Responsiveness of gynecologic tumors to chemotherapeutic agents in the 6-day subrenal capsule assay.
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Biomedical subjects
Publications and source records attributed to S D Reich.
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A general method of analysis of anthracycline concentrations was developed. Drug is extracted from plasma with organic solvent and separated from metabolites by high-pressure liquid chromatography on an aminocyanosilica column. Detection and quantitation are by the endogenous fluorescence of compounds having an intact tetracyclic ring structure. Limits of sensitivity are 5, 1, and 5 ng/ml of plasma for doxorubicin, carubicin, and marcellomycin, respectively. The assay can be used for studying the aldo-keto reductase and reductive glycosidase reactions with anthracyclines as the substrates and for the evaluation of the clinical pharmacology or pharmacodynamics of various doxorubicin analogs.
The in vivo kinetics of low-dose doxorubicin (0.05 mg/kg), entrapped in a carrier and magnetically targeted, were characterized in a rat tail model. Tissue concentrations of doxorubicin at a preselected target site and in various organs were followed over time. As late as 60 min postinjection, 3.7 microgram/g of drug was found at the target site with no detectable drug levels found in any organ. In comparison, a 100-fold higher dose (5.0 mg/kg iv) of free doxorubicin yielded drug concentrations of 1.8 microgram/g at the target site and 15.0 microgram/kg in the pooled organs. Therefore, 1% of the free intravenous dose targeted magnetically yielded approximately twice the local doxorubicin concentration at a preselected target site with no detectable systemic distribution. Magnetic targeting of particulate drug carriers to localized disease sites is suggested as an efficient method of obtaining high local drug concentrations and may reduce many unwanted side effects from unrestricted systemic circulation.
A graphite furnace atomic absorption spectrophotometric assay, capable of accurately determining nanogram amounts of platinum in serum and ultrafiltrate, was developed. A sample serum or ultrafiltrate was acidified with nitric acid and heated to destroy the protein-platinum bond. A measured excess of ammonium 1-pyrrolidinedithiocarbamate was added, and the platinum complex was extracted into isopropylacetone. The extract was injected into the graphite furnace. The sample was dried, charred, and atomized using optimal conditions. The resulting absorbance was used to determine the platinum content.
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Carminomycin was administered to four dogs and two human patients as a single intravenous dose. Plasma samples were obtained and assayed for carminomycin and carminomycinol by high pressure liquid chromatography with fluorescence detection. The plasma disappearance of carminomycin could be described by a three-compartment open model. Distribution was rapid and the apparent volume of distribution was greater than 100 l/m2 in both species. The terminal half-life of drug was 86 h in dogs and 20 h in humans. In both dogs and humans carminomycinol concentrations rapidly surpassed carminomycin levels, and terminal half-lives were longer than for the parent compound in the two species. Since carminomycinol has antitumor activity and host toxicity, this metabolite may play an important role in the efficacy and toxicity of carminomycin therapy.
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