Levodopa in Parkinsonism: Potentiation of Central Effects with a Peripheral Inhibitor

Papavasiliou, Paul S.; Cotzias, George C.; Düby, Simone E.; Steck, Andreas; Fehling, Clas; Bell, M A

doi:10.1056/nejm197201062860102

Cited by 109 publications

(53 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We were unable to show any improvement in the twelve patients treated in this study with massive doses of pyridoxine in addition to L-dopa and a dopa decarboxylase inhibitor. This is in agree ment with the findings of Papavasiliou et al [17] and suggests that the central effect of pyridoxine on dopa decarboxylation is negligible in par kinsonian patients.…”

Section: Discussionsupporting

confidence: 93%

“…Lechat et al [13] first demonstrated in animals that previous administration of a peri pheral dopa decarboxylase inhibitor would block the ability of pyridoxine to antagonize the antiparkinson properties of L-dopa. Our studies [11], as well as those of Yahr et al [21] and Papavasiliou et al [17], have clear ly shown this to be the case also in parkinsonian patients simultaneously treated with L-dopa and a dopa decarboxylase inhibitor. None of the pa tients showed loss of L-dopa effect when given pyridoxine.…”

Section: Discussionsupporting

confidence: 80%

“…However, they noted that there appeared to be enough activity remaining in the striatum to allow for tire formation of dopamine from L-dopa in patients treated with large doses of L-dopa. Papavasiliou et al [17] have suggested that the activation of these decarboxylases by pyridoxine could be the reason that beneficial effects have been reported in parkinsonian patients receiving massive doses of pyridoxine.…”

Section: Discussionmentioning

confidence: 99%

“…Paradoxically, they showed vi tamin B0 to cause a loss or reversal of the L-dopa effect [5,22]. Others have shown that vitamin B0 failed to reverse the clinical effect of L-dopa in patients receiving both L-dopa and a peripheral dopa decarboxylase in hibitor [11,17]. This suggests that B0-induced reversal of the L-dopa ef fect is due to accelerated decarboxylation of L-dopa to dopamine in extra cerebral tissues.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

L-Dopa, B6, and α-Methyldopa Hydrazine

Klawans

Ringel²

1973

Stereotact Funct Neurosurg

View full text Add to dashboard Cite

It has been suggested that L-dopa combines with pyridoxine (B₆) to form a specific antiparkinsonian molecule. This raises the possibility that the efficacy of L-dopa can be increased by giving patients both L-dopa and vitamin B₆. The administration of B₆ to parkinsonian patients receiving L-dopa reverses the L-dopa effect. It has been suggested that the L-dopa effect is not reversed by B₆ in patients receiving both L-dopa and a peripheral dopa decarboxylase inhibitor; thus, it is possible that administration of B₆ in large doses to patients receiving this combination might increase the antiparkinsonian efficacy of L-dopa. To systematically evaluate this possibility, 12 patients receiving oral L-dopa and α-methyldopa hydrazine (MK-486), a peripheral dopa decarboxylase inhibitor, were given pyridoxine daily for 5–10 days. This failed to increase the antiparkinsonian effect of L-dopa in all 12 patients. It also failed to reverse the L-dopa effect or alter any of the side effects. The failure of B₆ to reverse the dopa effect confirms the concept that B₆ reversal involves peripheral dopa decarboxylase. The failure of large amounts of B₆ to increase the L-dopa effect casts doubt on the concept that a Schiff base formed of L-dopa and B₆ is the specific antiparkinsonian agent mediating the effect of L-dopa.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

L-Dopa, B6, and α-Methyldopa Hydrazine

Klawans

Ringel²

1973

Stereotact Funct Neurosurg

View full text Add to dashboard Cite

show abstract

“…They do, however, permit the formulation of therapeutic protocols. It seems desirable, for example, to determine the therapeutic potential of nialamide in patients whose parkinsonism is suboptimally controlled even with the most recent improvement in the Ldopa treatment, a combination of L-dopa with a peripherally acting dopa decarboxylase inhibitor (31). This combination (Sinemet®, Merck Sharp & Dohme) curtails the synthesis of dopamine within peripheral tissues and has thus permitted the safe coadministration of a MAO inhibitor in the experimental animals hitherto studied (32).…”

Section: Discussionmentioning

confidence: 99%

Monoamine Oxidase and Cerebral Uptake of Dopaminergic Drugs

Cotzias¹,

Tang²,

Ginos³

1974

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The brain uptake of amines that do not enter the brain or enter it poorly was promoted by noncompetitive inhibitors of monoamine oxidase, as shown by behavioral and chemical criteria. Mice pretreated with water or enzyme inhibitors other than those mentioned were placid after receiving dopamine (3,4-dihydroxyphenethylamine). Mice pretreated with monoamine oxidase inhibitors (nialamide or iproniazid) showed upon treatment with dopamine the brisk motor responses characteristic of treatment with its precursor, L-dopa (3,4-dihydroxyphenylalanine). After receiving dopamine, intact nialamide-pretreated mice showed marked increases of brain dopamine, in contrast to water-pretreated test mice or water-treated controls. In unilaterally caudectomized, nialamide-pretreated mice, dopamine induced marked lateral curving of the body toward the lesion followed by running in that direction. Noradrenaline or adrenaline induced curving in caudectomized mice, whereas intact ones remained placid.These catecholamines are bound and inactivated by monoamine oxidase. The cerebral uptakes of chemicals that are bound but not inactivated by monoamine oxidase were thereafter tested. Nialamide induced increased behavioral responses to apomorphine and to N-propyl noraporphine, increased cerebral concentrations of both, and a deep coloration of the brain from methylene blue (bound by monoamine oxidase) but not Evans blue (bound by albumin). Even large doses of nialamide, however, failed to affect the behavioral responses to oxotremorine, which has cholinergic rather than adrenergic or dopaminergic properties. Mitochondrial monoamine oxidase seems therefore to play a specific regulatory role in the transport of substances that it binds, either to inactivate or to release them.

show abstract

Injected Apomorphine and Orally Administered Levodopa in Parkinsonism

Düby¹,

Cotzias²,

Papavasiliou³

et al. 1972

Archives of Neurology

130

View full text Add to dashboard Cite

Among 31 patients with parkinsonism three investigations were performed by injecting apomorphine hydrochloride or placebo: (1) to 17 patients with or without orally administered levodopa, (2) to 14 patients receiving levodopa during episodes of tremor, hypokinesia or involuntary movements, and 3 to 10 patients three to 6 times a day for 2 to 43 days. With or without levodopa, apomorphine diminished tremor and rigidity. It decreased bradykinesia in patients receiving levodopa. The respective side effects were not additive: the "awakening effect", involuntary movements, and nausea induced by levodopa were antagonized by apomorphine, whereas the sedative effect and the nausea of apomorphine were antagonized by levodopa. The dichotomy between synergistic and antagonistic effects may be explained by the molecule of apomorphine, part of which resembles dopamine and the other resembles phenylethylamine, which can displace neurotransmitters from cellular sites. (27:474-480, 1972) Increased cerebral content of dopamine is assumed to explain the therapeutic effects of levodopa1 in parkinsonism2 and in chronic manganese poisoning,3 but this assumption cannot be proven by giving dopamine. Since dopamine is both a primary amine and a catechol, it is readily inactivated by both monoamine oxidase4 and catechol O-methyl transferase,1 and therefore it cannot enrich the brain after systemic administration. The weak tertiary catecholamine, apomorphine, must be less labile because tertiary amines are poor substrates for monoamine oxidase.4 Schwab et al5 showed that apomorphine injections can bring about short-lived but marked improvement of parkinsonism. Al¬ though we were unaware of this discovery we confirmed it in a double-blind study6 and so have others.7·8 Questions arose whether the symptoms of parkinsonism respond dif¬ ferently to injected apomorphine than to orally administered levodopa and whether improvement and side effects are increased or decreased when both drugs are adminis¬ tered together. Tests addressed to these questions are reported here. ProceduresPatients.-Thirty-one patients with parkin¬ sonism were studied as inpatients in a metabol¬ ic ward. They were injected subcutaneously with apomorphine (a) without orally adminis¬ tered levodopa (patients 1 to 11 and 26 to 31); (b) with orally administered levodopa (7 to 26); (c) both with and without orally adminis¬ tered levodopa (7-11 and 26). Seven patients (8, 10 to 13, 25, and 26) participated in more than one of three experiments detailed below and in the Tables.

show abstract

Levodopa in Parkinsonism: Potentiation of Central Effects with a Peripheral Inhibitor

Cited by 109 publications

References 22 publications

<i>L</i>-Dopa, B<sub>6</sub>, and <i>α</i>-Methyldopa Hydrazine

<i>L</i>-Dopa, B<sub>6</sub>, and <i>α</i>-Methyldopa Hydrazine

Monoamine Oxidase and Cerebral Uptake of Dopaminergic Drugs

Injected Apomorphine and Orally Administered Levodopa in Parkinsonism

Contact Info

Product

Resources

About