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Biomedical subjects

R A Floyd

Publications and source records attributed to R A Floyd.

At least 145 records · Page 8Linked to original sources
PubMed1982

Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases.

The steady-state apparent total body clearances (TBC) of continuously infused 5-fluorouracil (5-FU) were determined in 16 adult male patients who were receiving combined 5-FU-radiation therapy. Seven patients (group A) had Stage III adenocarcinoma or epidermoid lung carcinomas; none had known metastases. Five patients had gastrointestinal carcinomas (group B), without known hepatic metastases. Four had gastrointestinal carcinomas with evidence of hepatic metastases (group C). TBCs were calculated from infusion rates and serum 5-FU concentration data. The means (standard errors) of the TBCs were: group A, 4.49 (0.53); group B, 6.51 (0.53); group C, 2.96 (0.91) L/kg/h. The difference among the means was found to be significant (p less than 0.002) by one-way ANOVA. Differences among the groups were then examined using 95 percent confidence intervals: group A was not different from group B or group C; however, groups B and C differed from each other. Patients with hepatic metastases have 5-FU TBCs about half that of those found in patients without hepatic involvement. Clinically, patients in group C attained the higher serum 5-FU concentrations known to be radiosensitizing more frequently than patients in the other two groups; differences in toxicity were not evident. This suggests that administration of an agent that can compete with 5-FU for hepatic metabolism to patients with rapid clearance might improve the therapeutic efficacy of 5-FU.

Adult↗
PubMed1981

Improved liquid chromatographic assay for serum fluorouracil concentrations in the presence of ftorafur.

An improved liquid chromatographic assay for serum ftorafur and fluorouracil is shown to be routine, sensitive, and reproducible using 200 micro l of serum. Dilute ammonium acetate buffer at pH 10.2 is used for solubilization of the evaporated ethyl acetate extract for injection into the liquid chromatograph. A stability study indicated little or no in vitro formation of fluorouracil from ftorafur under the conditions described. Low serum fluorouracil levels were found after administration of therapeutic doses of ftorafur.

Chromatography, Liquid↗
PubMed1981

A new technique of depositing phospholipid bilayers on quartz surfaces: its use in membrane spin-label studies.

We have developed a new improved technique termed the parallel-beam spattering (PBS) method for depositing phospholipid bilayers on quartz surfaces. This technique involves atomizing the phospholipid mixture with a stream of nitrogen gas and passing this atomized mixture through two orifices separated by a distance to achieve a parallel beam of atomized particles before deposition on the quartz plate. A static electric field can easily be applied to the quartz surface. Also a goniometer of new design has been constructed to allow precise positioning of the deposited phospholipid bilayers with reference to the magnetic field. We have utilized the PBS method to deposit phosphatidylcholine/nitroxyl labeled cholestane mixtures on quartz plates and have found that hydrated bilayers of these mixtures yield ESR spectra with essentially the same characteristics as those obtained using more conventional techniques. The distinct advantage of the new technique for depositing bilayers is that there is no spectral anomaly present which usually is present when the more conventional method of depositing bilayers is used. The spectral anomaly is apparently caused by a portion of the bilayers aligned in directions not directly parallel to the quartz surface. For precision work the spectral anomaly is unacceptable. It is not observed with the new PBS method which has yielded highly reproducible results.

Electron Spin Resonance Spectroscopy↗
PubMed1981

Free radicals in arylamine carcinogenesis.

Free radical processes and their involvement in carcinogenesis is an unresolved question but one subjected to intense investigation recently. Using in vitro systems, we demonstrated that certain heme compounds combined with hydroperoxides catalyzed the oxidation of N-hydroxy-2-fluorenylacetamide (N-OH-2-FAA) to nitroxyl free radical intermediate which dismutated to form 2-nitrosofluorene (2-NF) and N-acetoxy-2-fluorenylacetamide (N-AcO-2-FAA). Ascorbate and certain antioxidants inhibited this reaction. Lipid hydroperoxides were effective substrates for this reaction, especially in target tissue, rat mammary gland parenchymal cells. Cytochrome P420 in the high-spin state catalyzed the reaction effectively but low-spin cytochrome P420 or P450 were ineffective. Recently, we found that 2-NF added covalently to unsaturated carbon-carbon double bonds of membrane lipids to form an adduct termed 2-nitroso-fluorene lipid adduct (N-O-LAF), which, in it oxidized state, exists in the membrane as a nitroxyl free radical. This N-O-LAF undergoes reduction-oxidation changes in the natural membrane. Formation of N-O-LAF occurred in rat liver microsomal membranes by deacylation of N-OH-2-FAA, but the esterase inhibitor paraoxon, prevented its formation from N-OH-2-FAA. The mutagenicity of 2-NF was enhanced in Salmonella typhimurium TA98 if the bacteria were cultured to contain more unsaturated membrane lipids. However, synthesized adducts were only slightly mutagenic.

Amines↗
PubMed1980

Studies of the fatty acid composition and membrane microviscosity in Salmonella typhimurium TA98.

When the mutagen tester bacterial strain Salmonella typhimurium TA 98 was grown at different temperatures, we found that the unsaturated fatty acid composition increased at the lower growth temperatures. Membrane microviscosity, as assessed with spin-probe fatty acids using electron spin resonance, decreased as the unsaturated fatty acid content increased. These findings are of importance in understanding our recent observation that the mutagenic response of these bacteria was increased when they were grown at 27 degrees C vs. 37 degrees C, and indicate that membrane properties may play an important role in the sequence of events leading to mutagenesis.

Cell Membrane↗
PubMed1980

Binding and mutagenicity studies with 2-nitrosofluorene on Salmonella typhimurium TA98 grown at different temperatures.

The growth temperature of the histidine auxotroph Salmonella typhimurium TA98 influences the extent of binding of 2-nitrosofluorene (NOF) to this bacterium as well as the mutagenicity of this chemical carcinogen. Gas-liquid chromatography (GLC) of bacteria grown at 37, 27 and 17 degrees C revealed that the unsaturated (hexadecenoic plus octadecenoic) fatty-acid content increased from 15.0% at 37 degrees C to 20.5% at 27 degrees C and to 22.2% at 17 degrees C. It has been shown using both artificial and natural mammalian membranes that NOF adds to carbon-carbon double bonds in unsaturated fatty acids via an "Alder-ene" type reaction to produce a nitroxyl free radical adduct (N-O-LAF). The same adduct was formed when NOF was incubated with Salmonella typhimurium TA98. There was an increase in N-O-LAF formed in bacteria grown at 27 degrees C as compared to those grown at 37 degrees C, but very little formed in bacteria grown at 17 degrees C. Therefore the amount of N-O-LAF formed did not correlate with unsaturated fatty-acid content. 14C-labeled NOF uptake in bacteria grown at different temperatures showed a good correlation with mutagenicity data.

Carcinogens↗
PubMed1980

Planning for ambulatory pharmacy services.

To aid in the planning of patient-oriented pharmacy services in an ambulatory care center, the demographic profile of the patients visiting the pharmacist at the Sunol Health Center (SHC) pharmacy in Los Angeles, California was studied. Analysis of the data collected over a 6-month period revealed that female patient visits were double the number of male patient visits. Ten disease conditions requiring drug therapy accounted for 75% of all problems presented by the patients. The mean number of prescribed medications received per patient was 1.7. The ratio of newly prescribed medications versus refill medications was 2.5 to1 or 70% versus 30%. The proportion of new patient visits versus return patient visits was 55% versus 45%. With this information, the training of the pharmacist and the services of a pharmacy may be designed specifically to meet the needs of the patients in the community or the ambulatory care setting.

Age Factors↗
PubMed1980

The deacetylation of N-hydroxy-2-acetylaminofluorene by rat liver microsomes and carboxyl esterase.

We have demonstrated that incubation of rat liver microsomes with N-hydroxy-2-acetylaminofluorene (N-OH-AAF) leads to formation of a 2-nitrosofluorene-membrane lipid adduct. This adduct exists as a nitroxyl free radical, termed N-O-LAF, in its oxidized state. When microsomes were incubated with the sulfhydryl binding agent, rho-hydroxymercuribenzoate, a larger amount of N-OL-LAF formed. We interpret this as a slowdown in the rate of endogenous chemical reduction of carcinogen-membrane lipid adduct. In this paper we present evidence that N-OH-AAF is deacetylated by a microsomal enzyme to form N-hydroxy-2-aminofluorene and this is then oxidized to 2-nitrosofluorene which adds covalently to membrane lipid double bonds to form N-O-LAF. Various antioxidants, peroxidase inhibitors, and P450 substrates and inhibitors were ineffective in altering the amount of N-O-LAF formed from N-OH-AAF; but two esterase inhibitors, dietyl-rho-nitrophenylphosphate and alpha-toluene-sulfonyl fluoride, prevented N-O-LAF formation. Of the following purified enzymes tested: porcine liver carboxyl esterase, pepsin, chymotrypsin, cathepsin D, ficin, papain, leucine aminopeptidase, Naja naja phospholipase, acetylcholinesterase (type I), trypsin (type I and V) and epoxide hydrase; only carboxyl esterase was effective in deacetylating N-OH-AAF.

2-Acetylaminofluorene↗
PubMed1979

Drug utilization and prescribing patterns in a skilled nursing facility: the need for a rational approach to therapeutics.

A study was made of 50 patients drawn at random from a Skilled Nursing Facility (SNF) attended by seven physicians. For 59 percent of these patients, polypharmacy was practiced but no substantiating diagnoses were recorded. Approximately half of the drugs were administered pro re nata. More drugs were prescribed in potentially toxic dosages than in subtherapeutic dosages. The risk of an adverse drug reaction (ADR) was most often associated with anticholinergic agents, sedative-hypnotic drugs, and neuroleptics (thioridazine and chlorpromazine), particularly when prescribed concurrently. Risk of an ADR was highest when a drug was prescribed without recording a definite diagnostic indication. Lack of consistency by individual physicians in their approaches to the therapy of similar disease entities in comparable patients tended to support the concept of peer review in SNFs and also the need for teaching a rational approach to therapeutics in SNFs based on clinical pharmacology as applied to the elderly.

Aged↗
PubMed1979

Murine lymphoma alkaline phosphatase: a cell membrane carcinofetal enzyme.

Alkaline phosphatase (APase) has been shown to have a membrane-bound localization in the murine fetal thymus, in murine thymic lymphoma and in adult spleen. Since it was suggested from these previous experiments that the lymphoma APase might represent an embryonic function, a detailed biochemical comparison of the lymphoma APase with the fetal thymus, placenta, fetus and spleen APases was performed. The parameters investigated were pH optimum, activation, inhibition, heat inactivation, substrate ratios, Michaelis constant, and electrophoretic analysis in the presence and absence of neuraminidase with the substrates alpha-naphthyl phosphate, beta-glycerophosphate, and p-nitrophenyl phosphate. The results indicate that the lymphoma APase is very similar to the fetal thymus, placenta and spleen APases. Furthermore, these results lend support to the hypothesis that the APase activity which appears in thymic lymphoma might represent a derepressed embryonic function. Thus, the murine lymphoma APase may be termed a cell membrane carcinofetal enzyme.

Alkaline Phosphatase↗
PubMed1979

Improved methods for estimating initial heparin infusion rates.

Two methods of calculating heparin infusion rates for patients with venous thrombotic disease were compared; one method was based on a one-compartment pharmacokinetic model, the other on patient weight. Sixty-eight patients with presumed thromboembolic disease were started on continuous i.v. heparin sodium (porcine) using an infusion pump. Patients were divided into two groups--the infusion rate of Group I was based on patient weight (77 units/kg/4 hrs) and the infusion rate of Group 2 was determined by a pharmacokinetic equation based on a one-compartment heparin model. Heparin effect was measured by an activated partial thromboplastin time (APTT). The initial heparin infusion rate for Group 1 (4,784 +/- 672 units/4 hrs) was significantly greater (p less than 0.039, two-sample t-test) than that for Group 2 (4,413 +/- 779 units/4 hrs), but the variances of the rates were not significantly different (p = 0.40, ratio of variance F-test). Both methods for estimating initial heparin infusion rates gave mean APTT values in the center of the therapeutic range, but the variance in the APTTs of Group 2 patients was significantly smaller (p = 0.004) than that of Group 1. The pharmacokinetic model was more precise and reliable. This model should be valuable for insuring heparin's therapeutic effect without exposing patients to the potential risk of hemorrhage.

Adult↗
PubMed1979

Free radical activation of N-hydroxy-2-acetylaminofluorene by methemoglobin and hydrogen peroxide.

We have shown that N-hydroxy-2-acetylaminofluorene, a metabolite of 2-acetylaminofluorene, is converted via a nitroxide free radical into N-acetylaminofluorene and 2-nitrosofluorene by H2O2 in the presence of methemoglobin. Utilizing optical methods, we have demonstrated that the rate of 2-nitrosofluorene production parallels that of N-hydroxy-2-acetylaminofluorene oxidation. This evidence is consistent with a model whereby two molecules of N-hydroxy-2-acetylaminofluorene yield two nitroxide free radicals which then dismutate to form one molecule of N-acetoxy-2-acetylaminofluorene and one molecule of 2-nitrosofluorene. The Km of N-hydroxy-2-acetylaminofluorene for this reaction is 114 microM with a Vmax of 50 microM/min.

2-Acetylaminofluorene↗