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1.
Ying Yong Sheng Tai Xue Bao ; 32(10): 3437-3447, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34676704

RESUMO

With the commonly used variable-exponent taper models developed by Kozak (1988), Muhairwe (1999), Lee (2003) and Kozak (2004), we aimed to develop taper functions of diameter outside bark (DOB), heartwood diameter (HD), sapwood width (SW), and bark thickness (BT) based on the data of 2977 discs from 103 sample trees of Pinus koraiensis plantations under different conditions in Mengjiagang Forest Farm, Dongjingcheng and Linkou Forestry Bureau in Heilongjiang Province. We selected the optimal basic model after comparison. By using seemingly unrelated regression (SUR) method in the PROC MODEL of SAS software, we established an additive model system for the taper equations of DOB, HD, SW and BT. By introducing the region as a dummy variable, the models were evaluated by coefficient determination (Radj2), root mean square error (RMSE), Akaike information criterion (AIC) and Bayesian information criterion (BIC). The results showed that the taper model developed by Kozak (2004) was the optimal one for the DOB, HD, SW and BT. When satisfying the additivity of each component and total amount, the additivity model system got better prediction effect, with a prediction precision of more than 98%. The additive model system with dummy variables improved the prediction ability to varying degrees, especially the prediction precision of HD and SW models. Minor differences existed in DOB and BT among different regions, while enormous differences in HD and SW. The additive model system with dummy variables not only had high prediction accuracy but also satisfied the additive logic of DOB, HD, SW and BT, which provided a basis for accurate estimation of heartwood, sapwood and bark volume of P. koraiensis.


Assuntos
Pinus , Teorema de Bayes , China , Modelos Biológicos , Casca de Planta
2.
Ying Yong Sheng Tai Xue Bao ; 32(7): 2505-2513, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34313069

RESUMO

Forest parameters could be estimated without damage using terrestrial laser scanning (TLS). In this study, 1266 sets of branch parameters, including branch height, branch chord length, branch length, branch angle, branch diameter and the branch arc height, of 26 Larix trees were extracted based on TLS using point cloud processing software in the way of human-computer interaction. The average of extracted maximum relative height of the branches was 0.83. The accuracy of the extracted branch attributes followed the order of branch height > branch chord length > branch length > branchdiameter (with the branch diameter >20 mm) > branch arc height. After dividing the crown into four parts, it proved that the density of the branches increased while the extraction ratio and precision of branches decreased with the increase of crown height. Due to the low accuracy of branch diameter extraction, we developed a base diameter prediction model using the branch chord length, the height of branch, diameter at breast height and tree height as independent variables. The measured, extracted and model predicted values of different base diameter were compared, and discovered that accuracy of model prediction was greater than that of extraction by TLS. For timber production, the most worthy wood was the middle and lower section of the tree. The method could accurately extract tree height, diameter at breast height (DBH) and the branch attributes with the relative branch height of less than 0.8, providing the parameters that are necessary to develop a wood quality model.


Assuntos
Larix , Florestas , Humanos , Lasers , Luz , Árvores
3.
Exp Ther Med ; 22(2): 870, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34194548

RESUMO

Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria-associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription-quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO-induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO-induced cardiac hypertrophy.

4.
J Cell Mol Med ; 25(17): 8464-8478, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34322993

RESUMO

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that ß1 -adrenergic receptor autoantibody (ß1 -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that ß1 -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by ß1 -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that ß1 -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by ß1 -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by ß1 -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by ß1 -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by ß1 -AA in cardiomyocytes. This study is the first time to confirm that ß1 -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by ß1 -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with ß1 -AA-positive cardiac dysfunction.

5.
Acta Pharmacol Sin ; 42(12): 2155-2172, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33931765

RESUMO

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

6.
ACS Omega ; 6(14): 9973, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33869977

RESUMO

[This corrects the article DOI: 10.1021/acsomega.0c02634.].

7.
Brain Res Bull ; 170: 174-186, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33600886

RESUMO

Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood. In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. These findings suggested that as early as 1∼4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

8.
Adv Ther ; 38(1): 607-626, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33180318

RESUMO

INTRODUCTION: Apnoea of prematurity (AOP) is among the most common diagnoses in the neonatal intensive care unit. Caffeine treatment is a preferred treatment choice. However, neonatal caffeine therapy results in significant intersubject variability. This study aimed to determine the effects of plasma caffeine levels based on standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants. METHODS: This single-center and retrospective study examined data from 112 preterm infants (< 35 weeks gestational age) between July 2017 and July 2018. Subjects were divided into apnoea-free (n = 48) and apnoeic (n = 64) groups, and their clinical outcomes were summarized. Liquid chromatography-tandem mass spectrometry was used to measure levels of caffeine and its primary metabolites. Eighty-eight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system. RESULTS: Preterm infants in the apnoea-free group were associated with a reduction in the incidence of bronchopulmonary dysplasia and a reduced requirement for patent ductus arteriosus ligation. No significant association was observed between plasma-trough-concentration-to-dose (C0/D) ratio and birth weight, gestational age, or postnatal age in either group. Polymorphisms in CYP1A2 and aryl hydrocarbon receptor (AHR) genes did not affect plasma caffeine levels. Polymorphisms in adenosine receptor genes ADORA1 (rs10920568 and rs12744240), ADORA2A (rs34923252 and rs5996696), and ADORA3 (rs10776727 and rs2298191), especially in AHR (rs4410790) and adenosine deaminase (rs521704), play critical roles in the interindividual response to caffeine therapy. CONCLUSIONS: Genetic polymorphisms in caffeine's target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine therapy in preterm neonates. Future studies are needed to uncover how these genetic variants affect responses to caffeine therapy in this patient population.


Assuntos
Apneia , Cafeína , Apneia/tratamento farmacológico , Apneia/genética , Cafeína/uso terapêutico , China , Citratos , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Padrões de Referência , Estudos Retrospectivos
9.
Ying Yong Sheng Tai Xue Bao ; 31(9): 2943-2954, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-33345495

RESUMO

Based on 1207 knots from 49 sample trees of 29 standard plots of Korean pine plantations in Linkou and Dongjingcheng Forest Bureau of Heilongjiang Province, China, we extracted longitudinal sections of knots using the image processing software Digimizer and represented the shape of knots using two-dimensional scatter plots. According to the two-dimensional scatter plots, knots of Korean pine plantation were divided into three types: 1) alive knots (whole knot contained only sound knot portion); 2) non-occluded dead knots (whole knot contained both sound and loose knot portions); 3) occluded dead knots (the sound and loose portion of the knot were partially occluded by the bark). For all the three types of knots, the volume of sound knot was calculated by mathematical integral of the sound knot shape equation. The volume of loose knot was calculated using the volume equation of a cylinder. The total volume of knots was calculated as the sum of sound and loose knot volume. Finally, based on knot variables (diameter, relative height and total length of knots) and tree variable (diameter at breast height), we established the prediction models for sound knot volume, loose knot volume, and total volume of knot using the linear mixed model at plot level and tree level. Compared with fixed-effects model, the mixed effects models of the volume of sound knot, loose knot, and total knots provided more accurate parameter estimation, more uniform residual distribution, and higher model fitting precision. The validation results showed that prediction precision of each fixed-effect model was higher than 90%, while that of the mixed models with plot and tree effect was above 93%, indicating that the established model could well predict the volume of knot for Korean pine plantation.


Assuntos
Pinus , China , Florestas , República da Coreia , Árvores
10.
ACS Omega ; 5(38): 24356-24366, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33015452

RESUMO

In this work, an ion imprinted polymer (ReO4 --IIP) of the perrhenate ion based on acrylamide (AM) and acrylic acid (AA) was prepared by solution polymerization using ReO4 - as a template ion, N,N-methylenebisacrylamide (NMBA) as cross-linkers, hydrogen peroxide-vitamin C (H2O2-Vc) as an initiator, and a mixed solution of water (H2O) and methanol (CH3OH) with volume ratio v(H2O)/v(CH3OH) = 3:7 as a solvent. During the process of synthesis condition investigation and optimization, the adsorption capacity (Q) and the separation degree (R) in the equimolar concentration mixture solutions of NH4ReO4 and KMnO4 were adopted as indexes, and the obtained optimal conditions were as follows: the molar ratios of NMBA, NH4ReO4, AA, H2O2, and Vc to AM were 5.73, 0.052, 1.29, 0.02, and 0.003, and the temperature and time of polymerization were 40 °C and 28 h, respectively. Under optimal conditions, the sample with indexes, Q and R of 0.064 mmol/g and 3.20, were harvested. What is more, a further reusability study found that good adsorption selectivity was maintained after repeating the experiment 9 times. Taking the non-IP prepared under the same conditions as a control, Fourier transform infrared spectroscopy, transmission electron microscopy, and Brunauer Emmett Teller were used to characterize the structure of the ReO4 --IIP prepared under the optimal conditions. Finally, the kinetic study results showed that the zero-order kinetic model could better describe the adsorption process. The thermodynamic study results showed that the Langmuir model was more suitable for describing the isotherm adsorption process of the IIP.

11.
Sci Rep ; 10(1): 11664, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669616

RESUMO

A photosynthetic light-response (PLR) curve is a mathematical description of a single biochemical process and has been widely applied in many eco-physiological models. To date, many PLR measurement designs have been suggested, although their differences have rarely been explored, and the most effective design has not been determined. In this study, we measured three types of PLR curves (High, Middle and Low) from planted Larix olgensis trees by setting 31 photosynthetically active radiation (PAR) gradients. More than 530 million designs with different combinations of PAR gradients from 5 to 30 measured points were conducted to fit each of the three types of PLR curves. The influence of different PLR measurement designs on the goodness of fit of the PLR curves and the accuracy of the estimated photosynthetic indicators were analysed, and the optimal design was determined. The results showed that the measurement designs with fewer PAR gradients generally resulted in worse predicted accuracy for the photosynthetic indicators. However, the accuracy increased and remained stable when more than ten measurement points were used for the PAR gradients. The mean percent error (M%E) of the estimated maximum net photosynthetic rate (Pmax) and dark respiratory rate (Rd) for the designs with less than ten measurement points were, on average, 16.4 times and 20.1 times greater than those for the designs with more than ten measurement points. For a single tree, a unique PLR curve design generally reduced the accuracy of the predicted photosynthetic indicators. Thus, three optimal measurement designs were provided for the three PLR curve types, in which the root mean square error (RMSE) values reduced by an average of 8.3% and the coefficient of determination (R2) values increased by 0.3%. The optimal design for the High PLR curve type should shift more towards high-intensity PAR values, which is in contrast to the optimal design for the Low PLR curve type, which should shift more towards low-intensity PAR values.


Assuntos
Larix/efeitos da radiação , Modelos Estatísticos , Fotossíntese/efeitos da radiação , Folhas de Planta/efeitos da radiação , Taxa Respiratória/efeitos da radiação , Relação Dose-Resposta à Radiação , Agricultura Florestal , Florestas , Humanos , Larix/fisiologia , Luz , Fotossíntese/fisiologia , Folhas de Planta/fisiologia , Taxa Respiratória/fisiologia , Árvores/fisiologia , Árvores/efeitos da radiação
12.
Transl Psychiatry ; 10(1): 125, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350238

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Currently, the diagnosis of AD depends on clinical assessments and post-mortem neuropathology, which is unbenefited early diagnosis and progressive monitoring. In recent years, clinical studies have reported that the level of cerebrospinal fluid (CSF) and blood neurogranin (Ng) are closely related to the occurrence and subsequent progression of AD. Therefore, the study used meta-analysis to identify the CSF and blood Ng levels for the development of diagnosis biomarker of patients with AD and mild cognitive impairment (MCI). We searched the Pubmed, Embase, Cochrane Library, and Web of Science databases. A total of 24 articles eligible for inclusion and exclusion criteria were assessed, including 4661 individuals, consisting of 1518 AD patients, 1501 MCI patients, and 1642 healthy control subjects. The level of CSF Ng significantly increased in patients with AD and MCI compared with healthy control subjects (SMD: 0.84 [95% CI: 0.70-0.98], P < 0.001; SMD: 0.53 [95% CI: 0.40-0.66], P = 0.008), and higher in AD patients than in MCI patients (SMD: 0.18 [95% CI: 0.07-0.30], P = 0.002), and CSF Ng level of patients with MCI-AD who progressed from MCI to AD was significantly higher than that of patients with stable MCI (sMCI) (SMD: 0.71 [95% CI: 0.25-1.16], P = 0.002). Moreover, the concentration of Ng in blood plasma exosomes of patients with AD and MCI was lower than that of healthy control subjects (SMD: -6.657 [95% CI: -10.558 to -2.755], P = 0.001; and SMD: -3.64 [95% CI: -6.50 to -0.78], P = 0.013), and which in patients with AD and MCI-AD were also lower than those in patients with sMCI (P < 0.001). Furthermore, regression analysis showed a negative relationship between MMSE scores and CSF Ng levels in MCI patients (slope = -0.249 [95% CI: -0.003 to -0.495], P = 0.047). Therefore, the Ng levels increased in CSF, but decreased in blood plasma exosomes of patients with AD and MCI-AD, and highly associated with cognitive declines. These findings provide the clinical evidence that CSF and blood exosomes Ng can be used as a cognitive biomarker for AD and MCI-AD, and further studies are needed to define the specific range of Ng values for diagnosis at the different stages of AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Exossomos , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Humanos , Neurogranina , Fragmentos de Peptídeos , Proteínas tau
13.
BMC Vet Res ; 16(1): 76, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131821

RESUMO

BACKGROUND: Vibrio alginolyticus is an important pathogen that has to be closely monitored and controlled in the mariculture industry because of its strong pathogenicity, quick onset after infection and high mortality rate in aquatic animals. Fast, simple and specific methods are needed for on-site detection to effectively control outbreaks and prevent economic losses. The detection specificity towards the pathogenic strains has to be emphasized to facilitate pointed treatment and prevention. Polymerase chain reaction (PCR)-based molecular approaches have been developed, but their application is limited due to the requirement of complicated thermal cycling machines and trained personnel. RESULTS: A fast, simple and highly specific detection method for V. alginolyticus pathogenic strains was established based on isothermal recombinase polymerase amplification (RPA) and lateral flow dipsticks (LFD). The method targeted the virulence gene toxR, which is reported to have good coverage for V. alginolyticus pathogenic strains. To ensure the specificity of the method, the primer-probe set of the RPA system was carefully designed to recognize regions in the toxR gene that diverge in different Vibrio species but are conserved in V. alginolyticus pathogenic strains. The primer-probe set was determined after a systematic screening of amplification performance, primer-dimer formation and false positive signals. The RPA-LFD method was confirmed to have high specificity for V. alginolyticus pathogenic strains without any cross reaction with other Vibrio species or other pathogenic bacteria and was able to detect as little as 1 colony forming unit (CFU) per reaction without DNA purification, or 170 fg of genomic DNA, or 6.25 × 103 CFU/25 g in spiked shrimp without any enrichment. The method finishes detection within 30 min at temperatures between 35 °C and 45 °C, and the visual signal on the dipstick can be directly read by the naked eye. In an application simulation, randomly spiked shrimp homogenate samples were 100% accurately detected. CONCLUSIONS: The RPA-LFD method developed in this study is fast, simple, highly specific and does not require complicated equipment. This method is applicable for on-site detection of V. alginolyticus pathogenic strains for the mariculture industry.


Assuntos
Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Vibrio alginolyticus/isolamento & purificação , Animais , Penaeidae/microbiologia , Sensibilidade e Especificidade , Vibrioses/diagnóstico , Vibrioses/veterinária , Vibrio alginolyticus/genética , Virulência/genética
14.
Acta Pharm Sin B ; 9(5): 1035-1049, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31649852

RESUMO

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality via modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.

15.
J Pharm Anal ; 9(1): 25-33, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30740254

RESUMO

Methyl (S)-4-(6-amino-9H-purin-9-yl)-2-hydroxybutanoate (DZ2002) is a potent reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH). Due to its ester structure, DZ2002 is rapidly hydrolyzed in rat blood to 4-(6-amino-9H-purin-9-yl)-2-hydroxybutyric acid (DZA) during and after blood sampling from rats; this hampers accurate determination of the circulating DZ2002 and its acid metabolite DZA in rats. To this end, a method for determining the blood concentrations of DZ2002 and DZA in rats was developed by using methanol to immediately deactivate blood carboxylesterases during sampling. The newly developed bioanalytical assay possessed favorable accuracy and precision with lower limit of quantification of 31 nM for DZ2002 and DZA. This validated assay was applied to a rat pharmacokinetic study of DZ2002. After oral administration, DZ2002 was found to be extensively converted into DZA. The level of systemic exposure to DZ2002 was significantly lower than that of DZA. The apparent oral bioavailability of DZ2002 was 90%-159%. The mean terminal half-lives of DZ2002 and DZA were 0.3-0.9 and 1.3-5.1 h, respectively. The sample preparation method illustrated here may be adopted for determination of other circulating ester drugs and their acid metabolites in rodents.

16.
Acta Pharmacol Sin ; 39(12): 1935-1946, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30054600

RESUMO

Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing-TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and platelet-activating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compounds' unbound fractions in plasma were 45-92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6-15%. Bilobalide's bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4-7 h) after dosing ShuXueNing were shorter than their respective values (6-13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactones' exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparations' therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Ginkgolídeos/farmacocinética , Lactonas/farmacocinética , Fator de Ativação de Plaquetas/antagonistas & inibidores , Adulto , Animais , Fenômenos Bioquímicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Feminino , Ginkgo biloba/química , Ginkgolídeos/sangue , Ginkgolídeos/química , Ginkgolídeos/urina , Células HEK293 , Humanos , Lactonas/sangue , Lactonas/química , Lactonas/urina , Masculino , Coelhos , Adulto Jovem
17.
Br J Pharmacol ; 175(17): 3486-3503, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908072

RESUMO

BACKGROUND AND PURPOSE: Intravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated into the management of liver diseases in China. This investigation was designed to elucidate the molecular mechanism underlying hepatobiliary excretion of glycyrrhizin and to investigate its potential for drug-drug interactions on organic anion-transporting polypeptide (OATP)1B. EXPERIMENTAL APPROACH: Human transporters mediating hepatobiliary excretion of glycyrrhizin were characterized at the cellular and vesicular levels and compared with rat hepatic transporters. The role of Oatp1b2 in glycyrrhizin's elimination and pharmacokinetics was evaluated in rats using the inhibitor rifampin. A physiologically based pharmacokinetic (PBPK) model for glycyrrhizin, incorporating transporter-mediated hepatobiliary excretion, was established and applied to predict potential drug-drug interactions related to glycyrrhizin in humans. KEY RESULTS: Hepatobiliary excretion of glycyrrhizin involved human OATP1B1/1B3 (Oatp1b2 in rats)-mediated hepatic uptake from blood and human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (ABCP)/bile salt export pump (BSEP)/multidrug resistance protein 1 (Mrp2/Abcp/Bsep in rats)-mediated hepatic efflux into bile. In rats, rifampin impaired hepatic uptake of glycyrrhizin significantly increasing its systemic exposure. Glomerular-filtration-based renal excretion of glycyrrhizin was slow due to extensive protein binding in plasma. Quantitative analysis using the PBPK model demonstrated that OATP1B1/1B3 have critical roles in the pharmacokinetics of glycyrrhizin, which is highly likely to be a victim of drug-drug interactions when co-administered with potent dual inhibitors of these transporters. CONCLUSIONS AND IMPLICATIONS: Transporter-mediated hepatobiliary excretion governs glycyrrhizin's elimination and pharmacokinetics. Understanding glycyrrhizin's potential drug-drug interactions on OATP1B1/1B3 should enhance the therapeutic outcome of glycyrrhizin-containing drug combinations on liver diseases.


Assuntos
Ácido Glicirrízico/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/efeitos dos fármacos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Animais , Células Cultivadas , Interações Medicamentosas , Ácido Glicirrízico/farmacocinética , Células HEK293 , Humanos , Funções Verossimilhança , Masculino , Ratos , Ratos Sprague-Dawley
18.
Acta Pharmacol Sin ; 39(6): 1048-1063, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29620050

RESUMO

Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h-1·kg-1; dogs, 0.40±0.06 L·h-1/kg-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 µmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.


Assuntos
Indóis/administração & dosagem , Indóis/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida , Neoplasias do Colo/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Cães , Interações Medicamentosas , Feminino , Células HEK293 , Meia-Vida , Xenoenxertos , Humanos , Absorção Intestinal , Masculino , Espectrometria de Massas , Taxa de Depuração Metabólica , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Modelos Biológicos , Transplante de Neoplasias , Ligação Proteica , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição Tecidual
19.
J Sep Sci ; 40(7): 1470-1481, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28139096

RESUMO

Polyphenols derived from Danshen are responsible for the therapeutic effects of DanHong injection, a two-herb combination of Danshen and Honghua. Whether the pharmacokinetics of Danshen polyphenols is changed by coexisting Honghua constituents remains unknown. A sensitive ultra high performance liquid chromatography with tandem mass spectrometry method was developed in this study for simultaneous determination of eight Danshen polyphenols (i.e., protocatechuic aldehyde, protocatechuic acid, tanshinol, salvianolic acid D, rosmarinic acid, salvianolic acid A, lithospermic acid, and salvianolic acid B) in rat plasma and applied to a comparative pharmacokinetic study of DanHong injection and Danshen injection. Liquid chromatography conditions, mass spectrometry parameters, and sample preparation were optimized step by step. The calibration curves showed good linearity (r > 0.99) for all the polyphenols. The mean extraction efficiencies ranged from 62.2 to 88.7% with negligible matrix effects. The intrabatch and interbatch precision at all the quality control levels were less than 15% of the nominal concentrations with accuracy of 88.8-114%, except that precision and accuracy at lower limit of quantitation were 3.2-17.3 and 95.7-119%, respectively. Comparative pharmacokinetic study suggested that the coexisting Honghua constituents might have negligible influences on the pharmacokinetics of Danshen polyphenols from DanHong injection. The bioanalytical method could also be applied to pharmacokinetic studies of other Danshen herbal products.


Assuntos
Análise Química do Sangue/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Polifenóis/sangue , Salvia miltiorrhiza/química , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
20.
Drug Metab Pharmacokinet ; 31(1): 95-98, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26830081

RESUMO

XueBiJing injection, prepared from a five-herb combination, is extensively used as add-on therapy in routine sepsis care in China. Catechols, derived from the component herb Salvia miltiorrhiza roots (Danshen), are probably important because of their reported antiseptic properties. This study was designed to characterize pharmacokinetics of major circulating Danshen catechols in human subjects intravenously receiving the injection at the label doses. A total of 17 Danshen catechols were detected in XueBiJing injection (content level, 0.1-139.3 µmol/L). After dosing, tanshinol and salvianolic acid B exhibited relatively high levels of systemic exposure with mean elimination half-lives of 0.38 and 0.29 h, respectively. The total plasma clearance and apparent volume of distribution at steady state of tanshinol were 1.07 L/h/kg and 0.40 L/kg, respectively, whereas those of salvianolic acid B were 0.43 L/h/kg and 0.13 L/kg, respectively. Protocatechuic acid and five other catechols were also detected in plasma but at low exposure levels. Although protocatechuic aldehyde had the highest content level in the injection, like the remaining eight catechols, it was undetected in plasma. Protocatechuic aldehyde was extensively converted into protocatechuic acid and other metabolites. The information gained here facilitates understanding the roles of Danshen catechols in therapeutic actions of XueBiJing injection.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Catecóis/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Administração Intravenosa , Adulto , China , Feminino , Medicina Herbária/métodos , Humanos , Hidroxibenzoatos/administração & dosagem , Masculino , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Salvia miltiorrhiza/química , Adulto Jovem
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