阿霉素心脏毒性防治研究进展

阿霉素 (Ａｄｒｉａｍｙｃｉｎ ,ＡＤＭ )属蒽环类抗肿瘤抗生素 ,是目前最常用的抗肿瘤药物之一 ,但由于累积性心脏毒性这一主要不良反应 ,而使其长期使用受到限制 ,因此如何预防阿霉素的毒性发生日益得到重视。目前总体来说在该方面的研究可分为对ＡＤＭ本身用法、用量的进一步研究 ,以及心脏保护性药物 (又称化学保护剂 ,ｃｈｅｍｏｐｒｏｔｅｃｔｏｒ)的应用两方面 ,本文对此作一简要回顾。1　ＡＤＭ用药方式的研究通过改变ＡＤＭ的用药方式 ,以期在不影响临床疗效基础上降低其毒性反应是目前研究热点之一。主要采用如下两种方式 :①将短…     

阿霉素心脏毒性研究进展

阿霉素 (Adriamycin,ADM)属蒽环类抗生素 ,具有抗瘤谱广、作用强的特点 ,是目前最常用的抗肿瘤药物之一 ,但存在剂量累积的心脏毒性反应而不能长期、大剂量的应用。1　 ADM的心脏毒性机理ADM在心肌细胞中产生的氧自由基 (OFR)作用于细胞膜及各种细胞器膜上的磷脂中的多价不饱和脂肪酸 ,形成脂质自由基 ,引发脂质过氧化反应增强 ,损伤细胞膜及细胞器膜 ,改变膜上蛋白质功能及酶的活性 ,最终导致细胞内钙超载 ,核酸、蛋白质合成受抑制 ,能量代谢障碍 ,严重影响心肌的收缩及舒张功能。在正常情况下 ,细胞中存在着完整的抗 OFR酶系统 ,如…     

阿霉素心脏毒性的表现分析

目的 探讨阿霉素（DOX）心脏毒性的表现及其临床意义。方法 对83例肿瘤患者应用阿霉素的前后过程,结合病史及用护心药（辅酶Q10及维生素E）与否的心电图表现作比较分析。结果 心电图异常改变的增多与阿霉素用量、停药后的年限、原病史呈正相关。死亡前表现为窦性心动过速、低电压、QT－QTc延长明显增多（P＜0.05)。结论 阿霉素心脏毒性的心电图表现呈非专一性,但变化程度与预后密切相关。     

阿霉素对斑马鱼心脏毒性的评估及机制探索

目的 :通过观测阿霉素致斑马鱼胚胎产生心脏毒性的表型,及联用右丙亚胺保护剂,建立实验室心脏毒性药物评价及研究的模型。方法:选择受精后24 h的AB系野生型斑马鱼胚胎,分别暴露于不同浓度的阿霉素中后,选择心脏毒性表型最明显的阿霉素浓度,将其分别联用或不联用右丙亚胺作用48 h。在斑马鱼胚胎发育至受精后72 h时,在显微镜下观察其心血管系统的形态学改变,记录心率变化,并分别抽提斑马鱼胚胎RNA,检测心脏发育相关基因及氧化、抗氧化相关指标。结果:随着阿霉素浓度的升高,斑马鱼出现了如胚胎发育畸形、心包水肿等改变,且死亡率升高,心脏毒性表型最明显的阿霉素浓度为64.40μmol/L,而联用右丙亚胺(130.47μmol/L、260.93μmol/L)则可有效挽救阿霉素对斑马鱼心脏的毒性作用,并可分别将其胚胎生存率由35%显著提升至90%和88.3%(P<0.001),而右丙亚胺可有效清除丙二醛并恢复SOD活性。结论:成功建立了斑马鱼评价心脏毒药物的模型。阿霉素对斑马鱼胚胎的心脏毒性呈浓度依赖性增加,且与斑马鱼胚胎死亡率亦呈正相关,而右丙亚胺则可有效挽救阿霉素致斑马鱼胚胎的心脏毒性,并降低其死亡率,且此作用与斑马鱼心脏发育相关基因无关,但与氧化及抗氧化通路有明显的相关性。     

阿霉素和吡喃阿霉素对乳腺癌患者心脏毒性的临床观察

目的：探讨阿霉素和吡喃阿霉素对乳腺癌患者心脏毒性的临床观察。方法：对72例局部晚期乳腺癌患者随机分成2组，均是用环磷酰胺＋阿霉素＋5-氟脲嘧啶及环磷酰胺＋吡喃阿霉素＋5-氟脲嘧啶的联合化疗方案，通过检测患者心电图及心功能的变化，临床对照观察患者的心脏毒性反应。结果：吡喃阿霉素组较少出现心电图异常，4例心电图呈现一过性改变，较快2周恢复正常。阿霉素组，6例心电图改变，有4例在2周内恢复正常，1例有所减轻，但1例在1月后无改善，经超声心动图检测为充血性心力衰竭。结论：大多数患者能够较好地耐受阿霉素和吡喃阿霉素的化疗，吡喃阿霉素比阿霉素稍好，但经统计无显著性意义（P〉0．05）。     

吡柔比星与阿霉素对心脏毒性的临床比较

目的 :比较吡柔比星和阿霉素的临床心脏毒性。方法 :采用临床体检和心电图记录的方法 ,观察分别用含吡柔比星和含阿霉素方案化疗的 86例肿瘤病人的心脏毒性的发生率。结果 :无论是累积剂量小于 45 0mg组还是大于或等于 45 0mg组中 ,采用含阿霉素方案化疗的病人的心脏毒性的发生     

复方丹参滴丸治疗恶性肿瘤有阿霉素方案化疗致心脏毒性疗效观察

目的：观察复方丹参滴丸治疗有阿霉素方案化疗致心脏毒性疗效。方法：将64例恶性肿瘤采用有阿霉素方案化疗时出现的心脏毒性者分为治疗组和对照组。治疗组给予复方丹参滴丸10粒tid po、维生素C片0．3tid po、谷维素片20mg tid po、维生素B1片20mg rid po。对照组给予维生素C片0．3tid po、谷维素片20mg tid po、维生索B1片20mg tid op、治疗半月后复查心电图。结果：治疗组症状改善有效率89．4％。心电图改善有效率86．3％，明显优于对照组69．2％、66．7％。结论：复方丹参滴丸能有效减轻阿霉素的心脏毒性。     

卡维地洛对阿霉素心脏毒性的保护作用

阿霉素(adriamycin ADR)是最有效的广谱抗癌药物之一,但是,ADR严重的心脏毒性限制了其临床应用。ADR心脏毒性发生发展过程中氧化应激和细胞凋亡发挥重要作用,卡维地洛(carvedilol,CVD)是一种具有抗氧化、抗细胞凋亡的β受体阻滞剂。在该研究中探讨了卡维地洛对阿霉素心脏毒性的保护作用及其可能的机制。通过检测血流动力学、检测血清中超氧化物歧化酶的活性和丙二醛含量、检测心肌细胞凋亡,研究表明卡维地洛能改善阿霉索引起的血流动力学异常,通过抑制阿霉素引起的机体内过度的氧化应激及心肌细胞凋亡,卡维地洛对阿霉素引起心脏毒性具有潜在的保护作用。     

心脏MRI评估阿霉素诱导卵巢切除大鼠模型心肌毒性北大核心CSCD

目的观察心脏MRI成像(CMRI)评估以阿霉素诱导卵巢切除大鼠模型心肌毒性的价值。方法将48只SD大鼠随机分为阿霉素高剂量治疗组(高剂量组)、阿霉素低剂量治疗组(低剂量组)、卵巢切除组及假手术组,每组12只。切除前3组大鼠双侧卵巢。对高剂量组和低剂量组分别以2.5 mg/kg和1.5 mg/kg体质量静脉注射阿霉素,每周1次,共6周,建立心肌毒性模型;对其余2组注射生理盐水。分别于造模前(第0周)、阿霉素注射后每周(第1~6周)及注药结束后间隔2周行CMRI至第12周,比较组间左心室射血分数(LVEF)、左心室整体径向应变(LVGRS)、左心室整体周向应变(LVGCS)、左心室整体纵向应变(LVGLS)及左心室标准化心肌T2信号强度比值(T2 SIr)的差异。结果相比卵巢切除组和假手术组,高剂量组及低剂量组LVEF分别于第8周及第12周开始下降,LVGRS、LVGCS及LVGLS绝对值分别于第6周及第8周开始降低,左心室T2 SIr分别于第6周及第8周达峰(P均<0.05)。相比高剂量组,低剂量组LVEF于第8周,LVGRS和LVGLS于第6周始上升,LVGCS仅于第8周升高,第6、8、10周左心室T2 SIr差异均有统计学意义(P均<0.05);卵巢切除组与假手术组间各时间点各参数差异均无统计学意义(P均>0.05)。结论CMRI心肌应变和T2 mapping有助于早期评估卵巢切除后大鼠模型阿霉素诱导心肌毒性。     

舒血宁治疗阿霉素引起的心脏毒性的临床研究

目的探讨舒血宁对恶性肿瘤患者应用阿霉素引起的心脏毒性的防治作用。方法选择2010年3月至2012年12月收治的恶性肿瘤患者80例,全部患者按实际就诊顺序随机分为研究组和对照组。两组患者均给予含阿霉素化疗方案治疗,其中研究组患者每个化疗周期前额外加用舒血宁静脉滴注,每日一次,持续治疗2周。观察两组治疗后心肌酶谱及心电图改变情况,评价舒血宁对阿霉素引起的心脏毒性的防治作用。结果治疗后研究组肌酸激酶同工酶(CK-MB)、心肌肌钙蛋白I(c Tn I)、乳酸脱氢酶(LDH-1)及C反应蛋白(CRP)水平明显低于对照组,两组差异有统计学意义;治疗中研究组异常心电图情况明显少于对照组,差异有统计学意义(P0.05)。结论舒血宁辅助化疗可减轻阿霉素的心脏毒性,利于阿霉素化疗剂量的维持,保证了化疗效果,推荐在临床推广和应用。     

Remodeling of ventricular repolarization in a chronic doxorubicin cardiotoxicity rat model

Doxorubicin, one of the most effective anticancer drugs, is characterized by severe cardiotoxic effects, which induce cardiac remodeling and congestive heart failure. The aim of the study was to evaluate remodeling of ventricular repolarization heterogeneity in chronic doxorubicin cardiotoxicity in rats. Doxorubicin cardiotoxicity was produced by six equal intraperitoneal injections of the drug in a cumulative dose of 15 mg/kg in a 2‐week period. Electrophysiological mapping of the ventricular epicardium in situ was performed 6 weeks after the last injection of doxorubicin. Activation–recovery intervals (ARIs) were used for the evaluation of the heterogeneity in repolarization durations. The major findings were as follows: (1) ARIs on the ventricular epicardium of both ventricles were significantly prolonged in the doxorubicin group and (2) this inhomogeneous prolongation of ARIs on the ventricular epicardium resulted in (i) the increase in the dispersion of repolarization across the ventricular epicardium and (ii) the inhomogeneous alterations of the regional ARI gradients on the ventricular epicardium. These changes in repolarization could explain the electrocardiographic alterations, that is, the prolongation of the QT interval and flattening of the T wave.     

ADAR2 increases in exercised heart and protects against myocardial infarction and doxorubicin-induced cardiotoxicity

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Drug-induced cardiotoxicity due to aminophylline treatment: a case report

Background: Aminophylline, a theophylline compound that contains ethylenediamine, has untoward side effects on many organ systems.Objective: The goal of this case report was to illustrate the occurrence of acute adverse events (ie, chest discomfort and myocardial enzyme elevation) that may be associated with aminophylline treatment.Methods: To uncover previous studies/reports on this subject, a literature search (1950-2003) was conducted on MEDLINE, UpToDate, and Doctor's Guide, using the search terms aminophylline toxicity, theophylline toxokinetics, pharmacotoxic myocardial injury, hypersensitivity myocarditis, and diagnosis of myocardial infarction with biomarkers of cardiac injury. A 76-year-old, obese, female patient was admitted to University Hospital (Rion, Greece) for an acute exacerbation of chronic bronchitis. Beginning on day 0 of hospitalization, the patient was treated with aminophylline 750 mg IV, given in a 24hour constant infusion, for persistent wheezing. We monitored the patient's condition using electrocardiography, echocardiography, and blood chemistry analysis.Results: While undergoing aminophylline treatment, the patient developed vague chest discomfort and myocardial enzyme elevation due to aminophylline-induced cardiotoxicity. Mild wheezing was still present on physical examination on day 2 of hospitalization. The serum creatine kinase (CK) level was slightly increased. On day 6 of hospitalization, the patient's symptoms worsened, with mild epigastric discomfort, tachycardia, fatigue, and tightness in the chest. Blood gas analysis revealed mild hypoxia and hypocapnia. Pulmonary perfusion scan showed a low risk for pulmonary thromboembolism, as indicated by the absence of segmental perfusion defects. Blood chemistry analysis showed increased serum CK (×2.5) and CK isoenzyme (CK-MB) fraction (×8.6) levels. Echocardiography on day 7 showed a slight hypertrophy of the septum, with normal dimensions of the ventricles and a 70% ejection fraction. Aminophylline treatment was permanently discontinued, and the patient's signs and symptoms promptly improved.Conclusions: In the case presented here, the exclusion of usual causes of increased serum CK and CK-MB fraction levels, together with the increased serum aminophylline concentration and, most importantly, the rapid alleviation of symptoms and normalization of myocardial enzymes in absolute temporal relationship to the discontinuation of the drug, suggested that aminophylline treatment might be associated with elevated levels of myocardial enzymes. (Curr Ther Res Clin Exp. 2003;64:379-386)     

CTOP与CHOP治疗非霍奇金淋巴瘤的疗效及心脏毒性临床观察

目的比较环磷酰胺、吡喃阿霉素、长春新碱、泼尼松（CTOP）与环磷酰胺、多柔比星、长春新碱、泼尼松（CHOP）方案治疗非霍奇金淋巴瘤（NHL）的疗效及心脏毒性。方法将68例NHL患者随机分成两组,治疗组35例用CTOP方案化疗,对照组33例用CHOP方案化疗,评估两组疗效及心脏毒性。结果 6个疗程后治疗组总有效率80.0%,对照组为72.7%,但差异无统计学意义（P〉0.05）。心脏毒性方面：①心电图（ECG）变化：6个疗程后新增ECG异常在治疗组和对照组中分别为3例、10例,两组ECG变化差异有统计学意义（P〈0.05）。②超声心动图：化疗前及化疗6个疗程后的左心射血分数（LVEF）、缩短分数（FS）、二尖瓣口舒张期流速E/A值在治疗组分别为（62.06±4.37）%vs（61.37±4.72）%（P〉0.05）,（35.49±2.41）%vs（34.57±2.25）%（P〈0.01）,1.25±0.12 vs 1.21±0.09（P〈0.01）;在对照组分别为（61.55±4.46）%vs（60.27±5.28）%（P〈0.01）,（35.30±2.10）%vs（33.91±1.91）%（P〈0.01）,1.23±0.08 vs 1.08±0.13（P〈0.01）;LVEF值及FS值治疗组变化与对照组比较,差异均无统计学意义（P〉0.05）,而E/A化疗后治疗组明显高于对照组,差异有统计学意义（P〈0.01）。③心功能变化：6个疗程后新出现心功能异常或原有心功能异常加重在治疗组为3例,对照组为8例,但差异无统计学意义（P〉0.05）。结论 CTOP与CHOP方案治疗NHL疗效相近,但CTOP方案心脏毒性明显低于CHOP方案。     

Interleukin-1 signaling mediates acute doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is a potent anticancer drug, which is widely used in the treatments of a variety of solid and hematopoietic tumours, but its use is limited by its cardiotoxicity and dose-dependent congestive heart failure. After we found the high expression of interleukin-1 receptor I (IL-1RI) gene in mice cardiac tissues with DOX-induced cardiotoxicity, we assumed interleukin-1 (IL-1) signaling might mediate acute DOX-induced cardiotoxicity. In this report, Balb/c mice were intraperitoneally injected with different dosage of DOX followed by different days of study. We found both IL-1β and interleukin-1 receptor antagonist (IL-1Ra) concentrations in serum were highly induced after DOX treatment, associated with increased IL-1RI expression in cardiac tissues. Furthermore, IL-1 signaling was found to express higher with the increased dosage of DOX treatment. Histology score of cardiac tissues showed obvious cardiac damage after DOX treatment, while assessment with the Spearman rank correlation coefficient showed that histology score was closely correlated with IL-1β and IL-1Ra concentrations in serum and IL-1RI expression in cardiac tissue. Our results reveal a potential role of IL-1 signaling in acute DOX-induced cardiotoxic injury and lead to an assumption that this signal system might be a potential candidate agent that inhibits cardiomyocyte-toxicity in DOX-exposed patients.     

常规超声心动图对蒽环类化疗药物致心脏毒性的诊断价值

目的:探讨常规超声心动图对蒽环类化疗药物所致心脏毒性的诊断价值。方法:选取2014年2月至2017年6月在我院接受蒽环类药物化疗的乳腺癌术后患者136例,给予吡柔比星+环磷酰胺+多西他赛方案化疗6个周期。疗程结束后,根据患者是否发生心脏毒性分为心脏毒性组(N=48)和无心脏毒性组(N=76),对比患者化疗前后的超声心动图参数,分析常规超声心动图参数在早期心脏毒性诊断中的价值。结果:心脏毒性组TAPSE、E/A和E/a,值显著低于无心脏毒性组(P0.05)。ROC曲线分析,TAPSE、E/A和E/e'对应的曲线下面积分别为0.917(0.874,0.962)、0.902(0.853,0.957)、0.845(0.823,0.921)。TAPSE的截断值为20.78 mm、E/A的截断值为1.19、E/e'的截断值为8.59,Youden指数分别为0.842、0.761、0.712。结论:常规超声心动图在蒽环类药物心脏毒性诊断中具有一定价值。