Abeera Sikandar, Kulsoom Farhat, Ayesha Afzal, Khalida Ajmal, Mehwish Laeeq, Aamna Khokhar


Background: Trimetazidine (TMZ) is traditionally known for cardio protection, however various experimental studies are also evaluating its protective benefits in other tissues. Doxorubicin (DOX) is an extensively used chemotherapeutic drug but is associated with a high incidence of multi-organ damage. This study was aimed at countering DOX induced cardiac and hepatic toxicity by administering TMZ in two different study designs. Methods: It was a laboratory based randomized controlled trial conducted on 40 BALB/c mice divided into 5 groups (n=8). In the two study designs conducted, TMZ in a dose of 10 mg/kg was given orally for five and ten consecutive days. On the third and eighth day of the respective designs, 10 mg/kg DOX was administered intraperitoneally. Results: DOX induced significant elevation of four biochemical markers, namely creatine kinase MB (CKMB), lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (p-value ≤0.0001). Histological changes in heart were graded to be moderate while hepatic changes were graded as mild. Trimetazidine administration for ten days attenuated the enzyme upsurge significantly with p-value ≤0.05 for ALT and ≤0.0001 for AST, LDH and CKMB. However, five-day TMZ administration caused nonsignificant restoration in ALT and CKMB level (p-value >0.05). Hepatic and cardiac histological changes were restored accordingly in both groups. Conclusion: Treatment with TMZ for ten days, seven of which were prior to DOX administration, was concluded to be an effective strategy to counter cardiac and hepatic toxicity of DOX.

Keywords: Alanine aminotransferase; Aspartate aminotransferase; Cardiotoxicity; Creatine Kinase MB; Hepatotoxicity; Lactate Dehydrogenase; Trimetazidine

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Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol 2012;8(4):647–70.

Carvalho C, Santos R, Cardoso S, Correia S, Oliveira P, Santos M, et al. Doxorubicin: The Good, the Bad and the Ugly Effect. Curr Med Chem 2009;16(25):3267–85.

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52(6):1213–25.

Conway A, McCarthy AL, Lawrence P, Clark RA. The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review. BMC Cancer 2015;15(1):366.

Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology 2010;115(2):155–62.

Al-Zubaidy AA, Khattab YI. The Possible Protective Effect of Pentoxifylline against Doxorubicin-Induced Hepatotoxicity in Rabbits. Int J Adv Res 2014;2(9):95–101.

Hozayen WG, Seif HSA, Amin S. Protective Effects of Ruitn and / or Hesperidin Against Doxorubicin-Induced Hepatotoxicity. Int J Clin Nutr 2014;2(1):11–7.

Nagai K, Oda A, Konishi H. Theanine prevents doxorubicin-induced acute hepatotoxicity by reducing intrinsic apoptotic response. Food Chem Toxicol 2015;78:147–52.

Damodar G, Smitha T, Gopinath S, Vijayakumar S, Rao Y. An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin. Ann Med Health Sci Res 2014;4(1):74–9.

Thatishetty AV, Agresti N, O’Brien CB. Chemotherapy-Induced Hepatotoxicity. Clin Liver Dis 2013;17(4):671–86.

Grigorian A, O’Brien CB. Hepatotoxicity Secondary to Chemotherapy. J Clin Transl Hepatol 2014;2(2):95–102.

Salouege I, Ben Ali R, Ben Saïd D, Elkadri N, Kourda N, Klouz A. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Ther 2014;10(2):274–8.

Tsioufis K, Andrikopoulos G, Manolis A. Trimetazidine and Cardioprotection: facts and perspectoves. Angiology 2015;66(3):204–10.

Dézsi CA. Trimetazidine in Practice: Review of the clinical and experimental evidence. Am J Ther 2016;23(3):e871–9.

Liu F, Yin L, Zhang L, Liu W, Liu J, Wang Y, et al. Trimetazidine improves right ventricular function by increasing miR-21 expression. Int J Mol Med 2012;30(4):849–55.

Ateyya H, Yosef H, Nader MA. Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats. Can J Physiol Pharmacol 2015;94(2):225–30.

Bayram E, Atalay C, Kocatürk H, Yücel O. Effects of Trimetazidine on Lipid Peroxidation, Antioxidant Enzyme Activities and Plasma Brain Natriuretic Peptide Levels in Patients with Chronic Cor Pulmonale. J Int Med Res 2005;33(6):612–9.

Mahfoudh Boussaid A, Selmi R, Bejaoui M, Hadj Ayed K, Zaouali Ma, Ben Abdennebi H. Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver. Turk J Med Sci 2016;46(4):1258–64.

Mate V, Pandit VA, Wani DB, Dhande PP. Role of trimetazidine in carbon tetrachloride induced liver damage in rats. Int J Basic Clin Pharmacol 2014;3(1):164–70.

Jones CBA, USDA-APHIS. Animal Welfare Act and Animal Welfare Regulations. Usda-Aphis. 2013.

Klopfleisch R. Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology - a systematic review. BMC Vet Res 2013;9(1):123.

Valcovici M, Andrica F, Serban C, Dragan S. Cardiotoxicity of anthracycline therapy: current perspectives. Arch Med Sci 2016;12(2):428–35.

Ramanjaneyulu SV, Trivedi PP, Kushwaha S, Vikram A, Jena GB. Protective role of atorvastatin against doxorubicin-induced cardiotoxicity and testicular toxicity in mice. J Physiol Biochem 2013;69(3):513–25.

Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M. The Protective Effects of Silymarin against Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity in Rats. Molecules 2011;16(12):8601–13.

Divakaran SA, Nai CK. Amelioration of Doxorubicin Induced Cardiotoxicity in Tumor Bearing Mice by Ferulic Acid: A Mechanistic Study at Cellular and Biochemical Level. Int J Tumor Therap 2012;1(2):6–13.

Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology 2014;59(2):661–70.

Rashid S, Ali N, Nafees S, Ahmad ST, Arjumand W, Hasan SK, et al. Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats. Toxicol Mech Methods 2013;23(5):337–45.

Zhao X, Zhang J, Tong N, Chen Y, Luo Y. Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice. Biol Pharm Bull 2012;35(5):796–800.

Gava FN, Zacché E, Ortiz EMG, Champion T, Bandarra MB, Vasconcelos RO, et al. Doxorubicin induced dilated cardiomyopathy in a rabbit model: An update. Res Vet Sci 2013;94(1):115–21.

Henninger C, Huelsenbeck J, Huelsenbeck S, Grösch S, Schad A, Lackner KJ, et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol 2012;261(1):66–73.


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