Plasma DOPA response to levodopa administration in man: Effects of a peripheral decarboxylase inhibitor

Dünner, David L.; Keith, Haddow M.; Brodie, H. Keith H.; Goodwin, Frederick K.

doi:10.1002/cpt1971122part1212

Cited by 40 publications

(22 citation statements)

References 3 publications

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“…When the plasma levodopa after the standard oral dose was multiplied by this factor an index of the possible circulating plasma levodopa in each patient while taking their optimal dose was obtained. The implicit assumption of a linear relation between plasma levodopa concentration and dose of levodopa in the therapeutic range seems reasonable (Dunner, Brodie & Goodwin, 1971).…”

Section: Resultsmentioning

confidence: 99%

The Absorption and Metabolism of a Standard Oral Dose of Levodopa in Patients With Parkinsonism

Bergmann

Curzon

Friedel

et al. 1974

Brit J Clinical Pharma

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1 The metabolism of a standard oral dose of levodopa was studied in forty-two patients with Parkinsonism. Plasma levodopa and 3-o-methyldopa concentrations were estimated at intervals for 8 h after ingestion and the concentration of homovanillic acid (HVA) in the lumbar cerebrospinal fluid (CSF) was measured at 8 hours. Clinical responses 3 months after the test were compared with these findings. 2 Although therapeutic benefit correlated significantly with calculated estimates of both plasma levodopa concentration and CSF HVA at optimal levodopa dose, individual values were widely scattered. There was no significant correlation between toxic effects and plasma levodopa or CSF HVA; and 3-o-methyldopa concentrations similarly did not show a significant correlation with either toxic or therapeutic effects. 3 Blood and CSF levels of levodopa or the metabolites measured in this study were not significantly altered by concurrent treatment with either anticholinergic drugs or amantadine nor by previous treatment with levodopa.

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Section: Resultsmentioning

confidence: 99%

The Absorption and Metabolism of a Standard Oral Dose of Levodopa in Patients With Parkinsonism

Bergmann

Curzon

Friedel

et al. 1974

Brit J Clinical Pharma

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“…Currently, oral administration of the dopamine precursor L-dopa, in combination with the aromatic amino acid decarboxylase inhibitor carbidopa (Dunner et al, 1971), remains an important component of the therapeutic regimen for treating PD. Nonetheless, serious fluctuations in motor response gradually develop with continued use of oral L-dopa.…”

Section: Discussionmentioning

confidence: 99%

“…These motor symptoms result from the progressive degeneration of dopaminergic neurons in the pars compacta of the substantia nigra, which project to the striatum (Dunnett and Bjorklund, 1999). Administration of the dopamine precursor L-dopa (Cotzias et al, 1967) combined with the dopamine decarboxylase inhibitor carbidopa (Dunner et al, 1971) helps control the neurological manifestations of PD by enhancing dopamine levels in the surviving dopaminergic neurons of the substantia nigra, thereby restoring neurotransmission.L-dopa provides a clear therapeutic benefit for most early-stage PD patients, where the duration of its pharmacodynamic effects far exceeds its plasma half-life. This reflects the ability of dopaminergic neurons to decarboxylate L-dopa to dopamine and then store sufficient amounts of dopamine to maintain adequate motor function long after plasma L-dopa levels have fallen.…”

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confidence: 99%

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confidence: 99%

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A Pulmonary Formulation of l-Dopa Enhances Its Effectiveness in a Rat Model of Parkinson's Disease

Bartus¹,

Emerich²,

Snodgrass-Belt³

et al. 2004

J Pharmacol Exp Ther

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The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C(max) (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of l-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.

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“…Sufficient decarboxylase activity is probably present in normal (Lloyd and Hornykiewicz, 1970a) or even parkinsonian (Lloyd and Hornykiewicz, 1970 b) human brain to bring about an increase in striatal dopamine following L-Dopa administration, an effect considered by many (Hornykiewicz, 1973) to be responsible for the therapeutic benefit associated with drug administration. Two inhibitors of Dopa decarboxylase, carbidopa (Porter et aI., 1962) and benserazide (Burkard et aI., 1962), which do not themselves cross the blood-brain barrier, are now widely used in conjunction with reduced L-Dopa dosage; by limiting peripheral decarboxylation (Dunner et al, 1971;Messiha et aI., 1972), they allow a greater proportion of the dose to enter the brain. In the human subject, the peripheral inhibitory effect has so far been inferential and it has not hitherto been possible to quantify the in vivo response of individual patients during drug treatment.…”

Section: Introductionmentioning

confidence: 98%

In vivo assessment of decarboxylase inhibition or potentiation: Urinary dopamine and L-Dopa output after L-Dopa administration

Johnson

Ruthven

Goodwin

et al. 1976

J. Neural Transmission

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In the L-Dopa treated rat, a decreased urinary output of free and conjugated dopamine and an increase in free and conjugated L-Dopa excretion after administration of decarboxylase-inhibiting drugs provide a good in vivo index of Dopa decarboxylase inhibition. With the exception of free dopamine output, which showed an equivocal change, these measurements appear to provide a good yardstick of decarboxylase status in man also. Using this approach, it was not possible to find any evidence of facilitation of decarboxylase action, in L-Dopa-treated parkinsonians given pyridoxine supplements, to account for the ability of this compound to neutralize the beneficial effect of L-Dopa.

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Plasma DOPA response to levodopa administration in man: Effects of a peripheral decarboxylase inhibitor

Cited by 40 publications

References 3 publications

The Absorption and Metabolism of a Standard Oral Dose of Levodopa in Patients With Parkinsonism

The Absorption and Metabolism of a Standard Oral Dose of Levodopa in Patients With Parkinsonism

A Pulmonary Formulation of l-Dopa Enhances Its Effectiveness in a Rat Model of Parkinson's Disease

In vivo assessment of decarboxylase inhibition or potentiation: Urinary dopamine and L-Dopa output after L-Dopa administration

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