Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Vitamin E in Doxorubicin-Induced Acute Cardiotoxicity in Rats

Puri, Archana; Sk, Maulik; Ray, Ruma; Bhatnagar, Veereshwar

doi:10.1055/s-2005-872923

Cited by 35 publications

(33 citation statements)

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“…15) Other's study showed that EDA (3 mg/kg) effectively prevented DOX-induced chronic cardiac deterioration. 8) In agreement with other findings, [9][10][11] the acute cardiotoxicity of DOX (1.5 mg/kg) in dogs was characterized by conduction abnormalities (including decreased heart rate, ST segment elevation, QT intervals prolongation, inverted T wave, arrhythmia, and myocardial ischemia) and increased serum CK and AST. The serum CK and AST reached apogee at 24 h and dropped to baseline in 48-72 h after myocardial damage.…”

Section: Discussionsupporting

confidence: 74%

“…9,10) As shown in Fig. 2, dosing LBP or EDA daily has no significant effect on the durations of the electrocardiographic parameters.…”

Section: General Toxicitymentioning

confidence: 99%

“…Electrocardiography (ECG) is one of the standard methods used to assess cardiac function and is often performed to evaluate whether cardioprotective agents would improve DOX-induced conduction abnormalities. 9,10) Moreover, the usefulness of biochemical indicators such as serum creatine kinase (CK) and aspartate aminotransferase (AST) in assessment of DOX-associated cardiotoxicity in experimental animals has also been indicated by various studies.…”

mentioning

confidence: 99%

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Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Antioxidants in Acute Doxorubicin-Induced Cardiotoxicity in the Beagle Dogs

Xin

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX), a quinone-containing anthracycline antineoplastic, is used for the treatment of solid and hematopoietic tumors. However, its dose-dependent cardiotoxicity hampered its clinical application.1) Recent studies have suggested that DOX-induced cardiotoxicity involves the formation of reactive oxygen species (ROS) and amplification of mitochondrial dysfunction.1,2) Moreover, the anticancer effects of DOX do not follow the identical mechanisms of ROS. The majority of strategies to protect cardiomyocytes against DOX-induced oxidative injury in heart therefore focused on administering antioxidants in the past. 1)A number of antioxidants, such as lycopene, N-acetylcysteine and vitamin E were proved to ameliorate the DOXinduced cardiac cell damage without compromising its antitumor efficacy in the rats or mice model. [3][4][5] However, most of them were tried with limited success in preventing DOX-associated cardiotoxicity in large-sized animals such as dogs or pigs. 6)Lycium barbarum, a famous Chinese medicinal herb, has a long history of use as an antioxidant and to promote sexual fertility. Lycium barbarum polysaccharides (LBP), consisting of various botanic polysaccharide including arabinose, rhamnose, xylose, mannose, galactose and glucose, are the most important functional constituents in red-colored fruits Lycium barbarum. LBP and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, a potent free radical scavenger, EDA) were found to elicit a typical cardioprotective effect against DOXrelated oxidative stress in rats. 7,8) However, no similar cardioprotective effect of either LBP or EDA was reported in beagle dogs. Electrocardiography (ECG) is one of the standard methods used to assess cardiac function and is often performed to evaluate whether cardioprotective agents would improve DOX-induced conduction abnormalities.9,10) Moreover, the usefulness of biochemical indicators such as serum creatine kinase (CK) and aspartate aminotransferase (AST) in assessment of DOX-associated cardiotoxicity in experimental animals has also been indicated by various studies. 11)The present study aims to explore electrocardiographic and biochemical evidence for the cardioprotective effect of those two antioxidants in DOX-induced acute cardiotoxicity in beagle dogs. MATERIALS AND METHODSChemicals DOX was obtained from Pfizer Italia S.r.l. (Nerviano, Italy) as a 10 mg/bottle lyophilized powder. It was dissolved in 20 ml of 0.9% saline for injection. Lycium Chinese mill Polysaccharide was purchased from Zhejiang Doxorubicin (DOX) is a potent antitumor agent, but the cardiotoxicity mediated by the formation of reactive oxygen species limit its clinical use. The present study aims to explore electrocardiographic and biochemical evidence for the cardioprotective effect of two antioxidants, Lycium barbarum polysaccharides (LBP, the main antioxidant in Lycium barbarum) and edaravone (a potent free radical scavenger, EDA) against DOX-induced acute cardiotoxicity in beagle dogs. In this study, male beagle dogs received daily treat...

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Section: Discussionsupporting

confidence: 74%

“…9,10) As shown in Fig. 2, dosing LBP or EDA daily has no significant effect on the durations of the electrocardiographic parameters.…”

Section: General Toxicitymentioning

confidence: 99%

mentioning

confidence: 99%

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Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Antioxidants in Acute Doxorubicin-Induced Cardiotoxicity in the Beagle Dogs

Xin

Zhang

et al. 2011

Biological & Pharmaceutical Bulletin

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“…In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolarization period [7,8]. Electrocardiographic (ECG) measures of heart rate, the PR interval, the QT interval and the QRS interval are usually used to evaluate acute cardiotoxicity [5,9,10]. Administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine hydrogen maleate (MK-801) to rats and mice is often used to create an experimental model of schizophrenia.…”

mentioning

confidence: 99%

“…Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v.…”

mentioning

confidence: 99%

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

Sun¹,

Su²,

Cheng³

et al. 2010

Basic Clin Pharma Tox

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The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD 50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0,5,10,15,20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 lmol ⁄ kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.Risperidone, 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]py rimidine-4-one, is a serotonin 5-HT 2 and dopamine D 2 receptor antagonist and widely used in the treatment of schizophrenia as an atypical antipsychotic drug. In human beings, risperidone is mainly metabolized to 9-hydroxyrisperidone by cytochrome P450 in the liver [1]. Because of its antipsychotic activity, 9-hydroxyrisperidone has been reported under the name of paliperidone for the treatment of schizophrenia. Johnson and Johnson launched paliperidone under the trade name of Invega in the end of 2006. The poor absolute oral bioavailability (only 28%) and the high daily dose of Invega may lead to an increased risk of side effects [2]. Consequently, it is very important to search for new derivatives of paliperidone for the treatment of schizophrenia with higher oral bioavailability and lower side effects [3]. A series of paliperidone derivatives (PDs) were synthesized ( fig. 1) and their physical and chemical properties are listed in table 1.Among patients with schizophrenia, accelerated heart disease is a major cause of sudden death and the risk of dying from cardiovascular disease is two to three times higher than in the general population [4]. Numerous antipsychotic drugs are well-documented for their effects on the QT interval [5]. Prolongation of the QT interval by risperidone has also been reported in a clinical study [6]. In vitro electrophysiological studies showed that supra-therapeutic doses of risperidone induced the prolongation of ventricular repolarization in a dose-related and reverse use-dependent manner, which prolonged the terminal repolariza...

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Biodistribution and preclinical safety profile of legubicin: A novel conjugate of doxorubicin and a legumain‐cleavable peptide linker

Wang,

Wei,

Liu

et al. 2024

J of Applied Toxicology

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Legubicin is a novel conjugate of doxorubicin and a legumain‐cleavable peptide linker. It has been developed to ameliorate the side effects of doxorubicin. Biodistribution in tumor‐bearing mice, acute tolerance, and potential systemic toxic effects in Sprague–Dawley rats and beagle dogs of legubicin were assessed. Legubicin exists mainly as a protein complex in plasma after entering the circulation. Compared with conventional doxorubicin at an equal molar dose in mice, we found higher exposure to doxorubicin in tumor (approximately 1.7‐fold increase) while lower exposure in normal tissues (an ~3.26‐, 3.46‐, and 1.29‐fold reduction in heart, kidney, and plasma, respectively) in tumor‐bearing mice after intravenous injection of legubicin. The acute maximum tolerance dose (MTD) of legubicin was >16 mg/kg doxorubicin equivalent in female rats, 11 mg/kg doxorubicin equivalent in male rats (LD50 of conventional doxorubicin is 10.51 mg/kg), and >8 mg/kg doxorubicin equivalent in dogs (MTD of conventional doxorubicin is 1.5 mg/kg). Four‐week repeat‐dose toxicity studies of intravenous legubicin were conducted in rats (5, 10, and 25 mg/kg/dose once weekly) and dogs (3/1.5, 10/5, and 20/10 mg/kg/dose once weekly); the dose levels were reduced from the second dose due to intolerable legubicin‐associated toxicity at 20 mg/kg. Major organs of toxicity included the gastrointestinal tract, lymphoid and hematopoietic organs, kidney, skin, liver, reproductive organs, and peripheral nerves, which are all associated with doxorubicin. However, cardiotoxicity was only noted at MTD dose levels. Altogether, our results confirm an improved safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer.

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Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Vitamin E in Doxorubicin-Induced Acute Cardiotoxicity in Rats

Cited by 35 publications

References 2 publications

Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Antioxidants in Acute Doxorubicin-Induced Cardiotoxicity in the Beagle Dogs

Electrocardiographic and Biochemical Evidence for the Cardioprotective Effect of Antioxidants in Acute Doxorubicin-Induced Cardiotoxicity in the Beagle Dogs

Studies on the Acute Toxicity, Pharmacokinetics and Pharmacodynamics of Paliperidone Derivatives – Comparison to Paliperidone and Risperidone in Mice and Rats

Biodistribution and preclinical safety profile of legubicin: A novel conjugate of doxorubicin and a legumain‐cleavable peptide linker

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