RELATIONSHIP BETWEEN ANTIEPILEPTIC DRUGS AND BIOLOGICAL MARKERS AFFECTING LONG-TERM CARDIOVASCULAR FUNCTION IN CHILDREN AND ADOLESCENTS
Main Article Content
Keywords
Anticonvulsant/antiepileptic drugs, epilepsy, homocysteine, cardiovascular events, children
Abstract
Background
Epilepsy is a neurological disorder, relatively common in the paediatric population. These children are often treated with antiepileptic drugs (AEDs) for several years. The consequence of such long-term exposure may lead to variations in plasma homocysteine and serum lipoprotein concentrations.
Objective(s)
To review the cardiovascular effects of anticonvulsant therapy and their use in childhood epilepsy with special reference to homocysteine and lipoprotein.
Methods
A literature search was conducted on PubMed (1966-May 2009) and MEDLINE (1966-May 2009). Key terms included antiepileptic drugs, epilepsy, homocysteine, cardiovascular events, and children.
Results
Certain AEDs including carbamazepine, phenobarbital, phenytoin and valproic acid, as well as the presence of a homozygous 5-methylenetetrahydrofolate reductase polymorphism in the genotype, are potential causes of elevation in plasma homocysteine and serum lipoprotein concentrations.
Conclusions
Persistent elevation in these biochemical markers has shown to be associated with the development of long-term sequelae such as cardiovascular diseases, prompting concerns about the long-term implications of chronic AED use in children and cardiovascular risk. Further research is needed to assess the relationship between specific chronic AED use, homocysteine and lipoprotein concentrations, the influence of genotype, as well as the risk of long-term sequelae in the paediatric population.
References
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7. Vurucu S, Demirkaya E, Kul M, et al. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(3):844-8.
8. Ono H, Sakamoto A, Eguchi T, et al. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism 1997;46(8):959-62.
9. Huemer M, Vonblon K, Fodinger M, et al. Total homocysteine, folate, and cobalamin, and their relation to genetic polymorphisms, lifestyle and body mass index in healthy children and adolescents. Pediatr Res 2006;60(6):764-9.
10. Osganian SK, Stampfer MJ, Spiegelman D, et al. Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. JAMA 1999;281(13):1189-96.
11. Schwaninger M, Ringleb P, Annecke A, et al. Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients. J Neurol 2000;247(9):687-90.
12. Tumer L, Serdaroglu A, Hasanoglu A, Biberoglu G, Aksoy E. Plasma homocysteine and lipoprotein (a) levels as risk factors for atherosclerotic vascular disease in epileptic children taking anticonvulsants. Acta Paediatr 2002;91(9):923-6.
13. Voudris KA, Attilakos A, Katsarou E, et al. Early and persistent increase in serum lipoprotein (a) concentrations in epileptic children treated with carbamazepine and sodium valproate monotherapy. Epilepsy Res 2006;70(2-3):211-7.
14. Eiris J, Novo-Rodriguez MI, Del Rio M, Meseguer P, Del Rio MC, Castro-Gago M. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy. Epilepsy Res 2000;41(1):1-7.
15. Sozuer DT, Atakil D, Dogu O, Baybas S, Arpaci B. Serum lipids in epileptic children treated with carbamazepine and valproate. Eur J Pediatr 1997;156(7):565-7.
16. Eiris JM, Lojo S, Del Rio MC, et al. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45(6):1155-7.
17. Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res 2000;40(1):7-15.
18. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56(1):111-28.
19. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000;72(2):324-32.
20. Tonstad S, Refsum H, Sivertsen M, Christophersen B, Ose L, Ueland PM. Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res 1996;40(1):47-52.
21. Vilaseca MA, Moyano D, Artuch R, et al. Selective screening for hyperhomocysteinemia in pediatric patients. Clin Chem 1998;44(3):662-4.
22. Prengler M, Sturt N, Krywawych S, Surtees R, Liesner R, Kirkham F. Homozygous thermolabile variant of the methylenetetrahydrofolate reductase gene: a potential risk factor for hyperhomocysteinaemia, CVD, and stroke in childhood. DevMed Child Neurol 2001;43(4):220- 5.
23. Temple ME, Luzier AB, Kazierad DJ. Homocysteine as a risk factor for atherosclerosis. Ann Pharmacother 2000;34(1):57-65.
24. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989;114(5):473-501.
25. Apeland T, Mansoor MA, Strandjord RE. Antiepileptic drugs as independent predictors of plasma total homocysteine levels. Epilepsy Res 2001;47(1-2):27-35.
26. Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 1998;51(5 Suppl 4):S21-7.
27. Trabetti E. Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. J Appl Genet 2008;49(3):267-82.
28. Huang T, Yuan G, Zhang Z, Zou Z, Li D. Cardiovascular pathogenesis in hyperhomocysteinemia. Asia Pac J Clin Nutr 2008;17(1):8-16.
29. Jacobsen DW. Homocysteine and vitamins in cardiovascular disease. Clin Chem 1998;44(8 Pt 2):1833-43.
30. Hoffer LJ. Homocysteine remethylation and transsulfuration. Metabolism2004;53(11):1480-3.
31. Selhub J. Homocysteine metabolism. Annu Rev Nutr 1999;19:217-46.
32. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270(22):2693-8.
33. Farid FA, Faheem MS, Heshmat NM, Shaheen KY, Saad SS. Study of the homocysteine status in children with chronic renal failure. Am J Nephrol 2004;24(3):289-95.
34. Siniscalchi A, Mancuso F, Gallelli L, Ferreri Ibbadu G, Biagio Mercuri N, De Sarro G. Increase in plasma homocysteine levels induced by drug treatments in neurologic patients. Pharmacol Res 2005;52(5):367-75.
35. Mota C, Fonseca I, Santos MJ, et al. Homocysteine levels in pediatric renal transplant recipients. Transplant Proc 2003;35(3):1093-5.
36. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338(15):1042-50.
37. Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol 2000;57(10):1422-7.
38. Vilaseca MA, Moyano D, Ferrer I, Artuch R. Total homocysteine in pediatric patients. Clin Chem 1997;43(4):690-2.
39. Minniti G, Cerone R, Piana A, Armani U, Lorini R. Plasma and serum total homocysteine concentrations in paediatric patients, evaluated by high-performance liquid chromatography with fluorescence. Clin Chem Lab Med 2000;38(7):675-6.
40. Huemer M, Ausserer B, Graninger G, et al. Hyperhomocysteinemia in children treated with antiepileptic drugs is normalized by folic acid supplementation. Epilepsia 2005;46(10):1677-83.
41. Ubbink JB, van der Merwe A, Delport R, et al. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996;98(1):177-84.
42. Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlu S. Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12, and folic acid. Brain Dev 2003;25(2): 113-5.
43. Yoo JH, Hong SB. A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants. Metabolism 1999; 48(8):1047-51.
44. Lawrence de Koning AB, Werstuck GH, Zhou J, Austin RC. Hyperhomocysteinemia and its role in the development of atherosclerosis. Clin Biochem 2003;36(6):431-41.
45. Dean J, Robertson Z, Reid V, et al. Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR. Am J Med Genet A 2007;143A(19):2303-11.
46. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992;12:279-98.
47. Rang HP. Rang and Dale's Pharmacology. 6th ed. Philadelphia, PA: Churchill Livingstone /Elsevier, 2007.
48. Shorvon SD. Handbook of epilepsy treatment: forms, causes and therapy in children and adults. 2nd ed. Malden, Mass.; Oxford: Blackwell Pub., 2005.
49. Pellock JM, Bourgeois BFD, Dodson WE. Pediatric epilepsy: diagnosis and therapy. 3rd ed. New York: Demos Medical Publishing, 2008.
50. Wyllie E, Gupta A, Lachhwani DK. The treatment of epilepsy: principles & practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.
51. Attilakos A, Papakonstantinou E, Schulpis K, et al. Early effect of sodium valproate and carbamazepine monotherapy on homocysteine metabolism in children with epilepsy. Epilepsy Res 2006;71 (2-3):229-32.
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