Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs.
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Biomedical subjects
Publications and source records attributed to J T Wilson.
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Earlier, we reported that the 5' end of the normal beta-globin gene (beta) resides on a 1.14-kilobase DNA fragment, whereas the 5' end of the sickle cell gene (beta s) resides on a 1.34-kilobase fragment. In that blot hybridization analysis, we used genomic DNA digested with restricted endonuclease Mst II, and radioactive probes with short half-life. We demonstrate here that, if a biotinylated probe is used instead in a slightly modified procedure, sickle cell anemia can be quickly and directly detected if there is as much as 5 micrograms of total genomic DNA in the sample. This procedure obviates the special precautions necessary when radioactive materials are used.
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We investigated, by radionuclide ventriculography, left ventricular function in 10 fit elderly men and in 11 young volunteers. During exercise in the young subjects left ventricular ejection fraction (LVEF) rose from 63 +/- 3 to 73 +/- 1 (P less than 0.005) and end systolic volume (ESV) fell from 48 +/- 6 to 38 +/- 5 ml (P less than 0 +/- 0.005) but were unchanged in the elderly (57 +/- 3 to 55 +/- 3 and 57 +/- 6 to 64 +/- 7 ml, respectively (NS). End diastolic volume (EDV) did not change in either group; stroke volume rose significantly only in the younger subjects, cardiac output rose in both groups but less in the elderly (5 +/- 0.5 to 12 +/- 1 vs 6 +/- 0.5 to 18 +/- 11 min-1). We conclude that this data lend support to the hypothesis that increasing age is associated with reduced left ventricular contractile performance.
The fate of six organic compounds during rapid infiltration of primary wastewater through soil columns was studied. Feed solutions were prepared which contained all six compounds in individual concentrations ranging from 1 to 1,000 micrograms/liter and were applied to separate soil columns on a flooding-drying schedule. Feed solutions and column effluents were analyzed for the compounds by XAD resin (Rohm and Haas Co.) extraction and gas chromatography-mass spectrometry during each of three successive inundation cycles. Breakthrough profiles of o-phenylphenol were relatively consistent during the test, with fractional breakthrough (mass output/mass input) being independent of input concentration. Consistent profiles were also observed for 2-(methylthio)benzothiazole, although fractional breakthroughs were higher at lower input concentrations, indicating that removal processes were operating less efficiently at these levels. The behavior of p-dichlorobenzene was similar to that of 2-(methylthio)benzothiazole after the first inundation cycle, with the exception that increased fractional breakthroughs were observed at the highest input concentration as well. Microbial adaptation was evident for benzophenone, 2-methylnaphthalene, and p-(1,1,3,3-tetramethylbutyl)phenol, as indicated by increased removal efficiencies during successive inundation cycles, especially at the higher input concentrations. Column effluent concentrations of the latter two compounds were independent of input concentrations during the final stage of the test. Microbial activity and adaptation were confirmed for several of the compounds by using isotopes and measuring the extent of mineralization in batch tests with soil from one of the columns.(ABSTRACT TRUNCATED AT 250 WORDS)
When soil columns were operated aerobically on a flooding-drying schedule in a previous study, good removals were observed for several organic compounds at concentrations ranging from 1 to 1,000 micrograms per liter in primary wastewater. In this study, fractional breakthroughs of most compounds increased substantially once operating parameters were modified and the soil became anaerobic. These results imply that microbial removal of trace organic compounds can be inhibited if anaerobic conditions develop during rapid infiltration of wastewater.
The characteristic clinical heterogeneity of sickle cell anemia (HbSS) may be, in part, a result of its interactions with alpha-thalassemia. Although alpha-thalassemia clearly affects some hematologic features of HbSS, its role in modulating the vasoocclusive severity of disease is not clear. To further explore this relationship, we examined the incidence of painful episodes, acute chest syndrome, aseptic bone necrosis, and leg ulcers in 3 patient groups with sickle cell disease: (1) 2,147 patients over age 2 yr, stratified according to mean corpuscular volume (MCV); (2) 183 patients selected on the basis of microcytosis and elevated HbA2, on whom globin biosynthesis studies were done; and (3) 125 patients who had alpha-globin genotype assigned by restriction endonuclease gene mapping. When patients were stratified by MCV, there was a reciprocal relationship between HbA2 levels and MCV, reflecting the presence of patients with beta o and alpha-thalassemia in the low MCV groups. The erythrocyte indices and HbA2 levels in patients classified as HbSS-alpha-thalassemia, by either globin synthesis studies or gene mapping, were very similar to those previously reported by others. Neither microcytosis, beta o, or alpha-thalassemia appeared to provide any clear protection from the vasoocclusive complication evaluated, and the prevalence of aseptic necrosis was increased in patients with microcytosis over age 20 yr and in groups with alpha-thalassemia. The effects of a reduced MCV and mean corpuscular hemoglobin concentration (MCHC), of possible benefit by themselves, when accompanied by a reduction in hemolysis and rise in hemoglobin concentration, as in HbSS-alpha-thalassemia, may cause sufficient rise in blood viscosity in critical vascular beds to impair blood flow and negate any amelioration of vasoocclusive complications in HbSS.
The visual responses to stimulus onset and offset can be isolated psychophysically from the response to steady-state stimulation. Six experiments investigated the perception of onset and offset of dot bigrams within random-dot patterns. Onset and offset persistence were studied at two levels of stimulus luminance (8 and 45ft-L). Similar performance was obtained for targets defined by onset and offset; the lower luminance produced a decrement in response at offset. Onset and offset perceptibility were studied at six stimulus durations between 20 and 1260 msec. Effects of stimulus duration were distinguished from masking effects due to pattern offset. Decreasing stimulus duration had little or no effect on recognition of bigrams defined by onset but produced a large decrement in the perceptibility of bigrams defined by offset. A brief stimulus therefore seems to give a relatively strong on-response and a weak off-response. These psychophysical results are consistent with electrophysiological findings concerning on- and off-responses and contrast with the idea that persistence consists of a decaying trace of the steady-state properties of the stimulus.
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1. The dependency of product formation on reaction time and on enzyme concentration was studied with certain purified enzymes and liver microsomal mixed-function oxidase system. 2. The product-formation-time relation was estimated with different enzyme and/or substrate concentrations for the reactions limited by diffusion. 3. The kinetic constants of the product-time relations in these diffusion systems have been verified experimentally to give a more specific and detailed characterization of an enzyme system under a variety of physiologic and reaction conditions. 4. The influence of inhibitors and activators in vitro, the effect of enzyme preparation technic, aging, starvation, pretreatment with somatotropic hormone, phenobarbital or 3-methylcholanthrene, and the effect of a tumor were studied. 5. The influence of vitamin C deficiency in guinea pig was also studied.
A pharmacokinetic approach was used for gentamicin dosing in 19 children and young adults with cystic fibrosis. A one-compartment open-model analysis of steady-state gentamicin pharmacokinetics revealed a significantly larger apparent volume of distribution and total plasma clearance for patients with CF as compared to a similar population of children without the disease. The increase in the apparent volume of distribution for patients with CF produced a larger daily gentamicin dose requirement to maintain similar steady-state levels as compared to children without the disease. Significant differences in the elimination rate constant and half-life for gentamicin were not found between these populations. Linear correlations between creatinine clearance and kel for gentamicin, and total body body weight and the apparent volume of distribution were demonstrated for children with varying degrees of stable renal function but not patients with CF. Altered gentamicin disposition peculiar to CF precludes application of currently used dosing nomograms or guidelines derived from normal populations, and emphasizes the need for individualized gentamicin therapy guided by a pharmacokinetic approach in these patients.
We have reported the direct analysis of the allele for beta 2-globin by using restriction endonuclease Dde I coupled with blot-hybridization analysis. In that report we predicted that a major use of our analysis could be for the prenatal diagnosis of sickle cell anemia. Here we present such an analysis. In addition, this report also describes the use of a new enzyme Mst II, which also distinguish the beta s allele from the normal beta-globin allele. Blot-hybridization analysis with restriction endonuclease Mst II shows the 5' end of the normal beta-globin gene to reside on a fragment of approximately 1.14 kilobases, whereas the 5' end of the beta s-globin gene resides on a fragment of approximately 1.34 kilobases. Because the fragment sizes generated by Mst II are significantly larger than those generated by Dde I, one can easily perform a prenatal diagnosis for sickle cell by standard blot hybridizations onto nitrocellulose filters.
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A high-performance liquid chromatographic method for quantitation of ibuprofen from serum and application of this method to ibuprofen disposition in the dog is described. The drug was extracted from acidified plasma with dichloromethane. The internal standard used was a methanolic solution of 4-n-butylphenylacetic acid. A muBondapak C18 column was used for analysis; this mobile phase was methanol-water-glacial acetic acid (pH 3.4) (75 : 24 : 1, v/v). A wavelength of 272 nm was used to monitor ibuprofen and the internal standard. Method sensitivity was 0.5 microgram/ml serum using either 0.5 or 1.0 ml of sample, and no interference was found from endogenous compounds or other commonly used anti-inflammatory agents. The coefficients of variation of the method were 4.2% and 6.0% for sample containing 50.0 and 6.25 microgram/ml of ibuprofen, respectively, and the calibration curve was linear for the range of 0.5 to 100 microgram/ml. This method was demonstrated to be suitable for pharmacokinetic and/or biopharmaceutical studies of ibuprofen in man and the dog.
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