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Biomedical subjects

L A Sternson

Publications and source records attributed to L A Sternson.

At least 55 records · Page 3Linked to original sources
PubMed1981

Oxidation of phenylhydroxylamine in aqueous solution: a model for study of the carcinogenic effect of primary aromatic amines.

Phenylhydroxylamine is degraded in aqueous phosphate buffers at physiological pH values (6.8-7.4) to give nitrosobenzene, nitrobenzene, and azoxybenzene. The reaction is O2 dependent and subject to general acid and general base catalysis. At pH less than or equal to 5.8 in cacodylate buffer, it is converted to p-nitrosophenol in addition to nitrosobenzene, nitrobenzene, and azoxybenzene. Nitrobenzene and p-nitrosophenol appear to form directly from phenylhydroxylamine. A common intermediate generated from phenylhydroxylamine and O2 is suggested to account for the formation of nitrobenzene, nitrosobenzene, and p-nitrosophenol and is consistent with kinetic studies and 18O-labeling experiments. The results suggest that neither hydrogen peroxide nor superoxide (O-2) are involved in the oxidation sequence.

Buffers↗
PubMed1980

Paired-ion chromatographic analysis of tamoxifen and two major metabolites in plasma.

A method is described for the clinical analysis of the non-steroidal anti-estrogenic, antineoplastic agent, tamoxifen and its 4-hydroxy and N-desmethyl metabolites in human plasma. The analytes are extracted from biological fluid with diethyl ether and subsequently converted to fluorescent phenanthrene derivatives by irradiation with UV light. The fluorophores are separated by paired-ion chromatography on a reversed-phase (C18) column. Spectrofluorometric monitoring of the column eluent allows quantitation of analytes as their phenanthrene derivatives to levels of 100 pg/ml of plasma.

Chromatography, Ion Exchange↗
PubMed1980

High-performance liquid chromatographic assay for methylglyoxal bis(guanylhydrazone) (methyl GAG) in plasma and urine.

A clinically useful analytical method is described for monitoring both plasma and urine levels of methylglyoxal bis(guanylhydrazone) administered in the clinical management of certain neoplasms. The drug is initially separated from the biological matrix by retention on a small (2 cm) column packed with weak cation-exchange resin. The analyte is subsequently eluted quantitatively from the column with hydrochloric acid, and then separated and quantitated by paired ion high-performance liquid chromatography on an RP-18 column. The drug is detected to levels of 50 ng/ml of biological fluid by monitoring the column effluent spectrophotometrically at 280 nm. Absorbance was linearly related to drug concentration over the range 50 ng-50 microgram/ml of plasma or urine, and measurements could be made with a precision of +/- 4% over this range.

Chromatography, High Pressure Liquid↗
PubMed1979

High-performance liquid chromatographic analysis of emetine after oxidative activation to a fluorescent product.

A clinically useful analytical method is described for monitoring plasma levels of emetine. The drug is initially extracted from plasma with dichloromethane (0.3 volumes). The extract can be analyzed directly by paired-ion reversed-phase high-performance liquid chromatography to levels of 500 ng/ml of plasma by spectrophotometric monitoring of column effluent. For analysis of emetine at lower concentrations, the dichloromethane extracts are subjected to mild mercuric acetate oxidation prior to separation, thereby converting emetine to a fluorescent product. Spectrofluorometric monitoring of the column effluent readily extends the sensitivity of the assay to 10 ng of emetine/ml of plasma. At these levels measurements can be made with a precision of +/- 4%.

Chromatography, High Pressure Liquid↗
PubMed1979

Urine analysis of platinum species derived from cis-dichlorodiammineplatinum(II) by high-performance liquid chromatography following derivatization with sodium diethyldithiocarbamate.

A clinically useful method is described for the quantitative analysis of platinum species derived from cis-dichlorodiammineplatinum(II) in urine. The drug and its biodegradation products are derivatized directly in urine by reaction with sodium diethyldithiocarbamate (DDTC) to form a common product, a 2:1 DDTC-platinum adduct. This complex is stable and can be quantitatively extracted into 0.1 volumes of chloroform. An aliquot of the chloroform layer is then subjected to high-performance liquid chromatography on a muBondapak CN column and the eluent monitored spectrophotometrically at 254 nm. At this wavelength the DDTC-platinum adduct has a molar absorptivity of 43,000, and platinum levels of 25 ng/ml or urine can be detected with a precision of +/- 2.5% and an accuracy of +/- 4%.

Chromatography, High Pressure Liquid↗
PubMed1979

Loss of hydrophobic amine from solution by adsorption onto container surfaces.

The apparent loss of the hydrophobic amine drug alpha-[(dibutylamino)methyl]-6,8-dichloro-2-(3',4'-dichlorophenyl)-4-quinoline-methanol monohydrochloride from solution due to its adsorption onto the surface of its storage container was studied. The drug appeared to be adsorbed only as the free base. Therefore, any perturbations to the solution phase that will help solubilize the drug and thus lower its chemical potential will minimize adsorption. Multilayer drug adsorption to the container surfaces appeared to take place, with some evidence of a highly organized system in the adsorbed phase. Adsorption was minimized when the heterogenous polar functionalities on glass surfaces were covered by a layer of silicone or methacrylate polymer, which yielded less reactive, more hydrophobic surfaces. Loss was also minimized when the environment was kept acidic (pH less than or equal to 4,8), the drug was dissolved in a proton-donating solvent (e.g., chloroform), and an ion-pairing agent (e.g., trichloroacetate) was present to solubilize further the monocationic form of the drug in organic media.

Adsorption↗
PubMed1979

Analysis of hydrophobic amine antimalarials in biological fluids with the plastic ion-selective electrode.

Plastic ion-selective electrode analysis of the hydrophobic amine antimalarial mefloquine in blood samples was investigated. The direct electrode response in plasma samples provided poor drug sensitivity due to high mefloquine protein binding. The drug was analyzed in whole blood by initial extraction into ether as its trichloroacetate ion-pair. Mefloquine was monitored in whole blood extracts with the electrode to moderately low levels (to 0.4 microgram/ml). Rapid blood mefloquine level monitoring by this electrode was demonstrated in a bioavailability study. Mefloquine alkylation with various alkyl halides produced derivatives detectable by the electrode at much lower levels (up to two orders of magnitude) than the parent. A kinetic study of this alkylation reaction revealed that an alkyl amine base was necessary to scavenge the acid produced during reaction and to allow the reaction to go to completion. At room temperature, with benzyl bromide as the reagent, reaction was 99% complete in 30 min and mefloquine could be detected to approximately to 10(-8) M, a 100-fold improvement in sensitivity over electrode monitoring of underivatized mefloquine.

Amines↗
PubMed1979

Metabolic conversion of fluorenone oxime to phenanthridinone by hepatic enzymes.

Fluorenone oxime is converted to phenanthridinone by enzymes present in rat liver homogenates. The reaction is analogous to the chemical Beckman rearrangement. The oxime-amide rearrangement enzyme is localized primarily in the microsomes, with some activity in the cytosol. The reaction requires reduced nicotinamide adenine dinucleotide phosphate and observes Michaelis-Menten kinetics. The reaction is relatively slow (Vmax = 7.75 +/- 2.01 nmoles of phenanthridinone formed/100 mg of liver/15 min), but the enzyme reaches maximum velocity at relatively low substrate concentrations (Km = 3.90 +/- 1.85 x 10(-5) M). The reaction is strongly competitively inhibited by 1-decylimidazole (KI = 3.75 +/- 1.77 X 10(-7) M) and inhibited to a lesser extent by the chelating agents bipyridyl (KI = 1.33 +/- 0.21 X 10(-3) M) and ethylenediamine tetraacetate (KI = 1.00 +/- 0.28 X 10(-3) M) and the sulfhydryl binding agent p-chloromercuribenzoate (KI = 2.71 +/- 0.07 X 10(-4) M). Studies also suggest that the reaction mechanism does not involve initial enzymatic substrate esterification through acetylation, glucuronidation, phosphorylation, or sulfation.

Animals↗
PubMed1979

Analysis of nitrosamines in aqueous and biological fluids based on measurement of photochemically liberated nitrite.

A method is described for the analysis of nitrosamines in aqueous solution and in biological fluids (blood, plasma, and rat liver microsomal suspensions). The method is based on photochemical degradation of the nitrosamine in a controlled environment to yield the corresponding amine and nitrite ion, and the latter is subsequently used to form a chromophoric or fluorescent product. The analysis scheme is a modular three-component system consisting of a column to remove contaminating nitrite prior to photolysis, a photochemical reactor, and a chemical reactor. Additional modules are used to accommodate biological samples or large-volume (5--50 ml) aqueous samples. In this study, N-nitrosopyrrolidine, N-nitrosodimethylamine, and N,N-diethanolnitrosamine were utilized as substrates. Because of intersubstrate variability in the photochemical decomposition rate and overall nitrite yield, the structure (i.e., photochemical behavior) of the particular nitrosamine in the sample must be known prior to analysis. With a colorimetric readout, the sensitivity for analysis of N-nitrosopyrrolidine was 800 ng/ml for a 5-ml sample and the measurement precision was +/- 6% in the biological fluids. Fluorometric analysis improved sensitivity to 4 ng/ml with a precision of +/- 10% in biological media.

Animals↗
PubMed1978

Kinetics of digoxin stability in aqueous solution.

Digoxin hydrolysis was studied as a function of pH. Conversion of digoxin to digoxigenin was followed by high-pressure liquid chromatography and shown to proceed by the initial loss of one, two, or three sugars. The hydrolysis rate was directly proportional to parent drug concentration and hydrogen-ion activity. The individual hydrolysis rate constants of digoxin, digoxigenin bisdigitoxoside, and digoxigenin monodigitoxoside were determined by a simplex fitting procedure. Data are presented suggesting that at least some variation in the bioavailability of orally administered digoxin arises from observed variations in gastric pH; these variations influence the extent to which hydrolysis occurs and, thus, modify the composition of digoxin species available for absorption.

Chemical Phenomena↗
PubMed1978

Studies on the distribution of dianhydrogalactitol into the central nervous system of the rat.

The distribution of dianhydrogalactitol-C14 (DAG-C14) which had been administered to rats as an iv bolus injection was studied in plasma and brain tissue. Analysis of samples was carried out by a high-pressure liquid chromatography method which specifically responds to the parent drug. Samples were monitored by both ultraviolet and liquid scintillation spectrometry. Plasma level measurements indicate that intact DAG has a relatively short half-life in plasma (t1/2= 43.7 minutes) and brain (t1/2 = 50.3 minutes). These findings differ significantly from those studies which have measured total radioactivity when monitoring DAG levels; and should be considered in the design of DAG dose regiments. Data from both brain and plasma were consistent with a classic two-compartment open model.

Animals↗
PubMed1978

Atomic absorption spectrophotometry of free circulating platinum species in plasma derived from cis-dichlorodiammineplatinum(II).

We describe a method of analysis for free circulating platinum species derived from cis-dichlorodiammineplatinum(II) in blood plasma. Protein-bound and free platinum species were separated from each other by centrifugal ultrafiltration. Platinum in the ultrafiltrate was converted to a cationic complex by reaction with ethylenediamine, and the product was collected on paper impregnated with cation-exchange resin, where it could be stored indefinitely without loss. The platinum was eluted from the disk with 5 mol/liter hydrochloric acid, and an aliquot of this solution was then analyzed by flameless atomic absorption spectrophotometry. The overall analytical recovery of platinum was 80 +/- 2%. The minimum quantity of cis-dichlorodiammineplatinum detectable was 35 microgram/liter of plasma at the 99% confidence level. Detector response was linearly related to drug concentration in the range from 80 microgram to 290 mg of Pt per liter of plasma. Reaction variables were made optimal, so as to yield maximum sensitivity and reproducibility (+/- 2%) consistent with minimal sample transfers and manipulations.

Cisplatin↗
PubMed1978

Clinical analysis of tamoxifen, an anti-neoplastic agent, in plasma.

Tamoxifen, a phenylstilbene derivative, is currently being used to treat metastatic breast cancer. We describe an analytical method for monitoring the parent drug and its 4-hydroxylated derivative in whole blood and plasma. After extraction from biological media, the analytes are converted to highly fluorescent products by ultraviolet irradiation, and then separated by liquid-chromatography on a muBondapak CN column, with spectrofluorometric detection of components. Detection limits for tamoxifen and its 4-hydroxy derivative are 1 and 2 microgram/liter of biological fluid, respectively. Conditions have been optimized so that the reaction proceeds fast enough for convenient sample handling without jeopardizing fluorescence yield due to the photocatalyzed degradation of the fluorescent product. Evidence suggests that the fluorophore being monitored is a phenanthrene derivative.

Breast Neoplasms↗