Borneol-modified docetaxel plus tetrandrine micelles for treatment of drug-resistant brain glioma.

OBJECTIVE: Glioma is the most common and deadly primary malignant tumor in adults. Treatment outcomes are ungratified due to the presence of blood-brain barrier (BBB), glioma stem cells (GSCs) and multidrug resistance (MDR). Docetaxel (DTX) is considered as a potential drug for the treatment of brain tumor, but its effectiveness is limited by its low bioavailability and drug resistance. Tetrandrine (TET) reverses the resistance of tumor cells to chemotherapy drugs. Borneol (BO) modified in micelles has been shown to promote DTX plus TET to cross the BBB, allowing the drug to better act on tumors. Therefore, we constructed BO-modified DTX plus TET micelles to inhibit chemotherapeutic drug resistance. SIGNIFICANCE: Provide a new treatment method for drug-resistant brain gliomas. METHODS: In this study, BO-modified DTX plus TET micelles were prepared by thin film dispersion method, their physicochemical properties were characterized. Its targeting ability was investigated. The therapeutic effect on GSCs was investigated by in vivo and in vitro experiments. RESULTS: The BO-modified DTX plus TET micelles were successfully constructed by thin film dispersion method, and the micelles showed good stability. The results showed that targeting micelles increased bEnd.3 uptake and helped drugs cross the BBB in vitro. And we also found that targeting micelles could inhibit cell proliferation, promote cell apoptosis and inhibit the expression of drug-resistant protein, thus provide a new treatment method for GSCs in vitro and in vivo. CONCLUSIONS: BO-modified DTX plus TET micelles may provide a new treatment method for drug-resistant brain gliomas.

Non-vitamin K antagonist oral anticoagulants in venous thromboembolism patients: a meta-analysis of real-world studies.

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).

Correlation between single-nucleotide polymorphisms and statin-induced myopathy: a mixed-effects model meta-analysis.

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.

Associations between human leukocyte antigen polymorphisms and hypersensitivity to antiretroviral therapy in patients with human immunodeficiency virus: a meta-analysis.

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.

Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis.

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.

Population pharmacokinetics of vancomycin in Chinese infants
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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.
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Saliva and Plasma Monohydroxycarbamazepine Concentrations in Pediatric Patients With Epilepsy.

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.

Metformin versus insulin for gestational diabetes mellitus: a meta-analysis.

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.

Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease.

Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.

Predicting ischaemic events using platelet reactivity in patients receiving clopidogrel: Indirect meta-comparison among VerifyNow, light transmission aggregometry and thromboelastography.

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)-VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended.

The predictive value of circulating microRNAs for venous thromboembolism diagnosis: A systematic review and diagnostic meta-analysis.

OBJECTIVE: Venous thromboembolism (VTE) is a common cardiovascular disease, in which pulmonary embolism (PE) is potentially life-threatening. Accurate biological markers for the early diagnosis of VTE are needed. The purpose of this study was to analyze and validate the predictive value of microRNAs for the diagnosis of VTE. METHODS: A comprehensive literature review was conducted using the PubMed, Embase, and Cochrane Library databases and is current through Sep 27, 2018. The diagnostic value of microRNAs for VTE was analyzed by creating a summary receiver operating characteristic curve (SROC) and calculating the area under the curve (AUC). RESULTS: Our analysis included 12 articles assessing a total of 1057 individuals. The most frequently researched microRNA was miR-134, and the pooled results of the predictive ability of this miRNA with 95% confidence intervals (CIs) showed an average sensitivity of 0.82 (0.69-0.91) and an average specificity of 0.83 (0.68-0.92). The average AUC for the SROC curves was 0.89 (0.86-0.92). For other microRNAs, AUC values >0.8 were considered as potential diagnostic indices. These microRNAs included miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195. CONCLUSIONS: MicroRNAs may act as novel diagnostic biomarkers for VTE, and miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195 are prime candidates. Of these, research on miR-134 is the most extensive and reliable.

In Utero Oxcarbazepine Exposure and Neonatal Abstinence Syndrome: Case Report and Brief Review of the Literature.

Oxcarbazepine is a second-generation antiepileptic drug that is used to treat partial seizures. Although it has been increasingly used in pregnant women, its fetal safety has not been fully validated. We describe a 12-hour-old neonate who developed neonatal abstinence syndrome (NAS) after intrauterine exposure to oxcarbazepine. The neonate was born via cesarean section to a mother who took oxcarbazepine 300 mg/day for treatment of seizures throughout her pregnancy. Approximately 12 hours after birth, the infant developed paroxysmal jitter, which mainly presented as increased excitability, irritability, limb shaking, and increased muscle tone. These symptoms resolved by day 9 of life. Although NAS occurs most often after in utero exposure to opioids, exposure to other drugs during pregnancy may contribute to a small proportion of NAS cases. To our knowledge, this is the second case report of oxcarbazepine-induced NAS. Pregnant women with epilepsy should weigh the pros and cons of continuing oxcarbazepine during their pregnancy when they are prescribed this drug. For infants with in utero oxcarbazepine exposure, comprehensive assessments and examinations are necessary for screening oxcarbazepine-induced NAS.