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Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats.
J Pharm Pharmacol. 2006 Apr; 58(4):567-73.JP

Abstract

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.

Authors+Show Affiliations

Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sherifibrahem@yahoo.co.ukNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16597375

Citation

Saad, Sherif Y., et al. "Cardiotoxic Effects of Arsenic Trioxide/imatinib Mesilate Combination in Rats." The Journal of Pharmacy and Pharmacology, vol. 58, no. 4, 2006, pp. 567-73.
Saad SY, Alkharfy KM, Arafah MM. Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats. J Pharm Pharmacol. 2006;58(4):567-73.
Saad, S. Y., Alkharfy, K. M., & Arafah, M. M. (2006). Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats. The Journal of Pharmacy and Pharmacology, 58(4), 567-73.
Saad SY, Alkharfy KM, Arafah MM. Cardiotoxic Effects of Arsenic Trioxide/imatinib Mesilate Combination in Rats. J Pharm Pharmacol. 2006;58(4):567-73. PubMed PMID: 16597375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats. AU - Saad,Sherif Y, AU - Alkharfy,Khalid M, AU - Arafah,Maha M, PY - 2006/4/7/pubmed PY - 2006/8/19/medline PY - 2006/4/7/entrez SP - 567 EP - 73 JF - The Journal of pharmacy and pharmacology JO - J. Pharm. Pharmacol. VL - 58 IS - 4 N2 - Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/16597375/Cardiotoxic_effects_of_arsenic_trioxide/imatinib_mesilate_combination_in_rats_ L2 - https://doi.org/10.1211/jpp.58.4.0017 DB - PRIME DP - Unbound Medicine ER -