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1.
Clin Rheumatol ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674084

RESUMO

OBJECTIVES: Most patients with progressive pseudorheumatoid dysplasia (PPRD) are initially misdiagnosed because of disease rarity and lack of awareness by most clinicians. The purpose of this study was to provide further early diagnostic options and potential treatment to patients with PPRD. METHODS: A retrospective study was performed by collecting and organizing clinical manifestations, radiographic features, laboratory test results, genetic test outcome, treatment, and follow-up records of the patients with PPRD. Age of diagnosis and genotype-phenotype correlation were further analyzed. RESULTS: Nine PPRD children with causative CCN6 mutation were included. There were 3 pairs of siblings and 1 patient from inbred family. Five patients were primarily misdiagnosed as juvenile idiopathic arthritis (JIA). The interval between onset of symptoms and definite diagnosis of 8 patients varied from 3.6 to 20 years. Symptoms at the onset included enlarged and stiff interphalangeal joints of the fingers, gait disturbance, or joint pain. Laboratory tests revealed normal range of inflammatory parameters. Radiographic findings disclosed different degrees of abnormal vertebral bodies and epiphyseal enlargement of the interphalangeal joints. After the treatment of calcitriol in 5 patients with low level 25-hydroxyvitamin D3 for around 1.25 years to 1.75 years, 2 patients kept stable, while 3 of them improved gradually. CONCLUSIONS: Combining the patient's family history, clinical features, normal inflammatory markers, and the characteristic radiographic findings, the clinical diagnosis of PPRD for the patients could be obtained at very early stage of the disease. The patients with PPRD carrying c.624dupA variant in CCN6 may have delayed onset. Underlying vitamin D deficiency should be sought and corrected in patients with PPRD.

2.
PeerJ ; 9: e11801, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395074

RESUMO

Background: The relationship between impulsivity and suicide is inconsistent in different populations. Hence, the relationship between impulsivity and suicide still needs to be studied among the elderly population. The present study intends to explore the relationship between impulsivity and suicide among the rural Chinese elderly. Methods: A case-control psychological autopsy study was conducted from February 1, 2014 to December 18, 2015 among rural residents over the age of 60 who died by suicide. The sample consisted of 242 suicides as the case group and 242 living individuals as the control group. Data on demographic characteristics, impulsivity, previous history of suicide attempts, social support, negative life events, and suicidal behavior were collected. Results: Our study found that impulsivity increased the risk of suicide. The case group showed a higher Barratt Impulsiveness Scale score compared with the control group (p < 0.001), which indicates that impulsivity was higher among the elderly suicides. In addition, regression analyses show that impulsivity (odds ratio: 1.03, 95% confidence interval: 1.01-1.06) is an independent risk factor of suicide, after controlling for the effects of marital status, education, family annual income, being left behind, social support, and negative life events. Finally, compared with elderly who do not have a history of attempted suicide, elderly with a history of attempted suicide showed higher impulsivity (p = 0.001).

3.
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.

4.
Biomed Res Int ; 2021: 6679082, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195278

RESUMO

The aim of our study was to investigate the effects of single-dose Ougan (Citrus reticulata cv. Suavissima) juice application on the pharmacokinetics of erlotinib in vivo. Twelve Sprague-Dawley rats were randomly divided into the Ougan juice and control groups (n = 6 each). The rats were given a single dose of 1 mL/100 g Ougan juice or 1 mL/100 g normal saline (NS) by intragastric administration, followed by a single oral administration of 20 mg/kg erlotinib. The plasma concentration of erlotinib in rats was determined using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Erlotinib-d6 was used as the internal standard for chromatographic analysis on the UPLC BEH C18 analysis column (2.1 mm × 50 mm, 1.7 µm). The mobile phase was composed of acetonitrile and 0.1% formic acid eluting by gradient. Different pharmacokinetic (PK) parameters of erlotinib were calculated. The Ougan juice promoted the absorption of erlotinib and reduced the clearance of the drug. The area under the curve of erlotinib in the single-dose Ougan juice pretreatment group was approximately 1.87 times higher, and the maximum blood concentration (Cmax) was approximately 1.34 times higher than that in the control group. The mean residence time of erlotinib in the Ougan juice group was larger, and the clearance rate was smaller than those in the control group; the difference was statistically significant (P < 0.05). Ougan juice affected the PK spectrum of erlotinib in rats by improving the bioavailability of the drug and significantly increasing its plasma concentration.


Assuntos
Citrus/metabolismo , Cloridrato de Erlotinib/farmacocinética , Sucos de Frutas e Vegetais , Animais , Cromatografia Líquida , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Cloridrato de Erlotinib/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Estômago/efeitos dos fármacos , Espectrometria de Massas em Tandem
5.
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
6.
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.


Assuntos
Microssomos Hepáticos/metabolismo , Quinazolinas/farmacocinética , Quinazolinonas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Humanos , Concentração Inibidora 50 , Quinazolinas/administração & dosagem , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
7.
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.


Assuntos
Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Substituição de Aminoácidos , Animais , Grupo com Ancestrais do Continente Asiático/genética , Baculoviridae/genética , Catálise , Linhagem Celular , Citocromo P-450 CYP2C9/química , Diclofenaco/metabolismo , Humanos , Insetos , Losartan/metabolismo , Modelos Moleculares , Polimorfismo Genético , Conformação Proteica , Proteínas Recombinantes/metabolismo , Tolbutamida/metabolismo
8.
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.


Assuntos
Succinato de Desvenlafaxina/antagonistas & inibidores , Pirróis/farmacologia , Sulfonamidas/farmacologia , Cloridrato de Venlafaxina/antagonistas & inibidores , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Succinato de Desvenlafaxina/farmacocinética , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Pirróis/administração & dosagem , Pirróis/sangue , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Cloridrato de Venlafaxina/farmacocinética
9.
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.

10.
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
11.
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.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/uso terapêutico , Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Masculino , Pirimidinas/farmacocinética , Ratos
12.
Pharm Biol ; 58(1): 630-635, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32633174

RESUMO

CONTEXT: Rivaroxaban and ticagrelor are two common drugs for the treatment of atrial fibrillation and acute coronary syndrome. However, the drug-drug interaction between them is still unknown. OBJECTIVE: To investigate the effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats both in vivo and in vitro. MATERIALS AND METHODS: A sensitive and reliable UPLC-MS/MS method was developed for the determination of rivaroxaban in rat plasma. Ten Sprague-Dawley rats were randomly divided into ticagrelor pre-treated group (10 mg/kg/day for 14 days) and control group. The pharmacokinetics of orally administered rivaroxaban (10 mg/kg, single dose) with or without ticagrelor pre-treatment was investigated with developed UPLC-MS/MS method. Additionally, Sprague-Dawley rat liver microsomes were also used to investigate the drug-drug interaction between these two drugs in vitro. RESULTS: The C max (221.34 ± 53.33 vs. 691.18 ± 238.31 ng/mL) and the AUC(0-t) (1060.97 ± 291.21 vs. 3483.03 ± 753.83 µg·h/L) of rivaroxaban increased significantly (p < 0.05) with ticagrelor pre-treatment. The MRT(0-∞) of rivaroxaban increased from 4.41 ± 0.79 to 5.97 ± 1.11 h, while the intrinsic clearance decreased from 9.93 ± 2.55 to 2.89 ± 0.63 L/h/kg (both p < 0.05) after pre-treated with ticagrelor. Enzyme kinetic study indicated that ticagrelor decreased rivaroxaban metabolic clearance with the IC50 value of 14.04 µmol/L. CONCLUSIONS: Our in vivo and in vitro results demonstrated that there is a drug-drug interaction between ticagrelor and rivaroxaban in rats. Further studies need to be carried out to verify whether similar interactions truly apply in humans and whether these interactions have clinical significance.


Assuntos
Inibidores do Fator Xa/farmacocinética , Microssomos Hepáticos/metabolismo , Inibidores da Agregação Plaquetária/farmacocinética , Rivaroxabana/farmacocinética , Ticagrelor/farmacocinética , Animais , Interações Medicamentosas/fisiologia , Inibidores do Fator Xa/sangue , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Inibidores da Agregação Plaquetária/sangue , Ratos , Ratos Sprague-Dawley , Rivaroxabana/sangue , Ticagrelor/sangue
13.
Drug Des Devel Ther ; 14: 1909-1919, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546958

RESUMO

Purpose: The aim of the present study was to investigate the interactions of the main components of Lygodium root (ie, p-coumaric acid, acacetin, apigenin, buddleoside and Diosmetin-7-O-ß-D-glucopyranoside) with cytochrome P450 3A enzyme activity both in vitro and in vivo. Methods: In vitro inhibition of drugs was assessed by incubating rat liver microsomes (RLMs) with a typical P450 3A enzyme substrate, midazolam, to determine their 50% inhibitory concentration (IC50) values. For the in vivo study, healthy male Sprague Dawley rats were consecutively administered acacetin or apigenin for 7 days at the dosage of 5 mg/kg after being randomly divided into 3 groups: Group A (control group), Group B (acacetin group) and Group C (apigenin group). Results: Among the five main components of Lygodium root, only acacetin and apigenin showed inhibitory effects on the cytochrome P450 3A enzyme in vitro. The IC50 values of acacetin and apigenin were 58.46 µM and 8.20 µM, respectively. Additionally, the in vivo analysis results revealed that acacetin and apigenin could systemically inhibit midazolam metabolism in rats. The Tmax, AUC(0-t) and Cmax of midazolam in group B and group C were significantly increased (P<0.05), accompanied by a significant decrease in Vz/F and CLz/F (P<0.05). Conclusion: Acacetin and apigenin could inhibit the activity of the cytochrome P450 3A enzyme in vitro and in vivo, indicating that herbal drug interactions might occur when taking Lygodium root and midazolam synchronously.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Gleiquênias/química , Raízes de Plantas/química , Animais , Apigenina/química , Apigenina/isolamento & purificação , Apigenina/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Ácidos Cumáricos/farmacologia , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/isolamento & purificação , Relação Dose-Resposta a Droga , Flavonas/química , Flavonas/isolamento & purificação , Flavonas/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Glicosídeos , Masculino , Medicina Tradicional , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
Int J Anal Chem ; 2020: 7290470, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32550846

RESUMO

Lusutrombopag is a second oral thrombopoietin (TPO) receptor agonist that selectively acts on human TPO receptors. In the study, UPLC-MS/MS was used to establish a selective and sensitive method to determine lusutrombopag with poziotinib as IS (internal standard) in rat plasma. Samples were prepared by precipitating protein with acetonitrile as a precipitant. Separation of lusutrombopag and poziotinib was performed on a CORTECS UPLC C18 column (2.1 ∗ 50 mm, 1.6 µm). The mobile phase (acetonitrile and water containing 0.1% formic acid) with gradient elution was set at a flow rate of 0.4 ml/min. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of m/z 592.97 ⟶ 491.02 for lusutrombopag and m/z for poziotinib (IS) 492.06 ⟶ 354.55. The linear calibration curve of the concentration range was 2-2000 ng/ml for lusutrombopag, with a lower limit of quantification (LLOQ) of 2 ng/ml. RSD of interday and intraday precision were both no more than 9.66% with the accuracy ranging from 105.82% to 108.27%. The extraction recovery of lusutrombopag was between 82.15% and 90.34%. The developed and validated method was perfectly used in the pharmacokinetic study of lusutrombopag after oral administration in rats.

15.
Drug Des Devel Ther ; 14: 2199-2206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581516

RESUMO

Purpose: The purpose of this study was to examine the effects of voriconazole on the pharmacokinetics of vonoprazan. Methods: Fifteen Sprague-Dawley rats were randomly divided into three groups: five rats in each group, including control group, single-dose group (a single dose of 30 mg/kg of voriconazole), and multiple-dose group (multiple doses of 30 mg/(kg•day) per dose of voriconazole). Each group of rats was given an oral dose of 10 mg/kg vonoprazan 30 min after the administration of voriconazole or vehicle. After the oral administration of vonoprazan, 50 µL of blood was collected into 1.5-mL heparinized tubes via the caudal vein. The concentration of vonoprazan in plasma was quantified by ultra-performance liquid chromatography/tandem mass spectrometry. Both in vitro effects of voriconazole on vonoprazan and the mechanism of the observed inhibition were studied in rat liver microsomes. Results: When orally administered, voriconazole increased the area under the plasma concentration-time curve (AUC), prolonged the elimination half-life (t1/2), and decreased the clearance (CL) of vonoprazan; there was no significant difference between the single-dose and multiple-dose groups. Voriconazole inhibited the metabolism of vonoprazan at an IC50 of 2.93 µM and showed mixed inhibition. The results of the in vivo experiments were consistent with those of the in vitro experiments. Conclusion: Our findings provide the evidence of drug-drug interactions between voriconazole and vonoprazan that could occur with pre-administration of voriconazole. Thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of vonoprazan in clinical settings.


Assuntos
Pirróis/farmacocinética , Sulfonamidas/farmacocinética , Voriconazol/farmacologia , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Voriconazol/administração & dosagem
16.
Clin Immunol ; 214: 108387, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32194234

RESUMO

Biallelic variants in BLNK cause primary B-cell immunodeficiency that usually results in absence of B cells and immunoglobulin. Here, we identified disease-causing variant(s) in two unrelated Chinese patients with agammaglobulinemia. Patient 1 showed a moderate reduction in total B-cell count but demonstrated both extremely low levels of memory B-cells and lower levels of memory T cells relative to those in healthy controls. Whole-exome sequencing (WES) revealed a novel heterozygous splice variant (c.676+1G>A), and suggested exon 9 deletion from BLNK, which was subsequently validated by quantitative polymerase chain reaction. For Patient 2, WES revealed novel compound heterozygous of a frameshift variant (p.T152Pfs*6) and a synonymous variant (c.525G>A) that resulted in exon 6 skipping, according to cDNA sequencing. These findings represent the first report of a BLNK-deficient patient presenting with impaired memory B-cell and memory T-cell development. Furthermore, this study is the first reporting a pathogenic synonymous splice variant in BLNK.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Agamaglobulinemia/genética , Linfócitos B/patologia , Agamaglobulinemia/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Epilepsia/complicações , Éxons/genética , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Memória Imunológica , Contagem de Linfócitos , Masculino , Linhagem , Isoformas de Proteínas/genética , Recidiva , Infecções Respiratórias/complicações , Deleção de Sequência , Subpopulações de Linfócitos T/patologia , Sequenciamento Completo do Exoma
17.
Front Pharmacol ; 11: 593518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33746741

RESUMO

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 µM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 µM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.

18.
Orphanet J Rare Dis ; 14(1): 265, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752936

RESUMO

BACKGROUND: Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. METHODS: Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. RESULTS: Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. CONCLUSIONS: We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.


Assuntos
Mutação com Perda de Função/genética , Receptor ErbB-3/genética , Linhagem Celular Tumoral , Pré-Escolar , Feminino , Heterozigoto , Humanos , Immunoblotting , Imunoprecipitação , Linhagem , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sequenciamento Completo do Exoma
19.
Medicine (Baltimore) ; 98(38): e17252, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567995

RESUMO

Emerging evidence has shown that vitamin D deficiency may be related with community-acquired pneumonia (CAP), but individually published studies showed inconclusive results. The aim of this study was to quantitatively summarize the association between vitamin D and the CAP.We conducted this meta-analysis though a systematic literature search of PubMed, Medline, and EMBASE up to 31 September 2018 with the following keywords 'vitamin D' or 'cholecalciferol' or '25-hydroxyvitamin D' or '25(OH)D' in combination with 'community-acquired pneumonia' or 'CAP' or 'pneumonia' with no limitations. This meta-analysis was performed following the guidelines of Meta-analysis of Observational Studies in Epidemiology. The association between vitamin D levels and CAP were measured as odds ratio (OR) and weighted mean difference (WMD). Results were combined using a random-effect or a fix-effect meta-analysis, and sensitivity analyses were conducted to explore potential factors.Eight observational studies involving 20,966 subjects were included. In this meta-analysis, CAP patients with vitamin D deficiency (serum 25(OH)D levels <20 ng/mL) experienced a significantly increased risk of CAP (odds ratio (OR) = 1.64, 95% confidence intervals (CI): 1.00, 2.67), and an obvious decrease of -5.63 ng/mL (95% CI: -9.11, -2.14) in serum vitamin D was demonstrated in CAP patients. Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect.The evidence from this meta-analysis indicates an association between vitamin D deficiency and an increased risk of CAP patients. However, well-designed trails are required to determine the explicit effect of vitamin D supplementation.


Assuntos
Pneumonia Bacteriana/etiologia , Pneumonia Viral/etiologia , Deficiência de Vitamina D/complicações , Infecções Comunitárias Adquiridas/etiologia , Humanos , Fatores de Risco
20.
Artigo em Inglês | MEDLINE | ID: mdl-31207562

RESUMO

Talatisamine, as the efficacy ingredient of Aconitum, was known as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons. In this study, a rapid, selective and reproducible UPLC-MS/MS separation method was established and fully validated for the quantitative determination of talatisamine levels in ICR (Institute of Cancer Research) mouse blood. A total of 24 healthy male ICR mice were divided into four groups that was administered talatisamine via intravenous at a dose of 1 mg/kg and oral administration of three doses (2, 4, 8 mg/kg). All blood samples were protein precipitate by using acetonitrile with an internal standard (IS) deltaline. The effective chromatographic separation was carried out through an UPLC BEH C18 analytical column (2.1 mm × 50 mm, 1.7 µm) with an initial mobile phase that consisted of acetonitrile and 10 mmol/L ammonium acetate aqueous solution (containing 0.1% formic acid) with a gradient elution pumped at a flow rate of 0.4 mL/min. Also, an electrospray ionization (ESI) was applied to quantify the talatisamine in the positive ions mode. The method validation demonstrated good linearity over the range of 1-1000 ng/mL (r2 ≥ 0.9993) for talatisamine in mouse blood with a lower limit of quantification (LLOQ) at 1 ng/mL. The accuracy values of the method were within 89.4% to 113.3%, and the matrix effects were between 103.2% and 106.3%. The mean extraction recoveries for talatisamine obtained from four concentrations of QC blood samples were exceeded 71.7%, and the relative standard deviation (RSD) both of intra- and inter-day precision values for replicate quality control samples did not exceed 15% respectively for all analytes during the assay validation. This method was successfully applied to the evaluation of the pharmacokinetic of talatisamine, regardless of intragastric or intravenous administration in mice. Based on the pharmacokinetics data, the bioavailability of talatisamine in mice was >65.0% after oral administration, exhibiting an excellent oral absorption.


Assuntos
Aconitina/análogos & derivados , Cromatografia Líquida/métodos , Bloqueadores dos Canais de Potássio/farmacocinética , Espectrometria de Massas em Tandem/métodos , Aconitina/administração & dosagem , Aconitina/sangue , Aconitina/farmacocinética , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/sangue , Canais de Potássio
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