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Byline: Ruth Djaldetti (1), Eldad Melamed (1) Keywords: Key words Parkinson's disease; Levodopa; Therapy Abstract: In the last decade there has been a surge of new therapeutic strategies for the treatment of Parkinson's disease along with a change of concepts about how the disease should be treated. The gold standard remains levodopa preparations, which have a rapid and dramatic symptomatic effect by replenishing the reduced dopamine levels in caudate and putamen nuclei. However, keeping in mind the complications that may emerge following long-term treatment, its initiation should possibly be delayed to the more advanced stages of the illness, especially in younger patients, in favour of dopamine agonists monotherapy. The adverse reactions that become prominent and disabling in late stages of the disease, i. e., dyskinesias, response fluctuations, and psychiatric side effects, can currently be managed by novel pharmacological as well as surgical strategies. Future therapies will focus on transplantation of dopaminergic embryonic tissue, gene therapy, and neuroprotective treatments. Author Affiliation: (1) Chairman, Department of Neurology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Tel.: +972-3-937-6356, Fax: +972-3-922-3352, e-mail: emelamed@clalit.org.il, IL Article note: Received: 22 December 2000 / Accepted: 5 January 2001

Byline: Thomas Muller (1), Harald Hefter (2), Roland Hueber (3), Wolfgang H. Jost (4), Klaus L. Leenders (5), Per Odin (6), Johannes Schwarz (7) Keywords: levodopa; homocysteine; neurotoxicity; Parkinson's disease; midbrain neurons Abstract: Abstract. The objective of this workshop was to review and discuss the debate on neurotoxicity of levodopa in the treatment of Parkinson's disease (PD) with consideration of preclinical and clinical findings. We concluded that in particular preclinical outcomes of in vitro models of neurodegeneration describe neurotoxic effects of levodopa, whereas trials in animal models provided controversial results. To date, clinical trials in PD patients showed no convincing proof of direct neurotoxic effects of levodopa on progression of neurodegeneration with various applied functional imaging techniques particularly with specific radiotracers for nigral dopaminergic neurotransmission. However, the controversy on neurotoxicity of levodopa only partially considered indirect mechanisms, i. e. levodopa-associated homocysteine elevation. But there is accumulating evidence that this long-term side effect of chronic levodopa administration dose dependently individually contributes to progression of neurodegeneration due to increased release of neurotoxins, induction of oxidative stress and mitochondrial dysfunction according to results of in vitro and animal trials and to at least peripheral neuronal degeneration and increased risk for onset of atherosclerosis-related disorders according to clinical trials in PD patients. From this point of view we demand that future research on the efficacy and putative neurotoxicity of antiparkinsonian compounds should also consider putative toxic longterm effects of drug administration and should look for putative peripheral biomarkers and individual, environmental or nutritative risk factors in order to establish a preventive therapy, i. e. folic acid administration in the case of levodopa-associated homocysteine elevation. Author Affiliation: (1) Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany (2) Department of Neurology, Heinrich-Heine-University, Dusseldorf, Germany (3) Neurological practice, Bergisch Gladbach, Germany (4) Department of Neurology, Deutsche Klinik fur Diagnostik, Wiesbaden, Germany (5) Department of Neurology, Groningen University Hospital, Groningen, The Netherlands (6) Department of Neurology, Central Hospital, Bremerhaven, Germany (7) Department of Neurology, University of Leipzig, Leipzig, Germany Article History: Registration Date: 01/01/2004