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Biomedical subjects

L Brown

Publications and source records attributed to L Brown.

At least 307 records · Page 17Linked to original sources
PubMed1986

Morning amnestic effects of triazolam.

The effects of triazolam on immediate and delayed recall were evaluated in a double-blind placebo controlled study in 22 normal volunteers. Subjects were randomized to receive triazolam or a placebo as a single dose administered at bedtime. Immediate and delayed recall are tested using a modified version of the "Williams Word Memory Task" before and at .5, 8, and 14 hours after drug administration. Delayed recall was evaluated at the 14 hour time point for words recalled at the pre drug and 1/2 and 8 hour time points. No significant difference was noted between the triazolam and placebo group with regard to their immediate recall ability at any of the time points. The placebo group demonstrated no decrease in their delayed recall ability during any of the various post drug time points. However, when evaluating delayed recall in the triazolam group, a statistically significant (p less than .05) decrease compared to baseline in their recall ability of words remembered at the .5 and 8 hour time points was noted. This study suggests that triazolam's amnestic effect may extend beyond the duration of its generally accepted hypnotic efficacy. This is consistent with the hypothesis that amnestic potency among the benzodiazepines is related to benzodiazepine receptor binding affinity and lipophilicity.

Adult↗
PubMed1985

Oxidation of arylcyclopropanes by rabbit liver cytochrome P-450. Mechanistic implications of a multiple oxidation.

The arylcyclopropanes (cyclopropylarenes) cyclopropylbenzene and diphenylcyclopropane are oxidized by rabbit liver microsomal cytochrome P-450, both by the microsomal fraction and by the purified cytochrome in a reconstituted system. The products formed, principally benzoic acid, are due to an unusual triple oxidation of the substrate, which probably remains attached to the active site during the several steps of the oxidation. Both substrates were found to be inhibitors of the cytochrome P-450-dependent O-de-ethylation of 7-ethoxycoumarin. Model oxidation studies with cumene hydroperoxide as oxidizing agent and rabbit liver microsomal fraction as source of enzyme gave similar products to the microsomal and reconstituted systems. The significance of these results in the mechanism of oxidation catalysed by cytochrome P-450 is discussed.

Animals↗
PubMed1985

The inotropic effects of dopamine and its precursor levodopa on isolated human ventricular myocardium.

The direct positive inotropic effects of dopamine and its precursor, levodopa, were measured using isolated, contracting human papillary muscle strips taken from patients during mitral valve replacement. Levodopa did not produce any positive inotropic effect at concentrations up to 3 X 10(-3) M. The positive inotropic effects of dopamine were observed at concentrations above 1 X 10(-5) M with the maximal effect at 3 X 10(-3) M - concentrations higher than those observed in therapy. This inotropic effect was reduced by the beta 1-selective antagonist, 1-practolol (1 X 10(-6) M); the beta 2-selective antagonist, ICI 118,551 HCl (1 X 10(-6) M); the dopamine antagonist, haloperidol (3 X 10(-6) M); the neuronal uptake inhibitor, cocaine (3 X 10(-5) M), but not by the alpha 1-antagonist, prazosin (1 X 10(-7) M). This indicates that dopamine exerts its positive inotropic effects on human heart muscle mainly through release of noradrenaline, together with possible interactions at beta- and dopamine-receptors. The maximal inotropic effect of dopamine was about 50% that of calcium (15 mM, 6.2 +/- 0.7 mN) or ouabain (1 X 10(-7) M, 5.0 +/- 0.8 mN) when measured in the same muscle strips, possibly due to the reduced cardiac noradrenaline content together with the reduced beta-receptor number in congestive heart failure. This concentration of ouabain (1 X 10(-7) M) gave almost maximal inotropy without marked toxicity; when dopamine was then added, only toxicity developed without any further increases in force of contraction. Any haemodynamic benefits of dopamine therapy in optimally digitalis-treated patients are probably due to other cardiovascular effects such as vasodilatation.

Adult↗
PubMed1985

3H-Ouabain binding to human mononuclear leucocytes.

Specific binding of cardiac glycosides to intact human blood cells may be a suitable model for physiological or disease-induced changes in cardiac glycoside binding to human heart muscle. Since the erythrocyte contains no nucleus and has relatively few binding sites compared with heart muscle, intact mononuclear leucocytes were investigated in the present study. Using leucocyte suspensions from 34 normal subjects, 133 measurements of 3H-ouabain binding-were obtained. 3H-Ouabain bound to one type of binding site with an affinity (KD) of 2.8 +/- 1.2 X 10(-9) M, similar to that of human heart muscle. Association and dissociation were slow processes (k+1, 3.9 X 10(4) M-1 sec-1; k-1, 8.1 X 10(-5) sec-1, n = 2). The number of ouabain binding sites/leucocyte varied from 18,000 to 60,000 (mean +/- SD, 34,600 +/- 9,700), with no correlation with the proportion of monocytes present or with the serum K+-level of the donors. Large inter- and intra-individual differences in binding site number were measured which are probably a result of the heterogeneity of the cell suspension used. Thus, the ouabain binding site on human heart muscle and intact mononuclear leucocytes is probably identical. However, the number of binding sites in mixtures of mononuclear leucocytes shows large and inconsistent intraindividual variations, making these studies unsuitable for quantifying drug- or disease-induced changes in ouabain binding site number.

Adult↗
PubMed1985

Comparison of ouabain receptors in sheep myocardium and Purkinje fibres.

The conducting system of the heart has been reported to be more sensitive to the toxic effects of digitalis than the working myocardium. To investigate the molecular basis of these observations, we have characterized the ouabain receptor in Purkinje fibres and ventricular muscle of the digitalis-sensitive sheep heart using cell membrane preparations, crude homogenates and contracting heart tissues. [3H]-Ouabain binding has the following characteristics: in sheep left ventricular cell membranes, specific binding was of high affinity (KD 1.9 X 10(-9) M at 37 degrees); was co-incident with an inhibition of (Na+ + K+)-ATPase activity; and was inhibited by K+ and unlabelled cardiotonic steroids; in crude homogenates, the maximal binding capacity but not the affinity for ouabain varied in different parts of the sheep heart with Purkinje fibres containing markedly fewer binding sites (0.33 X 10(14)/g wet weight; left ventricle, 1.3 X 10(14)/g wet weight) and in isolated, contracting Purkinje fibres and right ventricular moderator band strips, concentration-response curves for [3H]-ouabain binding, increase in force of contraction and inhibition of [86Rb+]-uptake were co-incident. In both contracting tissues, a ouabain concentration of 3 X 10(-7) M occupied about 50% of the specific binding sites, gave the maximal inotropic effect without toxicity and inhibited [86Rb+]-uptake by about 50%. The maximal binding capacity was lower in contracting Purkinje fibres (2 X 10(14) binding sites/g wet weight) than in contracting moderator band strips (3.9 X 10(14) binding sites/g wet weight). The maximal inotropic effects were reached slightly faster in Purkinje fibres but toxicity also occurred faster in these fibers. We conclude that the specific ouabain binding site is the receptor mediating positive inotropy and inhibition of (Na+ + K+)-ATPase in the sheep heart. Further, this receptor is identical in both the conducting system and working myocardium but the conducting system contains many fewer receptors. This change in receptor number, rather than affinity, may underlie the increased ouabain toxicity observed in Purkinje fibres.

Animals↗
PubMed1985

Cloning and sequence analysis of an Ig lambda light chain mRNA expressed in the Burkitt's lymphoma cell line EB4.

A cDNA library was constructed from the mRNA of the Ig lambda producing Burkitt's lymphoma cell line, EB4. Overlapping clones encompassing the coding sequence of the Ig lambda mRNA were isolated and sequenced. The predicted amino acid sequence shows a short hydrophobic leader peptide and a mature polypeptide of 217 residues in which V, J and C regions can be distinguished. The V region belongs to subgroup VI and has greatest homology (80%) with the Amyloid-AR protein. The constant region is the Kern- Oz+ isotype. Probing normal human DNA with the subcloned V lambda coding sequence detects one gene at high stringency and a family of 11 members at low stringency. To date, no restriction enzyme site polymorphisms have been detected. The V lambda VI gene is rearranged on both chromosomes of EB4 and is deleted on both chromosomes in the Burkitt's lymphoma cell line BL2.

Base Sequence↗
PubMed1985

Effectiveness of scalene node biopsy for staging of lung cancer in the absence of palpable adenopathy.

Scalene node biopsy (SNB) has been performed in patients with lung cancer at the Saint Francis Hospital and Medical Center if any of the following criteria has been present: (1) potentially resectable central lesion by chest radiograph, or (2) significant cardiac or pulmonary dysfunction, thereby placing the patient at increased risk for thoracotomy, or (3) a diagnosis of adenocarcinoma prior to SNB. Within these guidelines, a retrospective study was undertaken to determine the benefit of routine SNB in the absence of clinically palpable scalene nodes. In a 2-year period beginning April 1981, 56 patients (37 males) presented with radiographic evidence of lung carcinoma without clinical evidence of scalene adenopathy. Approximately half of the lesions were of a central position. While the majority had symptoms of cough, hemoptysis, or chest pain, the primary lung lesion was identified on routine chest radiograph in 15 (27%). In only three was there no history of smoking, the remainder having at least a 20-pack-year history of cigarette use. Following a routine evaluation, 57 SNBs were performed alone or in concert with other surgical procedures (mediastinoscopy, bronchoscopy). Of these, only two (3.5%) were diagnostic and indicative of unresectable disease. While in one patient no additional procedure was performed, a simultaneous Chamberlain procedure in the other confirmed that the patient was unresectable for cure. In the remaining patients, tissue diagnosis of cancer was obtained through other maneuvers. Because of the low probability that SNB in the absence of clinically palpable nodes altered the management of lung cancer, we do not believe it to be of benefit in the diagnosis or staging of this disease.

Adenocarcinoma↗
PubMed1985

Surveys of natural radiation exposure in UK dwellings with passive and active measurement techniques.

A representative sample of over 2,000 UK dwellings was monitored for a year using thermoluminescent and etchable plastic dosemeters to measure gamma-ray dose rates and radon concentrations. The survey was carried out by post. Each householder completed a questionnaire on the type of dwelling and its characteristics. These data will be used in the assessment of the factors affecting indoor exposure. The mean gamma-ray dose rates were 0.062 and 0.057 microGy h-1 in air and the mean radon concentrations were 25 and 18 Bq m-3 for living areas and bedrooms respectively. Other results of the preliminary data analysis are given. More detailed surveys were conducted in areas where the local geology indicated that elevated exposures to natural radiation might occur. Over 800 dwellings were visited and measurements made of several parameters. The mean gamma-ray dose rates varied from 0.05 to 0.10 microGy h-1 in air. The mean radon concentrations varied from 14 Bq m-3 to 520 Bq m-3. Other findings related to equilibrium factors and regional differences are discussed.

Environmental Exposure↗
PubMed1985

Concentration-response curves of positive inotropic agents before and after ouabain pretreatment.

Current therapy for congestive heart failure (diuretics, digitalis, vasodilators) may be insufficient. Addition of a second positive inotropic substance to digitalised patients has been previously shown to increase cardiac index and decrease vascular resistance. To test the hypothesis that the positive inotropy of ouabain can be increased by other inotropic agents, the following studies were performed. Firstly, concentration-response curves of positive inotropic agents (ouabain, dobutamine, dopamine, orciprenaline, phenylephrine, theophylline, amrinone, sulmazole and histamine) were measured in contracting left atria and papillary muscles from cat and guinea pig hearts. The maximal increase in force of contraction was similar for all compounds except histamine and phenylephrine which gave decreased effects in guinea pig heart muscle. Secondly, these positive inotropic agents were added to the contracting heart muscles after maximal inotropy without toxicity of a ouabain concentration which gave more than 90% of the maximal increase in force of contraction. In guinea pig left atria, dobutamine was the only compound to give a significant, although transient, increase in force of contraction above the maximal ouabain response. Theophylline (2 X 10(-4) mol X litre-1, EC25) produced significant decreases in force of contraction. In papillary muscles, low concentrations of all positive inotropic compounds, except amrinone, significantly increased force of contraction after a submaximal ouabain concentration. However, the maximal increase in force of contraction after combined addition of ouabain and a second inotropic agent was not different from the maximal increase with ouabain, dobutamine or dopamine alone. Addition of higher concentrations of the second inotropic agents after ouabain pretreatment led to a markedly increased incidence of toxicity with only transient positive inotropic effects. These results indicate that any haemodynamic improvement observed in adequately digitalised patients after combined positive inotropic therapy is unlikely to result from directly additive inotropic effects but is probably a result of other cardiovascular effects such as vasodilatation.

Aminopyridines↗
PubMed1985

[Age-dependent regulation of cardiac glycoside receptors].

Specific binding of cardiac glycosides to their receptors precedes their actions on the myocardium. Thus changes in the number and affinity of these membrane bound receptors will vary the response to cardiac glycoside therapy and the incidence of side-effects. Several studies have reported an age-dependent decrease in the number of cardiac glycoside receptors in animals as well as in human erythrocytes. These results may explain the increase in cardiac glycoside sensitivity with age which is not accounted for by the reduction in kidney function. Furthermore, changes in both binding affinity and capacity are known to occur in several diseases which are more common in older patients. Therefore, we have measured the number and affinity of cardiac glycoside receptors in atrial samples from 209 patients and in papillary muscle samples from 59 patients taken during coronary bypass graft surgery or mitral valve replacement. Further, the maximal increase in force of contraction was measured using papillary muscle strips from some of these patients. Our results show no significant age-dependent alteration in the characteristics of the cardiac glycoside receptors but a reduced myocardial receptor density in males (3.47 +/- 0.14 X 10(14)/g protein) compared with females (4.44 +/- 0.21 X 10(14)/g protein) (p less than 0.001) which is more pronounced in older patients. About 30% fewer cardiac receptors either per g protein or per g wet weight are present in patients with coronary heart disease or dilative cardiomyopathy. The maximal inotropic effect of ouabain in human papillary muscle strips is correlated with the number of cardiac glycoside receptors present.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

An in vivo assay for chemoattractant activity.

We have devised an implantable device for the study of leukocyte chemoattraction. The device consists of a 0.25-mm thick patch of Dacron fabric coupled to a disc of ethylene vinyl acetate copolymer. Such polymers can release biologically active molecules at a constant rate for at least 18 days. Attracted cells invade and are trapped within the Dacron fabric. Upon removal from the host, the fabric patches are sectioned and stained to reveal the distribution of attracted cells. Distinct patterns of cellular accumulation can be seen for different chemoattractant molecules. These include the attraction of eosinophils by histamine, monocytes by tuftsin, and mast cells by glycyl-histidyl-lysine. Maximal accumulation of specific cell types occurs at postimplantation days 1 to 2 for neutrophils, days 3 to 5 for monocytes, and days 5 to 6 for macrophages and eosinophils. Control polymers fail to cause significant leukocyte accumulation, indicating that neither the polymer nor the Dacron fabric provokes an inflammatory response.

Alprostadil↗
PubMed1985

The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy.

Thirty patients with polysomnographically confirmed narcolepsy were treated with GHB (gamma-hydroxybutyrate) for up to 30 weeks. The number of nightly awakenings significantly decreased, while Stages 3 and 4 sleep substantially increased. The clinical symptoms of cataplexy, sleep paralysis, hypnogogic hallucinations, daily naps, and sleep attacks all showed significant improvements. Daytime sleepiness, while not completely eliminated, was controlled with lower doses of stimulant medication than patients were taking before the study. No patient developed tolerance to the drug, and no serious side effects were noted.

Adult↗