Improvement of the results of the therapy of Parkinson’s disease with the use of the drug levodopa of prolonged action

Approximately 60–80% of patients with Parkinson’s disease (PD) develop motor complications (fluctuations and dyskinesias) caused by levodopa, with 30% developing after only 3 years of treatment. Pulsatile stimulation of receptors is the main mechanism involved in the occurrence of these complications, so it is more appropriate to consider them as a result of the method of administration, rather than as an intrinsic effect of levodopa. Thus, with the development of the disease, its effectiveness decreases due to a short half-life and constant fluctuations in plasma concentration. More stable and longer concentrations of levodopa in plasma compared to other forms is provided by oral extended-release formulation of carbidopa-levodopa. Although the onset of clinical response is slower, it reduces the peak dose responses and «wearing-out» that occurs with conventional carbidopa/levodopa. According to the results of a multicenter, double-blind study, treatment with a long-acting formulation significantly reduced the daily duration of «off» periods and prolonged the «on» phase, providing a significant clinical improvement. At the same time, the frequency with which medicines should be taken, was more lower. Other studies show an improvement in the quality of sleep and long-term maintenance of its effect for years. Moreover, the extended-release formulation is able to prevent the appearance of motor complications. Levodopa of prolonged action is recommended for all stages of PD. In the early phase — as monotherapy, in the late, especially in patients with «exhaustion» phenomena, dyskinesias of peak doses and at night — in combination with other antiparkinson drugs.

References

1. Tysnes O.B., Storstein A. (2017) Epidemiology of Parkinson’s disease. J. Neural. Transm. (Vienna), 124(8): 901–905.
2. Lees A.J., Hardy J., Revesz T. (2009) Parkinson’s disease. Lancet, 373(9680): 2055–2066.
3. Poewe W. (2008) Non-motor symptoms in Parkinson’s disease. Eur. J. Neurol., 15(Suppl. 1): 14–20.
4. Greenland J.C., Williams-Gray C.H., Barker R.A. (2019) The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur. J. Neurosci., 49(3): 328–338.
5. Lang A.E. (2007) The progression of Parkinson disease: a hypothesis. Neurology, 68(12): 948–952.
6. Bezard E. (2013) Experimental reappraisal of continuous dopaminergic stimulation against L-dopa-induced dyskinesia. Mov. Disord. Off. J. Mov. Disord. Soc., 28: 1021–1022.
7. Cerri S., Blandini F. (2020) An update on the use of non-ergot dopamine agonists for the treatment of Parkinson’s disease. Expert Opin. Pharmacother., 21: 2279–2291.
8. Cabreira V., Soares-da-Silva P., Massano J. (2019) Contemporary Options for the Management of Motor Complications in Parkinson’s Disease: Updated Clinical Review. Drugs, 79(6): 593–608.
9. Ahlskog J.E., Muenter M.D. (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov. Disord., 16: 448–458.
10. Fahn S., Oakes D., Shoulson I. et al. (2004) Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med., 351: 2498–2508.
11. Cilia R., Akpalu A., Sarfo F.S. et al. (2014) The modern pre-levodopa era of Parkinson’s disease: Insights into motor complications from sub-Saharan Africa. Brain, 137: 2731–2742.
12. Schapira A.H.V., Emre M., Jenner P., Poewe W. (2009) Levodopa in the treatment of Parkinson’s disease. Eur. J. Neurol., 16: 982–989.
13. Sharma J.C., Ross I.N., Rascol O., Brooks D. (2008) Relationship between weight, levodopa and dyskinesia: the signifcance of levodopa dose per kilogram body weight. Eur. J. Neurol., 15(5): 493–496.
14. Warren Olanow C., Kieburtz K., Rascol O. et al. (2013) Factors predictive of the development of Levodopa-induced dyskinesia and wearing-of in Parkinson’s disease. Mov. Disord., 28(8): 1064–1071.
15. Doi H., Sakakibara R., Sato M. et al. (2012) Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J. Neurol. Sci., 319(1–2): 86–88.
16. Ku S., Glass G.A. (2010) Age of Parkinson’s disease onset as a predictor for the development of dyskinesia. Mov. Disord. Off. J. Mov. Disord. Soc., 25: 1177–1182.
17. Kwon D.K., Kwatra M., Wang J., Ko H.S. (2022) Levodopa-Induced Dyskinesia in Parkinson’s Disease: Pathogenesis and Emerging Treatment Strategies. Cells, 11(23): 3736.
18. Hauser R.A. (2009) Levodopa: past, present, and future. Eur. Neurol., 62(1): 1–8. doi: 10.1159/000215875.
19. Contin M., Martinelli P. (2010) Pharmacokinetics of levodopa. J. Neurol., 257: S253–S261.
20. AlDakheel A., Kalia L.V., Lang A.E. (2014) Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics, 11: 6–23.
21. Lee T.K., Yankee E.L. (2021) A review on Parkinson’s disease treatment. Neuroimmunology and Neuroinflammation, 8: 222.
22. Fahn S. (2006) Levodopa in the treatment of Parkinson’s disease. J. Neural. Transm. Suppl., 71: 1–15.
23. Hsu A., Yao H.M., Gupta S., Modi N.B. (2015) Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet(®) CR), and carbidopa-levodopa-entacapone (Stalevo(®)). J. Clin. Pharmacol., 55(9): 995–1003.
24. Aradi S.D., Hauser R.A. (2020) Medical Management and Prevention of Motor Complications in Parkinson’s Disease. Neurotherapeutics, 17: 1339–1365.
25. LeWitt P.A. (1992) Clinical studies with and pharmacokinetic considerations of sustained-release levodopa. Neurology, 42(1 Suppl. 1): 29–32.
26. Margolesky J., Singer C. (2017) Extended-release oral capsule of carbidopa-levodopa in Parkinson disease. Ther. Adv. Neurol. Disord., 11. doi: 10.1177/1756285617737728.
27. Карабань И.Н. (2018) Леводопа/карбидопа пролонгированного высвобождения в лечении болезни Паркинсона. Междунар. неврол. журн., 3(97): 48–58.
28. Olanow C.W., Nakano K., Nausieda P. et al. (1991) An open multicenter trial of Sinemet CR in levodopa-naive Parkinson’s disease patients. Clin. Neuropharmacol., Jun; 14(3): 235–40.
29. LeWitt P.A., Nelson M.V., Berchou R.C. et al. (1989) Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies. Neurology, 39(11 Suppl. 2): 45–53.
30. Deleu D., Jacques M., Michotte Y., Ebinger G. (1989) Controlled-release carbidopa/levodopa (CR) in parkinsonian patients with response fluctuations on standard levodopa treatment: clinical and pharmacokinetic observations. Neurology, 39(11 Suppl.2): 88–92.
31. Wolters E.C., Tesselaar H.J. (1996) International (NL-UK) double-blind study of Sinemet CR and standard Sinemet (25/100) in 170 patients with fluctuating Parkinson’s disease. J. Neurol., 243(3): 235–240.
32. Hutton J.T., Morris J.L., Bush D.F. et al. (1989) Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson’s disease. Neurology, 39(11 Suppl. 2): 67–72.
33. Gros P., Mery V.P., Lafontaine A.L. et al. (2016) Obstructive sleep apnоe in Parkinson’s disease patients: effect of Sinemet CR taken at bedtime. Sleep Breath, 20(1): 205–212. doi: 10.1007/s11325-015-1208-9.
34. Rascol O., Perez-Lloret S., Ferreira J.J. (2015) New treatments for levodopa-induced motor complications. Mov. Disord., 30: 1451–1460.
35. Cedarbaum J.M., Silvestri M., Clark M. et al. (1990) Results of long-term treatment with controlled-release levodopa/carbidopa (Sinemet CR). J. Neural. Transm. Park. Dis. Dement. Sect., 2(3): 205–213.