The pharmacology of Parkinson's disease: Basic aspects and recent advances

Abstract

Basic aspects and recent advances in the understanding of the pharmacological mechanism of action of the clinically most used antiparkinson drugs are reviewed. Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. In parkinsonian patients under long-term L-DOPA therapy monoamine oxidase inhibitors type B (MAO-B) e.g. (-)deprenyl and direct dopamine receptor agonists (bromocriptine, lisuride, pergolide etc.), due to their L-DOPA-sparing effects, alleviate in some cases L-DOPA-induced side-effects e.g. dyskinesias and on-off phenomena. However, since (-)deprenyl, due to its metabolism to (-)methamphetamine and (-)amphetamine, seem to have indirect sympathomimetic activity, new selective MAO-B inhibitors devoid of indirect sympathomimetic effects should be tested clinically to assess the functional role of pure MAO-B inhibition in the therapy of PD. The auxiliary therapy with direct dopamine receptor agonists of the D-2 subtype represents another valid approach which should be further investigated in order to find novel dopamine agonists, less expensive than bromocriptine, and strictly selective for D-2 receptor sites.

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

“…Consequently, it is unlikely that benserazide's Although known for more than two decades as a potent inhibitor of peripheral decarboxylase [20], its clinical mechanism of action is completely irreversible [22]. This is in accordance with findings obtained by Da Prada et al [23] pharmacology has been sparsely investigated. The main reasons for this lack of data are the complex analysis of who showed that the effect of a single dose of benserazide (1.5 mg kg −1 ) on endogenous levodopa levels decreased benserazide and/or its active metabolite(s) and the absence of a suitable direct marker of decarboxylase activity [3].…”

“…The t max of levodopa, 3-OMD and DOPAC were very similar marked dose-dependency in the inhibition of decarboxylase is anticipated for levodopa preparations containing carbidopa under the different benserazide regimens and t 1/2 only increased slightly at doses of 100-200 mg (Table 2). These since this inhibitor is less potent than benserazide [23,27]. The clinical development of COMT inhibitors should take results, together with the C max and AUC data, suggest that decarboxylase present in the gastrointestinal tract plays a these possible consequences of lowering the benserazide dose into consideration by the conduct of pharmacokinetic/ crucial role in the metabolism of levodopa to dopamine.…”

“…Plasma levels of heart rate and the ECG were recorded and brief neurological examinations performed at frequent intervals on the days of 3-OMD are an indirect marker for the degree of dopamine formation because in the presence of a decarboxylase levodopa/3-OMD/DOPAC determinations. Several routine laboratory safety tests on blood and urine were conducted inhibitor the metabolism of levodopa is shifted towards 3-OMD [13,14]. Plasma levels of 3,4-dihydroxyphenylacetic during the study.…”

Microdialysis Studies on the Action of Tolcapone on Pharmacologically‐Elevated Extracellular Dopamine Levels in Conscious Rats

“…When levodopa is given with a dopa decarboxylase inhibitor like carbidopa, the majority of surplus L-dopa is metabolized by peripheral COMT (Kuruma et al 1972;Messiha et al 1972;Fahn 1974;Da Prada et al 1984;Mannisto et al 1992b). During the combination therapy, 3-0-methyldopa is the major metabolite (Fahn 1974;Rivera-Calimlim et al 1977;Reilly et al 1980;Da Prada et al 1984;Hardie et al 1986), and the role of COMT inhibitors becomes extremely meaningful. The functional significance of this combination has been nicely demonstrated in the rat lesion model of Parkinson's disease where COMT inhibitors potentiate the effect of levodopa on contralateral turning behaviour ).…”

Rationale for Selective COMT Inhibitors as Adjuncts in the Drug Treatment of Parkinson's Disease

“…The role of COMT becomes even more important than before (Kuruma et al 1972;Messiha el al. 1972;Fahn 1974;Da Prada et al 1984). Using the combination therapy, 3-OMD is the major plasma metabolite and it's concentration in plasma is usually many times that of levodopa (Fahn 1974;RiveraCalimlim et al 1977;Reilly et al 1980 .…”