安罗替尼在治疗癌症患者中高血压的发生率和发生风险：一项系统评价和Meta分析

目的 为了明确癌症患者应用安罗替尼后高血压发生率和发生风险,同时比较安罗替尼与其他血管内皮生长因子受体（VEGFR）抑制剂之间高血压发生率的差异。方法 检索Pubmed、Cochrane Library、Embase、ASCO、中国知网、万方、维普和中国生物医学文献服务系统数据库,收集与安罗替尼相关的前瞻性Ⅱ期和Ⅲ期且有准确记录高血压不良反应发生情况的临床试验,采用R软件（3.6.0版本）对安罗替尼高血压不良反应发生率和发生风险进行Meta分析,使用SPSS软件（26.0版本）比较安罗替尼与其他VEGFR抑制剂之间高血压发生率的差异。结果 来自13项研究的1387名癌症患者被纳入Meta分析。使用安罗替尼的高血压总发生率约为47.1%（95% CI: 37.7%～56.6%）,高等级高血压发生率约为10.6%（95% CI: 7.4%～14.2%）,与安慰剂相比,安罗替尼可显著增加高血压发生风险（RR=5.58, 95% CI: 2.29～13.60, P<0.01）以及高等级高血压发生风险（RR=27.78, 95% CI: 3.56～216.86, P<0.01）。另外,安罗替尼高等级高血压发生率与阿昔替尼（RR=0.79, 95% CI: 0.61～1.02, P=0.066）和卡赞替尼（RR=0.87, 95% CI: 0.67～1.13, P=0.290）相似,其余均高于其他VEGFR抑制剂。结论 在使用安罗替尼的癌症患者中,高血压发生率较高,且显著增加发生高血压风险,建议临床对血压进行密切监测并及时治疗。     

双分子靶向药物联用的药学监护与分析

摘 要临床药师对晚期结肠癌患者在联用西妥昔单抗和阿帕替尼治疗过程中出现重度皮疹的原因进行分析,开展药学监护,通过查阅相关指南、文献探讨联合使用分别以表皮生长因子受体和血管内皮生长因子受体为靶点的分子靶向药物治疗晚期结肠癌患者的用药安全性,提出合理用药建议,为此类分子靶向药物在临床的合理应用提供参考。     

牡丹皮对脂多糖诱导大鼠系膜细胞的保护作用

目的 观察牡丹皮对脂多糖（LPS）诱导的大鼠系膜细胞（GMC）转化生长因子-β1（TGF-β1）、血小板衍生性生长因子（PDGF）和血管内皮生长因子(VEGF)表达的影响。方法 用脂多糖 (20 mg·L^-1)刺激大鼠系膜细胞,经牡丹皮(50、100、200 mg·L^-1)培养48 h后,采用ELISA法检测转化生长因子-β1的分泌水平;实时定量PCR方法检测血小板衍生性生长因子和血管内皮生长因子 mRNA的表达。结果 牡丹皮可以抑制脂多糖诱导的大鼠系膜细胞转化生长因子-β1的分泌,下调血小板衍生性生长因子和血管内皮生长因子的表达。结论 牡丹皮可能通过减少转化生长因子-β1的分泌,抑制血小板衍生性生长因子和血管内皮生长因子的表达,对受损的大鼠系膜细胞起保护作用。     

新一代治疗非小细胞肺癌酪氨酸激酶抑制药艾乐替尼

摘 要艾乐替尼是第二代用于治疗间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌的ALK酪氨酸酶抑制药,它能克服克唑替尼耐药的多个靶点,临床试验中具有很好的安全性及耐受性,本文对艾乐替尼的作用机制、药动学、临床疗效、安全性、耐药机制进行详细介绍。     

1例吉非替尼与华法林相互作用的案例报道及文献分析

目的 结合实际案例,对吉非替尼与华法林联用时华法林的剂量调整进行文献检索和分析,为给药方案的优化提供参考。方法 报道1例病例,同时查阅国内外相关文献并进行综述分析。结果 本例患者在合并使用吉非替尼26 d后,INR值明显升高（5.23）,停药后调整华法林剂量,将INR值控制在目标范围内。文献综述分析提示,吉非替尼及表皮生长因子受体酪氨酸激酶抑制剂与华法林联用时,有一部分人群可能会出现INR值升高,出血风险增加。结论 华法林和表皮生长因子受体酪氨酸激酶抑制剂联合使用时,建议在启用以及停药后,增加INR的监测频率,及时调整华法林剂量。     

血管内皮生长因子抑制剂结合活性试验两种结果分析方法比较

目的：对血管内皮生长因子抑制剂（VEGF Trap）结合活性试验两种结果分析方法进行比较,以考察两者的差异。方法：采用固定剂量的VEGF与系列稀释的VEGF Trap处理之后,检测未结合的VEGF的量,分别以未结合的VEGF量对VEGF Trap浓度梯度和未结合的VEGF检测板的OD值对VEGF Trap浓度梯度进行四参数方程拟合,两种方法计算该产品的结合活性。结果：两种方法均满足试验有效性条件,且血管内皮生长因子抑制剂供试品和标准品的半数抑制浓度（IC₅₀）均分别为3.68和3.6pmoL·L^-1,供试品的结合活性为102%。结论：证明了两种分析方法得到的结果完全一致。为同类产品结合活性计算方法的选择提供借鉴。     

益气生津活血颗粒对糖尿病大鼠心肌细胞IL-1、ET、NF-κB、TNF-α、VEGF含量的影响

目的 通过益气生津活血颗粒对链脲霉素（STZ）引发糖尿病大鼠心肌匀浆液中白介素-1（IL-1）、血浆内皮素(ET)、核因子κB（NF-κB）、肿瘤坏死因子α（TNF-α）以及血管内皮生长因子（VEGF）的影响来研究其对心肌微血管炎症损伤的防治作用机理。方法 雄性SD大鼠，用链脲霉素加高脂饲料造糖尿病大鼠模型，成模后分别按分组灌胃给药，4周后处死动物，腹腔静脉取血，一部分测血糖，另一部分离心留血清，-80 ℃冷藏备用；然后，取心脏，研磨成液，然后分别按白介素-1、血浆内皮素、核因子κB、肿瘤坏死因子说明书测含量；同时，分离心脏主动脉，进行免疫组化染色计算机定量分析，计算血管内皮生长因子值。结果 模型组与用药组比较，白介素-1、血浆内皮素、核因子κB、肿瘤坏死因子α、血管内皮生长因子含量都有显著性差异。结论 益气生津活血颗粒可降低链脲霉素引发糖尿病大鼠心肌中白介素-1、核因子κB、血浆内皮素、肿瘤坏死因子α、血管内皮生长因子含量，这或许是其对心肌微血管炎症损伤防治作用的机理。     

强效VEGFR抑制剂用于肾癌治疗或更具活性

辉瑞公司开发的新型血管内皮生长因子受体(VEGFR)抑制剂类抗血管生成药阿西替尼(axitinib)在其名为AXIS的第1项Ⅲ期临床试验中显示,作为二线治疗药,其较多激酶抑制剂索拉非尼(sorafenib)能更有效地提高转移性肾细胞癌(RCC)患者的无恶化存活率(PFS)。参加该项试验的650名受试者均为经辉瑞公司上市的多激酶抑制     

2009~2015年浙江省11家医院肺癌患者表皮生长因子受体酪氨酸激酶抑制药使用调查

摘 要 目的：了解2009~2015年浙江省11家医院肺癌患者表皮生长因子受体酪氨酸激酶抑制药（EGFR-TKI）的利用现状,分析其用药合理性。 方法: 抽取2009~2015年浙江省11家医院每年40天的医嘱数据,对肺癌患者使用EGFR-TKI的用药金额、用药频度（DDDs）、限定日费用（DDC）以及药物利用指数（DUI）进行统计分析。 结果: 埃克替尼、厄洛替尼和吉非替尼是目前最主要的3种EGFR-TKI,其中埃克替尼2013年之后才开始使用。EGFR TKI的用药总金额总体呈上升趋势,2015年的销售总金额是2009年的4.67倍;厄洛替尼的DDDs总体呈降低趋势,吉非替尼和埃克替尼的DDDs逐年升高;DDC排序最高的是厄洛替尼,吉非替尼次之,埃克替尼最低;3种靶向药物的DUI值均在1左右。 结论:浙江省11家医院EGFR TKI的用量逐年升高,但使用相对合理。     

润肺止嗽丸对慢性阻塞性肺疾病大鼠细胞凋亡的改善作用及其机制研究

目的研究中成药润肺止嗽丸对慢性阻塞性肺疾病（COPD）大鼠细胞凋亡的影响,并探讨其作用机制。方法 32只雄性Wistar大鼠随机分为对照组、模型组、润肺1月和3月组;使用烟熏联合气道滴入脂多糖法制备COPD大鼠模型;润肺1、3月组ig给予润肺止嗽丸0.9 g/kg,每天给药1次,分别连续给药1、3个月,对照组和模型组给予等体积的超纯水1个月;HE染色观察慢阻肺大鼠肺组织变化;TUNEL法检测凋亡细胞并计算凋亡指数（AI）;Elisa法检测肺泡灌洗液（BALF）中血管内皮生长因子（VEGF）水平;Western blotting法检测肺组织中VEGF和血管内皮生长因子受体2（VEGFR2）的蛋白表达。结果与对照组比较,模型组大鼠肺组织形态病变明显;AI显著升高;BALF中VEGF、肺组织中VEGF和VEGFR2水平均显著下降。与模型组比较,润肺1月和3月组肺组织形态明显好转;AI显著下降;BALF中VEGF、肺组织中VEGF和VEGFR2水平显著升高;且润肺3月组效果好于1月组。结论润肺止嗽丸可以改善慢阻肺细胞凋亡,机制可能与上调VEGF和VEGFR2相关。     

Preclinical Evaluation of Ixabepilone in Combination with VEGF Receptor and PARP Inhibitors in Taxane-Sensitive and Taxane-Resistant MDA-MB-231 Breast Cancer Cells

Long-term use of cytotoxic agents promotes drug-resistance in triple-negative breast cancer (TNBC). The identification of new drug combinations with efficacy against drug-resistant TNBC cells in vitro is valuable in developing new clinical strategies to produce further cancer remissions. We undertook combination analysis of the cytotoxic agent ixabepilone with small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and poly (ADP-ribose) polymerase (PARP) in taxane-sensitive (231C) and taxane-resistant (TXT) MDA-MB-231-derived cells. As single agents, the VEGFR inhibitors cediranib and bosutinib decreased both 231C and TXT cell viability, but four other VEGFR inhibitors and two PARP inhibitors were less effective. Combinations of ixabepilone with either cediranib or bosutinib synergistically decreased 231C cell viability. However, only the ixabepilone/cediranib combination was synergistic in TXT cells, with predicted 15.3-fold and 1.65-fold clinical dose reductions for ixabepilone and cediranib, respectively. Flow cytometry and immunoblotting were used to further evaluate the loss of cell viability. Thus, TXT cell killing by ixabepilone/cediranib was enhanced over ixabepilone alone, and expression of proapoptotic cleaved caspase-3 and the Bak/Bcl-2 protein ratio were increased. These findings suggest that the synergistic activity of the ixabepilone/cediranib combination in taxane-sensitive and taxane-resistant cells may warrant clinical evaluation in TNBC patients.     

The role of Cediranib in ovarian cancer

Introduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies.

Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib.

Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.     

卡瑞利珠单抗联合XELOX方案治疗晚期结肠癌的临床研究

目的 探讨卡瑞利珠单抗联合XELOX方案治疗晚期结肠癌的临床疗效。方法 选取2021年1月—2023年1月京山市人民医院收治的94例结肠癌患者,随机分为对照组(47例)和治疗组(47例)。对照组患者采用XELOX方案治疗,第1天静脉滴注注射用奥沙利铂,130mg/m²;第1～14天早、晚餐后口服卡培他滨片,1000mg/m²,2次/d。治疗组在对照组基础上静脉滴注注射用卡瑞利珠单抗,200mg/次,1次/3周,滴注2次。两组患者均治疗6周。观察两组患者临床疗效,比较治疗前后两组患者血清大肠特异性抗原-2(CCSA-2)、癌胚抗原(CEA)、糖类抗原19-9(CA19-9)、血管内皮生长因子(VEGF-A)、VEGF受体2(VEGFR2)及生活质量核心量表(QLQ-C30)评分。结果 治疗后,治疗组疾病控制率为80.85%,较对照组的61.70%明显升高(P<0.05)。治疗后,两组患者血清CCSA-2、CEA、CA19-9、VEGF-A、VEGFR2水平均较治疗前明显降低(P<0.05),且治疗组较对照组下降更显著(P<0....     

以岗位胜任力为导向的儿童药物临床研究专业人员培养的思考

目的 以岗位胜任力为导向，思考儿童药物临床研究专业人才的培养。方法 分析药物临床研究专业人员岗位胜任力研究现状，讨论构建儿童药物临床研究专业人员岗位胜任力模型的必要性，分析儿童药物临床研究专业人员的岗位胜任力元素，设定儿童药物临床研究专业人员的阶梯式、系统化培养目标。结果 迫切需要建立儿童药物临床研究专业人才岗位胜任力模型。结论 构建儿童药物临床研究岗位胜任力模型，是培养儿童药物临床研究专业人才的重要路径。     

聚乙二醇多柔比星脂质体及表柔比星在乳腺癌新辅助化疗中的应用比较

目的 比较聚乙二醇多柔比星脂质体及表柔比星在乳腺癌新辅助化疗中的疗效及不良反应。方法 回顾性分析2015年1月-12月行乳腺癌AC-T或EC-T新辅助化疗的146例患者,其中应用聚乙二醇多柔比星脂质体86例,应用表柔比星60例,分析其临床病理特征、化疗效果及不良反应,并应用Logistic回归分析影响新辅助化疗疗效的因素。结果 聚乙二醇多柔比星脂质体组与表柔比星组临床病理特征一致,无统计学差异。2组新辅助化疗的疗效无统计学差异。HER-2状态是影响新辅助化疗疗效的主要因素。聚乙二醇多柔比星脂质体组的白细胞降低、消化道反应、脱发及心电图异常等不良反应较表柔比星组明显减少,而手足综合征则明显增多,具有统计学差异。结论 聚乙二醇多柔比星脂质体与传统的表柔比星在乳腺癌新辅助化疗中疗效一致。     

The clinical application of fruquintinib on colorectal cancer

ABSTRACT

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect.

Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed.

Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.     

中药与多柔比星化疗联合运用的增效减毒作用

摘 要多柔比星作为蒽环类药物的一员,被广泛应用于肿瘤化疗中,但其明显的心脏毒性及细胞毒性作用在一定程度上限制了其运用。如何提高多柔比星化疗效果及减轻其不良反应是目前值得探索的课题。本文试图从临床和实验的角度,对新近15年来中药与多柔比星联合运用方面的研究进展进行评析,以为临床运用提供参考。     

Incidence and risk of hypertension associated with cabozantinib in cancer patients: a systematic review and meta-analysis

Introduction: Cabozantinib (XL184) is an oral inhibitor of multiplereceptor tyrosine kinases including mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2). Hypertension is one of its major side effects, but the incidence rate and overall risk has not been systematically studied. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing hypertension in cancer patients treated with cabozantinib.

Areas covered: Pubmed, Embase and oncology conference proceedings were searched for relevant studies. Eligible studies were phase II and III prospective clinical trials of cabozantinib in cancer patients with data on hypertension available. A total of 1,514 patients (cabozantinib, 1083; control, 431) with a variety of solid tumors from 8 prospective clinical trials were included for the meta-analysis. The use of cabozantinib was associated with significantly increased risk of developing all grade (RR 5.48; 95%CI, 3.76–7.99; p < 0.001) and high grade (5.09; 95% CI: 2.71–9.54, p < 0.001) hypertension in comparison with controls. Additionally, the risk of high grade hypertension with cabozantinib was substantially higher than other four approved VEGFR-TKIs (sorafenib, sunitinib, vandetanib and pazopanib).

Expert commentary: Cancer patients receiving cabozantinib have an increased risk of developing hypertension. Close monitoring and management of hypertension are recommended.