Biomedical subjects

E Nusser

Publications and source records attributed to E Nusser.

At least 19 recordsLinked to original sources

PubMed1992

Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes.

In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S-form of which is hydroxylated by a P450IIC isozyme, was carried out before amitriptyline therapy. Metabolites were determined in 24-hour urine samples collected on treatment day 8, and the contributions of individual compounds, including the four isomers of 10-hydroxyamitriptyline and 10-hydroxynortriptyline to total excretion were calculated. Formation of (-)-E-10-hydroxyamitriptyline and (-)-E-10-hydroxynortriptyline apparently depends on the activity of cytochrome P450IID6 because negative correlations existed between the log metabolic ratio of dextromethorphan and the relative quantities of these enantiomers. In contrast, correlations were positive for nortriptyline, (+)-E-10-hydroxynortriptyline, (-)-Z-10-hydroxynortriptyline, and (+)-Z-10-hydroxynortriptyline. The mephenytoin hydroxylase seems to participate in side-chain demethylation to the secondary and primary amines, because the log metabolic ratio of mephenytoin correlated negatively with the relative quantity of E-10-hydroxydidesmethylamitriptyline and positively with that of amitriptyline and its N-glucuronide.

Adult↗

PubMed1991

Excavations in drug chirality: 1. Cyclothiazide.

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.

Antihypertensive Agents↗

PubMed1990

Enantiomer analysis of E- and Z-10-hydroxyamitriptyline in human urine.

E- and Z-10-hydroxyamitriptyline (E- and Z-10-OH-AT) are racemic alcoholic metabolites of the antidepressant amitriptyline. Their enantiomers were separated by high-performance liquid chromatography as diastereomeric derivatives using R-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Mosher's reagent). Although E-10-hydroxyamitriptyline excreted in patient urine in free form or as the O-glucuronide consisted primarily of the (-)-enantiomer, the N-glucuronide contained similar amounts of the two enantiomers. Z-10-OH-AT was analysed in one patient and an excess of the (+)-isomer was found in the unconjugated, total conjugated and N-glucuronidated metabolite. The specific optical rotation of (-)-E-10-OH-AT was determined.

Amitriptyline↗

PubMed1990

Quaternary N-glucuronides of 10-hydroxylated amitriptyline metabolites in human urine.

1. Conjugated metabolites were isolated from the urine of patients receiving amitriptyline treatment using a combination of solid-phase extraction, h.p.l.c. and t.l.c. 2. By n.m.r. and mass spectrometry, N-glucuronides of E- and Z-10-hydroxyamitriptyline and of trans-10,11-dihydroxyamitriptyline were identified in addition to the previously described O-glucuronides of E- and Z-10-hydroxyamitriptyline and -nortriptyline and amitriptyline-N-glucuronide. 3. The quaternary ammonium glucuronides proved to be resistant to acid hydrolysis, but could be cleaved enzymatically. 4. In urine samples from three patients, 35-60% of conjugated 10-hydroxyamitriptyline was found in the form of N-glucuronides. 5. A volunteer given an i.v. infusion of amitriptyline-N-glucuronide excreted E- and Z-10-hydroxyamitriptyline-N-glucuronide; following ingestion of E-10-hydroxyamitriptyline its N-glucuronide could be measured in urine.

Adult↗

PubMed1985

Why does Coomassie Brilliant Blue R interact differently with different proteins? A partial answer.

Dimethyl sulfoxide was found to be effective for extraction of Coomassie Brilliant Blue R-250 (Coomassie R) from stained proteins on polyacrylamide gel slices. A good correlation was found between the ability of different proteins to bind Coomassie R and their capacity for interaction with Coomassie Brilliant Blue G-250 (Coomassie G) in solution. Scatchard analysis showed that the number of Coomassie R ligands bound to each protein molecule is approximately proportional to the number of positive charges on the protein, about 1.5-3 dye molecules/charge.

Electrophoresis, Polyacrylamide Gel↗

PubMed1973