ABSTRACT
To explore the potential value of serum glutamate dehydrogenase (GLDH) combined with inflammatory cytokines as diagnostic biomarkers for anti-tuberculosis drug -induced liver injury (ATB-DILI). We collected the residual serum from the patients who met the criteria after liver function tests. We have examined these parameters including GLDH which were determined by enzyme-linked immunosorbent assay and cytokines which were determined by cytokine combination detection kit. Multivariate logistics stepwise forward regression was applied to establish regression models. A total of 138 tuberculosis patients were included in the diagnostic markers study of ATB-DILI, including normal liver function group (n = 108) and ATB-DILI group(n = 30). Serum GLDH, IL-6 and IL-10 levels were significantly increased in the ATB-DILI group. Receiver operating characteristic curve (ROC) curve showed that the area under curve (AUC) of serum GLDH, IL-6 and IL-10 for the diagnosis of ATB-DILI were 0.870, 0.714 and 0.811, respectively. In logistic regression modeling, the AUC of GLDH combined with IL-10 as an ATB-DILI marker is 0.912. Serum IL-6ãIL-10 and GLDH levels began to rise preceded the increase in ALT by 7 days, with significant differences in IL-6 compared with 7 days. Serum GLDH, IL-6 and IL-10 levels were correlated with the severity of liver injury. In conclusion, we found that GLDH, IL-6 and IL-10 alone as diagnostic markers of ATB-DILI had good diagnostic efficacy. Logistic regression model established by GLDH and IL-10 had better diagnostic efficacy and IL-6 may be an early predictor of liver injury in the setting of ATB poisoning.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Humans , Glutamate Dehydrogenase , Interleukin-10 , Interleukin-6 , Biomarkers , Cytokines , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/etiology , Antitubercular Agents/adverse effectsABSTRACT
AIMS: To explore the potential value of serum glutamate dehydrogenase (GLDH), ferrochelatase (FECH), heme oxygenase-1 (HO-1) and glutathione-S-transferase-α (GST-α) as diagnostic biomarkers for liver injury caused by antituberculosis drugs. METHODS: We established a rat model of isoniazide-induced liver injury and recruited 122 hospitalized tuberculosis patients taking antituberculosis drugs. We detected the concentration of GLDH, FECH, HO-1 and GST-α by enzyme-linked immunosorbent assay. GraphPad Prism8 and SPSS 26.0 were used for statistical analysis. RESULTS: In the rat model, serum GLDH concentration gradually increased during isoniazid (INH) administration, while serum FECH, HO-1 and GST-α concentrations significantly increased after INH administration was stopped. The receiver operating characteristic curve showed that the areas under the curve (AUCs) of serum GLDH and FECH for the diagnosis of anti-tuberculosis (TB) drug-induced liver injury (anti-TB-DILI) were 0.7692 (95% confidence interval [CI] 0.5442-0.9943) and 0.7284 (95% CI 0.4863-0.9705) and the diagnostic accuracies were 81.25% and 78.79%, respectively. In clinical research, the AUCs of GLDH and FECH were 0.9124 (95% CI 0.8380-0.9867) and 0.6634 (95% CI 0.5391-0.7877), and the optimal thresholds were 10.40 mIU/mL and 1.304 ng/mL, respectively. The diagnostic accuracy, specificity and positive predictive value (PPV) of GLDH were 82.61%, 79.38% and 47.22%. We performed a joint diagnostic test for GLDH and FECH. The diagnostic accuracy (90.43%), specificity (91.75%) and PPV (65.21%) of serial tests were better than for GLDH and FECH alone. CONCLUSIONS: GLDH in the diagnosis of liver injury induced by anti-TB drugs has high sensitivity, but low specificity and low PPV. The combination of GLDH and FECH could significantly improve the specificity, PPV and diagnostic accuracy, and reduce the false-positive rate of anti-TB-DILI.
Subject(s)
Chemical and Drug Induced Liver Injury , Tuberculosis , Rats , Animals , Antitubercular Agents/adverse effects , Glutamate Dehydrogenase , Ferrochelatase , Liver , Biomarkers , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/etiology , Tuberculosis/diagnosis , Tuberculosis/drug therapyABSTRACT
OBJECTIVES: To evaluate the safety of each anti-TNF therapy for patients with rheumatoid arthritis (RA) and then make the best choice in clinical practice. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library. The deadline for retrieval is August 2021. The ORs, Confidence Intervals (CIs), and p values were calculated by STATA.16.0 software for assessment. RESULT: 72 RCTs involving 28332 subjects were included. AEs were more common with adalimumab combined disease-modifying anti-rheumatic drugs (DMARDs) compared with placebo (OR = 1.60, 95% CI: 1.06, 2.42), DMARDs (1.28, 95% CI: 1.08, 1.52), etanercept combined DMARDs (1.32, 95% CI: 1.03, 1.67); certolizumab combined DMARDs compared with placebo (1.63, 95% CI: 1.07, 2.46), DMARDs (1.30, 95% CI: 1.10, 1.54), etanercept combined DMARDs (1.34, 95% CI: 1.05, 1.70). In SAEs, comparisons between treatments showed adalimumab (0.20, 95% CI: 0.07, 0.59), etanercept combined DMARDs (0.39, 95% CI: 0.15, 0.96), golimumab (0.19, 95% CI: 0.05, 0.77), infliximab (0.15, 95% CI: 0.03,0.71) decreased the risk of SAEs compared with golimumab combined DMARDs. In infections, comparisons between treatments showed adalimumab combined DMARDs (0.59, 95% CI: 0.37, 0.95), etanercept (0.49, 95% CI: 0.28, 0.88), etanercept combined DMARDs (0.56, 95% CI: 0.35, 0.91), golimumab combined DMARDs (0.51, 95% CI: 0.31, 0.83) decreased the risk of infections compared with infliximab combined DMARDs. No evidence indicated that the use of TNF-α inhibitors influenced the risk of serious infections, malignant tumors. CONCLUSION: In conclusion, we regard etanercept monotherapy as the optimal choice for RA patients in clinical practice when the efficacy is similar. Conversely, certolizumab + DMARDs therapy is not recommended. SYSTEMATIC REVIEW REGISTRATION: identifier PROSPERO CRD42021276176.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Adalimumab/adverse effects , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Certolizumab Pegol/adverse effects , Etanercept/adverse effects , Humans , Infliximab/therapeutic use , Network Meta-Analysis , Tumor Necrosis Factor Inhibitors/adverse effects , Tumor Necrosis Factor-alpha/therapeutic useABSTRACT
As a serious infectious disease, tuberculosis threatens global public health. Isoniazid is the first-line drug not only in active tuberculosis but also in its prevention. Severe hepatotoxicity greatly limits its use. Curcumin, extracted from turmeric, has been found to relieve isoniazid-induced hepatotoxicity. However, the mechanism of isoniazid-induced hepatotoxicity and the protective effects of curcumin are not yet understood completely. We established both cell and animal models about isoniazid-induced hepatotoxicity and investigated the new mechanism of curcumin against isoniazid-induced liver injury. The experimental data in our study demonstrated that curcumin ameliorated isoniazid-mediated liver oxidative stress. The protective effects of curcumin were demonstrated and confirmed to be correlated with upregulating SIRT1/PGC-1α/NRF1 pathway. Western blot revealed that while inhibiting SIRT1 by the siRNA1 (a SIRT1 inhibitor), the expressions of SIRT1, PGC-1α/Ac-PGC-1α, and NRF1 decreased, and the protective effect that curcumin exerted on isoniazid-treated L-02 cells was significantly attenuated. Furthermore, curcumin improved liver functions and reduced necrosis of the isoniazid-treated BALB/c mice, accompanied by downregulating oxidative stress and inflammation in liver. Western blot revealed that curcumin treatment activates the SIRT1/PGC-1α/NRF1 pathway in the isoniazid-treated BALB/c mice. In conclusion, we found one mechanism of isoniazid-induced hepatotoxicity downregulating the SIRT1/PGC-1α/NRF1 pathway, and curcumin attenuated this hepatotoxicity by activating it. Our study provided a novel approach and mechanism for the treatment of isoniazid-induced hepatotoxicity.
Subject(s)
Chemical and Drug Induced Liver Injury , Curcumin , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Curcumin/metabolism , Curcumin/pharmacology , Isoniazid/toxicity , Mice , Mitochondria , Oxidative Stress , Sirtuin 1/genetics , Sirtuin 1/metabolismABSTRACT
Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.
Subject(s)
Antitubercular Agents/toxicity , Chemical and Drug Induced Liver Injury/diagnosis , Fatty Acid-Binding Proteins/blood , HMGB1 Protein/blood , Isoniazid/toxicity , Osteopontin/blood , Animals , Male , Rats , Rats, Sprague-Dawley , Transaminases/bloodABSTRACT
Bamlanivimab is routinely used in the treatment of coronavirus disease 2019 (COVID-19) worldwide. We performed a meta-analysis to investigate the efficacy and safety of bamlanivimab treatment in patients with COVID-19. We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, and medRxiv between January 30, 2020 and August 5, 2021. We selected randomized clinical trials (RCTs) and observational studies with a control group to assess the efficiency of bamlanivimab in treating patients with COVID-19. Our meta-analysis retrieved three RCTs and seven cohort studies including 14 461 patients. Bmlanivimab may help outpatients to prevent hospitalization or emergency department visits (RR 0.41, 95%CI 0.29-0.58), reduce ICU admission (RR 0.47, 95%CI 0.23-0.92), and mortality (RR 0.32, 95%CI 0.13-0.77) from the disease. The combination of bamlanivimab and etesevimab may have a greater potential for positive treatment outcomes. Bamlanivimab has demonstrated clinical efficacy on mild or moderate ill patients with COVID-19 to prevent hospitalization, reduce severity, and mortality from the disease. Combinations of bamlanivimab and etesevimab have a significant relative risk reduction for COVID-related hospitalization or death for patients than the monotherapy 700 mg group. Well-designed clinical trials to identify the clinical and biochemical characteristics in the COVID-19 patients' population that could benefit from bamlanivimab or plus etesevimab are warranted in the future.
Subject(s)
COVID-19 Drug Treatment , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Humans , SARS-CoV-2 , Treatment OutcomeABSTRACT
INTRODUCTION: The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. METHODS: A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. RESULTS: A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73-0.91; RR = 0.86, 95% CI: 0.75-0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. CONCLUSION: It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Prostatic Neoplasms , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Incidence , Male , Prostate , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/prevention & control , RiskABSTRACT
BACKGROUND: The benefit of IVIG (Intravenous Immunoglobulin) therapy for COVID-19 remains controversial. We performed a meta-analysis to investigate the efficacy of IVIG treatment in patients with COVID-19. METHODS: We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv between 1 January 2020 and February 17, 2021. We selected randomized clinical trials and observational studies with a control group to assess the efficiency of IVIG in treating patients with COVID-19. Subjects were divided into 'non-severe', 'severe' and 'critical' three subgroups based on the information of the study and the World Health Organization (WHO) definition of severity. We pooled the data of mortality and other outcomes using either a fixed-effect model or a random-effects model. RESULTS: Our meta-analysis retrieved 4 clinical trials and 3 cohort studies including 825 hospitalized patients. The severity of COVID-19 is associated with the efficiency of IVIG. In critical subgroup, IVIG could reduce the mortality compared with the control group [RR = 0.57 (0.42-0.79, I2 = 025%). But there was no significant difference in the severe or non-severe subgroups. CONCLUSION: IVIG has demonstrated clinical efficacy on critical ill patients with COVID-19. There may be a relationship between the efficacy of IVIG and the COVID-19 disease severity. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients' population that could benefit from IVIG are warranted in the future.
Subject(s)
COVID-19 Drug Treatment , Immunoglobulins, Intravenous/therapeutic use , SARS-CoV-2/drug effects , Databases, Factual , Humans , Mortality , Outcome Assessment, Health Care , Prospective Studies , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
Schizophrenia is a heterogeneous disorder in which there is an interaction between genetic and environmental factors. Accumulating data show that there may be an association between vitamin D deficiency and schizophrenia. We conducted an updated meta-analysis to investigate the relationship between schizophrenia and blood vitamin D level. All published observational articles have been searched from five databases until September 2019. In total, 36 articles with a total of 12528 participants were included in this study. Patients with schizophrenia have significantly lower levels of vitamin D than controls. The subgroup analyses based on study design, hospitalization status, quality score, type of biomarker [25-hydroxyvitamin D or 25-hydroxyvitamin D3], and the country did not explain between-study heterogeneity; however, meta-regression on match factors indicted that match of BMI could account for some degree of heterogeneity. No significant differences in publication bias were observed. Also, subjects with schizophrenia were more likely to have vitamin D deficiency or insufficiency compared to controls. In conclusion, our analyses are consistent with the hypothesis that vitamin D deficiency is associated with schizophrenia. More well-designed randomized control trials are needed to determine whether this association is causal.
Subject(s)
Observational Studies as Topic/methods , Schizophrenia/blood , Schizophrenia/epidemiology , Vitamin D Deficiency/blood , Vitamin D Deficiency/epidemiology , Vitamin D/analogs & derivatives , Biomarkers/blood , Humans , Vitamin D/bloodABSTRACT
Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.
ABSTRACT
OBJECTIVE: To characterize the pharmacokinetics of trazodone hydrochloride (HCl) sustained-release tablets (TSR) and trazodone immediate-release formulation (TIR) and investigate the effects of food on the pharmacokinetics of the drug in healthy subjects. MATERIALS AND METHODS: Three open-label, randomized crossover trials of single-dose, multiple-dose, and food-drug interaction testing were conducted. A validated high-performance liquid chromatography-fluorescence method was used to measure the plasma concentration of trazodone, and a non-compartment model was used to obtain the pharmacokinetic parameters. AUC and Cmax dose proportionality were analyzed using a power model. RESULTS: TSR lacked dose proportionality over a dose range of 25 - 150 mg. In the food-drug interaction study, no significant changes in the pharmacokinetic parameters of the drug under the fed conditions were observed. Multiple dosage of TSR and TIR reached steady state after 7 days, with no accumulation phenomenon observed. The peak time and peak concentrations of TSR were significantly longer and lower, respectively, than those of TIR. CONCLUSION: TSR showed clear sustained-release characteristics, and food exhibited no significant effects on the pharmacokinetic parameters of trazodone. TSR and TIR reached steady state levels after 7 consecutive days of administration, with no accumulation phenomenon observed.
Subject(s)
Delayed-Action Preparations/pharmacokinetics , Trazodone/pharmacokinetics , Area Under Curve , Cross-Over Studies , Food-Drug Interactions , Humans , TabletsABSTRACT
PURPOSE: Imrecoxib is one type of cyclooxygenase-2 inhibitor with the capability of reducing the potential cardiovascular risk caused by other NSAIDs. Co-administration with other medications can affect the cytochrome P450 (CYP) 2C9 enzyme function; thus, imrecoxib metabolism can be affected. The purpose of this research was to evaluate the effects of fluconazole, which is known to inhibit CYP2C9, on imrecoxib's pharmacokinetic (PK) parameters. METHODS: In this single-center, single-arm, open-label, self-controlled study, 12 healthy Chinese male volunteers (mean [SD] age, 22.6 [2.43] years) received the following 2 treatments separated by a washout period of 8 days under a fasting state: (1) a single oral dose of imrecoxib 100 mg; and (2) fluconazole 200 mg/d over 6 days followed by concurrent dosing of imrecoxib 100 mg and fluconazole 200 mg. Plasma concentrations of imrecoxib (M0) and its metabolites (4'-hydroxymethyl metabolite [M1] and 4'-carboxylic acid metabolite [M2]) for PK analysis were obtained at 0 (baseline) and 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, and 72 hours after imrecoxib dosing. Safety and tolerability assessments were performed throughout the study. FINDINGS: All subjects completed the study. There was 1 adverse event; drug-induced liver damage in 1 subject occurred after he received imrecoxib plus fluconazole, and the subject recovered without any sequelae. Coadministration with fluconazole resulted in much higher plasma imrecoxib concentrations, with an increase of 88% in Cmax and 72% in AUC0-t compared with only imrecoxib treatment, which showed that fluconazole may increase plasma exposure to imrecoxib. Fluconazole also caused a small, but not clinically relevant, decrease in M1 and M2 mean Cmax (13% and 14%, respectively), but there was minimal change in M1 and M2 mean AUC0-t (3% and 2%). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or adverse events between treatments. IMPLICATIONS: Concurrent administration of imrecoxib and fluconazole did not seem to change imrecoxib's safety profile. The ratio (imrecoxibâ¯+â¯fluconazole/imrecoxib) for AUC0-t was 1.72 (90% CI, 1.41-2.11) and for Cmax it was 1.88 (90% CI, 1.59-2.21). Hence, it is necessary to adjust the imrecoxib dose when it is concurrently used with other CYP2C9 inhibitors.
Subject(s)
Antifungal Agents/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Fluconazole/pharmacology , Pyrroles/pharmacokinetics , Sulfides/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , China , Cross-Over Studies , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/blood , Drug Interactions , Healthy Volunteers , Humans , Male , Pyrroles/adverse effects , Pyrroles/blood , Random Allocation , Sulfides/adverse effects , Sulfides/blood , Young AdultABSTRACT
The leading cause of drug withdrawal from market and clinical trials failure is drug-induced liver injury (DILI). Varying clinical, histological and laboratory features of DILI, as well as undefined underlying mechanisms, hinder patients to be diagnosed in the early-stage of the disease and receive effective treatments. Conventional indicators, like serum transaminases and bilirubin, have inevitable limitations referring to sensitive prediction and specific detection of DILI. In order to reduce the occurrence of DILI, researchers have attempted to discover potential biomarkers with higher specificity and sensitivity from blood and urine in recent years. This article aims to review recent advances in biomarkers of DILI.
Subject(s)
Biomarkers , Chemical and Drug Induced Liver Injury/diagnosis , Biomarkers/blood , Biomarkers/urine , Humans , Sensitivity and SpecificityABSTRACT
Co-treatment of isoniazid (INH) and rifampicin (RFP) is well known for clinically apparent liver injury. However, the mechanism of INH/RFP-induced liver injury is controversial. Emerging evidence shows links between inhibition of bile acids transporters and drug-induced liver injury (DILI). The present study investigates whether sodium taurocholate cotransporting polypeptide (NTCP/Ntcp; SLC10A1) and bile salt export pump (BSEP/Bsep; ABCB11) are involved in the anti-tuberculosis medicines induced liver injury. ICR female mice were intragastrically treated with INH (50 or 100 mg/kg), RFP (100 or 200 mg/kg), or the combination of INH/RFP (50 + 100 mg/kg or 100 + 200 mg/kg) for 14 consecutive days. Liver histopathological examination, serum biochemical and liver malondialdehyde tests were evaluated. Apparent histopathological alterations and hepatic oxidative stress showed in INH (100 mg/kg), RFP (200 mg/kg) and their combination group. The hepatoxic effect was also indicated by increased serum biomarkers, such as aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBil), total bilirubin (TBil) and total bile acids (TBA). Both doses of INH/RFP administration significantly down-regulated the expression of Ntcp and Bsep in liver. Furthermore, the combination of INH and RFP displayed stronger effect on the expression of Ntcp compared with the corresponding dose of INH or RFP alone. In conclusion, down-regulated expression of hepatic Ntcp and Bsep might play an important role in the development of INH and RFP induced liver injury.
Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , Antitubercular Agents/toxicity , Chemical and Drug Induced Liver Injury/metabolism , Isoniazid/toxicity , Liver/drug effects , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Rifampin/toxicity , Symporters/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 11 , ATP-Binding Cassette Transporters/biosynthesis , Animals , Bile Acids and Salts/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Dose-Response Relationship, Drug , Down-Regulation , Drug Synergism , Female , Liver/metabolism , Liver/pathology , Liver Function Tests , Mice, Inbred ICR , Organic Anion Transporters, Sodium-Dependent/biosynthesis , Symporters/biosynthesisABSTRACT
The first HILIC-tandem mass spectrometry (MS/MS) method for determination of vindesine (VDS) in human plasma using vinorelbine as an internal standard (IS) has been developed and validated. Plasma samples clean-up consisted of solid phase extraction with a strata™-X column. The compounds were separated on a HILIC column with an isocratic mobile phase consisting of acetonitrile and 15mM ammonium acetate buffer containing 0.15% formic acid (80:20, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer via electrospray positive ionization (ESI(+)). The ion transitions recorded in multiple reaction monitoring mode were m/z 754.6â123.8 for VDS and 779.4â323.3 for IS, respectively. Linear calibration curves were obtained in the concentration range of 0.3-28ng/ml and the lower limit of quantification for VDS was 0.3ng/ml. The coefficient of variation of the assay precision was less than 13%, and the accuracy exceeded 96%. The developed assay method was successfully applied for the evaluation of population pharmacokinetics of VDS after intravenous infusion of Xi Ai Ke Vial(®) (3mg of Vindesine Sulfate for Injection) to Chinese Han subjects with hematological malignant disorders.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Vindesine/pharmacokinetics , Adult , Antineoplastic Agents, Phytogenic/therapeutic use , Calibration , Female , Hematologic Neoplasms/drug therapy , Humans , Limit of Detection , Male , Middle Aged , Reference Standards , Reproducibility of Results , Solid Phase Extraction , Spectrometry, Mass, Electrospray Ionization/methods , Vinblastine/analogs & derivatives , Vinblastine/chemistry , Vindesine/therapeutic use , Vinorelbine , Young AdultABSTRACT
A liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of erythromycylamine, which is the predominant active metabolite of dirithromycin in human plasma. After solid-phase extraction, the analyte and internal standard (IS) were separated by using an isocratic mobile phase consisting of 20 mM ammonium acetate (pH 3.9, adjusted with formic acid)-acetonitrile (75:25, v/v) on a Phenyl-Hexyl column (150 × 2.1 mm, 3 µm) and then analyzed in positive ion mode under electrospray ionization. Azithromycin was selected as the IS because it has the most similar mass spectrometric and chromatographic behaviors to the analyte. The respective multiple reaction monitoring (MRM) transitions, m/z 368.5>83.2 for erythromycylamine and m/z 375.4>115.2 for IS were chosen to achieve high sensitivity and selectivity in determination. A more acidic mobile phase (pH 3.9) than those of previous reports and a special needle wash (ethylene glycol-acetonitrile-water, 50:30:20, v/v/v, adjusted to pH 3.9 using formic acid) were used to eliminate the carryover effects of the two macrolides. The method exhibited a linear dynamic range of 0.5-440.0 ng/mL for erythromycylamine in human plasma (r=0.9999). The lower limit of quantification (LLOQ) and limit of detection (LOD) were 0.5 and 0.05 ng/mL, respectively. The mean extraction recoveries were higher than 94.0% for the analyte and IS. The intra- and inter-day precisions ranged from 1.4 to 5.4% and from 1.6 to 4.0%, respectively. The accuracy varied between 91.2 and 101.2%. The established method was successfully applied to analyze the human plasma samples from 24 healthy subjects in a bioequivalence study of two dirithromycin enteric-coated formulations.
Subject(s)
Anti-Bacterial Agents/blood , Chromatography, High Pressure Liquid/methods , Erythromycin/analogs & derivatives , Tandem Mass Spectrometry/methods , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Erythromycin/blood , Erythromycin/chemistry , Erythromycin/pharmacokinetics , Female , Healthy Volunteers , Humans , Male , Molecular Structure , Therapeutic Equivalency , Young AdultABSTRACT
It has been confirmed that alternatively activated macrophages (M2) participate in tissue remodeling and fibrosis occurrence, but the effect of M2 on peritoneal fibrosis related to peritoneal dialysis (PD) hasn't been elucidated. This study was therefore conducted to assess the association between M2 and peritoneal fibrosis related to PD. In this study, peritoneal fibrosis was induced by intraperitoneal (i.p.) injection of Lactate-4.25% dialysate (100 mL/kg) to C57BL/6J mice for 28 days, and liposome-encapsulated clodronate (LC, the specific scavenger of macrophages) was used to treat the peritoneal fibrosis mice model by i.p. injection at day 18 and day 21. All animals were sacrificed at day 29. Parietal peritonea were stained with Masson's trichrome, and the expression of type I collagen (Col-I), fibronectin, mannose receptor (CD206), transforming growth factor beta (TGF-ß), chemokine receptor 7 (CCR7), chitinase 3-like 3 (Ym-1) and arginase-1 (Arg-1) was determined by Western blotting, immunofluorescence and quantitative real-time PCR. Our results revealed that peritoneal thickness, Col-I, fibronectin, CD206, TGF-ß, Ym-1 and Arg-1 were upregulated in the peritoneal fibrosis mice model, and all of these indexes were downregulated in those treated with LC. Additionally, there was no difference in the level of CCR7 between the model and treatment group. Our study indicated that peritoneal M2 played an important role in the process of peritoneal fibrosis related to PD and might be a potential target for intervention therapy of peritoneal fibrosis.
Subject(s)
Macrophage Activation , Macrophages, Peritoneal/metabolism , Peritoneal Dialysis , Peritoneal Fibrosis/metabolism , Animals , Arginase/genetics , Arginase/metabolism , Blotting, Western , Collagen Type I/genetics , Collagen Type I/metabolism , Female , Fibronectins/genetics , Fibronectins/metabolism , Lectins/genetics , Lectins/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Macrophages, Peritoneal/classification , Mannose Receptor , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/metabolism , Mice, Inbred C57BL , Microscopy, Confocal , Peritoneal Fibrosis/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , beta-N-Acetylhexosaminidases/genetics , beta-N-Acetylhexosaminidases/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Ranolazine was approved by the US Food and Drug Administration in January 2006 for the treatment of chronic angina pectoris, and is the first approved agent from a new class of anti-anginal drugs in almost 25 years. The primary objective of this study was to determine the concentration of ranolazine in human plasma using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetic properties of ranolazine after administration of single and multiple doses of ranolazine in healthy Chinese adult volunteers. METHODS: A randomized, open-label, single- and multiple-dose study design was used in the study. Subjects were randomized to receive a single dose of 500, 1,000, or 1,500 mg of ranolazine. Those who received the single dose continued on to the multiple-dose phase and received 500 mg twice daily for 7 days. In the single-dose phase, blood samples were collected from 0 to 48 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am and 8:00 pm on days 6 and 7 to determine the minimum steady-state plasma concentration (C(min,ss)) of ranolazine; on day 8, samples were collected from 0 to 48 h after drug administration. All values were expressed as means (standard deviations [SDs]). Adverse events (AEs) were monitored throughout the study via subject interview, vital signs, and blood sampling. RESULTS: The LC-MS/MS method was developed and validated. Twelve Chinese subjects (six men, six women) were enrolled in the single-dose phase of the pharmacokinetic study. The mean (SD) age of the subjects was 24.7 (1.6) years; their mean (SD) weight was 61.3 (6.4) kg, their mean (SD) height was 165.7 (4.5) cm, and their mean (SD) body mass index was 21.6 (6.6) kg/m(2). The main pharmacokinetic parameters [mean (SD)] for ranolazine after administration of a single oral dose of 500, 1,000, and 1,500 mg were as follows: maximum plasma concentration (C(max)) 741.5 (253.0), 1,355.0 (502.0), and 2,328.7 (890.5) ng/mL, respectively; area under the concentration-time curve from time zero to 48 h (AUC(48)) 9,071.9 (3,400.0), 16,573.5 (6,806.2), and 29,324.5 (10,857.2) ng·h/mL; AUC from time zero extrapolated to infinity (AUC(∞)) 9,826.7 (3,152.0), 16,882.4 (6,790.8), and 29,923.5 (10,706.3) ng·h/mL; time to reach C(max) (t(max)) 5.3 (1.4), 4.2 (1.2), and 5.9 (2.8) h; elimination half-life (t(½)) 6.4 (3.3), 6.4 (3.5), and 6.7 (4.3) h. Mean (SD) values for the main pharmacokinetic parameters for ranolazine after administration of multiple doses were as follows: steady-state C(max) (C(max,ss)) 1,732.9 (547.3) ng/mL; C(min,ss) 838.1 (429.8) ng/mL; steady-state AUC at time t (AUC(ss,(t))) 14,655.5 (5,624.2) ng·h/mL; average steady-state plasma drug concentration during multiple-dose administration (C(av,ss)) 1,221.3 (468.7) ng/mL; t(max) 3.46 (1.48) h; t(½) 6.28 (2.48) h. CONCLUSION: In this group of healthy Chinese subjects, AUC and C(max) increased proportionally with the dose, whereas t(½) was independent of the dose. The pharmacokinetic properties of ranolazine were linear after administration of single oral doses of 500 to 1,500 mg. Compared with the pharmacokinetic parameters of the subjects who received a single dose, those who received multiple doses (twice daily) of ranolazine had a larger AUC from time zero to the time of the last measurable concentration (AUC(last)), AUC(∞), C(max), and apparent total body clearance of drug from plasma after oral administration (CL/F), and shorter t(max) (all p < 0.05). Furthermore, some of the main pharmacokinetic parameters of ranolazine may reflect ethnic differences. This dosage was generally well tolerated by all the subjects.
Subject(s)
Acetanilides/adverse effects , Acetanilides/pharmacokinetics , Angina Pectoris , Asian People , Piperazines/adverse effects , Piperazines/pharmacokinetics , Acetanilides/administration & dosage , Adult , Angina Pectoris/drug therapy , Area Under Curve , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Delayed-Action Preparations/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Piperazines/administration & dosage , Ranolazine , Young AdultABSTRACT
Mildronate has been used as antianginal drug in parts of Europe for many years, but its pharmacokinetic (PK) properties in humans remain unclear. This study was designed to assess and compare the PK properties of mildronate capsules after single escalating oral dose and multiple doses in healthy Chinese volunteers. Volunteers were randomly assigned to receive a single dose of 250, 500, 1000, 1250 or 1500 mg of mildronate capsules. Those who received the 500-mg dose continued on the multiple-dose phase and received 500 mg three times a day for 13 days. Plasma drug concentrations were analysed by ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Tolerability was assessed throughout the study. A total of 40 Chinese volunteers were enrolled in the study. No period or sequence effect was observed. Area under the concentration and C(max) were increased proportionally with the dose levels, whereas t(1/2) and V(d)/f were dependent on the dose. Nonlinear PK properties were found at doses of 250-1500 mg. There was an accumulation after multiple-dose administration. No serious adverse events (AEs) were reported in the PK study. The formulation was well tolerated.
Subject(s)
Cardiotonic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Methylhydrazines/pharmacokinetics , gamma-Butyrobetaine Dioxygenase/antagonists & inhibitors , Adult , Calibration , Capsules , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/adverse effects , Cardiotonic Agents/blood , China , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Female , Half-Life , Humans , Limit of Detection , Male , Metabolic Clearance Rate , Methylhydrazines/administration & dosage , Methylhydrazines/adverse effects , Methylhydrazines/blood , Reproducibility of Results , Young AdultABSTRACT
A simple, sensitive and high-throughput ultra high-performance liquid chromatography electrospray ionization mass spectrometry (U-HPLC-ESI-MS/MS) method has been developed and validated for the determination of ranolazine in human plasma. Propafenone was employed as the internal standard (I.S.). The analytes were chromatographically separated on a BEH C(18) column (50 mm × 2.1 mm, 1.7 µm) with a mobile phase consisting of acetonitrile and aqueous ammonium acetate solution (0.06% formic acid, 7.5 mmol L(-1) ammonium acetate, 40:60, v/v). Detection of the analytes was achieved using positive ion electrospray ionization via multiple reactions monitoring mode. The mass transitions were m/z 428.3â279.3 for ranolazine and m/z 342.4â115.9 for propafenone. The assay was linear over the concentration range 1-3000 ng mL(-1), with correlation coefficients ≥0.997. The intra- and inter-day coefficients of variation were less than 8.9% in terms of relative standard deviation and accuracy ranged from 93.0 to 108.9% at all quality control levels. The validated method was a simple sample preparation procedure and short run-time (<2.0 min) method, which was successfully applied to a phase I pharmacokinetic study of ranolazine in Chinese healthy volunteers.