The Pharmacology of Levodopa in Treatment of Parkinson’s Disease: An Update

LeWitt, Peter A.

doi:10.1007/978-3-642-73899-9_13

Cited by 27 publications

(27 citation statements)

References 375 publications

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“…Unfortunately, the percentage of the patients benefitting from levodopa is not much increased by the combination therapy. The same is true of the degree of improvement of symptoms (LeWitt 1989).…”

Section: Levodopa Plus Peripheral Inhibitors Of Dopa Decarboxylasementioning

confidence: 78%

“…Especially nausea, vomiting and arrhytmias are significantly reduced (cf. LeWitt 1989). Secondly, the effective maintenance dose of levodopa can be reached more quickly with the concomitant administration of a dopa decarboxylase inhibitor since there is no need to wait for development of tolerance to the peripheral dopamine effects (cf.…”

Section: Levodopa Plus Peripheral Inhibitors Of Dopa Decarboxylasementioning

confidence: 99%

“…Since 3-OMD -in contrast to levodopa -easily equilibrates between peripheral tissues and brain, its distribution is apparently only partially dependent on this transport system (cf. LeWitt 1989).…”

Section: -0-methyldopamentioning

confidence: 99%

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

Männistö

Kaakkola

1990

Pharmacology & Toxicology

162

104

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Section: Levodopa Plus Peripheral Inhibitors Of Dopa Decarboxylasementioning

confidence: 78%

Section: Levodopa Plus Peripheral Inhibitors Of Dopa Decarboxylasementioning

confidence: 99%

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

Männistö

Kaakkola

1990

Pharmacology & Toxicology

162

104

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“…The weak COMT inhibiting activity of carbidopa and/or DOPA in the peripheral tissues (Baldessarini, 1972;Kaakkola et al, 1991) would rather have the opposite effect (LeWitt, 1989).…”

Section: Discussionmentioning

confidence: 99%

Different in vivo properties of three new inhibitors of catechol O‐methyltransferase in the rat

Männistö

Tuomainen

Tuominen

1992

British J Pharmacology

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1 We compared three new catechol O-methyltransferase (COMT) inhibitors (OR-611, Ro 40-7592 and CGP 28014; 10 and 30mgkg-1, i.p.) in male rats given levodopa (L-DOPA, 50mgkg-1, i.p.) and carbidopa ((-)-L-x-methyl dopa, 50mg kg-1, i.p.). In some studies pretreatment with pargyline (80mg kg-1, i.p.) was used to block the function of monoamine oxidase (MAO). 2 Decreases of hypothalamic and striatal 3-O-methyl-dopa (3-OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3-methoxytyramine (3-MT; after pargyline) levels. 3 The three COMT inhibitors studied had different individual characteristics. OR-611 was primarily a peripherally acting COMT inhibitor, decreasing 3-OMD levels in the striatum (to 31-52%) and in the hypothalamus (to 16-27%) both in the control and pargyline-treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3-MT. 3 Ro 40-7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3-OMD (always to <30%), HVA (to <50%) and 3-MT levels (to <23%) significantly both at 1 and 3 h. It was more potent than OR-61 1. 4 CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3-OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3-MT levels at 1 h (to 37-22% and 42-35% in the striatum, and to 57-33% and 64-35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR-611 and Ro 40-7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.

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“…Several approaches benserazide and carbidopa have not yet been investigated in * This paper is dedicated to the memory of the late Professor Mosè detail. The influence of relatively high doses of carbidopa Da Prada (1934-1995 who for more than 30 years was engaged on the pharmacokinetics of levodopa has been described in research on levodopa and benserazide.…”

mentioning

confidence: 99%

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

Dingemanse¹,

Kleinbloesem²,

Zürcher

et al. 1997

Brit J Clinical Pharma

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Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple‐dose regimens. Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3‐O‐methyldopa (3‐OMD) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. Results Endogenous concentrations of levodopa and 3‐OMD increased dose‐dependently (from 8 up to 52 μg l−1 and from 0.02 up to 0.50 mg l−1, respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration‐time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l−1 h at benserazide doses of 100–200 mg three times daily. Benserazide caused a dose‐dependent increase in the AUC of 3‐OMD from 7.4 to 106 mg l−1 h at doses of 200 mg. Formation of DOPAC was dose‐dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. Conclusions The benserazide‐dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

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The Pharmacology of Levodopa in Treatment of Parkinson’s Disease: An Update

Cited by 27 publications

References 375 publications

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

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

Different in vivo properties of three new inhibitors of catechol O‐methyltransferase in the rat

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

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