Toxic Effects of Violamycin BI,Carminomycin and Daunorubicin on the Myocardium of Rabbits

Abstract: Cardiac toxicity of the new anthracycline antitumour antibiotics violamycin BI (V) and carminomycin (C) was studied in comparison with daunorubicin (D). Rabbits were intravenously given total doses of 0.1–1.5 mg/kg V or C, and 0.64–18 mg/kg D, respectively, twice weekly for one month. When examined two to six days, two and four weeks, respectively, after the last drug administration the gross findings consisted of hydropericard, hydrothorax and ascites in some animals. Histologically, loss of striation and focal necrosis of cardiac muscle cells and subsequently chronic inflammatory reactions and/or proliferation of mesenchyma cells were mostly found. These alterations were somewhat more pronounced in rabbits treated with V than in animals received D or C. At equitoxic doses of the antibiotics tested the ultrastructural lesions in the myocardial cells were altogether less marked after treatment with D than with C or V.     

Protective effect of selected flavonoids on in vitro daunorubicin-induced cardiotoxicity

Flavonoids are an ubiquitous group of polyphenolic substances with varied chemical structures present in foods of plant origin and act as free radical scavenging and chelating agents with a variety of biological activities. Using a model of spontaneously beating, cultured adult rat cardiomyocytes, this study examined the cardioprotective role of quercetin, naringenin, pycnogenol and a model antioxidant, trolox, against daunorubicin-induced toxicity. Cardiomyocyte protection was assessed by MTT test and extracellular lactate dehydrogenase detection. Protection of cardiomyocytes was concentration/dose dependent for quercetin > naringenin > pycnogenol > trolox. Quercetin (10(-4)-10(-6) mol/L) after 24 h of co-incubation with daunorubicin significantly increased the cardiomyocyte survival in all tested concentrations (p < 0.001). The cytoprotective effect of naringenin (10(-4)-10(-6) mol/L) was similar to those of quercetin (p < 0.001 and p < 0.01, respectively). Pycnogenol was the least effective of the flavonoids studied. On the other hand, all tested flavonoids had significantly better protective effects than trolox. The leakage of lactate dehydrogenase induced by daunorubicin was also prevented by the studied compounds and was in accordance with their cytoprotective activity.     

Imipramine Cardiotoxicity: An Electrocardiographic and Haemodynamic Study in Rabbits

Abstract The purpose of the present study was to investigate the cardiotoxicity of the tricyclic antidepressant imipramine. The experiments were carried out in rabbits during continous intravenous infusion of imipramine, and electrocardiographic and haemodynamic changes were observed. The blood flows were measured using the radioactive microsphere method based upon the principles of Fick and Stewart Hamilton. It was found that the decrease in heart rate and the changes in heart rhythm were always preceded by a fall in arterial blood pressure and cardiac contractility, expressed by a fall in dp/dt_max. On the basis of the results it is concluded that a direct depressing action on the myocardium is of importance in the development of cardiac complications, although both a depressing influence on cardiac conduction, an anticholinergic effect, and an influence on adrenergic factors may also contribute. The possibility of positive correlations between the changes in plasma- imipramine concentration and the changes in the dp/dt_max and the QRS complex cannot be excluded.     

A toxicoproteomic study on cardioprotective effects of pre-administration of docetaxel in a mouse model of adriamycin-induced cardiotoxicity

Studies suggest that pre-administration of docetaxel (DOC) in adriamycin (ADR)-DOC combination anticancer therapy results in stronger antitumor effects and fewer ADR-induced cardiotoxic deaths in mouse model, yet no mechanism explaining this effect has been established. The aim of this study was to identify cellular processes in mouse heart tissue affected by different ADR/DOC dosing protocols using a toxicoproteomic approach. We applied fluorogenic derivatization-liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS) - which consists of fluorogenic derivatization, separation and fluorescence detection by LC, and identification by LC-tandem mass spectrometry - to the proteomic analysis of heart tissue from control, intermittent-dosing (DOC-ADR), and simultaneous-dosing (ADR&DOC) groups. In DOC-ADR group, ADR was administered 12 h after DOC injection; in ADR&DOC group, both drugs were administered simultaneously; in control group, saline was administered at the same timing as ADR injection of other groups. Heart samples were isolated from all mice 1 week after the treatment. The highly reproducible and sensitive method (FD-LC-MS/MS) identified nine proteins that were differentially expressed in heart tissue of control and the two treatment groups; seven of these nine proteins participate in cellular energy production pathways, including glycolysis, the tricarboxylic acid cycle, and the mitochondrial electron transport chain. Significantly higher expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was observed in the DOC-ADR group, the group with the fewer cardiotoxic deaths, than in the ADR&DOC group. Therefore, GAPDH may have potential as a drug target for protective intervention and a biomarker for evaluation of the cardioprotective effects in pre-clinical studies.     

Treatment of poisoning induced cardiac impairment using cardiopulmonary bypass: a review

Severe poisoning can cause potentially fatal cardiac depression. Cardiopulmonary bypass (CPB) can support the depressed myocardium, but there are no clear indications or guidelines available on its use in severe poisoning. A review was conducted of relevant papers in the available literature (seven single case reports of both deliberate and accidental ingestion of cardiotoxic drugs and two animal studies). Although CPB is rarely used in the management of poisoning, it may have potential benefits for haemodynamic instability not responding to conventional measures. At present there is insufficient evidence concerning the use of CPB as a treatment for severe cardiac impairment due to poisoning (grade C). This review suggests that in patients with severe and potentially prolonged reversible cardiotoxicity there is potential for full survival with CPB, provided that the patient has not already sustained hypoxic cerebral damage due to resistant hypotension prior to its use.     

血浆B型利钠肽在多柔比星致心脏损害中动态改变的实验研究

目的 拟通过检测多柔比星注射前后兔血浆BNP含量,了解兔心脏损害随时间变化与血浆BNP含量之间的关系.方法 选择雄性健康新西兰大白兔80只,实验兔耳缘静脉注射多柔比星溶液,每次2mg/kg,每周1次,共8周,总量约相当于16mg/kg,每周检测血浆BNP含量、超声检测EF值和病理学检查,8周后停止注射,继续观察8周,全部实验过程共计16周.结果 血浆BNP含量在给药后第5周起开始逐步上升(P＜0.05),第10周时达到高峰,停药后BNP浓度开始逐步下降,第15周后血浆BNP浓度不再出现有统计学意义的下降.结论 血浆BNP含量检测能够反映心功能减低的状态,但是与病理检查相比存在一定的滞后,对于早期发现和监测多柔比星造成的心脏损害具有一定的价值.     

Toxicity of the antimalarial artemisinin and its dervatives

As long as no effective malaria vaccine is available, chemotherapy belongs to the most important weapons fighting malaria. One of the most promising new drug developments is the sesquiterpene artemisinin (ARS) and its derivatives, e.g., artemether, arteether, and sodium artesunate. Large clinical studies and meta-analyses did not show serious side effects, although proper monitoring of adverse effects in developing countries might not be a trivial task. There is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity. Therefore, a final and definitive statement on the safety of artemisinins still cannot be made. In contrast, animal experiments show considerable toxicity upon application of artemisinins. In the present review, the authors give a comprehensive overview on toxicity studies in cell culture and in animals (mice, rats, rabbits, dogs, monkeys) as well as on toxicity reported in human clinical trials. The authors emphasize the current knowledge on neurotoxicity, embryotoxicity, genotoxicity, hemato- and immunotoxicity, cardiotoxicity, nephrotoxicity, and allergic reactions. The lesson learned from animal and human studies is that long-term availability rather than short-term peak concentrations of artemisinins cause toxicity. Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intramuscular (i.m.) injection. This explains why considerable toxicities were found in the majority of animal experiments, but not in human studies. In addition, there are drug-related differences, i.e., intramuscular application of artemether or arteether, but not to artesunate, which is safe and gives good profiles after i.m. administration in severe malaria. Although there is no need to increase doses of artemisinins for uncomplicated malaria, this has to be taken into account for cerebellar involvement in severe malaria. It might also be important in determining dose limitations for treatment of other diseases such as cancer.     

RAC2基因遗传多态性与柔红霉素引起心肌损伤的相关性研究

目的通过研究急性白血病(AL)患儿还原型辅酶Ⅱ(NADPH)氧化酶亚基RAC2基因的遗传多态性,探讨其与柔红霉素引起心肌损伤的关系。方法选取42例接受正规化疗的AL患儿(AL组)和25名健康儿童(正常对照组),采集所有儿童的外周静脉血并抽提DNA,采用PCR技术扩增RAC2基因单核苷酸多态性(SNP)位点的上、下游片段,基因测序法检测rs13058338位点的RAC2基因遗传多态性,比较各组间RAC2基因遗传多态性的分布频率。结果 67名被研究者出现RAC2基因遗传多态性的总体阳性率为19.4%,AL组和正常对照组的分布频率基本一致(P=0.531)。AL组中,氨基未端脑利钠肽(NT-proBNP)(>125pg/mL)升高组和NT-proBNP(0～125pg/mL)正常组的RAC2基因遗传多态性频率分别为25.9%(7/27)和0(0/15),差异有统计学意义(P=0.035);柔红霉素累积剂量为60～120mg/m2组和>120mg/m2组的分布频率分别为20.0%(5/25)和11.8%(2/17),差异无统计学意义(P=0.681)。NT-proBNP升高组中,7例出现AT等位基因患儿的NT-pro...