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。     

基于药动学及代谢物组学研究多柔比星在大鼠体内的心脏毒性

目的 测定多柔比星大剂量给药后原型药物及代谢产物的药动学特征及组织分布,以明确代谢产物在多柔比星急性心脏毒性中的作用。方法 测定多柔比星血清及心脏组织源性代谢物的变化特点,寻找与心脏毒性发生相关的代谢生物标志物及心脏毒性的潜在机制。利用LC-MS/MS测定多柔比星及多柔比星醇的浓度,利用GC-MS进行血清及心脏组织的代谢物组学分析。结果 多柔比星大鼠体内单剂量给药后,在心脏组织呈现高分布,且高剂量（10 mg·kg^-1）时分布显著增加。多柔比星醇的代谢转换率很低,且在心脏组织中的分布较低。代谢物组学研究结果表明,小分子能量物质酮体及脂肪酸为血清样本中的主要差异性物质。心脏组织中主要差异性物质为脂肪酸和甘油单酯。结论 多柔比星单剂量给药后,其在心脏中分布较高,且高剂量时特异性分布增加。多柔比星醇在血清及心脏组织中的浓度较低,推测其在急性毒性中的作用有限。多柔比星单剂量给药会引起心脏组织内的以脂质代谢为主的能量代谢异常,能量代谢对多柔比星相关的急性心肌毒性具有重要作用。     

脂质体多柔比星治疗恶性肿瘤临床疗效及安全性的系统评价

目的 评价脂质体多柔比星（脂质体阿霉素）治疗恶性肿瘤的临床疗效及安全性。方法 计算机检索中国学术文献总库（CNKI）、万方数字化期刊库、中国生物医学文献数据库（CBM）、维普中文科技期刊数据库（VIP）,PubMed数据库、Embase数据库和Cochrane Library数据库,脂质体多柔比星治疗恶性肿瘤的中英文随机对照试验,检索年限从建库至2017年1月。采用RevMan 5.3软件对各效应指标进行Meta分析。结果 纳入23篇RCT文献,计5 546名恶性肿瘤患者。Meta分析结果显示：治疗前后临床疗效I²=63%、OR=1.14[1.02,1.27],P=0.002;两组化疗后心脏毒性不良事件I²=0%,OR=0.18[0.10,0.33],P<0.000 01;脱发不良事件I²=77%,OR=0.24[0.17,0.35],P<0.000 01;神经毒性不良事件I²=46%,OR=0.65[0.42,0.99],P=0.05。结论 脂质体多柔比星治疗恶性肿瘤的临床疗效优于其他化疗方案,且毒副作用低,尤其在改善心脏毒性、脱发等不良事件方面明显优于其他化疗方案。     

多种方法综合评价有色注射液盐酸多柔比星的体外溶血作用

目的 盐酸多柔比星溶液为红色澄明液体,不适宜采用常规的肉眼观察法进行溶血性评价,需采用多种方法综合评价有色注射液盐酸多柔比星的体外溶血作用,为临床用药安全性提供参考。方法 采用常规家兔红细胞为实验对象,盐酸多柔比星溶液高、低质量浓度为4.0、2.0 mg/mL,分别采用血球计数法、酶标仪直接比色法和间接比色法综合评价注射用盐酸多柔比星的体外溶血作用。结果 3种不同测定方法的评价结果一致：盐酸多柔比星溶液4.0 mg/mL质量浓度下各管溶血率均远远大于5%,即发生严重溶血;2.0 mg/mL质量浓度下仅加样0.1 mL管（按试管中药物浓度折算该管相当于0.4 mg/mL药物浓度下加样0.5 mL）无溶血发生,其他各管溶血率均远远大于5%,即发生严重溶血。结论 临床直接将2.0 mg/mL的盐酸多柔比星溶液进行静脉推注发生溶血的可能性较大,建议将盐酸多柔比星溶液适当稀释后（终质量浓度不超过0.4 mg/mL）静脉给药安全性更好。     

多柔比星心脏毒性保护剂的研究进展

蒽环类抗肿瘤抗生素多柔比星（又称阿霉素）具有高效、广谱的抗肿瘤活性,临床上广泛应用于治疗各种恶性肿瘤,但急性和长期心脏毒性限制了其应用。多柔比星抗肿瘤活性和心脏毒性机制仍存在很大争议,不过很多研究结果显示可以降低或缓解心脏毒性的发生。临床上常用以降低多柔比星心脏毒性的方法包括调整剂量和化疗方案、同系物替代、联合使用心脏保护剂等,效果最好、最具有临床应用前景的是联合使用心脏保护剂。我们就国内外近年来关于降低多柔比星心脏毒性的保护剂研究进行综述。     

多柔比星-五味子乙素共载脂质体克服多药耐药的机制研究

目的 探讨多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药机制。方法 制备多柔比星-五味子乙素共载脂质体,以人慢性髓系白血病耐药细胞株K562/DOX为模型细胞,分别探讨不同温度、内吞抑制剂存在下的细胞摄取药物的情况,并检测耐药细胞P-gp表达和细胞凋亡情况。结果 共载脂质体在4℃及氯喹、叠氮钠和甘露醇内吞抑制剂存在下进入耐药细胞的药物量明显减少;流式细胞仪检测多柔比星-五味子乙素共载脂质体可抑制P-gp表达且诱导凋亡。结论 多柔比星-五味子乙素共载脂质体进入K562/DOX细胞主要通过耗能的内吞途径;而多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药可能是通过抑制P-gp表达和促进凋亡双通道途径。     

多柔比星载药微球经导管动脉化疗栓塞治疗肝癌临床疗效观察

摘 要 目的：观察多柔比星载药微球治疗肝癌患者的临床疗效及安全性。方法: 129例无手术切除指征肝癌患者随机分为观察组（DCB TACE）60例和对照组（cTACE）69例。观察组给予装载50 mg多柔比星的载药微球（直径150~400μm）肝动脉化疗栓塞（TACE）治疗;对照组给予装载40~60 mg多柔比星的5~10 ml传统碘化油混合乳剂TACE治疗。两周进行一次治疗,3个月后观察肿瘤疾病进展情况。结果:观察组完全缓解率为55.0%,显著高于对照组的23.1%（P<0.001）。观察组患者的肿瘤进展时间和存活率均显著优于对照组（P＜0.05）; 两组药品不良反应发生率比较,差异无统计学意义（P>0.05）。结论:多柔比星载药微球可显著延长肝癌进展期、不良反应轻度,临床应用前景广阔。     

多柔比星心脏毒性及其中药防治研究进展

多柔比星是一种高效广谱抗肿瘤药物,由于严重的细胞毒性,其临床应用受到一定影响,且目前缺乏有效的预防和治疗方法。该文探讨了多柔比星的心脏毒性及其作用机制,并从中药、中药活性成分、中药注射液、中成药和煎剂等方面就近年来国内外有关中药预防多柔比星心脏毒性的研究进展进行归纳总结,以期为临床防治多柔比星毒性提供参考。     

1例多发性骨髓瘤患者化疗后静脉血栓栓塞的用药分析和药学监护

摘 要 目的：探讨临床药师在多发性骨髓瘤患者化疗后静脉血栓栓塞病例中发挥的作用。方法: 临床药师积极参与1例多发性骨髓瘤患者化疗后静脉血栓栓塞的治疗,对沙利度胺、多柔比星脂质体、地塞米松联合化疗后静脉血栓栓塞的原因进行总结分析,提出处理意见,对患者进行用药教育。结果: 临床药师与医师合作,发挥自身专业特点,提出治疗建议,提高了治疗效果和用药安全,增加了患者的依从性。结论: 临床药师参与临床治疗,可以从药物角度为临床提供治疗参考,保障患者用药安全,提高患者的满意度。     

多柔比星对心脏毒性的探讨及相关心电图分析

目的观察多柔比星对心脏的毒性反应。方法对544例接受多柔比星化疗的患者的前后心电图改变进行观察和对比。结果544例患者用多柔比星化疗前心电图均正常,化疗后出现窦性心动过速、窦性心动过缓、房性及室性期前收缩、ST段压低、T波低平、T波倒置、肢导联QRS波群低电压、心房纤颤、房室传导阻滞176例（异常率32．3％）。结论多柔比星有较强的毒性作用,而心电图作为一种化疗过程中对心肌毒性的监测方法,经济实用简便,重复性好,在一定程度上能够提供多柔比星对心脏毒性产生的信息。     

Outcomes and safety of rapid desensitization for chemotherapy hypersensitivity

Importance of the field: The incidence of hypersensitivity reactions (HSRs) to chemotherapy agents has increased because of increasing number of cancer survivors are exposed to repeated courses of sensitizing agents. Replacement with an alternative chemotherapy regimen is often limited by tumor sensitivity. Rapid desensitization offers an effective mean to allow continuation of the treatment to which patients have presented HSRs.

Areas covered in this review: We review the methods, outcome and safety of the rapid desensitization protocol developed at Brigham and Women's Hospital, Harvard Medical School Affiliate, based on our recent publication “‘Hypersensitivity reactions to chemotherapy: outcome and safety of rapid desensitization in 413 cases”. Literature search was conducted through Medline (from January 1976 to September 2009), using PubMed.

What the reader will gain: The article will give insight to clinical manifestations of immediate HSR to various chemotherapy agents and their presumably different immunopathomechanism. Risk assessment, including skin testing in those presented HSRs to platins and details on rapid desensitization process and its pitfalls will be discussed.

Take home message: Standa"rd protocol of rapid desensitization, administering under multidisciplinary team approach, is safe and effective in overcoming immediate HSRs to platins, taxanes, doxorubicin and rituximab via both intravenous and intraperitoneal routes.     

HER-2阳性乳腺癌患者2种新辅助化疗方案的药物经济学评价

目的 对乳腺癌新辅助化疗方案多柔比星联合环磷酰胺序贯紫杉醇和曲妥珠单抗（AC-TH方案）及多西他赛联合卡铂和曲妥珠单抗（TCH方案）进行药物经济学分析,为该病治疗的选择提供决策依据。方法 建立Markov模型,对接受AC-TH与TCH新辅助化疗方案的患者进行模拟,综合应用临床试验研究结果、其他公开发表的文献和两大型综合性医院的病例资料,评价2种化疗方案的成本效果比,并进行敏感度分析。结果 成本效果分析显示,TCH组治疗乳腺癌的5年健康结果值为3.6质量调整生命年（quality-adjusted life years,QALYs）,比AC-TH组多0.2QALYs;AC-TH组的成本为207 987元,比TCH组多45 940元,增量成本-效果比为-229 700元/QALY。结论 从中国医疗卫生体系角度出发,5年内新辅助化疗方案TCH比AC-TH对Her-2阳性乳腺癌患者更具成本效果比。     

结直肠癌住院患者分阶段药学监护模式的构建与实践

目的 探讨临床药师参与结直肠癌（CRC）住院患者分阶段药学监护模式。方法 制定住院CRC患者分阶段的药学监护模式及监护内容,依据该监护模式对1例使用FOLFIRI方案（伊立替康+左亚叶酸钙+氟尿嘧啶）发生3度迟发性腹泻及2度口腔溃疡的CRC患者进行分阶段药学监护。具体内容包括化疗前的药学监护,如肝肾功能及血常规的评估、既往不良反应程度的评估、化疗药物剂量调整的评估;化疗中的药学监护,如化疗药物预处理的合理性、化疗药物致吐级别的评估与监护;化疗后的药学监护,如不良反应监测、出院带药建议及患者用药教育。结果 通过制定并实施CRC患者分阶段药学监护模式,患者得到了个体化的治疗方案,药品不良反应得到了及时发现与干预。结论 通过制定住院CRC患者分阶段药学监护模式,临床药师可以对该类患者进行有效的用药监护;本模式可为临床药师参与临床药物治疗工作模式提供一定的参考。     

DC Bead embolic drug-eluting bead: clinical application in the locoregional treatment of tumours

Introduction: DC Bead is an embolic drug-eluting bead designed to be loaded with chemotherapeutic agents (such as doxorubicin and irinotecan), delivered intra-arterially into tumor blood vessels to block nutrient flow and then to deliver the drug locally in a sustained fashion. This product is finding increasing use in the treatment of patients with both primary and secondary liver cancers.

Areas covered: This review positions DC Bead in the field of targeted embolic drug delivery and with respect to other competitive technologies in the treatment of liver cancer. An overview of the studies that demonstrate the product's performance, safety and efficacy is presented. The clinical application of the doxorubicin loaded DC Bead is firstly reviewed, in the context of treatment of patients with various stages of hepatocellular carcinoma. Its combination with other therapies is also discussed, together with consideration of the treatment of other liver tumors. Secondly, the use of irinotecan loaded DC Bead, primarily for the treatment of colorectal cancer metastases to the liver, but also some additional rare metastases, is summarized.

Expert Opinion: An opinion is proffered as to how this technology and its application is evolving, illustrating a move towards synergistic combination therapies and into other cancer indications.     

Pharmacokinetic/Pharmacodynamics Modeling of Drug-Loaded PLGA Nanoparticles Targeting Heterogeneously Vascularized Tumor Tissue

Purpose

Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration.

Methods

Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously.

Results

This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth.

Conclusions

The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.

     

Farmacocinética poblacional de doxorubicina aplicada a la personalización de su dosificación en pacientes oncológicos

ObjectiveTo develop and internally validate a population pharmacokinetic model for doxorubicin and to evaluate its predictive performance for dose individualization in cancer patients.MethodsDoxorubicin plasma concentrations were determined in thirty-three cancer patients treated with intravenous doxorubicin. A three-compartment pharmacokinetic model was implemented in the NONMEN VI programme to determine the doxorubicin pharmacokinetic parameters. The identifiability of the parameters was assessed by parametric bootstrap and model validation was performed using nonparametric bootstrap, visual predictive check, and numerical predictive check. The final model‘s predictive performance was evaluated in terms of accuracy and precision of plasma concentration predictions during the first and second cycles of chemotherapy.ResultsDoxorubicin clearance was 58.8L/h, with interpatient variability of 29.2% and intrapatient variability of 18.9%. The estimated volume of distribution at steady state was 2294L, with inter-and intrapatient variability of 7.3% and 26.1%, respectively. Internal validation confirmed that the population pharmacokinetic model is appropriate to describe the time course of the doxorubicin plasma concentrations and its variability in this population. The accuracy and precision of an a posteriori prediction of doxorubicin plasma concentrations improved by 63% and 41% compared to the a priori prediction.ConclusionThe Bayesian population pharmacokinetic model characterised the time course of doxorubicine plasma concentrations and can be accurately and precisely used to optimise doxorubicine dosing regimens in cancer patients.     

Sustained Release Chemotherapeutic Microspheres Provide Superior Efficacy over Systemic Therapy and Local Bolus Infusions

Purpose. The present studies evaluated the ability of injectable, biodegradable microspheres releasing carboplatin, doxorubicin, or 5-fluorouracil to suppress the growth of solid tumors implanted subcutaneously or intramuscularly. Methods. Seven to 10 days after implantation of MATB-III cells, rats received systemic chemotherapy, intratumoral bolus chemotherapy, or injections of chemotherapeutic microspheres into the tumor center or multiple sites along the outer perimeter of the tumor. Results. A single treatment with carboplatin, doxorubicin, or 5-fluorouracil microspheres along the perimeter of the tumors produced a significant, dose-related suppression in tumor growth, relative to injections directly into the tumor center. Moreover, five temporally-spaced microsphere treatments along the tumor perimeter (with either doxorubicin or 5-fluorouracil microspheres) completely eradicated 100% of the subcutaneous tumors and 40-53% of the intramuscular tumors. Polypharmacy, accomplished by blending doxorubicin- and 5-fluorouracil-loaded microspheres and injecting them into the tumors was even more efficacious than sustained delivery of either drug alone. Comparable doses of systemic chemotherapy or intratumoral bolus chemotherapy were ineffective. Conclusions. Injectable microspheres might be ideal for local, sustained delivery of chemotherapeutic agents to solid tumors. However, attention must be paid to the placement of the microspheres, for injections around the tumor perimeter may be required for efficacy.