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Biomedical subjects

H Hall

Publications and source records attributed to H Hall.

At least 109 records · Page 6Linked to original sources
PubMed1993

[11C]NNC 687 and [11C]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investigation in monkey.

NNC 687 and NNC 756 [(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl- 8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine and (+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine] are two new potent dopamine D-1 receptor antagonists. [11C]NNC 687 and [11C]NNC 756 were both prepared by N-methylation of the corresponding desmethyl compounds with [11C]methyl iodide. The reactions were performed in acetone with subsequent normal-phase semi-preparative HPLC and resulting in 50-60% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min and a radiochemical purity higher than 99%. The specific radioactivity obtained at time of injection was about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 687 and [11C]NNC 756 binding in post-mortem human brain sections showed specific binding in the striatum, a region with high density of dopamine D-1 receptors. PET examination of the radioligands in a Cynomolgus monkey demonstrated accumulation of radioactivity predominantly in the striatum. The ratio between radioactivities in the striatum and the cerebellum was about 2 and 8 for [11C]NNC 687 and [11C]NNC 756 after 60 min. [11C]NNC 756 should have potential as PET ligand for examination of central dopamine D-1 receptors in man.

Alkylation↗
PubMed1993

Binding of [3H]SCH 39166 to human post mortem brain tissue.

The dopamine D1 antagonist SCH 39166 was labelled with tritium and used for in vitro binding and autoradiography using human post mortem brain tissue. Competition studies on tissue from human nucleus caudatus showed that SCH 23390 inhibited the binding of [3H]SCH 39166 biphasically. The non-specific binding of [3H]SCH 39166 in both nucleus caudatus and cerebellum was lower after the addition of SCH 23390 or SCH 39166 than after flupentixol (10 microM). Autoradiography showed specific [3H]SCH 39166 binding in the caudate nucleus and putamen in the brain sections. The binding of [3H]SCH 39166 in the medial part of the caudate nucleus was very dense and similar to that obtained with [3H]SCH 23390, which was used as a reference ligand. Dense binding of [3H]SCH 39166 was also found in cortical regions, and binding was also obtained in the cerebellum and in the hippocampus. Addition of flupentixol (10 microM) abolished some but not all the binding of [3H]SCH 39166. The binding of [3H]SCH 39166 to caudate and putamen was not totally abolished by the addition of excess SCH 23390, while excess SCH 39166 diminished the binding of [3H]SCH 23390 in all regions. The present study indicates that [3H]SCH 39166, similar to [3H]SCH 23390, binds to dopamine D1 receptors in the human brain. It is concluded that [3H]SCH 39166 has a slightly different binding pattern than [3H]SCH 23390, which can be due to labelling of one or two additional binding site(s) pharmacologically unrelated to dopamine D1 receptors.

Autoradiography↗
PubMed1993

Effects of remoxipride's metabolites on dopamine D2 receptors and receptor functions in the rat.

The main metabolites of remoxipride formed in rat and man were examined for their affinities for the [3H] SCH 23390-labelled DA D1 and [3H]-raclopride-labelled D2 receptors in rat striatal homogenates. In addition, their effectiveness in blocking postsynaptic DA receptor activity in vivo was measured by the use of several different test models in the male rat. Phenolic metabolites formed mainly in the rat retained (similar to remoxipride) their selectivity for the D2 receptor with very low affinities for the D1 receptor. The pyrrolidone metabolites formed mainly in man showed very low affinities for both the D1 and D2 receptors. The ability of the metabolites to block postsynaptic DA receptor activity in vivo correlated with their affinities for the D2 receptor. Among the metabolites tested, the phenolic compounds FLA 797 (-) and FLA 908 (-) were much more effective than remoxipride in inducing catalepsy, which is consistent with a higher affinity for [3H] raclopride labelled striatal D2 receptors. However, analysis of the effectiveness of the DA receptor blockade (blockade of d-amphetamine locomotion or DA agonist hypothermia) after intraperitoneal or subcutaneous administration suggested that FLA 797 (-)/FLA 908 (-) may only contribute marginally to the D2 receptor-blocking activity of remoxipride in the rat. This conclusion was further supported by the observation that the atypical antipsychotic profile of remoxipride was not mimicked by the active metabolites. The weak DA D2 blocking effect of the pyrrolidone metabolites indicated that remoxipride is responsible for the clinical action.

Amphetamine↗
PubMed1993

Intra-articular fractures of the calcaneus. A critical analysis of results and prognostic factors.

Forty-four patients who had had fifty-two calcaneal fractures were managed with open reduction and internal fixation. The results were reviewed retrospectively, between four and fourteen years after the operation, with use of an evaluation system for the hindfoot and with plain radiographs. The characteristics of the patients that were associated with an unsatisfactory outcome were an age of more than fifty years, a greater body weight, work involving strenuous labor, and increased time missed from work due to the injury. Other prognostic variables associated with an unsatisfactory result included subtalar incongruity, osteoarthrosis of the talonavicular joint and the ankle, an increased heel width, a decreased fibulocalcaneal space, and a decreased Böhler-angle ratio of the fractured to the normal side. The heel height, fat-pad height, arch angle, talocalcaneal angle, and length of the Achilles-tendon fulcrum were not related to the outcome. Patients who had had a tongue-type fracture had a better result than those who had had a central depression fracture, while those who had had a central depression fracture had a better outcome than those who had had a comminuted fracture. Comminution of tongue and large central-depression fractures was associated with a worse prognosis. The most common most painful area in the patients who had a satisfactory outcome was the lateral aspect of the hindfoot, while in those who had an unsatisfactory result, it was the heel pad.

Absenteeism↗
PubMed1993

The impact of relaxation/imagery on high level noise exposure: a pilot study.

In this study the detrimental impact of high level noise on temporary threshold shift (TTS) (i.e., hearing loss), was reduced when subjects were given suggestions of imaginary ear muffs attenuating the amplitude and aversive aspects of the noise. This effect was small, however, and only apparent when subjects' responses to noise under a relaxation/imagery (self-regulation) condition was compared to exposure while working on crossword puzzles. The subject's level of hypnotic susceptibility was not related to the outcome. Implications of these findings were discussed.

Adult↗
PubMed1992

Gpp(NH)p stimulates [3H]raclopride binding to homogenates from human putamen and accumbens.

The effects of the stable GTP analogue Gpp(NH)p (5'-guanylyl imido diphosphate) were examined on in vitro [3H]raclopride binding to dopamine D2 receptors in preparations from post mortem human brains. The estimated number of receptors in the brain was 29% and 38% higher in putamen and accumbens, respectively, when determined in the presence of Gpp(NH)p as compared to its absence. The interaction of agonists was biphasic confirming the two affinity state model of the receptor--G-protein complex. The addition of Gpp(NH)p to the assay abolished the two site competition of apomorphine with [3H]raclopride binding in both regions studied. The non-specific binding at high concentrations of apomorphine was not significantly affected by the addition of Gpp(NH)p, indicating that only the specific binding of [3H]raclopride to the dopamine D2 receptor is increased.

Apomorphine↗
PubMed1992

[11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding. Preparation, autoradiography and positron emission tomography.

Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with 11C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [11C]Ro 15-4513 was 30-40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [11C]Ro 15-4513 bound specifically predominantly in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent alpha 6-containing BZ receptors. PET examination of [11C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [11C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.

Animals↗
PubMed1992

Effect of raclopride on dopamine D2 receptor mRNA expression in rat brain.

Prolonged treatment with dopamine D2 receptor antagonists is known to elevate the density of dopamine D2 receptor binding sites in caudate-putamen and nucleus accumbens in rat and human brain. In this study we used the dopamine D2 receptor antagonist raclopride (3 mumol/kg, s.c.) to determine if a single injection or daily administration of this drug for up to 18 days changed the expression of dopamine D2 receptor mRNA in rat caudate-putamen and accumbens as measured by in situ hybridization. A single injection of raclopride did not significantly change the numerical density of dopamine D2 receptor mRNA-expressing neurons in any of the regions examined. A daily administration of raclopride for 18 days resulted in a 31% increase in the number of cells expressing detectable amounts of dopamine D2 receptor mRNA in dorsolateral caudate-putamen and in a 20% increase in the area of silver grains over individual hybridization-positive neurons in this brain region measured on emulsion-dipped slides. The region-specific increase in the D2 receptor mRNA level in dorsolateral caudate-putamen was confirmed by measurement of the hybridization signal on X-ray film autoradiograms. The levels of D2 receptor mRNA remained unchanged in medial caudate-putamen and accumbens after 18 days' treatment. The region-selective increase in dopamine D2 receptor mRNA expression in dorsolateral caudate-putamen indicates a differential regulation of dopamine D2 receptor mRNA expression in a subpopulation of caudate-putamen neurons by this neuroleptic. We suggest that the increase in dopamine D2 receptor density in caudate-putamen known to follow prolonged dopamine D2 receptor blockade to some extent is regulated at the level of gene expression.

Analysis of Variance↗
PubMed1992

Saturation analysis in receptor binding assays: an evaluation of six different calculation techniques.

Randomized errors to varying extents have been introduced in a constructed data set stimulating receptor binding saturation analyses. The parameters Bmax and Kd were then determined using six different evaluation techniques, four linear and two non-linear. It is concluded that a non-linear evaluation gives more reliable results, especially when errors are large. Furthermore, an inevitable correlation between Bmax and Kd regardless of evaluation technique results in possible misinterpretations of simultaneous changes in both parameters.

Computer Simulation↗
PubMed1992

Positron emission tomography--examination of chemical transmission in the living human brain. Development of radioligands.

The imaging technique Positron Emission Tomography (PET) allows examination of chemical neurotransmission in brain. Of key importance for PET-research on neuroreceptors is the development of suitable radiolabelled tracers (ligands). This paper illustrates the multidisciplinary research activities necessary for ligand development. The selective D1- and D2-dopamine receptor antagonists SCH 23390 and raclopride (CAS 84225-95-6), respectively, were labelled with [3H] and characterized in biochemical studies in vitro on human brain homogenates and in autoradiographic studies on cryosections from human hemispheres. The experimental information was used to interpret and support the PET-findings with [11C]-labelled SCH 23390 and raclopride in vivo in humans. In conclusion, these ligands can be used to quantitatively examine dopamine receptors in the human basal ganglia in vivo. An applied study for PET-determination of D1- and D2-dopamine receptor occupancy during antipsychotic drug treatment indicates that the D2-dopamine receptor and possibly also the D1-dopamine receptor are targets for neuroleptic drug action.

Autoradiography↗
PubMed1992

Self-regulation and assessment approaches for vaso-occlusive pain management for pediatric sickle cell anemia patients.

An interdisciplinary program with the goal of teaching self-regulation and minimizing excessive narcotic use in the management of vaso-occlusive pain (V-O) in pediatric sickle cell anemia patients is described. A small group of patients do not respond well to any of our outpatients or inpatients medical regimens, leading us to suspect that psychological factors are influencing pain reports. We outline our multi-faceted assessment approach to evaluating such psychological factors, which includes a pain flow sheet, symptom check list, and a psychophysiologic profile. Published reports of self-regulation training including biofeedback, relaxation/imagery, and hypnosis have been associated with decreased pain symptoms, reduced number of emergency room and hospital visits for pain, decreased narcotic use, and increased school attendance. A case study of a nine-year-old patient with sickle cell disease is described before and after self-regulation training. Finally, other alternative approaches that avoid excessive narcotic use are discussed with some case reports.

Adaptation, Psychological↗
PubMed1991

Synthesis and binding properties of the fluorinated substituted benzamide [3H]NCQ 115, a new selective dopamine D2 receptor ligand.

[3H]NCQ 115 [R)-5-bromo-2,3-dimethoxy-N-[1-([2,5-3H]-4- fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide) was prepared by acylation of (R)-(2-aminomethyl)-1- ([2,5-3H]-4-fluorobenzyl)pyrrolidine, which was obtained in a stereo-conservative synthesis from (R)-prolinamide. Purification by reversed phase high performance liquid chromatography (HPLC) gave [3H]NCQ 115 with a radiochemical purity of greater than 99% and a specific activity of 0.97 GBq/mumol (36 Ci/mmol). Saturation analyses, association and dissociation kinetics as well as binding competition with several compounds of various classes were performed with [3H]NCQ 115 in rat striatal homogenates. Saturation analyses in vitro showed that [3H]NCQ 115 bound to a single binding site with a Kd = 214 pM and Bmax = 35.4 fmol/mg. The binding of [3H]NCQ 115 was dependent upon sodium ions, since the number of binding sites was altered when sodium ions were excluded from the incubation medium. NCQ 115 inhibited the binding of [3H]raclopride to dopamine D2 receptors with high affinity (Ki = 147 pM), having much lower affinity for other receptors. The affinity of this substituted 1-benzyl-2-pyrrolidinylmethyl benzamide was confined to the (R)-enantiomer, which contrasts with that of the corresponding N-ethyl derivatives such as FLB 457, raclopride, eticlopride, sulpiride and NCQ 298, where the pharmacological activity is found in the (S)-enantiomer. It can be concluded that [3H]NCQ 115 binds to dopamine D2 receptors in the rat striatum with high affinity and high selectivity. [3H]NCQ 115 can also be used for in vivo binding studies of the brain. [18F]NCQ 115 may be a suitable ligand for positron emission tomography (PET) studies of the human brain in vivo.

Animals↗
PubMed1991

NCQ 298, a new selective iodinated salicylamide ligand for the labelling of dopamine D2 receptors.

NCQ 298 ((S)-3-iodo-N-[(l-ethyl-2-pyrrolidinyl)methyl]-5,6- dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with 123I and 125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys. [125I]NCQ 298 bound in vitro to a single binding site with a KD = 19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D2 receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [125I]NCQ 298 was entirely reversible (T1/2 = 17.5 min at 37 degrees C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [125I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D2 receptor antagonist raclopride. In SPECT studies with [123I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclo-pride to one of the monkeys there was a substantial decrease in striatal radioactivity. [125I]NCQ 298 is a suitable ligand for the labelling of dopamine D2 receptors in vitro and in vivo. The specific properties of [123I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D2 receptors in man.

Animals↗
PubMed1991

11C-SCH 39166, a selective ligand for visualization of dopamine-D1 receptor binding in the monkey brain using PET.

The new selective D1-dopamine receptor antagonist SCH 39166 was labelled with the positron emitting isotope 11C and used as ligand for visualization of dopamine-D1 receptor binding in Cynomolgus monkeys by PET. After intravenous administration of the ligand a marked uptake of radioactivity was recorded in the D1-dopamine receptor-rich striatum and neocortex but not in the dopamine receptor-poor cerebellum. The uptake of radioactivity in striatum and neocortex was markedly displaced after the intravenous injection of a high dose of the D1-dopamine receptor antagonist SCH 23390 but not after the 5-HT2 receptor antagonist ketanserine. 11C-SCH 39166 should be a useful tool to explore D1-dopamine receptor characteristics in the living human brain by PET.

Animals↗
PubMed1991

A comparative PET-study of five carbon-11 or fluorine-18 labelled salicylamides. Preparation and in vitro dopamine D-2 receptor binding.

Five 11C- or 18F-labelled salicylamides ([11C]raclopride (I), [11C]eticlopride (II), [18F]NCQ 258 (III), [18F]NCQ 134 (IV) and [18F]NCQ 135 (V] were prepared. The total radiochemical yields of I-V from EOB were 3-30% (decay-corrected) with an overall synthesis time of 40-110 min. All compounds were isolated by semi-preparative HPLC and the radiochemical purity was greater than 99%. I-V were in separate experiments injected into Cynomolgus monkeys for PET-examination of ligand distribution in brain in vivo. I-V passed rapidly across the blood-brain barrier. With both analogs I and II there was a high uptake in the striatum, a region with a high density of dopamine D-2 receptors. With the 18F-labelled analogs III and IV, the uptake in the striatum was almost identical to that in the dopamine receptor poor cerebellum whereas the striatal uptake of V was clearly higher than in the cerebellum. Unlabelled I-V (raclopride, eticlopride, NCQ 258 (VII), NCQ 134 (VIII) and NCQ 135 (IX)) were also prepared and examined in vitro using [3H]raclopride and [3H]spiperone binding to rat striatal dopamine D-2 receptors. A significantly lower affinity was shown for NCQ 258 and NCQ 134 (5 times) compared to that of raclopride and eticlopride, respectively, whereas the affinity of NCQ 135 was similar to that of eticlopride.

Animals↗