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1.
Biol Pharm Bull ; 45(4): 409-420, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35370265

RESUMEN

Ginkgolide B (GKB) is a well-established neuroprotectant for acute ischemia stroke. However, its cerebral exposure and real-time response remain elusive in acute ischemia/reperfusion stage, and it hinders its usage in therapeutic window of ischemia stroke. Therefore, we investigate the exposure-response relationship of GKB (10 mg/kg, intravenously (i.v.)) as well as its neuroprotective mechanism in acute ischemia/reperfusion rats. Cerebral and plasma exposure of GKB is comparatively explored in both of normal rats and acute ischemia/reperfusion rats. Correspondingly, neurological function and brain jury indexes were assessed at each time point, and superoxide dismutase (SOD), malondialdehyde (MDA), platelet activator factor (PAF) and thromboxane A2 (TXA2) are indexed as pharmacological response to GKB. Exposure-response relationships are analyzed by using linear regression. Additionally, cerebral expressions of proteins in PAF-regulated pathways are tested at each time point. Results show cerebral and plasma concentrations of GKB are much higher in acute ischemia/reperfusion rats than those in normal rats. Cerebral infarction, neurological function (NF) score, abnormal PAF and excessive MDA are significantly alleviated in 24 h after GKB injection, and PAF is reduced in exposure-response manner with significant concentration-response relationship (R2 = 0.9123). Regarding downstream proteins in intracellular PAF-regulated pathway, GKB progressively inhibits Bax, Caspase-3, p-p65 and p-IKK, while gradually restoring LC3B, p62 and p-mammalian target of rapamycin (mTOR) to the basic level within 24 h. Conclusively, GKB exhibits greater cerebral exposure in acute ischemia/reperfusion rats and neuroprotective effect through reducing PAF in exposure-response manner and mediating PAF-regulated intracellular signaling pathways. Our finding highlights clinical implications of GKB in therapeutic time window of ischemic stroke.


Asunto(s)
Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Ginkgólidos , Lactonas , Mamíferos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Reperfusión , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo
2.
Int J Clin Pharmacol Ther ; 58(10): 575-582, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32729819

RESUMEN

PURPOSE: Memantine is currently the only drug that acts on the glutamate energy system to treat Alzheimer's disease. A generic memantine tablet was developed to offer an alternative to the marketed tablet formulation. The purpose of this study was to assess the bioequivalence of two different memantine formulations among healthy male Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: We carried out single-center, randomized, single-dose, open-label, two-period, cross-over studies which including 20 healthy male Chinese subjects under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 240 hours after dosing. Key pharmacokinetic parameters including area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t), area from time zero to infinite (AUC0-∞), and Cmax were used for bioequivalence assessment. RESULTS: Under fasting condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 106.5 - 114.0% for Cmax, 99.4 - 107.9% for AUC0-t, and 100.0 - 109.6% for AUC0-∞. Under fed condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 94.8 - 104.3% for Cmax, 98.2 - 110.5% for AUC0-t, and 99.2 - 113.0% for AUC0-∞. CONCLUSION: The observed pharmacokinetic parameters of memantine of the test drug were similar to those of the reference formulation both in the fasting and fed state. That is to say, the test formulation of memantine 10-mg tablet is bioequivalent to the reference formulation (Ebixa 10-mg tablet).


Asunto(s)
Ayuno , Área Bajo la Curva , Estudios Cruzados , Humanos , Masculino , Memantina , Comprimidos , Equivalencia Terapéutica
3.
Biomed Chromatogr ; 32(8): e4240, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29529709

RESUMEN

An accurate and sensitive LC-MS/MS method for determining thalidomide, 5-hydroxy thalidomide and 5'-hydroxy thalidomide in human plasma was developed and validated using umbelliferone as an internal standard. The analytes were extracted from plasma (100 µL) by liquid-liquid extraction with ethyl acetate and then separated on a BETASIL C18 column (4.6 × 150 mm, 5 µm) with mobile phase composed of methanol-water containing 0.1% formic acid (70:30, v/v) in isocratic mode at a flow rate of 0.5 mL/min. The detection was performed using an API triple quadrupole mass spectrometer in atmospheric pressure chemical ionization mode. The precursor-to-product ion transitions m/z 259.1 → 186.1 for thalidomide, m/z 273.2 → 161.3 for 5-hydroxy thalidomide, m/z 273.2 → 146.1 for 5'-hydroxy thalidomide and m/z 163.1 → 107.1 for umbelliferone (internal standard, IS) were used for quantification. The calibration curves were obtained in the concentrations of 10.0-2000.0 ng/mL for thalidomide, 0.2-50.0 ng/mL for 5-hydroxy thalidomide and 1.0-200.0 ng/mL for 5'-hydroxy thalidomide. The method was validated with respect to linear, within- and between-batch precision and accuracy, extraction recovery, matrix effect and stability. Then it was successfully applied to estimate the concentration of thalidomide, 5-hydroxy thalidomide and 5'-hydroxy thalidomide in plasma samples collected from Crohn's disease patients after a single oral administration of thalidomide 100 mg.


Asunto(s)
Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Talidomida/sangre , Talidomida/farmacocinética , Estabilidad de Medicamentos , Humanos , Modelos Lineales , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Talidomida/química
4.
Int J Clin Pharmacol Ther ; 55(10): 832-838, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28766500

RESUMEN

OBJECTIVE: The aim of the current study is to evaluate the bioequivalence between the test and reference formulations of memantine in a single-dose, two-period and two-sequence crossover study with a 44-day washout interval. MATERIALS AND METHODS: A total of 20 healthy Chinese male volunteers were enrolled and completed the study, after oral administration of single doses of 10 mg test and reference formulations of memantine. The blood samples were collected at different time points and memantine concentrations were determined by a fully validated HPLC-MS/MS method. The evaluated pharmacokinetic parameters (test vs. reference) including Cmax (18 ± 3.2 vs. 17.8 ± 3.4), AUC0-t (1,188.5 ± 222.2 vs. 1,170.9 ± 135.7), and AUC0-∞ (1,353.3 ± 258.6 vs. 1,291.3 ± 136.7) values were assessed for bioequivalence based on current guidelines. RESULTS: The observed pharmacokinetic parameters of memantine test drug were similar to those of the reference formulation. The 90% confidence intervals of test/reference ratios for Cmax, AUC0-t, and AUC0-∞ were within the bioequivalence acceptance range of 80 - 125%. CONCLUSION: The results obtained from the healthy Chinese subjects in this study suggests that the test formulation of memantine 10 mg tablet is bioequivalent to the reference formulation (Ebixa®10 mg tablet).
.


Asunto(s)
Memantina/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Disponibilidad Biológica , Química Farmacéutica/métodos , Estudios Cruzados , Semivida , Voluntarios Sanos , Humanos , Masculino , Comprimidos/farmacocinética , Equivalencia Terapéutica , Adulto Joven
5.
Biomed Chromatogr ; 29(10): 1506-13, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25776729

RESUMEN

A rapid and sensitive liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to determine clonidine in human plasma was developed and fully validated. Sample preparation was involved an one-step extraction with diethyl ether. Donepezil was employed as the internal standard (IS). Chromatographic separation was performed on a Hypersil BDS C18 column (i.d. 2.1 × 50 mm, particle size 3µm) with a mobile phase of methanol-water (containing 0.1% formic acid; 60:40, v/v) at a flow rate of 200 µL/min. The peaks were detected by mass spectrometry using the electrospray ion source in selected reaction monitoring mode. The extraction recovery was 72.53-85.25%. The method was found to be linear in a concentration range of 0.02-6.00 ng/mL and the lower limit of quantification was 0.02 ng/mL. The within- and between-batch precisions at three concentrations were 4.33-16.47 and 7.24-17.24% with accuracies of -2.47-10.91 and 1.86-10.19%, respectively. This validated method was successfully used for a bioequivalence study of two clonidine transdermal patches on healthy volunteers. The results suggested that the test formulation of clonidine patch met the regulatory criterion for bioequivalence to the reference formulation, but a larger sample size should be needed for the estimation of bioequivalence.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Clonidina/sangre , Clonidina/farmacocinética , Adulto , Área Bajo la Curva , Calibración , Clonidina/administración & dosificación , Voluntarios Sanos , Humanos , Masculino , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Equivalencia Terapéutica , Parche Transdérmico
6.
Eur J Drug Metab Pharmacokinet ; 38(2): 105-13, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22797870

RESUMEN

Astragalus injection (AI) and Astragalus granules (AG) are the two representative clinical preparations from Astragali Radix. In order to investigate the regulation of metabolism, AI and AG were tested for their ability to affect the major enzyme cytochrome P450 3A isoforms in vivo and in vitro. In the study of CYP3A1 enzyme activity, male rats were pretreated with AI and AG. The "cocktail" approach-based LC-MS/MS results showed that AI pretreatment at 0.16, 0.8 and 4 g kg(-1) day(-1) significantly increased the rat liver microsome CYP3A1 activity by 1.62-, 1.68- and 2.00-fold, and AG pretreatment at 32, 160 and 800 mg kg(-1) day(-1) significantly increased the rat CYP3A1 activity by 1.86-, 2.16- and 1.76-fold. The effects of AI and AG on liver microsome CYP3A1 mRNA expression in rats were analyzed using real-time PCR technique. The results showed that AI and AG pretreatments significantly increased the CYP3A1 mRNA expression. The induction of CYP3A4 enzyme activity by AI and AG in vitro was measured using a CYP3A4 luciferase reporter gene assay in transiently transfected human intestinal LS174T cells. Compared to the control group, AI at 62.5-1,000 mg/ml could significantly induce CYP3A4 reporter gene luciferase activity of 1.36- to 1.88-fold for 48-h incubated PXR-transfected LS174T cells, and AG at 62.5-1,000 µg/ml significantly transactivated CYP3A4 reporter gene luciferase activity of 1.36- to 2.05-fold. However, the CYP3A4 reporter gene construct was not significantly transactivated by the AI and AG in CAR-transfected LS174T cells. These CYP3A isoforms upregulation results can help us to use AI and AG rationally in the clinic.


Asunto(s)
Planta del Astrágalo , Citocromo P-450 CYP3A/genética , Medicamentos Herbarios Chinos/farmacología , Animales , Células Cultivadas , Citocromo P-450 CYP3A/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inyecciones , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba
7.
Materials (Basel) ; 16(7)2023 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-37048996

RESUMEN

It has been found that the mechanic-electric response of cement-based piezoelectric composites under impact loading is nonlinear. Herein, we prepared a 2-2 cement-based piezoelectric composite material using cutting, pouring, and re-cutting. Then, we obtained the stress-strain and stress-electric displacement curves for this piezoelectric composite under impact loading using a modified split Hopkinson pressure bar (SHPB) experimental apparatus and an additional electrical output measurement system. Based on the micromechanics of the composite materials, we assumed that damage occurred only in the cement paste. The mechanical response relationship of the piezoelectric composite was calculated as the product of the viscoelastic constitutive relationship of the cement paste and a constant, where the constant was determined based on the reinforcement properties of the mechanical response of the piezoelectric composite. Using a modified nonlinear viscoelastic Zhu-Wang-Tang (ZWT) model, we characterized the stress-strain curves of the piezoelectric composite with different strain rates. The dynamic sensitivity and stress threshold of the linear response of the samples were calibrated and fitted. Thus, a mechanic-electric response equation was established for the 2-2 type cement-based piezoelectric composite considering the strain rate effects.

8.
Int J Urol ; 17(7): 666-72, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20482659

RESUMEN

OBJECTIVES: To clarify the relationship between a decreased major histocompatibility complex class I (MHC-I) expression on bladder tumors and decreased immunological efficacy of tumor antigen-pulsed dendritic cell vaccine in a rat bladder carcinoma model induced by N-methyl-N-nitrosourea irrigation. METHODS: Enzyme-linked immunosorbent assay was used to evaluate interferon-gamma concentration in the serum and colorimetric lactate dehydrogenase release assay in vitro was used to test the cytotoxicity capability of T lymphocytes. MHC-I expression on tumor cells was detected by flow cytometry and analyzed with CellQuest software. RESULTS: The tumor antigen sensitized dendritic cell vaccine group showed decreased hyperplastic formations, lower pathological stages in rat bladders and more potent cytotoxicity activity (P < 0.001) than the dendritic cell vaccine group. Additionally, immunization with pulsed dendritic cell vaccine induced higher specific cytokine production of interferon-gamma. Nevertheless, a decreased MHC-I expression on bladder tumors was tested after immunotherapy by pulsed dendritic cell vaccine on week 15. As expected, the cytotoxic activity of T lymphocytes from rats on tumor cells with low MHC-I expression was also decreased to 19.70 +/- 4.82% as compared with tumor cells with high MHC-I (52.10 +/- 8.66%, P = 0.005). CONCLUSIONS: Tumor antigen sensitized dendritic cell vaccine has beneficial activity on N-methyl-N-nitrosourea-induced bladder cancer in situ in rats, but therapeutic responses are accompanied by decreased MHC-I expression on tumors, possibly suggesting poor long-term therapeutic outcomes.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Antígenos de Histocompatibilidad Clase I/biosíntesis , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Animales , Células Dendríticas , Femenino , Ratas , Ratas Endogámicas F344
9.
World Neurosurg ; 138: 740-748, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31953102

RESUMEN

BACKGROUND: We evaluated the improvement in the gray and white matter functional areas in children with cerebral palsy (CP) after common carotid artery sympathetic neural network ablation. We also analyzed the relationship between the values of the diffusion kurtosis imaging (DKI) parameters and clinical signs in children with CP. METHODS: We collected data from 22 children with unilateral spastic CP who had undergone common carotid sympathetic neural network ablation in our hospital from January 1, 2014 to December 1, 2018, using magnetic resonance kurtosis imaging technology parameters. RESULTS: The study found that the changes from preoperatively to postoperatively in the kurtosis fractional anisotropy (KFA) values for the frontal lobe, parietal lobe, temporal lobe, internal sac forelimb, and corpus callosum were statistically significant. However, the changes in the internal sac forelimb, corpus callosum, and KFA values were not statistically significant. The changes from preoperatively to postoperatively in the mean kurtosis (MK) values for the frontal lobe, parietal lobe, temporal lobe, hindlimb of the internal capsule, corpus callosum, and caudate nucleus were statistically significant. However, the MK values for the forelimb, corpus callosum, and thalamus were not statistically significant. The 66-item gross motor function measure scores correlated negatively with the KFA value and positively with the MK value. CONCLUSION: Therefore, it can be concluded that DKI technology can more accurately reflect the gray and white matter damage in children with CP, and the DKI parameters can be used as a monitoring and evaluation index for children with CP.


Asunto(s)
Arteria Carótida Común/inervación , Sustancia Gris/diagnóstico por imagen , Simpatectomía/métodos , Sustancia Blanca/diagnóstico por imagen , Estudios de Casos y Controles , Núcleo Caudado/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Parálisis Cerebral , Niño , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Cápsula Interna/diagnóstico por imagen , Masculino
10.
J Am Chem Soc ; 131(6): 2094-5, 2009 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-19159295

RESUMEN

In this communication, we have demonstrated that SiO(2) nanoparticles can be generated by simply scratching the quartz or silicon wafer with a SiO(2) layer and confirmed it to be active for the growth of SWNTs for the first time. Furthermore, the SWNTs from SiO(2) has a much narrower size distribution. This may open a way to control the diameter of the SWNTs. More importantly, our work has found a series of oxides including Al(2)O(3), TiO(2), and rare earth oxides to be active for SWNT growth as well. These findings not only provide an alternative new type of catalysts for the growth of SWNTs but also give more insight into the role of the catalysts and a deeper understanding of the growth mechanism of SWNTs. The effective catalysts and catalytic activity for SWNT growth seem to be more size-dependent than the catalysts. Long oriented SWNTs generated from these catalysts enable us to rule out the relationship between the catalysts and the structures of the SWNTs. Thus controlled growth of SWNTs including the diameter and chirality is expected to be eventually realized.

11.
BMC Cancer ; 9: 354, 2009 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-19807915

RESUMEN

BACKGROUND: Biomarkers that predict clinical response, tumor recurrence or patient survival are severely lacking for most cancers, particularly for oral and pharyngeal cancer. This study examines whether gene-promoter methylation of tumor DNA correlates with survival and recurrence rates in a population of patients with oral or pharyngeal cancer. METHODS: The promoter methylation status of the DNA repair gene MGMT and the tumor suppressor genes CDKN2A and RASSF1 were evaluated by methylation-specific PCR in 88 primary oral and pharyngeal tumors and correlated with survival and tumor recurrence. Quantitative MGMT methylation was also assessed. RESULTS: 29.6% of the tumors presented with MGMT methylation, 11.5% with CDKN2A methylation and 12.1% with RASSF1 methylation. MGMT promoter methylation was significantly associated with poorer overall and disease-free survival. No differences in methylation status of MGMT and RASSF1 with HPV infection, smoking or drinking habits were observed. A significant inverse trend with the amount of MGMT methylation and overall and disease-free survival was observed (ptrend = 0.002 and 0.001 respectively). CONCLUSION: These results implicate MGMT promoter methylation as a possible biomarker for oral and pharyngeal cancer prognosis. The critical role of MGMT in DNA repair suggests that defective DNA repair may be correlative in the observed association between MGMT promoter methylation and tumor recurrence. Follow-up studies should include further quantitative MSP-PCR measurement, global methylation profiling and detailed analysis of downstream DNA repair genes regulated by promoter methylation.


Asunto(s)
Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Neoplasias de la Boca/genética , Neoplasias Faríngeas/genética , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/genética , Anciano , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Neoplasias Faríngeas/metabolismo , Neoplasias Faríngeas/mortalidad , Neoplasias Faríngeas/patología , Recurrencia , Sobrevida , Proteínas Supresoras de Tumor/metabolismo
12.
Clin Pharmacol Drug Dev ; 8(2): 217-222, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29659187

RESUMEN

Anastrozole is currently used as first-line treatment in locally advanced or metastatic breast cancer. A generic anastrozole tablet was developed to offer an alternative to the marketed tablet formulation. The aim of the current study was to evaluate the bioequivalence between the test and reference formulations of anastrozole in a single-dose, 2-period, 2-sequence crossover study with a 14-day washout interval. A total of 20 healthy male Chinese volunteers were enrolled and completed the study, after oral administration of a single dose of 1.0-mg test and reference formulations of anastrozole. The blood samples were collected at different times and were determined by a fully validated high-pressure liquid chromatography-tandem mass spectrometry method. The evaluated pharmacokinetic parameters, including Cmax , AUC0-t , and AUC0-∞ , were assessed for bioequivalence based on current guidelines. The observed pharmacokinetic parameters of anastrozole of the test drug were similar to those of the reference formulation. The 90% confidence intervals of test/reference ratios for Cmax , AUC0-t , and AUC0-∞ were within the bioequivalence acceptance range of 80%-125%. The results obtained from these healthy Chinese subjects in this study suggest that the test formulation of anastrozole 1.0-mg tablet is bioequivalent to the reference formulation (Arimidex 1.0-mg tablet).


Asunto(s)
Anastrozol/administración & dosificación , Anastrozol/farmacocinética , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , China , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Voluntarios Sanos , Humanos , Masculino , Comprimidos , Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Adulto Joven
13.
J Am Chem Soc ; 130(36): 11860-1, 2008 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-18702491

RESUMEN

In this Communication, we have demonstrated a facile and effective approach to identify the structure of the superlong well-aligned single-walled carbon nanotubes (SWNTs) by the combination of electrodeposition of metal (Ag) with Raman spectroscopy. The suitable density and the visibility of the Ag-deposited long oriented nanotubes make it possible to acquire Raman spectra from isolated individual nanotubes very easily. The results reveal that the well-oriented SWNT arrays on SiO2/Si wafer fabricated by EtOH chemical vapor deposition using Fe/Mo nanoparticles as catalyst exhibit a low percentage of metallic SWNTs (5%). Among other SWNTs about 62.3% are semiconducting SWNTs, and a small amount of nanotubes are quasimetallic. About 32% are a so-called quasi-insulator, which is caused inevitably by the defects during growth. Furthermore, the structural uniformity of the long SWNTs can be also evaluated by the deposition of Ag along the length and Raman spectroscopy. This method also provides an approach to deposit other metals on long SWNTs, which could have various potential applications such as for use as sensors, etc. More importantly, this facile method can be applied to long SWNT arrays fabricated from other different catalytic systems so that the relationship between the growth conditions and the structures of SWNTs are expected to be ruled out.

14.
J Pharm Biomed Anal ; 134: 71-76, 2017 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-27886572

RESUMEN

Great attentions have been drawn by quinoline for its broad bioactivity as anti-fungal, anti-bacterial and anti-tumor activities. Compared with cisplatin, 83b1, a quinoline derivative, showed equal activity in anti-tumor and lower cyctotoxicity in normal cell. In this study, a simple, rapid and sensitive method for determination of 83b1 in rat plasma using UHPLC-MS/MS was developed for the first time. Loratadine was used as an internal standard (IS). Separation was performed on an Xterra MS C18 column by isocratic elution using acetonitrile: water solution with 1‰ formic acid (90:10, v/v) as mobile phase at a flow rate of 0.3mL/min. A triple quadrupole mass spectrometer operating in the positive ion-switching electron spray ionization mode with selection reaction monitoring (SRM) was employed to determine 83b1 and IS transitions of m/z 321.82→147.84, 382.71→258.76 for 83b1 and Loratadine, respectively. The values of specificity, linearity and lower limit of quantification, intra- and inter- day precision and accuracy, extraction recovery, matrix effect and stability for this method satisfied the acceptable limits. The lower limit of quantification was 0.5ng/mL with a linear range of 0.5-1500ng/mL. The validated method was employed to study the bioavailability of 83b1 in rat by dosing with intravenous injection (1mg/kg) and gavage (10mg/kg), and the oral bioavailability of 83b1 in rat was calculated as 20.9±8.8%.


Asunto(s)
Antineoplásicos/sangre , Quinolinas/sangre , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión/métodos , Masculino , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Ratas Sprague-Dawley
15.
J Pharm Biomed Anal ; 125: 303-9, 2016 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-27070132

RESUMEN

A simple, sensitive and accurate ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of AKI603 in rat plasma has been firstly developed and validated. After a simple liquid-liquid extraction (LLE) with ethyl acetate, the analytes were separated on C18 column (2.1×100mm, 1.9µm, Thermo) by gradient elution with mobile phase of water (A) (containing 5mM ammonium acetate and 0.1% formic acid) and methanol (B) with a flow rate of 0.3mLmin(-1) and then analyzed by mass spectrometry in the positive multiple reactions monitoring (MRM) mode. The mass transitions monitored were m/z 410.0→352.9, m/z 457.1→367.9 for AKI603 and internal standard (Ly-7z), respectively. The developed method was validated for specificity, linearity and lower limit of quantification, intra- and inter-day precision and accuracy, extraction recovery, matrix effect and stability whose values satisfied the acceptable limits. The calibration curves for AKI603 was linear in concentration ranges of 0.025-5000ngmL(-1). The method has been successfully used to the bioavailability study of AKI603 administered to rats intravenously (2.5mg/kg) or orally (25mg/kg). The oral bioavailability of AKI603 in rats was calculated as 28.7±9.7%.


Asunto(s)
Cromatografía Liquida/métodos , Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Disponibilidad Biológica , Ratas
16.
Chin Med J (Engl) ; 116(11): 1733-6, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14642147

RESUMEN

OBJECTIVE: To study the human dystrophin gene molecular deletion mechanism, we analyzed breakpoint regions within junction fragments of deletion-type patients and investigated whether the dystrophin gene's intron structure might be related to intron instability. METHODS: Junction fragments corresponding to exon 46 and 51 deletions were cloned. The breakpoint regions were sequenced, and the features of introns with available Genebank sequences were analyzed. RESULTS: An analysis of junction fragment sequences corresponding to exon 46 and 51 deletions showed that all 5' and 3' breakpoints are located within repeat sequences. No small insertions, small deletions, or point mutations are located near the breakpoint junctions. By analyzing the secondary structure of the junction fragments, we demonstrated that all junction fragment breakpoints are located in non-matching regions of single-stranded hairpin loops. A high concentration of repetitive elements is found to be a key feature of many dystrophin introns. In total, 34.8% of the overall dystrophin intron sequences is composed of repeat sequences. CONCLUSION: Repeat elements in many dystrophin gene introns are the key to their structural bases and reflect intron instability. As a result of the primary DNA sequences, single-stranded hairpin loops form, increasing the instability of the gene, and forming the base for breaks in the DNA. The formation of the single-stranded hairpins can result in reattachment of two different breakpoints, producing a deletion.


Asunto(s)
Distrofina/genética , Intrones/genética , Humanos , Eliminación de Secuencia
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 20(5): 376-80, 2003 Oct.
Artículo en Zh | MEDLINE | ID: mdl-14556187

RESUMEN

OBJECTIVE: To study the exons deletion mechanisms for dystrophin gene, the molecular characters of breakpoints of junction fragments for deletion-type Duchenne muscular dystrophy (DMD) patients with 46 and 51 exons deletion were compared and analyzed. METHODS: Deletion-type DMD patients were detected by multiplex polymerase chain reaction(mPCR). The breakpoints of junction fragments with 46 and 51 exons deletions were cloned and sequenced respectively. RESULTS: Analysis of sequences of deletion-junction fragment of exon 46 showed that the 5'breakpoint was located in AT-rich region of intron 45 and the 3' breakpoint was in medium reiteration repeats (MER1) sequence. There existed 2 bp(ta) junction homology between two breakages. No small insertion, small deletion or point mutation was located near the junction point. Similarly, analysis of sequences of deletion-junction fragment of exon 51 showed that the 5 breakpoint was located in transposon-like human elements (THE1) of intron 50 and the 3' breakpoint was in L2 sequence. There existed 3 bp(cta) junction homology between two breakages. No small insertion, small deletion or point mutation was located near the junction point. By analyzing the secondary structure of junction fragments with 46 and 51 exons deletions, it was demonstrated that all breakpoints of junction fragments were located at the non-matching regions of single-strand hairpin. CONCLUSION: By comparing the junction fragments with 46 or 51 exons deletion, it was found that all of breakpoints were located in repeat sequences and the repeat sequences formed the single-strand hairpin which could make the introns instable and result in exon deletion.


Asunto(s)
Distrofina/genética , Intrones/genética , Distrofia Muscular de Duchenne/genética , Eliminación de Secuencia , Secuencia de Bases , ADN/química , ADN/genética , Análisis Mutacional de ADN , Exones/genética , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Secuencias Repetitivas de Ácidos Nucleicos/genética
18.
J Zhejiang Univ Sci ; 4(5): 560-4, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12958715

RESUMEN

In this paper, the axisymmetric general solutions of transversely isotropic magnetoelectroelastic media are expressed with four harmonic displacement functions at first. Then, based on the solutions, the analytical three-dimensional solutions are provided for a simply supported magnetoelectroelastic circular plate subjected to uniform loads. Finally, the example of circular plate is presented.


Asunto(s)
Magnetismo , Electricidad Estática , Fuerza Compresiva , Modelos Teóricos
19.
Int J Biol Markers ; 28(2): 161-7, 2013 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-23564622

RESUMEN

Obesity is associated with breast cancer in post-menopausal women, and breast density is a marker of breast cancer risk. Leptin is produced by the adipose tissue, acts through receptors that are polymorphic in nature, and is considered a cancer growth factor. The relationship between body mass index, leptin, leptin receptors and breast density is not well studied. A cross-sectional analysis in 392 post-menopausal healthy women was conducted; participants provided permission to obtain copies of their most recent screening mammogram. Non-fasting plasma leptin levels were determined using a commercially available leptin ELISA kit. Analysis of the Q223R genotypes of the LEPR gene were performed by PCR followed by restriction fragment length polymorphism analysis using DNA extracted from buffy coat samples. A statistically significant positive relationship was observed between leptin levels and body mass index (p<0.0001); leptin was significantly positively associated with mammography total breast area and non-dense breast area (p<0.0001), while it was inversely associated with percent breast density (p<0.0001). Leptin levels varied across the LEPR Q223R polymorphism, and were higher in women homozygous for the AA variant. Percent breast density decreased across the LEPR Q223R genotype, with lower percent density in women with the AA genotype. When dense area was considered according to quartiles of leptin and stratified by LEPR Q223R, a significant inverse trend between leptin levels and dense breast area was observed only among women with the G/G genotype (p-trend<0.001). After adjustment for possible confounders, leptin levels were significantly inversely associated with percent breast density (p=0.01). A significant interaction between body mass index and leptin levels on percent breast density was observed (p=0.03). These findings suggest that the association between leptin and breast density may vary by LEPR Q223R genotype, and that body mass index and leptin may act in an interactive way in determining breast density.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Leptina/sangre , Glándulas Mamarias Humanas/anomalías , Receptores de Leptina/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Densidad de la Mama , Neoplasias de la Mama/patología , Estudios Transversales , Detección Precoz del Cáncer , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Leptina/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
20.
J Chromatogr B Analyt Technol Biomed Life Sci ; 879(30): 3452-8, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21983196

RESUMEN

A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and fully validated to determine HS270, a new histone deacetylase (HDAC) inhibitor, in rat plasma using SAHA as the internal standard (IS). After a single step liquid-liquid extraction with acetoacetate, analytes were subjected to LC-MS/MS analysis using positive electro-spray ionization (ESI(+)) under selected reaction monitoring mode (SRM). The chromatographic separation was achieved on a Hypurity C(18) column (50 mm × 2.1 mm, i.d., 5 µm). The MS/MS detection was conducted by monitoring the fragmentation of m/z 392.3→100.1 for HS270, m/z 265.1→232.1 for IS. The method had a chromatographic running time of 2.5 min and linear calibration curves over the concentrations of 0.5-1000 ng/mL. The recovery of the method was 70.8-82.5% and the lower limit of quantification (LLOQ) was 0.5 ng/mL. The intra- and inter-batch precisions were less than 15% for all quality control samples at concentrations of 1.0, 100.0, and 750.0 ng/mL. The validated LC-MS/MS method has successfully applied to a HS270 pharmacokinetic study after oral doses of 25, 50, 100, 200 mg/kg, and i.v. dose of 5 mg/kg to rats.


Asunto(s)
Cromatografía Liquida/métodos , Inhibidores de Histona Desacetilasas/sangre , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacocinética , Ácidos Hidroxámicos/análisis , Modelos Lineales , Ratas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray , Vorinostat
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