited endocytosis of passive CDT nanoagents with low penetrating capability resulted in unsatisfactory anticancer efficacy. Herein, we propose the successful fabrication of a self-propelled biodegradable nanomotor system based on hollow MnO2 nanoparticles with catalytic activity for active Fenton-like Mn2+ delivery and enhanced CDT. Compared with the passive counterparts, the significantly improved penetration of nanomotors with enhanced diffusion is demonstrated in both the 2D cell culture system and 3D tumor multicellular spheroids. After the intracellular uptake of nanomotors, toxic Fenton-like Mn2+ is massively produced by consuming overexpressed intracellular glutathione (GSH), which has a strong scavenging effect on ·OH, thereby leading to enhanced cancer CDT. The as-developed MnO2-based nanomotor system with enhanced penetration and endogenous GSH scavenging capability shows much promise as a potential platform for cancer treatment in the near future.

6.
Adv Healthc Mater ; 10(13): e2100335, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960139

RESUMO

Micro/nanomotors (MNMs) are miniature machines that can convert chemical or external energy into their own mechanical motions. In previous decades, significant efforts have been made to improve the performance of MNMs. For practical applications, the biodegradability of MNMs is an important aspect that must be considered, particularly in the biomedical field. In this review, recent progress in the biodegradability of MNMs and their potential applications are summarized. Different biodegradable materials, including metals and polymers, or other strategies for the fabrication of MNMs, are presented. Current challenges and future perspectives are also discussed.


Assuntos
Nanoestruturas , Nanotecnologia , Metais , Movimento (Física) , Polímeros
7.
Biomater Sci ; 9(11): 3945-3953, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34018531

RESUMO

Cancer vaccines play a key role in the prevention and treatment of early and recurrent tumors. Although they have been widely studied during the past few decades, designing an efficient and economical cancer vaccine is still challenging. Here, we propose an injectable live cell cancer vaccine (InLCCV) using live tumor cells as immunogenic sources for cancer immunoprophylaxis and immunotherapy. InLCCV is fabricated by loading live mouse breast cancer cells (4T1 cells), gold nanorods (GNRs), and super-low-dose lipopolysaccharide (LPS) into a biocompatible Pluronic F127 in situ hydrogel matrix. After in situ inactivation by the photothermal effect of GNRs upon near-infrared (NIR) laser irradiation, immunogenic cell death (ICD) of 4T1 cells is induced and tumor-associated antigens (TAAs) together with loaded LPS are released subsequently. Therefore, dendritic cells and macrophages are activated accordingly, further stimulating the systemic anti-tumor immune response. After vaccinating with InLCCV, the tumor-free percentage of the mice is 60% and the survival rate during the observation period reaches up to 80%. For lung metastasis, the metastatic foci are 3.9-fold less than those of the control group. The as-developed InLCCV shows much promise as a potential platform for breast cancer immunoprophylaxis and immunotherapy.


Assuntos
Vacinas Anticâncer , Nanotubos , Neoplasias , Animais , Linhagem Celular Tumoral , Ouro , Imunoterapia , Raios Infravermelhos , Camundongos , Fototerapia
8.
Biomater Sci ; 9(8): 3171, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33881044

RESUMO

Correction for 'A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy' by Yujie Zhang et al., Biomater. Sci., 2021, 9, 1232-1236, DOI: 10.1039/D0BM02099K.

9.
Nano Lett ; 21(8): 3518-3526, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33848170

RESUMO

Inducing neural stem cells to differentiate and replace degenerated functional neurons represents the most promising approach for neural degenerative diseases including Parkinson's disease, Alzheimer's disease, etc. While diverse strategies have been proposed in recent years, most of these are hindered due to uncontrollable cell fate and device invasiveness. Here, we report a minimally invasive micromotor platform with biodegradable helical Spirulina plantensis (S. platensis) as the framework and superparamagnetic Fe3O4 nanoparticles/piezoelectric BaTiO3 nanoparticles as the built-in function units. With a low-strength rotational magnetic field, this integrated micromotor system can perform precise navigation in biofluid and achieve single-neural stem cell targeting. Remarkably, by tuning ultrasound intensity, thus the local electrical output by the motor, directed differentiation of the neural stem cell into astrocytes, functional neurons (dopamine neurons, cholinergic neurons), and oligodendrocytes, can be achieved. This micromotor platform can serve as a highly controllable wireless tool for bioelectronics and neuronal regenerative therapy.


Assuntos
Óxido Ferroso-Férrico , Células-Tronco Neurais , Diferenciação Celular , Neurônios Dopaminérgicos , Campos Magnéticos
10.
Pharm Biol ; 59(1): 457-464, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33899675

RESUMO

CONTEXT: Dacomitinib and poziotinib, irreversible ErbB family blockers, are often used for treatment of non-small cell lung cancer (NSCLC) in the clinic. OBJECTIVE: This study investigates the effect of dacomitinib on the pharmacokinetics of poziotinib in rats. MATERIALS AND METHODS: Twelve Sprague-Dawley rats were randomly divided into two groups: the test group (20 mg/kg dacomitinib for 14 consecutive days) and the control group (equal amounts of vehicle). Each group was given an oral dose of 10 mg/kg poziotinib 30 min after administration of dacomitinib or vehicle at the end of the 14 day administration. The concentration of poziotinib in plasma was quantified by UPLC-MS/MS. Both in vitro effects of dacomitinib on poziotinib and the mechanism of the observed inhibition were studied in rat liver microsomes and human liver microsomes. RESULTS: When orally administered, dacomitinib increased the AUC, Tmax and decreased CL of poziotinib (p < 0.05). The IC50 values of M1 in RLM, HLM and CYP3A4 were 11.36, 30.49 and 19.57 µM, respectively. The IC50 values of M2 in RLM, HLM and CYP2D6 were 43.69, 0.34 and 0.11 µM, respectively, and dacomitinib inhibited poziotinib by a mixed way in CYP3A4 and CYP2D6. The results of the in vivo experiments were consistent with those of the in vitro experiments. CONCLUSIONS: This research demonstrates that a drug-drug interaction between poziotinib and dacomitinib possibly exists when readministered with poziotinib; thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of poziotinib in clinical settings.

11.
Biomater Sci ; 9(4): 1232-1236, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33570052

RESUMO

A mitochondria-targeted dual-functional aggregation-induced emission luminogen, TPP-TPEDCH, was rationally designed and developed for intracellular mitochondrial imaging and photodynamic therapy. TPP-TPEDCH clearly showed the movements of mitochondria at various time points. Moreover, both in vitro and in vivo results demonstrated its excellent ROS generation ability and strong antitumor activity.


Assuntos
Fotoquimioterapia , Mitocôndrias
12.
Nano Lett ; 21(5): 1982-1991, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33624495

RESUMO

Hydrogen therapy is an emerging and highly promising strategy for the treatment of inflammation-related diseases. However, nonpolarity and low solubility of hydrogen under the physiological conditions results in a limited therapeutic effect. Herein, we develop a biocompatible magnesium micromotor coated with hyaluronic acid as a hydrogen generator for precise rheumatoid arthritis management. The hydrogen bubbles generated locally not only function as a propellant for the motion but also function as the active ingredient for reactive oxygen species (ROS) and inflammation scavenging. Under ultrasound guidance, the micromotors are injected intra-articularly, and the dynamics of the micromotors can be visualized. By scavenging ROS and inflammation via active hydrogen, the oxidative stress is relieved and the levels of inflammation cytokines are reduced by our micromotors, showing prominent therapeutic efficacy in ameliorating joint damage and suppressing the overall arthritis severity toward a collagen-induced arthritis rat model. Therefore, our micromotors show great potential for the therapy of rheumatoid arthritis and further clinical transformation.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Hidrogênio , Magnésio , Ratos , Espécies Reativas de Oxigênio
13.
Artigo em Inglês | MEDLINE | ID: mdl-33432521

RESUMO

Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor.

14.
Pharmacol Res Perspect ; 9(1): e00718, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33508175

RESUMO

Cytochrome P450 2C9 (CYP2C9) is one of the most important drugs metabolizing enzymes and accounts for the metabolism of about 13%-17% of clinical drugs. Like other members in CYP2 family, CYP2C9 gene exhibits great genetic polymorphism among different races and individuals. CYP2C9*18 is one CYP2C9 allelic variant identified in a Southeast Asian population and is estimated to cause the amino acid substitutions of I359L and D397A in CYP2C9 enzyme simultaneously. Limited by the low expression level in bacteria and COS-7 cells, no valuable enzyme kinetics have been reported on this CYP2C9 variant. In this study, the baculovirus-based system was used for the high expression of recombinant CYP2C9 s in insect cells. As a result, together with I359L substitution, D397A could significantly decrease the protein expression of CYP2C9.18 in insect cells, although substitution of D397A alone had no effect on the expression of CYP2C9 in vitro. As compared with that of wild-type enzyme, both CYP2C9.18 variant and D397A variant could decrease more than 80% of the catalytic activity of CYP2C9 enzyme toward three probe substrates, suggesting that caution should be exercised when patients carrying CYP2C9*18 taking medicines metabolized by CYP2C9 enzyme with a narrow therapeutic window.

15.
J Med Chem ; 63(24): 15946-15959, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33264007

RESUMO

A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Descoberta de Drogas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/farmacocinética , Neoplasias Hepáticas , Éteres Fenílicos/química , Piperidinas/farmacologia , Piperidinas/farmacocinética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resorcinóis/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Inibidores de Checkpoint Imunológico/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Piperidinas/química , Ratos Sprague-Dawley , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Drug Des Devel Ther ; 14: 4815-4824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204067

RESUMO

Purpose: The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo. Methods: The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague-Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Results: We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 µM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine. Conclusion: Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.

17.
Front Pharmacol ; 11: 01079, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041783

RESUMO

Background: Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in herbal medicine. The aim of this study was to investigate the interactions between imperatorin and diazepam in vitro and in vivo and to provide evidence-based guidance for the safe clinical use of the drug. Methods: In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC50 values and the type of inhibition. For in vivo assessment, six rats were pretreated with 50 mg/kg imperatorin for two weeks, six were administered saline, and a single dose of 10 mg/kg diazepam was administered orally to both groups 30 min after the administration of imperatorin. Results: Imperatorin inhibited the in vitro metabolism of diazepam via the competitive mechanism of CYP450. The IC50 values of imperatorin to nordazepam and temazepam were 1.54 µM and 1.80 µM, respectively. The inhibitory constant values for temazepam and nordazepam were 1.24 µM and 1.29 µM, respectively. Long-term administration of imperatorin significantly increased the AUC(0-12h), AUC(0-∞), and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly (P < 0.05). In turn, the AUC(0-12h), AUC(0-∞), and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly (P < 0.05). Conclusions: This study demonstrates that imperatorin inhibits the metabolism of diazepam both in vitro and in vivo. These results indicated that more attention should be paid when taking diazepam together with food or herbs containing IMP, although further investigation is still needed.

18.
Thorac Cancer ; 11(10): 2775-2781, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32812378

RESUMO

BACKGROUND: Avitinib is one type of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third-generation TIKI, both in vitro and in vivo. METHODS: The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC50 values. For the in vivo study, 18 Sprague-Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS-MS was used for the determination of the concentration of osimertinib in plasma. RESULTS: In vitro analysis revealed that the IC50 value of osimertinib in rat liver microsomes was 27.6 µM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its Cmax and Tmax were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05). CONCLUSIONS: Both in vitro and in vivo results demonstrated that a drug-drug interaction between avitinib and osimertinib occurred and more attention should be paid when avitinib and osimertinib are synchronously administered in clinic. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Osimertinib is the only market available third-generation EGFR-TKI and it has been reported that some drugs could have drug-drug interactions with it. WHAT THIS STUDY ADDS: For the first time, we systematically investigated the effect of avitinib, one newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model.

19.
Chem Biol Interact ; 329: 109147, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32738202

RESUMO

Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 µM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (Cmax) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Flavonas/metabolismo , Animais , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/química , Flavonas/química , Flavonas/farmacocinética , Meia-Vida , Concentração Inibidora 50 , Cinética , Masculino , Microssomos Hepáticos/metabolismo , Curva ROC , Ratos , Ratos Sprague-Dawley
20.
Angew Chem Int Ed Engl ; 59(49): 21954-21958, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32851781

RESUMO

A tandem Bischler-Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine-type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids.

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