右丙亚胺联合参麦注射液在减少急性白血病化疗中心脏毒性的临床研究

目的：观察比较右丙亚胺注射液单用,参麦注射液单用及右丙亚胺参麦注射液联合使用对急性白血病患者化疗期间心脏毒性的影响。方法将2010年1月-2014年6月该院收治的105例已明确诊断为急性白血病的患者随机分为3组,每组35例。每组患者均应用含有蒽环类药物的化疗方案。A组：右丙亚胺组,在应用蒽环类药物化疗前30 min将右丙亚胺注射液快速静脉滴注。 B组：参麦注射液组,对化疗患者给予参麦注射液保护心脏治疗,用法为50 mg/d静脉滴注。 C组：联合用药组,化疗同时联合应用右丙亚胺及参麦注射液保护心脏。每组药物均在化疗期间使用,化疗结束后停止使用。观察并记录3组患者心肌酶数值变化,心电图改变及左心室射血分数的变化。结果比较3组患者化疗前后的心电图变化,心肌酶变化及左心室射血分数变化,观察其心脏损害的程度及比例。结果表明C组患者各种心脏损害的指标均低于A,B两组。结论右丙亚胺及参麦注射液联合应用对于接受以蒽环类药物为基础的化疗方案的患者,可明显减轻其心脏毒性作用,可作为降低蒽环类药物心脏毒性的新途径。     

Amifostine and Dexrazoxane Enhance the Rapid Loss of Bone Mass and Further Deterioration of Vertebrae Architecture in Female Rats

Doxorubicin (DOX) is widely used in combination cocktails for treatment of childhood hematologic cancers and solid tumors. A major factor limiting DOX usage is DOX-induced cardiotoxicity. Dexrazoxane (DXR) is an iron-binding compound and the only approved cardioprotectant for use with DOX. Amifostine (AMF) is a free radical scavenger and approved as a broad-spectrum cytoprotectant. We have shown that when female rats are treated with AMF, AMF + DOX, or AMF + DXR + DOX there is a significant decrease in the right femoral and lumbar vertebral bone mineral density (BMD) (P < 0.05) but not in the left femoral BMD. Furthermore, the relative bone volume (BV/TV) was significantly smaller in the lumbar vertebral bodies of rats treated with AMF (21.1%), AMF + DOX (34.4%), and AMF + DXR + DOX (38.4%), as was the trabecular number (Tb.N) with AMF (15.5%), AMF + DOX (29.9%), and AMF + DXR + DOX (32.3%). AMF + DOX– and AMF + DXR + DOX–treated vertebrae also exhibited deterioration in the microarchitecture of the trabecular bone and spinous processes as ascertained by microcomputerized tomography (micro CT). This information will be useful in designing better cancer combination therapies that do not lead to bone deterioration. Grant Sponsor: Heart and Stroke Foundation of Quebec; Grant Sponsor: Canadian Institutes of Health Research; Grant Sponsor: Canadian Orthopaedic Foundation; Grant Sponsor: Rx&D Health Research Foundation.     

Prevention of chronic anthracycline cardiotoxicity in the adult Fischer 344 rat by dexrazoxane and effects on iron metabolism

Purpose: Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1–IRE binding, may be an important mechanism of anthracycline cardiotoxicity. Methods: This study examined the role of IRP1–IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5–6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1–IRE binding. Results: Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin. Conclusions: IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.The authors state there are no conflicts of interest regarding the work in this paper.     

DEXRAZOXANE - A PROMISING ANTIDOTE IN THE TREATMENT OF ACCIDENTAL EXTRAVASATION OF ANTHRACYCLINES

Accidental extravasation of chemotherapy containing anthracycline often causes mutilating complications as a result of extensive tissue necrosis. Treatment therefore consists of extensive surgical debridement. We present the case of a 41-year-old woman with breast cancer who experienced extravasation of epirubicin. She was treated with an intravenous infusion of dexrazoxane for three successive days and recovered without surgical treatment and only slightly dysaesthesia in the surrounding tissue. Although infusion of dexrazoxane for this indication is still experimental we consider it a promising treatment for patients who have accidental extravasation of anthracyclines.     

注射用右丙亚胺制备、质量控制及稳定性考察

目的制备注射用右丙亚胺,建立其质量控制方法并考察其稳定性。方法制备注射用右丙亚胺;采用高效液相色谱法测定其含量及有关物质,并对制剂进行稳定性考察。结果本品处方以100mg/瓶甘露醇作为赋形剂,用0.1mol/L盐酸调节pH为1.9;右丙亚胺在4.4～44μg/ml浓度范围内线性关系良好,r=0.9999（n=5）,恒温加速试验6个月及长期留样24个月时主药含量及有关物质未见明显变化。结论该制剂处方工艺可行,质量可控,稳定性良好;所建立的含量测定方法重复性好,专属性强,结果准确可靠。     

右丙亚胺用于乳腺癌术后化疗所致患者心肌损害的有效性和安全性

目的 探讨右丙亚胺对乳腺癌患者采用蒽环类化疗时心肌的保护作用.方法 选择乳腺癌术后接受CAF(环磷酰胺+阿霉素+5-氟尿嘧啶)方案和TE(多西他赛+表柔比星)方案化疗的患者98例.按照随机数字法将患者分为试验组和对照组各49例.对照组及实验组均采用CAF方案和TE方案化疗,试验组在给予阿霉素或表柔比星30 min前给予右丙亚胺(奥诺先)静脉滴注(右丙亚胺:阿霉素或表柔比星=10:1),30 min内滴完.结果 与治疗前比较,试验组治疗12个月以后出现血清BNP升高,对照组治疗6个月以后出现升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清BNP低于对照组,差异有统计学意义(P<0.05).与治疗前比较,2组患者治疗6个月以后血清cTnT升高,差异有统计学意义(P<0.05);治疗6个月,12个月及24个月,试验组血清cTnT低于对照组,差异有统计学意义(P<0.05).试验组患者治疗后血清CK-MB与治疗前差异无统计学意义(P>0.05);对照组治疗12个月以后升高,差异有统计学意义(P<0.05).试验组治疗期间,LVEF与治疗前差异无统计学意义(P>0.05);对照组治疗6个月以后LVEF下降,差异有统计学意义(P<0.05);治疗6个月以后,对照组LVEF低于观察组,差异有统计学意义(P<0.05).2组患者不良反应发生情况差异无统计学意义(P>0.05).结论 右丙亚胺用于乳腺癌术后化疗可以明显减轻蒽环类药物的心脏毒性,保护心肌细胞,且不增加化疗的不良反应,提高患者化疗药物耐受性.     

In vitro and in vivo study on the antioxidant activity of dexrazoxane

Objectives

The iron chelator dexrazoxane has been shown to significantly reduce anthracycline-induced cardiac toxicity in several randomized controlled studies. Aim of the present study was to assess the in vitro and in vivo antioxidant effects of dexrazoxane.

Methods

The in vitro antioxidant activity of dexrazoxane as its total oxyradical scavenging capacity (TOSC) was assessed and compared to that of some classic antioxidants such as reduced glutathione (GSH), uric acid and trolox. The plasma antioxidant activity of 20 newly-diagnosed non-Hodgkin lymphoma (NHL) patients scheduled to receive anthracycline-containing chemotherapy (ProMECE-CytaBOM) was also evaluated. Results were expressed as TOSC units.

Results

Dexrazoxane exhibited an in vitro scavenging capacity towards hydroxyl radicals 320% higher than that of GSH (p < 0.00001), 20% higher than that of uric acid (p < 0.001), and 100% higher than that of trolox (p < 0.001). In the clinical study, ProMECE-CytaBOM infusion significantly reduced plasma TOSC in NHL patients (p = 0.0001). Dexrazoxane supplementation was able to restore plasma antioxidant activity in two hours from the end of the ProMECE-CytaBOM infusion.

Conclusions

Dexrazoxane has in vitro antioxidant capacity. In vivo, it is able to reduce the epirubicin-induced free radical production. The intrinsic antioxidant effect of this compound could explain the reduction of the anthracyclines-induced toxicity in those patients treated with dexrazoxane supplementation.     

Cardioprotection by dexrazoxane (Cardioxane; ICRF 187): Progress in supportive care

The dose-limiting toxicity of the widely used anticancer agent, doxorubicin, is a destructive, irreversible and progressive cardiomyopathy. Prevention of this cardiotoxicity without reduction of antitumour efficacy or the production of new toxicities has therefore been a long-time therapeutic goal. It has now been largely achieved by prior administration of dexrazoxane (DXRz; Cardioxane in Europe; Zinecard in North America; ICRF 187). Six randomized, controlled clinical trials in breast and lung cancer and in soft tissue sarcomas of children have shown a 90% reduction in doxorubicin-induced cardiotoxicity. The results of all these trials lead to the conclusion that DXRz permits: (1) cardiotoxic doses of doxorubicin to be given without cardiotoxicity; (2) patients with increased cardiac risk factors to be treated with full doses of dioxorubicin; (3) second-line treatment with other cardiotoxic drugs.Presented in part as an invited lecture at the 7th International Symposium: Supportive Care in Cancer, Luxembourg, 20–23 September 1995     

Dexrazoxane (ICRF-187) protects cardiac myocytes against hypoxia-reoxygenation damage

Dexrazoxane is a cardioprotective antioxidant that is clinically used to reduce the cardiotoxicity of the chemotherapeutic drug doxorubicin. We examined the hypothesis that dexrazoxane also may be able to protect neonatal rat cardiac myocytes from hypoxia-reoxygenation damage. Hypoxia-reoxygenation damage is thought to involve oxidative stress on the heart muscle, possibly by the production of hydroxyl radicals mediated by iron. The results of this study showed that dexrazoxane was highly effective in protecting myocytes from hypoxia-reoxygenation-induced lactate dehydrogenase release. The metal chelating hydrolysis product of dexrazoxane, ADR-925, also protected myocytes from hypoxia-reoxygenation damage, although it was less effective than dexrazoxane. This study also showed that ADR-925 and dexrazoxane rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. These results suggest that dexrazoxane may protect myocytes against hypoxia-reoxygenation-induced damage by chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage. Thus, dexrazoxane or its analogs may have some clinical utility in preventing tissue damage that occurs after a stroke or heart attack.     

Other uses of dexrazoxane: savene,the first proven antidote against anthracycline extravasation injuries

Dexrazoxane has been in clinical use for more than 25 years for prevention of cardiotoxicity in anthracycline based anticancer therapy. However, we discovered another property of the compound, i.e. the ability to prevent the devastating tissue necrosis after accidental extravasation of anthracyclines. The preclinical and clinical studies leading to the clinical implementation of Savene™ (dexrazoxane) as the first and only proven antidote in anthracycline extravasation are described in short.