Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations.

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agonist apomorphine was investigated in parkinsonian patients with end-of-dose motor fluctuations. The relation between levodopa plasma concentrations and motor response was examined in a double-blind, randomized, crossover design in 10 patients with idiopathic Parkinson's disease with end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each patient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores (sigma score) of the Columbia University Rating Scale (CURS) were used as effect parameters for pharmacodynamic assessment. A sigmoidal Emax model was fitted to the data using a semiparametric pharmacokinetic-pharmacodynamic approach. Levodopa pharmacokinetics were not significantly modified by the coadministration of apomorphine. The area under the curve was 1599 +/- 615 ng.ml-1 h. (levodopa + saline) and 1821 +/- 625 ng.ml-1.h (levodopa + apomorphine). Cmax was 1094 +/- 476 ng.ml-1 (levodopa + saline) and 1129 +/- 435 ng.ml-1 (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (Emax) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.ml-1 (levodopa + saline) to 315 +/- 123 ng+ml-1 (levodopa + apomorphine) (95% confidence interval [CI] 0.51 -0.98, point estimator 0.75). The mean duration of the motor response rose from 1.9 +/- 0.5 h (levodopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold levels for levodopa (EC50) was accompanied by approximately 50% gain in on-phase duration, but not in an increased magnitude of the motor response (Emax).

Fluctuations in Parkinson's disease. Pathogenetic significance of levodopa's cerebral pharmacokinetics and pharmacodynamics.

The pathogenetic mechanisms which are responsible for the clinical manifestation of motor-fluctuations are poorly understood. Peripheral pharmacokinetics do obviously not play a significant role. For a better understanding of fluctuations exact knowledge and precise characterization of the levodopa induced motor-response (MR) might be useful. In a number of studies it has been demonstrated that this MR follows the "all or none" rule after a levodopa threshold concentration has been exceeded. Such a threshold is considered to exist in the plasma-compartiment as well as in the cerebral effect-compartiment. The specific character of the MR can be modified by the coadministration of dopamine-agonists. Dopamine-agonists lower the levodopa threshold and they reduce the time-lag between levodopa plasmaconcentration and MR. The duration of the MR can be prolonged but the intensity (amplitude) of the MR cannot be augmented. Most of these data to levodopa pharmacodynamics can be explained by a model which is presented in this paper and which is mainly based on cerebral pharmacokinetic mechanisms.

Lamotrigine in Parkinson's disease--a double blind study.

Antiglutamatergic acting substances are considered to be useful tools for the treatment of hypokinesia in animal models for Parkinson's disease (PD). Moreover, most known antiglutamatergic compounds act postsynaptically and are either toxic or weak with regard to their clinical potency. The antiepileptic drug "Lamotrigine (LTG)" inhibits presynaptic glutamate release and may therefore provide a novel approach for PD therapy. Encouraging results from a pilot project led us to establish a placebo controlled trial including 20 patients with PD. The substance was generally well tolerated. There was a significant difference in the investigator's overall assessment of efficacy (6/10 vs. 2/10 improvement; p < 0.05) and a tendency for LTG to exhibit a beneficial effect in some registration parameters, but no significant differences in motor response were found between the two groups. We failed to confirm that LTG mediates a strong antiparkinsonian effect in this small study, but to clearly demonstrate slight or moderate beneficial effects larger groups are required.