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BACKGROUND & AIMS: As the first approved medication for metabolic dysfunction-associated steatohepatitis (MASH), thyroid hormone receptor-beta (THR-ß) agonist MGL-3196 (Resmetirom) is highly spotlighted as the liver-directed, bioactive oral drug. However, it was also identified with remarkable heterogeneity of individual clinical efficacy and its interference with gut microbiota in host hepatoenteral circulation was still undocumented. METHODS: We compared MASH attenuation by MGL-3196 and its derivative drug HSK31679 between germ-free (GF) and specific-pathogen free (SPF) mice to evaluate the role of gut microbiota. Then cross-omics analyses of microbial metagenome, metabolome and single-cell RNA-sequencing were applied into the randomized, double-blind, placebo-controlled multiple-ascending-dose (MAD) cohort of HSK31679 treatment (n = 40), to comprehensively investigate the altered gut microbiota metabolism and circulating immune signatures. RESULTS: HSK31679 outperformed MGL-3196 in ameliorating MASH diet-induced steatohepatitis of SPF mice but not GF mice. In the MAD cohort of HSK31679, relative abundance of B. thetaiotaomicron was significantly enriched to impair glucosylceramide synthase (GCS)-catalyzed monoglucosylation of microbial Cer(d18:1/16:0) and Cer(d18:1/24:1). In stark contrast to the non-inferiority MASH resolution between MGL-3196 and HSK31679 for GFBTΔGCS mice, HSK31679 manifested superior steatohepatitis alleviation than MGL-3196 for GFBTWT mice, due to its steric hindrance with R123 and Y401 of gut microbial GCS. For participants with high fecal GCS activity, the administration of 160 mg HSK31679 induced a shift in peripheral compartments towards an immunosuppressive niche, characterized by decreased CD8α+ dendritic cells and MINCLE+ macrophages. CONCLUSIONS: This study provided novel insights into the indispensable gut microbiota for HSK31679 treatment, which revealed microbial GCS may serve as its prognostic biomarker of MASH treatment, as well as the new target for further strategies of microbiota-based MASH therapeutics. IMPACT AND IMPLICATIONS: Remarkable heterogeneity of individual clinical efficacy of THR-ß agonists and their interferences with microbiome in host hepatoenteral circulation are poorly understood. In our current germ-free mice models and randomized, double-blind multiple-dose cohort study, we identified microbial GCS as the prognostic biomarker of HSK31679 treatment, as well as the new target for further strategies of microbiota-based MASLD therapeutics.
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BACKGROUND: The real-world studies on recurrent venous thromboembolism (VTE) and bleeding events of non-vitamin K antagonist oral anticoagulants (NOACs) in VTE patients have reported conflicting findings. Our study aimed to provide the direct comparison evidence of different NOACs for VTE patients in clinical practice settings. METHODS: Search of the medical literature was conducted using PubMed, Web of Science, EMBASE, Clinical Trials.gov, and the Cochrane Library from inception to March 22, 2021. Among the 19,996 citations retrieved, a total of 63,144 patients from 6 studies were analyzed. Clinical outcomes included recurrent VTE, death, and different bleeding events. RESULTS: Adjusted hazard ratio (HR) analysis suggested that apixaban had significant lower bleeding riskthan rivaroxaban (major, minor and any bleeding: HR = 0.61, 0.56, 0.70; p = 0.008, < 0.0001, 0.006, respectively), but no statistics difference found in recurrent VTE events (HR = 1.02, 95% confidence interval (CI) 0.71-1.47, p = 0.93). There was no significant difference of major bleeding between dabigatran and rivaroxaban (odds ratios (OR) = 0.41, 95% CI 0.09-1.90, p = 0.25), apixaban and dabigatran (OR 0.64, 95% CI 0.15-2.72, p = 0.83). No significant difference was found in the comparison of edoxaban and other NOACs in VTE recurrence, major bleeding and composite outcome. CONCLUSIONS: In the prevention of bleeding events, apixaban was associated with a lower risk than rivaroxaban, but equivalent efficacy for different NOACs in prevention of recurrent VTE. Evidence generated from the meta-analysis based on real-world data can help to guide selection between apixaban and rivaroxaban in routine clinical practice. TRIAL REGISTRATION: This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology statements and was registered with PROSPERO (CRD42019140553).
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Tromboembolia Venosa , Administração Oral , Anticoagulantes/efeitos adversos , Dabigatrana/uso terapêutico , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologiaRESUMO
The thrombopoietin mimetic peptide for injection is a second-generation thrombopoietin receptor agonist (TPO-RA) used in the treatment of patients with immune thrombocytopenia. The aim of the present study was to assess the safety, tolerance, pharmacokinetic and pharmacodynamic properties of thrombopoietin mimetic peptide for injection in Chinese healthy volunteers. A randomized, placebo-controlled, double-blind, dose-escalation study was conducted in healthy Chinese subjects aged 18-50 years. Thirty subjects received single subcutaneous injection of 0.3 µg/kg, 1.0 µg/kg, 2.0 µg/kg thrombopoietin mimetic peptide or placebo. Thrombopoietin mimetic peptide was safe and well tolerated at doses of 0.3-2.0 µg/kg. There was no significant change in mean platelet count (PLT) from baseline at the 0.3 µg/kg or placebo groups. The mean PLT of subjects in the 1.0 µg/kg and 2.0 µg/kg groups peaked at day 12 (± 1), began to decline around day 17, and returned to the baseline level at day 28 (± 1). Platelet aggregation rates of the three dose groups showed no significant change before and after administration. Serum concentrations of thrombopoietin mimetic peptide in all subjects were below the quantization limit. This was the first study to demonstrate that subcutaneous injection of thrombopoietin mimetic peptide at doses of 0.3-2.0 µg/kg was safe and well tolerated in Chinese healthy subjects. As a second-generation TPO-RA, thrombopoietin mimetic peptide is effective at improving PLT after single subcutaneous injection at dose of ≥1 µg/kg.Pâlain lâanguage sâummaryWhat is the context?â Immune thrombocytopenia (ITP) is a rare, serious autoimmune disorder characterized by low platelet count (PLT) without an alternate cause. The treatment goal of ITP is to increase the platelet count to a safe level that can stop active bleeding and reduce the risks of future bleeding.â Thrombopoietin receptor agonists (TPO-RAs, e.g. eltrombopag, avatrombopag, hetrombopag, and romiplostim) have shown high response rates in stimulating platelet production and reducing the risk of bleeding. TPO-RAs provide ITP patients with well-tolerated, long-term treatment choices.What is new?â The thrombopoietin mimetic peptide for injection is a new TPO-RAs developed by Shandong Quangang Pharmaceutical Co., Ltd. (China).â This study showed that thrombopoietin mimetic peptide is effective at improving PLT after a single subcutaneous injection.â The thrombopoietin mimetic peptide is safe and well-tolerated in Chinese healthy subjects.What is the impact?â This study provides evidence for the further development potential of the thrombopoietin mimetic peptide.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Método Duplo-Cego , Humanos , Peptídeos , Preparações Farmacêuticas , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/efeitos adversos , Trombocitopenia/etiologia , Trombopoetina/efeitos adversosRESUMO
PURPOSE: A meta-analysis was performed to evaluate the correlation between single-nucleotide polymorphisms (SNPs) and risk of statin-induced myopathy (SIM). METHODS: We retrieved the studies published on SIM until April 2019 from the PubMed, Embase, and Cochrane Library databases. We collected data from 32 studies that analyzed 10 SNPs in five genes and included 21,692 individuals and nine statins. RESULTS: The analysis of the heterozygous (p = 0.017), homozygous (p = 0.002), dominant (p = 0.005), and recessive models (p = 0.009) of SLCO1B1 rs4149056 showed that this SNP increases the risk of SIM. Conversely, heterozygous (p = 0.048) and dominant models (p = 0.030) of SLCO1B1 rs4363657 demonstrated that this SNP is associated with a reduced risk of SIM. Moreover, an increased risk of SIM was predicted for carriers of the rs4149056 C allele among simvastatin-treated patients, whereas carriers of the GATM rs9806699 A allele among rosuvastatin-treated patients had a lower risk of SIM. CONCLUSION: The meta-analysis revealed that the rs4149056 and rs4363657 SNPs in SLCO1B1 and the rs9806699 SNP in GATM are correlated with the risk of SIM.
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Amidinotransferases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Humanos , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
BACKGROUND: Vancomycin remains a mainstay of the treatment of Gram-positive bacterial infections. It is crucial to accurately determine vancomycin serum concentration for adequate dose adjustment. OBJECTIVES: To evaluate the precision and accuracy of commercial assay techniques for vancomycin concentration and to assess the comparability of vancomycin detection methods in Chinese laboratories. METHODS: Human serum samples spiked with known concentrations of vancomycin were provided to laboratories participating in the external quality assessment scheme (EQAS). Assay methods included chemiluminescence, enzyme immunoassay (EIA) and so on. The dispersion of the measurements was analysed and the robust coefficient of variation (rCV), relative percentage difference (RPD) and satisfactory rate for method groups were calculated. Moreover, performance of the Chinese laboratories was assessed. RESULTS: A total of 657 results from 75 laboratories were collected, including 84 samples from 10 Chinese laboratories. The median rCV, median RPD and satisfactory rates classified by methods ranged from 1.85% to 15.87%, -14.75% to 13.34% and 94.59% to 100.00%, respectively. Significant differences were seen in precision, between kinetic interaction of microparticles in solution (KIMS) and other methods, and in accuracy, between enzyme-multiplied immunoassay technique (EMIT), fluorescence polarization immunoassay (FPIA) and other techniques. Vancomycin detection in China mainly depended on the chemiluminescence and EMIT methods, which tended to result in lower measurements. CONCLUSIONS: Although almost all assays in this study achieved an acceptable performance for vancomycin serum concentration monitoring, obvious inconsistencies between methods were still observed. Chinese laboratories were more likely to underestimate vancomycin concentrations. Thus, recognizing inconsistencies between methods and regular participation in vancomycin EQAS are essential.
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Monitoramento de Medicamentos , Vancomicina , Antibacterianos , China , Técnica de Imunoensaio Enzimático de Multiplicação , Imunoensaio de Fluorescência por Polarização , HumanosRESUMO
AIMS: The aim of the present meta-analysis was to evaluate the efficacy and safety of fingolimod in patients with relapsing multiple sclerosis (RMS). METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for relevant studies. Two authors independently selected the studies, assessed the risk of bias, and extracted the data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. RESULTS: Ten studies met the inclusion criteria. In patients with RMS, fingolimod demonstrated a significantly lower annualized relapse rate (0.5 mg/d: mean difference [95% confidence interval] = -0.22 [-0.29 to -0.14]; 1.25 mg/d: -0.26 [-0.36 to -0.16]; 5 mg/d: -0.41 [-0.72 to -0.10]) than placebo. Fingolimod also exhibited a favorable performance on other magnetic resonance imaging outcomes and improved the quality of life in patients. No significant difference was noted in the prevalence of adverse events between the fingolimod treatment group and the placebo/disease-modifying therapy groups. CONCLUSIONS: Fingolimod may offer benefits for RMS patients and presents an acceptable safety profile.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Cloridrato de Fingolimode/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Qualidade de Vida , RecidivaRESUMO
PURPOSE: The aim of the present study was to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of remimazolam besylate following single ascending dose (SAD) and continuous infusion in healthy Chinese volunteers. METHODS: This was a randomized phase I study conducted in two parts. Part I was a double-blind, placebo- and midazolam-controlled, SAD study among healthy Chinese participants with a remimazolam dose of 0.025-0.4 mg/kg. Part II was an open-label, midazolam-controlled, continuous infusion study. Bispectral index (BIS) monitoring and Modified Observers Assessment of Alertness and Sedation (MOAA/S) score assessment were used to assess the PD properties. RESULTS: The half-life range of remimazolam was from 34.1 ± 8.1 to 59.8 ± 20.5 min in the SAD study. The sedation function was initially observed at the dose of 0.05 mg/kg remimazolam. Doses of ≥ 0.075 mg/kg exerted a peak sedation effect within 1-2 min after injection, resulting in a deeper and more rapid sedation. In the 2 h continuous infusion, remimazolam showed a deeper sedation and more rapid recovery than midazolam. For general anesthesia, an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h can achieve a satisfactory efficacy effect. CONCLUSIONS: Remimazolam was safe and well tolerated in healthy Chinese participants. Based on the phase I clinical study, we suggest that remimazolam besylate demonstrates greater sedation and quicker recovery from sedation than midazolam.
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Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Relação Dose-Resposta a Droga , Adulto , Povo Asiático , Benzodiazepinas/uso terapêutico , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/uso terapêutico , Infusões Intravenosas/métodos , Masculino , Midazolam/efeitos adversos , Midazolam/farmacocinética , Midazolam/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: To establish a population pharmacokinetic (PopPK) model of cyclosporine A (CsA) in Chinese patients with nephrotic syndrome (NS) and to use the model to guide the adjustment of individualized dosage regimens. MATERIALS AND METHODS: 216 CsA therapeutic drug monitoring (TDM) concentration observations were collected from 127 Chinese patients with NS. The basic model was developed as a one-compartment PK model with first-order absorption and linear elimination. The first-order conditional estimation (FOCE) method was applied to establish the final model with covariates using NONMEM software. The final model was evaluated through internal validation including goodness-of-fit analysis and bootstrap method as well as external validation using 39 additional PK observations from 35 patients with NS. RESULTS: A PopPK model of CsA was established in Chinese NS patients with influence of body weight on clearance. The internal and external validation results showed that the final model was stable. CONCLUSION: The established population model adequately characterized the PK of CsA in Chinese patients and could support individualized medication during treatment of NS with CsA.
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Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Síndrome Nefrótica/tratamento farmacológico , Povo Asiático , China , Humanos , Modelos Biológicos , SoftwareRESUMO
OBJECTIVE: In patients with asthma and chronic obstructive pulmonary disease (COPD), disease control is still suboptimal-incorrect inhalation technique and medication non-adherence are two important reasons for this outcome. Pharmacists' interventions have been shown to have a positive effect on the clinical outcomes of asthma and COPD. Quantitative assessment of the efficacy of pharmacist-led interventions, mainly on inhalation techniques and medication adherence, is needed. Evidence for different interventions is not totally conclusive, and no results of theory-based adherence promotion interventions for asthma and COPD have been published. The objective of our study is to evaluate the effect of pharmacist-led interventions on asthma and COPD management, focusing mainly on inhalation technique and medication adherence, and whether the content of interventions (categorized based on Information-Motivation-Behavioural skills (IMB) model) affects the effectiveness and whether the IMB model is worthy of clinical promotion and application in adults with asthma or COPD. METHODS: The PubMed, EMBASE, The Cochrane Library, Web of Science and ClinicalTrials.gov databases were searched for randomized controlled trials that involved pharmacist-led interventions among patients with asthma or COPD. We used database-specific vocabulary (eg, Medical Subject Headings) and free text terms expanding from 'asthma', 'COPD' and 'pharmacist' to identify relevant articles. Two reviewers independently selected the studies, assessed the risk of bias and extracted the data. The meta-analysis was performed in Review Manager 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019144793. RESULTS AND DISCUSSION: Thirteen studies were eligible for qualitative analysis, and 12 studies were included in the meta-analysis. Pharmacist-led interventions showed a positive effect on medication adherence (1.34 [95% CI 1.18-1.53], P < .0001) and inhalation technique (1.85 [95% CI 1.57-2.17], P < .00001) in COPD and asthma patients. In the subgroup meta-analysis, significant medication adherence improvement was found only in COPD patients (1.41 [1.24-1.61], P < .0001). The subgroup meta-analysis also noted that interventions that included all three Information-Motivation-Behavioural skills (IMB) constructs had a significant improvement in medication adherence (1.41 [1.24-1.61], P < .0001). Subgroup meta-analysis conducted between different diseases, different intervention contents, and different measure tools did not significantly change the heterogeneity. WHAT IS NEW AND CONCLUSION: Pharmacist-led interventions can improve inhalation technique in adult asthma and COPD patients. Significant improvement in medication adherence was found only in COPD patients. The effect among asthmatic patients requires further study. Interventions based on the IMB model may be worthy of clinical promotion and application. More future research is needed to establish solid evidence base for effective interventions and uniform measurement of medication adherence.
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Asma/tratamento farmacológico , Farmacêuticos/organização & administração , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adulto , Humanos , Adesão à Medicação/estatística & dados numéricos , Assistência Farmacêutica/organização & administração , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.
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Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/metabolismo , COVID-19/virologia , Humanos , Pneumonia/virologiaRESUMO
BACKGROUND: Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. METHODS: We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. RESULTS: The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy. CONCLUSIONS: The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.
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Fármacos Anti-HIV/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Razão de ChancesRESUMO
WHAT IS KNOWN AND OBJECTIVES: Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10-hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. METHODS: Ninety-one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modelling approach. The goodness-of-fit (GOF) plots, bootstrap method, prediction-corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady-state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. RESULTS: A one-compartment model with first-order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h-1 , respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20-30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. WHAT IS NEW AND CONCLUSION: A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.
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Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Modelos Biológicos , Oxcarbazepina/administração & dosagem , Adolescente , Anticonvulsivantes/farmacocinética , Povo Asiático , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Método de Monte Carlo , Dinâmica não Linear , Oxcarbazepina/farmacocinética , Guias de Prática Clínica como Assunto , Medicina de Precisão , Estudos RetrospectivosRESUMO
Numerous studies have illustrated the relationship between SLCO1B1 T521C polymorphism and statin-induced myopathy risk; however, this association is not consistent. Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from inception to October 2017 to identify potential studies. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from different genetic models by using a random-effects model. Fourteen studies comprising 3265 myopathy patients and 7743 controls were included. The summary ORs suggested that 521CC (OR: 2.31; 95% CI: 1.15-4.63; P = 0.019), 521TC (OR: 1.34; 95% CI: 1.02-1.76; P = 0.034), and 521CC + TC (OR: 1.82; 95% CI: 1.32-2.51; P < 0.001) were associated with a greater risk of statin-induced myopathy than 521TT. The higher incidence of statin-induced myopathy was found to be significantly correlated with the C allele compared with the T allele (OR: 1.89; 95% CI: 1.36-2.62; P < 0.001). In addition, we observed that 521CC + TC was associated with an increased risk of myopathy in individuals who received simvastatin (OR: 2.35; 95% CI: 1.08-5.12; P = 0.032) or rosuvastatin (OR: 1.69; 95% CI: 1.07-2.67; P = 0.024) when compared with 521TT. The 521C allele was associated with a greater risk of cerivastatin-induced myopathy than the T allele (OR: 1.95; 95% CI: 1.47-2.57; P < 0.001). The findings of this study indicated that SLCO1B1 T521C was associated with a significantly higher risk of statin-induced myopathy, especially for simvastatin, rosuvastatin, and cerivastatin. Future studies should be conducted in subjects receiving specific types of drugs, and any potential adverse events need to be explored.
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Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Doenças Musculares/induzido quimicamente , Doenças Musculares/genética , Variantes Farmacogenômicos , Polimorfismo Genético , Idoso , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Farmacogenética , Piridinas/efeitos adversos , Medição de Risco , Fatores de Risco , Rosuvastatina Cálcica/efeitos adversos , Sinvastatina/efeitos adversosRESUMO
A total of twenty-two compounds were isolated from the 95% EtOH extract of Eclipta prostrata by various purification steps, and their structures were established as ecliptalignin A (1)ï¼ecliptasaponin â (2), ecliptasaponin â ¡ (3), echinocystic acid (4), 3-oxo-16α-hydroxy-olean-12-en-28-oic acid (5), acacetin-7-O-rutinoside (6), luteoloside (7), apigenin (8), luteolin (9), acacetin (10), skullcapflavone â ¡ (11), kaempferol (12), kaempferide (13), quercetin (14), 4',7-dihydroxyl-3',6'-dimethoxylisoflavone-7-O-glucoside (15), ecliptal (16), 5-hydroxymethyl-(2,2',5',2â³)-terthienyl tiglate (17), psoralen (18), isopsoralen (19), wedelolactone (20), crinumaquine (21), and 2,3,9,12-tetramethoxyprotoberberine (22) mainly based on the spectroscopic techniques, of which 1 was a new lignin analogue, and 5, 6, 10-13, 15, 18, 19, 21 and 22 were isolated form this plant for the first time.
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Eclipta/química , Compostos Fitoquímicos/análise , Flavonas/análise , Flavonas/isolamento & purificação , Lignina/análise , Lignina/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Saponinas/análise , Saponinas/isolamento & purificaçãoRESUMO
Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder characterized by a mismatch between acetabulum and femoral head. Mechanical force plays an important role during the occurrence and development of abnormities in acetabulum and femoral head. In this study, we established a mechanical force model named cyclic compressive stress (Ccs). To analyze the effect of Ccs on DDH, we detected special genes in chondrocytes and osteoblasts. Results showed that Ccs downregulated chondrogenesis of ADTC5 in a concentration-dependent manner. Moreover, the mRNA level of Scinderin (Scin) considerably increased. We established lentivirus-SCIN(GV144-SCIN) to transfect hBMSCs, which were treated with different Ccs levels (0.25 Hz*5 cm, 0.5 Hz*5 cm, and 1 Hz*10 cm); the result showed that overexpression of Scin upregulated osteogenesis and osteoclastogenesis. By contrast, expression of chondrocyte-specific genes, including ACAN, COL-2A, and Sox9, decreased. Further molecular investigation demonstrated that Scin promoted osteogenesis and osteoclastogenesis through activation of the p-Smad1/5/8, NF-κB, and MAPK P38 signaling pathways, as well as stimulated the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Moreover, Scin-induced osteogenesis outweighed osteoclastogenesis in defective femur in vivo. The results of the analysis of Micro-CT confirmed these findings. Overall, Ccs influenced the development of DDH by promoting osteogenesis and cartilage degradation. In addition, Scin played a vital role in the development of DDH.
Assuntos
Gelsolina/genética , Regulação da Expressão Gênica , Luxação Congênita de Quadril/genética , Estresse Mecânico , Animais , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Condrócitos/metabolismo , Condrogênese/genética , Progressão da Doença , Gelsolina/metabolismo , Luxação Congênita de Quadril/metabolismo , Luxação Congênita de Quadril/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Camundongos Nus , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteogênese/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante HeterólogoRESUMO
OBJECTIVE: To determine the pharmacokinetics (PK) of vancomycin in Chinese infant patients using a population pharmacokinetic (PKK) approach in order to provide support for individualized vancomycin therapy. METHOD: The data included 72 sets of steady-state peak and trough serum concentrations from 61 infants (0 - 1 years). PPK analysis was performed using the nonlinear mixed-effects modeling software. Inter- and intraindividual variability was estimated for the clearance and distribution volume of vancomycin. The potential effects of patient sex, postnatal age, postconceptional age, height, weight, body surface area, body mass index, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, white blood cell count, serum creatinine, and concomitant medications on vancomycin PKs were explored. RESULTS: A one-compartment linear model with first-order elimination was used to describe the data. Weight and postnatal age had a significant influence on vancomycin clearance. The typical population parameter estimates of clearance and distribution volume were 0.46 L/h and 4.45 L, respectively. Goodness-of-fit plots and bootstrap outcomes confirmed the relatively good stability and prediction capability of the model. CONCLUSION: This study initially established a vancomycin PPK model to estimate individual PK parameters in Chinese infant patients.â©.
Assuntos
Antibacterianos/farmacocinética , Modelos Biológicos , Vancomicina/farmacocinética , Administração Intravenosa , Fatores Etários , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Povo Asiático , Peso Corporal , China , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Estudos Retrospectivos , Vancomicina/administração & dosagem , Vancomicina/sangueRESUMO
BACKGROUND: Monohydroxycarbamazepine (MHD, 10-hydroxy-carbamazepine) is the main active metabolite of oxcarbazepine (OXC). The present study aims to investigate the relationship between plasma and saliva concentrations of MHD in Chinese children with epilepsy. METHODS: Plasma and saliva samples were collected and MHD levels were measured by high-performance liquid chromatography system. Linear regression analysis was conducted between the dose of OXC and saliva concentrations, between the dose of OXC and plasma concentrations, and between the saliva concentrations and plasma concentrations. Student's t-test was used for unpaired data. A one-way analysis of variance was used for analyzing co-medication in subgroups of patients. RESULTS: A total of 58 blood samples and 58 saliva samples were obtained from 52 pediatric epileptic patients, with a median age of 5.67 years (0.58-15 years, 23 males and 29 females). There was an apparent positive correlation between the plasma and saliva MHD concentrations [Y = 0.77x - 0.85 (n = 58), R = 0.908, P < 0.01]. MHD plasma and saliva concentrations were positively correlated to daily drug dose (r = 0.461 and 0.417; P < 0.01 respectively). The saliva/plasma MHD ratio was around 0.71 and had no significant difference with age, gender, and combined medications. When data were analyzed for subgroups (one group taking OXC as monotherapy, the second group taking OXC in add-on with non-enzyme-inducing antiepileptic drugs, and the third group taking OXC in add-on with hepatic-enzyme-inducing antiepileptic drugs or moderate inducers), no significant difference was found between plasma and saliva MHD concentrations in all the above 3 groups. CONCLUSIONS: High correlation between plasma and saliva MHD levels supported the use of saliva as an alternative to plasma for OXC monitoring in children with epilepsy.
Assuntos
Anticonvulsivantes/farmacocinética , Carbamazepina/análogos & derivados , Monitoramento de Medicamentos/métodos , Epilepsia/tratamento farmacológico , Adolescente , Anticonvulsivantes/administração & dosagem , Povo Asiático , Carbamazepina/administração & dosagem , Carbamazepina/farmacocinética , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Modelos Lineares , Masculino , Oxcarbazepina , Estudos Prospectivos , Saliva/químicaRESUMO
The aim of the present meta-analysis was to determine the efficacy and safety of metformin for the treatment of women with gestational diabetes mellitus (GDM). We searched databases, including PubMed, Embase and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing metformin and insulin treatments in women with GDM. We carried out statistical analyses using RevMan 2011 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the primary outcomes. We analysed eight studies involving 1592 subjects. Meta-analysis of the RCTs showed that metformin had statistically significant effects on pregnancy-induced hypertension [PIH; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.31, 0.91]. However, its effects on neonatal hypoglycaemia (RR 0.80; 95% CI 0.62, 1.02), rate of large-for-gestational age infants (RR 0.77; 95% CI 0.55, 1.08), respiratory distress syndrome (RR 1.26; 95% CI 0.67, 2.37), phototherapy (RR 0.94; 95% CI 0.67, 1.31) and perinatal death (RR 1.01; 95% CI 0.11, 9.53) were not significant. Our analyses suggest that there is no clinically relevant difference in efficacy or safety between metformin and insulin; however, metformin may be a good choice for GDM because of the lower risk of PIH. The advantages of metformin in terms of glycaemic control, PIH incidence and gestational age at birth are unclear, and should be verified in further trials.
Assuntos
Diabetes Gestacional/tratamento farmacológico , Insulina/uso terapêutico , Metformina/efeitos adversos , Metformina/uso terapêutico , Feminino , Humanos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Gravidez , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The tachykininergic neurotransmitters have been proved to be involved in the inflammatory progress and chronic pain in series of disease. The present study was undertaken to evaluate the levels of substance P (SP) and its receptors NK-1 receptor (NK-1R) in both serum and synovial tissues of hip joint from patients with different stages of DDH, and to detect the possible correlation of serum SP levels with pain sensation and dysfunction of the hip joint. METHODS: SP levels in serum and synovial tissues from patients with DDH and DDH combined with osteoarthritis (DDH&OA) group were compared through immunohistochemistry (IHC), ELISA, and 2-step acetic acid extraction method respectively. Expression of NK-1R in synovial tissues was compared through IHC, quantitive Real-Time PCR (QRT-PCR) and Western-Blot. The severities of pain sensation and the functional activities of hip joint were assessed by Visual analogue scale (VAS) and Harris hip score (HHS). Correlations of serum SP levels with VAS, HHS and erythrocyte sedimentation rate (ESR) were evaluated respectively in these groups. RESULTS: Significantly elevated serum SP levels were detected in group of DDH and DDH&OA compared to that in normal group. IHC, QRT-PCR as well as tissue Elisa showed that SP levels in synovial tissue of DDH&OA group is stronger than that in DDH group. Serum SP levels in each group have no gender differences. The enhanced SP levels in synovial tissue mainly came from the segregation of peripheral nerve endings. Serum SP correlated with VAS and HHS in patients with DDH&OA (Male + Female). Serum SP correlated with HHS in patients with DDH (Male). Serum SP levels also correlated with erythrocyte sedimentation rate (ESR) in patients with DDH&OA (Male + Female). Up-regulated expression of NK-1R was also observed in synovial tissue of patients with DDH&OA compared to patients with DDH, through western-blot, IHC, and QRT-PCR. CONCLUSIONS: These findings indicated that the increasing SP levels in serum and synovial tissues, observed from patients with DDH to patients with DDH&OA, might associate with the loss of function and chronic pain sensation in hip joint. SP along with its receptors NK-1R might be involved in the progression of DDH into DDH&OA. In the future, inhibitors of SP as well as NK-1R may represent a novel pharmacotherapy target for pain relieving, inflammation alleviating and joint degeneration delaying for patients with DDH.