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Objective evidence for tolerance, against a background of improvement, during maintenance therapy with controlled release levodopa/carbidopa

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Summary

We have investigated whether the potential benefits of a controlled release formulation of levodopa (200 mg)/carbidopa (50 mg), Sinemet CR, are realised during maintenance therapy.

Eight sufferers from idiopathic Parkinsonism, mean age 69.9 y, were studied: all exhibited “end of dose” effect within 4 h of a dose of their maintenance therapy with levodopa (100 mg)/carbidopa (25 mg) in a conventional release formulation, Sinemet Plus. They received, in random order, initial single dose challenges with one tablet of Sinemet Plus, one and two tablets of Sinemet CR and placebo alone, each on a separate day. After a mean of 21 weeks on maintenance therapy with Sinemet CR, subsequent single dose challenges with Sinemet CR and placebo were made. Objective measures of performance and blood sampling for assay of plasma concentrations of levodopa and the major peripheral metabolite, 3-0-methyldopa (30MD) were carried out immediately before (10.00 h) and serially until 6 h after each challenge.

The overall mean stride length was significantly greater in relation to the subsequent (679 mm) than the initial (517 mm) placebo challenge. Moreover, stride length immediately before the challenges was significantly greater on the subsequent occasions. Improved performance, also seen for free walking speed, was not explained by plasma levodopa or 30MD concentrations.

In the initial challenges, the mean increment in stride length achieved by active treatment, as compared with placebo, did not differ significantly between the one (210 mm) and two (235 mm) tablet doses of Sinemet CR: a maximal response had been obtained. The increment over placebo values following two active tablets did not differ significantly between initial and subsequent (192 mm) challenges. However, the increment produced by one active tablet in the subsequent (79 mm) challenge was significantly less than that produced by two, and than that which had been produced by one tablet in the initial challenge. Findings for free coalting speed mirrored those for stride length. These differences could, in part, be accounted for by attenuation of the effect of levodopa by 30MD.

The improvement in baseline performance, in relation to the subsequent challenges, possibly resulted from striatal dopamine stores being more replete during maintenance therapy with the controlled release formulation. It was seen despite evidence of tolerance to an acute challenge with the lower dose.

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References

  1. Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL (1984) The “on-off” phenomenon in Parkinson's disease. N Engl J Med 310: 483–488

    Google Scholar 

  2. Nutt JG, Woodward WR (1986) Levodopa pharmacokinetics and pharmacodynamics in fluctuating Parkinsonian patients. Neurology 36:739–744

    Google Scholar 

  3. Shoulson I, Glaubiger GA, Chase TN (1975) On-off response. Clinical and biochemical correlations during oral and intravenous administration in Parkinsonian patients. Neurology 25: 1144–1148

    Google Scholar 

  4. Quinn NP (1984) Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 34:1131–1136

    Google Scholar 

  5. Nutt JG (1987) On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics. Ann Neurol 22: 535–540

    Google Scholar 

  6. Yeh KC, August TF, Bush DF, Lasseter KC, Musson DG, Schwartz S, Smith ME, Titus DC (1989) Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 39 [Suppl 2]: 25–38

    Google Scholar 

  7. Unified Parkinson's Disease Rating Scale (1989) In: Munsat TL (ed) Quantification of neurologic deficit. Butterworth, Stoneham, pp 302–307

    Google Scholar 

  8. Leeman AL, O'Neill CJA, Nicholson PW, Deshmukh AA, Denham MJ, Royston JD, Dobbs RJ, Dobbs SM (1987) Parkinson's disease in the elderly: response to and optimal spacing of nighttime dosing with levodopa. Br J Clin Pharmacol 24: 637–643

    Google Scholar 

  9. Weller C, Dobbs RJ, Tate MA, Telford A, Klenerman L (1989) Biotelemetry X. Monitoring gait characteristics in orthopaedic and neurological patients by infra-red telemetry. In: Amlaner CJ (ed) Proceedings of the Tenth International Symposium on Biotelemetry. The University of Arkansas Press, Fayetteville London, pp 575–580

    Google Scholar 

  10. Bowes SG, Clark PK, Leeman AL, O'Neill CJA, Weller C, Nicholson PW Deshmukh AA, Dobbs SM, Dobbs RJ (1990) Determinants of gait in the elderly Parkinsonian on maintenance levodopa-carbidopa therapy. Br J Clin Pharmacol 30:13–24

    Google Scholar 

  11. Weller C, Bowes SG, Kirk CAA, Nicholson PW Dobbs RJ, Dobbs SM (1991) Measurement of axial rotation: its relevance to screening for night-time hypokinesia in old age and Parkinsonism. Age Ageing 20:3–7

    Google Scholar 

  12. Hughes RJ, Bowes SG, Leeman AL, O'Neill CJA, Deshmukh AA, Nicholson PW Dobbs SM, Dobbs RJ (1990) Parkinsonian abnormality in foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy? Br J Clin Pharmacol 29:179–186

    Google Scholar 

  13. GLIM (1986) Release 3.77. In: Payne CD (ed) Generalised linear interactive modelling. Numerical Algorithms Group Ltd, Oxford

    Google Scholar 

  14. McCullagh PP, Nelder JA (1989) Generalised linear models. Chapman and Hall, London

    Google Scholar 

  15. Abeyasekera S, Curnow RN (1984) The desirability of adjusting for residual effects in a crossover design. Biometrics 40:1071–1078

    Google Scholar 

  16. Royston JP (1982) An extension of Shapiro and Wilk's W test for normality to large samples. Appl Statist 31:115–125

    Google Scholar 

  17. Schweder T (1981) A simple test for a set of sums of squares. Appl Statist 31:115–125

    Google Scholar 

  18. Frith CD, Bloxham CA, Carpenter KN (1986) Impairments in the learning and performance of a new manual skill in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 49: 661–668

    Google Scholar 

  19. Bowes SG, Clark PK, Charlett A, O'Neill CJA, Leeman AL, Weller C, Nicholson PW Deshmukh AA, Dobbs SM, Dobbs RJ (1991) Objective outcome criteria in trials of anti-Parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady- and hypo-kinesia. Br J Clin Pharmacol 31: 295–304

    Google Scholar 

  20. O'Neill CJA, Charlett A, Dobbs RJ, Deshmukh AA, Bowes SG, Weller C, Nicholson PW, Milledge A, Dobbs SM (1992) Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients. Br J Clin Pharmacol 33: 167–178

    Google Scholar 

  21. Collet J-P, Boissel J-P, VALIDATA Group (1991) Sick population-treated population: the need for a better definition. Eur J Clin Pharmacol 41:267–271

    Google Scholar 

  22. Cederbaum JM, Breck L, Kutt H, McDowell FH (1987) Controlled-release levodopa/carbidopa II Sinemet CR4 treatment of response fluctuations in Parkinson's disease. Neurology 37: 1607–1612

    Google Scholar 

  23. Bowes SG, O'Neill CJA, Nicholson PW Leeman AL, Deshmukh AA, Dobbs RJ, Dobbs SM (1991) Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease. Eur J Clin Pharmacol 41: 459–462

    Google Scholar 

  24. Nutt JG, Woodward WR, Gancher ST, Merrick D (1987) 3-Omethyldopa and the response to levodopa in Parkinson's disease. Ann Neurol 21: 584–588

    Google Scholar 

  25. Cederbaum JM, Kutt H, McDowell FH (1988) Clinical significance of the relationship between O-methyldopa levels and levodopa intake. Neurology 38: 533–536

    Google Scholar 

  26. Sage JI, Mark MH (1988) Comparison of controlled-release Sinemet (CR4) and standard Sinemet (25 mg/100 mg) in advanced Parkinson's disease: a double-blind, crossover study. Clin Neuropharmacol 11:174–179

    Google Scholar 

  27. Cederbaum JM, Hoey M, McDowell FH (1989) A double-blind crossover comparison of Sinemet CR4 and standard Sinemet 25/100 in patients with Parkinson's disease and fluctuating motor performance. J Neurol Neurosurg Psychiatry 52: 207–212

    Google Scholar 

  28. Cederbaum JM, Kutt H, McDowell FH (1989) A pharmacokinetic and pharmacodynamic comparison of Sinemet CR (50/200) and standard Sinemet. Neurology 39 [Suppl 2]: 38–44

    Google Scholar 

  29. Goetz CG, Tanner CM, Shannon KM, Carroll VS, Klawans HL, Carvey PM, Gilley DL (1988) Controlled-release levodopa/ carbidopa (CR4-Sinemet) in Parkinson's disease patients with and without motor fluctuations. Neurology 38:1143–1146

    Google Scholar 

  30. Bush DF, Liss CL, Morton A, Sinemet CR Multicenter Study Group (1989) An open multicenter long-term treatment evaluation of Sinemet CR. Neurology 39 [Suppl 2]:101–104

    Google Scholar 

  31. LeWitt PA, Nelson MV, Berchou RC, Galloway MP, Kesaree N, Kareti D, Schlick P (1989) Controlled-release carbidopa/levodopa (Sinement 50/200 CR4): clinical and pharmacokinetic studies. Neurology 39 [Suppl 2] 45–53

    Google Scholar 

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Authors and Affiliations

  1. Therapeutics in the Elderly, Clinical Research Centre, Northwick Park Hospital, Watford Road, HA1 3UJ, Harrow, Middlesex, UK

    S. G. Bowes,  R. J. Dobbs, C. J. A. O'Neill, A. G. Purkiss & S. M. Dobbs

  2. Division of Medical Statistics, Clinical Research Centre, Harrow, UK

    M. Henley & A. Charlett

  3. Division of Bioengineering, Clinical Research Centre, Harrow, UK

    C. Weller

  4. University College and Middlesex Hospital Medical School, London, UK

    P. W. Nicholson

Authors
  1. S. G. Bowes
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  2. R. J. Dobbs
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  3. M. Henley
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  4. A. Charlett
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  5. C. J. A. O'Neill
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  6. P. W. Nicholson
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  7. A. G. Purkiss
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  8. C. Weller
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  9. S. M. Dobbs
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Bowes, S.G., Dobbs, R.J., Henley, M. et al. Objective evidence for tolerance, against a background of improvement, during maintenance therapy with controlled release levodopa/carbidopa. Eur J Clin Pharmacol 43, 483–489 (1992). https://doi.org/10.1007/BF02285089

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  • DOI: https://doi.org/10.1007/BF02285089

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