Influence of dopamine-agonists on the pharmacokinetics and pharmacodynamics of levodopaBackground: Despite the broad clinical use of levodopa and dopamine-agonists and their well established clinical efficacy in parkinsonian patients, little is known about the exact pharmacodynamics of both substances and their pharmaeodynamic interactions. However, exact knowledge of pharmacodynarrdcs is essentially for the optimization of therapeutic regimens and maximal clinical efficacy especially in fluctuating patients.Methods: An oral single dose challenge using 100 mg levodopa 25 mg benserazide was performed under standardized conditions in 10 parkinsonian patients with clear-cut wearing-off fluctuations. A continuous s.c. infusion of apomorphine in a clinical subthreshold dosage was coadmimstered to the levodopa challenge under double blind conditions vs. NaC1 in each patient. Levodopa serum-concentrations (LSC) and the actual motor disability (AMD) as the efficacy parameter were measured in 15 rain intervalls over 4 h. AMD was semiquantitatively measured by Columbia-University-Rating-Scale (CURS) sum-scoring, LSC was measured by HPLC. Calculation of main pharmacodynamic parameters (LPC-effect analysis) was performed individually using a semiparametric approach. Data were fitted by an Emax model.Results: Levodopa pharmacokinetics were not significantly influenced by the coadministration of apomorphine with exception of a slight increase of AUC. Pharmacodynamics were significantly altered by apomorphine. Starting from a similar level of basic disability Emax (19.9 _+ 7.7 vs. 19.7 -+ 7.7 pts.) was similar under both regimen but clear differences were seen in Teq (26-+ 8 vs. 19 + 10 min), MRTe (1.9 + 0.5 vs. 3.0 + 0.9 h) and EC50 (430 _+ 163 vs. 315 + 123 ng/ml). The slope factor N showed some decrease under apomorphine but remained still on a high level (17 vs. 7). Our data have shown that the "all or nothing" character of the motor response to levodopa ist preserved under coadministration of a dopamine-agonist and that the mnplitude of motor improvement remains unchanged whereas the duration of the on phase is clearly increased.

The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.3 microgram or 1.5 micrograms FeCl3. The low dose of iron stimulates while 1.5 micrograms inhibits the spontaneous dopaminedependent locomotor night and explorative activity. The low concentration of ionic iron injected intrastriatally also increases lipid peroxidation in striatal and hippocampal tissues. These results suggest that the functional integrity of the ventral striatum and the regulation of the iron metabolism are critical for the sensorimotor performance.

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