Criteria for the certification of internationally acceptable reference materials.
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Biomedical subjects
Publications and source records attributed to H Schimmel.
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The absolute and relative bioavailability of metoclopramide following the administration of a single suppository--test (Gastrosil) and reference preparations--containing 20 mg of the pure drug or after i.v. injection of 17.8 mg was compared in 12 sex matched healthy volunteers according to an open, three-way cross-over, intra-individual design. The metoclopramide plasma levels were determined up to 32 h following rectal administration and 24 h following intravenous application using a modified and specific HPLC-assay. The areas under the concentration-time curves were either calculated to the last time-interval measured (AUC-1) by using the trapezoidal rule or by extrapolating to infinity (AUC(0-infinity] in a model-dependent manner. Pair-differences and ratios were taken for the individual AUC-values and for the maximum plasma levels (cmax-values) at the corresponding time values (tmax-values) for test and reference formulations and tested for statistical significance. The results showed the mean AUC-1 and AUC (0-infinity)-values respectively to be 10.7% and 9.5% lower for the test suppository. The mean tmax-values were found to be 21% and 11.6% lower and the mean cmax-values were found to be about 4.3% larger than the corresponding parameters for the reference formulation. The 95% Wilcoxon confidence limits for both test and reference preparation were found to range from 80.2-108.9% for all AUC-values and to lie in the region 83.5-120.3% and 57.8-100% for the cmax- and tmax-values, respectively. Thus, with respect to the pharmacokinetic target parameters, little difference can be found between the two suppository forms each containing 20 mg metoclopramide-base and under trial in this study.(ABSTRACT TRUNCATED AT 250 WORDS)
The concept of generally increased lipid synthesis during the initial 2/3 of picornaviral infectious cycles, held by several authors, needs differentiation. In mengovirus-infected Ehrlich ascites tumor cells, an increase in the rate of synthesis of phosphatidylcholine could be confirmed, but for phosphatidylethanolamine constant to decreasing rates of synthesis were found. Moreover, phosphatidylinositol was increasingly synthesized in the midst of the infectious cycle. The changes observed might have their functional expression in the proliferation of smooth cytoplasmic membrane systems that provide the structural framework for the replication of picornaviral RNA and virus assembly. The alterations in the labeling patterns of phosphatidylinositol, phosphatidylglycerol and diphosphatidylglycerol late in virus infection point to increased turnover of these compounds, possibly mediated by phospholipase D. The formation of lysophosphatidylcholine (cytolytic effect) and bis(monoacylglyceryl)phosphate in the final phase of the infectious cycle might be correlated with the liberation of lysosomal enzymes and the development of the cytopathic effect.
The interaction of nonepithelial intermediate filament (IF) proteins with vesicles produced from total Ehrlich ascites tumor cell lipids results in the formation of complexes which in sucrose density gradient centrifugation attain positions distinctly different from those of the original reactants. In KBr density gradient equilibrium centrifugation, the IF protein-lipid adducts accumulate as thin proteolipid films on top of the KBr gradients, whereas in the absence of lipids the proteins remain distributed within the density gradients. Similar results were obtained with vesicles derived from individual phospholipids and a mixture thereof. The affinity of IF proteins for negatively charged phospholipids is greater than that for vesicles derived from uncharged phospholipids. Limited digestion of IF proteins with various proteinases demonstrated that for optimal association of the reactants IF proteins must carry an intact N terminus and that the isolated N-terminal polypeptide itself shows strong reactivity with lipid vesicles. Arginine-phosphate interactions between the N terminus and phospholipids seem to be partly responsible for this association. However, as shown by hydrophobic interaction chromatography on phenyl- and octyl-Sepharose 4B, IF proteins and their proteolytic derivatives also appear to have high affinities for aromatic and aliphatic substructures of biologically important molecules. The results are discussed in terms of a possible functional role of IF protein-lipid interactions in the association of nonepithelial intermediate filaments with intracellular membrane systems.
A 6-item Orientation-Memory-Concentration Test has been validated as a measure of cognitive impairment. This test predicted the scores on a validated 26-item mental status questionnaire of two patient groups in a skilled nursing home, patients in a health-related facility, and in a senior citizens' center. There was a positive correlation between scores on the 6-item test and plaque counts obtained from the cerebral cortex of 38 subjects at autopsy. This test, which is easily administered by a nonphysician, has been shown to discriminate among mild, moderate, and severe cognitive deficits.
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Normative studies were carried out with 8 adult subjects whose averaged evoked responses to auditory stimuli were scored visually and by a number of differently defined quantitative methods (machine scoring). In order to compare different scoring methods a common signal-to-noise ratio measure was introduced based on a model where noise is distributed normally and signal is additive. Visual and machine scoring proved to be approximately equally sensitive, but the latter lends itself to a superior testing procedure which takes only one-third as long for equivalent results and is not contaminated by subjective error. The authors believe that the greatest promise for improving evoked response audiometry lies in the exploration of the new techniques proposed earlier. Progress in proving out one of these techniques, fast periodic stimulation, is reported.
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The (+/-) reference is defined as the result of alternate addition and subtraction and division by N (the number of sample functions). Under suitable conditions both the (+/-) reference and the variable component (noise) of the usual average tend to be derived from the same Gaussian process, and the former can be used as a measure of the latter. This property is most easily applied when the noise is derived from a stationary process. Application of the (+/-) reference and the average of the square of the voltage in studies of evoked response is discussed.
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The relationship between daily deaths and daily concentrations of Smoke and SO2 in London, England for 14 winters during the years 1958-1959 through 1971-1972 has been explored. Three types of analyses were used: (1) year-by-year multiple regression; (2) stratification using nested quartiles of one pollutant within quartiles of the other; and (3) multiple regression of a special subset of high pollution days. An association was found with Smoke, but not with SO2. Whether a linear model with zero threshold or a threshold model best fits could not be determined unambiguously because of a statistical artifact. Reasons for preferring a threshold-type quadratic model are given.
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