Treatment With Levodopa

Levodopa was first synthesized almost 100 years ago. It took almost half a century until Arvid Carlson discovered that this compound could reverse the reserpine-induced motor symptoms similar to the ones in idiopathic PD in rats. The next step was the successful administration of levodopa in PD patients, which was initially performed by various clinicians in the late 1950s and early 1960s. There is no doubt that levodopa is the most efficacious and best tolerated antiparkinsonian compound, as recently demonstrated by the ELLDOPA trial (14,15). A drawback of this drug was the short half-life in plasma from the beginning of levodopa administration in PD. The additional administration of an aromatic amino acid decarboxylase inhibitor (DDI) markedly reduced the peripheral levodopa degradation and thus improved the efficacy of levodopa on motor symptoms in PD patients (16). Two different DDIs are available, benserazide is administered with levodopa on a 1:4 basis and carbidopa on a 1:10 basis. All idiopathic PD patients respond to levodopa/DDI with a distinct improvement of predominant akinesia and rigidity, and to a lesser extent, tremor. This also serves as a specific diagnostic criterion (17-19). A missing response may indicate a gastrointestinal absorption problem or makes the diagnosis uncertain (20). Since levodopa is administered with peripherally acting DDI, it is predominantly converted to its metabolite 3-O -methyldopa (3-OMD) by the ubiquitous enzyme catechol-O -methyltransferase (COMT) in blood, peripheral tissues and nigrostri-atal neurons. Therefore, inhibition of COMT improves the efficacy of the levodopa/DDI, since this delays the levodopa metabolism and thus increases its antiparkinsonian efficacy due to the increased bioavailability of levodopa in the brain (21). This principle of LD application was simplified and thus improved from the patient's view with the launch of the compound Stalevo®, which combines levodopa, carbidopa and the peripherally acting COMT inhibitor entacapone in a single tablet. This mode of levodopa administration may also contribute to more stable levodopa plasma levels and thus delivers levodopa to the brain in a more steady fashion. This dopamine substitution in a more continuous manner may reduce the threshold problems of levodopa at striatal postsynaptic dopamine uptake sites, reduce non-physiologic alternating striatal dopamine levels and thus the frequency, that these receptors alter between off and on (22-25). Accordingly, animal trials showed a decreased onset of levodopa-associated motor complications in the long-term, when a treatment with levodopa/DDI and entacapone was started right from the beginning (23). Thus, this mode of levodopa application does not only improve the clinical efficacy of oral levodopa intake on motor symptoms of PD patients (21,26), it may also postpone the onset of motor complications, which still needs to be proven in ongoing clinical trials.

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