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Biomedical subjects

S McLean

Publications and source records attributed to S McLean.

At least 109 records · Page 6Linked to original sources
PubMed1988

An examination of the opiate receptor subtypes labeled by [3H]cycloFOXY: an opiate antagonist suitable for positron emission tomography.

17-Cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan (cycloFOXY) is a fluorinated derivative of naltrexone suitable for labeling opiate receptors using positron emission transaxial tomography. Using the quantitative ligand binding method "binding surface analysis," in vitro autoradiography, and site-directed alkylating agents, [3H]cycloFOXY is shown to label mu and kappa opiate binding sites in vitro. Similar results were obtained using [3H]naloxone. Additional experiments demonstrate that [3H]cycloFOXY administered in vivo also labels mu and kappa binding sites. The relevance of these findings are discussed from clinical and basic science perspectives.

Animals↗
PubMed1988

Axonal transport of opiate receptor subtypes.

The axonal transport of mu and delta receptors in the rat was examined by autoradiography in three fiber systems: vagus nerve, fasciculus retroflexus and corpus callosum. Following ligature or knife cut, sections were incubated with [125I]D-Ala2-MePhe4-Met(O)5-ol-enkephalin to label mu receptors or [125I]D-Ala2-D-Leu5-enkephalin in the presence of 30 nM oxymorphone to selectively label delta receptors. Ligature of the vagus and knife cut of the fasciculus retroflexus produced a time-dependent proximal build-up of mu receptors indicating anterograde axonal flow. In contrast, the corpus callosum has delta but not mu receptors, and these could not be demonstrated to undergo axonal flow. The results suggest that in the fiber tracts examined, mu but not delta opiate receptor subtypes are anterogradely transported toward nerve terminals where they may be inserted in presynaptic membranes.

Animals↗
PubMed1988

Autoradiographic visualization of haloperidol-sensitive sigma receptors in guinea-pig brain.

The distribution of sigma receptors in guinea-pig brain is demonstrated using quantitative autoradiography and the new selective sigma receptor probe, 1,3-di(2[5-(3)H]tolyl)guanidine. Pharmacological analysis, using slide-mounted brain sections, reveals that this site is saturable and has a drug-specificity profile similar to that found in homogenate binding studies. Autoradiography reveals a moderate to high density of discrete, specific labeling superimposed on a lower level of homogeneous 1,3-di(2[5-(3)H]tolyl)guanidine binding. Both patterns are displaced by incubation with 10 microM haloperidol or 1,3-di-ortho-tolyl-guanidine. In the forebrain, the highest density of binding is associated with the magnocellular-neuroendocrine and limbic systems; lower densities are distributed in non-limbic nuclei and the lowest levels occur in the extrapyramidal system. In the midbrain and hindbrain, motor nuclei involved in voluntary and involuntary motor behavior are discretely labeled, as are many of the cranial nerve nuclei. The anatomical distribution of the haloperidol-sensitive sigma receptors is distinct from the pattern of phencyclidine receptors and suggests sigma compounds may effect endocrine, emotional and motor behavior.

Animals↗
PubMed1988

Warfarin dosage requirements: prospective clinical trial of a method for prediction from the response to a single dose.

We have previously described a model for predicting individual daily maintenance dosage (MD) requirements of warfarin 24 h after the administration of a single dose. This model relies on measurement of the initial anticoagulant response as the 24 h percentage fall in plasma clotting factor VII activity. It permits prediction of the individual MD given the size of the initial dose, a baseline and desired maintenance value of the prothrombin ratio, and a baseline and 24 h plasma level of factor VII activity. We now present the results of a prospective clinical trial of the method. Data from 65 patients were suitable for analysis. The mean daily MD of warfarin was 4.0 mg (range 1-10 mg). There was a moderately strong linear relationship between predicted and actual MDs of warfarin (r = 0.66, P less than 0.001). Actual vs predicted MDs in individual patients were not significantly different. The mean difference was 0.39 mg. The results of this prospective trial suggest that our model predicts warfarin MD requirements with reasonable accuracy. Nevertheless, the accuracy of the model is not sufficient to replace careful clinical and haematological monitoring of each patient commencing warfarin therapy.

Adolescent↗
PubMed1988

Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass-binding method.

1. Amiodarone is an effective antiarrhythmic drug whose therapeutic usefulness is limited by variable pharmacokinetics and considerable toxicity. Total plasma concentrations are not reliably related to therapeutic effect, but if plasma protein binding varies between patients, then free drug concentrations may provide a better measure of drug effectiveness. 2. The plasma protein binding of amiodarone was measured by erythrocyte partitioning, and found to be the same in six healthy subjects and eight patients being treated for cardiac arrhythmias (mean = 99.98%; range 99.97-99.99%). The free fraction of amiodarone was independent of the total drug concentration (r = -0.41, P greater than 0.50) and albumin level (r = -0.31, P greater than 0.50). 3. These data show no advantage in monitoring free concentrations of amiodarone. On the other hand, the patients in this study did not receive very high doses of amiodarone, and were free from drug side effects and biochemical abnormalities. Possibly a more heterogeneous group of patients would show variability in amiodarone binding. This should be examined, especially for patients with variations in alpha 1-acid glycoprotein, a major ligand for basic drugs and a likely major binding protein for amiodarone.

Adult↗
PubMed1987

Chronic morphine upregulates a mu-opiate binding site labeled by [3H]cycloFOXY: a novel opiate antagonist suitable for positron emission tomography.

CycloFOXY (17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta- fluoromorphinan) is a novel opiate antagonist synthesized as a ligand suitable for in vivo visualization of opiate receptors using positron emission transaxial tomography. In this paper we report that [3H]cycloFOXY labels two distinct opiate binding sites in rat brain membranes, tentatively identified as mu and kappa. Furthermore, chronic administration of morphine results in a selective up-regulation of the mu binding site. The implications of this finding for models of the opioid receptors and the mechanism of the sodium effect are discussed.

Alkylating Agents↗
PubMed1987

Drugs, alcohol and road accidents in Tasmania.

Drug analyses were performed on 200 blood samples that were taken for alcohol analysis from road users in Tasmania. Alcohol at a concentration of above 0.5 g was found in 75% of the samples, and other drugs were found in 17% of the samples. Cannabis was the most prevalent of these other drugs: it was detected in 6% of road users; benzodiazepine drugs were detected in 5% of road users; and barbiturate drugs were detected in 2% of road users. Alcohol was found in 50% and other drugs were found in 25%, of drivers, riders and pedestrians who were involved in road accidents that were serious enough to cause death or injury. In addition to alcohol, other drugs may be making a significant contribution to road accidents because all the drugs that were identified are capable of impairing psychomotor performance. Of particular concern is the prevalence of cannabis, which is an illegal drug, and barbiturate drugs, which are now prescribed rarely. A well-controlled study is required to quantitate the contribution of drugs other than alcohol to road accidents. In the meantime, drivers should be warned that drugs that depress the central nervous system can be expected to impair driving ability and to increase the risk of an accident.

Accidents, Traffic↗
PubMed1987

Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster.

The distribution of enkephalin and dynorphin immunoreactivity in the hippocampus of four rodent species (gray squirrel, guinea pig, rat, and hamster) is compared with the pattern of opiate receptor subtypes (mu, delta, and kappa). The distribution of opioid peptides is fairly consistent in the anterior hippocampus of these four species. Intense immunoreactivity for dynorphin and enkephalin is found in the hilus of the dentate gyrus and in the mossy fiber system. Occasional immunoreactive processes are seen in the dentate molecular layer and scattered throughout the CA1 and CA3 fields. In the rat and hamster, an additional plexus of enkephalinergic fibers straddles both sides of the hippocampal fissure. Cells immunoreactive for both opioid peptides are located in and just superficial to the dentate granule cell layer. Opiate receptors are variably distributed in these rodent species. In the squirrel, guinea pig, and hamster, mu and kappa binding is dense in the stratum lucidum of CA3 and the molecular layer of the dentate gyrus. In the rat, dense mu and kappa binding is localized within and adjacent to the pyramidal and granule cell layers. Delta receptor patterns show additional species differences. In the rat, the delta distribution is similar to the mu and kappa patterns. In the other species, the delta binding pattern is generally the inverse of the mu/kappa pattern: most areas of the hippocampus are enriched in delta sites, whereas the stratum lucidum and the pyramidal cell layer are receptor-sparse. Thus, the stratum lucidum--site of dense terminations of mossy fibers containing opioid peptides--is characterized by selectively sparse delta receptors in four species and by selectively dense kappa receptors in three species. The three receptor subtypes, taken either individually or together and compared to the peptides, are more variably and more widely distributed throughout the hippocampus and fail to show a correspondence with opioid-peptide-containing terminals. The mismatches suggest that receptor locations and densities are organized without relation to the sites of relevant transmitter release.

Animals↗
PubMed1987

[3H]cyclofoxy, a ligand suitable for positron emission tomography, labels mu and kappa opioid receptors.

The autoradiographic distribution of [3H]cyclofoxy (6-deoxy-6 beta-fluoronaltrexone) after in vivo administration or in vitro incubation suggests that it labels mu and kappa opioid receptors. In the rat, the pattern of [3H]cyclofoxy binding is similar to the distribution of mu receptors, however labeling is also present in the neural lobe of the pituitary, the central nucleus of the amygdala and the hypothalamus, areas where kappa receptors outnumber mu receptors. In the guinea pig, [3H]cyclofoxy binding sites are dense in the deep layers of the cortex, an area enriched in kappa receptors. These results are consistent with [3H]cyclofoxy binding to mu and kappa receptors.

Animals↗
PubMed1987

Assessing dementia. Part II: Clinical, functional, neuropsychological and social issues.

Comprehensive assessment of the dementing person entails looking beyond syndromal diagnosis to broader aspects of the individual's functioning and circumstances. Systematic attempts are being made to conceptualize the stage, severity and sub-type of dementia and these may prove useful in daily practice. Clinical aspects of a broader assessment include attention to possible coexisting psychiatric syndromes and the disruptive behavioural changes common in dementia. In addition, alternative perspectives to the medical model can contribute valuable information for future planning. Functional assessment can delineate lost abilities that limit the person's adaptive capacity and indicate retained skills necessary for independent living. The neuropsychological approach can identify spared abilities and specific impairments, as well as quantifying changes over time. Attention to social issues can clarify the strengths and deficiencies of the support network and define the burdens of caring. A general approach, which emphasises the need for dementia assessment to be comprehensive, multidisciplinary, naturalistic, intervention oriented, practical and longitudinal, is proposed. This assessment approach is closely linked to the most important role of the clinician, that of continuing care and management.

Alzheimer Disease↗
PubMed1987

Characterization of two [3H]ketanserin recognition sites in rat striatum.

Two [3H]ketanserin recognition sites are present in the rat striatum. The high-affinity site (KD, 0.39 nM) is similar to the 5-hydroxytryptamine2 (5-HT2) site previously characterized by various investigators. The low-affinity site (KD, 21.8 nM) has a unique pharmacologic specificity and is preferentially localized to rat striatum and septum. Conventional 5-HT2 antagonists as well as 5-HT and 5-HT uptake inhibitors are ineffective at inhibiting [3H]-ketanserin binding to this low-affinity site. Also, chronic treatment with p-chlorophenylalanine, which depletes brain 5-HT, upregulates only the high-affinity site. Thus, in the striatum and septum, [3H]ketanserin labels a unique recognition site. This site has recently been shown to be associated with dopaminergic nerve endings and may regulate biogenic amine release.

Animals↗