Cardiotoxicity In Rabbits Research Articles

Cardio-Protective Effect of Coenzyme Q10 Against Nitrofurantoin-induced Cardiotoxicity in Rabbits

Cardio-Protective Effect of Coenzyme Q10 Against Nitrofurantoin-induced Cardiotoxicity in Rabbits

Investigation of phytotherapeutic potential of herbal mixtures and their effects on salbutamol induced cardiotoxicity and hyperlipidemia in rabbits

BackgroundCardiovascular diseases (CVDs) are the major cause of deaths all over the world. The high level of blood cholesterol and oxidative stress are major risk factors for heart diseases. The phytotherapeutics have attracted attention as potential agents for preventing and treating oxidative stress associated diseases. The objective of present study was to evaluate the synergetic cardio-protective and antilipidemic potential of medicinal plants viz. Coriandrum sativum, Piper nigrum and Cactus grandiflorus. Cardio-protective and anti-lipidemic potential of herbal mixture was evaluated against salbutamol induced cardiotoxicity in rabbits. For this purpose, rabbits were divided into six groups as normal control, salbutamol control, curative and standard drug curative.ResultsSalbutamol significantly (p < 0.05) increased the level of serum cardiac biomarkers (ALT, CK-MB, AST and LDH) and lipids (LDL, triglycerides, cholesterol) in rabbits. The prior and post administration of herbal mixture significantly (p < 0.05) lowered the elevated level of serum cardiac biomarkers and lipids equal to normal control. Gross pathological examination revealed that heart of salbutamol control animals became hardened, congested and were enlarged than preventive and curative groups. The phytotherapeutic analysis of medicinal plants revealed the presence of phenols, tannins, alkaloids and steroids.ConclusionThe results showed that this herbal mixture has strong cardio-protective and anti-lipidemic potential.

Electrocardiographically study of protective effect of Eruca Sativa M. versus doxorubicin induced cardiotoxicity in rabbits

Cardiotoxicity is defined as drug-induced damage to the heart muscle, which can result in cardiac failure or cardiac arrest. Cardiotoxicity is a common side effect of traditional anticancer drugs such as doxorubicin, taxanes, 5-fluorouracil, and cyclophosphamide, as well as newer agents such as biological antibodies such as Nivo. Cardiotoxicity is also caused by the long-term use of neurologic/psychiatric medications. This study was designed to determine the effect of eruca sativa mill (Gergeer) leaves extract on cardiotoxicity induced by doxorubicin in rabbits. The thirty-five rabbits used in this study were obtained from a local rabbit breeder. Animals ranged between 1-1.3 years old, and their weight was approximately 1-2kg without specifying gender. experiment: Thirty-five adult rabbits (n=35) will be randomly divided into four groups (7 rabbits/each group) first group: seven rabbits will receive distal water (D.W) orally (-ve control), Second group: fourteen rabbits divided into two subgroup equally administrated with doxorubicin 4 mg/kg B.W (I.P) between day to day for 14 days to induce cardiotoxicity (the first subgroup leave two weeks then killed, while the second subgroup leaves to 28 days without treatment),

Ethanolic Artichoke Extract improves outcome in a rodent model of 5- Fluorouracil Induced Cardio toxicity

Background: During treatment, many drugs may become cause of cardiac system toxicity, cytotoxic drugs therapy cause cardiac toxicity, including 5- Fluorouracil (5- FU). It is regarded as antimetabolite which cause its toxic effects during S phase of the cell cycle and got its activation by conversion of thymidine phosphorylase into fluorodeoxyuridylate (5 fluoro 2'deoxyuridine 5'monophosphate, 5-FdUMP) which cause inhibition of thymidylate synthase, which ultimately cause prevention of synthesis of DNA. Aim: To focus on evaluation of ethanolic artichoke extract (Cynara scolymus L) with respect to its cardio protective properties against 5-fluorouracil (5-FU) induced cardio-toxicity in rabbits by estimation of Alanine aminotransferase, creatine kinase and aspartate aminotransferase enzymes in serum. Methods: 4 groups consisting of 8 rabbits each were made for collected 32 rabbits who were albinos. Group I: (negative control) administered dimethyl sulfoxide (DMSO) (2 ml/kg /day) orally on daily basis for duration of 10 days. Group II: (positive control) administered DMSO (2 ml/kg /day) daily via oral route for duration of 10 days and subsequently received dose of 5-FU (150 mg/kg) (single) by intraperitoneal injection, on day 8th day in connection with DMSO. Groups III: administered ethanolic artichoke extract (200 mg/kg/day) orally on daily basis for duration of 10 days. Groups IV: administered ethanolic artichoke extract (200 mg/kg/day) daily on oral basis for 10 days with subsequently single intraperitoneal dose of 5-FU (150 mg/kg) on day 8th day. Results: Before intoxication via 5-FU, treatment of ethanolic artichoke extract note worthily reduces the increase serum levels of AST,CK &amp; ALT enzymes due to cardio toxicity induced via 5-FU- in case of rabbits . Conclusions: With respect to present scenario, extracts of ethanolic artichoke serve as powerful modulator in reducing or masking cardiac toxicity cause by induction of 5-FU in case of rabbits. Keywords: Artichoke Extract, Fluorouracil Induced Cardio toxicity, Ethanolic

The Protective Effect of Metformin Against Doxorubicin Induced Cardiotoxicity in Rabbits

Back ground: Doxorubicin is a very effective anticancer therapy of the anthracycline's family used in many pediatric and adult cancers. However, due to severe cardiotoxicity adverse effect, the uses of doxorubicin are limited. Metformin reducing basal and&#x0D; postprandial glucose levels. Metformin has a good treatment efficacy and safety profile in treatment of T2DM in conjunction with lifestyle modification. Metformin have a cardioprotective effect in addition to reducing basal and postprandial levels of glucose by decreasing the production of reactive oxygen species, maintaining energy homeostasis and apoptosis regulation by its activation of adenosine monophosphate-activated protein kinase. &#x0D; Method: Thirty-six white male rabbits randomly divided to six groups, each comprising of six rabbits. 1- Control group injected 2 ml saline single dose intraperitoneally. 2- Metformin group 300 mg/kg/daily for 14 days orally. 3- Acute doxorubicin induction group 16 mg/ kg intraperitoneally as a single dose. 4- Chronic doxorubicin induction group 4mg/kg intraperitoneally twice a week for two weeks. 5- Metformin+ acute doxorubicin induction group 16 mg/kg intraperitoneally single dose and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. 6- Metformin + chronic doxorubicin induction group 4 mg/kg intraperitoneally, twice a week for two weeks and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. &#x0D; Result: our results revealed the treatment with metformin significantly (p &lt; 0.05) reduced the serum level of troponin I and MMP2 in Metformin+ acute doxorubicin induction and Metformin + chronic doxorubicin induction groups in comparison with the acute doxorubicin and chronic doxorubicin groups.&#x0D; Conclusion: From these results in this study, we can conclude that metformin has a cardioprotective effect against doxorubicin induced cardiotoxicity in acute and also the chronic induction by decreasing serum level of troponin I and MMP2.

The Protective Effect of Metformin Against Doxorubicin Induced Cardiotoxicity in Rabbits

Back ground: Doxorubicin is a very effective anticancer therapy of the anthracycline's family used in many pediatric and adult cancers. However, due to severe cardiotoxicity adverse effect, the uses of doxorubicin are limited. Metformin reducing basal and postprandial glucose levels. Metformin has a good treatment efficacy and safety profile in treatment of T2DM in conjunction with lifestyle modification. Metformin have a cardioprotective effect in addition to reducing basal and postprandial levels of glucose by decreasing the production of reactive oxygen species, maintaining energy homeostasis and apoptosis regulation by its activation of adenosine monophosphate-activated protein kinase. Method: Thirty-six white male rabbits randomly divided to six groups, each comprising of six rabbits. 1- Control group injected 2 ml saline single dose intraperitoneally. 2- Metformin group 300 mg/kg/daily for 14 days orally. 3- Acute doxorubicin induction group 16 mg/ kg intraperitoneally as a single dose. 4- Chronic doxorubicin induction group 4mg/kg intraperitoneally twice a week for two weeks. 5- Metformin+ acute doxorubicin induction group 16 mg/kg intraperitoneally single dose and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. 6- Metformin + chronic doxorubicin induction group 4 mg/kg intraperitoneally, twice a week for two weeks and Metformin 300 mg/kg/daily for 14 days orally, three days before doxorubicin treatment. Result: our results revealed the treatment with metformin significantly (p &lt; 0.05) reduced the serum level of troponin I and MMP2 in Metformin+ acute doxorubicin induction and Metformin + chronic doxorubicin induction groups in comparison with the acute doxorubicin and chronic doxorubicin groups. Conclusion: From these results in this study, we can conclude that metformin has a cardioprotective effect against doxorubicin induced cardiotoxicity in acute and also the chronic induction by decreasing serum level of troponin I and MMP2.

Protective Effect of Benfotiamine against Doxorubicin-Induced Cardiotoxicity in Rabbits

The protective effect of benfotiamine against doxorubicin-induced cardiotoxicity was evaluated in rabbits. Pretreatment of rabbits with 70mg/kg benfotiamine orally 7 days before induction of cardiotoxicity with I.V 15mg/kg doxorubicin. injection resulted in significant reduction of the activities of lactate dehydrogenase and creatine phosphokinase enzyme in the serum compared to doxorubicin treated animals; benfotiamine also improves the histological changes produced by doxorubicin in the cardiac muscle compared to control. In conclusion, benfotiamine when used concomitantly with doxorubicin protects the myocardium against the cardiotoxicity induced by this cytotoxic drug.

Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings?

Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.

Cardiotoxicity in rabbits after long-term nandrolone decanoate administration.

Abuse of anabolic androgenic steroids is linked to a variety of cardiovascular complications. The aim of our study was to investigate the possible cardiovascular effects of nandrolone decanoate on young rabbits using echocardiography, histology and monitoring of telomerase activity, oxidative stress and biochemical markers. Fourteen rabbits were divided into three administration groups and the control group. Doses of 4mg/kg and 10mg/kg of nandrolone decanoate, given intramuscularly and subcutaneously, two days per week for six months were applied. A 4-months wash-out period followed. Focal fibrosis and inflammatory infiltrations of cardiac tissue were observed in the high dose groups. Thiobarbituric acid-reactive species (TBARS) levels were significantly increased in the high dose groups, while catalase activity decreased. Myocardial Performance Index (MPI) is the main echocardiographic index primarily affected by nandrolone administration in rabbits. Despite the preserved systolic performance, histological lesions observed associated with distorted MPI values, point to diastolic impairment of the thickened myocardium due to nandrolone treatment. Oxidative stress accumulates and telomerase activity in cardiac tissue rises. Subcutaneous administration seems to be more deleterious to the cardiovascular system, as oxidative stress, telomerase activity and biochemical markers do not appear to return into normal values in the wash-out period.

STUDY OF MOLECULAR MECHANISMS INVOLVED IN CARDIOPROTECTIVE ACTION OF DEXRAZOXANE AGAINST ANTHRACYCLINE CARDIOTOXICITY IN RABBITS

So far dexrazoxane (DEX) is the only drug approved for prevention of chronic anthracycline (ANT) cardiotoxicity. However, molecular mechanisms responsible for its cardioprotective effects remain unclear. This report addresses traditional as well as alternative mechanisms of its cardioprotective action against chronic ANT cardiotoxicity. Daunorubicin (DAU, 3 mg/kg/week for 10 weeks) was used to induced cardiotoxicity in rabbits and DEX (60 mg/kg) was administered prior each DAU dose. LV myocardium was analyzed for oxidative stress, mitochondrial damage, changes in mtDNA and mtDNA/nDNA ratio, and perturbations in mitochondrial proteins expression. DEX ability to interact with iron was addressed in H9c2 cardiomyoblasts. In addition, topoisomerase-2β (TOP2b) expression was studied after DEX exposure in vitro and in vivo. DEX completely prevented DAU-induced heart damage as well as mitochondrial damage. This protection was not directly based on protection from oxidative damage of myocardium or common deletion in mtDNA. Instead, DEX was able to prevent DAU-induced significant decrease in expression of mitochondrial biogenesis regulators (e.g. TFAM) and OXPHOS subunits encoded by both nDNA and mtDNA. Noteworthy, in vitro experiments showed inability of DEX to mobilize iron from cells. Finally, DEX exposure decreased TOP2b protein levels which can correspond with recent data showing that ANT cardiotoxicity may beTOP2b-mediated. The present data suggest that DEX cardioprotective effects need not be based on iron chelation and prevention of oxidative stress or mtDNA deletions. Instead, DEX-induced depletion of TOP2b may be important for cardioprotection and merit further study. Supported by GACR 13–15008S and PRVOUK P37/05.

Cardiotoxicity in rabbits after a low-level exposure to diazinon, propoxur, and chlorpyrifos.

Lethal cardiac complications leading to death and various arrhythmias have been reported after organophosphate and/or carbamate poisonings. The present study focuses on the long-term effects of repeated low-level exposure to diazinon, propoxur, and chlorpyrifos (CPF) on cardiac function in rabbits. The yearly based experimental scheme of exposure consisted of two oral administration periods, lasting 3 months and 1 month each, interrupted by an 8-month washout period (total duration 12 months). At the end of the experimental scheme, the rabbits underwent an echocardiographic evaluation under sedation, after which they were killed and the tissue and serum samples were collected. A mild localized cardiotoxic effect was established by echocardiography for the three pesticides tested. Severe histological alterations were identified, especially in the diazinon-treated animals in agreement with increased persistence of this pesticide established in the cardiac tissue. In addition, all pesticides tested increased the oxidative stress and oxidative modifications in the genomic DNA content of the cardiac tissues, each one following a distinct mechanism.

Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Tailored Liposomes in Rabbit Clomipramine Toxicity

Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity. Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6mg/kg/min for 30minutes. BIC (3mL/kg 8.4%), ILE (3mL/kg 20%), or LIP (24mg/kg) were infused as rescue treatments at toxicity and were repeated at 10minutes (n=5 in each group). Thirty-minute MAP was greatest in ILE-treated animals: 61mmHg ILE (interquartile range [IQR]= 49 to 64mmHg), 43mmHg LIP (IQR= 36.5 to 49mmHg), and 10mmHg BIC (IQR= 10 to 44mmHg; all p=0.02). Two of the five BIC-treated animals survived to 30minutes, compared with all five of the ILE-treated animals and all five of the LIP-treated animals (p=0.044). Both ILE and LIPs improved hemodynamic recovery compared with bicarbonate in clomipramine-induced cardiotoxicity in rabbits. Greater 30-minute MAP was observed in the ILE group.

Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits

Despite incomplete understanding to its mechanism of action, dexrazoxane (DEX) is still the only clearly effective cardioprotectant against chronic anthracycline (ANT) cardiotoxicity. However, its clinical use is currently restricted to patients exceeding significant ANT cumulative dose (300mg/m2), although each ANT cycle may induce certain potentially irreversible myocardial damage. Therefore, the aim of this study was to compare early and delayed DEX intervention against chronic ANT cardiotoxicity and study the molecular events involved. The cardiotoxicity was induced in rabbits with daunorubicin (DAU; 3mg/kg/week for 10 weeks); DEX (60mg/kg) was administered either before the 1st or 7th DAU dose (i.e. after ≈300mg/m2 cumulative dose). While both DEX administration schedules prevented DAU-induced premature deaths and severe congestive heart failure, only the early intervention completely prevented the left ventricular dysfunction, myocardial morphological changes and mitochondrial damage. Further molecular analyses did not support the assumption that DEX cardioprotection is based and directly proportional to protection from DAU-induced oxidative damage and/or deletions in mtDNA. Nevertheless, DAU induced significant up-regulation of heme oxygenase 1 pathway while heme synthesis was inversely regulated and both changes were schedule-of-administration preventable by DEX. Early and delayed DEX interventions also differed in ability to prevent DAU-induced down-regulation of expression of mitochondrial proteins encoded by both nuclear and mitochondrial genome. Hence, the present functional, morphological as well as the molecular data highlights the enormous cardioprotective effects of DEX and provides novel insights into the molecular events involved. Furthermore, the data suggests that currently recommended delayed intervention may not be able to take advantage of the full cardioprotective potential of the drug.

Heart fatty acid-binding protein may not be an early biomarker for anthracycline-induced cardiotoxicity in rabbits

The objective of this study was to investigate the feasibility of using serum heart fatty acid-binding protein (H-FABP) concentrations as an early biomarker for doxorubicin-induced myocardial damage. Forty-four male rabbits were randomly divided into a control (8 rabbits) or one of four doxorubicin groups (8 rabbits in each group). Rabbits in the control group received saline, whereas rabbits in the doxorubicin group received 2 mg/kg doxorubicin weekly for 1-8 weeks. Rabbits in the doxorubicin groups received doxorubicin 2 mg/kg for one (Group 1, 8 rabbits), two (Group 2, 8 rabbits), four (Group 3, 9 rabbits), or eight (Group 4, 11 rabbits) weeks. Echocardiography was performed to measure left ventricular ejection fraction (LVEF), shortening fraction (FS), and E/A ratio. Cardiotoxicity scores were assessed by light microscopy using Billingham's method and also by electron microscopy. Serum H-FABP concentrations were quantified by a rabbit-specific enzyme-linked immunosorbent assay. Decreased LVEF, FS, and E/A ratio were detected in Group 4 (P < 0.05). Billingham cardiomyopathy scores of the rabbits in Group 3 were significantly higher (P < 0.05) than those of rabbits in the control group or Groups 1 or 2. Billingham cardiomyopathy scores in Group 4 were the highest of all groups (P < 0.05). Myocardial injury was demonstrable by electron microscopy in rabbits in Groups 2, 3, and 4. Compared with the control group, serum H-FABP concentrations increased only in Group 4 (P < 0.05). Serum H-FABP concentrations may not be a sensitive method for assessing early cardiotoxicity of doxorubicin.

Insulin effect on bupivacaine-induced cardiotoxicity in rabbits

BackgroundResuscitation following bupivacaine-induced cardiovascular collapse is difficult and often refractory to conventional treatment. This study was performed to assess the effect of insulin on bupivacaine-induced cardiovascular collapse in pentobarbital-anesthetized rabbits.MethodsBupivacaine was administered at 0.75 mg/kg/min until the heart rate decreased to 65 beats/min. A bolus of regular insulin (2 U/kg) was administered intravenously at the bupivacaine infusion endpoint (BIE) in the insulin group (n = 8), and 2 mL of 0.9% NaCl was administered to the control group (n = 8).ResultsAll animals in the insulin group survived and four animals died in the control group. Arrythymia was rare 10 minutes after the BIE in the insulin group.ConclusionsBupivacaine-induced cardiovascular collapse can be effectively reversed with an insulin injection, probably through facilitation of cardiac conduction and contraction.

Oxidative stress markers may not be early markers of doxorubicin-induced cardiotoxicity in rabbits

This study was performed to determine whether oxidative stress markers may be early markers of doxorubicin-induced cardiotoxicity. Forty-four male rabbits were randomly divided into four doxorubicin groups and one control group (8 rabbits). The control group received saline, and rabbits in the doxorubicin groups received 2 mg/kg doxorubicin weekly for 1 (group 1, 8 rabbits), 2 (group 2, 8 rabbits), 4 (group 3, 9 rabbits) or 8 (group 4, 11 rabbits) weeks. Echocardiography was performed to measure left ventricular ejection fraction, fractional shortening and the E/A ratio. Cardiotoxicity scores were determined by light microscopy using Billingham's method and by electron microscopy. Serum glutathione peroxidase (GPx) and superoxide dismutase (SOD) concentrations were quantified by a rabbit-specific enzyme-linked immunosorbent assay (ELISA). The Billingham cardiomyopathy scores for the rabbits in groups 3 or 4 were significantly higher (p<0.05) compared to the scores for the control group or groups 1 and 2. Myocardial injury was demonstrable by electron microscopy in groups 2, 3 and 4 (p<0.05). Serum GPx concentrations decreased only in group 4 compared to the control group (p<0.05). No changes were measured in serum SOD concentration. The results indicate that oxidative stress markers may not be early markers of doxorubicin-induced cardiotoxicity.

Proteomic analysis of the chronic anthracycline cardiotoxicity in rabbits

Proteomic analysis of the chronic anthracycline cardiotoxicity in rabbits

Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each). Surprisingly, no significant changes in LV-filling pattern were observed through the study, most likely due to the xylazine-containing anesthesia, necessary for appropriate resolving of the E and A waves. In contrast to the echographic measurement, the dP/dt(min) index obtained invasively at the end of the study revealed a significant impairment in LV relaxation, which was further supported by observed disturbances in myocardial collagen content and calcium homeostasis. However, at the same time cTnT plasma levels were progressively rising in the daunorubicin-treated animals from the fifth week (0.024+/-0.008 microg/l) until the end of the experiment (0.186+/-0.055 microg/l). Therefore, in contrast to complicated non-invasive evaluation of diastolic function, cTnT is shown to be an early and sensitive marker of anthracycline-induced cardiotoxicity in the rabbit model.

Cardioprotective Effects of a Novel Iron Chelator, Pyridoxal 2-Chlorobenzoyl Hydrazone, in the Rabbit Model of Daunorubicin-Induced Cardiotoxicity

Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU. Instead, o-108 itself moderately inhibited cell proliferation. In vivo, chronic DAU treatment (3 mg/kg weekly for 10 weeks) induced mortality (33%), left ventricular (LV) dysfunction, a troponin T rise, and typical morphological LV damage. In contrast, all animals treated with 10 mg/kg o-108 before DAU survived without a significant drop in the LV ejection fraction (63.2 +/- 0.5 versus 59.2 +/- 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt(max)) was significantly higher than in the DAU-only group (1131 +/- 125 versus 783 +/- 53 kPa/s, p < 0.05), which corresponded with histologically assessed lower extent and intensity of myocardial damage. Although higher o-108 dose (25 mg/kg) was well tolerated when administered alone, in combination with DAU it led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. In conclusion, we show that shielding of free intracellular iron using a potent lipophilic iron chelator is able to offer a meaningful protection against chronic anthracycline cardiotoxicity. However, this approach lost its potential with the higher chelator dose, which suggests that iron might play more complex role in the pathogenesis of this disease than previously assumed.

Valrubicin.

Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug. Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. Complete response rates were 18 and 29% in patients with carcinoma in situ of the bladder which was refractory to intravesical BCG in 2 non-comparative trials of prophylactic intravesical valrubicin. In patients with recurrent superficial papillary tumours, the complete response rate was 46%. Adverse events were generally transient in patients who received intravesical valrubicin. Bladder irritation occurred in 88% of patients. Systemic absorption of intravesically administered valrubicin was minimal. Accordingly, systemic adverse events generally occurred in < or =5% of patients. Valrubicin was less toxic to chick embryos and haematopoietic stem cells in vitro and produced a lower incidence of cardiotoxicity in rabbits, compared with doxorubicin.