BackgroundRoflumilast, a highly selective phosphodiesterase 4 inhibitor, is used to treat with chronic obstructive pulmonary disease and psoriasis. We aim to determine potential roflumilast-associated adverse events (AEs) and the differences in AE signals among diverse populations.MethodsRoflumilast’s AE reports between the first quarter of 2011 and the fourth quarter of 2024 were obtained from the FDA Adverse Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Database (CVARD). The signal strength was measured by four disproportionality analysis methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).ResultsIn FAERS, population aged ≥65 years and oral medication users accounted for a predominant proportion in the reported cases. FDA-unlabeled respiratory, thoracic and mediastinal disorders was the only one signal categorized by system organ class met all four algorithms. Newly identified AEs such as dyspnea, condition aggravated, cough, and tachycardia could contribute valuable safety considerations for clinical practice. The analysis of the available time-to-onset data suggested that cases often occurred within the first 30 days post-treatment. These results were externally validated in CVARD, suggesting consistent findings. Notably, headache was more frequently reported among users of topical formulations and female patients, while suicidal ideation and weight loss were more commonly reported in male patients and oral medications, respectively.ConclusionThis study confirmed established adverse reactions and identified novel AEs in real-world clinical practice by dual-database pharmacovigilance analysis. Clinicians should remain vigilant for AEs that differ by gender and route to enable early intervention and improve prognosis. The findings highlight personalized safety management, while underscoring the necessity of prospective studies to validate results and further characterize roflumilast’s safety profile.

Tacrolimus-induced chronic nephrotoxicity (TICN) limits its clinical application without prevention strategies. Identifying a specific target and finding corresponding drug are critical for its prevention. We previously found that transcription factor EB (TFEB), a substrate of calcineurin, is key to TICN. Further exploration of drugs targeting TFEB without compromising tacrolimus efficacy holds promise for preventing TICN. Astragaloside IV (AS-IV), the major bioactive component of Astragali Radix, can alleviate various renal diseases. However, its regulatory effect on TFEB and the underlying mechanism remain unknown. Herein, we found that AS-IV significantly reactivated TFEB and restored tacrolimus-impaired renal function and pathology, autophagy flux and DNA repair. These effects were reversed upon TFEB knockdown. Further studies revealed that AS-IV did not affect calcineurin but activated TFEB by inhibiting mTOR, which dominantly phosphorylated TFEB Ser211. Altogether, this study suggested that AS-IV mitigated TICN via mTOR-TFEB without affecting calcineurin, making it a promising therapeutic agent for TICN.

Background and objectivesLacosamide (LCM) is a third-generation concomitant antiseizure medication (ASM) that is widely used in epilepsy treatment. Reported data on the predictors of efficacy of LCM in children with epilepsy are scarce. This study aimed to explore the predictors of LCM efficacy in pediatric patients with epilepsy.MethodsThis single-center retrospective cohort study was conducted in China, consecutively enrolled pediatric epilepsy patients receiving lacosamide treatment; the study period for data collection was September 2021 to April 2025. Demographic data, LCM daily dose, serum concentration, concentration-to-dose ratio (CDR), ASMs, and seizure frequency before and after treatment were collected. Patients were categorized into effective (≥50% seizure reduction) and ineffective groups. Univariate analysis and ridge regression were used to assess the impact of the factors on the efficacy of LCM. The receiver operating characteristic (ROC) curve was used to evaluate the predictive performance of the ridge regression model.ResultsA total of 71 children with epilepsy were enrolled in this study (boys: 35, 49.3%; girls: 36, 50.7%). The overall effectiveness rate was 81.69%. Univariate analysis showed a significantly higher CDR in the effective group compared to the ineffective group (0.768 vs. 0.58, P = 0.031). In this exploratory pilot analysis, ridge regression implied that CDR has a positive effect on the efficacy of LCM. The AUC of the predictive performance of the ridge regression model was 0.767 (95% CI: 0.651–0.875).DiscussionCDR, reflecting weight- and dose-adjusted LCM exposure, is a predictor of LCM efficacy in pediatric epilepsy. These findings support the use of CDR for guiding individualized LCM therapy. Further multicenter studies with larger samples are warranted to validate these results and establish an optimal CDR range.

Tacrolimus-induced chronic nephrotoxicity (TICN) hinders long-term use of tacrolimus, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate nuclear factor of activated T cells. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain and loss of function rescued and exacerbated, respectively, the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation by both phosphorylation site mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-Seq data. We identified growth arrest and DNA damage-inducible 45α (GADD45α) as a transcriptional target of TFEB via ChIP and dual-luciferase reporter assays. Then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro and vice versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of the TFEB/GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention in TICN.

Background/Objectives: This study aimed to characterize the pharmacokinetic profiles of clobazam (CLB) and its active metabolite, N-desmethylclobazam (N-CLB), by establishing a population pharmacokinetic (PPK) model in Chinese children with epilepsy to propose individualized dosing regimens that achieve better clinical outcomes. Methods: This study examined plasma samples collected from 103 pediatric patients with refractory epilepsy undergoing CLB treatment. The plasma concentrations of CLB and its active metabolite N-CLB were measured. The developmental characteristics, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators of the children with epilepsy were considered potential factors affecting the pharmacokinetic characteristics of CLB and N-CLB and analyzed using a PPK modeling approach. Results: A total of 156 samples were attained for PPK model development. The pharmacokinetic profiles of CLB and N-CLB were described using a tandem one-compartment model with first-order elimination. Body weight and CYP2C19 genotype showed statistical significance for CLB and/or N-CLB clearance. The N-CLB/CLB metabolic ratios of AUC24h, Cmin, and Cmax in a steady state were as follows: normal metabolizers (NMs) < intermediated metabolizers (IMs) < poor metabolizers (PMs). The final model achieved good prediction performance and stability. Monte Carlo simulations demonstrated that the trough concentrations of CLB and N-CLB in children with epilepsy could reach satisfactory target values under varying dose regimens in CYP2C19 NMs and IMs, whereas there was a failure to achieve the desired trough concentrations of CLB and N-CLB simultaneously in CYP2C19 PMs due to the accumulation of N-CLB. Conclusions: Body weight and CYP2C19 genotype had an impact on CLB and/or N-CLB clearance in children with epilepsy. To ensure safe treatment, it is recommended to use the concentration of N-CLB as the target indicator for therapeutic drug monitoring and dose adjustments in CYP2C19 PMs. These results provide evidence for guiding the precise use of CLB.

OBJECT:To explore the influencing factors of lacosamide serum concentration in children with epilepsy, and to provide evidence-based guidance for individualized dosing strategies. METHODS:Clinical data of pediatric epilepsy patients treated with lacosamide from September 2021 to January 2025 were retrospectively analyzed. Participants were stratified by age into ≤6, 6-12, and >12 years groups. Non-parametric tests were employed to compare differences in daily dose, weight-adjusted daily dose, serum concentration, and concentration-to-dose ratio (CDR) across sex, age, and concomitant antiepileptic drugs (AEDs) groups. Multiple linear regression analysis was conducted to identify independent factors influencing serum concentration. RESULTS:The study enrolled 438 patients (boys: 261, 59.59%; girls: 177, 40.41%), with age distribution as follows: ≤ 6 years (n = 85, 19.41%), 6-12 years (n = 294, 67.12%), and >12 years (n = 59, 13.47%). The > 12 years group exhibited significantly higher daily dose, weight-adjusted daily dose, and CDR compared to younger cohorts. Concomitant use of non-hepatic enzyme-inducing AEDs resulted in elevated serum concentration and CDR relative to lacosamide monotherapy. Regression analysis identified body weight, weight-adjusted daily dose, and coadministration of non-hepatic enzyme-inducing AEDs as independent predictors of serum concentration. CONCLUSION:Age and concomitant non-hepatic enzyme-inducing AEDs therapies significantly influence lacosamide exposure, underscoring the necessity for age-based dynamic dose optimization and rigorous evaluation of polypharmacy regimens to achieve precision therapeutics.

[This corrects the article DOI: 10.3389/fphar.2020.610102.].

Thrombocytopenia is one of the side effects of VPA. This study aimed to evaluate the incidence and risk factors of thrombocytopenia after intravenous VPA treatment in children with neurosurgical operations. Pediatric patients undergoing neurosurgical operations treated with intravenous VPA were enrolled in this retrospective study. According to platelet count after intravenous injection of VPA, the pediatric patients were divided into the thrombocytopenia group and the non-thrombocytopenia group. Binary logistic regression analysis was used to explore the risk factors for thrombocytopenia. A total of 252 children with neurosurgical operations were included in this study, and the incidence of thrombocytopenia was 12.3% (31/252). Univariate analysis showed that baseline platelet count, duration of VPA therapy, and blood loss were associated with the occurrence of thrombocytopenia after intravenous administration of VPA. Binary logistic regression revealed that baseline platelet count (OR 0.995, 95% CI 0.991-0.999) and blood loss (OR 0.995, 95% CI 0.991-0.999) were independent risk factors for thrombocytopenia after intravenous VPA in children undergoing neurosurgical operations. Our data show that thrombocytopenia is common in neurosurgical operations children treated with intravenous VPA, and that baseline platelet count is an independent risk factor for thrombocytopenia. Regular monitoring of baseline platelet count is important for whether to short-term prophylactic use intravenous VPA in children undergoing neurosurgical operations.

ObjectiveThe aim of this study was to develop a population pharmacokinetic model for ceftazidime in critically ill children in the pediatric intensive care unit (PICU) and optimize an appropriate dosing regimen for this population.MethodsWe performed a prospective pharmacokinetic study on critically ill children aged 0.03–15 years. A population pharmacokinetic model was developed using the NLME program. Statistical and graphical methods were used to assess the stability and predictive performance of the model. Monte Carlo simulations were conducted to determine the optimal ceftazidime dosing regimen to achieve 70% fT > minimum inhibitory concentration (MIC).ResultsThis study included 88 critically ill children and 100 ceftazidime serum concentrations. The pharmacokinetic characteristics of ceftazidime were best described by a one-compartment linear elimination model. The weight and estimated glomerular filtration rate (eGFR) were determinant covariates for the clearance (CL) of ceftazidime. The recommended ceftazidime dosage regimens achieved a probability of target attainment (PTA) >90% for critically ill children at MIC values of 2, 4, and 8 mg/L. For bacterial infection at an MIC of 16 mg/L, it is difficult to achieve effective pharmacodynamic (PD) targets in vivo with the commonly used dose of ceftazidime.ConclusionThe population pharmacokinetic model of ceftazidime was established in critically ill children. Based on this model, we recommend evidence-based, individualized dosing regimens for subgroups with different weights and renal functions. The current daily dosage for children adequately meets the treatment requirements for MICs of 2, 4, and 8 mg/L, while for bacterial infection at an MIC of 16 mg/L, an elevated dosage regimen may be required.Clinical Trial Registrationhttps://www.medicalresearch.org.cn/login, Identifier MR-42-22-000220.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

目的 了解抗菌药物在儿童患者个体化治疗中的开展情况.方法 对全国30家儿童医院和综合医院儿科开展抗菌药物个体化治疗的情况进行问卷调查,使用Microsoft Excel 2007和SPSS 26.0软件对调查数据进行统计分析.结果 本次调查共收回75份问卷,其中有效问卷53份,有效率为70.7％.调查发现,86.7％(26/30)的医院以不同形式开展了儿童抗菌药物个体化治疗.临床需求是推动多家医院开展个体化治疗的主要动力,而人员设备不足是最大障碍.开展循证药学、治疗药物监测(TDM)、模型引导的精准用药(MIPD)和抗菌药物相关基因检测的医院占比分别为70.0％、80.0％、30.0％和33.3％.各医院开展TDM的检测方式多样,涉及的儿童抗菌药物以万古霉素和伏立康唑为主.有近一 半的药师对MIPD尚不甚了解.结论 TDM是目前各医疗机构开展儿童抗菌药物个体化治疗的主要方式,但其监测覆盖范围及检测标准均有待提高.MIPD和抗菌药物相关的基因检测技术仍需在临床进一 步推广.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

OBJECTIVE:To study the medication in children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Wuhan, China, and to provide a reference for rational drug use in clinical practice. METHODS:A retrospective analysis was performed on the medical data of the children who were diagnosed with SARS-CoV-2 infection from January 26 to March 5, 2020. The children were divided into an asymptomatic group with 41 children and a symptomatic group with 73 children. A subgroup analysis was performed to investigate the effect of different antiviral regimens (monotherapy, double therapy, or triple therapy) and whether interferon α-1b was used in combination with azithromycin on the length of hospital stay and the clearance time of SARS-CoV-2 nucleic acid. RESULTS:A total of 114 children with SARS-CoV-2 infection (72 boys and 42 girls) were enrolled. The median age of the children was 7.1 years. The median length of hospital stay was 10 days and the clearance time of SARS-CoV-2 nucleic acid was 6 days. In either group, the subgroup analysis showed no significance differences in the length of hospital stay and the clearance time of SARS-CoV-2 nucleic acid between the subgroups treated with different combinations of antiviral drugs and the subgroups treated with interferon α-1b alone or in combination with azithromycin (P > 0.05). CONCLUSIONS:It is not recommended to use the routine combinations of antiviral drugs for children with SARS-COV-2 infection or combine with azithromycin for the purpose of antiviral therapy.

Abstract We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolising enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated. UGT2B7 rs7668258 (C>T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β=–0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in paediatric patients with UGT1A6 rs2070959 (A>G) GG genotype compared to those AA genotype (β=–0.270, p = 0.021). This research indicated that UGT2B7 rs7668258 (C>T) and UGT1A6 rs2070959 (A>G) polymorphisms may be correlated to the normalised plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

目的:探讨他克莫司治疗儿童肾病综合征(NS)时的最佳血药浓度范围.方法:选择2015年1月至2018年3月在武汉儿童医院住院,接受他克莫司治疗的难治性NS患儿95例,随访至少1年,每例患儿均在用药过程中监测他克莫司血药浓度,观察患儿的缓解率和不良反应情况.运用受试者工作特征曲线(ROC)分析浓度与疗效的关系.结合ROC分析结果和文献报道,将患儿分为A (＜3 ng·mL-1)、B(3～4 ng· mL-1)、C (4～5 ng·mL-1)和D(5～10 ng·mL-1)4组,使用卡方或Fisher检验比较各组间的疗效和不良反应.结果:54例患者完全缓解,22例部分缓解,19例治疗无效,3种疗效组间他克莫司浓度存在显著性差异.以谷浓度作为疗效预测因子构建的ROC曲线下面积为0.77,谷浓度临界值为3.40 ng· mL-1.将95例患儿按浓度分组,A组疗效显著低于D组,B组和C组的疗效与D组无显著性差异,4组间不良反应发生率无显著性差异.我们进一步分析了他克莫司治疗不同类型NS时的最佳浓度,结果发现激素耐药型NS和频复发型NS患儿中,只有A组疗效显著低于D组;在病理为微小病变的患儿中,A组和B组疗效显著低于D组;在系膜增生性肾小球肾炎患儿中,只有A组疗效显著低于D组.结论:他克莫司治疗儿童NS的疗效与谷浓度水平密切相关,在诱导缓解期其治疗窗的下限可由5 ng·mL-1降低至4 ng·mL-1,此浓度既能达到满意的治疗效果,又能降低患儿的治疗费用.

Tic disorders, which are mainly characterized by motor and/or vocal tics, are common pediatric neuropsychiatric disorders.Pharmacotherapy is an important part of the management of tic disorders.In addition to the individualized grasp of its indications, medicine selection also needs to weigh the risks and benefits.This article made an overview and evaluation of pharmacological treatments for children with tic disorders, so as to acquire the best available evidence on the efficacy and safety of the relevant medicines and to improve clinical decision-making.

目的 提高新型冠状病毒肺炎(简称新冠肺炎)疫情下医院药学服务质量.方法 基于笔者在派驻武汉某新冠肺炎定点医院期间的工作经历,总结分析该院药师疫情期间开展紧缺物资保障供应、药学科普教育、药学监护和临床会诊、新药疗效评价、精麻药品管理等工作.结果 该院通过建立西药房、中药房、住院药房、急诊药房、药库"五位一体"的药房管理模式,从药品申请流程源头杜绝药品滥用,智能信息化控制冷链温湿度,信息化动态监控药品信息,建立药学监护分类管理模式及监护要点,参与隔离病房药学查房,提供药学专业保障并分享临床经验,创新麻醉药品管理模式,真实、完整、系统管理捐赠药品等措施,确保了疫情期间药房药学服务的优质、高效.结论 该院疫情期间的药学服务实践经验值得借鉴.

目的:筛选黄芪改善他克莫司慢性肾毒性的活性组分,并初步阐明其作用机制.方法:将48只C57BL/6小鼠随机分为6组:空白对照组、模型组、黄芪总提取物组、黄芪总黄酮组、黄芪多糖组和黄芪总皂苷组,每组8只.除空白对照组外,其余各组采用他克莫司诱导慢性肾毒性模型,各治疗组同时灌胃给予相应的治疗药物,qd,连续28d.末次给药后,检测各组小鼠尿量、体质量、血肌酐(SCr)、尿素氮(BUN);HE和Masson染色观察肾组织病理改变,Western blot检测肾组织转化生长因子β1(TGF-β1)、Ⅰ型胶原蛋白(Collagen Ⅰ)和α-平滑肌肌动蛋白(α-SMA)的表达,应用试剂盒测定超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛(MDA)水平.结果:与模型组相比,黄芪总提取物组、黄芪多糖和黄芪总皂苷可显著降低小鼠SCr、BUN、肾小管间质纤维化程度、TGF-β1 、Collagen Ⅰ和α-SMA的蛋白表达(P＜0.05或P＜0.01),增加抗氧化酶SOD、CAT和GSH-Px的活性(P＜0.05或P＜0.01),显著降低MDA水平(P＜0.05或P＜0.01),而黄芪总黄酮无明显作用(P＞0.05).结论:黄芪多糖和黄芪总皂苷可能是黄芪发挥肾毒性保护作用的活性组分,其作用机制可能与减少氧化应激相关.

目的 探讨重症先天性膈疝患儿围手术期的药学监护要点.方法 回顾性分析临床药师参与的1例先天性膈疝合并肺动脉高压患儿围手术期治疗过程,从优化镇静镇痛、抗感染方案制定以及血管活性药物选择等方面讨论该病种患儿药学监护思路及策略.结果 临床药师以维持患儿呼吸循环稳定、控制术后感染为主要出发点提供药学技术支撑,协助临床医师进行用药决策,使该患儿成功度过术后危险期.结论 临床药师积极参与先天性膈疝用药监护,通过紧密结合各类药物不同品种药理学特性与患儿病理生理学特点进行综合分析,可以提高重症患儿个体化用药水平.

Today, an increase in vancomycin dose has been proposed to ensure efficacy. However, the risk of nephrotoxicity will increase with the dose. The aim of this study was to evaluate the dosage regimens of vancomycin in pediatric patients based on pharmacokinetics/pharmacodynamics (PK/PD) and to optimize dosage individualization. Population pharmacokinetics analysis was performed on 155 Chinese children (aged 1 month to 16 years), which were divided into various renal function subpopulations. Monte Carlo simulation was carried to evaluate the efficacy and safety of vancomycin dosage regimens on each subpopulation. Compared with children with normal renal function as glomerular filtration rate (GFR) ≥ 90 mL/min·1.73 m2, the clearance of vancomycin decreased by 39.4% and the half life increased 1.74 fold respectively in children with moderate renal inadequacy (30 ≤ GFR < 60 mL/min·1.73 m2). When vancomycin was administered as conventional dosage (40-60mg·kg-1·d-1) to against methicillin-resistant staphylococcus aureus (MRSA) with higher MICs of 1-2 mg·L-1 for children with normal renal function, the probability of efficacy target attainment ( PTA) at AUC0-24h/MIC ≥ 400 (where AUC is the area under curve and MIC is the minimum inhibitory concentration) achieved ≤ 63.64%. While vancomycin dosage exceeded 70mg·kg-1·d-1 for children with normal renal function, 50mg·kg-1·d-1 for mild renal inadequacy (60 ≤ GFR < 90 mL/min·1.73 m2), 30 mg·kg-1·d-1 for moderate renal inadequacy respectively, the PTA at trough concentration above 20 mg·L-1 achieved > 20%, that not to be suggested for high risk of nephrotoxicity. Considering both efficacy and safety, the conventional vancomycin dosage is not enough and adjustable interval is narrow for pediatric patients with MIC 1-2 mg·L-1 MRSA infection and normal renal function.