The Impact of L-DOPA and Entacapon Therapy on Plasma Level of Homocysteine in Parkinson’s Disease Patients

Czech version

Authors: M. Nevrlý ¹; P. Kaňovský ¹; H. Vranová ¹; I. Nestrašil ¹; K. Langová ²
Authors‘ workplace: Neurologická klinika LF UP, FN Olomouc, 2Ústav lékařské biofyziky, UP Olomouc ¹
Published in: Cesk Slov Neurol N 2008; 71/104(1): 55-60
Category: Original Paper

Overview

Introduction:
Homocysteine (HCY) is a risk factor for vascular diseases, cognitive impairment and dementia. Peripheral metabolism of L-DOPA via enzyme catechol-O-methyltransferase (COMT) is one of the possible sources of HCY. Some retrospective studies showed increased plasma HCY concentrations in patients suffering from Parkinson´s disease (PD) and long-term treated with L-DOPA. The aim of the study was to assess plasma HCY levels in L-DOPA treated PD patients and its influence by adding the inhibitor COMT (entacpone).

Methods:
Patients were divided into 3 groups: 1 – patients long-term treated with L-DOPA with added entacapone (30 patients, aged 50-82 years, mean 68,5 ± 8,5); 2 – L-DOPA naive patients, in which was start combined treatment with L-DOPA and entacapone (10 patients, aged 56-74 years, mean 67,7 ± 6,6); 3 – control group of subjects did not suffering of any neurodegenerative disease and were not treated with L-DOPA and entacapone (21 patients, aged 38-78 years, mean 51,7 ± 11,1).

Results:
In Group 1 was mean plasma HCY concentration 17,6 ± 6,6 (9,2-44,4) µmol/l and 8 weeks after adding entacapone 16,4 ± 5,5 (7,4-31,1) µmol/l. In Group 2 was found mean plasma HCY level 14,6 ± 4,7 (8,9-22,1) µmol/l and 8 weeks after combined therapy of L-DOPA and entacapone 15,1 ± 7,3 (8,1-31,1) µmol/l. In control group was found mean plasma HCY level 9,7 ± 2,8 (6,6-16,5) µmol/l.

Discussion:
Results of this study confirm, that patients long-term treated with L-DOPA have increased plasma HCY concentrations. However, do not confirm hypothesis, that combined treatment with L-DOPA and entacapone significantly decrease HCY plasma levels.

Key words:
homocysteine, Parkinson´s disease, entacapone, L-DOPA

Sources

1. Jellinger KA. Prevalence of cerebrovascular lesions in Parkinson's disease. A post mortem study. Acta Neuropathol (Berl) 2003; 105: 415-419.

2. Kubová D, Rektor I. Vaskulární parkinsonský syndrom - historie a současnost. Česk Slov Neurol N 2001; 64/97: 75-81.

3. Levy G, Tang MX, Louis ED, Cote LJ, Alfaro B, Mejia H et al. The association of incident dementia with mortality in PD. Neurology 2002; 59: 1708-1713.

4. Morris MS. Homocysteine and Alzheimer's disease. Lancet Neurol 2003; 2: 425-428.

5. Rektorová I. Účinek donepezilu na demenci u Parkinsonovy nemoci a Alzheimerovy nemoci. Pilotní studie. Česk Slov Neurol N 2004; 67/100: 359-363.

6. Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A et al. Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease. Clin Chem 2001; 47: 1102-1104.

7. Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2003; 60: 1125-1129.

8. Müller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson's disease. Lancet 1999; 354: 126-127.

9. Ozer F, Meral H, Hanoglu L, Aydemir T, Yilsen M, Cetin S et al. Plasma homocysteine levels in patiens treated with levodopa: motor and cognitive associations. Neurological Research, 2006; 28(8): 853-858.

10. Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch Neurol 2003; 60: 59-64.

11. Valkovič P, Benetin J, Blažíček P, Valkovičová Ľ, Gmitterová K, Kukumberg P. Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord 2005; 11: 253-256.

12. Yasui K, Nakaso K, Kowa H, Takeshima T, Nakashima K. Levodopa-induced hyperhomocysteinaemia in Parkinson's disease. Acta Neurol Scand 2003; 108: 66-67.

13. Zoccolella S, Lamberti P, Armenise E, de Mari M, Lamberti SV, Mastronardi R et al. Plasma homocysteine levels in Parkinson's disease: role of antiparkinsonian medications. Parkinsonism Relat Disord 2005; 11: 131-3.

14. Ostrem JL, Kang GA, Subramanian I, Guarnieri M, Hubble J, Rabinowicz AL, et al. The effect of entacapone on homocysteine levels in Parkinson disease. Neurology 2005; 64(8): 1482.

15. Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 1998; 157 Suppl 2: S40-S44.

16. Selhub J. Homocysteine metabolism. Annu Rev Nutr 1999; 19: 217-46.

17. American Society of Human Genetics/American College of Medical Genetics Test and Transfer Committee Working Group. Measurement and use of total plasma homocysteine. Am J Hum Genet 1998; 63: 1541-1543.

18. Genest JJ, Jr., McNamara JR, Upson B, Salem DN, Ordovas JM, Schaefer EJ et al. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 1991; 11: 1129-1136.

19. Haynes WG. Hyperhomocysteinemia, vascular function and atherosclerosis: effects of vitamins. Cardiovasc Drugs Ther 2002; 16: 391-399.

20. Morris MS, Jacques PF, Rosenberg IH, Selhub J, Bowman BA, Gunter EW et al. Serum total homocysteine concentration is related to self-reported heart attack or stroke history among men and women in the NHANES III. J Nutr 2000; 130: 3073-3076.

21. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: 1395-1398.

22. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332: 286-291.

23. Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J et al. DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med 2003; 41: 1392-1403.

24. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003; 26: 137-146.

25. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56: 111-128.

26. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042-1050.

27. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B₁₂, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998; 55: 1449-1455.

28. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346: 476-483.

29. Muller T, Renger K, Kuhn W: Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Arch Neurol. 2004; 61(5): 633-634.

30. Valkovič P, Blažíček P, Benetin J, Kukumberg P, Homocysteín, levodopa a Parkinsonova choroba. Česk Slov Neurol N 2006; 69/102(3): 183-188.

31. Allain P, Le BA, Cordillet E, Le QL, Bagheri H, Montastruc JL. Sulfate and cysteine levels in the plasma of patients with Parkinson's disease. Neurotoxicology 1995; 16: 527-529.

32. Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H, Kretschmer A, et al. Elevated plasma levels of homocysteine in Parkinson's disease. Eur Neurol 1998; 40: 225-227.

33. Miller JW. Homocysteine, folate deficiency, and Parkinson's disease. Nutr Rev 2002; 60: 410-413.

34. Nakaso K, Yasui K, Kowa H, Kusumi M, Ueda K, Yoshimoto Y et al. Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L-DOPA, homocysteine, and MTHFR genotype. J Neurol Sci 2003; 207: 19-23.

35. O'Suilleabhain PE, Bottiglieri T, Dewey RB, Jr., Sharma S, Diaz-Arrastia R. Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease. Mov Disord 2004; 19: 1403-1408.

36. Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K. Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology 2000; 55: 437-440.

37. Daniel SE, Lees AJ. Disease Society Brain Bank, London: overview and research.

J Neural Transm Suppl 1993; 39: 165-172.

38. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50(1): 3-32.

39. Lamberti P, Zoccolella S, Armenise E, Lamberti SV, Fraddosio A, de Mari M et al. Hyperhomocysteinemia in L-dopa treated Parkinson's disease patients: effect of cobalamin and folate administration. Eur J Neurol 2005; 12: 365-368.

40. Bareš M, Kaňovský P, Rektor I. Úloha inhibitorů katechol-O-metyl-transferázy (COMT)

v léčbě pozdních komplikací Parkinsonovy nemoci - účinnost a bezpečnost entakaponu (Comtan®). Česk Slov Neurol N 2002; 65/98: 69-75.