Plasma concentrations of L-dopa and 3-methoxydopa and improvement in clinical ratings and motor performance in patients with Parkinsonism treated with L-dopa alone or in combination with amantadine.

Abstract

SYNOPSIS Six patients with idiopathic Parkinsonism were treated with a combination of amantadine and L-dopa and after 12 to 24 weeks amantadine was replaced by placebo for a six week period in a double-blind trial. Although there was a tendency for clinical disability ratings and scores on objective ratings of motor skills to deteriorate initially after amantadine removal, there was no significant deterioration in clinical improvement or motor performance during the period of amantadine withdrawal. Amantadine withdrawal also failed to cause any significant change in plasma concentrations of L-dopa or its metabolite 3-methoxy-dopa in these patients. In a group of 27 patients seen regularly as outpatients measurements of plasma L-dopa failed to correlate significantly with either oral dose or with clinical improvement scores. The plasma concentration of 3-methoxy-dopa, however, was on average 2.8 times higher than that of L-dopa, and there was a significant correlation between plasma levels of this metabolite and clinical improvement. It is suggested that 3-methoxy-dopa may contribute significantly to the therapeutic actions of L-dopa in Parkinsonism.Amantadine and L-dopa are in widespread use, either singly or in combination, in the treatment of patients with Parkinsonism. The combination of amantadine and L-dopa has been claimed to be more effective than L-dopa alone, although not all trials have confirmed this synergism (for review see Parkes et al., 1973). Amantadine has also been shown to decrease the daily L-dopa therapeutic dosage requirements and it has been suggested that amantadine may decrease the extracerebral metabolism of L-dopa, thus rendering more drug available to the central nervous system (Peaston et al., 1973). In the present study we present clinical and biochemical findings in a group of patients treated with the combination preliminary experiments showed that both compounds were stable under these storage conditions. Plasma samples (4 ml) were deproteinized by addition of 4 ml ice-cold O.4N perchloric acid, and stand-

Clinical Pharmacokinetics of Levodopa in Parkinson??s Disease

“…Hare et al (1973) found no correlation between peak plasma levels of levodopa and clinical response in 11 patients. Pilling et al (1975) likewise demonstrated no significant correlation between plasma levels and clinical improvement scores in 27 patients; However, they reported difficulty in 'obtaining plasma samples at a fixed time interval after the last dose of L-dopa'. Finally, Rinne et al (1973b) showed that clinical improvement during chronic levodopa administration was not correlated Significantly with total circulating levels or peak concentrations of levodopa in 173 patients.…”

“…The difference in pyridoxine-induced levotration of levodopa achieved following oral dopa metabolism between parkinsonian patients administration (Rivera-Calimlim et aI., 1971; and normal control subjects may reflect an adapMearrick et aI., 1974). For example, in parkin-tive alteration in the decarboxylase system due to sonian patients with markedly slowed gastric chronic administration of levodopa (Mars, 1975). o~emptyffigYates~~levodopa'may~not provide~ade-~--This~alteI~tig!L@Y r~~ul!…”

Clinical Pharmacokinetics of Anti-Parkinsonian Drugs

“…This phenomenon does not appear to be as prevalent or as pronounced in patients taking levodopa concurrently (Fahn & Isgreen 1975). However, there are no known pharmacokinetic interactions between the two drugs (Pilling et al 1975). Amantadine can also alleviate the Parkinsonian side effects of the major tranquillisers (Greenblatt et al 1977).…”

Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?

“…In our patient group, no correlation was detected between the magnitude of the 2 h treatment effect and the corresponding difference in levodopa concentrations between active and placebo days, despite a more than thirteen fold variation between patients in the latter. Rinne et al (1973), Hare et al (1973 and Pilling et al (1975) were also unable to find any between patient relationship of plasma levodopa concentrations to response, and no therapeutic range has been established.…”