“Early detection of Doxorubicin-induced Cardiotoxocity and its prevention by Carvedilol.”

Abstract

INTRODUCTIONDoxorubicin (Dox) is a potent anticancer agent for the chemotherapy of frequently occurring malignancies (breast, colorectal and lung cancer and childhood malignancies) but its adverse effects to the myocardium prevent its use at the maximum doses for the required number of courses.1,2 About 20% patients receiving Dox may develop adverse cardiac effects.3 The quantitative estimation of sensitive biomarker cardiac troponin I (cTnI) leads to early recognition of cardiotoxicity and have pertinent economic impact in oncologic patient management. 4 Dox exerts its cytotoxic actions through DNA intercalation and inhibition of DNA topoisomerase II 1 while cardiotoxicity is produced by virtue of its quinone group based metabolites that generate reactive oxygen species (ROS) and free radicals. Cardiomyocytes are inherently more susceptible to oxidative stress. Free radicals and ROS inflict mitochondrial and nuclear DNA lesions in cardiomyocytes with disruption of mitochondrial bioenergetics and impaired expression of cardiac proteins.5 Dox metabolites also cause disturbances in calcium release from sarcoplasmic reticulum and lipid peroxidation, degradation of myofilaments and cytoskeletal proteins.6 These processes lead to cardiomyocyte death either by necrosis or by apoptosis, 7 releasing the cardiospecific contractile proteins, cTnI and cytosolic energy ABSTRACT Background: The objective was to detect doxorubicin (Dox) -induced myocardial injury at early stage by quantitative estimation of cardio specific protein, cardiac troponin I (cTnI) and to explore the cardioprotective effects of carvedilol. Methods: The study design was lab-based randomized controlled in-vivo in rabbits conducted from January to August 2012. Cardiotoxicity was produced by single intravenous injection of 12 mg/kg body weight (BW) of Dox in a group of rabbits, control group was treated with normal saline only and the rabbits of third group were pre-treated with carvedilol 30 mg/kg of BW for 10 days before injecting Dox. Results: Dox induced cardiotoxicity was depicted by markedly raised serum levels of cTnI, creatine kinase-MB, lactate dehydrogenase, and Grade 3 necrosis of the heart tissue in rabbits. The pre-treatment with carvedilol resulted in improved serum levels of these biomarkers and the histological picture of heart tissue. Conclusions: Quantitative serum estimation of cTnI detects the presence of cardiotoxicity much before cardiac dysfunctions can be revealed by any other diagnostic technique. It can lead to significant economic impact in the management of cancer patients because the troponin-negative subjects can be excluded from long-term cardiac monitoring programs that involve high costs imaging techniques. The outcome of Dox chemotherapy can be made successful with the concurrent use of carvedilol.

Evaluation of potential acute cardiotoxicity of biodegradable nanocapsules in rats by intravenous administration

“…52 In addition, studies of cardiotoxicity in rabbits and rats without any evidences of heart diseases found serum baseline levels of 0.033 ng/mL to rats 53 and 0.03 ng/mL to rabbits. 54,55 With respect to potassium levels, the PS80, LNC1 and LNC2 groups, presented higher values 24 hours after acute treatment compared to their results at 14 days, when the values reached the same level to all groups. It was also observed that the group whose potassium concentrations remained at baseline levels was the LNC3 group, which received only LNCs during the treatment.…”

“…Studies with induced cardiotoxicity often find cardiomyocellular vacuolation, perivascular and interstitial fibrosis, congestion, hemorrhage, infiltration of leukocytes, degeneration in myocytes and nuclear material clumping. 40,52,55,56 The international cardiology society guidelines cite the importance of identification of the left ventricular ejection fraction (LVEF) that is the most common method to screening of toxic effects on the heart. 2 The LVEF near to 90% represents a normal function of heart and when decreased to less than 50% indicates cardiac insufficiency.…”

Treatment Of Albino Rats With Oltipraz (4-MethyL-5-PyrazinyL-3H-1,2-Dithiole-3-Thione Protects Against Doxorubicin-Induced Cardiotoxicity

“…The elevated serum levels of CK-MB have been considered as a reliable marker of doxorubicin-induced cardiotoxicity [43]. The doxorubicin has been reported to increase the activity of CK-MB in mice, rats, and rabbits earlier [44][45][46][47][48][49][50][51][52][53]. The administration of rats with oltipraz reduced serum levels of CK-MB indicating that it protected the heart against the toxic effect of doxorubicin.…”

“…Oltipraz has been reported to protect rats against isoproterenol-induced heart failure [54]. Earlier a polyherbal preparation, antarth, Agele marmelos (bael), naringin, hesperidin, ellagic acid, carvedilol metformin, berberine, vanillic acid and chia seed oil have been reported to protect mice, rats and rabbits against the doxorubicininduced cardiotoxicity by reducing CK-MB activity and increasing antioxidants [44][45][46][47][48][49][50][51][52][53]. The iron chelator dexrazoxane (ICRF-187) has been used to reduce doxorubicin-induced cardiotoxicity in mice, rats, rabbits, dogs, swine, and humans [55][56][57].…”