Background The value of pharmaceutical services for Chinese patients with cardiovascular chronic conditions was not recognized. Aim To investigate the comprehensive value of pharmaceutical services in China and find factors influencing patient benefits. Design and setting This was a systematic review with multilevel meta-analysis of 183 randomized control trials focusing on the benefits of pharmaceutical services for patients with cardiovascular chronic conditions in China. Methods English databases (PubMed, EMBASE, the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure, WanFang database) were searched from database inception to March 27, 2023 for studies focusing on the comparation of benefits between pharmaceutical services and usual care. Results Our analysis of 187 studies involving 23,895 patients demonstrated significant benefits of pharmaceutical services, particularly in reducing readmission (OR: 0.32; 95%CI: 0.2 to 0.52; I2=50.12%), mitigating ADR (OR: 0.28; 95%CI: 0.24 to 0.33; I2=18.07%), and improving patient adherence. However, no benefit was observed in terms of mortality rate and the cost of hospitalization and medication and the risk of bias was generally existed among the included studies. Conclusions This study highlights the significant benefits of pharmaceutical services for clinical outcomes and adherence among Chinese patients with cardiovascular chronic conditions. However, the benefits in terms of economic outcomes remain unclear. The influence of population-specific factors, such as disease and age, underscores the need for context-specific and disease-tailored studies to provide precise evidence regarding the advantages of pharmaceutical services. And our findings provide some new ideas for the subsequent research and design, standard formulation and policy implementation. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Crisaborole ointment, 2%, is a non-steroidal, topical anti-inflammatory phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. To date, a specific analytic method of crisaborole in plasma has not been reported. The aim of this study was to develop a rapid, sensitive and robust UHPLC-MS/MS method for the quantitative detection of crisaborole in human plasma by using deuterated crisaborole-d4 as the internal standard (IS). The analyte was well extracted from human plasma with acetonitrile and subsequently eluted with gradient acetonitrile and water in short run time of 3.3 min. Negative electrospray ionization in multiple reaction monitoring mode was employed to acquire the quantification ion pairs of m/z 250.0→118.0 for crisaborole and m/z 254.0→121.9 for IS. The assay met the regulations of the US Food and Drug Administration and the European Medicines Agency for assay validation with a good linearity in the calibration range of 0.20-80 ng/mL. Intra-day and inter-day precision was less than 9.17% and the accuracy was - 2.29%-6.33% across all the quality control samples. The average extraction recovery of analyte and IS was 84.61% and 91.43%, respectively, and consistent over different quality control samples. The fully validated method was successfully used for the drug level measurement in ten healthy Chinese subjects receiving crisaborole ointment. Our novel UPLC-MS/MS assay for the quantification of plasma crisaborole concentrations in human samples may be easily used in clinical practice and help to reveal the pharmacokinetic profiles of crisaborole in Chinese population.

Background: Medication therapy management (MTM) services is a method that can effectively improve patients’ conditions, but the efficacy of economic and humanistic outcomes remain unclear. This systematic review and meta-analysis aim to use economic, clinical and humanistic outcomes to evaluate the multi-benefits of MTM services.Method: A systematic review and meta-analysis was conducted by retrieving PubMed, EMBASE, the Cochrane Library and ClinicalTrial.gov from the inception to April 2022. There were two reviewers screening the records, extracting the data, and assessing the quality of studies independently.Results: A total of 81 studies with 60,753 participants were included. MTM services were more effective in clinical outcomes with decreasing the rate of readmission (OR: 0.78; 95% CI: 0.73 to 0.83; I2 = 56%), emergency department visit (OR: 0.88; 95% CI: 0.81 to 0.96; I2 = 32%), adverse drug events (All-cause: OR: 0.68; 95% CI: 0.56 to 0.84; I2 = 61%; SAE: OR: 0.51; 95% CI: 0.33 to 0.79; I2 = 35%) and drug-related problems (MD: −1.37; 95% CI: −2.24 to −0.5; I2 = 95%), reducing the length of stay in hospital (MD: −0.74; 95% CI: −1.37 to −0.13; I2 = 70%), while the economic and humanistic outcomes were less effective.Conclusion: Our systematic review and meta-analysis demonstrated that MTM services had great ability to improve patients’ clinical conditions while the efficacy of economic and humanistic outcomes, with some of the outcomes showing high degree of heterogeneity and possible publication bias, required more future studies to provide stronger evidence.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349050], identifier [CRD42022349050].

BACKGROUND:Nivolumab improves overall survival (OS) and is associated with less adverse events (AE) compared with sorafenib in the first-line treatment of advanced hepatocellular carcinoma (HCC). But which approach is the most cost-effective remains uncertain. This study aimed to evaluate the cost-effectiveness of nivolumab vs sorafenib as first-line therapy for patients with advanced HCC from the perspective of Chinese healthcare system.METHODS:A partitioned survival mode was constructed to evaluate the health and economic outcomes of nivolumab vs sorafenib as first-line treatment for advanced HCC. The clinical data and outcomes were obtained from CheckMate 459 trial. Medical costs and utilities were collected from published sources. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. Additional subgroup and scenario analyses were performed.RESULTS:Treatment with nivolumab yielded an additional 0.27 QALYs with an incremental cost of $65,579.19 compared with sorafenib, leading to an ICER of $236,765.93/QALY in China. One-way sensitivity analysis found the model outputs to be most affected for hazard ratio (HR) of OS and the cost of nivolumab. Probabilistic sensitivity analysis showed that the probability of nivolumab being cost-effective was 0% at the willingness-to-pay (WTP) threshold of $38,201.19/QALY. The scenario analyses indicated altering the time horizon of the model did not reverse the economic results.CONCLUSION:Nivolumab as first-line treatment could gain more health benefits for advanced HCC compared with sorafenib, but was estimated not to be cost-effective at the commonly adopted WTP threshold of China.

Imatinib is an oral tyrosine kinase inhibitor (TKI) and first-line therapy for patients with chronic myeloid leukemia (CML). There is a positive correlation between serum imatinib concentrations and treatment response. However, the specific relationship between the blood concentration of imatinib and its influencing factors remains unclear. This study collected basic information from 102 patients using imatinib as first-line treatment for CML. Further, we analyzed the individual differences in imatinib concentration and explored its influencing factors. Through intra-day and inter-day precision studies, we found that the precision for the imatinib assay methodology was within +/- 13% and that the recovery rate was above 85%. There is notable individual variation in the blood concentration of imatinib; the recommended treatment concentration is 860-1500 ng/mL, with only 41.40% of patients achieving this concentration. Also, there was a negative correlation between age and imatinib trough concentration (C-trough), as is observed between age and N-desmethyl imatinib. Moreover, compared with the adolescent group, the serum imatinib C-trough for groups aged 17-47 and 48-68 years was significantly reduced. Further analysis shows that imatinib C-trough values reaching therapeutic concentrations (59%) increased dramatically for patients with CML aged 17-47 years. Moreover, groups dosed with 400 mg/day resulted in therapeutic imatinib concentrations for 68% of patients with CML, which was the best performance. The established method was validated, with acceptable accuracy, precision, linearity, and stability, as required, and then successfully applied to the therapeutic drug monitoring of imatinib. Age, dose, and metabolites can influence the imatinib concentration and its therapeutic effect in patients with CML.

BackgroundSemaglutide was approved for treatment of type 2 diabetes mellitus (T2DM) and chronic weight management in obesity or overweight adults. However, real-world data regarding its long-term gastrointestinal safety and tolerability in large sample population are incomplete. We evaluated semaglutide-associated gastrointestinal safety signals by data mining of the FDA pharmacovigilance database.MethodsReporting odds ratio (ROR) was employed to quantify the signals of semaglutide-related gastrointestinal adverse events (AEs) from 2018 to 2022. Serious and non-serious cases were compared by Mann-Whitney U test or Chi-squared (χ2) test, and signals were prioritized using a rating scale.ResultsWe identified 5,442 cases of semaglutide-associated gastrointestinal AEs, with 45 signals detected, ranging from a ROR025 of 1.01 (hypoaesthesia oral) to 42.03 (eructation), among which 17 AEs were identified as new and unexpected signals. Patient age (p < 0.001) and body weight (p = 0.006) rather than sex (p = 0.251) might be associated with an increased risk of gastrointestinal AEs severity. Notably, the association between semaglutide and gastrointestinal disorders remained when stratified by age, body weight, sex and reporter type. One strong, 22 moderate and 22 weak clinical priority signals were defined. The median time-to-onset (TTO) for strong clinical priority signal was 23 days, while for moderate and weak, they were 6 and 7 days, respectively. All of the disproportionality signals had early failure type features, suggesting that the risk of gastrointestinal AEs occurrence gradually decreased over time.ConclusionOur study provided a deeper and broader understanding of semaglutide's gastrointestinal safety profiles, which would help healthcare professionals to mitigate the risk of gastrointestinal AEs in clinical practice.

目的:对帕博利珠单抗和纳武利尤单抗的不良事件(ADE)信号进行挖掘分析,为临床安全用药提供参考.方法:从美国食品药品管理局不良事件报告系统(FAERS)提取2016年第1季度至2021年第3季度共23个季度的ADE报告,数据去重后,利用报告比值比法(ROR)和比例报告比值法(PRR)对帕博利珠单抗和纳武利尤单抗的ADE报告进行数据筛选与分析,挖掘ADE信号.结果:共获得以帕博利珠单抗和纳武利尤单抗为首要怀疑药物的ADE报告67844份,最终得到ADE信号1368个(帕博利珠单抗641个,纳武利尤单抗727个),累及22个系统,主要涉及呼吸系统疾病、全身性疾病及给药部位各种反应和内分泌系统疾病等.报告数和信号强度前20位的ADE中未在说明书中出现的信号2个(帕博利珠单抗1个,纳武利尤单抗1个).结论:本研究挖掘出的常见ADE信号和其累及系统与说明书一致,但ADE具有免疫介导性且发现新信号,可为临床安全用药提供一定的参考.

OBJECTIVE:Poly ADP-ribose polymerase inhibitors (PARPis) have significantly improved clinical effects in gynecological oncology. However, PARPis could also induce severe organ system toxicities, including the hematological system. Our study aimed to extensively characterize the hematological toxicities of PARPis based on the real-world data. METHODS:Disproportionality analysis was used to evaluate the association between PARPis and hematotoxicity adverse events. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database between January 2015 and September 2021. The characteristics of PARPi-associated hematological toxicities, and the onset time and fatality proportion were further analyzed. RESULTS:Out of 24,045 adverse events reports, 4088 hematotoxicity reports (17.00%) were analyzed, with a median age of 64.95 (interquartile range [IQR] 51-71) years. All PARPis were detected with positive safety signals of hematological toxicities in four detection methods. Unexpected significant adverse events such as lymphadenopathy, lymphoedema, and metastases to lymph nodes might also occur. The median time-to-onset was 28 (IQR 10-101) days and the fatality proportion of hematological toxicities with PARPis was 8.76%, with a statistical difference in different PARPis. CONCLUSION:Hematological toxicities caused by PARPis preferred to occur early and might result in serious outcomes. Early identification and response to the PARPi-related hematological toxicities were important and further basic research were needed to confirm the mechanism of results in this study.

目的:建立高效液相色谱-串联质谱法测定雷公藤制剂中雷公藤甲素、雷公藤内酯酮、雷公藤晋碱、雷公藤次碱和雷公藤红素的含量.方法:采用电喷雾正电离模式和多反应监测模式.雷公藤甲素、雷公藤内酯酮、雷公藤晋碱和雷公藤次碱含量测定,以含5 mmol·L-1碳酸氢铵的水溶液和纯甲醇作为流动相,采用梯度洗脱方式在ACE UltraCore SuperPhenylHexyl(2.1 mm×50.0 mm,5 μm)色谱柱上进行分离.雷公藤红素含量测定,以含0.5％甲酸的水溶液和含0.1％甲酸的乙腈作为流动相,采用等度洗脱在ACE Excel C18-AR(2.1 mm×50.0 mm,5 μm)色谱柱上进行分离.结果:雷公藤甲素、雷公藤内酯酮、雷公藤晋碱、雷公藤次碱和雷公藤红素分别在2.4～1 200,2.0～1 000,80～40 000,80～40 000和10～5 000 ng·mL-1范围内线性关系良好,平均加样回收率分别为94.56％,102.36％,93.27％,95.67％和99.82％,RSD均低于5.13％.结论:本方法运行时间短,灵敏度高,精密度和重复性好,适用于雷公藤制剂中雷公藤甲素、雷公藤内酯酮、雷公藤晋碱、雷公藤次碱和雷公藤红素5种活性成分定量检测,可为雷公藤制剂多指标质量控制提供实验依据.

目的 探讨奥拉帕利在铂敏感复发性浆液性卵巢癌维持治疗中的成本-效果.方法 基于已发表的一项临床随机对照试验,根据疾病发展过程建立Markov模型,将卵巢癌患者的疾病发展过程划分为无进展生存状态、疾病进展状态和死亡状态,对奥拉帕利组与安慰药组进行成本-效果分析,并通过单因素敏感性分析和概率敏感性分析方法对结果的不确定性进行评价.结果 根据Markov模型分析结果,奥拉帕利组对比安慰药组的ICER值为70 076.70元/质量调整生命年(QALY),低于我国居民的意愿支付阈值(217 341.00元/QALY),具有成本-效果优势.单因素敏感性分析结果提示,奥拉帕利药物治疗费用对成本-效果分析结果的影响最大.结论 与安慰药方案相比,医保报销75％后奥拉帕利用于铂敏感复发性浆液性卵巢癌的维持治疗具有成本-效果优势.

Objective The purpose of this study was to evaluate the cost-effectiveness of nivolumab plus chemotherapy vs. chemotherapy as first-line therapy in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma from the perspective of the Chinese healthcare system. Methods This economic evaluation used a state-transition Markov model to assess the cost and effectiveness of nivolumab plus chemotherapy vs. chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma. The characteristics of patients in the model came from a phase 3 open-label randomized clinical trial (CheckMate 649). Key clinical data were based on the CheckMate 649 trial conducted from March 2017 to April 2019, and costs and utilities were collected from the published literature. The total cost of treatment per patient, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated for the two treatment strategies. Deterministic sensitivity analysis and probabilistic sensitivity analysis were performed. Results In the baseline analysis, the incremental effectiveness and cost of nivolumab plus chemotherapy vs. chemotherapy were 0.28 QALYs and $78,626.53, resulting in an ICER of $278,658.71/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The model was sensitive to the duration of progression-free survival (PFS) for the nivolumab plus chemotherapy group, the cost of nivolumab per 100 mg, and the utility of PFS. Conclusion Nivolumab plus chemotherapy was clearly not a cost-effective treatment strategy compared with chemotherapy as first-line therapy for patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma in China. Reducing the price of nivolumab may improve its cost-effectiveness.

目的 分析培美曲塞+贝伐珠单抗(Pem-Bev)维持治疗晚期非鳞状非小细胞肺癌的经济性.方法 基于已发表的一项Ⅲ期临床随机对照试验,根据疾病进展历程建立Markov模型,将患者的疾病发展过程归为疾病无进展(PFS)、疾病进展(PD)及死亡(Death)3种状态,对Pem-Bev方案与贝伐珠单抗(Bev)方案进行成本-效果分析,采用单因素敏感性分析和概率敏感性分析法评估模型结果的稳定性.结果 Markov模型输出结果显示,Pem-Bev方案对比Bev方案的增量成本-效果比(ICER)值为562006.38元/QALY,高于我国患者支付意愿(WTP)阈值(3倍GDP,217341.00元/QALY);单因素敏感性分析结果显示,对成本-效果分析结果影响最大的因素依次是PD状态治疗成本、Bev成本、PFS状态效用值;概率敏感性分析结果显示,WTP值为3倍GDP时,Pem-Bev方案具有成本-效果优势的概率为1.91％.结论 与Bev方案相比,Pem-Bev方案维持治疗晚期非鳞状非小细胞肺癌不具有成本-效果优势.

Purpose: Secukinumab was approved for the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. However, the long-term safety of secukinumab in large sample population was unknown. The current study was to evaluate the secukinumab-assocaited adverse events (AEs) through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports in the FAERS from the first quarter of 2015 (FDA approval of secukinumab) to the third quarter of 2021 were collected and analyzed. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed in data mining to quantify the signals of secukinumab-related AEs. Results: A total of 89,228 reports of secukinumab as the “primary suspected (PS)” and 254,886 AEs induced by secukinumab were identified. Secukinumab-induced AE occurrence targeted 27 system organ classes (SOCs). A total of 257 signals of secukinumab-induced AEs in 19 SOCs were detected after conforming to the four algorithms simultaneously. Common significant signals of infections, respiratory disorders, skin and subcutaneous tissue disorders, immune system disorders, and ear and labyrinth disorders have emerged. Unexpected significant AEs such as injection site pain, vessel puncture site haemorrhage, arthralgia, hypokinesia, Bell’s palsy, parotid gland enlargement, and stress might also occur. The median onset time of secukinumab-associated AEs was 56 days (interquartile range [IQR] 5–214 days), and most of the onsets occurred within the first 1, 2, 3, and 4 months after initiation of secukinumab. Conclusion: Our study found potential new AE signals and provided a broader understanding of secukinumab’s safety profiles, supporting its rational use in chronic systemic inflammatory diseases.

目的:建立高效液相色谱串联质谱法(HPLC-MS/MS)测定人血浆中霉酚酸的浓度,并与酶放大免疫分析法(EMIT)测定的结果进行对比.方法:经霉酚酸治疗的患者血浆样本共111份,以EMIT法进行常规监测后再用HPLC-MS/MS法复测,采用Kolmogorov-Smirnova检验、配对t检验、Pearson相关分析、Passing-Bablok回归法和Bland-Altman 一致性限度图研究2种方法测定结果的相关性和一致性,并进行经济学分析.结果:EMIT法和HPLC-MS/MS法测定霉酚酸血浆药物浓度结果的差异有统计学意义,EMIT法检测值(CEMIT)比HPLC-MS/MS法检测值(CHPLC-MS/MS)高(27.28±28.62)％,Passing-Bablok回归方程为CHPLC-MS/MS=0.931×CEMIT-0.367,r=0.988.此外,HPLC-MS/MS法检测单个样本的成本比EMIT法低35.4元.结论:该研究建立的HPLC-MS/MS法与EMIT法具有较好的相关性,与EMIT法相比,HPLC-MS/MS法成本低,减轻了患者的经济负担,可替代EMIT法用于霉酚酸的常规监测.

Background: Medication therapy management (MTM) service is an effective method to reduce medication-related problems and improve patients' multiple kinds of outcomes. However, the lack of comprehensive review for MTM services has hindered its development. As a result, we are aiming to evaluate the current benefits of MTM services with multiple outcomes. Method: An electronic search will be performed for randomized controlled trials (RCTs) or non-randomized control trials (NRCTs) that reported MTM services or pharmaceutical services as interventions from PubMed, The Cochrane Library, Embase, and ClinicalTrial. gov. The odds ratios, mean differences, and standard mean differences and their 95% confidence intervals (95% confidence intervals) will be calculated with fixed or random effect models. Results: This study will evaluate the multiple benefits of MTM services in clinical endpoints, quality of life, economy, and drug-related problems. Conclusion: The results will review eligible studies released in the past twenty years and provide more comprehensive evidence of the efficacy of MTM services. Ethics and dissemination: Ethical approval is not applicable for this study.

Objective: The purpose of this study was to estimate the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system.Methods: A Markov model was developed to simulate the outcomes and direct medical costs of osimertinib or standard EGFR-TKI in the first-line treatment of patients with previously untreated EGFR-mutated advanced NSCLC. Individual patient survival data were extracted from the FLAURA randomized clinical trial. Clinical costs and utilities’ input estimates were collected from the local hospital and available literature reports. The quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were calculated for the two treatment strategies over a 10-year lifetime horizon. In addition, one-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to test the robustness of the model.Results: On baseline analysis, osimertinib achieved additional 0.39 QALYs and $15,443.78 incremental costs compared with standard EGFR-TKI (gefitinib or erlotinib), which resulted in the ICER of $39,369.53/QALY. The INMB was -$755.11, and the INHB was -0.02 QALYs at a WTP threshold of $37,663.26/QALY in China. The one-way sensitivity analysis showed that the utility of PFS had the strongest association with the ICER. Osimertinib had approximately 46.4% probability of being cost-effective at the WTP threshold of $37,663.26/QALY.Conclusion: First-line osimertinib therapy might not be cost-effective in China for patients with EGFR-mutated advanced NSCLC compared with standard EGFR-TKI based on its current marketed price. A significantly more favorable cost-effectiveness could be achieved when the price of osimertinib was reduced by 5%.

OBJECTIVE:In 2017, China launched a new round of medical reform (NMR) to address the inaccessibility of high-priced drugs for patients with serious diseases. This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies (mAbs), and the effective promotion policies after the NMR.METHODS:We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province, China. By interviewing hospital pharmacy experts, we identified the potential value of the current NMR in improving the access to therapeutic mAbs.RESULTS:The average availability of 13 mAbs increased by 8.1% in the surveyed hospitals of Hubei province after the NMR. The median unit price of 10 mAbs dropped by 34.3%. The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident (56.2% reduction). The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs. However, the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs.CONCLUSION:Not all current NMR policies play a positive role in promoting the accessibility of mAbs. To further improve the accessibility of mAbs in the future in China, it is therefore critical to increase the investment in independent research and development of high-quality mAbs, establish localized guidelines for the rational use of mAbs in clinical practice, and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.

ETHNOPHARMACOLOGICAL RELEVANCE:Tacrolimus (TAC) was widely used in various renal diseases while high recurrence rate and high expense restricted its applications. Traditional herbal medicine has become increasingly popular as an adjuvant therapy to minimize the adverse effects of TAC. Colquhounia root tablet (CRT), a prescribed drug prepared from the water extract of the peeled root of Tripterygium hypoglaucum (H. Lév.) Hutch., showed excellent anti-inflammatory, analgesic and immunosuppressive pharmacological properties. TAC used in combination with CRT was substantially more efficacious and safer than the monotherapy for the treatment of nephrotic syndrome. However, studies on their herb-drug interaction were scanty. AIM OF THE STUDY:The study was proposed to examine the effect of CRT on the pharmacokinetics of TAC in rats and identify the key natural constituents in CRT that affected the metabolism of TAC. MATERIALS AND METHODS:TAC was orally and intravenously administered to rats alone or in combination with CRT and the pharmacokinetic parameters of TAC were compared. After pretreatment with CRT for 15 d, the expressions of the drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs) were determined by polymerase chain reaction and western blotting and compared with the control group. The hepatic microsomal incubation system was employed to confirm the inhibitory effects of CRT and its major components on rat cytochrome P450 (CYP) 3A2. The roles of the primary components in the regulation of human CYP3A4 and mouse P-gp activities were evaluated by using docking analysis. RESULTS:The blood concentrations of TAC were significantly increased in a dose- and pretreatment time-dependent manner after combined administration of CRT. The maximal effect was found at 300 mg/kg (43.70 ± 8.77 ng/mL and 141.45 ± 21.58 h·ng/mL) in a single dose run and the pharmacokinetic parameters gradually returned to the normal levels at 24 h interval of long-term CRT pretreatment. In contrast, CRT had no effect on the pharmacokinetics of intravenous TAC. Further study indicated that the mRNA and protein expressions of DMEs and DTs, such as CYP3A1, CYP3A2, P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 in rat intestine and liver were down-regulated, whereas the expressions of NRs like constitutive androstane receptor and pregnane X receptor were up-regulated after multiple oral doses of CRT. Molecular docking showed the binding potency of five CRT major constituents with both human CYP3A4 and mouse P-gp. Celastrol, wilforgine and wilforine were the strongest inhibitors towards midazolam metabolism in rat liver microsomes, with the 50% inhibition concentrations being at 8.33 μM, 22.18 μM and 22.22 μM, respectively. CONCLUSIONS:Our results revealed that co-dosing of CRT could lead to a significant increase in blood concentration of TAC and this effect could be ascribed to the resultant co-regulation of DMEs, DTs and NRs. Our study provided an experimental basis for the combination use of CRT and TAC in clinical practice.

国际糖尿病联盟(International Diabetes Federa-tion,IDF)最新报告显示,2019年全球约4.63亿20～79岁成人患糖尿病,其年龄标化患病率高达8.3％,预计2030年和2045年上升为9.2％和9.6％[1].最新全国流行病学调查结果显示,我国大陆地区糖尿病总体患病率为12.8％,糖尿病前期患病率为35.2％.胰岛素是治疗糖尿病的重要药物,在我国的使用非常广泛[2].

Presented here was a rapid, sensitive and robust UHPLC-MS/MS method for the quantitative detection of crisaborole in human plasma by using deuterated crisaborole-d 4 as the internal standard (IS). The analyte was separated on a reverse-phase ACE Excel C 18 AR column (2.1 mm × 50.0 mm, i.d., 1.7 μm) and gradiently eluted with acetonitrile and water as mobile phases. Negative electrospray ionization in multiple reaction monitoring mode was employed to acquire the quantification ion pairs of m/z 250.0→118.0 for crisaborole and m/z 254.0→121.9 for IS. Crisaborole and IS were well extracted from human plasma with acetonitrile. A short run time of 3.3 min served the purpose of high through-put analysis and a low flow rate of 0.4 mL/min minimized the waste of organic solvents in total sample analysis. Crisaborole had a good linearity in the calibration range of 0.20-80 ng/mL. Intra-day and inter-day precision was less than 9.17% and the accuracy was -2.29%-6.33% across all the quality control samples. The average extraction recovery of analyte and IS was 84.61% and 91.43%, respectively. The fully validated method was successfully used for the drug level measurement in ten healthy Chinese subjects receiving crisaborole ointment.