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Biomedical subjects

R E Becker

Publications and source records attributed to R E Becker.

At least 19 recordsLinked to original sources
PubMed1992

Determination of heptylphysostigmine in plasma by high-performance liquid chromatography with electrochemical detection.

An analytical method was developed with sensitivity to detect clinically significant concentrations of heptylphysostigmine (HP), a new physostigmine derivative with potent and long-lasting inhibitory activity on cholinesterase. HP, an experimental drug for Alzheimer disease, was measured in human plasma by high-performance liquid chromatography with electrochemical detection with use of a normal-phase column and acetonitrile buffer containing tetrahydrofuran and sodium acetate, pH 4.6. The limit of detection of the method was 0.125 ng/ml using a 2-ml sample of plasma. Analytical recovery of HP was 53.04 +/- 7.75% for plasma in the range 0.25-2.5 ng/ml. Stability studies conducted at 37 degrees C indicated that the drug was stable in 1 M hydrochloric acid, 1 M hydrogen peroxide and sodium acetate-buffered solution at pH 4 for at least 6 h but at pH 7 it degraded slightly to 79% at 6 h and was unstable in 1 M sodium hydroxide with only 9% of the parent compound remaining at 30 s. HP was stable when exposed to ultraviolet light at 22 degrees C or 100% relative humidity at 37 degrees C, with almost 80 and 75% of the parent compound remaining after 4 and 28 days, respectively. HP was stable in plasma at 4 degrees C for 0.25 h, and it slowly degraded to 56 and 28% of the original concentration by 1 and 2 h, respectively. HP was highly unstable in plasma at higher temperatures; at 22 and 37 degrees C it degraded immediately to 48 and 36% of the original concentration and was not detected after 0.5 and 0.25 h, respectively.

Cholinesterase Inhibitors↗
PubMed1992

High-performance liquid chromatographic method using ultraviolet detection for measuring metrifonate and dichlorvos levels in human plasma.

We report high-performance liquid chromatographic methods using ultraviolet detection, developed for the first time in our laboratory with sensitivity to detect clinically significant concentrations of metrifonate (MTF), an experimental drug for Alzheimer disease, and its active anticholinesterase metabolite, dichlorvos (DDVP). The determination limit of the method for MTF and DDVP was 1 microgram/ml and 40 ng/ml, respectively. Stability of MTF and DDVP at various temperatures in water, buffered solutions and in human plasma were also studied.

Chromatography, High Pressure Liquid↗
PubMed1992

Inhibition of human brain and RBC acetylcholinesterase (AChE) by heptylphysostigmine (HPTL).

Heptylphysostigmine (HPTL), a derivative of the AChE inhibitor physostigmine (PHY), is under investigation as a therapeutic agent in Alzheimer's disease. HPTL is active against human RBC AChE both in vitro and in vivo. Activity of HPTL against human brain has not been documented. We have developed an in vitro assay system using particulate membrane fractions which permits comparison of inhibition and recovery kinetics of human RBC (primarily globular dimer) and brain (primarily globular tetramer) membrane-bound forms. Under these conditions the HPTLIC50 is similar for the two forms. RBC AChE inhibition spontaneously reverses in 24 h, as occurs in vivo. In striking contrast, activity of inhibited brain enzyme does not recover on overnight incubation. DDVP-induced inhibition, but not HPTL inhibition, can be reversed by the oxime 2-PAM. Some recovery of HPTL inhibition, but not to the level seen with RBC AChE, occurs on addition of heat-stable fractions from serum or CSF. Brain enzyme recovers rapidly from PHY in this system. Responses of brain and RBC AChE to HPTL indicate that these forms are functionally as well as structurally distinct. Since brain inhibition apparently does not spontaneously reverse like RBC inhibition, peripheral measurements of patient responses should be assessed with caution during treatment with HPTL.

Acetylcholinesterase↗
PubMed1991

Stability of peripheral hematological parameters after chronic acetylcholinesterase inhibition in man.

Acetylcholinesterase (AChE; EC 3.1.1.7) is present in both primitive and mature erythroid cells, and a role has been suggested for the enzyme in regulation of differentiation in the human erythron. AChE is also a major enzyme in the central nervous system; alteration of its activity has been proposed as a therapeutic strategy in Alzheimer disease. We recently treated 18 Alzheimer disease patients with metrifonate, a long-acting AChE inhibitor, over periods up to 7 months, with resulting erythrocyte AChE inhibition as high as 82 per cent of baseline values. Despite chronic reduction of enzyme activity, no significant alterations were noted in erythrocyte, leukocyte or platelet characteristics or numbers that would suggest a deleterious effect of AChE inhibition on normal differentiation. Thus, any modification of developmental pathways appears to be compensated by other regulatory mechanisms in the intact organism.

Alzheimer Disease↗
PubMed1991

Parallel distributed processing and neural networks: origins, methodology and cognitive functions.

Parallel Distributed Processing (PDP), a computational methodology with origins in Associationism, is used to provide empirical information regarding neurobiological systems. Recently, supercomputers have enabled neuroscientists to model brain behavior-relationships. An overview of supercomputer architecture demonstrates the advantages of parallel over serial processing. Histological data provide physical evidence of the parallel distributed nature of certain aspects of the human brain, as do corresponding computer simulations. Whereas sensory networks follow more sequential neural network pathways, in vivo brain imaging studies of attention and rudimentary language tasks appear to involve multiple cortical and subcortical areas. Controversy remains as to whether associative models or Artificial Intelligence symbolic models better reflect neural networks of cognitive functions; however, considerable interest has shifted towards associative models.

Artificial Intelligence↗
PubMed1990

DSM-III-R subtypes of social phobia. Comparison of generalized social phobics and public speaking phobics.

Social phobic patients who fear most or all social interaction situations are labeled generalized social phobics in DSM-III-R. Thirty-five patients who met this criterion were compared with 22 social phobic patients whose fears were restricted to public speaking situations. Generalized social phobics were younger, less educated, and less likely to be employed, and their phobias were rated by clinical interviewers as more severe than those of public speaking phobics. Generalized social phobics appeared more anxious and more depressed and expressed greater fears concerning negative social evaluation. They performed more poorly on individualized behavioral tests and differed from public speaking phobics in their responses to cognitive assessment tasks. The two groups showed marked differences in their patterns of heart rate acceleration during the behavioral test. The implications of these findings for the classification and treatment of social phobic individuals are discussed.

Adult↗
PubMed1990

Regulation of low molecular weight insulin-like growth factor binding proteins in experimental diabetes mellitus.

Circulating insulin-like growth factor (IGF) bioactivity is reduced in animals and patients with diabetes mellitus. We sought to determine whether the availability and levels of specific IGF binding proteins (BPs) are altered in animals with experimental diabetes, and might contribute to changes in circulating IGF bioactivity in experimental diabetes. Female Sprague-Dawley rats were administered streptozotocin or citrate buffer iv, and then killed either 3 days later, or else after 4-day insulin treatment (7.5 U/kg human NPH twice daily), or 2 days after insulin was discontinued. Serum [125I]IGF-I binding activity was markedly increased in diabetic animals compared to controls when analyzed by Sephacryl S-200 chromatography, dot blot, and affinity labeling techniques, due to increased binding to low mol wt BPs (81 +/- 4% of ligand eluting with low mol wt BPs in diabetic serum vs. 22 +/- 3% in control, P less than 0.001). In contrast, activated charcoal removed ligand from these BPs and underestimated the availability of BPs in diabetes. Serum binding activity fell toward control levels during insulin therapy, then rose again after insulin was withdrawn, corresponding to changes in metabolic status. To distinguish changes in specific BPs, serum proteins were separated by 13% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, then transferred to nitrocellulose. Ligand blotting with [125I]IGF-I demonstrated that serum levels of a 32 K mol wt IGF BP are markedly increased in diabetic rats and decline during insulin therapy. Levels of this 32 K IGF BP rose again after insulin was discontinued, demonstrating regulation in accordance with changes in insulin and metabolic status. Western analysis and affinity labeling with immunoprecipitation revealed that this 32 K protein is distinct from the 34 K fetal rat BP, and is immunologically related to the type 1 human IGF BP. We conclude that circulating [125I]IGF-I binding activity is markedly increased in animals with acute streptozotocin-induced diabetes, due to changes in low mol wt proteins, including a 32 K type 1 IGF BP that is regulated by changes in insulin and/or metabolic status. Regulation of low mol wt IGF BPs by insulin, and perhaps other factors, may play an important role in the modulation of tissue growth factor bioactivity in metabolic disease.

Adsorption↗
PubMed1990

Different tissue distribution and hormonal regulation of messenger RNAs encoding rat insulin-like growth factor-binding proteins-1 and -2.

The insulin-like growth factor-binding proteins IGFBP-1 and IGFBP-2 are low mol wt IGFBPs that are similar in structure. They are not glycosylated and have a homologous amino acid sequence, including the number and position of 18 cysteine residues and a carboxyl-terminal Arg-Gly-Asp sequence that can be recognized by cell adhesion receptors. The present study demonstrates that expression of mRNAs encoding the two BPs differs in some fetal rat tissues and in the livers of adult rats after hypophysectomy, fasting, or streptozotocin-induced diabetes. As determined by Northern blot hybridization using cDNA probes for rat IGFBP-2 or human IGFBP-1, both mRNAs are expressed at high levels in liver of 21-day gestation and 1-day-old rats and at lower levels in 21- and 65-day-old rat liver. Levels of both mRNAs are higher in liver than in other fetal rat tissues. The relative abundance of the two mRNAs in most fetal tissues is similar to that in liver, except that kidney and brain have 8-fold and more than 25-fold higher relative levels of IGFBP-2 mRNA, respectively. IGFBP-2 mRNA is about 10- to 20-fold increased after hypophysectomy or fasting, whereas IGFBP-1 mRNA is relatively unchanged. IGFBP-2 mRNA levels are decreased completely by refeeding fasted rats for 3 days, but only partially decreased by treatment of hypophysectomized rats with GH, cortisone acetate, T4, and testosterone for 4 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

Identification of a type 1 insulin-like growth factor binding protein (IGF BP) in serum from rats with diabetes mellitus.

Circulating insulin-like growth factor binding protein (IGF BP) activity is increased in animals with streptozotocin-induced diabetes. Separation of BPs by SDS/PAGE for ligand and immunoblot analysis revealed that a 32,000 molecular weight BP is present and increased in diabetic serum. This BP is immunologically distinct from the low molecular weight fetal rat BP (rBP2) and is related to the human amniotic fluid BP (hBP1) that is increased in patients with insulin dependent diabetes mellitus.

Affinity Labels↗
PubMed1989

Neuropsychological "systems efficiency" and positron emission tomography.

Positron emission tomography (PET) has dramatically improved our ability to examine the functioning of the living brain. PET studies of neural pathways of the major sensory modalities--auditory, visual, somatosensory--have confirmed many traditional neuropsychological concepts, such as cross-lateral representation and regional functioning to particular primary sensory cortical areas. Other PET studies have used radioisotopes to examine relationships between radiopharmaceutical agents and neurobehavioral functioning in both normal and neuropathological states. In some areas, PET methodology requires further refinement. For example, effort should be made to develop the technology to do multiple scans within a short time frame; statistical procedures to examine relationships between neuropsychological tasks and the activity or presence of radiopharmaceutical agents in multiple sites; adequate controls for experimental error; and activation paradigms controlling the nonspecific effects of simple arousal. PET activation models of cognition suggest that a "systems efficiency" approach to assessing neuropsychological test performance involving both serial and parallel processing would be useful. These developments will improve empirical methodology and our understanding of brain-behavior relationships.

Arousal↗
PubMed1989

Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent Alzheimer's disease.

Tetrahydroaminoacridine (THA) was administered to a small number of patients with Alzheimer's disease. A minority of patients received the drug for longer than one week. Only one investigator [Summers et al. 1986] has reported dramatic palliative effects from the administration of THA. All investigators other than Summers reported side effects, especially troublesome is the frequent appearance of indications of hepatotoxicity. The efficacy and safety of THA are unknown. There is evidence that THA may have complex modes of action in addition to the inhibition of cholinesterases. There is a need for careful clinical assessment of THA and for further investigation of possible mechanisms of action.

Alzheimer Disease↗
PubMed1989

Determination of physostigmine in plasma and cerebrospinal fluid by liquid chromatography with electrochemical detection.

Physostigmine (Phy) was determined in plasma and cerebrospinal fluid (CSF) by HPLC with electrochemical detection, with use of a normal-phase column and methanolic sodium acetate buffer, pH 4.6. The detection limit of the method was 0.5 micrograms/L for a 2-mL sample of plasma or 0.5 mL of CSF. Analytical recovery of Phy in the range from 0.5 to 40 micrograms/L was 60% (SD 5%) for plasma and 78% (SD 8%) for CSF. Excellent chromatographic separation of Phy without column deterioration during extended usage and constant recovery for a wide range of Phy concentrations makes the routine monitoring of plasma from patients with Alzheimer's disease economically feasible. Using our method, we measured Phy in 13 such patients' plasmas at 105 and 135 min after a 135-min intravenous infusion of 300, 600, and 900 micrograms of Phy per square meter of body surface. Mean values significantly increased with dose (P = 0.001), but differences between 105 and 135 min (P = 0.229) or between dose and time (P = 0.949) were not significant.

Alzheimer Disease↗
PubMed1988

Depression in schizophrenia.

Depressive syndromes that occur during the course of schizophrenia are not clearly understood but have important implications for the treatment of the schizophrenic patient. In this review of the literature on depression secondary to schizophrenia, the author notes that lack of tested diagnostic criteria has led to a misunderstanding of its relatively high frequency and its association with poor outcome features such as impaired psychosocial functioning, schizophrenic relapse, and suicide. Differential diagnosis, including ruling out akinetic depression, is essential, he believes, partly because the concept of schizophrenic depression as postpsychotic is not supported by evidence. Clinical management must address such increased risk factors as relapse and suicide, but evidence indicates that secondary depression in schizophrenia does not respond to antidepressant medication.

Depressive Disorder↗
PubMed1987

Genes for immunodominant protein antigens are highly homologous in Mycobacterium tuberculosis, Mycobacterium africanum, and the vaccine strain Mycobacterium bovis BCG.

The relatedness of immunodominant protein antigens in Mycobacterium tuberculosis, M. africanum, and M. bovis BCG was investigated by comparing the genes that encode major protein antigens in M. tuberculosis with their counterparts in the other two mycobacteria. Genes encoding homologs of M. tuberculosis major protein antigens were isolated from M. africanum and M. bovis BCG by constructing lambda gt11 recombinant DNA expression libraries and screening them with murine monoclonal antibodies and DNA probes. The antibodies were directed against four major protein antigens of M. tuberculosis with molecular masses of 71, 65, 19, and 14 kilodaltons. The isolated M. africanum and M. bovis BCG DNA clones were mapped with restriction endonucleases, and the maps of the mycobacterial genes were confirmed by Southern analysis of mycobacterial genomic DNA. The restriction maps of DNA containing the four genes in M. tuberculosis, M. africanum, and M. bovis BCG are identical, indicating that the immunodominant proteins that they encode are highly homologous in the three mycobacteria. Thus, the immunity against tuberculosis engendered by M. bovis BCG vaccination could be provided, at least in part, by the immune response to these homologous antigens.

Antigens, Bacterial↗