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Biomedical subjects

W R Sherman

Publications and source records attributed to W R Sherman.

At least 73 records · Page 4Linked to original sources
PubMed1981

Evidence that lithium alters phosphoinositide metabolism: chronic administration elevates primarily D-myo-inositol-1-phosphate in cerebral cortex of the rat.

The administration of LiCl (3.6 mequiv./kg/day) to adult male rats for 9 days results in an increase in the cerebral cortex level of myo-inositol-1-phosphate (M1P) to 4.43 +/- 0.52 mmol/kg (dry weight) compared with a control level of 0.24 +/- 0.02 mmol/kg. This establishes that the previously observed acute effect of lithium on M1P (Allison et al., 1976) is both prolonged and augmented by repeated doses of lithium. Larger doses of LiCl over a 3-5 day period result in even larger increases in M1P and a 35% decrease in myo-inositol. In each case, 90% of the increase is due to the D-enantiomer, evidence that lithium is largely producing this effect via phospholipase C-mediated phosphoinositide metabolism. Data are presented showing that lithium is an uncompetitive inhibitor of the hydrolysis of both D- and L-M1P by M1P'ase.

Animals↗
PubMed1980

The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain.

myo-Inositol-1-phosphatase has been partially purified from bovine brain. The enzyme has a molecular weight of about 58,000. Both L-myo-inositol 1-phosphate and D-myo-inositol 1-phosphate are hydrolyzed by the enzyme as well as (-)-chiro-inositol 3-phosphate and 2'-AMP. Triphosphoinositide is not a substrate. The phosphatase is completely dependent on Mg2+, which has a Km of 1 mM. Calcium and manganese ions are competitive inhibitors of Mg2+ binding with Ki values of 18 microM and 2 microM, respectively. Lithium chloride inhibits the hydrolysis of both L- and D-myo-inositol 1-phosphate to the extent of 50% at a concentration of 0.8 mM. The phosphatase from testis is similarly inhibited by lithium. Lithium ion is a noncompetitive inhibitor of Mg2+ binding and an uncompetitive inhibitor of myo-inositol 1-phosphate binding. Because lithium chloride administration elicits both an increase in the levels of myo-inositol 1-phosphate and a decrease in the levels of myo-inositol in rat brain (Allison, 1978), and because these actions are blocked by anticholinergic agents, we examined the effects of cholinergic agonists and antagonists on the enzyme and found none. The possibility that the inhibition of this enzyme by lithium ion is related to the pharmacological actions of lithium is discussed.

Animals↗
PubMed1980

L-myo-Inositol-1-phosphate synthase from bovine testis: purification to homogeneity and partial characterization.

L-myo-Inositol-1-phosphate synthase has been purified to homogeneity from bovine testis by (NH4)2SO4 precipitation on Celite followed by reverse (NH4)2SO4 gradient elution, DEAE chromatography, gel filtration, and hydroxylapatite chromatography. The enzyme is then pure by the criteria of elution profile from the hydroxylapatite, electrophoresis, and sedimentation properties. We find no overall (gluconeogenic) reversibility of the enzyme using 6 mM DL-myo-inositol-1-P. The first three steps of the reaction are reversible as determined by uptake of isotope from a D2O incubation medium into the 6 position of D-glucose-6-P. Thus, substrate binding, dehydrogenation, and proton removal prior to the aldol cyclization are all reversible steps. The enzyme is less than 5% NAD+ independent and is not inhibited by substrate or product (5 mM D-glucose-6-P or 0.8 mM DL-myo-inositol-1-P). The enzyme is twofold stimulated by either 50 mM NH4+ or 50 mM K+; the activation by these ions is not additive. Sodium ions inhibit the enzyme by 78% at 153 mM. The effect of sodium and potassium is not on the Km of D-glucose-6-P but on Vmax. We propose that K+ activates the enzyme by stabilizing a carbanion intermediate. Ethanol stimulates the enzyme 2-fold and 2.5-fold with added K+. The effect of ethanol appears to be via lowering of the D-glucose-6-P Km. In the presence of ethanol the effect of salt on Vmax disappears.

Animals↗
PubMed1980

Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry.

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.

Diabetes Mellitus, Type 1↗
PubMed1978

scyllo-inositol and myo-inositol levels in tissues of the skate Raja erinacea.

1. Many organs of the skate Raja erinacea have been found to contain scyllo-inositol levels that are much higher than myo-inositol, the opposite to that found in mammals. 2. Both inositols were found in all skate organs studied. 3. myo-Inosose-2 was found to accompany the inositols in many of these organs.

Animals↗
PubMed1977

Incubations of testis myo-inositol-1-phosphate synthase with D-(5-18O)glucose 6-phosphate and with H218O show no evidence of Schiff base formation.

myo-Inositol-1-P synthase (EC 5.5.1.4) purified from rat testis and from bovine testis was allowed to react with D-[5-18O]glucose-6-P. myo-Inositol, obtained in these reactions, retained all of the 18O originally in the glucose-6-P. When these enzyme preparations were incubated with unlabeled glucose-6-P in a medium enriched in H2 18O no uptake of the oxygen isotope occurred that could be ascribed to the myo-inositol-1-P synthase reaction. By these criteria this enzyme, which is considered to use an aldolase mechanism in the cyclization step, cannot form a Schiff base during the reaction. In addition, these enzymes are not inhibited by 10 mM EDTA. One interpretation of this evidence is that the myo-inositol-1-P synthases we have studied are neither Class I nor Class II aldolases, and simply use base catalysis in the cyclization step.

Animals↗
PubMed1977

In-vivo measurement of glucose and alanine metabolism with stable isotopic tracers.

This report describes sensitive, precise microtechniques that allow quantification of glucose and alanine metabolism in vivo using stable isotope tracers. By combined gas chromatography--mass spectrometry and selected ion monitoring--deuterium and carbon-13 enrichment in blood glucose and alanine were measured with an error of less than 2 per cent. Estimation of glucose and alanine flux in dogs by stable isotope tracer techniques was compared with simultaneous measurements made in the same animal with conventional radiotracer dilution methods. Application of the described stable isotope methods to determination of glucose and alanine turnover as well as alanine-2,3-13C incorporation into glucose in adult men confirmed the safety and validity of these techniques for human investigation.

Alanine↗
PubMed1976

Electron beam ionization mass fragmentographic analysis of tricyclic antidepressants in human plasma.

A method for the measurement, in human plasma, of all tertiary and secondary tricyclic antidepressants prescribed in the United States is described. The method uses electron beam ionization GLC-mass spectrometry, employing a computer-controlled multiple-ion detector. This method, mass fragmentography, is used with internal standards for each drug. Plasma levels to as low as 10 ng/ml of the following drugs can be measured: amitriptyline, nortriptyline, doxepin, desmethyldoxepin, imipramine, desipramine, and protriptyline. Deuterium-labeled amitriptyline and imipramine are used as internal standards for those two drugs; for the other drugs, deuterated amitriptyline, nortriptyline, desmethyldoxepin, or desipramine is used. The method can measure up to 15 samples/hr, making it practical for large-scale studies of these drugs in patients. Spectra of each drug and examples of their analysis are given.

Adult↗
PubMed1976

Measurement of tricyclic antidepressant levels in an outpatient clinic.

Although definitive studies regarding the correlation between tricyclic antidepressant plasma levels and therapeutic effect are lacking, preliminary data suggest that measurement of tricyclic antidepressant plasma levels provides a rational approach to improve clinical management of the depressed patient. Data were collected to determine if the routine measurement of plasma tricyclic antidepressant levels was practical in a large clinic population, and to determine if such levels could improve patient care. Individual differences in drug metabolism and frequent unreliable ingestion of medication make the measurement of drug plasma levels the only sure means of determining if a patient is receiving a fair therapeutic trial on a particular tricyclic antidepressant. Plasma analysis revealed both the failure to ingest adequate amounts of medication as prescribed and also the abuse of medications. Although generalizations regarding individual variation in drug metabolism or generalizations concerning drug compliance do little to improve patient care, whenever such problems are met on an individual basis, many clinical management problems can be resolved.

Adult↗
PubMed1976

Mass fragmentography of morphine: relationship between brain levels and analgesic activity.

Morphine levels in rat brain were measured by the multiple ion detection method (mass fragmentography), using a computer-controlled gas chromatograph-mass spectrometer, and were correlated with the analgesic activity of the narcotic at intervals up to 6 hours after the injection. Morphine levels in brain reached a peak of 346 ng/g of tissue wet weight 30 minutes after the subcutaneous injection of 10 mg/kg of morphine sulfate and then declined rapidly over the next 3 hours. Between 3 and 6 hours after the injection of morphine, the brain concentration decreased slightly but was still readily detectable at 6 hours after injection. An excellent correlation (r = 0.923) was found between the concentration of morphine in brain and analgesic activity, as measured by the hot plate method. The multiple ion detection method for the measurement of morphine appears to meet all of the criteria necessary for any drug assay: sensitivity, specificity and ease of analysis.

Analgesics, Opioid↗