Predicting cancer therapy-induced cardiotoxicity: the role of troponins and other markers.

Several anticancer drugs have been associated with cardiac toxicity, especially the anthracyclines and trastuzumab. The pathogenesis of anthracycline-associated toxicity has been well described, whereas the mechanism of trastuzumab-associated toxicity is unknown. Although routine cardiac imaging studies (e.g. echocardiogram or multiple gated acquisition scans) may identify subclinical evidence of myocardial dysfunction, available data do not support their routine use for monitoring asymptomatic patients undergoing cancer therapy. Other modalities such as nuclear medicine scintigraphy with indium-111-antimyosin antibody and endomyocardial biopsy have been shown to be useful in identifying early cardiac damage, but their routine use is limited by practical considerations such as feasibility and cost. Consequently, there is significant interest in developing simple and reproducible methods for identifying patients at risk for treatment-induced myocardial damage. Available data suggest that circulating markers such as troponins and natriuretic peptides could potentially be useful for this purpose. Measurement of plasma troponin levels are commonly used in clinical practice in order to provide diagnostic and prognostic information in patients with myocardial ischaemia. Elevated levels may likewise correlate with anthracycline-induced cardiac damage, although plasma levels are only minimally elevated (well below that associated with ischaemia), and elevations may persist for weeks or months after anthracycline exposure. Clinical trials are currently evaluating the role of these markers in predicting both early and late, clinical and subclinical damage associated with anthracyclines and trastuzumab.     

In vivo and in vitro cardiotoxicity of a gold-containing antineoplastic drug candidate in the rabbit

Bis[1,2-bis(diphenylphosphino)ethane] gold(I) chloride (Au(DPPE)+2), a cytotoxic antineoplastic drug candidate, was cardiotoxic in rabbits. Intravenous administration of Au(DPPE)+2 (15 mg/kg) as a single dose produced multiple, 2- to 5-mm subendocardial and myocardial lesions, macroscopically appearing as pale tan foci. Histologically, these lesions consisted of widely scattered zones of myocardial cell necrosis and mineralization. The myocardium also contained multifocal areas of contraction band necrosis in which aggregated clumps of disorganized myofilaments were contiguous with areas of sarcoplasm which were relatively devoid of myofilaments. In a series of in vitro studies, electron microscopic examination of isolated rabbit myocytes treated with 30 microM Au(DPPE)+2 for 15 min showed evidence of mitochondrial swelling and electron translucent mitochondrial matrices. After 60 min of incubation, myocytes had mitochondria that were condensed and disrupted but the cristae had retained their tubular profiles. Isolated rabbit myocytes exposed to 30 microM Au(DPPE)+2 had significant increases in the leakage of lactate dehydrogenase, an index of cell death. Cellular ATP content in myocytes exposed to 30 microM Au(DPPE)+2 was significantly reduced by 30 min. State 4 respiration in isolated rabbit mitochondria was significantly increased by Au(DPPE)+2 (30 microM) while state 3 respiration was unaffected. Au(DPPE)+2 also caused a rapid dissipation of the mitochondrial inner membrane electrochemical potential in a concentration-dependent manner and was accompanied by a ruthenium red-sensitive calcium efflux. These data suggest that disruption of mitochondrial function, leading to uncoupling of oxidative phosphorylation, decreased ATP synthesis, and altered mitochondrial calcium homeostasis, may be a contributing factor leading to cardiac myofibril necrosis produced by Au(DPPE)+2.     

Troponin as a marker of myocardiac damage in drug-induced cardiotoxicity

Cardiac troponins T and I (cTnT and cTnI) are becoming the serum biomarkers of choice for monitoring potential drug-induced myocardial injury in both clinical and preclinical studies. The utility of cardiac troponins has been mainly demonstrated following the administration of antineoplastic drugs and β-sympathomimetics, although the routine use of these markers in the monitoring in patients who received anthracyclines therapy is far from settled. Unlike the previous markers, which suffered from numerous shortages, the main advantages of cardiac troponins are their high specificity and sensitivity, wide diagnostic window and the possibility to use commercially available assays in clinical settings as well as in a broad range of laboratory animals. Nevertheless, in spite of vigorous research in this area, a number of questions are still unanswered and these are discussed in this review. The main problems seem to be the lack of standardisation of variety of troponin immunoassays, the assessment of suitable cutoff for drug-induced cardiotoxicity and determination of critical diagnostic window related to the optimal tim-ing of sample collection, which may be drug-dependent.     

Troponin as a marker of myocardiac damage in drug-induced cardiotoxicity

Cardiac troponins T and I (cTnT and cTnI) are becoming the serum biomarkers of choice for monitoring potential drug-induced myocardial injury in both clinical and preclinical studies. The utility of cardiac troponins has been mainly demonstrated following the administration of antineoplastic drugs and beta-sympathomimetics, although the routine use of these markers in the monitoring in patients who received anthracyclines therapy is far from settled. Unlike the previous markers, which suffered from numerous shortages, the main advantages of cardiac troponins are their high specificity and sensitivity, wide diagnostic window and the possibility to use commercially available assays in clinical settings as well as in a broad range of laboratory animals. Nevertheless, in spite of vigorous research in this area, a number of questions are still unanswered and these are discussed in this review. The main problems seem to be the lack of standardisation of variety of troponin immunoassays, the assessment of suitable cutoff for drug-induced cardiotoxicity and determination of critical diagnostic window related to the optimal timing of sample collection, which may be drug-dependent.     

In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity

The clinical usefulness of anthracycline antineoplastic drugs is limited by their cardiotoxicity. Its mechanisms have not been fully understood, although the induction of oxidative stress is widely believed to play the principal role. Glutathione is the dominant cellular antioxidant, while glutathione peroxidase (GPx) together with glutathione reductase (GR) constitutes the major enzymatic system protecting the cardiac cells from oxidative damage. Therefore, this study aimed to assess their roles in anthracycline cardiotoxicity. Ten-week intravenous administration of daunorubicin (DAU, 3 mg/kg weekly) to rabbits induced heart failure, which was evident from decreased left ventricular ejection fraction and release of cardiac troponins to circulation. However, no significant changes in either total or oxidized glutathione contents or GR activity were detected in left ventricular tissue of DAU-treated rabbits when compared with control animals. GPx activity in the cardiac tissue significantly increased. In H9c2 rat cardiac cells, 24-h DAU exposure (0.1–10 μM) induced significant dose-dependent toxicity. Cellular content of reduced glutathione was insignificantly decreased, oxidized glutathione and GR activity were unaffected, and GPx activity was significantly increased. Neither buthionine sulfoximine (BSO, glutathione biosynthesis inhibitor) nor 2-oxo-4-thiazolidine-carboxylic acid (OTC, glutathione biosynthetic precursor) had significant effects on DAU cytotoxicity. This contrasted with model oxidative injury induced by hydrogen peroxide, which cytotoxicity was increased by BSO and decreased by OTC. In conclusion, our results suggest that the dysfunction of glutathione antioxidant system does not play a causative role in anthracycline cardiotoxicity.     

In vitro validation of drug-induced phospholipidosis

Intracellular accumulation of phospholipids with lamellar bodies is a hallmark of drug-induced phospholipidosis (PLD) which is caused by impaired phospholipid metabolism of the lysosome. Although it remains uncertain whether PLD is associated with the adverse effects, sponsors generally terminate the development of a candidate drug when PLD is observed in an organ. For drugs that are used without serious adverse events, there should be labels indicating that the drug can induce PLD. We conducted LipidTox and NBD-PE assays for detecting PLD to compare and validate the methods. In the case of contrary results in both assays, electron microscopy was performed to confirm the data. We selected 12 chemicals and divided them into 4 categories: P+S+, PLD and steatosis positive; P+/S-, PLD positive and steatosis negative; P-S+, PLD negative and steatosis positive; P-/S-, PLD and steatosis negative. In general, results showed very good agreement with the known information with some minor discrepancies. LipidTox assay is proven to be a very sensitive method. Considering the contrary results of acetaminophen and menadione in LipidTox and the NBD-PE assay, the combination of two methods using different phospholipids is advantageous to reduce false positives. The finding that acetaminophen was positive in LipidTos assay and increased the frequency of lamellar body implies that acetaminophen is a weak inducer of PLD.     

Davallialactone protects against adriamycin-induced cardiotoxicity in vitro and in vivo

Adriamycin (ADR) is a potent anticancer drug. Its clinical applications are limited due to its cardiotoxicity. Oxidative stress is responsible for cardiomyopathy induced by ADR. Previous studies have demonstrated that davallialactone (DAVA), extracted from mushroom Inonotus xeranticus, has potential antiplatelet aggregation activity and free radical scavenging properties. In this study, we investigated whether DAVA has protective effects against ADR-induced free radical accumulation and apoptosis in cardiac muscle cells and compared the effects of DAVA with N-acetylcysteine, a potent antioxidant. We evaluated the effect of DAVA on ADR-induced cytotoxicity by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and crystal violet staining, the reactive oxygen species (ROS) production by flow cytometry, and the expression of stress-related proteins like Cu/Zn superoxide dismutase (SOD), Mn-SOD, and the involvement of mitogen-activated protein kinase pathway by Western blot analysis. Apoptosis was assessed by nuclear condensation and the expression levels of pro-apoptotic proteins, such as caspase-3 and polyadenosine diphosphate-ribose polymerase (PARP). The cardio-protective effects of DAVA were also evaluated in an in vivo study in an animal model of ADR-induced acute cardiomyopathy. Our results showed that DAVA significantly increased the viability of doxorubicin-injured H9c2 cells and inhibited ADR-induced ROS production, apoptosis, and the expression of Cu/Zn SOD and Mn-SOD. DAVA also inhibited the expression of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which was activated by ADR. In the in vivo animal model, treatment involving DAVA significantly reduced cardiomyocyte lesions. These results suggest that DAVA is a potentially protective agent for ADR-induced cardiotoxicity in cardiomyocytes and can be a potential candidate to protect against cardiotoxicity in ADR-treated cancer patients.     

Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro

The long-term clinical usefulness of doxorubicin (DOX), an anthracycline with potent antitumor activity, is limited by DOX-induced cardiotoxicity. Kaempferol, one of the most common dietary flavonoids, is known to have anti-apoptotic, anti-oxidative, and anti-inflammatory properties. The current study aimed to investigate the possible protective effect of kaempferol against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were intraperitoneally (i.p.) treated with DOX (3 mg/kg) every other day for a cumulative dose of 9 mg/kg. After 28 days, DOX caused retarded body and heart growth, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. In contrast, kaempferol pretreatment (10 mg/kg i.p. before DOX administration) attenuated the DOX-induced apoptotic damage in heart tissues. In vitro studies also indicated that kaempferol may have used the mitochondrion-dependent pathway to counteract the DOX-induced cardiotoxicity. This counteraction was achieved by inhibiting p53 expression and its binding to the promoter region of the Bax proapoptotic gene, but not to the Bcl-2 antiapoptotic gene. Kaempferol also effectively suppressed DOX-induced extracellular signal-regulated kinase (ERK) 1/2 activation, but had no effect on p38 and JNK. Therefore, kaempferol protected against DOX-induced cardiotoxicity, at least, partially, by inhibiting the activation of p53-mediated, mitochondrion-dependent apoptotic signaling, and by being involved in an ERK-dependent mitogen-activated protein kinase pathway. These findings elucidated the potential of kaempferol as a promising reagent for treating DOX-induced cardiotoxicity, and may have implications in the long-term clinical usefulness of DOX.     

Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo

BACKGROUND AND PURPOSE: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. EXPERIMENTAL APPROACH: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. KEY RESULTS: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.     

Cardiac troponins as biomarkers of drug- and toxin-induced cardiac toxicity and cardioprotection

Cardiac troponin T and I (cTnT, cTnI) are sensitive biochemical markers of myocardial cell necrosis and have been adopted as the gold standard tests for acute myocardial infarction. Subtle elevations in cTn above the detection limits of the currently available commercial assays confers poor prognosis. These markers are superior to classical enzyme markers of necrosis due to their cardiospecificity. The diagnosis of drug-induced cardiac toxicity using the classical enzymes is problematic due to the high elevations of these markers in skeletal muscle necrosis. cTnT and cTnI are now being adopted as sensitive biomarkers of drug-induced cardiac toxicity.     

In vitro assays and biomarkers for drug-induced phospholipidosis

Drug-induced phospholipidosis is the cytoplasmic accumulation of phospholipids as a result of xenobiotic exposure. This accumulation results in a unique histological effect in cells noted as electron-dense lamellar inclusions or whorls in the cytoplasm when observed with transmission electron microscopy. Electron microscopy has been the widely accepted standard for classification of the phospholipidosis effect. Molecules that have been prone to induce such an effect are made up of a lipophilic region and a positively charged region. Phospholipidosis has most commonly been associated with drugs that are cationic, amphiphilic drugs and can occur in a variety of tissues. Although phospholipidosis is not considered adverse in isolation, depending on the tissue affected or the occasional circumstance of concurrent toxicity, phospholipidosis can be perplexing if identified in early drug development. In most circumstances, characterisation of the effect with in vivo studies allows for determination of exposure and the magnitude of the effect. On occasion in drug development, there may be an interest to screen early stage compounds to minimise phospholipidosis. In such circumstances, in silico and in vitro assays can be employed in a strategy with in vivo assessments. In addition, there may be an interest to monitor for the potential development of phospholipidosis in longer-term animal studies. In such cases, biomarker approaches could be used. The challenge in the overall assessment of phospholipidosis remains the question of the possible relevance to any toxicity, and, therefore, any screening approach, while assessing the potential to induce phospholipidosis, must be considered in relation to prediction of findings in vivo. The status of current assays and biomarkers is presented with strategies for screening.     

In vivo and in vitro protective effects of shengmai injection against doxorubicin-induced cardiotoxicity

ContextShengmai injection (SMI) has been used to treat heart failure.ObjectiveThis study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX).Materials and methodsIn vivo, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. In vitro, H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed.ResultsSMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group in vivo. Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway.ConclusionsThis study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.     

In vitro and animal models of drug-induced blood dyscrasias

Drug-induced blood dyscrasias can be either acute and predictable or delayed and unpredictable (idiosyncratic). The predictable toxicity is relatively easy to reproduce with in vitro models, although they may not work for drugs that require bioactivation. It is very unlikely that idiosyncratic blood dyscrasias can be modeled in vitro, although some drugs (or their reactive metabolites) that cause idiosyncratic reaction are toxic to bone marrow cells in vitro. Although the mechanisms of idiosyncratic reactions are poorly understood, there is evidence that most are due to reactive metabolites and some are immune-mediated. Therefore screening drugs for their bioactivation by myeloperoxidase, the major oxidative enzyme in bone marrow, may provide some measure of the risk that a drug will cause blood dyscrasias. Several examples of drug-induced idiosyncratic agranulocytosis, aplastic anemia and thrombocytopenia are presented, but better in vivo models are clearly needed to gain a clearer understanding of these adverse reactions.     

Tricyclic antidepressants as antimuscarinic drugs: In vivo and in vitro studies

The antagonistic activity of nortriptyline, amitriptyline and imipramine to the hypothermic and tremorgenic activity of oxotremorine was determined in mice. The peripheral anticholinergic relative potencies of these drugs were evaluated by following the dose-dependent time profiles of their mydriatic activity. The binding constants of the antidepressant agent toward the central muscarinic receptor from the mouse whole brain homogenate were determined in vitro, and could be correlated with the ed₅₀ values found for the three drugs' in vivo responses. The three antidepressants tested were found to be 100-fold less active than scopolamine. HBr in all four biological preparations selected. Their anticholinesterase activity towards the enzyme in whole mouse brain homogenate was found to be too low to make any possible contribution to their activity in vivo. The relationships between structure and function and the possible contribution of their antimuscarinic property to the observed in vivo effects are discussed.     

以c-Met为靶点的抗肿瘤系列化合物体内外药效筛选

目的　从8个LY系列肝细胞生长因子受体（c-Met）酪氨酸激酶抑制剂中筛选具有抗肿瘤活性的化合物,并进一步评价其体内外抗肿瘤作用。方法　首先采用均相时间分辨荧光技术（HTRF）对LY系列化合物进行初步筛选,观察它们对c-Met酪氨酸激酶的抑制作用;采用CCK8法观察筛选出的活性化合物在体外对人胃癌MKN-45、人神经胶质瘤U87MG、人肾癌Caki-1、人前列腺癌PC-3细胞株的增值抑制作用。建立人恶性胶质母细胞瘤U87MG裸小鼠移植瘤模型,考察活性化合物的抑瘤效果。结果　HTRF结果显示有4个活性较好的化合物（LY22,LY25,LY28,LY32）,其中LY28对c-Met抑制作用优于阳性对照药Crizotinib;CCK8结果显示这些活性化合物对选用的4种靶细胞均有不同程度的抑制作用,其中LY28对肿瘤细胞增殖抑制作用最明显;裸小鼠移植瘤实验显示,LY28可显著抑制U87MG裸小鼠移植瘤的增殖,40 mg/kg LY28抑瘤率达到78.13%。结论　化合物LY28具有较好抗肿瘤活性,具有进一步研发的价值。     

Calcium dynamics in cardiac myocytes as a target of dichloromethane cardiotoxicity

The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca²⁺ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca²⁺]_i binding. In cultured myocytes, cumulative exposure to 0.64–40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca²⁺]_i transients with IC₁₀ and IC₅₀ values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca²⁺]_i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1–12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl₂-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca²⁺]_i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca²⁺ dynamics during excitation-contraction coupling.     

Health benefits of spices in individuals with chemotherapeutic drug-induced cardiotoxicity

Cardio-oncology is an emerging field that mainly focuses on a series of cardiovascular diseases caused by chemotherapy and radiotherapy. In the history and culture of human nutrition, spices have been emphasized for their wide range of economic and medical applications in addition to being used as a food-flavoring agent and food preservative. Currently, an increasing number of studies have focused on the health benefits of spices in preventing cardiovascular diseases, particularly their antioxidant effects against cardiovascular damage. This review summarizes the cardioprotective effects of black pepper, cardamom, clove, garlic, ginger, onion, and other spices against chemotherapeutic drug-induced cardiotoxicity and the potential mechanisms. Here, we recommend dietary adjustments with spices for patients with cancer to prevent or mitigate the cardiotoxicity induced by chemotherapeutic agents.     

妥舒沙星的体内外抗菌作用研究

测定妥舒沙星的体内外抗菌活性。以同类氟喹诺酮类及其他抗菌药物为对照,测定了６８９株临床分离菌对药物的敏感性,结果显示,妥舒沙星对需氧革兰氏阳性球菌（除ＭＲＳＡ外）均有良好的抗菌作用,对金葡球菌、肺炎球菌和溶血性链球菌的抗菌活性高;妥舒沙星对需氧革兰氏阴性菌具强大的抗菌作用,对肠杆菌科细菌、流感杆菌和淋球菌的抗菌作用尤强;妥舒沙星对脆弱拟杆菌等厌氧菌亦具良好抗菌作用。妥舒沙星对需氧革兰氏阳性球菌及厌氧菌的作用明显优于环丙沙星、氧氟沙星和诺氟沙星,对需氧革兰氏阴性杆菌的作用与其他受试氟喹诺酮类相仿。妥舒沙星对小鼠实验性细菌感染具有明显保护作用,口服或静注妥舒沙星对金葡球菌的体内抗菌作用明显优于环丙沙星;对大肠埃希氏菌的抗菌作用优于或与环丙沙星相似;对铜绿假单胞菌的作用与环丙沙星相似。     

Protective effect of tetrahydroxystilbene glucoside on cardiotoxicity induced by doxorubicin in vitro and in vivo

Aim:

To test the effect of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) on doxorubicin (DOX)-induced cardiotoxicity.

Methods:

We used neonate rat cardiomyocytes and an acute mouse model of DOX-induced cardiotoxicity to examine the protective effect of THSG.

Results:

In the mouse model, administration of THSG significantly reduced DOX-induced cardiotoxicity, including animal mortality, histopathological changes, and levels of serum creatine kinase (CK) and lactate dehydrogenase (LDH). Moreover, THSG was able to attenuate the increased malondialdehyde (MDA) and decreased reduced glutathione (GSH) caused by DOX. In in vitro studies, THSG 10−300 μmol/L ameliorated DOX-induced cardiomyocyte apoptosis in a concentration-dependent manner. Further studies showed that THSG inhibited reactive oxygen species (ROS) generation and prevented DOX-induced loss of mitochondrial membrane potential, caspase-3 activation and upregulation of Bax protein expression. We observed a protective response against damage after DOX treatment. The level of Bcl-2 protein was increased. Additionally, THSG inhibited a DOX-induced [Ca²⁺] increase.

Conclusion:

These results showed that THSG protected against DOX-induced cardiotoxicity by decreasing ROS generation and intracellular [Ca²⁺] and by inhibiting apoptotic signaling pathways.     

药物超敏反应安全评价体外替代方法的研究进展

超敏反应是药物的严重不良反应之一,严重时可危及患者生命。目前超敏反应(Ⅰ,Ⅳ型)临床前评价方法多为整体动物实验方法,基于动物福利和3R原则的考虑,以及体外替代方法的迅速发展,目前已建立了数种药物致敏性评价的体外替代方法,包括根据肥大细胞和嗜碱性粒细胞在Ⅰ型超敏反应中发挥的关键作用,用实验室易获得的肥大细胞和嗜碱性粒细胞系如RBL-2H3和KU812研究药物的Ⅰ型超敏反应,另外鉴于树突状细胞在Ⅳ型超敏反应中抗原呈递作用,用THP-1细胞构建的h-CLAT试验体系和LC-SA试验体系在皮肤致敏性的评价方面都显示出较好的发展前景。本文综合近年的国内外文献,对超敏反应的体外替代方法进行了综合论述和评估。