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Biomedical subjects

H E Smith

Publications and source records attributed to H E Smith.

At least 91 records · Page 5Linked to original sources
PubMed1988

(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[125I]iodo- 2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors.

From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.

Animals↗
PubMed1986

A further indigenous case of 'North American' blastomycosis from South Africa. Importance of skin lesions in early diagnosis.

A case of disseminated blastomycosis is reported. The patient presented with lung involvement, lupus vulgaris-like lesions, mainly of the face, and subcutaneous abscesses overlying areas of bone destruction. The diagnosis was confirmed by mycological microscopy and culture of skin material from involved areas. The importance of early diagnosis and the favourable response to treatment are emphasized.

Amphotericin B↗
PubMed1983

Cutaneous flavobacteriosis--polymorphous skin granulomas from Flavobacterium capsulatum. A case report.

A case of multiple eruptive skin granulomas caused by Flavobacterium capsulatum is described. The organism was resistant or poorly sensitive to all antibiotics except carbenicillin. Cure was brought about by using maximal doses of this drug. The source of the infection could not be proved, but it dated from an orthopaedic procedure to the elbow which was followed by a chronic cellulitis at the operation site. Since this is an organism known to occur in stored water, it was presumed that the flavobacterium was introduced into the wound from bottles of boiled and cooled water used in the operating theatre.

Bacterial Infections↗
PubMed1982

Doctors and society: a Northern Thailand study.

This paper presents findings from a survey together with other observations to characterize the medical profession in Northern Thailand. Data were obtained in early 1976 using a self-administered questionnaire which was completed by 132 physicians in three Northern Thai provinces. Officially approved Thai medicine is 'Western' in nature and is predominantly an urban phenomenon. Practitioners of indigenous medicine are widespread and although illegal, they are tolerated. Training of doctors conforms very largely to Western standards. This plus the limited demand for private medical care results in a high proportion of the graduates of Thai medical schools migrating abroad. Results of the survey indicate that doctors in Northern Thailand were predominantly government employees or staff of a private hospital. Less than 5% were solely in self-employment. However, most 'employee' doctors had a private 'after hours' practice. Two types of medical professionals were identified: the 'cosmopolitan' and the 'local' doctor. Difficulties in communicating with patients were indicated by about 30% of the respondent doctors. The level of dissatisfaction expressed by the doctors surveyed was relatively high--43%. Items most often mentioned were: over-work, low compensation and lack of cooperation of patients. Satisfaction most often mentioned were: service to others, independent occupation and prestige with which doctors are regarded. In the analysis, the influence of several independent variables on type of professionalism and on satisfaction-dissatisfaction was determined.

Adult↗
PubMed1982

Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain.

10-(4-Methylpiperazino)dibenz[b,f]oxepins were prepared and evaluated as potential antipsychotic agents using specific clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine] binding sites in rat forebrain that are noncholinergic and nondopaminergic in nature and from which [3H]clozapine is displaced by known antipsychotic agents. [3H]Clozapine binding in the presence of atropine represents nonmuscarinic binding, while binding in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding. The relative affinity for dopamine binding sites was determined by displacement of [3H]spiroperidol from binding sites in rat caudate nuclei. Thus, clozapine, its 2-chloro isomer, its dechloro analogue, and their 5H-dibenzo[a,d]cycloheptene and dibenz[b,f]oxepine analogues have about the same relative affinity for the nonmuscarinic clozapine binding sites. At the spiroperidol (dopaminergic) sites, both the nature of the tricyclic system and the presence of a chlorine atom on the tricyclic system have a substantial effect on the binding affinity. Within each series, shift or a chlorine atom from the position distal to the piperazino group to the proximal position increases the binding affinity by a factor of about nine, but removal of the chlorine atom substantially decreases the binding affinity. Nevertheless, 10-(4-methylpiperazino)dibenz[b,f]oxepin has a threefold greater affinity for the dopaminergic binding sites than does clozapine itself.

Animals↗
PubMed1982

Differential competition by L-alpha-methyldopa metabolites for adrenergic receptors in rat forebrain.

The capacity of a series of intraneuronal metabolites of L-alpha-methyldopa to compete for alpha-1 ([3H]prazosin, alpha-2([3H]clonidine and beta ([3H]dihydroalprenolol) receptor binding in rat forebrain was studied. Each metabolite studied had a unique order of activity at each receptor. These data show that (-)-erythro-alpha-methylnorepinephrine and (-)-erythro-alpha-methylepinephrine compete with high affinity for alpha-2 receptors, thereby supporting the suggestion that alpha-2 receptors mediate hypotensive effects of L-alpha-methyldopa . Furthermore, these metabolites of L-alpha-methyldopa competed with high potency for beta-1 receptors in forebrain and (-)-erythro-alpha-methylepinephrine was more potent than (-)-epinephrine, (-)-norepinephrine and (-)-erythro-alpha-methylnorepinephrine in competing for beta-2 receptors on human lymphocytes. These data suggest that beta receptor stimulation may be important in determining the net effects of L-alpha-methyldopa. L-alpha-Methyldopa metabolites were much less potent than (-)-epinephrine and (-)-norepinephrine in competition for alpha-1 receptors. (+/-)-alpha-Methyldopamine was less potent than other l-alpha-methyldopa metabolites at all three receptors, suggesting that it is unlikely to be an important hypotensive metabolite of L-alpha-methyldopa.

Animals↗
PubMed1981

Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain.

Analogues of clozapine, some prepared by a novel, shorter synthesis than those described previously, were evaluated as potential antipsychotic agents using clozapine binding sites in rat forebrain that are nonmuscarinic and nondopaminergic in nature and from which [3H]clozapine is displaced by known antipsychotic agents. The binding of clozapine to muscarinic sites is inhibited in the presence of atropine. Displacement of [3H]clozapine by an analogue of clozapine in the presence of atropine represents nonmuscarinic binding, while displacement in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding. The relative affinity of the analogues for dopamine binding sites was determined by their ability to displace [3H]spiroperidol from binding sites in rat caudate nuclei. To the extent which binding affinity for nonmuscarinic clozapine sites in rat forebrain reflects the antipsychotic potential of a particular drug, dibenzo-5H-cycloheptene analogues of clozapine are as effective as clozapine itself. Strong binding to nonmuscarinic clozapine sites is not dependent on the presence of a chlorine atom on th tricyclic system. One or both of the nitrogen atoms in the dibenzo-5H-[1,4]diazepine ring of clozapine appear to be necessary for the strong inhibition of clozapine binding to spiroperidol sites in rat caudate nuclei. Anticholinergic activity is substantially higher for clozapine and its dibenz[1,4]oxazepine analogue than for its benzo-5H-cycloheptene analogue.

Animals↗
PubMed1981

(alpha S)-erythro-alpha-methylepinephrine: preparation and stereoselective binding to adrenergic receptors in rat forebrain.

The enantiomers of a number of catecholamines, including (alpha S)- and (alpha R)-erythro-alpha-methylepinephrine, were evaluated for their capacity to compete for binding sites in rat forebrain homogenates with [3H]prazosin, a ligand which selectively binds to adrenergic receptors of the alpha 1 subtype. (alpha R)-erythro-alpha-Methylepinephrine is devoid of apparent biological activity, but the activity of the alpha S isomer is substantial. The latter is less active than the endogeneous catecholamines, (R)-norepinephrine and (R)-epinephrine, but the stereospecific competition for [3H]prazosin binding sites by the catecholamine isomers with the beta R configuration is additional evidence that (alpha S)-erythro-alpha-methylepinephrine may be a biologically active metabolite of L-alpha-methyl-3,4-dihydroxyphenylalanine.

Animals↗
PubMed1980

Peroxisome-associated aldehyde dehydrogenase in normal rat liver.

We have combined subcellular fractionation and cytochemical staining techniques to study the distribution of aldehyde dehydrogenase in rat liver. In addition to confirming the mitochondrial and microsomal localization of aldehyde dehydrogenase, this combined approach has allowed us to demonstrate that peroxisome-like organelles possess significant aldehyde dehydrogenase. When peroxisomal fractions are cytochemically stained for aldehyde dehydrogenase, activity is observed along membranes of structures resembling peroxisomal ghosts. These bodies lack a matrix but many appear to enclose peroxisomal cores. Moderate to dense reaction product is also located in single membrane-limited structures present in fractions containing morphologically recognizable peroxisomes. On occasion, the osmiophilic precipitate is also present in the matrix of intact peroxisomes. The aldehyde dehydrogenase activity in these peroxisome-like organelles prefers aliphatic aldehydes, including acetaldehyde in both millimolar and micromolar concentrations, and NAD. Aromatic aldehydes and NADP are also metabolized, but to a lesser extent. These results indicate that peroxisome-like organelles contain an aldehyde dehydrogenase activity possessing properties compatible with a role in ethanol metabolism.

Acid Phosphatase↗
PubMed1980

Photoaffinity labeling of rat androgen binding protein.

The photoinactivation and photoaffinity labeling of androgen binding sites present in cytosol prepared from intact sexually mature rat epididymides have been demonstrated by using unlabeled and [3H]-labeled 17 beta-hydroxy-4,6-androstadien-3-one. Both photoinactivation and photolabeling are dependent upon exposure to light. These processes are inhibited when photolysis is conducted in the presence of the photoinert compound 17 beta-hydroxy-5 alpha-androstan-3-one, suggesting that steroid-specific sites are involved in the reactions. The labeled steroid-specific product of photolysis is macromolecular with a molecular weight of 47,000 as determined by electrophoresis on polyacrylamide gels containing NaDodSO4, and proteinaceous because digestion of the cytosol with pronase before photolysis eliminates steroid-specific binding. After photolysis, the protein-steroid complex has the ability to withstand dissociation during electrophoresis under denaturing conditions, and unlabeled 17 beta-hydroxy-5 alpha-androstan-3-one fails to displace the label from the complex. Thus, the binding of [3H]17 beta-hydroxy-4,6-androstadien-3-one to the cytosolic protein is covalent. This steroid-specific product is identified as an androgen binding protein of testicular origin by its comigration with native androgen binding protein on nondenaturing polyacrylamide gels and by its molecular weight which is within the range reported for androgen binding protein subunits.

Affinity Labels↗
PubMed1978

Structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in the rat limbic forebrain.

The present studies were undertaken to assess the structural and steric requirements for beta-phenethylamines as agonists of the noradrenergic cyclic AMP generating system in slices of the rat limbic forebrain. Significant agonist activity of beta-phenethylamines requires a beta-3,4-dihydroxyphenethylamine with a beta-hydroxyl group in the R configuration. Thus, dopamine did not stimulate the system at concentrations up to 10(-3) M. Moreover, beta-hydroxyphenethylamines without a 3,4-catechol group (octopamine, phenylephrine, p-hydroxynorephedrine, metaraminol and methoxamine) - though exerting alpha-agonist activity in peripheral tissues - lack agonist activity in this particular cyclic AMP generating system. The effects of (R)-norepinephrine and (R)-isoproterenol at maximal concentrations were not additive. The results lend further support to the view that the cyclic AMP generating system in slices of the limbic forebrain is part of a norepinephrine receptor coupled adenylate cyclase system with a subpopulation of receptors that are beta in nature.

Animals↗