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D Deleu

Publications and source records attributed to D Deleu.

At least 55 records · Page 3Linked to original sources
PubMed1994

Simultaneous in vivo microdialysis in plasma and skeletal muscle: a study of the pharmacokinetic properties of levodopa by noncompartmental analysis.

This in vivo study compared the pharmacokinetics of intravenously (iv) administered levodopa (L-dopa) in plasma and skeletal muscle. For this purpose, a single iv dose of L-dopa (25 mg/kg) was given to an anesthetized beagle dog, and L-dopa as well as its O-methyl metabolite, 3-O-methyldopa (3-OMD), were monitored in plasma and skeletal muscle simultaneously by microdialysis. The plasma and muscle dialysates were continuously collected during a 3-h period after the iv administration of the drug. The pharmacokinetic variables were then compared in both tissues with noncompartmental modeling. The mean maximum concentration (Cmax) for L-dopa in plasma was 173.10 +/- 9.85 ng/mL, whereas in skeletal muscle extracellular fluid, it was 14.56 +/- 2.27 ng/mL. The area under the curve of concentration versus time from time zero to infinity (AUC0- > inf) values for L-dopa were 20 times higher in plasma compared with muscle. The difference in half-life between the two tissues probably indicated the large contribution of the distribution phase in either or both tissues over the 3-h time interval. Interestingly enough, the AUC0- > 3h values for 3-OMD were within the same range in both tissues. These data demonstrated that over a period of 3 h, no distribution equilibrium for L-dopa was reached over the two tissues. The very low L-dopa/3-OMD ratios suggested that, in contrast to L-dopa, 3-OMD is accumulating in skeletal muscle. Whether these findings have any implication for the therapeutic response to L-dopa in Parkinson's disease remains to be determined.

Animals↗
PubMed1993

The effect of carbidopa on the pharmacokinetics and metabolism of intravenously administered levodopa in blood plasma and skeletal muscle.

The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (L-dopa) in blood plasma and skeletal muscle extracellular fluid (ECF) has been studied by repeated measurements in one beagle dog. The administration of a single dose of L-dopa (25 mg/kg i.v.) without carbidopa pretreatment (controls) resulted in an increase in the concentrations of L-dopa and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle ECF dialysates. This effect was clearly potentiated for L-dopa in blood plasma (186% increase in AUC) and 3-OMD in skeletal muscle dialysates (108% increase in AUC) after pretreatment with carbidopa (100 mg/day). In addition, carbidopa prolonged the half-life of the elimination of L-dopa in blood plasma by 48% and in skeletal muscle ECF by 66% but did not influence its blood plasma distribution half-life (t 1/2 alpha = 0.17 h). The elimination half-life of L-dopa in the controls was higher in muscle (t 1/2 beta = 1.76 h) than in blood plasma (t 1/2 beta = 0.50 h). Carbidopa pretreatment resulted in a relatively small increase (29%) in the L-dopa content of skeletal muscle ECF as indicated by the AUC. The accumulation of 3-OMD in muscle dialysates, in contrast to that in plasma, was significantly enhanced after the administration of L-dopa following treatment with carbidopa. In the control experiments, dopamine (DA) was detectable only in the dialysates from muscle ECF.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Simultaneous monitoring of levodopa, dopamine and their metabolites in skeletal muscle and subcutaneous tissue in different pharmacological conditions using microdialysis.

Microdialysis, in combination with ion-pair reversed-phase liquid chromatography and electrochemical detection is described for the simultaneous determination of levodopa, dopamine, 3-O-methyldopa and 3,4-dihydroxyphenylacetic acid in the extracellular space of skeletal muscle and subcutaneous tissue in vivo in beagle dog. The relative recoveries in vitro for levodopa, dopamine, 3-O-methyldopa and 3,4-dihydroxyphenylacetic acid with a 16 mm probe at a flow rate of 5 microliters min-1 were 29.1, 25.1, 34.7 and 30.1%, respectively. This technique was then applied for three types of pharmacological experiments. In the first experiment L-dopa was administered without carbidopa pretreatment, in the second one, L-dopa was administered following carbidopa pretreatment, and in the last experiment, following pretreatment with both carbidopa and the catechol-O-methyltransferase inhibitor, OR-611. After the administration of levodopa without carbidopa pretreatment, all four compounds could be detected in dialysates from skeletal muscle, whereas dopamine and 3,4-dihydroxyphenylacetic acid were not found in dialysates from subcutaneous tissue. After the administration of levodopa following carbidopa pretreatment and following pretreatment with both carbidopa and OR-611 all compounds could be measured except for dopamine. This method enables the pharmacokinetics and metabolism of levodopa to be studied in subcutaneous tissue and skeletal muscle simultaneously.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

High-performance liquid chromatography with electrochemical detection for the determination of levodopa, catecholamines and their metabolites in rat brain dialysates.

A high-performance liquid chromatographic assay with electrochemical detection is described for the simultaneous determination of levodopa, 3-O-methyldopa, dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, noradrenaline, adrenaline, 3-methoxy-4-hydroxyphenylethylene glycol and 5-hydroxyindoleacetic acid in rat brain dialysates. Samples are obtained in vivo using the microdialysis technique. Microdialysis probes are placed in the brain area to be studied and neurochemicals are collected by perfusion of the probe with modified Ringer's solution. Direct injection of the dialysates allows rapid and reliable results to be obtained.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Levodopa.

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Dyskinesia, Drug-Induced↗
PubMed1992

Biotransformation of L-dopa in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study.

Microdialysis was used to study the biotransformation of L-DOPA in the striatum and substantia nigra of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. The animals were pretreated with carbidopa (50 mg/kg p.o.) for 5 days. They were anaesthetized, and microdialysis probes were implanted into the intact and denervated striatum and into the intact and lesioned substantia nigra. The biotransformation of L-DOPA (5 mg/kg i.p.) in these regions was investigated. These results were compared with those obtained after administration of a much higher dose of L-DOPA (100 mg/kg i.p.). Changes in extracellular L-DOPA, 3-O-methyldopa (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC with electrochemical detection. Although rats with a unilateral nigrostriatal lesion did not show rotational behaviour after 5 mg/kg L-DOPA, DA levels were increased significantly both in the intact and the denervated striatum and in the intact and the lesioned substantia nigra. This increase was most pronounced in the denervated striatum. At 100 mg/kg L-DOPA, the increases in extracellular dopamine in intact and denervated striatum were about twice as high as the increases observed at the lower dose. A similar increase was observed in the intact substantia nigra. However, in the lesioned substantia nigra there was a fourfold increase. L-DOPA, at both doses, was evenly distributed between the brain areas studied and the lesion had no effect on the uptake of the drug at the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Dorsolateral pontine hemorrhage producing pure sensory stroke.

Pure sensory stroke predominantly results from lacunar infarction in the posteroventral nucleus of the thalamus. We report the history of a young nonhypertensive male presenting with pure sensory stroke due to hemorrhage of a small arteriovenous malformation in the dorsolateral part of the pons. In contrast to the extent of the lesion, only minor degree of objective sensory loss was observed. Furthermore, our observation is unique in that it is the first presentation of this syndrome with that particular location.

Adult↗
PubMed1991

In vivo pharmacokinetics of levodopa and 3-O-methyldopa in muscle. A microdialysis study.

In the present study in vivo microdialysis sampling coupled to high-performance liquid chromatography with electrochemical detection, was used to study the pharmacokinetics of levodopa and 3-O-methyldopa in skeletal muscle in dog, after intravenous administration of levodopa. For comparison, the pharmacokinetic parameters of both compounds were simultaneously determined in plasma using blood collection. Muscle microdialysis samples and blood were continuously collected for 4 h after the administration of levodopa (25 mg/kg). Pharmacokinetic profiles of levodopa in plasma and muscle were different. The mean Tmax value of levodopa in plasma and muscle was 0.16 h and 1.0 h, respectively. The AUC0----inf for levodopa in plasma was nearly 18-fold higher in plasma than in muscle. The 3-O-methyldopa concentration increased very rapidly after the administration of levodopa, to reach a plateau after 2.5 h and 3 h in plasma and muscle, respectively. The AUC0----4 for 3-O-methyldopa was 3.6-fold higher in plasma than in muscle. The ratio levodopa/3-O-methyldopa, reflecting the metabolic rate of levodopa, was 3.5 times higher in plasma than in muscle, at the peak value of levodopa, and then rapidly declined to values lower than 1, one hour after administration of the drug. We compared our results with literature data from postmortem studies done in rat experiments. We concluded that levodopa is not accumulating in muscle as such, but is converted to 3-O-methyldopa probably before leaving the plasma compartment.

Animals↗
PubMed1991

Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa.

The clinical effects and pharmacokinetics of orally and intraduodenally administered levodopa, in four patients with Parkinson's disease have been compared. The patients had unpredictable fluctuations in motor function and episodic unresponsiveness to single doses of levodopa. The pharmacokinetic and clinical data of these patients were compared retrospectively with those of Parkinsonian patients with fluctuations in motor performance but with preserved clinical responses to single oral doses of levodopa. There was a threshold plasma concentration of levodopa associated with the "switch on or off" effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response. All the patients had delayed absorption of levodopa related to delayed and erratic gastric emptying, which contributed to the fluctuation in motor response. In contrast, the patients with fluctuating motor effects but a preserved clinical response after levodopa showed an absorption pattern comparable to that of four patients studied after duodenal delivery of levodopa. It is suggested that there is a subgroup of patients with fluctuating responses due mainly to altered peripheral pharmacokinetics of levodopa. The findings demonstrate the relevance of routine measurements of plasma levodopa in patients with Parkinson's disease in whom there are fluctuations in motor performance.

Administration, Oral↗
PubMed1991

Continuous intravenous monitoring of levodopa and 3-O-methyldopa by microdialysis and high-performance liquid chromatography with electrochemical detection.

Microdialysis, in association with ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection, was applied in vitro for the determination and quantification of levodopa and 3-O-methyldopa in blank spiked plasma and blood. The method presented gave accurate results; the calibration graphs for plasma were linear over the range of the expected values for both compounds. When using a dialysis probe with a membrane length of 1.6 cm at a 5 microliters min-1 perfusion speed, the recovery rate in plasma for levodopa was 30.1% and 68.5% for 3-O-methyldopa. However, less reproducible results were obtained for plasma levodopa levels in the range of 0.5 microliter ml-1 and lower. The microdialysis technique was subsequently successfully applied for the continuous intravenous monitoring of levodopa and 3-O-methyldopa in a levodopa-treated dogs.

Animals↗
PubMed1989

Vertical one-and-a-half syndrome. Supranuclear downgaze paralysis with monocular elevation palsy.

A patient with bilateral infarction in the mesodiencephalic region showed impairment of all downward rapid eye movements (including vestibulo-ocular movements) and foveal smooth pursuit (nondissociated downgaze paralysis) associated with monocular paralysis of elevation (vertical one-and-a-half syndrome). Bell's phenomenon and all types of horizontal eye movements were preserved. The lesions may have affected the efferent tracts of the rostral interstitial nucleus of the medial longitudinal fasciculus bilaterally and the premotor fibers to the contralateral superior rectus subnucleus and ipsilateral inferior oblique subnucleus, either before or after decussation in the posterior commissure.

Cerebral Infarction↗
PubMed1989

Clinical and pharmacokinetic evaluation of controlled-release levodopa/carbidopa (CR-4) in parkinsonian patients with severe motor fluctuations: a six month follow-up study.

The results of a six month open-label study comparing the efficacy of controlled-release levodopa-carbidopa (Sinemet CR-4 200 mg/50 mg) with standard levodopa/carbidopa (250 mg/25 mg) in 17 patients with idiopathic Parkinson's disease and severe response fluctuations, are reported. Major clinical benefits included; improvement of disability, reduction of the number of 'off' periods (predominantly end-of-dose hypokinesia) and a slight increase in 'on' time. No improvement was observed in two of our patients. Mean levodopa plasma levels were comparable between the two types of formulations during optimal treatment, however systemic bioavailability was significantly higher with CR-4. Delayed onset of antiparkinsonian effect of CR-4, resulting from an increase of Tmax for levodopa, was one of the major complaints and required additional small amounts of standard levodopa in three patients.

Adult↗