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Biomedical subjects

G Ebinger

Publications and source records attributed to G Ebinger.

At least 37 records · Page 2Linked to original sources
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

In vitro and in vivo microdialysis calibration for the measurement of carbamazepine and its metabolites in rat brain tissue using the internal reference technique.

Microdialysis, as in vivo sampling technique, can be used for determining exogenous compounds in the extracellular fluid of freely moving animals and in humans. Usually, calibration of the microdialysis probe is determined by in vitro relative recovery (RR) (dialysate extraction fraction). However, due to different diffusion properties of the compound in tissue, the RR in vivo is different from the RR in vitro. In this study, the evaluation of the internal reference technique as in vivo calibration method was established. To determine the RR in vivo, the relative loss (RL) was defined as the loss of a compound from the perfusate. RL was determined in vitro and in vivo by adding an internal standard (IS) to the perfusate. This internal reference technique was applied for the determination of carbamazepine (CBZ) and its 2 major metabolites, carbamazepine-10,11-epoxide (CBZ-EPO) and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-DIOL) using 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide (m-CBZ) as IS. In vitro and in vivo, the loss of m-CBZ and the recovery of CBZ are identical. The ratios of the RR of CBZ-EPO and CBZ-DIOL to the RL of m-CBZ are constant, in vitro and in vivo. Therefore, m-CBZ can be used as IS for CBZ, CBZ-EPO and CBZ-DIOL determinations in brain tissue. It is shown that the internal reference technique is a useful method to estimate the true concentration of exogenous compounds in the extracellular space of tissues.

Animals↗
PubMed1993

Serotonin binding proteins in bovine retina: binding of serotonin and catecholamines.

Serotonin binding proteins (SBP) are present in the soluble fraction of bovine retina homogenates. These proteins can be precipitated with 30% ammonium sulphate and their binding and physicochemical characteristics are very similar to those of SBP in bovine and rat brain. Binding of [3H]serotonin to bovine retina SBP requires Fe2+ but not Fe3+. In the presence of an optimal concentration of Fe2+ (0.1 mM), these proteins behave as a single class of non-cooperative sites for [3H]serotonin (Bmax = 242 +/- 10 pmol/mg protein, KD = 0.22 +/- 0.44 microM). Competition binding studies reveal that serotonin analogs possessing an hydroxyl group on the indole ring and catecholamine analogs possessing an intact catechol moiety are potent competitors (K1 from 0.12 to 0.3 microM). In both cases, the affinity is strongly decreased if aromatic hydroxyl groups are methoxylated. Catecholamine SBP interactions can also be demonstrated directly by binding experiments with [3H]dopamine. Binding of this catecholamine is greatly enhanced by Fe2+, to a lesser extent by Cu2+ and Mn2+, but not by Fe3+. The Fe(2+)-dependent binding component is saturable (Bmax = 505 +/- 30 pmol/mg protein. KD = 0.34 +/- 0.04 microM). The SBP from bovine retina show the same physicochemical properties as SBP from bovine and rat brain: they elute immediately after the void volume on a Sephacryl S100 HR (1.6 x 140 cm) gel filtration column (reflecting aggregation) and they migrate with apparent molecular weights of respectively 43 kDa and 57 kDa on native polyacrylamide gel electrophoresis. The serotonin-storing role of SBP in serotonergic neurones has already been well documented.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonium Sulfate↗
PubMed1993

Soluble serotonin and catecholamine binding proteins in the bovine adrenal medulla.

The soluble serotonin-binding proteins (SBP) present in the adrenal medulla and in chromaffin cells, are very similar to those reported for the bovine brain and retina. Binding of [3H]serotonin and [3H]dopamine to these SBP is increased by Fe2+ but not by Fe3+. At an optimal concentration of Fe2+ (0.1 mM) these proteins behave as a single class of non-cooperative sites for [3H]serotonin (Bmax = 124 +/- 28 pmol/mg protein, KD = 0.51 +/- 0.13 microM) and [3H]dopamine (Bmax = 685 +/- 118 pmol/mg protein, KD = 0.46 +/- 0.06 microM). Binding of [3H]dopamine is also increased by Cu2+ and Mn2+, but to a lesser extent than by Fe2+. Catecholamines are good competitors for [3H]serotonin binding (Ki = 0.31 microM for dopamine, 0.6 microM for adrenaline and 0.9 microM for noradrenaline). The serotonin binding proteins from adrenal medulla elute in the void volume of a Sephacryl 100 HR gel filtration column, reflecting aggregation, and migrate mainly with an apparent molecular weight of 45 kDa in native polyacrylamide gel electrophoresis experiments. Subcellular localization studies and release experiments suggest that SBP are not present in chromaffin granules, but in the cytosol of purified chromaffin cells. The present data suggest that these proteins must have other functions than storing monoamines in synaptic vesicles.

Adrenal Medulla↗
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

Microbore liquid chromatography with dual electrochemical detection for the determination of serotonin and 5-hydroxyindoleacetic acid in rat brain dialysates.

A microbore liquid chromatographic assay with dual electrochemical detection is described for the determination of serotonin and its metabolite 5-hydroxyindoleacetic acid in rat brain dialysates. The concentration of serotonin in these samples is usually in the low nanomolar range (fmol per 20 microliters range). To optimize separation and detection, several adaptations were made to the system with respect to the injection valve, flow-rate of the pump, connections between injector, column and detector, and cell volume of the detector. These aspects are discussed, as well as the procedure developed for optimal peak identification of serotonin and correct estimation of 5-hydroxyindoleacetic acid. The assay allows the measurement of basal serotonin release without the use of a re-uptake inhibitor added to the perfusion fluid.

Animals↗
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

Serotonin-binding proteins in the bovine cerebral cortex: interaction with serotonin and catecholamines.

The soluble serotonin-binding proteins (SBP) present in bovine frontal cortex are very similar to those reported in rat brain. Binding of [3H]serotonin to SBP, present in ammonium sulphate-precipitated proteins from bovine cortex, requires Fe2+ but not Fe3+. In the presence of an optimal concentration of Fe2+ (0.1 mM), bovine SBP behave as a single class of non-cooperative sites for [3H]serotonin binding (Bmax = 120 +/- 12 pmol/mg protein, KD = 0.12 +/- 0.04 microM, n = 3). Binding of [3H]serotonin is decreased by nucleotides and by reagents which modify sulfhydryl groups and reduce disulfide bonds and by metal ion chelators. Serotonin analogs possessing an hydroxyl group on the indole ring and catecholamine analogs possessing an intact catechol moiety are effective competitors (Ki from 0.1 to 0.3 microM). In both cases, the aliphatic amino group does not contribute to the binding, but the affinity is strongly decreased if aromatic hydroxyl groups are methoxylated. Catecholamine-SBP interactions can also be demonstrated directly by binding experiments. Binding of [3H]dopamine is greatly enhanced by Fe2+, Cu2+ and Mn2+, but not by Fe3+. The Fe(2+)-dependent binding component of [3H]dopamine is saturable (Bmax = 279 +/- 64 pmol/mg protein, KD = 0.19 +/- 0.02 microM, n = 3), and possesses the same physicochemical properties as SBP: it elutes immediately after the void volume on a Sephacryl S100 HR (1.6 x 140 cm) gel filtration column (reflecting aggregation) and it migrates with an apparent molecular weight of 57-58 kDa on native polyacrylamide gel electrophoresis. Whereas the serotonin-storing role of SBP in serotonergic neurons has already been well documented, the present data advocate that these proteins may also possess catecholamine-storing properties.

Animals↗
PubMed1992

Idiopathic hemiparetic parkinsonism, a syndrome distinct from idiopathic parkinsonism.

Two women had a syndrome of progressive parkinsonism with ipsilateral rigidity, mild resting tremor, paresis, hyperreflexia, and an extensor plantar response. Symptoms had started 24 and 3 months after a surgical procedure in the affected limb. Neuroimaging studies were unhelpful. Both the parkinsonian features and the pyramidal tract signs responded well to dopaminergic drug treatment. We propose that the syndrome be called "idiopathic hemiparetic parkinsonism".

Adult↗
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↗
PubMed1991

Autoradiographic distribution of alpha 2 adrenoceptors, NAIBS, and 5-HT1A receptors in human brain using [3H]idazoxan and [3H]rauwolscine.

The regional distribution of [3H]idazoxan and [3H]rauwolscine was studied autoradiographically in human brain. [3H]Idazoxan binds with high affinity to alpha 2 adrenoceptors as well as to non-adrenergic sites (NAIBS). [3H]Rauwolscine, besides binding to alpha 2 adrenoceptors, also binds to 5-HT1A receptors. Both radioligands labelled the same population of alpha 2 adrenoceptors, defined as the epinephrine-displaceable binding component. The highest densities of alpha 2 adrenoceptors occur in the leptomeninges, cerebral cortex and claustrum; lower densities were visualised in the basal ganglia, thalamus, pons, substantia nigra, cerebellum and medulla oblongata; no alpha 2 adrenoceptors were detected in amygdala and nucleus ruber. NAIBS were present in all the examined brain areas, with the highest densities found in the basal ganglia and substantia nigra. The finding that certain brain regions, such as the amygdala, contained NAIBS but no detectable alpha 2 adrenoceptors, suggests that the binding sites are independent from each other. The regional distribution of 5-HT1A receptors labelled by [3H]rauwolscine is in agreement with previous studies using [3H]8-OH-DPAT.

Adult↗
PubMed1991

Central-nervous-system demyelination after immunisation with recombinant hepatitis B vaccine.

2 patients had neurological symptoms and signs, with evidence of central-nervous-system demyelination, 6 weeks after administration of recombinant hepatitis B vaccine. 1 had known multiple sclerosis but the other had no history of neurological disease; both had HLA haplotypes DR2 and B7, which are associated with multiple sclerosis. A causal link between vaccination and demyelination cannot be established from these 2 case-reports, but the time interval would fit a proposed immunological mechanism.

Adult↗
PubMed1991

Distribution of monoamines in human brain: evidence for neurochemical heterogeneity in subcortical as well as in cortical areas.

Norepinephrine, epinephrine, dopamine, serotonin and their major metabolites were measured by high-performance liquid chromatography with electrochemical detection in 49 regions of the human brain. The regional distribution of the different monoamines in the subcortical areas was similar to previous reports. We report here the distribution pattern of the 4 monoamines observed in the cerebral cortex. Regional differences in concentration were observed for norepinephrine, epinephrine and serotonin, with high concentrations in the frontal and parietal regions. However, no regional difference in dopamine concentrations was detected. The possible role of norepinephrine and serotonin as conventional transmitters, and of dopamine and epinephrine as neurotransmission modulators is discussed.

Aged↗
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↗