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J Bergman

Publications and source records attributed to J Bergman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity.

[18F]Bromofluoromethane was synthesised from dibromomethane by substitution of bromine with [18F]fluoride. The synthesis and separation of the [18F]bromofluoromethane were automated. [18F]Bromofluoromethane was used to convert a phenolic and a thiophenolic precursor into a labelled ether and thioether, respectively. The specific radioactivity of these labelled products was determined with both high-performance liquid chromatography (with UV-absorbance detection) and liquid chromatography (with mass spectrometric detection). The median for the specific radioactivity, corrected at the end of radionuclide production, was 934GBq/micromol (range 40-9900 GBq/micromol; n = 83).

Automation↗
PubMed2001

Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter.

The present study describes the synthesis of the [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) as a new potential tracer for the serotonin transporter. In vitro binding studies have shown that FMe-McN displays only slightly lower affinity for the serotonin transporter (K(i) = 2.3 +/- 0.1 nM) than (+)-McN5652 (K(i) = 0.72 +/- 0.2 nM). The radiofluorinated tracer [18F]FMe-McN was prepared by reaction of normethyl (+)-McN5652 with the fluoromethylation agent [18F]bromofluoromethane in an overall radiochemical yield of 5 +/- 1% (decay-corrected, related to [18F]fluoride) and with high specific radioactivity (200-2,000 GBq/micromol at the end of synthesis).

Animals↗
PubMed2001

Tacrolimus clinical studies for atopic dermatitis and other conditions.

The first topical immunomodulator approved for human use, tacrolimus ointment (Protopic, Fujisawa, Healthcare, Inc, Deerfield, IL), has been shown to be effective and safe in the treatment of children (aged 2 years and older) and adults with atopic dermatitis (AD). Clinical trials conducted worldwide have involved 12,000 patients, with safety and efficacy data available for up to 3 years of treatment. In addition to its beneficial effects in the management of AD, topical tacrolimus has also been reported to be of benefit in other immunologically mediated skin diseases including: hand dermatitis, contact dermatitis, eyelid dermatitis, erosive lichen planus, steroid-induced rosacea, pyoderma gangrenosum, and graft-versus-host disease. This article reviews the clinical experience of topical tacrolimus in the treatment of AD and other skin conditions.

Administration, Cutaneous↗
PubMed2001

Increased frontal [(18)F]fluorodopa uptake in early Parkinson's disease: sex differences in the prefrontal cortex.

Previous imaging studies in Parkinson's disease have focused mainly on the striatum, a region with very high dopaminergic activity. Using modern high-sensitivity 3D [(18)F]fluorodopa (Fdopa)-PET, mesocortical monoamine projections can be studied. To study the frontal monoaminergic system in unmedicated early Parkinson's disease in vivo, we examined 20 early Parkinson's disease patients (10 women, 10 men) and 16 healthy subjects (nine women, seven men) with 3D Fdopa-PET, using standard region-of-interest-based analysis with MRI co-registration. Women with Parkinson's disease had 87% higher Fdopa uptake in the right dorsolateral prefrontal cortex (area 46) compared with men with Parkinson's disease, whereas there was no sex difference in the control group (sex x disease interaction, P = 0.03). The uptake in the right dorsolateral prefrontal cortex was 82% higher in men with Parkinson's disease and 219% higher in women with Parkinson's disease compared with control groups (effect of disease, P < 0.0001). Also in the left dorsolateral prefrontal cortex and in the medial frontal cortex, early Parkinson's disease patients had significantly (18-94%) higher Fdopa uptake compared with healthy controls. In the putamen, both men and women with Parkinson's disease had a significantly lower (27-46%) uptake compared with healthy controls. These results indicate that frontal monoaminergic activity is increased and that there is a sex difference in the prefrontal monoaminergic system in early Parkinson's disease. The reported sex difference may be linked to clinical sex differences in the symptoms and treatment response in Parkinson's disease.

Aged↗
PubMed2001

Enadoline discrimination in squirrel monkeys: effects of opioid agonists and antagonists.

Squirrel monkeys were trained to discriminate i.m. injections of the kappa-opioid receptor agonist enadoline (0.0017 mg/kg) from saline in a two-lever drug-discrimination procedure. Enadoline produced a reliable discriminative stimulus that was reproduced by the kappa-selective agonists PD 117302, U 50,488, GR 89686A, (-)-spiradoline, ICI 204448, and EMD 61753, and by the mixed-action kappa/mu-agonists bremazocine and ethylketocyclazocine. The discriminative stimulus effects of enadoline were not reproduced by the mu-selective agonist morphine, the delta-selective agonist BW373U86, the mixed-action opioids nalbuphine and nalorphine, or by the less active enantiomers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respectively. The selective mu-opioid antagonist beta-funaltrexamine (10.0 mg/kg) did not appreciably alter the dose-effect function for enadoline in any subject. However, the nonselective and kappa-selective opioid antagonists quadazocine (0.03-3.0 mg/kg) and nor-BNI (3-10 mg/kg), and the mixed-action opioid nalbuphine (0.3-30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were long-lasting and did not distinguish between drugs purported to act at different kappa-receptor subtypes. The present results bolster the view that common discriminative stimulus effects of enadoline and other opioids are mediated by kappa-agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine support the idea that it acts with low efficacy at kappa-opioid receptors.

Animals↗
PubMed2001

Pharmacokinetics of [18F]FETNIM: a potential marker for PET.

UNLABELLED: 18F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [18F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied. METHODS: Radio-thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene-induced rat mammary carcinoma. Biodistribution of [18F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection. RESULTS: Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [18F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation-3%-70%-in the radioactivity represented by unchanged [18F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [18F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of 18F. The tumor-to-blood ratio reached a maximum of 1.80 +/- 0.64 at 2 h. CONCLUSION: We conclude that [18F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.

Animals↗
PubMed2001

Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET.

UNLABELLED: Hypoxia is a characteristic feature of malignant tumors that should be evaluated before the start of therapy. (18)F-labeled fluoroerythronitroimidazole (FETNIM) is a possible candidate for imaging tumor hypoxia with PET. Quantitative analysis of [(18)F]FETNIM uptake in vivo is necessary before proceeding to assays predicting hypoxia. METHODS: Eight patients with untreated head and neck squamous cell carcinoma were enrolled in the study. All patients underwent dynamic PET imaging with [(18)F]FETNIM, coupled with measurements of blood flow with [(15)O]H(2)O and blood volume with [(15)O]CO. The metabolically active tumor volume was determined from [(18)F]FDG PET performed on a separate day. [(18)F]FETNIM uptake in the tumor was correlated with that in neck muscles and arterial plasma and compared with the findings of other PET studies. RESULTS: Blood flow in tumor was 5- to 30-fold greater than in muscle, in contrast to blood volume, which did not significantly differ in the 2 tissues. With [(18)F]FETNIM PET, muscle activity remained invariably less than plasma activity, whereas activity in whole tumors was always greater than that in muscle. In 4 instances, the maximum tumor uptake of [(18)F]FETNIM was 1.2-2.0 times higher than plasma activity in the late dynamic phase. A kinetic model developed for calculation of distribution volume of reversibly trapping tracers was successfully applied in the [(18)F]FETNIM studies. Tumor distribution volume correlated strongly with the standardized uptake value of [(18)F]FETNIM between 60 and 120 min and with blood flow but not with the standardized uptake value of [(18)F]FDG. The relationship between [(18)F]FETNIM uptake and the blood flow of the tumor was less obvious on a pixel-by-pixel level. CONCLUSION: Uptake of [(18)F]FETNIM in head and neck cancer is highly variable and seems to be governed by blood flow at least in the early phase of tissue accumulation. Maximum tumor-to-muscle tracer uptake ratios > 180 min were in the range of 1-4, comparing favorably with those reported previously for [(18)F]fluoromisonidazole. Assessment of the distribution volume of [(18)F]FETNIM after the initial blood-flow phase is feasible for subsequent evaluation of hypoxia-specific retention.

Aged↗
PubMed2000

Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites.

The metabolism of benzo[a]pyrene (BP) is known to lead to a large number of oxygenated compounds, some of which can bind covalently to DNA. We have studied the integrated metabolism of BP in vivo in germ-free rats given (14)C-labeled BP. Urinary metabolites were separated into groups according to acidity using lipophilic ion exchangers. The groups were analyzed by mass spectrometry and were further fractionated by high-performance liquid chromatography. The fraction of urinary metabolites previously shown to contain N-acetylcysteine and glucuronic acid conjugates was found to contain derivatives of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid as major components. These compounds, which were identified by mass spectrometry and NMR, accounted for about 30% of the total metabolites in urine, demonstrating that, surprisingly, ring opening is a major pathway for metabolism of BP in the germ-free rat. The dicarboxylic acid may be excreted in urine as an ester glucuronide. By using the single cell gel electrophoresis or COMET assay, we were able to demonstrate that the anhydride of 7-oxo-benz[d]anthracene-3, 4-dicarboxylic acid was an efficient inducer of DNA damage. Taken together, these results indicate that the novel ring opening metabolic pathway may provide alternative mechanisms for the toxicity of BP.

Animals↗
PubMed2000

An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome.

The authors investigated nine drug-naive patients with periodic limb movement disorder and restless legs syndrome (PLMD-RLS) and 27 healthy controls with PET using 6-[18F]fluoro-L-dopa (FDOPA). In the patients, the FDOPA uptake (Ki(occ)) in the caudate nucleus was 88% and in the putamen 89% of the control mean values. This equal affection of the caudate and the putamen differs, for example, from the dopaminergic dysfunction in Parkinson's disease, which affects the putamen earlier and more severely than the caudate. The current results indicate mild nigrostriatal presynaptic dopaminergic hypofunction in PLMD-RLS.

Adult↗
PubMed2000

Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study.

OBJECTIVE: To investigate the role of the brain dopaminergic system in cognitive impairment in patients with Parkinson disease (PD). DESIGN: We studied 28 patients with PD and 16 age-matched healthy control subjects using [18F] fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD showed a variable degree of cognitive impairment, which was assessed using the Mini-Mental State Examination and detailed neuropsychologic assessment, including tests sensitive for frontal lobe function. RESULTS: [18F] Fluorodopa uptake was reduced in the putamen (to 36% of the control mean; P<.001), the caudate nucleus (to 61% of the control mean; P<.001), and the frontal cortex (to 45% of the control mean; P<.001) in patients with PD compared with controls. There was no significant association between the degree of overall cognitive impairment of patients and [18F] fluorodopa uptake values. The influx constant (Ki(occ)) in the caudate nucleus had a negative association with performance in the attention-demanding Stroop interference task, especially with the interference time. The Ki(occ) in the frontal cortex had a positive correlation with performance in the digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus, the better the patient performed in tasks demanding immediate and working memory and executive strategies, the better the [18F] fluorodopa uptake in the frontal cortex. In the putamen, no significant correlation was seen between the Ki(occ) value and any of the cognitive tests. The severity of the motor symptoms of PD and [18F]fluorodopa uptake showed a negative correlation in the putamen (r = -0.38; P = .04), and in the caudate nucleus a similar trend was seen (r = -0.36; P = .06). CONCLUSIONS: Reduced [18F]fluorodopa uptake in PD in the caudate nucleus (and frontal cortex) is related to impairment in neuropsychologic tests measuring verbal fluency, working memory, and attentional functioning reflecting frontal lobe function. This indicates that dysfunction of the dopamine system has an impact on the cognitive impairment of patients with PD. However, our results do not exclude the possibility of more generalized cognitive impairment in PD, the pathophysiology of which is probably different and more generalized.

Aged↗
PubMed2000

Risk for Parkinson's disease: twin studies for the detection of asymptomatic subjects using [18F]6-fluorodopa PET.

Positron emission tomography (PET) studies were carried out with [18F]6-fluorodopa ([18F]6-FD) in monozygotic (MZ) and dizygotic (DZ) twins for the clarification of dopaminergic function. Four MZ and four DZ pairs of twins, each pair consisting of a parkinsonian index case and an asymptomatic co-twin, were collected from the Nationwide Twin Cohort. The control group comprised 14 healthy volunteers. [18F]6-FD PET examinations with a Siemens/CTI 931/08 scanner were performed dynamically over 90 min. The regions-of-interest analysis included the caudate, the putamen and the occipital reference regions. Patlak plots were calculated using occipital tissue input function. The accumulation of [18F]6-FD in the putamen of the asymptomatic co-twins was significantly lower than that in the normal subjects. This result implies that there may be a preclinical stage of Parkinson's disease in the apparently normal co-twins at the time of the PET study.

Analysis of Variance↗
PubMed2000

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands.

BACKGROUND: The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. OBJECTIVES: The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. EXPERIMENTAL DATA: The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of mu-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. CONCLUSIONS: Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.

Animals↗
PubMed2000

Effects of dopamine D1-like and D2-like agonists in rats trained to discriminate cocaine from saline: influence of experimental history.

Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Reproducibility and effect of levodopa on dopamine transporter function measurements: a [18F]CFT PET study.

The objective of this article was to study the reproducibility and effect of levodopa on dopamine transporter function measurements using 2beta-carbomethoxy-3beta-(4-[18F]fluorophenyl)tropane ([18F]CFT) positron emission tomography (PET). Seven de novo patients with Parkinson's disease (PD) were studied twice, before and after three months of levodopa medication. Eight healthy volunteer subjects participated in the reproducibility study. The [18F]CFT PET scan was done twice with an interval of approximately 2.5 months. The regions of interest (anterior and posterior putamen, caudate nucleus, and cerebellum) were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images, and copied onto the PET images. The [18F]CFT uptake was calculated as the region-cerebellum:cerebellum ratio at 180 to 210 minutes. Three-month levodopa treatment in PD patients had no significant effect on [18F]CFT uptake in any striatal subregion between the two PET scans. In PD patients, the percent change from baseline was 4.1% in the anterior putamen, 1.9% in the posterior putamen, and 4.0% in the caudate nucleus. No significant differences in [18F]CFT uptake between the first and second PET scan in any striatal subregion occurred in healthy controls. The intraclass correlation, indicating the reproducibility of the PET scan within subjects, was 0.94 for the anterior putamen, 0.86 for the posterior putamen, and 0.91 for the caudate nucleus. The percent change from baseline was 4.0% in the anterior putamen, 1.1% in the posterior putamen, and 2.8% in the caudate nucleus. Long-term levodopa treatment in PD patients had no effect on the [18F]CFT uptake in the striatum and the test-retest reproducibility was very high. These findings confirm [18F]CFT as a suitable ligand to monitor progression of PD.

Adult↗
PubMed2000

Parameters characterizing electromagnetic wave polarization

In this paper, generalizations of the Stokes parameters and alternative characterizations of three-dimensional (3D) time-varying electromagnetic fields is introduced. One of these characteristics is the normal of the polarization plane, which, in many cases of interest, is parallel (or antiparallel) to the direction of propagation. Others are the two spectral density Stokes parameters which describe spectral intensity and circular polarization. The analysis is based on the spectral density tensor. This tensor is expanded in a base composed of the generators of the SU(3) symmetry group, as given by Gell-Mann and Y. Ne'eman [The Eight-fold Way (Benjamin, New York, 1964)] and the coefficients of this expansion are identified as generalized spectral density polarization parameters. The generators have the advantage that they obey the same algebra as the Pauli spin matrices, which is the base for expanding the 2D spectral density tensor with the Stokes parameters as coefficients. The polarization parameters introduced are formulated in the frequency domain, thereby further generalizing the theory to allow for wide-band electromagnetic waves in contrast to the traditional quasi-monochromatic formulation.

Journal Article↗
PubMed2000

Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography.

OBJECTIVE: Recent in vivo imaging studies indicate a dysregulated presynaptic function of the striatal dopaminergic system in patients with schizophrenia. To further explore the basis of this phenomenon, the authors studied brain dopamine transporter binding in vivo in patients with first-episode, never-medicated schizophrenia. METHOD: Nine patients with schizophrenia and nine healthy matched comparison subjects were recruited. Striatal dopamine transporter binding was measured with positron emission tomography and a specific dopamine transporter ligand, [(18)F]CFT, a radiolabeled form of 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane. RESULTS: Average caudate and putamen dopamine transporter binding potentials were almost identical in the patients and comparison subjects, but the patients lacked the right-left asymmetry of the caudate dopamine transporter binding seen in the comparison group. CONCLUSIONS: Average striatal dopamine transporter density is unaltered in neuroleptic-naive patients with schizophrenia. However, patients lack asymmetry in caudate dopamine transporter binding, which conforms with disrupted brain lateralization in this disorder.

Adult↗
PubMed2000

Prediction of detached personality in healthy subjects by low dopamine transporter binding.

OBJECTIVE: Low striatal dopamine D(2) receptor binding in healthy human subjects has been associated with detached personality in studies using positron emission tomography (PET) and the Karolinska Scales of Personality questionnaire. The authors investigated whether a similar correlation exists between striatal dopamine transporter binding and detached personality. METHOD: Eighteen healthy volunteers participated in a PET study with the specific dopamine transporter ligand [(18)F]CFT ([(18)F]WIN 35,428) and completed the Karolinska Scales of Personality questionnaire form. RESULTS: Age-corrected dopamine transporter binding in the putamen, but not in the caudate, correlated negatively with detachment personality scores, especially in the right hemisphere. CONCLUSIONS: This finding supports the hypothesis that low dopaminergic neurotransmission is associated with detached personality. Furthermore, since [(18)F]CFT binding is thought to reflect the density of dopaminergic nerve terminals in the brain, the authors suggest that the neurodevelopmental formation of the brain dopaminergic system may influence adult personality traits.

Adult↗