A randomized, double-blind, placebo controlled, phase 3 trial to evaluate the efficacy and safety of cetagliptin added to ongoing metformin therapy in patients with uncontrolled type 2 diabetes with metformin monotherapy.

AIM: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. METHODS: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance. RESULTS: After 24 weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17 ± 0.794%, -1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment ß-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. CONCLUSIONS: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy.

Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

A double-blind, randomized, placebo and positive-controlled study in healthy volunteers to evaluate pharmacokinetic and pharmacodynamic properties of multiple oral doses of cetagliptin.

AIMS: This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin. METHODS: Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study. RESULTS: Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied. CONCLUSION: Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.

Disposition study of the novel dipeptidyl peptidase 4 inhibitor cetagliptin in rats.

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a class of oral antihyperglycemic agents and therapeutic approach for type 2 diabetes. Cetagliptin is a novel oral and selective DPP-4 inhibitor and developed as a promising candidate for treatment of type 2 diabetes mellitus.This study aimed to evaluate the metabolism and excretion of cetagliptin in Sprague-Dawley (SD) rats, and to detect and identify metabolites of cetagliptin.The SD rats were administered with a single oral dose of 6 mg/kg with approximately 100 µCi of [14C] cetagliptin. The mean total recovery of radioactivity was 90.20% within 168h in SD rats excreta. Cetagliptin was the major radioactive component in SD rats plasma, urine and eliminated primarily by faecal excretion. The recovery of cetagliptin in urine and feces was 25.15% and 13.85% of the dose, respectively. Cetagliptin was well absorbed after oral administration in SD rats based on the total recovery of radioactivity in BDC SD rats bile and urine.Six major metabolites were observed and identified in SD rats, comprising 0.20 to 4.53% of total plasma AUC. These major metabolites were the hydroxylated, N-sulphate and N-carbamoyl glucuronic acid conjugates of the cetagliptin, two metabolites formed by glucuronide of a hydroxylated metabolite.

The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] cetagliptin in healthy volunteers.

The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50µCi [14C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration.

Response of Leucine-Rich Repeat Domain-Containing Protein in Haemaphysalis longicornis to Babesia microti Infection and Its Ligand Identification.

Haemaphysalis longicornis is a blood-feeding hard tick known for transmitting a variety of pathogens, including Babesia How the parasites in the imbibed blood become anchored in the midgut of ticks is still unknown. Leucine-rich repeat domain (LRR)-containing protein, which is associated with the innate immune reaction and conserved in many species, has been detected in H. longicornis and has previously been indicated in inhibiting the growth of Babesia gibsoni However, the detailed mechanism is unknown. In this study, one of the ligands for LRR from H. longicornis (HlLRR) was identified in Babesia microti, designated BmActin, using glutathione transferase (GST) pulldown experiments and immunofluorescence assays. Moreover, RNA interference of HlLRR led to a decrease in the BmActin mRNA expression in the midgut of fully engorged ticks which fed on B. microti-infected mice. We also found that the expression level of the innate immune molecules in H. longicornis, defensin, antimicrobial peptides (AMPs), and lysozyme, were downregulated after the knockdown of HlLRR. However, subolesin expression was upregulated. These results indicate that HlLRR not only recognizes BmActin but may also modulate innate immunity in ticks to influence Babesia growth, which will further benefit the development of anti-Babesia vaccines or drugs.

Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus.

INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

Population pharmacokinetics of mycophenolic acid in pediatric patients with juvenile dermatomyositis and optimization of limited sampling strategy.

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS). Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09-16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was developed. Height and co-administered cotrimoxazole were added as the covariates to the model. Concentrations at different time points were simulated and area under the concentration-time curve (AUC0-12 h) was calculated. By removing one sampling point at a time, AUC0-12 h from three-point sampling strategy was re-calculated via Bayesian approach. AUC0-12 h from the three-point sampling strategy (by removing the point at 20 minutes post-dose) had the strongest correlation with AUC0-12 h from the four-point sampling strategy (Pearson's r = 0.971).

In vitro study of the drug-drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers.

Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug-drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin.Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn't have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp).The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC0-120 (GMR, 99.25%; 90% CI, 95.96%-102.65%). There was a slightly increase in cetagliptin Cmax (GMR, 117.33%; 90% CI, 102.54%-134.25%). Coadministration with cetagliptin did not affect the metformin's AUC0-24 (GMR, 108.54%; 90% CI, 101.41%-116.17%) or Cmax (GMR, 97.67%; 90% CI, 90.96%-104.89%).Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug-drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.

Development and validation of an ultrasensitive LC-MS/MS method for the quantification of cetagliptin in human plasma and its application in a microdose clinical trial.

This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C18 analytical column (50 × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0 mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000 pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.

A cysteine protease of Babesia microti and its interaction with tick cystatins.

Babesiosis is a tick-borne protozoonosis caused by Babesia, which can cause fever, hemolytic anemia, hemoglobinuria, and even death. Babesia microti is a parasite found in rodents and can be pathogenic to humans. In this study, the full-length cDNA of a B. microti cysteine protease (BmCYP) was expressed and the recombinant rBmCYP protein analyzed and characterized. BmCYP is encoded by an ORF of 1.3 kb, with a predicted molecular weight of 50 kDa and a theoretical pI of 8.5. The amino acid sequence of BmCYP exhibits an identity of 32.9 to 35.2% with cysteine proteases of Babesia ovis, Babesia bovis, and Theileria, respectively. The results of the proteinase assays show that rBmCYP has cysteine protease enzymatic activity. In addition, we demonstrate that tick cystatins rRhcyst-1 and rRhcyst-2 were able to effectively inhibit the activity of rBmCYP; the inhibition rates were 57.2% and 30.9%, respectively. Tick cystatins Rhcyst-1 and Rhcyst-2 were differentially expressed in ticks that fed on Babesia-infected mice relative to non-infected control ticks. Our results suggest that BmCYP is a functional enzyme with cysteine protease enzymatic activity and may be involved in tick-B. microti interactions.

Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants.

OBJECTIVES: To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population. METHODS: We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children's Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC0-24 was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC0-24 ≥ 400. RESULTS: The analysis included a total of 330 concentration-time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25-42 weeks and 0.88-5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC0-24/MIC of ≥400. For MIC values of ≤0.5 mg/L, AUC0-24/MIC ≥400 was achieved for 95% of the newborn infants with vancomycin troughs of 5-10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5-10 mg/L achieved AUC0-24/MIC ≥400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC0-24 ≥ 400 in 90% of infants with a PMA of 30-32 and 32-34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36-38 and 38-40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA ≥44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5-15 mg/L were highly predictive of an AUC0-24 of ≥400 when treating invasive MRSA infections with an MIC of ≤1 mg/L. CONCLUSIONS: The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies.

Target attainment analysis and optimal sampling designs for population pharmacokinetic study on piperacillin/tazobactam in neonates and young infants.

OBJECTIVES: Population pharmacokinetic (popPK) analyses for piperacillin/tazobactam in neonates and infants of less than 2 months of age have been performed by our group previously. The results indicate that a dose of 44.44/5.56 mg/kg piperacillin/tazobactam every 8 or 12 h may not be enough for controlling infection in this population. In order to determine the appropriate dosing regimen and to provide a rationale for the development of dosing guidelines suitable for this population, further popPK studies of piperacillin/tazobactam would need to be conducted. The aim of the present study was to determine the appropriate dosing regimen and optimal sampling schedules in neonates and infants of less than 2 months of age. METHODS: Pharmacodynamic profiling of piperacillin using Monte Carlo simulation was performed to explore the target attainment probability of different dosing regimens for infections caused by different isolated pathogens. D-optimal designs for piperacillin and tazobactam were conducted separately, and the times that overlapped were chosen as the final sampling scheme for future popPK studies in neonates and young infants of less than 2 months of age. RESULTS: Our findings revealed that compared to the current empirical piperacillin/tazobactam dose regimen (50 mg/kg every 12 h by 5-min infusion in our hospital), the clinical outcome could be improved by increasing doses, increasing administration frequency, and prolonging intravenous infusion in neonates and infants of less than 2 months of age. The following optimal sampling windows were chosen as the final sampling scheme: 0.1-0.11, 0.26-0.29, 0.97-2.62, and 7.95-11.9 h administered every 12 h with 5-min infusion; 0.1-0.12, 0.39-0.56, 2.86-4.95, and 8.91-11.8 h administered every 12 h with 3-h infusion; 0.1-0.11, 0.22-0.29, 0.91-1.96, and 5.56-7.93 h administered every 8 h with 5-min infusion; 0.1-0.11, 0.38-0.48, 2.54-3.82, and 6.86-7.93 h administered every 8 h with 3-h infusion; 0.1-0.11, 0.25-0.28, 0.84-1.69, and 4.55-5.94 h administered every 6 h with 5-min infusion; and 0.1-0.11, 0.37-0.54, 3.13-3.72, and 5.57-5.99 h administered every 6 h with 3-h infusion. CONCLUSIONS: The dosing regimen and sampling schedules proposed in this study should be evaluated in future popPK studies of piperacillin/tazobactam in neonates and infants. To the best of our knowledge, this is the first study that combined optimal sampling design with Monte Carlo simulation for designing popPK studies of piperacillin/tazobactam.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese paediatric patients with epilepsy: Model-based dose optimization.

The pharmacological activity of oxcarbazepine (OXC) is primarily exerted through its active 10-monohydroxy metabolite (MHD). Nonetheless, there is limited pharmacokinetic information available regarding paediatric patients with epilepsy treated with OXC, especially in infants and toddlers. Concurrently, this drug exhibits substantial variability in pharmacokinetics and therapeutic response across different individuals. We aimed to develop a model to quantitatively investigate factors that affect MHD pharmacokinetics to formulate a dosage guideline for OXC in Chinese paediatric patients. A total of 297 MHD trough concentrations were obtained from 287 epileptic children. Six body weight (BW)-based allometric models were used for population pharmacokinetic modelling, while investigating the impact of other covariates on the apparent clearance. The one-compartment model and age cut-off model for the apparent clearance (CL/F) were established to describe the pharmacokinetics of MHD. The probability to obtain target trough concentration ranges (TTCRs) of MHD between 3 and 35 mg/L was determined by Monte Carlo simulations for doses ranging from 8 to 90 mg/kg/day. A new dose optimization strategy combining the dosage guidelines and Bayesian method provides a tailored approach for Chinese paediatric epileptic patients based on their individual BW and desired TTCRs of MHD, and also supports current dose recommendations, with the exception of children weighing ≤5 kg.

Local protective effects of oral 45S5 bioactive glass on gastric ulcers in experimental animals.

Bioactive glass has been shown to stimulate bone regeneration and soft tissue healing. In this study, we evaluated the local protective effects of bioactive glass on experimental gastric ulcers, in comparison with omeprazole and hydrotalcite. Single and multiple gavage of 45S5 bioactive glass dose-dependently protected stress ulcers in mice and chronic ulcers in rats. Multi-daily gavage of bioactive glass for 7 days prevented chronic ulcer recurrence by 50 %. Bioactive glass ionic dissolution produced marked proliferation of ethanol-injured GES-1 human gastric mucosa epithelial cells 48 and 72 h after exposure. Bioactive glass was shown to be hardly absorbed after single or multi-daily gavage. This study, for the first time, demonstrates that bioactive glass is effective in protecting against gastric ulcers, with its high efficacy comparable to omeprazole and superior to hydrotalcite. The lack of oral absorption makes bioactive glass a potential for treatment of peptic ulcers omitting systemic toxicity or side-effects.

A novel drug selection decision support model based on real-world medical data by the hybrid entropic weight TOPSIS method.

BACKGROUND: The medicine selection method is a critical and challenging issue in medical insurance decision-making. OBJECTIVES: This study proposed a real-world data-based multi-criteria decision analysis (MCDA) model with a hybrid entropic weight Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) algorithms to select satisfactory drugs. METHODS: The evaluation index includes two levels: primary criteria and sub-criteria. Firstly, we proposed six primary criteria to form the value health framework. The primary criteria's weights were derived from the policymakers' questionnaire. Meanwhile, clinically relevant sub-criteria were derived from high-quality (screened by GRADE scores) clinical-research literature. Their weights are determined by the entropy weight (EW) algorithm. Secondly, we split the primary criteria into six mini-EW-TOPSIS models. Then, we obtained six ideal closeness degree scores (ICDS) for each candidate drug. Thirdly, we get the total utility score by linear weighting the ICDS. The higher the utility score, the higher the ranking. RESULTS: A national multicenter real-world case study of the ranking of four generic antibiotics validated the proposed model. This model is verified by comparative experiments and sensitivity analysis. The whole ranking model was consistent and reliable. Based on these results, medical policymakers can intuitively and easily understand the characteristics of each drug to facilitate follow-up drug policy-making. CONCLUSION: The ranking algorithm combines the objective characteristics of medicine and policy makers' opinions, which can improve the applicability of the results. This model can help decision-makers, clinicians, and related researchers better understand the drug assessment process.

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy.

AIMS: Resistance to valproic acid (VPA) is a major challenge for epilepsy treatment. We aimed to explore the mechanism underlying this resistance. METHODS: Pentylenetetrazol-induced chronic epileptic rats were administered VPA (250 mg/Kg) for 14 days; rats with controlled seizure stages (seizure score14th-before ≤0) and latent time (latent time14th-before ≥0) were considered VPA-responsive, while the others were considered nonresponsive. Differentially expressed genes (DEGs) between the VPA-responsive and nonresponsive rat hippocampus transcriptomes were identified, and their functions were evaluated. The roles of postsynaptic density (PSD) and Homer1 were also determined. Furthermore, a subtype of Homer1 (Homer1b/c) was overexpressed or silenced in HT22 cells to determine its effect on VPA efficacy. Moreover, the membrane levels of mGluR1/5 directly bound to Homer1b/c were assessed. RESULTS: Overall, 264 DEGs commonly enriched in the PSD between VPA-responsive and nonresponsive rats. Among them, Homer1 was more highly expressed in the hippocampus of nonresponses compared to that of responses. Overexpression of Homer1b/c interrupted VPA efficacy by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium content. Furthermore, it induced the overexpression of mGluR1 and mGluR5. CONCLUSION: Overexpression of Homer1b/c influenced VPA efficacy, revealing it could be a target to improve the efficacy of this treatment.

First vaccination after birth: serious adverse events of Bacillus Calmette-Guérin (BCG) in real-world.

The Bacillus Calmette-Guérin (BCG) vaccine is a free vaccine in China, and more than 300 million newborns have been vaccinated. Inevitably, the BCG vaccine will have some rare adverse events on the first day of life (24 hours after birth), but related reports are extremely rare. In this commentary, the authors searched the Chinese legal documents database for documents related to serious adverse events caused by BCG from January 2010 to January 2022. Fourteen pediatric cases were identified, including 7 preterm infants and 7 full-term infants. The events included 4 cases of interstitial pneumonia, 3 cases of lymphadenitis, 3 cases of septicemia, 1 case of myocarditis, 1 case of muscle atrophy, 1 case of epilepsy, and 1 case of disseminated BCG vaccine. The mortality rate of preterm infants was 100% and that of full-term infants was 28.6% (2/7). All deaths occurred within one day. The BCG vaccine has good safety for the vast majority of newborns.

To our knowledge, we present the largest case series of BCG vaccine-induced serious adverse events in neonates.The BCG vaccine has good safety for the vast majority of newborns.The incidence of serious adverse events with BCG vaccine may be as low as eight per million.

Inspiration to mRNA-based COVID-19 vaccination: Serious adverse case reports with hepatitis B vaccine in real-world.

Objectives: The hepatitis B vaccine comprises hepatitis B surface antigen (HBsAg) produced by transgenic yeast cells. There are few serious adverse events (SAE) reports after Hepatitis B vaccination. Methods: The authors searched the Chinese legal documents database for all SAE with Hepatitis B vaccination from January 2010 to January 2022. Results: All seven patients received yeast-derived recombinant hepatitis B vaccine. Three cases of myocarditis (death), 2 cases of interstitial pneumonia (death), and 2 cases of encephalitis. The mean time of onset of SAE was 8.3 ± 4.3 h after vaccination. Conclusion: The mechanism of vaccine-induced myocarditis may come from immune protein reactions. Based on the experience of Hepatitis B vaccine adverse events, we present new insights into the mechanism of myocarditis caused by the COVID-19 vaccine.