Main Article Content
Background:ALL is the most common childhood malignancy. ALL are treated with methotrexate (MTX) based chemotherapy protocols. MTX can cause unpredictable serious hepato-renal side effects. Sylimarin has antioxidant and anti-inflammatory activities, membrane stabilizing effect,stimulate tissue regeneration and inhibit deposition of collagen fibers.This study aims to evaluate the protective effects of Sylimarin on MTX induced hepato-nephrotoxicity in children with ALL. Patients and Methods: 80 children with newly diagnosed ALL were included in the study. They were divided randomly into: Group I that included 40 children with ALL with their ages ranging from 4-13 years and mean age of 6.85± 2.89 years who received Sylimarin 420 mg/day in 3 divided doses for one week after each MTX dose and Group II that included 40 children with ALL with their ages ranging from 4-12 years and mean age value of 7.30±2.6 years who received placebo for one week after MTX therapy.For all patients liver functions including serum bilirubin, serum protein and its fractions albumin, globulin and albumin globulin ratio, alkaline phosphatase, ALT and AST, prothrombin time and activityand renal functions including blood urea and serum creatinine, serum cystatin C and urinary N-acetyl-beta-D-glucosaminidase were doneto assess hepatic and renal toxicity before and after chemotherapy. Results: There were significant differences in ALT, AST and alkaline phosphatase levels and Prothrombin time and activity between group I and II after chemotherapy, with higher level of ALT and AST (P value = 0.000), alkaline phosphatase (P value= 0.017), and lower Prothrombin activity (P value= 0.020) and prolonged prothrombin time (P value= 0.001) in group II compared with group I. There were no significant differences as regard total bilirubin (P. value=0.563), serum protein and albumin levels between group I and II. There were no significant differences between studied groups as regard kidney functions before chemotherapy while after chemotherapy, there was significant reduction in blood urea and serum creatinine, and cystatin C and urinary N-acetyl-beta-D-glucosaminidase in group I compared with group II.Conclusion: Sylimarin improved some hepatic and renal functions in children with ALL who received MTX therapy. Recommendations: Sylimarin could be recommended adjuvant hepatic and renal protective agent in patients with ALL who received MTX therapy.
Downloads month by month
1. Piatkowska, M.; Styczynski, J. Pediatric acute lymphoblastic leukemia: state of the art and new trends. Journal of Pediatric Sciences 2010; 2(3):22.
2. Styczynski, J.; Wysocki, M. Methotrexate resistance in acute leukemias. Pol Merkur Lekarski, 2001 Aug; 11(62): 175-9.
3. Navarro, V.J.; Senior, J.R. Drug-related hepatotoxicity. N Engl J Med 2006; 354(7): 731-739.
4. Ghaffari, A.R.; Noshad, H.; Ostadi, A.; Ghojazadeh, M.; Asadi, P. the effect of milk thestile on hepatic fibrosis due to methotrexate in rat. Hepat Mon 2011; 11(6):464-468.
5. Widemann, B.C.; Adamso, P.C. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006; 11: 694-703
6. Moss, R.W. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther 2006;5: 63-82.
7. Hagag, A.A.; AbdElaal, A.M.; Elfaragy, M.S.; Hassan, S.M.; Elzamarany, E. Therapeutic value of black seed oil in methotrexate hepatotoxicity in Egyptian children with acute lymphoblastic leukemia. Infect Disorder Drug Targets 2015; 15(1):64-71.
8. Ramasamy, K.; Agarwal, R. Multitargeted therapy of cancer by Silymarin, Cancer Letters 2008; 269(2): 352–362.
9. Saller, R.; Meier, R.; Brignoli, R. The use of silymarin in the treatment of liver diseases, J Gastroenterol Hepatol 2001; 61(14):2035- 2063.
10. Polyak, S.J.; Morishima, C.; Lohmann, V.; Pal, S.; Lee, D.Y.; Liu, Y.; Graf, T.N.; Oberlies, N.H. Identification of hepatoprotective flavonolignans from silymarin. Proc Natl Acad Sci U S A. 2010 Mar 30; 107(13):5995-9. doi: 10.1073/pnas.0914009107. Epub 2010 Mar 15.
11. Pui, C.H. Acute lymphoplastic leukemia: Overview. In: Lichtman MA, Beulter E, Seligsonn U, Kipps TO, Kaushansky K, Prchal J (editors). William Textbook of Hematology. 17th edition, Chapter 91. New York: McGraw-Hill Companies, Inc.; Part XI: Neoplastic Lymphoid Diseases, 2007; 91: 1141-53.
12. Chauvenet, A.R.; Martin, P.L.; Devidas, M.; Linda, S.B.; Bell, B.A.; Kurtzberg, J.; Pullen, J.; Pettenati, M.;, Carroll, A.; Shuster, J.J.; Camitta, B. Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from the Children’s Oncology Group Study P9201. Blood 2007 Aug 15; 110(4):1105-11. Epub 2007 Apr 18.
13. Seibel, N.L.; Steinherz, P.G.; Sather, H.N.; Nachman, J.B.; Delaat, C.; Ettinger, L.J.; Freyer, D.R.; Mattano, L.A Jr, Hastings, C.A.; Rubin, C.M.; Bertolone, K.; Franklin, J.L.; Heerema, N.A.; Mitchell, T.L.; Pyesmany, A.F.; La, M.K.; Edens, C.; Gaynon, P.S. Early post induction intensification therapy improves survival for children and adolescents with high risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group Blood 2008 Mar 1; 111(5):2548-55. Epub 2007 Nov 26.
14]. Lanzkowsky, P.H. Leukemias. In: Lanzkowsky Philip (editor), Manual of Pediatric Hematology and Oncology. 4th ed. Churchill livingstane. Nek, London, Madrid, 2011; 17: 518- 566.
15. Goldberg, J.M.; Silverman, L.B.; Levy, D.E.; Dalton, V.K.; Gelber R.D.; Lehmann, L.; Cohen, H.J.; Sallan S.E.; Asselin, B.L. Childhood T cell acute lymphoblastic leukemia. The Dana-Farber Cancer Institute. Acute Lymphoblastic Leukemia Consortium experience. J Clin Oncol. 2003 Oct 1;21(19):3616-22.
16. Rahiem, Ahmed YAA; Hasan, Y. Prevention and Management of High Dose Methotrexate Toxicity. J Cancer Sci Ther 2013; 5: 106-112. doi:10.4172/1948-5956.1000193.
17. Gharagozloo, M.; Khoshdel, Z.; Amirghofran, Z. The effect of an iron chelator, silybin, on the proliferation and cell cycle of Jurkat cells: A comparison with desferrioxamine. Eur J Pharmacol, 2008, 589(1-3), 1-7.
18. Margolin, J.F.; Rabin, K.R.; Steuber, C.P.; Poplack, D.G. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG. (eds). Principles and Practice of Pediatric Oncology, 6th edition. 2011:518-565. Philadelphia.
19. Harris, N.L.; Jaffe, E.S.; Diebold, J.; Flandrin, G.; Muller-Hermelink, H.K.; Vardiman, J.; Lister, T.A, Bloomfield, C.D. . World Health Organization Classification neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November. J Clin Oncol. 1999 Dec; 17(12):3835-49.
20. Pui, C.H. Acute lymphoblastic leukemia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U: (eds.) Williams Hematology. 2012; 97:1141-1162. New York: McGraw-Hill.
21. Catovsky, D.; Hoffbrand, A.V. Acute myeloid leukaemia. In: A.V. Hoffbrand and S.M. Lewis (eds) Postgraduate Haematology, 5th edition, Oxford, UK: Reed Educational and Professional Publishing Ltd. 2005; 509-524.
22. George-Gay, B.; Parker, K. Understanding the Complete Blood Count with Differential. J Perianesth Nurs 2003; 18(2):96-114; quiz 115-7.
23. Yang, D.T.; Robetorye, R.S.; Rodgers, G.M. Home prothrombin time monitoring: A literature analysis. Am J Hematol 2004 Oct; 77(2):177-86.
24. Doumas, B.T.; Watson W.A.; Biggs, H.G. Albumin standards and the measurement of serum albumin with bromcresol green. Clin.Chem Acta 1997; 258(1): 21- 30.
25. Gella, F.J.; .Olivella, T.; Cruz Pastor, M.; Arenas, J.; Moreno, R.; Durban, R, Gomez, J.A. A simple procedure for the routine determination of aspartate aminotransferase and alanine aminotransferase with pyridoxal phosphate. Clin Chem Acta 1985; 153(3): 241-47.
26. Kaplan, A. Urea. Kaplan A. et al 1984: Clin Chem. The C.V. Mosby Co. St Louis. Toronto. Princeton: 1257-1260 and 437 and 418.
27. Hossain, M.A.; Emara, M.; El Moselhi, H.; Shoker A. Comparing measures of cystatin C in human sera by three methods. Am J Nephrol. 2009; 29(5):381–91.
28. Vaidya VS, Waikar SS, Ferguson MA, et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2008; 1(3):200–8.
29. Heba, S. Assal.; Salwa, Tawfeek.; Enas, A. Rasheed.; Dali, El- Lebedy.; Eman, H. Thabet. Serum Cystatin C and Tubular Urinary Enzymes as Biomarkers of Renal Dysfunction in Type 2 Diabetes Mellitus. Clin Med Insights Endocrinol Diabetes. 2013 Jul 31; 6: 7–13. Doi: 10.4137/CMED.S12633.
30. Petrie, A.; Sabin, C. Medical statistics at a glance. Blackwell publishing, Oxford, 2nd edition 2005; 978(1):4051-8051.
31. Howlader N.; Noone, A.M.; Krapcho, M.; Garshell, J.; Neyman, N.; Altekruse, S.F.; Kosary, C.L. Childhood cancer. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute, based on November 2012 SEER data submission, posted to the SEER web site 2013.
32. Saif, M.M.; Farid, S.F.; Khaleel, S.A.; Sabry, N.A.; El-Sayed, M.H. Hepatoprotective Efficacy of Ursodeoxycholic Acid in Pediatrics’ Acute Lymphoblastic Leukemia. Pediatric Hematology and Oncology. Informa Healthcare 2012; 29(7): 627-632.
33. Dabak, D.O.; Kocaman, N. Effects of silymarin on methotrexate-induced nephrotoxicity in rats Ren Fail. 2015 May; 37(4):734-9. doi: 10.3109/0886022X.2015.1012984. Epub 2015 Feb 24
34. Bahmani, M.; Shirzad, H.; Rafieian, S.; Rafieian-Kopaei, M. Silybum marianum: Beyond Hepatoprotection. Journal of evidence -Based Complementary and Alternative Medicine 2015; 2156587215571116.
35. Ladas, E.J.; Kroll, D.J.; Oberlies, N.H.; Cheng, B.; Ndao, D.H.; Rheingold, S.R.; Kelly, K.M. A randomized, controlled, double‐blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Cancer 2010 Jan 15; 116(2): 506-513. doi: 10.1002/cncr.24723.
36. Al–Fakhri, F. Ilham.; Abid, T. Firas. Effect of maintenance therapy for childhood with acute lymphoblastic leukaemia by combination of methotrexate and 6-mercaptopurine on the liver. Al-Mustansiriyah Journal for Pharmaceutical Sciences 2005; 2(2):18-23.
37. Philip, D. Clinical Chemistry in Diagnosis and Treatment. In: Andrew Day, Philip Mayne, Philip D Mayne (eds): 6th Ed. USA, Oxford University press, Inc, 1994: 284 -85, 295, 297.
38. Neuman, M.; Cameron, R.G.; Haber, J.A.; Katz, G.G.; Malkiewicz, I.M.; Shear, N.H. Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytoxicity. Clin Biochem. 1999 Oct; 32(7):519-36.
39. Pradhan, S.; Girish, C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian Journal of Medical Research 2006; 124(5): 491.
40. Price, R.G. The role of NAG (N-acetyl-beta-D-glucosaminidase) in the diagnosis of kidney disease including the monitoring of nephrotoxicity. Clin Nephrol. 1992; 38 Suppl 1:S14-9.