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1.
J Pharm Biomed Anal ; 242: 116012, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354539

RESUMO

Linaprazan (AZD0865, TX07) is one of potassium-competitive acid blockers. However, linaprazan is rapidly excreted from the body, shortening its acid inhibition property. Linaprazan glurate (X842) is a prodrug of linaprazan with a prolonged inhibitory effect on gastric acid secretion. Linaprazan glurate has entered clinical trials, but few studies have reported its metabolism in non-clinical and clinical settings. In this study, we studied the pharmacokinetics, tissue distribution, mass balance, and metabolism of linaprazan glurate in rats after a single oral dose of 2.4 mg/kg (100 µCi/kg) [14C]linaprazan glurate. The results demonstrated that linaprazan glurate was mainly excreted via feces in rats with 70.48% of the dose over 168 h. The plasma AUC0-∞ of linaprazan glurate in female rats was 2 times higher than that in male rats. Drug-related substances were mainly concentrated in the stomach, eyes, liver, small intestine, and large intestine after administration. In blood, drug-related substances were mostly distributed into plasma instead of hemocytes. In total, 13 metabolites were detected in rat plasma, urine, feces, and bile. M150 (2,6-dimethylbenzoic acid) was the predominant metabolite in plasma, accounting for 80.65% and 67.65% of AUC0-24h in male and female rats, respectively. Based on the structures, linaprazan glurate was mainly hydrolyzed into linaprazan, followed by a series of oxidation, dehydrogenation, and glucuronidation in rats. Besides, CES2 is the main metabolic enzyme involved in the hydrolysis of linaprazan glurate to linaprazan.


Assuntos
Líquidos Corporais , Compostos Heterocíclicos com 2 Anéis , Ratos , Masculino , Feminino , Animais , Fezes/química , Bile/metabolismo , Plasma , Administração Oral
2.
Org Lett ; 26(1): 193-197, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38147844

RESUMO

In this study, a multicomponent reaction via the Mannich intermediate was developed using methanol, secondary amine, and sulfonamide as starting materials. This method uses methanol as a green C1 source. The substrate scope is wide, and the yield is good. The mechanistic study shows that methanol generates formaldehyde under electrochemical conditions, and sulfonyl amidine as a nucleophile reacts with Schiff base intermediates to form N-sulfonyl amidine in a single step.

3.
J Org Chem ; 88(9): 5760-5771, 2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37027491

RESUMO

Azoles and organoselenium compounds are pharmacologically important scaffolds in medicinal chemistry and natural products. We developed an efficient regioselective electrochemical aminoselenation reaction of 1,3-dienes, azoles, and diselenide derivatives to access selenium-containing allylazoles skeletons. This protocol is more economical and environmentally friendly and features a broad substrate scope; pyrazole, triazole, and tetrazolium were all tolerated under the standard conditions, which could be applied to the expedient synthesis of bioactive molecules and in the pharmaceutical industry.

4.
Org Biomol Chem ; 21(15): 3177-3182, 2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-36961319

RESUMO

The electrocatalytic ring-opening dihydroalkoxylation of N-aryl maleimides with alcohols under metal- and oxidant-free conditions is described. This electrochemical process consists of anodic single-electron transfer oxidation, cathodic radical reduction, rearrangement-ring cleavage and nucleophilic addition cascade, which employs tetrabutylammonium bromide not only as a redox catalyst but also as an efficient supporting electrolyte, and offers a practical and environmentally friendly route to ring-opening difunctionalization products.

5.
Support Care Cancer ; 30(8): 7031-7038, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35585204

RESUMO

PURPOSE: The purpose of this study was to identify the incidence, sites and main pathogens, and risk factors for infectious complications occurring in patients with adult acute myeloid leukemia (AML) during the first course of venetoclax combined with decitabine or azacitidine. METHODS: A retrospective cohort analysis was performed of 81 patients with AML older than 14 years who received the first cycle of venetoclax combined with a hypomethylating agent (HMA) between March 2018 and March 2021 at our institution. Infectious complications, if any, were documented. RESULTS: Among a total of 81 cases of AML, 59 (72.8%) patients occurred infections, including fever without an identifiable source (28.8%), clinically documented infections (40.7%), and microbiologically documented infections (30.5%). The most commonly isolated organism in culture was Candida albicans, followed by Klebsiella pneumonia, and Pseudomonas aeruginosa. The 4-week and 8-week mortality rates were 3.7% and 7.4%, respectively. In multivariate analysis, a high proportion of blasts in bone marrow, decreased hemoglobin level, and fever with or without a documented infection at baseline were significant independent risk factors for infectious complications. CONCLUSION: Compared with conventional chemotherapy, the incidence of infectious complications of venetoclax combined with decitabine or azacitidine significantly decreased. Pretreatment high leukemia burden and fever were independent risk factors for infections.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes , Decitabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Retrospectivos , Sulfonamidas , Resultado do Tratamento
6.
J Chromatogr Sci ; 60(1): 61-67, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33912896

RESUMO

A high performance liquid chromatography-tandem mass spectrometry assay for the determination of afatinib (AFT) in human plasma was established. A simple sample preparation of protein precipitation was used and separation was achieved on a C18 column by the gradient mixture of mobile Phase A of water (containing 0.1% ammonia) and the mobile Phase B of acetonitrile and water (V:V = 95:5, containing 0.2% ammonia). The multiple reaction monitoring mode was used to monitor the precursor-to-production transitions of m/z 486.2 â†’ m/z 371.4 for AFT and m/z 492.2 â†’ m/z 371.3 for AFT-d6 (internal standard) at positive ionization mode. The calibration curve ranged from 0.100 to 25.0 ng·mL-1 and the correlation coefficient was greater than 0.99. The intra- and inter-batch precision was less than or equal to 10.0%. Accuracy determined at four concentrations was in the range of 92.3-103.3%. In summary, our method was sensitive, simple and reliable for the quantification of AFT and was successfully applied to a bioequivalence study.


Assuntos
Espectrometria de Massas em Tandem , Afatinib , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Equivalência Terapêutica
7.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-954596

RESUMO

Objective:To investigate the clinical significance of protein disulfide isomerase A3 (PDI) A3 (PDIA3) expression in hepatocellular carcinoma tissues and its effect of PDIA3 on the expression of IL6 and IL17 in hepatocellular carcinoma cells.Methods:Immunohistochemistry was used to detect the expression of PDIA3 in the tissues of 72 patients with liver cancer and their adjacent tissues. HepG2 cells were divided into experimental group and control group. The cells in the experimental group were transfected with PDIA3-siRNA plasmid, and the cells in the control group were transfected with MOCK-siRNA plasmid. Fluorescence quantitative PCR was used to detect the content of PDIA3 mRNA in each group of cells. The expressions of PDIA3, IL6 and IL17 in each group of cells were detected by Western blot. The proliferation ability of each group of cells was detected by CCK8.Results:The positive rate of PDIA3 in liver cancer tissues was 85.22% (75/88), and the expression rate in adjacent tissues was 6.81% (6/88). The expression rate of PDIA3 in liver cancer tissues was significantly higher than that in adjacent tissues. The difference was statistically significant ( P<0.001). After transfection of siRNA, the expression levels of PDIA3 mRNA in HepG2 cells in the experimental group and control group were 1.23±0.20 and 0.43±0.12, respectively, and the expression levels of PDIA3 protein were 1.19±0.11 and 0.23±0.08, respectively. The expression levels of IL6 were 1.11±0.15 and 0.57±0.09, respectively. The expression levels of IL17 were 1.19±0.14 and 0.45±0.08, respectively, and the expressions of IL6 and IL17 were significantly decreased (all P<0.05). The absorbance of HepG2 cells in the experimental group and the control group at 120 h was 2.28±0.10 and 1.11±0.09, respectively, and the cell proliferation ability of the experimental group was significantly decreased ( P<0.05) . Conclusions:The expression of PDIA3 is significantly increased in hepatocellular carcinoma, which may be related to the malignancy of hepatocellular carcinoma. PDIA3 affects the proliferation of hepatocellular carcinoma cells by regulating the expression of IL6 and IL17.

8.
World J Clin Cases ; 9(30): 9144-9150, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34786398

RESUMO

BACKGROUND: The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored. CASE SUMMARY: Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed. CONCLUSION: We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

9.
Anim Sci J ; 92(1): e13617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34405917

RESUMO

Granulosa cells (GCs) play an important role in the development of follicles. In this study, we investigate the impact of heat stress at 41°C and 43°C on duck GCs' proliferation and steroids secretion. And, the transcriptomic responses to heat treatment were examined using RNA-sequencing analysis. Digital gene expression profiling was used to screen and identify differentially expressed genes (fold change ≥ 2 and Q value < 0.05). Further, the differential expression genes (DEGs) were classified into GO categories and KEGG pathways. The results show that duck GCs blocked in the G1 phase were increased on exposure to heat stress. Meanwhile, the expression of proliferative genes, which were essential for the transition from G1 to S phase, was inhibited. At the same time, heat stress inhibited the estradiol synthesis of GCs by decreasing CYP11A1 and CYP19A1 gene expression. A total of 241 DEGs including 181 upregulated and 60 downregulated ones were identified. Transcriptome result shows that heat shock protein and CXC chemokines gene were significantly activated during heat stress. While collagenases (MMP1 and MMP13) and strome lysins (MMP3) were downregulated. And, the hedgehog signaling pathway may be a prosurvival adaptive response under heat stress. These results offer a basis for better understanding the molecular mechanism underlying lay-eggs-less in ducks under heat stress.


Assuntos
Proliferação de Células/genética , Patos/fisiologia , Estradiol/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Expressão Gênica , Células da Granulosa/fisiologia , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Ovulação/fisiologia , Animais , Aromatase/genética , Aromatase/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Regulação para Baixo , Feminino , Células da Granulosa/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Hedgehog/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
10.
Huan Jing Ke Xue ; 42(8): 3913-3923, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34309278

RESUMO

In China, high heavy metal concentrations in cultivated soil are mainly distributed in carbonate-covered areas. The migration and transformation of heavy metals in such soils are influenced by interactions between natural processes and human activities. This study examined the profiles of nine paddy soils, derived from carbonate rocks in Guangxi. The Cd, As, Zn, Cr, Cu, Hg, Ni, and Pb contents we determined, and soil properties such as pH, Corg content, and fractions of Cd, As, Zn, and Cr were tested. Based on the above data, we assessed the vertical distribution of heavy metal fractions, as well as the ecological risks and factors affecting the migration ability of heavy metals, under the influence of human activities and natural soil formation. The results show that compared with the carbonate rocks in Guangxi, the soil profile of the study area is significantly enriched with all eight heavy metals. Among them, Cd, As, Zn, and Cr exceeded China's agricultural land (paddy field) pollution risk screening values, and Cd and As partially exceed the risk intervention values. All fractions of Cd in the soil profiles are widely distributed. The proportion of water-soluble and ion-exchange Cd fractions with high ecological risk decreased significantly from the surface to greater depths in the soil profile. As, Zn, and Cr in the soil profile were mainly in residual states, and the proportion of water-soluble and ion-exchange fractions did not change considerably with increasing depth. The evaluation results of RAC and RSP show that Cd pollution risk in the study area is relatively high, whereas As, Zn, and Cr are generally pollution-free or risk-free. In naturally developed soil in the study area, the clay mineral content and degree of soil development have significant effects on Cd migration, whereas in the cultivated layer affected by human activities, the soil pH and organic matter content are the main controlling factors. The migration ability of soil As is mainly related to soil organic matter, Fe2O3 content, and soil development degree, but organic matter has an obviously enhanced effect in the tillage layer. The main controlling factor of Zn and Cr migration in soil is pH, and the effects are more intense under the disturbance of human activities.


Assuntos
Metais Pesados , Poluentes do Solo , Carbonatos , China , Monitoramento Ambiental , Humanos , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise
12.
Sci Rep ; 11(1): 7573, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828187

RESUMO

In quantitative PCR research, appropriate reference genes are key to determining accurate mRNA expression levels. In order to screen the reference genes suitable for detecting gene expression in tissues of the reproductive axis, a total of 420 (males and females = 1:5) 3-year-old Magang geese were selected and subjected to light treatment. The hypothalamus, pituitary and testicular tissues were subsequently collected at different stages. Ten genes including HPRT1, GAPDH, ACTB, LDHA, SDHA, B2M, TUBB4, TFRC, RPS2 and RPL4 were selected as candidate reference genes. The expression of these genes in goose reproductive axis tissues was detected by real-time fluorescent quantitative PCR. The ΔCT, geNorm, NormFinder and BestKeeper algorithms were applied to sort gene expression according to stability. The results showed that ACTB and TUBB4 were the most suitable reference genes for the hypothalamic tissue of Magang goose in the three breeding stages; HPRT1 and RPL4 for pituitary tissue; and HPRT1 and LDHA for testicular tissue. For all three reproductive axis tissues, ACTB was the most suitable reference gene, whereas the least stable reference gene was GAPDH. Altogether, these results can provide references for tissue expression studies in geese under light treatment.


Assuntos
Gansos/genética , Gansos/fisiologia , Actinas/genética , Algoritmos , Animais , Proteínas Aviárias/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Hipotálamo/fisiologia , Luz , Masculino , Hipófise/fisiologia , Reprodução/genética , Reprodução/fisiologia , Testículo/fisiologia , Tubulina (Proteína)/genética
13.
Huan Jing Ke Xue ; 42(3): 1514-1522, 2021 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742949

RESUMO

To understand the main factors influencing the translocation and accumulation of cadmium (Cd) in soil-crop systems in typical karst areas, 68 sets of paddy soil and rice grain samples were collected in Guangxi Province. These were used to analyze Cd concentrations and soil properties (pH, organic matter (OM) content, oxide content, and texture). Spearman's correlation coefficients and principal component analysis (PCA) were used to examine the effects of soil properties on Cd concentrations and identify the main influencing factors. The studied soils were highly enriched in iron oxide (TFe2O3), aluminum oxide (Al2O3), and manganese oxide (MnO) compared to background levels, with average concentrations of 20.2%, 19.0%, and 0.2%, respectively. However, the soils are relatively depleted in silica (SiO2), with an average concentration of 41.0%. The soils are strongly weathered and leached in study area, giving rise to rich occurrences of Fe-Mn nodules. The concentrations of TFe2O3 and MnO in the study soils were significantly correlated with soil Cd, rice seed Cd, and the Cd bioconcentration factor (BCF). The PCA analysis further showed that TFe2O3 and MnO in soils were the main factors affecting the migration and enrichment of Cd while soil pH, OM, and Al2O3 had less of an influence. Furthermore, SiO2 and soil texture indirectly affected the migration and enrichment of Cd. It is suggested that the Fe-Mn nodules effectively adsorb and immobilize Cd in the study area soils, acting as a heavy metal scavenger that reduced the biological accessibility of Cd.

14.
J Chromatogr Sci ; 59(9): 823-829, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33517421

RESUMO

A sensitive high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of sildenafil and N-desmethyl sildenafil in human plasma. The protein precipitation was used for extraction and the gradient elution of the mobile phase A of water (containing 0.01% formic acid) and the mobile phase B of acetonitrile, and methanol (V:V = 1:1, containing 0.01% formic acid) was used for chromatographic separation on a C18 column. Quantification was performed by multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 â†’ m/z 283.3 for sildenafil, m/z 461.4 â†’ m/z 283.2 for N-desmethyl sildenafil, m/z 483.3 â†’ m/z 108.1 for sildenafil-d8 (IS) and m/z 469.2 â†’ m/z 283.3 for N-desmethyl sildenafil-d8 (IS) at the positive ionization mode. The intra- and inter-day relative standard deviations were less than 6.8% and 4.1% for sildenafil and N-desmethyl sildenafil, respectively. Accuracy at four levels ranged from 93.1% to 115.9% for sildenafil and 95.6% to 112.5% for N-desmethyl sildenafil. The present method was sensitive and reliable for simultaneous quantification of sildenafil and its active metabolite and was successfully applied to a pharmacokinetic study of an oral low dose of sildenafil in Chinese healthy volunteers.


Assuntos
Plasma , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Citrato de Sildenafila
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(6): 1991-1997, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33283731

RESUMO

OBJECTIVE: To evaluate the efficacy of decitabine combined with low-dose CEG regimen (DCEG) and decitabine combined with low-dose CAG regimen (DCAG) in the treatment of elderly patients with MDS and MDS-transformed acute myeloid leukemia (AML). METHODS: A prospective study was conducted in 7 medical centers, 45 patients with MDS (≥ 60 years old) and MDS-transformed AML from October 2016 to January 2019 were enrolled, with the median age of 68.5 years old. The risk stratification of patients was poor or very poor, according to IPSS-R score. The treament results of decitabine combined with CEG and decitabine combined with CAG were compared. RESULTS: The comparison of the two regiem showed that the DCEG regimen had advantages on total effective rate (ORR, 86.4% vs 47.8%, respectively), overall survival time (OS) (10.0 months vs 6.0 months, respectively) and progression-free survival time (PFS) (9.0 months vs 3.0 months, respectively). About 50% of MDS patients treated by DCEG regimen achieved PR or CR, with a median OS of 31 months. Multivariate analysis showed that patients with PR or CR after induction therapy and DCEG regimen had longer survival time (31months). The incidence of bone marrow suppression, infection and treatment-related mortality rate were similar between the two groups. CONCLUSION: Decitabine combined with CEG regimen could improve the survival of patients with high-risk MDS and MDS-transformed AML. The conclusion of the reaserch needs to be validated by a larger prospective randomized clinical trial.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Aclarubicina , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina/uso terapêutico , Citarabina/uso terapêutico , Decitabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Estudos Prospectivos , Resultado do Tratamento
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1631-1636, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067965

RESUMO

OBJECTIVE: To investigate the influence of MRD status in newly diagnosed MM patients with VGPR and above after treatment on clinical prognosis. METHODS: Clinical data of 210 newly diagnosed MM patients with VGPR and above after treatment in Fifth People's Hospital of Chendu city. from January 2010 to January 2018 were collected and retrospectively analyzed. The patients were divided into 2 groups: group A (152 patients with MRD-) and group B (58 patients with MRD+). The influencing factors of progression free survival and overall survival of patients were analyzed, and the correlation between MRD status and high-risk cytogenetic abnormalities, treatment plan and response to treatment were evaluated. RESULTS: There were no significant difference in clinical characteristics between the patients in 2 groups (P>0.05). Single factor analysis showed that ASCT and MRD status were related with progression free survival of patients with newly diagnosed MM (P<0.05). Multivariate analysis by Cox regression model showed that MRD+ persistence was the independent risk factor for progression free survival of patients with newly diagnosed MM (P<0.05). The cumulative progression free survival rate in 2-year with follow-up of patients in group A was significantly higher than that in B group (P<0.05). The median progression free survival time and overall survival time of patients with persistent MRD- were significantly longer than those of MRD+ (P<0.05). The single factor analysis showed that MRD- maintenance time was the influencing factor of PFS and OS time of newly diagnosed MM patients (P<0.05). The cumulative overall survival rate in 2-year with follow-up of patients with MRD- maintenance for 6 months was significantly higher than that of patients with MRD- maintenance for<6 months (P<0.05). The cumulative progression free survival rate and overall survival rate in 2 years with follow-up of patients with MRD- maintenance for ≥12 months were significantly higher than those of MRD-maintenance for <12 months(P<0.05). The median progression free survival time of patients with MRD- was significantly longer than that of patients with MRD+ who had≥ one kind of high-risk cytogenetic abnormality (P<0.05). The MRD- rate of patients received ASCT was significantly higher than that of patients without ASCT (P<0.05). The median progression free survival time of patients with MRD- was significantly longer than that of patients with MRD+ (P<0.05). The maintenance time of MRD- in patients with bortezomib treatment was significantly longer than that of patients without bortezomib treatment in population with MRD- (P<0.05). The median progression free survival time of patients with bortezomib treatment was significantly longer than patients without bortezomib treatment (P<0.05). CONCLUSION: MRD+ maintenance in newly diagnosed MM patients with VGPR and above after treatment closely relates with poor long-term prognosis, however, the MRD- maintenance time can be used for prognosis evaluation. MRD+ suggests that patients possess the possibility of early recurrence, and dynamic monitoring of MRD status in treatment can be helpful to clinical determination of treatment opportunity for relapsed MM patients.


Assuntos
Mieloma Múltiplo , Humanos , Neoplasia Residual , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
17.
Biomed Chromatogr ; 34(10): e4927, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32562289

RESUMO

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.


Assuntos
Cromatografia Líquida/métodos , Citrato de Sildenafila/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Citrato de Sildenafila/análogos & derivados , Citrato de Sildenafila/farmacocinética , Adulto Jovem
19.
Front Pharmacol ; 11: 582929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33551797

RESUMO

Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.

20.
Huan Jing Ke Xue ; 41(1): 449-459, 2020 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854948

RESUMO

This study uses 68 sets of paddy soil and rice grain samples collected from an area of carbonate rocks in Guangxi Province, China, to explore the ecological risks of heavy metals (As, Cd, Cr, Cu, Hg, Pb, Ni, and Zn) in soils from a high background area. We analyzed the concentrations of these heavy metals in soil and grain samples, and their chemical speciation in soil, and use these data to assess the associated ecological risks by means of statistics, a geo-accumulation index, bioconcentration factors (BCF), and correlation analysis. The arithmetic mean values of heavy metals concentrations in soil samples from the study area were (75.8±50.1), (1.91±1.02), (467.0±253.1), (48.5±9.8), (0.21±0.08), (76.2±28.1), (84.2±25.0), and (258.0±122.6) mg·kg-1 for As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn, respectively, which were remarkably higher than of those from other regions within Guangxi Province and China. In comparison to China's soil environmental quality standard risk screening values (GB 15618-2018), the over-standard rates of Cd, As, and Cr were 95.6%, 86.8%, and 69.1%, respectively. In comparison to risk intervention values, the over-standard rates of Cd, As, and Cr were 27.9%, 17.6%, and 5.9%, respectively. Speciation analysis on heavy metals indicated that As, Cr, Cu, Ni, Pb, and Zn were mainly found in a residual form, and accounted for>80% of the total concentrations, and had a low bioavailability. The bioactive components (F1+F2+F3) of Cd accounted for 21%, and the bioactivity of Cd was higher than other elements. The potential bioavailable components (F4+F5+F6) of Hg accounted for 44%, with low total concentrations, which are understood to have little potential ecological harm for crops. However, the over-standard rates of Pb, Cd, and Cr in rice grains were only 23.5%, 8.8%, and 2.9%, respectively. Correlation analysis showed that there was no significant correlation between the concentrations of heavy metals in soils and the corresponding rice grains. The mean BCFs of each heavy metal were <0.1, and the BCFs of Hg, Pb, As, Cr, and Ni were <0.05. Overall, we found relatively high concentrations, low activity, and low ecological risks for heavy metals in the study area. For high geological background materials such as carbonate rocks, factors such as metal speciation, biological activity, and crop over-standard rates should be taken into account along with the traditional use of the total amount of heavy metals in a soil as the evaluation standard when formulating pollution control policies.


Assuntos
Carbonatos , Monitoramento Ambiental , Metais Pesados/análise , Poluentes do Solo/análise , Disponibilidade Biológica , China , Medição de Risco , Solo
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