Journal of Neural Transmission

, Volume 103, Issue 6, pp 699–715 | Cite as

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study

  • H. Przuntek
  • D. Welzel
  • M. Gerlach
  • E. Blümner
  • W. Danielczyk
  • H. -J. Kaiser
  • P. H. Kraus
  • H. Letzel
  • P. Riederer
  • K. Überla
Parkinson's Disease and Allied Conditions
Received:
Accepted:

Summary

Long-term levodopa treatment in Parkinson's disease is typically associated with “motor side effects” consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit.

Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p=0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p=0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with >50% substitution by bromocriptine exhibited half the risk observed in those with <30% (p=0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p=0.046).

In conclusion, partial substitution of levodopa by bromocriptine (>30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Keywords

Parkinson's disease bromocriptine L-DOPA levodopa motor fluctuations adverse effects early combination therapy long-term treatment 
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References

  1. Armitage P, Berry G (1987) Statistical methods in medical research, 2nd edn. Blackwell, Oxford, p 205Google Scholar
  2. Bakheit AMO, Henderson LM, Moore AP, Simpson JA, Thomas M (1990) Long-term double masked trial of early treatment with L-Dopa plus bromocriptine versus L-Dopa alone in Parkinson's disease. Eur Neurol 30: 108–111PubMedGoogle Scholar
  3. Ben-Shlomo Y, Marmot MG (1995) Survival and cause of death in a cohort of patients with parkinsonism: possible clues to aetiology? J Neurol Neurosurg Psychiatry 58: 293–299PubMedGoogle Scholar
  4. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455PubMedGoogle Scholar
  5. Boomsma F, Meerwaldt JD (1989) Treatment of idiopathic parkinsonism with L-dopa in the absence and presence of decarboxylase inhibitors: effects on plasma levels of L-dopa, dopa decarboxylase, catecholamines and 3-O-methyl-dopa. J Neurol 236: 223–230PubMedGoogle Scholar
  6. Boyce S, Rupniak NMJ, Steventon MJ, Iversen SD (1990) Characterisation of dyskinesias induced by L-dopa in MPTP-treated squirrel monkeys. Psychopharmacology 102: 21–27PubMedGoogle Scholar
  7. Calne DB (1993) Treatment of Parkinson's disease. N Engl J Med 329: 1021–1027PubMedGoogle Scholar
  8. Cox DR (1972) Regression models and life-tables. J R Stat Soc [B] 34: 187–220Google Scholar
  9. Eichstädt H (1993) unpublished resultsGoogle Scholar
  10. Falk RH, DeSilva RA, Lown B (1981) Reduction in vulnerability to ventricular fibrillation by bromocriptine, a dopamine agonist. Cardiovasc Res 15: 175–180PubMedGoogle Scholar
  11. Fischer PA, Przuntek H, Majer M, Welzel D (1984) Kombinationsbehandlung früher Stadien des Parkinson-Syndroms mit Bromocriptin und Levodopa. Ergebnisse einer multizentrischen Studie. Dtsch Med Wochenschr 109: 1279–1283PubMedGoogle Scholar
  12. Gawel M, Riopelle R, Libman I (1986) Bromocriptine in the treatment of Parkinson's disease. A double-blind study against L-Dopa/carbidopa. Adv Neurol 45: 535–538Google Scholar
  13. Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63: 793–807PubMedGoogle Scholar
  14. Gerlach M, Riederer P, Youdim MBH (1995) Neuroprotective therapeutic strategies: comparison of experimental and clinical results. Biochem Pharmacol 50: 1–16PubMedGoogle Scholar
  15. Götz ME, Künig G, Riederer P, Youdim MBH (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 63: 37–122PubMedGoogle Scholar
  16. Graham WC, Sambrook MA, Crossman AR (1993) Differential effect of chronic dopaminergic treatment on dopamine-D(1) and dopamine-D(2) receptors in the monkey brain in MPTP-induced parkinsonism. Brain Res 602: 290–303PubMedGoogle Scholar
  17. Hely MA, Morris JGL, Rail D, Reid WGJ, O'Sullivan DJ, Williamson PM, Genge S, Broe G (1989) The Sydney multicentre study of Parkinson's disease: a report on the first 3 years. J Neurol Neurosurg Psychiatry 52: 324–328PubMedGoogle Scholar
  18. Hoehn HM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17: 427–442PubMedGoogle Scholar
  19. Kao A, Kriett JM, Tobler HG, Detloff BL, Pritzker MR, Benson DW Jr, Benditt DG (1984) Bromocriptine treatment of digitalis-induced ventricular tachyarrhythmias: studies in a canine model. JACC 4: 1188–1194PubMedGoogle Scholar
  20. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481Google Scholar
  21. Lange KW, Rausch W-D, Gsell W, Naumann M, Oestreicher E, Riederer P (1994) Neuroprotection by dopamine agonists. J Neural Transm 43 [Suppl]: 183–201Google Scholar
  22. LeWitt PA, Calne DB (1981) Recent advances in the treatment of Parkinson's disease: the role of bromocriptine. J Neural Transm 51: 175–184PubMedGoogle Scholar
  23. Lieberman A, Goldstein M (1989) Dopamine agonists in advanced Parkinson's disease. In: Lieberman A, Lataste X (eds) Parkinson's disease. The role of dopamine agonists. The Parthenon Publishing Group, Carnforth, pp 35–53Google Scholar
  24. Marsden CD, Parkes JD (1976) “On-off” effects in patients with Parkinson's disease on chronic levodopa therapy. Lancet i: 292–296Google Scholar
  25. Muenter MO, Sharpies NS, Tyce GM, Darley FL (1977) Patterns of dystonia (“I-D-I” and “D-I-D”) in response to L-dopa therapy for Parkinson's disease. Mayo Clin Proc 52: 163–174PubMedGoogle Scholar
  26. Nakanishi T, Mizuno Y, Goto I, Iwata M, Kanazawa I, Kowa H, Mannen T, Nishitani H, Ogawa N, Takahashi A, Tashiro K, Tohgi H, Yanagisawa N (1991) A nation-wide collaborative study on the long-term effects of bromocriptine in patients with Parkinson's disease. The fourth interim report. Eur Neurol 31 [Suppl 1]: 3–16PubMedGoogle Scholar
  27. Nilsson A, Hökfelt B (1978) Effect of the dopamine agonist bromocriptine on blood pressure, catecholamines and renin activity in acromegalics at rest, following exercise and during insulin induced hypoglycemia. Acta Endoc 88 [Suppl 216]: 83–96Google Scholar
  28. Ogawa N, Tanaka K, Asanuma M, Kawai M, Masumizu T, Kohno M, Mori A (1994) Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro. Brain Res 657: 207–213PubMedGoogle Scholar
  29. Olanow CW (1993) A radical hypothesis for neurodegeneration. TINS 16: 439–444PubMedGoogle Scholar
  30. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SU, Mantel N, McPherson K, Peto J, Smith PG (1976) Design and analysis of randomized clinical trials requiring prolonged observations of each patient. I. Introduction and design. Br J Cancer 34: 585–612PubMedGoogle Scholar
  31. Przuntek H, Welzel D, Blümner E, Danielczyk W, Letzel H, Kaiser H-J, Kraus PH, Riederer P, Schwarzmann D, Wolf H, Überla K (1992a) Bromocriptine lessens the incidence of mortality in L-Dopa-treated parkinsonian patients: prado-study discontinued. Eur J Clin Pharmacol 43: 357–363PubMedGoogle Scholar
  32. Przuntek H, Welzel D, Schwarzmann D, Letzel H, Kraus P (1992b) Primary combination therapy of early Parkinson's disease. Eur Neurol 32 [Suppl 1]: 36–45PubMedGoogle Scholar
  33. Rinne UK (1985) Combined bromocriptine-levodopa therapy early in Parkinson's disease. Neurology 35: 1196–1198PubMedGoogle Scholar
  34. Starke K, Majewski H, Ensinger H, Szabo B, Hedler L (1986) In vivo operation of prejunctional adrenoceptors in the peripheral sympathetic nervous system. In: Grobecker H, et al (eds) New aspects of the role of adrenoceptors in the cardiovascular system. Springer, Berlin Heidelberg New York Tokyo, pp 43–56Google Scholar
  35. Tanaka M, Sotomatsu A, Yoshida T, Hirai S (1995) Inhibitory effects of bromocriptine on phospholipid peroxidation induced by DOPA and iron. Neurosci Lett 183: 116–119PubMedGoogle Scholar
  36. Van Loon GR, Sole MJ, Bain J, Ruse JL (1979) Effects of bromocriptine on plasma catecholamines in normal men. Neuroendocrinology 28: 425–434PubMedGoogle Scholar
  37. Webster DD (1968) Critical analysis of the disability in Parkinson's disease. Mod Treatment 5: 257–282Google Scholar
  38. Weiner WJ, Factor SA, Sanchez-Ramos JR, Singer C, Sheldon C, Cornelius L, Ingenito A (1993) Early combination therapy (bromocriptine and levodopa) does not prevent motor fluctuations in Parkinson's disease. Neurology 43: 21–27PubMedGoogle Scholar
  39. Wooten GF (1988) Progress in understanding the pathophysiology of treatment-related fluctuations in Parkinson's disease. Ann Neurol 24: 363–365PubMedGoogle Scholar
  40. Yoshikawa T, Minamiyama Y, Naito Y, Kondo M (1994) Antioxidant properties of bromocriptine, a dopamine agonist. J Neurochem 62: 1034–1038PubMedGoogle Scholar
  41. Ziegler MG, Lake CR, Williams AC, Teychenne PF, Shoulson I, Steinsland O (1979) Bromocriptine inhibits norepinephrine release. Clin Pharmacol Ther 25: 137–142PubMedGoogle Scholar
  42. Zung WW (1965) A self-rating depression scale. Arch Gen Psychiatry 12: 63–70PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • H. Przuntek
    • 1
  • D. Welzel
    • 2
  • M. Gerlach
    • 1
    • 4
  • E. Blümner
    • 5
  • W. Danielczyk
    • 6
  • H. -J. Kaiser
    • 3
  • P. H. Kraus
    • 1
  • H. Letzel
    • 5
  • P. Riederer
    • 4
  • K. Überla
    • 7
  1. 1.Neurologische KlinikRuhr-Universität, St. Josef-HospitalBochum
  2. 2.Institut für PharmakologieUniversität RegensburgGermany
  3. 3.Sandoz AGNuremberg
  4. 4.Klinische NeurochemieUniversitäts-NervenklinikWürzburg
  5. 5.Staticon, Medizinische Forschungsgesellschaft mbHPlaneggGermany
  6. 6.Neurologische AbteilungPflegeheim der Stadt Wien-Lainz, Ludwig-Boltzmann-Institut für AltersforschungViennaAustria
  7. 7.Institut für Medizinische Informationsverarbeitung, Biometrie und EpidemiologieUniversität MünchenGermany

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