Acquired von Willebrand syndrome and post-operative drainage: a comparison of patients with aortic stenosis versus coronary artery disease.

OBJECTIVE: Degenerative aortic stenosis and coronary artery disease are considered to be the most prevalent cardiovascular diseases in industrialized countries. This study aims to determine the change over time in von Willebrand factor antigen, von Willebrand factor activity, and factor VIII and where there is a correlation with total post-operative drainage. METHODS: The single-center retrospective study included 203 consecutive patients (64.5% male), undergoing coronary artery bypass surgery between March 1, 2019 and June 30, 2020 at the University Clinical Center of Serbia in the Clinic for Cardiac Surgery in Belgrade, Serbia. All patients 18 years or older who presented with isolated, hemodynamically significant aortic stenosis were included. The control group consisted of patients who presented with only coronary artery disease. RESULTS: Between patients with only coronary artery disease and patients with coronary artery diseases and aortic stenosis, there was a statistically significant difference between pre-op and 1-month post-op fibrinogen, factor VIII, von Willebrand factor antigen, and von Willebrand factor (p < 0.001), post-op drainage, with overall lower drainage in coronary artery disease patients, and consistent increase in von Willebrand factor antigen, von Willebrand factor activity, and Factor VIII post-operatively in patients with coronary artery diseases and aortic stenosis. CONCLUSION: This study has shown that there is a correlation between von Willebrand factor antigen, von Willebrand factor activity and total drainage to the level of statistical significance in aortic stenosis patients and in the overall study population.

Perceval Sutureless Bioprosthesis for Degenerative Aortic Valve Stenosis: Initial Experience With 67 Patients.

OBJECTIVE: The objective of this prospective study was to evaluate the characteristics (positive and negative) of Perceval S valve in patients undergoing aortic valve replacement with a biological prosthesis. The study included 67 patients operated on at our institution and a mean follow-up period of 18 months. METHODS: From June 2016 to November 2019, 209 patients underwent aortic valve replacement with a biological prosthesis. Of these, 67 patients were included in the study based on the exclusion and inclusion criteria set before the study began. Their data were recorded during their hospital stay (preoperative, intraoperative, and early and late postoperative time). RESULTS: Fifty-four patients underwent isolated aortic valve replacement (group I) with a Perceval S prosthesis, and 13 patients had combined aortic valve replacement procedures and CABG procedures (group II). Patients were implanted with the following prosthesis sizes: S (N = 12), M (N = 18), L (N = 28), or XL (N = 9). The Perceval S valve successfully was implanted in 67 (91.8%) patients (in 6 patients, the preoperative transthoracic echocardiographic data did not coincide with intraoperative TEE and surgical measurement of the size of the annulus in the suture). Surgical approaches in patients were medial sternotomy (N = 48), mini sternotomy (N = 15), and thoracotomy through the second intercostal space to the right (N = 4). The mean clamping time of the aorta and CPB length for isolated cases was 54 and 82 minutes, respectively, and 96 and 120 minutes for combined procedures. Four (5.9%) patients died within 30 days. CONCLUSION: Early postoperative results showed that the Perceval S valve was safe. Further follow up is required to evaluate the long-term duration of patients with this bioprosthesis.

Surgical Challenges of Heart Mate 3 Pump Implantation in Aneurysmally Changed Heart Ventricles.

We presented surgical treatment of three patients indicated for implantation of a permanent mechanical circulatory support device and with the associated left ventricular aneurysms. In order to evade the left ventricular rupture, adverse thromboembolic events and provide safe implantation of the inflow cannula, LVAD HM3 implantation together with the reconstruction of the left ventricular aneurysmal wall was performed in two patients. Regarding the third patient, LVAD implantation upon the reconstruction of the left ventricular wall was abandoned because there was no safe location for placement of the inflow cannula.

Investigation of the Postoperative Complications Rate and Predictors in Patients Undergoing Surgery due to Associated Carotid and Coronary Occlusive Disease.

BACKGROUND: The aim of this study was to evaluate the frequency of postoperative complications in patients who underwent coronary artery bypass grafting (CABG) and simultaneous carotid endarterectomy (CEA) and find predictors of postoperative complications. METHODS: We retrospectively evaluated 86 patients after simultaneous CABG and CEA. Inclusion criteria were: patients with asymptomatic carotid stenosis with a reduction of the carotid lumen diameter of more than 70% detected with Doppler ultrasound and diagnosed with one, two, or three vessel coronary artery disease with coronary stenosis more than 75% and hemodynamic significant stenosis of the left main artery. Exclusion criteria were patients with urgent and previous cardiac surgery and patients with myocardial infarction and stroke in the past one month. We monitored preoperative (ejection fraction, coronarography status), operative (number of grafts, on-pump or off-pump technique) and postoperative (extubation, unit care and hospital stay, bleeding and reoperation) details and complications (myocardial infarction, neurological events, inotropic agents and transfusion requiry, infection, arrhythmic complication, renal failure, mortality). RESULTS: Postoperative complications were observed in 18 (29.9%) patients. Two patients (2.3%) had postoperative stroke and one patient (1.2%) had transient ischemic attack (TIA). Previous stroke was a predictor for increased postoperative neurological events (P < .05). Intrahospital mortality was 8.1%. CONCLUSION: Simultaneous CEA and CABG were performed with low rates of stroke and TIA. Previous stroke was identified as a predictor for increased postoperative neurological complications.

Nanoformulations of doxorubicin: how far have we come and where do we go from here?

Nanotechnology, focused on discovery and development of new pharmaceutical products is known as nanopharmacology, and one research area this branch is engaged in are nanopharmaceuticals. The importance of being nano has been particularly emphasized in scientific areas dealing with nanomedicine and nanopharmaceuticals. Nanopharmaceuticals, their routes of administration, obstacles and solutions concerning their improved application and enhanced efficacy have been briefly yet comprehensively described. Cancer is one of the leading causes of death worldwide and evergrowing number of scientific research on the topic only confirms that the needs have not been completed yet and that there is a wide platform for improvement. This is undoubtedly true for nanoformulations of an anticancer drug doxorubicin, where various nanocarrriers were given an important role to reduce the drug toxicity, while the efficacy of the drug was supposed to be retained or preferably enhanced. Therefore, we present an interdisciplinary comprehensive overview of interdisciplinary nature on nanopharmaceuticals based on doxorubicin and its nanoformulations with valuable information concerning trends, obstacles and prospective of nanopharmaceuticals development, mode of activity of sole drug doxorubicin and its nanoformulations based on different nanocarriers, their brief descriptions of biological activity through assessing in vitro and in vivo behavior.

Hepatoprotective effect of fullerenol/doxorubicin nanocomposite in acute treatment of healthy rats.

In our recent studies we have designed fullerenol/doxorubicin nanocomposite (FNP/DOX) as the new drug nanocarrier. This research has demonstrated that this novel nanocomposite has had better implications on the liver tissue in vivo (Wistar rats treated intraperitoneally), than treatment based only on DOX. FNP/DOX has been characterised by DLS, TEM and AFM measurements which have shown that DOX loaded onto FNP did not influence fullerenol nanoparticle's size. FNP/DOX affected oxidative status in blood causing a significant decrease of catalase and SOD activity in comparison to DOX, implicating the reduction in oxidative stress. qRT-PCR results on the mRNA level of antioxidative enzymes (catalase and MnSOD) revealed that the effect of oxidative stress is significantly reduced by the treatment with FNP/DOX (p < .05). The ultrastructural analysis of the liver tissue has revealed that FNP/DOX nanocomposite generated considerably less damage in the liver tissue, than DOX applied at the same dose. Hence, our results have indicated that FNP, within FNP/DOX nanocomposite, exhibits protective effects to the liver tissue of the healthy rats.

Evaluation of predictive value of 1H MR spectroscopy for response of neoadjuvant chemotherapy in musculoskeletal tumors.

PURPOSE: Bone and soft tissue tumors are rare. There is a variety of types and each one has its own particular behavior, treatment and patient outcome. The assessment of treatment response following the 3rd cycle of chemotherapy is one of the most important aspects of patient care, as therapeutic options and the timing of surgery may vary depending on the achievement of response. Hence, we focused on the advanced imaging technique, proton magnetic resonance spectroscopy (1H MRS), aiming at improving the diagnostic accuracy and the tumor response to therapy, based on the absolute concentration of choline (Cho) as biomarker of malignancy. METHODS: Twenty patients were studied. All of them had a pathological diagnosis after biopsy. MRI examinations were performed using a 1.5 T MR scanner (Avanto; Siemens, Erlangen, Germany). Single-voxel 1H MR spectroscopy was performed by using a PRESS with TR/TE 1530/100 ms, before chemotherapy and after the 3rd cycle. 1H MRS was processed in LCmodel. RESULTS: Of 20 patients, 7 responded to neoadjuvant chemotherapy and 13 did not. In responders, the mean concentration of tCho before therapy was 4.7±2.5 mmol/kg, which showed statistically significant reduction after therapy. In non-responders, the mean tCho concentration before therapy was 2.9±0.9 mmol/kg which remained the same or increased after the 3rd cycle of neoadjuvant chemotherapy (2.7±2.5 mmol/kg; range from 2.05 to 5.79 with no statistical significance). Compared to reference healthy group, tCho concentrations were increased in all cases. CONCLUSIONS: 1H MRS appears to be valuable technique for evaluation of response to neoadjuvant chemotherapy of patients with musculoskeletal tumors (MSK).

Treatment results of childhood Ewing's sarcoma of the bone in Serbia.

PURPOSE: The purpose of this study was to present treatment results of childhood Ewing's sarcoma (ES) of the bone in Serbia and to analyze prognostic factors. METHODS: We performed a detailed analysis on a series of 107 patients with ES of the bone treated at the Institute for Oncology and Radiology of Serbia between 2000 and 2014, using modern multimodal therapy. RESULTS: Median age at the time of diagnosis was 14 years, with 56.07% of the patients being ≤14 years. There was a male predominance (59.81%). The most common primary sites were pelvis (25.23%), femur (17.76%) and tibia (12.15%). Thirty-four patients (31.78%) had metastatic disease, 17 of which had isolated lung metastases, 9 bone metastases and 8 patients had both. Tumor size ≤ 8 cm had 38.32% and >8 cm had 61.68% patients. Overall, 51.4% patients underwent surgery and radiotherapy as a local treatment modality after neoadjuvant chemotherapy. Radiotherapy alone was performed in 24 patients. The 5-year overall survival (OS) was 43.8%. For patients with localized disease, the 5-year OS was 56.4% and for patients with metastatic disease 17.6%. In patients with initially nonmetastatic disease, age under 14 years, with tumor size <8 cm and a good response to the neoadjuvant chemotherapy, the OS correlated with better outcome. CONCLUSIONS: Modern multidisciplinary approach in treatment of childhood ES of the bone in accordance with the recommended pediatric protocols, gives good treatment results. Therapy should be performed in referral centers.

Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

Synergistic mitotoxicity of chloromethanes and fullerene C60 nanoaggregates in Daphnia magna midgut epithelial cells.

Adsorption of non-polar compounds by suspended fullerene nanoaggregates (nC60) may enhance their toxicity and affect the fate, transformation, and transport of non-polar compounds in the environment. The potential of stable fullerene nanoaggregates as contaminant carriers in aqueous systems and the influence of chloromethanes (trichloromethane and dichloromethane) were studied on the midgut epithelial cells of Daphnia magna by light and electron microscopy. The size and shape of fullerene nanoaggregates were observed and measured using dynamic light scattering, transmission electron microscopy, and low vacuum scanning electron microscopy. The nC60 in suspension appeared as a bulk of aggregates of irregular shape with a surface consisting of small clumps 20-30 nm in diameter. The presence of nC60 aggregates was confirmed in midgut lumen and epithelial cells of D. magna. After in vivo acute exposure to chloromethane, light and electron microscopy revealed an extensive cytoplasmic vacuolization with disruption and loss of specific structures of D. magna midgut epithelium (mitochondria, endoplasmic reticulum, microvilli, peritrophic membrane) and increased appearance of necrotic cells. The degree of observed changes depended on the type of treatment: trichloromethane (TCM) induced the most notable changes, whereas fullerene nanoaggregates alone had no negative effects. Transmission electron microscopy also indicated increased lysosomal degradation and severe peroxidative damages of enterocyte mitochondria following combined exposure to chloromethane and fullerene nanoaggregates. In conclusion, the adsorption of chloromethane by fullerene nanoaggregates enhances their toxicity and induces peroxidative mitochondrial damage in midgut enterocytes.

Fullerenol/doxorubicin nanocomposite mitigates acute oxidative stress and modulates apoptosis in myocardial tissue.

Fullerenol (C60(OH)24) is present in aqueous solutions in the form of polyanion nanoparticles with particles' size distribution within the range from 15 to 42 nm. In this research it is assumed that these features could enable fullerenol nanoparticles (FNPs) to bind positively charged molecules like doxorubicin (DOX) and serve as drug carriers. Considering this, fullerenol/doxorubicin nanocomposite (FNP/DOX) is formed and characterized by ultra-performance liquid chromatography tandem mass spectrometry, dynamic light scattering, atomic force microscopy and transmission electron microscopy. Measurements have shown that DOX did not significantly affect particle size (23 nm). It is also assumed that FNP/DOX could reduce the acute cardiotoxic effects of DOX in vivo (Wistar rats treated i.p.). In this study, quantitative real time polymerase chain reaction results have shown that treatment with DOX alone caused significant increase in mRNA levels of catalase (p < 0.05) enzyme indicating the presence of oxidative stress. This effect is significantly reduced by the treatment with FNP/DOX (p < 0.05). Furthermore, mRNA levels of antiapoptotic enzyme (Bcl-2) are significantly increased (p < 0.05) in all treated groups, particularly where FNP/DOX was applied, suggesting cell resistance to apoptosis. Moreover, ultrastructural analysis has shown the absence of myelin figures within the mitochondria in the heart tissue with FNP/DOX treatment, indicating reduction of oxidative stress. Hence, our results have implied that FNP/DOX is generally less harmful to the heart compared to DOX.

Carbon nanomaterials: Biologically active fullerene derivatives.

Since their discovery, fullerenes, carbon nanotubes, and graphene attract significant attention of researches in various scientific fields including biomedicine. Nano-scale size and a possibility for diverse surface modifications allow carbon nanoallotropes to become an indispensable nanostructured material in nanotechnologies, including nanomedicine. Manipulation of surface chemistry has created diverse populations of water-soluble derivatives of fullerenes, which exhibit different behaviors. Both non-derivatized and derivatized fullerenes show various biological activities. Cellular processes that underline their toxicity are oxidative, genotoxic, and cytotoxic responses.The antioxidant/cytoprotective properties of fullerenes and derivatives have been considered in the prevention of organ oxidative damage and treatment. The same unique physiochemical properties of nanomaterials may also be associated with potential health hazards. Non-biodegradability and toxicity of carbon nanoparticles still remain a great concern in the area of biomedical application. In this review, we report on basic physical and chemical properties of carbon nano-clusters--fullerenes, nanotubes, and grapheme--their specificities, activities, and potential application in biological systems. Special emphasis is given to our most important results obtained in vitro and in vivo using polyhydroxylated fullerene derivative C60(OH)24.

Effects of fullerenol C60(OH)24 nanoparticles on a single-dose doxorubicin-induced cardiotoxicity in pigs: an ultrastructural study.

Cardioprotective effects of fullerenol C60(OH)24 nanoparticles (FNP) were investigated in pigs after a single treatment with doxorubicin (DOX). Semithin and ultrathin sections of myocardial tissue routinely prepared for transmission electron microscopy were analyzed. Extensive intracellular damage was confirmed in cardiomyocytes of DOX-treated animals. By means of ultrastructural analysis, a certain degree of parenchymal degeneration was confirmed even in animals treated with FNP alone, including both the oral and the intraperitoneal application of the substance. The cardioprotective effects of FNP in animals previously treated with DOX were recognized to a certain extent, but were not fully confirmed at the ultrastructural level. Nevertheless, the myocardial morphology of DOX-treated animals improved after the admission of FNP. Irregular orientation of myofibrils, myofibrillar disruption, intracellular edema, and vacuolization were reduced, but not completely eliminated. Reduction of these cellular alterations was achieved if FNP was applied orally 6 h prior to DOX treatment in a dose of 18 mg/kg. However, numerous defects, including the inner mitochondrial membrane and the plasma membrane disruption of certain cells persisted. In FNP/DOX-treated animals, the presence of multinuclear cells with mitosis-like figures resembling metaphase or anaphase were observed, indicating that DOX and FNP could have a complex influence on the cell cycle of cardiomyocytes. Based on this experiment, further careful increase in dosage may be advised to enhance FNP-induced cardioprotection. These investigations should, however, always be combined with ultrastructural analysis. The FNP/DOX interaction is an excellent model for the investigation of cardiomyocyte cell death and cell cycle mechanisms.

Modification of antioxidative and antiapoptotic genes expression in irradiated K562 cells upon fullerenol C60(OH)24 nanoparticle treatment.

Recent data established the prospective applications for fullerenol (C60(OH)24) nanoparticle (FNP) in many fields, such as antioxidants, neuroprotective agents, and potential anti-radiation drugs. Leukemia cell sensitization to apoptosis induced by ionizing radiation is achieved by upregulation of ROS production and/or downregulation of antioxidative enzymes. Therefore, our aim was to analyze the potential role of fullerenol nanoparticle in modulation of the leukemic cellular response to irradiation. We used the qRT-PCR to analyze the expression level of mRNA for 11 genes in irradiated and FNP pre-treated irradiated K562 cells, and compared the gene expression level with the overall cell survival. Our results of the improved cell survival in FNP-treated irradiated cells and significant overexpression of anti-apoptotic Bcl-2 and Bcl-xL and cytoprotective genes such as GSTA4, MnSOD, NOS, CAT and HO-1 genes, may indicate that FNP exerts cytoprotective function in K562 leukemic cells, rendering K562 cells more tolerant to radiotherapy.

Effect of fullerenol C(60)(OH) (24) on lipid peroxidation of kidneys, testes and lungs in rats treated with doxorubicine.

The aim of this study is to investigate the protective effect of fullerenol C60(OH)24 in various doses, on lipid peroxidation of rat's kidneys, testes and lungs after application of doxorubicin. The experiment was performed on healthy male Wistar rats. The animals were randomly divided into five experimental groups and treated with saline (0.9 % NaCl i.v.), doxorubicin alone (10 mg/kg i.v.), combination of doxorubicin/fullerenol (50 and 100 mg/kg fullerenol, respectively, 30 min before the introduction of doxorubicin) and fullerenol alone (100 mg/kg), respectively. Animals were killed on the 2nd and 14th day after treatment. Products of lipid peroxidation and thiobarbituric acid are determined spectrophotometrically from the crude homogenate fraction of the kidney, testis and lung tissues of the rats. Fullerenol, applied as a pre-treatment of doxorubicin, significantly reduced or completely prevented the appearance of doxorubicin toxicity in kidneys and testes, in both tested doses. A dose of 100 mg/kg i.p. exhibited a better protective effect. When fullerenol was applied alone, at a dose of 100 mg/kg i.p, it did not significantly affect the intensity of lipid peroxidation in all tested organs.

Fullerenol C60(OH)24 prevents doxorubicin-induced acute cardiotoxicity in rats.

Results obtained in vitro suggested that fullerenol's antiproliferative properties and protective effects against doxorubicin (DOX) cytotoxicity are mediated by antioxidative and hydroxyl radical scavenger activity. The aim of this study was to examine the influence of fullerenol on acute cardiotoxicity after the administration of a single high dose of DOX in vivo. The experiment was performed on male Wistar rats randomly divided into five groups, each containing eight individuals, that were treated as follows: I) 0.9% NaCl, II) 10 mg/kg DOX, III) 50 mg/kg fullerenol 30 min before 10 mg/kg DOX, IV) 100 mg/kg fullerenol 30 min before 10 mg/kg DOX, and V) 100 mg/kg fullerenol. A functional, biochemical, hematological, and pathomorphological examination of the heart as well as an evaluation of oxidative stress parameters was conducted on days 2 and 14 after DOX administration. The function of the heart was investigated by monitoring heart contractility after the adrenaline infusion. Fullerenol, applied alone, did not alter basal values of investigated animals. Both doses of fullerenol, used as a pretreatment, did not alter the basal parameters of the animals. The 100 mg/kg dose of fullerenol showed better protection. Considering the mechanisms of DOX toxicity, fullerenol likely exerts its protective role as a free radical sponge and/or by removing free iron through the formation of a fullerenol-iron complex. Our results suggest that fullerenol might be a potential cardioprotective agent in DOX-treated individuals.

[Surgical treatment of ishemic mitral regurgitation: repair, replacement or revascularization alone?].

INTRODUCTION: Treatment of ischemic mitral regurgitation in patients that require revascularization of myocardium is still debatable. OBJECTIVE: The aim of this study was to compare three surgical approaches: valve repair and revascularization; valve replacement and revascularization, and revascularization alone. METHODS: In 2006 and 2007 at the Institute for Cardiovascular Diseases, Clinical Centre of Serbia, Belgrade, 1,040 patients with coronary disease underwent surgery. Forty-three patients (4.3%) had also mitral insufficiency 3-4+. The patients were examined clinically, echocardiographically and haemodynamically. In group I there were 14 (32.3%) patients, in group II 16 (37.2%) patients and in group III 3 (30.5%) patients. Ninety-three per cent of patients were classified as New York Heart Association (NYHA) class III and IV, and three (7%) patients had congestive heart weakness with ejection fraction < or =30%. The decision as to surgical procedure was made by the surgeon. Postoperatively, patients were checked clinically and echocardiographically after 3, 6 and 12 months. The follow-up period was approximately 15 months (8-20). RESULTS: Hospital mortality for the whole group was 6.9% (3 patients). In group I mortality was 14.2% (2 patients), in group II 6.25% and in group III there was no mortality. Long term results, up to 15 months, showed 100% survival in groups I and II, and in group III one patient died (7.7%). CONCLUSION: Short term results upto 30 days were best in group III, but longer term results were better in groups I and II.

Antioxidant properties of fullerenol C60(OH)24 in rat kidneys, testes, and lungs treated with doxorubicin.

Clinical use of doxorubicin continues to be challenged by its undesirable systematic toxicity, caused mainly by oxidative stress. The aim of this study was to investigate the effectiveness of fullerenol C(60)(OH)(24) polyanion nanoparticles, an antioxidant agent, against doxorubicin-induced nephro-, testicular, and pulmonary toxicity. Results obtained in vitro suggest that fullerenol's anti-proliferative property and protective effect against doxorubicin cytotoxicity are mediated by the antioxidative and radical scavenging activity. Male Wistar rats were divided into five treatment groups: the control group (I) received 0.9% NaCl (1 mL/kg, i.p.). Groups II, III, IV, and V received a single dose of doxorubicin (10 mg/kg i.p.), doxorubicin/fullerenol (100 and 50 mg/kg i.p. of fullerenol 30 min prior to 10 mg/kg i.p. of doxorubicin), and fullerenol (100 mg/kg i.p.), respectively. On the 2(nd) and 14(th) days, organ samples were taken for the measurement of lipid peroxidation and activities of superoxide dismutase, catalase, glutathione-peroxidase, -reductase, and -transferase. Doxorubicin induced a significant increase of lipid peroxidation and alterations of antioxidant enzyme activities, while the fullerenol pre-treatment prevented the effects of doxorubicin on investigated parameters. Fullerenol, applied alone, did not alter basal values of the investigated animals. Considering the mechanisms of doxorubicin toxicity, it can be concluded that fullerenol exerts its protective role by acting as a free radical sponge and/or by removing free iron through formation of fullerenol-iron complex. Results of this study support the hypothesis of testicular, pulmo-, and nephroprotective efficacy of fullerenol in preventing oxidative stress induced by doxorubicin.

Activity of antioxidative enzymes in erythrocytes after a single dose administration of doxorubicin in rats pretreated with fullerenol C(60)(OH)(24).

In earlier in vitro investigations, fullerenol was shown to have a strong antioxidative capability. The present study examined the role of fullerenol as a potential antioxidative protector for doxorubicin-induced oxidative stress in the blood of rats through an investigation of the activity of glutathione-dependent enzymes (glutathione-S-transferase and glutathione peroxidase). It also assessed the influence of fullerenol on the number of blood cells (leukocytes and erythrocytes) as well as on the content of hemoglobin after a single dose administration of doxorubicin. Experiments were performed on six groups of adult male Wistar rats, each group containing eight individuals. Doxorubicin was administrated i.v. (tail vein) in a single dose of 10 mg/kg. Fullerenol C(60)(OH)(24) was administrated to the treated animals i.p. (in doses 50, 100, 200 mg/kg) 30 min before the dosing with doxorubicin. The control group animals were given saline (1 ml/kg; i.p.). One group of animals was treated only with fullerenol (100 mg/kg i.p.). The animals were sacrificed 2 and 14 days after the treatment. Each experiment was repeated twice. The results may indicate that fullerenol induces a decrease in the antioxidative capacity of erythrocytes in oxidative stress conditions, whereas, without doxorubicin, the application of fullerenol did not induce any changes in the enzyme activity of erythrocytes. The results of GST activity might indicate that 50 mg/kg are not sufficient to protect from doxorubicin toxicity, while 200 mg/kg might be toxic for animals, judging from the increase in GST activity.

Acute doxorubicin pulmotoxicity in rats with malignant neoplasm is effectively treated with fullerenol C60(OH)24 through inhibition of oxidative stress.

The aim of this study was to investigate the possible protective role of fullerenol (FLR, C(60)(OH)(24) on doxorubicin (DOX)-induced lung toxicity using biochemical and histopathological approaches. Rats (Sprague-Dawley outbred) were randomly divided into five groups. The healthy control group received no medication (saline only). The other four groups had chemically induced breast cancer (1-methyl-1-nitrosourea; 50 mg/kg, ip). The second group was the cancer control group (saline only). The other three groups were DOX (8 mg/kg, ip), FLR/DOX (100 mg/kg, ip, 30 min before DOX; 8 mg/kg, ip), and FLR (100 mg/kg, ip), respectively. The levels of malondialdehyde (MDA) and oxidized glutathione (GSSG) in the lung tissue were higher in the group treated with DOX alone than in the control groups. The activities of catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and lactate dehydrogenase (LDH) were found to be increased in the lung tissue of the animals in the DOX group over all the other groups, while GSH-Px significantly decreased in activity compared with the control and FLR groups. There was no significant difference in MDA and GSSG levels and enzyme activities in either control (healthy; cancer) or FLR (FLR/DOX; FLR) groups. The acute change found in the DOX group was subpleural edema. In contrast, the groups treated with FLR appeared to be virtually histopathologically normal. In conclusion, this study clearly indicates that DOX treatment markedly impairs pulmonary function and that pre-treatment with FLR might prevent this toxicity in rats through inhibition of oxidative stress.