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Biomedical subjects

C R Clark

Publications and source records attributed to C R Clark.

At least 145 records · Page 8Linked to original sources
PubMed1987

Catecholamines and attention. II: Pharmacological studies in normal humans.

Part I of this review [17] found evidence from animal and clinical studies of a role for catecholamines in the control of attention. This part of the review examines the results of a systematic study of the acute effects of a number of catecholamine active drugs on measures of attention in normal adults. The results are interpreted within the context of a general capacity model of information processing in which level of arousal determines the capacity to process stimulus information and level of activation the capacity for processing response demands. Whilst the dopamine antagonist, droperidol, and the alpha agonist, clonidine, had similar effects on behavioural indices of processing capacity and reports of the degree of effort required to carry out processing, they differentially affected subjective state and measures of activation and arousal. These differences provide some support for the hypothesis that central noradrenaline and dopamine modulate the capacity for early and late processing of information, respectively, in humans.

Adolescent↗
PubMed1987

Synthesis and binding affinities of analogues of cholecystokinin-(30-33) as probes for central nervous system cholecystokinin receptors.

CCK-30-33 has been identified as the minimum fragment of CCK with nanomolar affinity for the central CCK receptors, as assayed by displacement of [3H]-Boc-beta-alanyl-CCK-30-33 (pentagastrin) in homogenized mouse cerebral cortex. Examination of binding using this assay in the two series Boc-Trp-X-Phe-NH2 when X = Met-Asp (Boc-CCK-30-33), Gly-Asp, Met-Gly, and Gly-Gly and when X = (CH2)n (n = 0-4) reveals that modification of the tetrapeptide reduces affinity to a maximum of micromolar affinity (Boc-Trp-Gly-Asp-Phe-NH2; Ki = 2 X 10(-6) M), whereas in the series when n = 0 and 2 pentamolar affinity is still retained (Boc-Trp-Phe-NH2, Ki = 7 X 10(-5) M; Boc-Trp NH CH2-CH2-CO-Phe-NH2, Ki = 3 X 10(-5) M). Modification of the tetrapeptide CCK-30-33 reduces affinity 1000-fold, whereas di- and tripeptide fragments are identified that reduce affinity only a further 10-fold. This structure-activity relationship establishes a basis to design "peptoid" analogues of CCK that have therapeutic potential.

Amino Acid Sequence↗
PubMed1987

Synthesis and anticonvulsant activity of analogues of 4-amino-N-(1-phenylethyl)benzamide.

A group of amides and amines related to 4-amino-N-(1-phenylethyl)benzamide, 1, were prepared in a study on the relationship of structure to anticonvulsant activity in this compound. Acylation and alkylation of the amino group of 1 resulted in almost total loss of anticonvulsant activity. Insertion of a methylene between the 4-amino group and the aromatic ring of 1 produced a slight increase in anticonvulsant potency and a significant increase in toxicity. Hydride reduction of the amide carbonyl in 1 also yielded compounds having a slightly lower ED50 against convulsions induced by electroshock and a much lower TD50 in the rotorod assay. Modification of the 1-phenylethyl group of 1 also decreased anticonvulsant potency.

Animals↗
PubMed1987

Discovery and anticonvulsant activity of the potent metabolic inhibitor 4-amino-N-(2,6-dimethylphenyl)-3,5-dimethylbenzamide.

Compound 2 [4-amino-N-(2,6-dimethylphenyl)benzamide] is an effective anticonvulsant in several animal models. For example, following oral administration to mice, it antagonized maximal electroshock (MES) induced seizures with an ED50 of 1.7 mg/kg. During drug disposition studies with 2, we found that it was rapidly metabolized by N-acetylation. Thirty minutes after oral administration of 1.7 mg/kg of 2 to mice, plasma concentrations of parent drug and the N-acetyl metabolite 5 were 1.09 and 0.41 microgram/mL, respectively. Six hours postadministration the concentrations were 0.23 and 0.22 microgram/mL, respectively. In order to sterically preclude or diminish the rate of metabolic N-acetylation, we synthesized analogues of 2 possessing either one (3) or two (4) methyl groups ortho to the 4-amino substituent. Both compounds antagonized MES-induced seizures after administration to mice; oral ED50 values for 3 and 4 were 3.5 and 5.6 mg/kg, respectively. Compound 3 was rapidly metabolized by N-acetylation. However, 4 provided exceptionally high and long-lived plasma concentrations of parent drug; no N-acetyl metabolite could be detected. While 2 and 3 had no pharmacologically relevant effects on hexobarbital-induced sleeping time in mice, 4 was a potent, dose-dependent potentiator of sleeping time. Oral administration of 375 micrograms/kg led to a 61% increase in sleeping time relative to control values. Thus, 4 represents one of the most potent potentiators of hexobarbital-induced sleeping time described to date.

Acetylation↗
PubMed1987

Management of spine trauma and deformity: an orthopaedic perspective.

This presentation concerns orthopaedic surgery and discusses the present state of art and possible future developments pertaining to the management of injury of the spine and other deforming conditions. It briefly highlights some of the recent advances in the area of neuroradiographic evaluation, closed management and surgical management of traumatic and other deforming conditions of the spine.

Humans↗
PubMed1987

Liquid chromatographic determination of the enantiomeric composition of amphetamine prepared from norephedrine and norpseudoephedrine.

The stereochemical course of the synthesis of amphetamine from norephedrine and norpseudoephedrine is investigated using liquid chromatography. The results show that the chiral carbon common to both compounds remains unaffected during the reaction sequence. The presence of individual amphetamine enantiomers in the reaction products is determined by reversed-phase liquid chromatographic separation on an achiral stationary phase (C18) following precolumn derivatization with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The GITC derivatization procedure allows for the liquid chromatographic separation of the individual enantiomers of amphetamine, norephedrine, norpseudoephedrine, and the intermediate 1-chloro-1-phenyl-2-aminopropanes.

Amphetamine↗
PubMed1987

Liquid chromatographic optimization of reaction conditions for the synthesis of 2,2-dimethyl-N-benzylmalonamide, a new anticonvulsant.

Reversed-phase liquid chromatographic (RP/LC) procedures are used to optimize the reaction conditions for the large scale preparation of 2,2-dimethyl-N-benzylmalonamide, 1. In acute studies using mice and rats, compound 1 is a very effective anticonvulsant agent. Large quantities of 1 (ca. 300 g) are needed for detailed studies of its chronic effects. LC monitoring of the synthesis of intermediate products and 1 result in the optimum use of reagents, increased product yields, and decreased reaction times.

Anticonvulsants↗
PubMed1987

Liquid chromatographic determination of sulindac and metabolites in serum.

An improved liquid chromatographic procedure is described for the quantitative determination of sulindac, sulindac sulfone, and sulindac sulfide from serum. The procedure makes use of acetonitrile extraction of the compounds of interest from acidified serum samples. Under these conditions extraction efficiencies in the 85 percent range are obtained for each of the compounds. The liquid chromatographic separation of the compounds of interest and the internal standard (indomethacin) is accomplished in an isocratic elution procedure using a nitrile (CN) stationary phase. The HPLC separation procedure is completed in less than 10 minutes, giving excellent resolution and peak shape.

Biotransformation↗
PubMed1987

A technique to evaluate an internal spinal device by use of the Selspot system: an application to Luque closed loop.

A technique to study the effects of spinal injury and stabilization in terms of load-deformation behavior is described. Fresh human cadaveric ligamentous spine segments (T12-sacrum) were potted and clinically relevant loads applied through the loading frame attached to the topmost vertebra of the specimen. The resulting three-dimensional motion responses of each vertebra for the normal specimen were recorded with the Selspot II System. The specimen was injured at the L4-5 motion segment to represent a typical surgical decompression used in treating patients with spinal stenosis and tested again. The decompressed (or injured) motion segment was stabilized with a Luque closed-loop (Luque rectangle) system before repeating the test protocol. The data of these tests indicate that the injury (surgical decompression) at the L4-5 motion segment leads to a significant increase in motion--in flexion, extension, and axial modes--indicating the possible necessity for stabilization of the injured segment. The closed-loop system reduces the motion at the injured level, with respect to normal specimen behavior, by 35%. Therefore, the system does not provide complete immobilization (100% reduction with respect to normal specimen behavior). The stabilizing effects of the closed loop in lateral bending are not significant and are marginal in axial motion. The motion across the L3-4 motion segment in flexion increases significantly after stabilization. The clinical implications and the need for further studies are also discussed.

Adult↗
PubMed1987

Delineation of receptor-mediated colony-stimulating factor (CSF-1) utilization and cell production by precursors of mononuclear phagocytic series at various stages of differentiation.

Colony-stimulating factor-1 (CSF-1) is a specific haematopoietic growth factor that stimulates the production of macrophages by both bone marrow macrophage precursors (GM-CFC) and certain more mature peripheral tissue macrophages. The relationship of CSF-1 utilization and cell production by macrophage precursors at various stages of differentiation was studied. Bone marrow GM-CFC had the highest proliferative capacity followed by blood monocytes and peritoneal exudate macrophages (PEM) as determined by their cell doubling time (DT) which was also dependent on the concentrations of exogenous CSF-1. PEM had the longest initial lag period before commencing cell proliferation. Exogenous CSF-1 was constantly utilized by the growing cells; depletion of available CSF-1 resulted in growth arrest and, subsequently, cell death. The production of macrophage progeny, per amount of CSF-1, correlated with parent macrophage maturity; for each 100 U of CSF-1 consumed, bone marrow precursor cells and blood monocytes were capable of producing 17.9 x 10(4) and 13.4 x 10(4) progeny, respectively, whereas PEM generated only 4.6 x 10(4) daughter cells. Thus, the removal and destruction of CSF-1 by more mature, less proliferative tissue macrophages may provide a possible mechanism by which CSF-1 levels are reduced and the production of early haemopoietic macrophage precursors controlled.

Animals↗
PubMed1986

Pharmacokinetics of pralidoxime chloride in the rat.

The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.

Animals↗
PubMed1986

Measurement and characterization of neuronal cholecystokinin using a novel radioreceptor assay.

This study describes a novel radioreceptor assay (RRA) for cholecystokinin (CCK) which is the first to measure and characterize brain CCK using a technique not dependent on the generation of peptide antibodies. The CCK RRA utilizes the mouse cerebral cortex CCK receptor as the binding source and [125I]BH-CCK-8 as the radiolabelled probe. [125I]BH-CCK-8 bound to the central CCK receptor with a Kd of 1.82 nM and a Bmax of 1.21 pmol/g tissue. Unlabelled CCK-8 displaced the specific binding of [125I]BH-CCK-8 with an inhibition constant of 3.84 nM. CCK was extracted (90% methanol) from discrete brain regions (mouse) and quantified using the CCK RRA. The amygdala contained the highest concentration of CCK (394 +/- 21 pmol/g tissue), followed by the olfactory bulbs (306 +/- 19 pmol/g tissue) and cerebral cortex (298 +/- 21 pmol/g tissue). Moderate levels of CCK were found in the hippocampus (212 +/- 18 pmol/g tissue), striatum (146 +/- 15 pmol/g tissue) and hypothalamus (129 +/- 9 pmol/g tissue). Low levels of CCK were recorded in the pons (45 +/- 5 pmol/g tissue), medulla (41 +/- 3 pmol/g tissue) and spinal cord (29 +/- 3 pmol/g tissue), whilst no CCK was detected in the cerebellum. The molecular forms of CCK in amygdala, cerebral cortex and hypothalamus were characterized using RRA in conjunction with HPLC. CCK-8 was identified as the major molecular form (88%, 94% and 91% of total CCK activity in amygdala, cortex and hypothalamus, respectively) with a smaller component attributable to CCK-4 (8%, 5% and 6% of the total CCK activity).

Amygdala↗
PubMed1986

Interleukin 3 (IL 3) regulates the in vitro proliferation of both blood monocytes and peritoneal exudate macrophages: synergism between a macrophage lineage-specific colony-stimulating factor (CSF-1) and IL 3.

The effect of interleukin 3 (IL 3) on regulation of macrophage proliferation was examined. Although IL 3 alone stimulates the colony formation in bone marrow cells, it fails to stimulate the colony formation by both peritoneal exudate macrophages (PEM) and blood monocytes. However, IL 3 greatly enhances the proliferative capacity of both PEM and monocytes in responding to suboptimal concentrations of CSF-1. At supraoptimal concentrations of CSF-1, IL 3 did not increase the number of colonies, but greatly increased colony size. Kinetic studies showed that IL 3 enhances CSF-1-induced macrophage proliferation by shortening the cell doubling time. Monocytes were more sensitive to the action of IL 3 and possessed higher proliferative potential than PEM. Binding studies with radioactive labeled CSF-1 (125I-CSF-1) showed that IL 3 treatment induced an increased expression of CSF-1 receptor activity by PEM which appears to be a result of increased number of available receptor sites. The effect of IL 3 on the expression of receptor activity is both dose- and time-dependent. IL 3 also augments the rate of receptor-mediated CSF-1 endocytosis by PEM which appears to be a direct result of increased expression of CSF-1 binding sites. These results demonstrate that, in addition to stimulating the growth and differentiation of several blood cell lineages by hemopoietic stem cells, IL 3 also possesses the ability to modulate CSF-1 receptors, thereby affecting proliferation of more mature blood monocytes and tissue-derived macrophages.

Animals↗
PubMed1986

Role of monoamine pathways in the control of attention: effects of droperidol and methylphenidate in normal adult humans.

Methylphenidate (0.65 mg/kg), droperidol (15 micrograms/kg) or placebo were administered to normal adult males undertaking a dichotic auditory attention task. Performance following placebo, as measured by the ability of subjects to detect nominated target words and discriminate them from phonemically distracting words, was superior when attention was focused on one ear than when divided between the ears. Following droperidol, target detection and discrimination were reduced for both divided and focused attention and in the latter case responses were also slowed. However, these effects were small compared to the striking withdrawn behaviour of the subjects, who reported an unwillingness to attend to external events. Methylphenidate reversed all of these effects when administered following droperidol. Administered alone, methylphenidate had no effect on dichotic measures of attention but had marked effects on spontaneous behaviour, when most subjects reported a substantial increase in both the field and distractibility of attention. These results are interpreted as implicating central dopaminergic pathways in the regulation of attention without precluding a role for other neurotransmitter systems including ascending noradrenaline and serotonin pathways to cerebral cortex. The disparity between these objective and subjective assessments of the effects of the drugs on attention is discussed in terms of the degree of mental effort voluntarily brought to bear by subjects in the selective allocation of their attentional capacity.

Adolescent↗
PubMed1986

Role of monoamine pathways in attention and effort: effects of clonidine and methylphenidate in normal adult humans.

Methylphenidate (0.65 mg/kg), clonidine (200 micrograms) or placebo were administered to normal adult males undertaking a dichotic monitoring task in which they were required to detect nominated target words and discriminate them from phonemic distractors. Following placebo, performance was better when attention was focused than when divided. Following clonidine, subjects were poorer and slower at discriminating targets during both divided and focused attention and subjectively were withdrawn and reported difficulties with concentration. Methylphenidate had no effect on target discrimination or response time but raised the rate of response and had marked effects on spontaneous behaviour in which an increased attention capacity was generally reported. The effects on attention of the pharmacological agents employed in this study are attributed to their effects on central monoamines. The disparity noted between objective and subjective assessments of attention is discussed in terms of the voluntary allocation of effort.

Adolescent↗
PubMed1986

High concentrations of cholecystokinin receptor binding sites in the ventromedial hypothalamic nucleus.

The detailed distribution of cholecystokinin (CCK) receptors in rat hypothalamic nuclei has been mapped using the technique of in vitro receptor autoradiography. Using 125I-CCK-8 as the radiolabelled probe, high levels of CCK receptor binding sites were observed in the ventromedial hypothalamic nucleus (VMN), with lower levels in the compact zone of the dorsomedial nucleus (CDMN). Computer-generated colour-coded image analysis of the VMN indicated that the level of 125I-CCK-8 binding in this nucleus approximated to that in the CCK-receptor rich cerebral cortex. Detailed distribution studies throughout the VMN indicated a marked differential localization of CCK receptor binding sites, with 125I-CCK-8 localized in a "halo" formation within the nucleus. The presence of CCK receptors within the VMN is supportive of an important role for CCK and its receptors in homeostatic processes mediated by the hypothalamus.

Animals↗