Pharmacodynamic modeling of oral levodopa in Parkinson's disease.

Annals of Neurology (Impact Factor: 11.19). 12/2001; 50(5):687-8. DOI: 10.1002/ana.1268
Source: PubMed
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    ABSTRACT: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.
    Clinical Pharmacokinetics 02/2001; 40(5):383-93. · 5.49 Impact Factor
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    ABSTRACT: Almost all patients with Parkinson's disease will eventually require levodopa during the course of their disease. The effectiveness of levodopa is evident, but earlier use and higher doses are causative of the emergence of motor fluctuations. About one half of patients develop motor fluctuations 4–6 years after starting levodopa therapy for parkinsonian symptoms. Peripheral and central pharmacokinetic mechanisms are related to motor fluctuations. It was reported that time to peak concentration (Tmax) and elimination half-life (T1/2) of levodopa decreased especially in patients with wearing-off (peripheral pharmacokinetics). On the other hand, there are several reports demonstrating no change in peripheral pharmacokinetics in patients on long-term levodopa therapy. The reduced capacity for presynaptic storage of dopamine by nigral neurons is believed to be another important factor responsible for motor fluctuations (central pharmacokinetics). In addition, a mathematical model that was recently established based on the hypothesis that dopamine release is subject to probabilistic variations in the quantity of dopamine has indicated that motor fluctuations might be explained by presynaptic mechanisms. On the other hand, several studies demonstrated that changes in postsynaptic mechanisms (pharmacodynamics) play an important role in shortening the duration of levodopa action in advanced stages. In clinical practice therapeutic strategies for motor fluctuations are focused on continuous dopaminergic stimulation at postsynaptic dopamine receptors. Once motor fluctuations appear, therapeutic regimens should be individualized to retain optimal control of the symptoms based on accurate assessment of each patient's levodopa cycle and responses to drugs. Symptom diaries kept by patients or caregivers are useful for this purpose.
    Journal of Neurology 01/2007; 254:32-40. · 3.58 Impact Factor
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    ABSTRACT: Parkinson's disease is a chronic progressive disease with symptoms of tremors, rigidity, and akinesia. Parkinson's disease is a major risk factor for postoperative complications and it is difficult to manage patients with Parkinson's disease after gastrointestinal surgery. This report presents the cases of three patients with Parkinson's disease who underwent gastrointestinal surgery and had no serious postoperative complications. Antiparkinsonian medications were reduced before surgery and replaced by an intravenous infusion of levodopa until the patients could take oral antiparkinson drugs after surgery to prevent malignant syndrome or exacerbate parkinsonism. Prokinetics were also used for the prevention of paralytic ileus. These cases demonstrate an effective method to administer antiparkinson drugs during perioperative management of patients with Parkinson's disease and also indicate that sufficient doses of antiparkinson drugs can control the symptoms of parkinsonism and prevent complications in cases of surgery with parkinsonism.
    Surgery Today 01/2009; 39(9):807-10. · 0.96 Impact Factor