药物治疗是目前应对肿瘤的有效手段之一,但在获得疗效的同时往往也会引发多种毒副作用,制约了其临床应用.黄芪为传统补益中药,主要含皂苷、黄酮及多糖等成分,具有提高免疫力、抗氧化、抗炎等作用,在肿瘤的中医治疗中应用广泛.现代医学和药理学研究发现,黄芪的单体成分、注射液及复方在减轻抗肿瘤药物的毒副作用方面效果显著.本文综述了近年来黄芪及其复方制剂在预防和治疗化学制剂、免疫抑制剂等抗肿瘤药物诱导的胃肠道、肝、肾、心脏等靶器官毒性中的作用及机制研究进展,以期为黄芪的深入开发和临床合理应用提供参考.

Ethnopharmacological relevance: Astragali Radix (AR) is a popular traditional Chinese medicine that has been used for more than 2000 years. It is a well-known tonic for weak people with chronic diseases, such as heart failure and cerebral ischemia. Previous studies have reported that AR could support the "weak heart" of cancer patients who suffered from doxorubicin (DOX)-induced cardiotoxicity (DIC). However, the underlying mechanism remains unclear. Aim of the study: This study aimed to uncover the critical pathways and molecular determinants for AR against DIC by fully characterizing the network-based relationship. Materials and methods: We integrated ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) profiling, database and literature searching, and the human protein-protein interactome to discover the specific network module associated with AR against DIC. To validate the network based findings, a low-dose, long-term DIC mouse model and rat cardiomyoblast H9c2 cells were employed. The levels of potential key metabolites and proteins in hearts and cells were quantified by the LC-MS/MS targeted analysis and western blotting, respectively. Results: We constructed one of the most comprehensive AR component-target network described to date, which included 730 interactions connecting 64 unique components and 359 unique targets. Relying on the network based evaluation, we identified fatty acid metabolism as a putative critical pathway and peroxisome proliferator-activated receptors (PPAR alpha and PPAR gamma) as potential molecular determinants. We then confirmed that DOX caused the accumulation of fatty acids in the mouse failing heart, while AR promoted fatty acid metabolism and preserved heart function. By inhibiting PPAR gamma in H9c2 cells, we further found that AR could alleviate DIC by activating PPAR gamma to maintain fatty acid homeostasis. Conclusions: Our findings imply that AR is a promising drug candidate that treats DIC by maintaining fatty acid homeostasis. More importantly, the network-based method developed here could facilitate the mechanism discovery of AR therapy and help catalyze innovation in its clinical application.

A rapid and sensitive UHPLC-MS/MS method was developed and fully validated for the quantification of verinurad in rat plasma. Lesinurad was used as an internal standard (IS), and simple protein precipitation was utilized to prepare the analytes from the matrix. Chromatographic separation was carried out on a Zorbax SB C18 column. The mobile phase consisted of water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B) at a flow rate of 0.3 mL/min. The short run time of 4 min made it possible to analyze more than 300 samples per day. The ion transitions were quantified in negative mode with multiple reaction monitoring (MRM) transitions of 347.1 → 261.1 for verinurad and 404.2 → 178.9 for the IS. The validated linear ranges of verinurad were 10-5000 ng/mL in rat plasma. The validated UHPLC-MS/MS method was further applied to the pharmacokinetic study of verinurad in rat plasma after intragastric (2 mg/kg) and intravenous (1 mg/kg) administrations. The pharmacokinetic study revealed that verinurad showed high clearance and high bioavailability (78.1%). To the best of our knowledge, this is the first report of the bioavailability study of verinurad.

为揭示柴胡皂苷d(SSd)的体内外肠道吸收机制,采用Caco-2单层和大鼠在体单向肠灌流模型,研究了不同实验条件(时间、浓度、温度、pH、肠段)、转运蛋白抑制剂、细胞旁途径增强剂、代谢酶抑制剂等因素对SSd体内外肠道吸收的影响.研究结果表明,SSd的表观渗透系数(Papp)和有效渗透系数(Peff)分别为4.75×10-7～6.38×10-7 cm/s和0.19×10-4～0.27×10-4 cm/s,提示其属于低渗透性化合物,SSd的跨膜转运具有浓度(0.5～5 μmol/L)和时间(0～180 min)依赖性,回肠是其主要吸收部位;P-糖蛋白抑制剂和细胞旁途径增强剂均显著增强SSd的体内外吸收(P＜0.05);有机阴离子转运多肽(OATPs)抑制剂和有机阳离子转运蛋白(OCTs)抑制剂对SSd肠道吸收影响的体内外相关性较差,这可能与上述转运蛋白在空肠中表达量较低有关.本研究结果表明,SSd的肠道吸收涉及被动扩散、主动转运以及细胞旁通路途径等方式,P-糖蛋白在SSd的主动转运中发挥重要作用.

Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein–protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration–time curve (AUC, 1303.35 ± 271.74 μg/L*h versus 1208.74 ± 145.35 μg/L*h, p > 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 μg/L versus 1411.01 ± 368.38 μg/L, p > 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h, p > 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p < 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.

药源性糖尿病(DIDM)是由药物引起的一种继发性糖尿病,影响因素众多且发病机制复杂.临床资料显示,包括钙调神经磷酸酶抑制剂、糖皮质激素、抗高血压药物、调脂及抗动脉粥样硬化和抗精神病药物等在内的多种常用药均可引发DIDM.对引发DIDM的药物类别及近年来DIDM发病机制的研究情况进行综述,旨在为DIDM的预防与进一步治疗提供参考.

目的 开发与格列美脲片体内溶出行为相关的体外溶出方法,并预测两种片剂的人体生物等效性.方法 采用GastroPlusTM软件建立格列美脲片人体药代动力学(PK)模型;基于模型预测原研片剂在人体中的溶出行为;以预测结果指导体外溶出方法开发;通过虚拟生物等效性试验,利用体外溶出数据预测B、C两种格列美脲片的人体生物等效性(BE)结果;利用比格犬BE进行佐证.结果 模型的准确性与可靠性良好;原研片剂在人体胃肠道中呈线性溶出,于2h时溶出完全;流通池开环模式(pH 7.0缓冲液,14 mL·min-1)可基本模拟格列美脲片在人体中的溶出行为;经虚拟生物等效性试验,预测B与原研片剂生物等效,而C与其不等效;比格犬BE试验结果与人体虚拟BE结果一致.结论 基于体外溶出数据,预测格列美脲片人体生物等效性的方法具有一定可行性.

Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.

在仿制药研究过程中通过体外评价方法替代体内生物等效性研究可以减少临床资源消耗,加快药品上市进度,这是基于生物药剂学分类系统(BCS)的生物等效性豁免的主要原因.随着我国仿制药的快速发展,企业基于BCS的生物豁免申请需求越来越迫切,当药物制剂为具有全身作用的普通口服制剂,且药物活性成分符合溶解性和渗透性(BCS Ⅰ和Ⅲ类)标准,受试制剂剂型和规格与参比制剂相同,可适用基于BCS的生物等效性豁免.对国内外的基于BCS分类的生物豁免研究进展和法规进行综述,并对具体操作及申报要求提出一些思考.

急性肾损伤(AKI)、慢性肾病(CKD)与肾癌(RCC)是临床上典型的肾脏疾病,其发病机制复杂且易诱发多种并发症而造成全身性损伤.近年来的研究揭示,色氨酸代谢与抑郁症、自身免疫性疾病、神经退行性疾病与癌症等疾病的发生发展密切相关,其在肾脏疾病的发生发展过程中亦发挥着重要作用.本文综述了色氨酸代谢与急性肾损伤、慢性肾病及肾癌等肾脏疾病的互作研究进展,总结分析了靶向色氨酸代谢的肾脏疾病干预策略,以期为肾脏疾病诊断和防治提供借鉴.

为探讨胰岛素及油酸对结肠癌血清代谢物的调节作用,建立结肠癌细胞HCT116皮下移植瘤模型.裸鼠随机分为4组,每组6只,分别为对照组(CON)、胰岛素组(INS,每日皮下注射胰岛素2.5 U/kg)、油酸组(OA,每日灌胃油酸2.0 g/kg)、胰岛素及油酸联合给药组(IO,每日皮下注射胰岛素2.5 U/kg、灌胃油酸2.0 g/kg).采用气质联用(GC/MS)及液质联用(LC-IT-TOF/MS)技术对各组血清样本进行非目标代谢组学分析.数据经前处理如峰识别、去卷积和峰对齐后,导入SIMCA-P软件进行多元统计分析.结果表明,IO组裸鼠体重最轻但瘤体最重,且IO组与CON组相比,血清代谢轮廓发生显著变化,主要差异代谢物为尿素、阿拉伯糖、胆固醇、L-乙酰肉碱和鞘氨醇;OA及INS组与对照组之间无明显差异.本研究表明,胰岛素和油酸联合给药促进了结肠癌发展,扰动了代谢物轮廓,研究结果可为结肠癌生物标志物发现及早期诊断提供理论依据.

研究中药黄芪对小鼠心脏、大脑及血液代谢稳态的影响,从代谢调控角度阐明黄芪"修心健脑"的作用机制.13只ICR雄性小鼠随机分为两组,分别连续10 d灌胃给予超纯水和黄芪水提液,采用液相色谱-质谱(LC-MS)和气相色谱-质谱(GC-MS)联用分析全面表征小鼠血清、心脏和脑组织代谢指纹图谱,结合多元统计分析与非参数检验筛选、鉴定差异代谢物,聚焦相关代谢通路.多元统计分析表明,与对照组相比,黄芪干预后小鼠机体的代谢轮廓变化显著,在血清、心脏、脑中分别鉴定出15、19和17个差异代谢物,其中差异代谢物棕榈酸和LysoPC(20:3)为3种生物样本共有且变化趋势一致.代谢通路富集分析结果显示,氨基酸代谢、磷脂代谢、脂肪酸代谢和三羧酸循环等通路受到显著影响.研究结果显示,黄芪可能通过调节能量代谢、氨基酸代谢及脂代谢稳态发挥心脑血管保护作用.

Radix Bupleuri is a hepatoprotective traditional Chinese medicine (TCM) used for thousands of years in clinical, which was reported to be linked with liver damage. Previous studies have revealed that saikosaponins are the major types of components that contribute to the hepatotoxicity of Radix Bupleuri. However the underlying molecular mechanism is far from being understood. In order to clarify whether these structural analogues exert toxicity effects through the same molecular targets, a systematic comparison study was done in this paper. The effects of SSa, b2, c, and d on isolated rat liver mitochondria and human hepatocyte L02 cells were explored, respectively. The collective results indicated that although saikosaponins share the similar structures but they have quite different mechanisms. SSb2 and SSd showed most serious damage on the function of mitochondria and survival rate of cell, respectively. SSb2 could cause mitochondrial permeability transition pore (mPTP) opening and collapse of mitochondrial membrane potential (ΔΨm) by impairing the mitochondrial respiratory chain complex III. While SSd destroyed plasma membrane and led to the release of lactate dehydrogenase (LDH) mainly through activating caspase-1. Furthermore, the combine index (CI) demonstrated that the combined hepatotoxicity of SSb2 and SSd could be additive. This finding might yield more in depth understanding of hepatotoxicity of Radix Bupleuri possess many different saikosaponins.

由尿苷二磷酸葡萄糖醛酸转移酶(UGTs)介导的葡萄糖醛酸结合反应是多种内源性和外源性化合物在体内代谢、消除的重要途径.酚类化合物由于其多样的药理活性而受到广泛关注和研究,此类物质在体内易经UGTs代谢,生物利用度低.综述近年来酚类化合物经UGTs代谢及由UGTs介导的药物相互作用的研究进展.

Realgar nanoparticles are a nano-drug prepared from the traditional Chinese medicine realgar, with high bioavailability, strong targeting and other biological characteristics. This paper reviewed the research progress of pharmacological and toxic effects of realgar nanoparticles in recent years and provided references for further research and development.

杂质影响药物的稳定性和质量,降低疗效,并带来可能的毒副作用,分析并控制杂质含量对保证药物质量和用药安全十分重要,是新药研发和仿制药质量疗效一致性评价的一项重要内容.本文以临床抗高血压一线用药二氢吡啶类药物为例,讨论了杂质研究所涉及的杂质来源、检测方法、杂质限度以及评价标准等相关内容,并对可能出现的问题提出了解决建议,为药物的杂质研究提供参考.

为改善我国部分仿制药质量与国际先进水平还存在一定差距的现状,《国家药品安全”十二五”规划》中明确提出了开展仿制药一致性评价,全面提高仿制药质量的任务.氯雷他定片作为抗过敏药物的主要品种之一,需在2018年底前完成一致性评价.基于现有质量和疗效一致性评价指导原则与相关研究报道,针对氯雷他定原料药的晶型研究、原辅料杂质的比较研究、片剂溶出曲线的比较方法以及生物等效性试验研究等进行了总结和概括,并对有待解决的共性问题进行了讨论.

Irinotecan (CPT-11) is a potent chemotherapeutic agent, however, its clinical usage is often limited by the induction of severe gastrointestinal (GI) toxicity, especially late-onset diarrhea. HuangQin Decoction (HQD), commonly used for the treatment of GI ailments, has been proved could significantly ameliorate the intestinal toxicity of CPT-11. To reveal the mechanisms of CPT-11-induced toxicity and the modulation effects of HQD, a previous untargeted metabolomics study was performed and the results indicated that HQD may protect the GI tract by altering the metabolism of bile acids (BAs). Nevertheless, the untargeted assays are often less sensitive and/or efficient. In order to further confirm our previous findings, here in this paper, serum and tissues metabolic profiles of 17 BAs were analyzed using liquid chromatography-tandem mass spectrometry based targeted metabolomics. The results indicated that serum and tissues levels of most BAs were significantly decreased after CPT-11 administration, except some hydrophobic BAs. Co-treatment with HQD could markedly attenuate CPT-11-induced GI toxicity and reverse the alterations of hydrophobic BAs. Despite the fact that the BAs pool size remained unchanged, the balance of BAs had shifted leading to decreased toxicity after HQD treatment. The present study demonstrated for the first time that the precise interaction between HQD, CPT-11-induced intestinal toxicity and BAs’ homeostasis.

Stroke remains a major public health problem worldwide; it causes severe disability and is associated with high mortality rates. However, early diagnosis of stroke is difficult, and no reliable biomarkers are currently established. In this study, mass-spectrometry-based metabolomics was utilized to characterize the metabolic features of the serum of patients with acute ischemic stroke (AIS) to identify novel sensitive biomarkers for diagnosis and progression. First, global metabolic profiling was performed on a training set of 80 human serum samples (40 cases and 40 controls). The metabolic profiling identified significant alterations in a series of 26 metabolites with related metabolic pathways involving amino acid, fatty acid, phospholipid, and choline metabolism. Subsequently, multiple algorithms were run on a test set consisting of 49 serum samples (26 cases and 23 controls) to develop different classifiers for verifying and evaluating potential biomarkers. Finally, a panel of five differential metabolites, including serine, isoleucine, betaine, PC(5:0/5:0), and LysoPE(18:2), exhibited potential to differentiate AIS samples from healthy control samples, with area under the receiver operating characteristic curve values of 0.988 and 0.971 in the training and test sets, respectively. These findings provided insights for the development of new diagnostic tests and therapeutic approaches for AIS.