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Biomedical subjects

P Hartvig

Publications and source records attributed to P Hartvig.

At least 55 records · Page 3Linked to original sources
PubMed1996

Serotonin-2 and dopamine-1 binding components of clozapine in frontal cortex and striatum in the human brain visualized by positron emission tomography.

The specific binding of N-methyl-11C-clozapine in the human brain was studied in five healthy volunteers with positron emission tomography (PET). Four of the volunteers were reexamined after treatment with the dopamine D1 and D2 receptor antagonist flupenthixol, and all five volunteers were reexamined after pretreatment with the serotonin2 receptor antagonist ritanserin. The examinations after flupenthixol and ritanserin treatment were performed on different occasions. In the flupenthixol part of the study, two of the subjects were given an oral dose of 1 mg flupenthixol 2-3 h before the posttreatment study with PET. The other two subjects received 0.5 mg orally three times during the 24 h preceding the posttreatment PET study, with the last dose being administered < or = 4 h before the scan. All five ritanserin-treated subjects followed the same dosing regimen. During the 5 days preceding the posttreatment PET study, they were given a 10-mg tablet of ritanserin in the evening. The last dose was administered 2-1/2 hours before the study. Both flupenthixol and ritanserin pretreatment were associated with decreased binding of N-methyl-11C-clozapine in dorsolateral and medial frontal cortical regions. These results support previous findings that clozapine has affinity for both dopamine D1 and serotonin 5-HT2 receptors in the human frontal cortex. No consistent change of binding was observed in striatal regions following flupenthixol or ritanserin pretreatment. The clinical aspects of this feature are discussed, both with respect to efficacy and side effects.

Adult↗
PubMed1996

Analysis of L-[methyl-11C]methionine and metabolites in human plasma by an automated solid-phase extraction and a high-performance liquid chromatographic procedure.

A fully automated method for separation of L-[methyl-11C]Methionine from metabolites in patient plasma was developed. L-[methyl-11C]Methionine was isolated from plasma by solid-phase extraction (SPE). The radioactivity retained on the SPE column was eluted and injected onto the HPLC system for separation of in vivo formed L-[methyl-11C]methionine radiolabeled metabolites. The yield through the isolation procedure and HPLC analysis was greater than 95% with a precision better than 5% (R.S.D.). The calculated rate of L-[methyl-11C]methionine transport into tumor tissue was markedly different with and without compensation for radiolabeled metabolites in patient plasma.

Chromatography, High Pressure Liquid↗
PubMed1996

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin and infusion of L-tyrosine on the in vivo L-[beta-11C] DOPA disposition in the monkey brain.

The effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and L-tyrosine infusion on [11C]dopamine synthesis was analyzed in the striatum of Rhesus using positron emission tomography (PET). The rate for decarboxylation from L-[beta-11C]DOPA to [11C]dopamine was calculated using a graphical method with cerebellum as a reference region. Although the peripheral administration of 6R-BH4 at low dose (2 mg/kg) did not provide a significant increase in the rate of dopamine biosynthesis, a high dose of 6R-BH4 (20 mg/kg) induced an elevation of the rate. This 6R-BH4-induced elevation of the dopamine synthesis rate was further dose-dependently enhanced by the continuous infusion of L-tyrosine (0.2 and 1.0 mumol/min/kg). L-Tyrosine infusion with a rate of 1.0 mumol/min/kg caused an enhancement of the rate even during low dose administration of 6R-BH4 (2 mg/kg). L-Tyrosine infusion alone did not induce any elevation of the dopamine biosynthesis rate. The analysis of plasma indicated that the metabolic ratios of L-[beta-11C]DOPA to each metabolite were not affected by 6R-BH4 and/or L-tyrosine infusion. The results suggest that the low dose loading of tyrosine facilitates the activity of 6R-BH4 on the presynaptic dopamine biosynthesis, and also that the combined effects can be monitored by PET using L-[beta-11C]DOPA as a biochemical probe.

Animals↗
PubMed1996

Concentration-effect relationships of eltanolone given as a bolus dose or constant rate intravenous infusion to healthy male volunteers.

BACKGROUND: The primary purpose of this study was to evaluate concentration-effect relationships of the new steroid anesthetic eltanolone during recovery from a bolus dose and constant rate intravenous infusion in healthy male volunteers. METHODS: Ten subjects received a bolus dose of 0.75 mg/kg eltanolone over 20 s. A 2-h constant rate intravenous infusion of eltanolone was given to five subjects at a rate of 2 mg.kg-1.h-1 and to another five subjects at a rate of 3.5 mg.kg-1.h-1. Recovery performance was assessed as the time required to reach different end-points and by means of three different psychomotor tests. RESULTS: A low interindividual variability was found in the serum concentration of eltanolone at the pharmacodynamic end-points during recovery. The Cp50 value for "eye opening" was 382 micrograms/L (95% confidence interval, 285-489) after a bolus dose corresponding to a median time of 16 min (range 8-25). After eltanolone infusion, the Cp50 value for "eye opening" was 507 micrograms/L (95% confidence interval, 425-605) and the corresponding median time was 21 min (range 8-25) in the low-dose group and 49 min (range 31-66) in the high-dose group. The Cp50 values at the same effect end-points in the bolus group were less than those in the infusion groups, probably because of insufficient equilibration time between serum and the effect compartment. CONCLUSIONS: Recovery characteristics of eltanolone were predictable because of a relatively low interindividual variability in serum concentrations but with a slow blood:effect compartment equilibration.

Adolescent↗
PubMed1996

Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [11C]raclopride displacement and PET.

Changes in striatal binding of [11C]raclopride, a dopamine D2 receptor antagonist, induced by acute levodopa administration, were evaluated with PET in 10 patients with idiopathic Parkinson's disease (PD). The patients were scanned on two occasions: drug-free and 15 minutes after a 5-minute intravenous infusion of 3 mg/kg levodopa. Levodopa administration produced reductions in striatal [11C]raclopride uptake index with a rostrocaudal gradient. The most pronounced reduction was found in the posterior putamen (to 82% of baseline), followed by the anterior putamen (to 88% of baseline) and the caudate nucleus (to 94% of baseline). The magnitude of [11C]raclopride uptake index reduction correlated with drug-free disability. Moreover, in four hemiparkinsonian patients, a reduction in [11C]raclopride uptake index was measured in the putamen contralateral to the parkinsonian symptoms. The present results demonstrate a positive correlation between striatal dopaminergic nerve-terminal deficiency and the capacity for levodopa to increase synaptic dopamine and displace [11C]raclopride binding, which corresponds to an accelerated amine turnover in dopamine-depleted striatal tissue. We therefore suggest that dopaminergic degeneration in PD is paralleled by a progressive acceleration of amine turnover. This mechanistic consequence of nigrostriatal degeneration, the selective restoration of synaptic dopaminergic neurotransmission in denervated striatal subregions, may explain the effectiveness of levodopa in producing symptomatic benefits in early PD. However, we also suggest that in the vastly denervated striatum, as in advanced PD, an excessive acceleration of amine turnover results in swings in levodopa-induced synaptic dopamine levels that are far beyond normal. This phenomenon most likely plays a key role in the pathogenesis underlying the development of motor-response complications in PD.

Aged↗
PubMed1996

Excretion of ketobemidone in human breast milk.

The excretion of ketobemidone into human breast milk was investigated in three women who obtained ketobemidone as postoperative pain relief after Cesarean section and two women premedicated with 5 mg of ketobemidone before currettage after delivery. The highest observed concentration of ketobemidone in breast milk was 36 ng/ml three hours after administration, and 4-7 hours after administration the concentration was 3-5 fold that in maternal plasma. It could be estimated that the newborn will be exposed to less than 2 micrograms of ketobemidone during the first 24 hours.

Analgesics, Opioid↗
PubMed1995

Neurological Wilson's disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers.

Four patients with neurological Wilson's disease were investigated using magnetic resonance imaging (MRI) and positron emission tomography (PET). All patients had dystonia as their major clinical manifestation but also had dysarthria and at the presentation of the disease had choreoathetoid movements in at least one limb. A multitracer approach with PET was used to visualize various aspects of dopaminergic function; [11C]-(+)-nomifensine (NMF), [11C]raclopride (RAC) and [11C]-L-DOPA (one patient). Correlation analysis of RAC and NMF binding as well as putamen/caudate uptake ratios showed corresponding reductions. The patient investigated with [11C]-L-DOPA had a normal striatal uptake. Generally, structural changes as shown by MRI corresponded to reductions both in NMF and RAC binding. There was no evident correspondence between PET findings and the severity of clinical symptoms seen in the individual patient. In two patients with discrete neurological impairment at the time of investigation, PET showed serious presynaptic dopaminergic lesions in the putamen. Our data suggest that the striatal degeneration seen in Wilson's disease comprises a complex pathology involving both afferent and efferent projections. The discrete neurological impairment seen in some patients with gross striatal pathology might be due to concomitant lesions in functionally counteracting basal ganglia circuits.

Adult↗
PubMed1995

Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography.

The influence of the co-factor pyridoxine, vitamin B6, on the activity of aromatic amino acid decarboxylase enzyme was studied by positron emission tomography, PET in the brain of the Rhesus monkey using the precursor for serotonin synthesis 5-hydroxy-L-tryptophan (5-HTP) radiolabelled with 11C in the beta-position. The rate constant for the formation of serotonin in the corpus striatum was calculated using a two tissue compartment model with reference area in the brain. In baseline investigations, the mean rate constants (+/-S.D:) for selective utilization of [11C]5-HTP to form [11C]serotonin in the corpus striatum was 0.0080 +/- 0.0011 min(-1). Pretreatment with intravenous pyridoxine hydrochloride 10 mg/kg bodyweight before doing a second PET study resulted in an enhanced rate constant by a mean of 20%. The rate increase was statistically significant. The increase varied considerably in different monkeys from no effect to more than 60%. The effect of pyridoxine on aromatic amino acid decarboxylase activity supported a regulatory role of pyridoxine on the synthesis of neurotransmitter in vivo, and may be of importance in diseases with deficiencies in neurotransmitter function.

Animals↗
PubMed1995

Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers.

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.

Adult↗
PubMed1995

Liquid chromatographic analysis of brain homogenates and microdialysates for the quantification of L-[beta-11C]DOPA and its metabolites for the validation of positron emission tomography studies.

The clinical use of positron emission tomography, PET, with selected radiolabelled tracer molecules visualizing and quantitating physiological processes in the tissue relies in many situations on compartmental models for the interpretation of the radiosignal. Validation of such models must, therefore, include chromatographic analysis of the radioactivity composition of the signal. Rapid and sensitive liquid chromatographic methods amenable for automation for the analysis of [11C] labelled L-DOPA and its metabolites were therefore developed and validated for the quantitation of radioactivity composition in rat brain microdialysates as well as homogenates. Analysis included a simple isolation step, separation using reversed phase liquid chromatography with radiometric detection and permitted assay following tracer doses with an analysis time of 15 min. The analysis of radioactivity composition in the rat striatum showed that peripherally formed O-methyl L-DOPA constituted less than 20% of the radioactivity 40 min after injection of L-[beta-11C]DOPA. In the extracellular space the main component was [11C]-homovanillic acid which increased with time indicating rapid formation but slow elimination. The cumulation of radioactivity in the striatum corresponded to the radioactivity signal of dopamine and derived metabolites. The formation rate of dopamine in the rat corresponded closely to the utilization rate in the striatum of monkey and man measured with PET. This indicated that the rate constants measured with PET correlates well to the dopamine synthesis rate.

Animals↗
PubMed1995

An automated liquid chromatographic plasma analysis of amino acids used in combination with positron emission tomography (PET) for determination of in vivo plasma kinetics.

Quantification of physiological processes measured with positron emission tomography (PET) requires an "input" function which can be the concentration of administered radio-tracer in plasma. Radioactive nuclides used in PET have short half lives (2-20 min) and a limited time is available for the PET investigation including analysis of the composition of the radioactive signal in plasma. Therefore, an automated method for the analysis and separation of beta-[11C]-L-5-hydroxy-tryptophan ([11C]-L-5-HTP), beta-[11C]-L-3,4-dihydroxy-phenylalanine ([11C]-L-DOPA) and L-[methyl-11C]-methionine and their respective metabolites in plasma was developed. A size exclusion exclusion column was used for isolation of the low molecular weight fraction. In the case of [11C]-L-5-HTP and [11C]-L-DOPA, the low molecular weight fraction was injected onto a liquid chromatographic system for separation of radioactive tracer from in vivo formed radio-labelled metabolites. The elution volume from the size exclusion column was 7.0, 5.0 and 3.5 ml for [11C]-L-5-HTP, [11C]-L-DOPA and L-[methyl-11C]-methionine, respectively. An interaction with the column matrix and the solutes was observed for both [11C]-L-5-HTP and [11C]-L-DOPA. The yield in the isolation step was > 98%. Separation of [11C]-L-5-HTP and [11C]-L-DOPA from their respective metabolites was performed with high-performance liquid chromatography with automated collection of fractions of the eluate corresponding to those of administered tracer and metabolites. The fractions were measured for radioactivity in a well counter.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1995

CSF and plasma pharmacokinetics of the NMDA receptor antagonist CPP after intrathecal, extradural and i.v. administration in anaesthetized pigs.

The N-methyl-D-aspartate (NMDA) receptor complex plays a central role in the modulation of neuronal information in the central nervous system. This study was designed to examine the pharmacokinetics of the NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) in plasma and cerebrospinal fluid (CSF) and rostral spread in the CSF after lumbar intrathecal, extradural and i.v administration. Anaesthetized pigs were given a lumbar intrathecal, lumbar extradural or an i.v. injection of a mixture of [3H]-labelled and unlabelled CPP. CSF was sampled over 10 h through intrathecal catheters positioned at the L1, T5 and C1 vertebral levels. Blood samples were obtained over the same period. Haemodynamic and arterial blood-gas variables and acid-base balance were monitored during the study. The area under the radioactivity concentration-time curves showed a gradient between cervical and lumbar CSF radioactivity of about 1:2500 after intrathecal administration and about 1:140 after extradural administration, indicating that only small fractions of lumbar administered CPP spread rostrally. About 2% of an extradurally administered dose was found in the CSF. After i.v. administration of [3H]CPP, clearance was mean 122 (SEM 16) ml min-1 and the CSF: serum radioactivity gradient was approximately 1:4. The half-life of [3H]CPP varied little (mean range 94-191 min) irrespective of the route of administration or the level of sampling. Cervical radioactivity after lumbar intrathecal administration probably resulted from rostral transport via CSF bulk flow, whereas after extradural administration, systemic absorption and redistribution via the blood-brain barrier probably contributed.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗
PubMed1995

Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains--in vivo assessment using positron emission tomography.

A compartment model has been developed and validated for the kinetic analysis of (S)(-)11C-nicotine binding in the brain including a compensation for the influence of regional cerebral blood flow (rCBF). The model was applied to eight patients with Alzheimer disease (AD) and three age-matched healthy volunteers who received intravenous injections of (S)(-)11C-nicotine and 11C-butanol. The uptake and time course of radioactivity in different brain regions were assessed by positron emission tomography (PET). The rate constant k2* was formulated by dividing the K2 rate constant for 11C-nicotine with the K1 rate constant for 11C-butanol and thereby minimizing the influence of CBF on the quantitated binding of 11C-nicotine. The rate constant k2* for 11C-nicotine giving a quantitative measure of binding in the brain tissue was significantly higher in the temporal and frontal cortices as well as in the hippocampus of AD brains as compared with controls, indicating deficits in specific nicotinic binding in these brain areas of AD patients. A significant and negative correlation was obtained between cognitive function (Mini-Mental State Examination) and k2* of 11C-nicotine in the temporal and frontal cortices as well as in the hippocampus. The described kinetic model allowed in vivo quantification of nicotinic receptor binding in brain, which will be of importance in the future for evaluation of diagnosis, progress of disease, as well as the therapeutic effects in the treatment of AD.

Aged↗
PubMed1995

Long-term treatment of Wilson's disease with triethylene tetramine dihydrochloride (trientine).

Long-term treatment with triethylene tetramine dihydrochloride, (trientine, TETA) was evaluated in 19 patients with Wilson's disease (WD). Two were given the drug as first choice and 17 after treatment with penicillamine. The change was made because of side-effects, lack of improvement or worsening of neurological symptoms. All penicillamine-induced side-effects reverted. Thirteen patients still receive trientine, and the mean total observation time on this treatment is 8.5 years/patient. Seven of the 13 are free from symptoms related to WD, five have mild to moderate neurological symptoms, mainly dysarthria. One patient with neurological symptoms who received trientine from the start of treatment deteriorated rapidly and is now severely dystonic. The symptoms initially worsened and later improved in one patient. All other patients improved during trientine treatment. Three patients died: two from a multifocal cancer including the liver and one non-complier from a ruptured spleen. Two patients underwent liver transplantation for progressive liver failure: one non-complier and one with liver cirrhosis whose liver function deteriorated despite treatment; both are now free from symptoms. Unexpectedly, two patients developed a serious colitis, one with duodenitis as well, that improved after withdrawal of the drug. No other unfavourable effects of trientine were recorded.

Adolescent↗
PubMed1994

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the extracellular levels of dopamine and serotonin in the rat striatum: a microdialysis study with tyrosine or tryptophan infusion.

The present study demonstrates the effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) on turnover of dopamine and serotonin (5-HT) in rat striatum during continuous infusion of the amino acids tyrosine and tryptophan. By monitoring with microdialysis, it was found that the increase in dopamine and homovanillic acid (HVA) concentrations in rat striatal extracellular fluid (ECF) induced by 6R-BH4 was further enhanced by the continuous infusion of tyrosine at a relatively low dose (1 mumol/min/kg) as compared with the concentration which saturates tyrosine hydroxylation. This dose of tyrosine alone did not induce the elevation of dopamine and HVA concentrations in ECF. In contrast, though the concentration of 5-HT and 5-HIAA in striatal ECF was gradually increased by tryptophan infusion, 6R-BH4 had no further effect. Although the higher output of dopamine into ECF was induced by the dialytic perfusion of 6R-BH4 via the microdialysis probe into striatum, tyrosine infusion had no further effect on dopamine concentration in the dialysates. The in vivo measurement of DOPA accumulation during NSD 1015 perfusion suggests that the enhancement of dopamine concentration in ECF induced by tyrosine infusion and 6R-BH4 might be attributable to an increase in tyrosine hydroxylase activity in striatum. Tryptophan hydroxylase was also activated by tryptophan infusion and/or 6R-BH4, however, it did not induce an increase in 5-HT concentration in striatal ECF.

Amines↗
PubMed1994

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on in vivo L-[beta-11C]dopa turnover in the rat striatum with infusion of L-tyrosine.

L-[11C]DOPA, combined with positron emission tomography (PET), has made possible the assessment of dopamine turnover in vivo. Before the evaluation of PET study with L-[11C]DOPA in the primate, the effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and/or L-tyrosine infusion on L-[11C]DOPA turnover was analyzed in the rat striatal tissue and in the striatal extracellular fluid using microdialysis. L-[11C]DOPA was rapidly taken up into the brain after intravenous injection and converted to [11C]dopamine, [11C]DOPAC and [11C]HVA in the striatal tissue. Small amount of 3-O-methyl-[11C]DOPA, a product of DOPA by 3-O-methylation in peripheral tissues, was also detected in the striatal tissue. The striatum/cerebellum ratio of total radioactivity uptake was linear against time up to 40 min after L-[11C]DOPA injection. The uptake ratio, increased by 6R-BH4 administration, was further increased by L-tyrosine infusion. The in vivo microdialysis technique was further applied to determine L-[11C]DOPA and its metabolites in striatal extracellular fluid (ECF). The peripheral administration of 6R-BH4 (50 mg/kg) induced elevation of [11C]DOPA concentration in ECF in the early phase after injection, following higher radioactivity in [11C]dopamine and [11C]HVA fractions than those in control animals at late phase. The 6R-BH4-induced elevation of [11C]DOPA uptake and the radioactivity of its metabolites was further enhanced by the continuous infusion of L-tyrosine at a dose of 1.0 mumol/min/kg. L-Tyrosine infusion alone did not induce the elevation of radioactivity. The results suggest that [11C]DOPA might be a useful probe to evaluate the effect of 6R-BH4 and/or L-tyrosine loading in the primate.

Animals↗
PubMed1994

Brain kinetics of (R)- and (S)-[N-methyl-11C]ketamine in the rhesus monkey studied by positron emission tomography (PET).

The regional brain kinetics of the two enantiomers of the NMDA channel blocker ketamine radiolabelled with 11C was studied in the Rhesus monkey by means of positron emission tomography (PET). The uptake in brain areas which showed high radioactivities was blocked in a dose-dependent manner for both 11C-labelled enantiomers with simultaneous doses of the respective unlabelled (S)- or (R)-ketamine, indicating specific binding. The binding in the striatum and cortical areas of (S)-[N-methyl-11C]ketamine was selective and displaceable by the (R)-enantiomer and by MK-801.

Animals↗