RESUMO
The detoxification effects of licorice are believed to be related to its pharmacokinetic (PK) interference. This paper aimed to evaluate the effects of licorice water extracts (LWE) on the pharmacokinetics of brucine. Rats were administered brucine and/or LWE. The pharmacokinetic behavior of brucine and bioactive components of licorice were quantified by HPLC-MS/MS. P-glycoprotein (P-gp) inhibitor verapamil, real time PCR, vesicular transport assay and everted gut sacs were employed to investigate its possible mechanism. We found LWE reduced the Cmax and AUC of oral brucine in a dose-dependent way. In contrast, the AUC values of intraperitoneal brucine showed no significant difference between LWE treated and untreated rats, which indicating the intestinal absorption of brucine was influenced by LWE. We found that high dose of LWE activated the transport activity of P-gp in vesicular transport assay, while the mRNA level of P-gp in the intestinal was not affected by licorice. Moreover, high dose of LWE decreased the intestinal absorption of brucine in the everted gut sacs model, which could over turned by verapamil. These results suggested that a single high dose of LWE could impair the intestine absorption of brucine, and its potential mechanism may be mediated by P-gp in intestine.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Glycyrrhiza , Interações Ervas-Drogas , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Estricnina/análogos & derivados , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Glycyrrhiza/química , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Estricnina/administração & dosagem , Estricnina/farmacocinéticaRESUMO
Many studies have examined the associations between paraoxonase-1 (PON1) genetic polymorphisms (Q192R, rs662 and L55M, rs854560) and the susceptibility to type 2 diabetes mellitus (T2DM) across different ethnic populations. However, the evidence for the associations remains inconclusive. In this study, we performed a meta-analysis to clarify the association of the two PON1 variants with T2DM risk. We carried out a systematic search of PubMed, Embase, CNKI and Wanfang databases for studies published before June 2017. The pooled odds ratios (ORs) for the association and their corresponding 95% confidence intervals (CIs) were calculated by a random- or fixed-effect model. A total of 50 eligible studies, including 34 and 16 studies were identified for the PON1 Q192R (rs662) and L55M (rs854560) polymorphism, respectively. As for the PON1 Q192R polymorphism, the 192R allele was a susceptible factor of T2DM in the South or East Asian population (OR > 1, P < 0.05) but represented a protective factor of T2DM in European population (OR = 0.66, 95% CI = 0.45-0.98) under a heterozygous genetic model. With regard to the PON1 L55M polymorphism, significant protective effects of the 55M allele on T2DM under the heterozygous (OR = 0.77, 95% CI = 0.61-0.97) and dominant (OR = 0.80, 95% CI = 0.65-0.99) genetic models were found in the European population, while no significant associations in the Asian populations under all genetic models (P > 0.05). In summary, by a comprehensive meta-analysis, our results firmly indicated that distinct effects of PON1 genetic polymorphisms existed in the risk of T2DM across different ethnic backgrounds.
Assuntos
Arildialquilfosfatase/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Alelos , Povo Asiático/genética , Diabetes Mellitus Tipo 2/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Fatores de Risco , População Branca/genéticaRESUMO
BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.
Assuntos
Antifúngicos/farmacocinética , Citocromo P-450 CYP2C19/genética , Transplante de Rim/efeitos adversos , Fígado/fisiologia , Voriconazol/farmacocinética , Adolescente , Adulto , Antifúngicos/uso terapêutico , Feminino , Genótipo , Humanos , Transplante de Rim/tendências , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/genética , Estudos Retrospectivos , Transplantados , Voriconazol/uso terapêutico , Adulto JovemRESUMO
PURPOSE: To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. METHODS: A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. RESULTS: The calibration range was 9.2 - 4213.8 ng×mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC0â36h and Cmax were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 ± 15.7%. No gender difference was observed in pharmacokinetic parameters. CONCLUSIONS: A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.â©.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Valsartana/farmacocinética , Administração Oral , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Área Sob a Curva , Povo Asiático , Calibragem , China , Cromatografia Líquida de Alta Pressão/normas , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Padrões de Referência , Reprodutibilidade dos Testes , Comprimidos , Equivalência Terapêutica , Valsartana/administração & dosagem , Valsartana/efeitos adversos , Valsartana/sangue , Adulto JovemRESUMO
OBJECTIVE: To assess and compare the pharmacokinetic properties and bioavailability of a newly developed formulation of amisulpride with those of a conventional formulation in healthy Chinese volunteers under fasting state. MATERIALS AND METHODS: A single-dose, two-sequence crossover study was designed. 20 healthy subjects (14 males and 6 females) were randomized into two groups. A single oral dose of amisulpride (200 mg) was given after an overnight fast of 12 hours. Blood samples were taken at scheduled time spots and separated by a washout period of 14 days. Plasma concentration of amisulpride was measured by high-performance liquid chromatography-fluorescence detector (HPLC-FLD) method. RESULTS: The pharmacokinetic parameters of AUC0-tlast, AUC0-∞, and Cmax for the 20 subjects after a single oral dose of the trial preparation or the reference preparation were 4,767.2 and 4,856.3 ng×h×mL-1; 4,891.7 and 5,043.2 ng×h×mL-1; 584.7 and 586.3 ng×mL-1, respectively. The relative bioavailability was 98.9 ± 14.5%. No significant difference was found among the main pharmacokinetic parameters in the two preparations by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax and AUC0-tlast were 90.7 - 109.1% and 92.5 - 103.6%, respectively, meeting the predetermined criteria (80 - 125%) for bioequivalence. No serious adverse events were reported. CONCLUSION: The study demonstrated that the two preparations met the regulatory criteria for bioequivalence and both formulations were well tolerated.â©.
Assuntos
Medicamentos Genéricos/farmacocinética , Sulpirida/análogos & derivados , Comprimidos/farmacocinética , Administração Oral , Adulto , Amissulprida , Área Sob a Curva , Povo Asiático , Disponibilidade Biológica , Química Farmacêutica/métodos , Estudos Cross-Over , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Sulpirida/farmacocinética , Equivalência Terapêutica , Adulto JovemRESUMO
Isoliquiritigenin, a flavonoid found in licorice, has been considered as an antioxidive and hepato-protective agent. Recent studies have shown that a possible mechanism for triptolide-induced hepatotoxicity is related to oxidative damage induced by reactive oxygen species. This study was done to investigate the protection effect of isoliquiritigenin against triptolide-induced hepatotoxicity and the mechanism involved. An acute liver injury model was established by intraperitoneal injection of triptolide (1.0 mg · kg-1) in mice. Different doses of isoliquiritigenin (12.5, 25 and 50 mg · kg-1) were employed as protection. The activities of AST, ALT, ALP and LDH in serum and levels of GSH, GPx, SOD, CAT and MDA in liver tissue were detected. The histopathological changes of liver tissues were observed after HE staining. The protein expression of Nrf2 was detected by western blot. Pretreatment with isoliquiritigenin significantly prevented the triptolide-induced hepatotoxicity indicated by reduced activities of AST, ALT, ALP and LDH. Moreover, isoliquiritigenin pretreatment also prevented from triptolide-induced hepatotoxicity by inhibiting MDA and restoring the levels of GSH, GPx, SOD and CAT. In addition, isoliquiritigenin could attenuate histopathological changes induced by triptolide. Furthermore, the results indicated that isoliquiritigenin pretreatment caused an increase in the protein expression of Nrf2. These results indicated that isoliquiritigenin could protect against triptolide-induced hepatotoxicity via activation of the Nrf2 pathway.
Assuntos
Chalconas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Diterpenos/antagonistas & inibidores , Diterpenos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Fenantrenos/antagonistas & inibidores , Fenantrenos/toxicidade , Substâncias Protetoras/farmacologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Compostos de Epóxi/antagonistas & inibidores , Compostos de Epóxi/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Malondialdeído/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Tripterygium wilfordii has exihibited multiple pharmacological activities, such as anti-inflammatory, immune modulation, anti-tumor and anti-fertility. T. wilfordii have been used for the therapy of inflammation and autoimmune diseases including rheumatoid arthritis, immune complex nephritis and systemic lupus erythematosus clinically. However, it is well known that T. wilfordii has small margin between the therapeutic and toxic doses and could cause serious injury on digestive, reproductive and urogenital systems. Among all the organs, liver is one of the most remarkable targets of T. wilfordii-induced toxicities, and the damage is more serious than others. It is generally accepted that T. wilfordii-induced liver injury is a result of the combined effects of toxic elements of T. wilfordii. It is reported in several studies that the mechanism of T. wilfordii-induced liver injury may be related to lipid peroxidation, cell apoptosis and immune damage, and so on. Licorice is one of the most commonly used Chinese herbal medicine, with effects of heat- clearing and detoxicating, anti-inflammatory and hepatoprotective, reconciling various drugs, and so on. Licorice often accompany T. wilfordii in clinical application which can significantly reduce the liver injury induced by T. wilfordii. The attenuated effect is exact, but the mechanism is still a lack of in-depth study. This paper reviews the studies on T. wilfordii-induced liver injury and the related mechanism as well as licorice and other traditional Chinese medicine accompany T. wilfordii to reduce the injury in recent years, so as to provide reference for related research in the future.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glycyrrhiza , Tripterygium , Animais , Humanos , Inativação Metabólica , Medicina Tradicional ChinesaRESUMO
PURPOSE: To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans. METHODS: Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05. RESULTS: All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC(0-∞) for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3 ± 724.3 and 1,988.2 ± 649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC(0-∞) and C (max) fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC(0-∞), AUC(0-24), C (max), t (max), t (½)) for talinolol. CONCLUSIONS: Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Ácido Glicirrízico/administração & dosagem , Propanolaminas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Análise de Variância , Área Sob a Curva , China , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Propanolaminas/administração & dosagem , Propanolaminas/sangue , Software , Espectrofotometria Ultravioleta , Comprimidos , Adulto JovemRESUMO
Early findings propose that impaired neurotransmission in the brain plays a key role in the pathophysiology of schizophrenia. Recent advances in understanding its multiple etiologies and pathogenetic mechanisms provide more speculative hypotheses focused on even broader somatic systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we compared metabolic signatures consisting of monoamine and amino acid neurotransmitter (NT) metabolites in plasma/urine simultaneously between first-episode neuroleptic-naïve schizophrenia patients (FENNS) and healthy controls before and after a 6-week risperidone monotherapy, which suggest that the patient NT profiles are restoring during treatment. To detect and identify potential biomarkers associated with schizophrenia and risperidone treatment, we also performed a combined ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and 1H nuclear magnetic resonance (NMR)-based metabolomic profiling of the same samples, indicating a further deviation of the patients' global metabolic profile from that of controls. The NTs and their metabolites together with the 32 identified biomarkers underpin that metabolic pathways including NT metabolism, amino acid metabolism, glucose metabolism, lipid metabolism, energy metabolism, antioxidant defense system, bowel microflora and endocrine system are disturbed in FENNS. Among them, pregnanediol, citrate and α-ketoglutarate (α-KG) were significantly associated with symptomatology of schizophrenia after Bonferroni correction and may be useful biomarkers for monitoring therapeutic efficacy. These findings promise to yield valuable insights into the pathophysiology of schizophrenia and may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.
Assuntos
Antipsicóticos/uso terapêutico , Risperidona/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/urina , Adolescente , Adulto , Antipsicóticos/farmacologia , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Metaboloma/efeitos dos fármacos , Análise Multivariada , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Adulto JovemRESUMO
Abnormalities in plasma monoamine metabolism reflect partly the illness of schizophrenia and sometimes the symptoms. Such studies have been repeatedly reported but have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. In this study, the monoamines, their metabolites, turnovers and between-metabolite ratios in plasma were measured longitudinally in 32 schizophrenic patients treated with risperidone for 6 weeks, to examine possible biochemical alterations in schizophrenia, and to examine the association between treatment responses and psychopathology assessed according to the Positive and Negative Syndrome Scale (PANSS). The results showed lower level of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) in relapsed versus first-episode schizophrenic patients, higher norepinephrine (NE) turnover rate (TR) in undifferentiated in comparison to paranoid schizophrenic patients and relatively higher metabolic activity of dopamine (DA) to serotonin (5-HT) in first-episode versus relapsed schizophrenic patients. Risperidone treatment induced a decrement of plasma DA levels and increments of plasma DOPAC and DA TR in the total group of schizophrenic patients. The turnover rate of 5-HT was was reduced in undifferentiated and relapsed subgroups of schizophrenic patients. The linkages between 5-HT TR, DA/NE relative activity and clinical symptomatology were also identified. These findings are consistent with an involvement of these systems in the pathogenesis of schizophrenia as well as in the responses to treatment, and the usefulness of certain biochemical indices as markers for subgrouping.
Assuntos
Antipsicóticos/uso terapêutico , Monoaminas Biogênicas/sangue , Risperidona/uso terapêutico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Ácido 3,4-Di-Hidroxifenilacético/sangue , Adulto , Análise de Variância , Monoaminas Biogênicas/metabolismo , Dopamina/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Estudos Longitudinais , Masculino , Nordefrin/sangue , Escalas de Graduação Psiquiátrica , Serotonina/sangue , Estatística como Assunto , Estatísticas não Paramétricas , Fatores de Tempo , Adulto JovemRESUMO
Diabetic neuropathic pain (DNP) has a huge impact on quality of life and can be difficult to treat. Oral treatment is the most frequently used method for DNP, but its use is often limited by systemic side effects. Topical use of drugs as an alternative option for DNP treatment is currently gaining interest. In the present review, a summary is provided of the available agents for topical use in patients with DNP, including lidocaine plasters or patches, capsaicin cream, gel or patches, amitriptyline cream, clonidine gel, ketamine cream, extracts from medicinal plants including nutmeg extracts and Citrullus colocynthis extract oil, and certain compounded topical analgesics. Furthermore, the potential efficacy of these treatments is addressed according to the available clinical research literature. It has been indicated that these topical drugs have the potential to be valuable additional options for the management of DNP, with adequate safety and continuous long-term treatment efficacy. Compounded topical agents are also effective and safe for patients with DNP and could be another area worthy of further investigation based on the strategy of using low-dose, complementary therapies for DNP. The findings indicate that developing topical drugs acting on different targets in the process of DNP is a valuable area of future research.
RESUMO
Licorice, one of the most widely used medicinal herbs in East Asia, has effects such as anti-inflammation, antioxidant, and detoxifying. This study aimed to evaluate the protective effect of licorice on brucine-induced nephrotoxicity. Sprague Dawley rats were administered with brucine intraperitoneally for 7 consecutive days with or without treatment with licorice. The content of blood urea nitrogen and creatinine in serum, the activities of superoxide dismutase and content of glutathione, malonaldehyde in kidney tissue were detected. Hematoxylin-eosin staining was employed to observe the histopathological changes of kidney. The expression and phosphorylation levels of protein were evaluated by Western blotting and immunohistochemical analysis. The results illustrated that treatment with licorice extracts (LE) significantly protected against the brucine-induced nephrotoxicity by reducing the content of blood urea nitrogen and serum creatinine, attenuating pathologic damage. The unbalance of oxidative stress was repaired by LE via increasing the level of glutathione, promoting the activities of superoxide dismutase and decreasing the content of malonaldehyde. In addition, LE overturned the influence of brucine on apoptosis-related protein and signal transducer and activator of transcription-3 (STAT3) activation. Taken together, these data demonstrate that licorice may attenuate brucine-induced nephrotoxicity via inactivation of oxidative stress and mitochondrial-mediated apoptosis pathway. More importantly, the renoprotective effects may be mediated, at least partly, by preventing the activation of STAT3 protein.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Glycyrrhiza/química , Mitocôndrias/metabolismo , Extratos Vegetais/administração & dosagem , Fator de Transcrição STAT3/metabolismo , Estricnina/análogos & derivados , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Injeções Intraperitoneais , Masculino , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Estricnina/efeitos adversos , Superóxido Dismutase/metabolismoRESUMO
Semen Strychni is known for its treatment of rheumatic arthritis with a low therapeutic index. Liquorice contributes a lot in herb detoxification according to the traditional Chinese medicine theory. A simple, rapid, and sensitive liquid chromatography-mass spectrometric method (LC-MS) was developed and validated for simultaneous determination of main bioactive ingredients in liquorice and Semen Strychni in rat plasma. Using moclobemide and cyproterone acetate as the internal standards, the analytes were pretreated via protein precipitation with methanol. An Ultimate AQ-C18 column (3.0 µm, 3.0 × 100 mm) was employed for chromatographic separation, combining with gradient elution. The mobile phase consisted of 0.07% formic acid and 0.12% ammonium acetate in aqueous phase (A) and acetonitrile in organic phase (B). The elution program was as follows: 0-0.5 min, 20% B; 0.5-1 min, 20-60% B; 1-7 min, 60-85% B; and 7-7.5 min, returned to 20% B, then continued to 12 min. Selected reaction monitoring was performed in both positive and negative ESI. Positive mode was adopted for detection of strychnine, brucine, and moclobemide, while negative mode was used for glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, liquiritin, and cyproterone acetate. The method was validated for specificity, linearity, matrix effect, recovery, precision, accuracy, and stability. The results show that this method is sensitive, accurate and robust for biological matrix analysis. Moreover, the proposed method was applied to a pharmacokinetic study in Sprague-Dawley rats for investigating the mechanism of which liquorice detoxifies Semen Strychni.
Assuntos
Cromatografia Líquida/métodos , Flavanonas/química , Glucosídeos/química , Glycyrrhiza/química , Ácido Glicirrízico/química , Plasma/química , Sêmen/química , Estricnina/análogos & derivados , Animais , Flavanonas/metabolismo , Glucosídeos/metabolismo , Glycyrrhiza/metabolismo , Ratos , Reprodutibilidade dos Testes , Estricnina/química , Estricnina/farmacocinéticaRESUMO
Danshen, an efficacious agent for cardiovascular diseases, has been found to play an essential role in kidney injury. In the present study, the effect of Danshen on cisplatin-induced renal dysfunction was investigated in a mouse model. Danshen was administered to mice at a dose of 3 g/kg 4 days before and 3 days after cisplatin treatment. A single intraperitoneal injection of 20 mg/kg cisplatin was used to induce nephrotoxicity. The mice were sacrificed 72 h after cisplatin intoxication. Biochemical parameters including serum creatinine and blood urea nitrogen were analyzed. Histopathological changes of kidney tissues were detected using HE staining. Antioxidant enzymes (GSH-Px and SOD) and peroxidative product (MDA) were detected. Protein expressions of Nrf2 and its target genes including HO-1 and NQO1 were measured by Western blotting. The results showed that pretreatment with Danshen significantly reduced serum creatinine and blood urea nitrogen in the cisplatin-treated mice. Histopathological examination showed that Danshen mitigated the renal damage induced by cisplatin. Moreover, Danshen restored the activities of antioxidant enzymes (GSH-Px and SOD) and normalized the MDA contents in renal tissues. Western blotting revealed that Danshen enhanced the expressions of Nrf2 and its target genes in cisplatin-exposed mice. It was suggested that Danshen protects against the cisplatin-induced renal impairment in the mice, which is potentially associated with the upregulation of Nrf2-mediated signaling pathway.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Injúria Renal Aguda/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica , Masculino , Camundongos , Salvia miltiorrhiza , Transdução de Sinais/efeitos dos fármacosRESUMO
A robust and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of pericyazine in human plasma. The plasma sample was alkalized with sodium hydroxide solution and handled by liquid-liquid extraction with ethyl acetate after adding perphenazine as an internal standard (IS). The analytes were separated on an Ultimate™ AQ-C18 analytical column at 40°C, with a gradient elution consisting of A (aqueous phase: 5mM ammonium acetate buffer solution containing 0.1% formic acid) and B (organic phase: acetonitrile) at a flow rate of 0.350mL/min. The detection was conducted on an API 4000 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) transitions, m/z 366.5>142.4 for pericyazine, m/z 382.5>142.4 for its 7-hydroxy and sulphoxide metabolites and m/z 404.3>171.3 for IS were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity (LLOQ of 0.021ng/mL) and good linearity over the concentration range of 0.021-9.90ng/mL. The intra- and inter-day precision, accuracy, and stability results were within the acceptable limits and no matrix effect was observed. This method was successfully applied in a bioequivalence study to evaluate the pharmacokinetics in 20 healthy male Chinese volunteers. Additional exploratory analyses of 7-hydroxy and sulphoxide metabolites of pericyazine in the same samples suggest that the unchanged drug is predominant in the plasma and suitable for the bioequivalence comparison after a single oral administration of 10mg pericyazine.
Assuntos
Povo Asiático , Fenotiazinas/sangue , Sulfóxidos/sangue , Espectrometria de Massas em Tandem/normas , Adulto , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Estudos Cross-Over , Voluntários Saudáveis , Humanos , Masculino , Fenotiazinas/análise , Sulfóxidos/análise , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica , Adulto JovemRESUMO
Background and Objective: Apolipoprotein E (APOE) plays important roles in lipoprotein metabolism and cardiovascular disease. Evidence suggests the APOE gene epsilon2/epsilon3/epsilon4 (ε2/ε3/ε4) polymorphisms might be associated with the susceptibility of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, no clear consensus has yet been established. Therefore, the aim of this meta-analysis is to provide a precise conclusion on the potential association between APOE ε2/ε3/ε4 polymorphisms and the risk of CAD in patients with T2DM based on case-control studies. Methods: Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for all relevant studies prior to August 2017 in English and Chinese language. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the relationships. The between-study heterogeneity was evaluated by Cochran's Q-test and the I2 index to adopt fixed- or random- effect models. Results: A total of 13 studies were eligible for inclusion. There was evidence for significant associations between APOE ε4 mutation and the risk of CAD in patients with T2DM (for ε3/ε4 vs. ε3/ε3: OR = 1.69, 95% CI = 1.38-2.08, P < 0.001; for ε4/ε4 vs. ε3/ε3: OR = 2.72, 95% CI = 1.61-4.60, P < 0.001; for ε4/ε4+ε3/ε4 vs. ε3/ε3: OR = 1.83, 95% CI = 1.52-2.22, P < 0.001; for ε4 allele vs. ε3 allele: OR = 1.64, 95% CI = 1.40-1.94, P < 0.001). In contrast, no significant associations were found in genetic model of APOE ε2 mutation (for ε2/ε2 vs. ε3/ε3: OR = 1.67, 95% CI = 0.90-3.09, P = 0.104; for ε2/ε3 vs. ε3/ε3: OR = 1.18, 95% CI = 0.93-1.51, P = 0.175; for ε2/ε2+ε2/ε3 vs. ε3/ε3: OR = 1.26, 95% CI = 0.88-1.82, P = 0.212; for ε2 allele vs. ε3 allele: OR = 1.34, 95% CI = 0.98-1.84, P = 0.07). Conclusions: The APOE gene ε4 mutation is associated with an increased risk of CAD in patients with T2DM, while the ε2 variation has null association with this disease.
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To investigate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in licorice ethanol extract (LEE) against triptolide- (TP-) induced hepatotoxicity, HepG2 cells were exposed to LEE (30, 60, and 90 mg·L-1) for 12 h and then treated with TP (50 nM) for 24 h. Besides, an acute liver injury model was established in ICR mice by a single dose of TP (1.0 mg·kg-1, i.p.). Relevant oxidant and antioxidant mediators were analyzed. TP led to an obvious oxidative stress as evidenced by increasing levels of ROS and decreasing GSH contents in HepG2 cells. In vitro results were likely to hold true in in vivo experiments. LEE protected against TP-induced oxidative stress in both in vitro and in vivo conditions. Furthermore, the decreased level of Nrf2 in the TP-treated group was observed. The mRNA levels of downstream genes decreased as well in ICR mice liver, whereas they increased in HepG2 cells. In contrast, LEE pretreatment significantly increased the level of Nrf2 and its downstream genes. LEE protects against TP-induced oxidative stress partly via the activation of Nrf2 pathway.
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Triptolide (TP), an active ingredient of Tripterygium wilfordii Hook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 µM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.
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ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhizae radix), the root of Glycyrrhiza uralensis Fisch. (Leguminosae), is mainly used to moderate the characteristics of toxic herbs in Traditional Chinese Medicine, which could be partly interpreted as detoxification. However, the underlying mechanism is still not fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the protection against toxic xenobiotics. In our previous research, we have identified that extracts from Glycyrrhiza uralensis induced the expression of Nrf2 nuclear protein and its downstream genes. This research aims to screen the most potent Nrf2 inducer isolated from Glycyrrhiza uralensis and examine its effect on Nrf2 signaling pathway and detoxification system. MATERIALS AND METHODS: Four compounds derived from Glycyrrhiza uralensis (glycyrrhetinic acid, liquiritigenin, isoliquiritigenin and liquiritin) were screened by ARE-luciferase reporter. The most potent ARE-luciferase inducer was chosen to further examine its effect on Nrf2 and detoxification genes in HepG2 cells. The role of Nrf2-dependent mechanism was tested by using Nrf2 knockout mice (Nrf2 KO) and Nrf2 wild-type mice (Nrf2 WT). RESULTS: ARE-luciferase reporter assay showed these four compounds were all potent Nrf2 inducers, and isoliquiritigenin was the most potent inducer. Isoliquiritigenin significantly up-regulated the expression of Nrf2 and its downstream detoxification genes UDP-glucuronosyltransferase 1A1 (UGT1A1), glutamate cysteine ligase (GCL), multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) in vitro and in vivo. Additionally, isoliquiritigenin showed Nrf2-dependent transactivation of UGT1A1, GCLC and MRP2. CONCLUSIONS: Isoliquiritigenin, isolated from Glycyrrhiza uralensis, stimulates detoxification system via Nrf2 activation, which could be a potential protective mechanism of licorice.
Assuntos
Chalconas/farmacologia , Glycyrrhiza uralensis , Fator 2 Relacionado a NF-E2/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Elementos de Resposta Antioxidante , Feminino , Flavanonas/farmacologia , Glucosídeos/farmacologia , Glucuronosiltransferase/genética , Glutamato-Cisteína Ligase/genética , Ácido Glicirretínico/farmacologia , Células Hep G2 , Humanos , Luciferases de Renilla/genética , Luciferases de Renilla/metabolismo , Camundongos Endogâmicos ICR , Camundongos Knockout , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , RNA Mensageiro/metabolismoRESUMO
Brucine is a central agonist that can pass through the blood-brain barrier (BBB). The goal of this study is to examine whether brucine is one of the substrates of the drug transporter P-glycoprotein (P-gp) and to examine the effects of P-gp on the brucine transport at the in vitro BBB model. The P-gp ATPase assay was utilized to investigate the in vitro affinity of P-gp to brucine. Results suggested that K(m) of brucine (11.4 µmol/l) was smaller than the positive control, verapamil (16.4 µmol/l). In this study, we developed an in vitro BBB model, comprising a co-culture of primary rat brain microvessel endothelial cells and astrocytes for the transport study. The validated model was correct and available. Transendothelial electrical resistance reached (283.78 ± 18.85) Ω cm(2). The model displayed limited permeability to fluorescein sodium and [(125)I]albumin, with the apparent permeability coefficient Papp of (10.36 ± 0.86) × 10(-6) cm/s and (6.00 ± 0.78) × 10(-6)cm/s, respectively. The quantity of the bidirectional transport of brucine was determined by ultra-performance liquid chromatography-tandem mass spectrometry. In the absence of verapamil, the transport of brucine from basolateral compartment to apical compartment (BL-AP) was higher than from AP to BL at low, middle, and high concentrations (P<0.05). The excretion rate was 1.32, 1.56, and 1.54, respectively. However, following exposure to verapamil, the excretion rate at three different concentrations was decreased (P<0.05). All the results suggest that P-gp prevented brucine from passing through the in vitro BBB model.