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PubMed1994

A strategy for sampling on a sphere applied to 3D selective RF pulse design.

Conventional constant angular velocity sampling of the surface of a sphere results in a higher sampling density near the two poles relative to the equatorial region. More samples, and hence longer sampling time, are required to achieve a given sampling density in the equatorial region when compared with uniform sampling. This paper presents a simple expression for a continuous sample path through a nearly uniform distribution of points on the surface of a sphere. Sampling of concentric spherical shells in k-space with the new strategy is used to design 3D selective inversion and spin-echo pulses. These new 3D selective pulses have been implemented and verified experimentally.

Humans↗

PubMed2002

Rapid prenatal diagnosis of trisomy 21 in 5049 consecutive uncultured amniotic fluid samples by fluorescence in situ hybridisation (FISH).

OBJECTIVES: This was a retrospective study on the results of interphase fluorescence in situ hybridization (FISH), performed routinely for chromosome 21 and on ultrasonographic indications for chromosomes 13, 18, X and Y in a series of 5049 amniotic fluid samples. METHODS: Interphase FISH for chromosome 21 was performed in 5049 consecutive amniotic fluid samples for the rapid prenatal diagnosis of Down syndrome. Aneuploidy for four other chromosomes (13, 18, X and Y) was tested following ultrasonographic indications. Karyotypes from standard cytogenetic analysis were compared to the FISH results. RESULTS: Using conventional cytogenetics 3.6% (183/5049) chromosomal anomalies were detected. After exclusion of familial chromosome rearrangements, i.e. balanced autosomal reciprocal or Robertsonian translocations (30/5049) and inversions (19/5049), 2.65% chromosomal anomalies (134/5049) were diagnosed. Of this group 0.18% (9/5049) were chromosomal rearrangements not detectable by FISH and 2.47% (125/5049) were numerical chromosomal anomalies detectable by interphase FISH for chromosomes 13, 18, 21, X and Y. With routine interphase FISH for chromosome 21 and FISH on echographic indication for the other four chromosomes we detected 107/125 of these numerical chromosomal anomalies, i.e. 85.6%. All 70 cases of trisomy 21 were detected by FISH and confirmed with conventional cytogenetics (sensitivity=100%) and there were no false-positive results (specificity=100%). Maternal cell contamination of amniotic fluid samples occurred in 1.27% (64/5049) of samples; 0.26% (13/5049) of these samples were uninformative by FISH due to maternal cell contamination (12/5049) or absence of nuclei in one sample (1/5049). CONCLUSION: In this group of 5049 samples we found that FISH is a reliable technique for the rapid prenatal diagnosis of trisomy 21. The number of uninformative cases due to maternal cell contamination was low. The strategy to perform FISH for chromosome 21 in all samples and only on ultrasonographic indication for the four other chromosomes (13, 18, X and Y) followed by standard cytogenetics is effective.

Amniocentesis↗

PubMed2004

Exposure misclassification as a result of free sample drug utilization in automated claims databases and its effect on a pharmacoepidemiology study of selective COX-2 inhibitors.

PURPOSE: Free drug samples are widely used in clinical practice. We were concerned about free sample drug utilization as a source of misclassification in pharmacoepidemiology research using claims data that may result in biased effect estimates. METHODS: We investigated the magnitude of potential bias with sensitivity analyses based on a published study that examined cardiovascular risk associated with selective cyclooxygenase 2 (COX-2) inhibitors. We derived an estimate of free sample drug utilization with market data for rofexcoxib and calculated sensitivity of the exposure ascertainment method using claims data. We corrected the incidence rate ratio assuming the observed unexposed incidence rate was actually a weighted average rate of the truly unexposed and free sample drug users. The impact of exposure misclassification measured as the percentage change from a corrected to the reported crude incidence rate ratio was examined under a range of free sample drug utilization proportions and unexposed cohort sizes. RESULTS: The proportion of free sample drug utilization of all rofecoxib use in our base case scenario was 15.48%, resulting in sensitivity of 84.52% for exposure ascertainment. The magnitude of bias was an underestimation of the unadjusted incidence rate ratio by 0.03%. With a free sample drug utilization proportion of 1.48% and the same unexposed cohort size of 237 975 person-years, the underestimation was 0.003%. If the unexposed cohort were 975 person-years given a 15.48% proportion, the underestimation was 8.82%. CONCLUSIONS: In the pharmacoepidemiology study, we examined that uses claims data to ascertain drug exposure, our results suggest that adjustment for free sample drug utilization is probably not warranted.

Bias↗

PubMed2005

A proteomic study of the HUPO Plasma Proteome Project's pilot samples using an accurate mass and time tag strategy.

Characterization of the human blood plasma proteome is critical to the discovery of routinely useful clinical biomarkers. We used an accurate mass and time (AMT) tag strategy with high-resolution mass accuracy cLC-FT-ICR MS to perform a global proteomic analysis of pilot study samples as part of the HUPO Plasma Proteome Project. HUPO reference serum and citrated plasma samples from African Americans, Asian Americans, and Caucasian Americans were analyzed, in addition to a Pacific Northwest National Laboratory reference serum and plasma. The AMT tag strategy allowed us to leverage two previously published "shotgun" proteomics experiments to perform global analyses on these samples in triplicate in less than 4 days total analysis time. A total of 722 (22% with multiple peptide identifications) International Protein Index redundant proteins, or 377 protein families by ProteinProphet, were identified over the six individual HUPO serum and plasma samples. The samples yielded a similar number of identified redundant proteins in the plasma samples (average 446 +/- 23) as found in the serum samples (average 440 +/- 20). These proteins were identified by an average of 956 +/- 35 unique peptides in plasma and 930 +/- 11 unique peptides in serum. In addition to this high-throughput analysis, the AMT tag approach was used with a Z-score normalization to compare relative protein abundances. This analysis highlighted both known differences in serum and citrated plasma such as fibrinogens, and reproducible differences in peptide abundances from proteins such as soluble activin receptor-like kinase 7b and glycoprotein m6b. The AMT tag strategy not only improved our sample throughput but also provided a basis for estimated quantitation.

Blood Proteins↗

PubMed2006

Efficient extraction of proteins from woody plant samples for two-dimensional electrophoresis.

Protein extraction from plant samples is usually challenging due to the low protein content and high level of contaminants. Therefore, the 2-DE pattern resolution is strongly influenced by the procedure of sample preparation. Efficient solubilization of proteins strictly depends on the chaotrope and detergent in the extraction buffer. Despite the large number of detergents that have been developed for the use in protein extraction and IEF, there is no single compound able to efficiently extract proteins from any source. Hence, optimization has to be performed for each type of sample. We tested several chaotrope/detergent combinations to achieve optimal solubilization and separation of proteins from Norway spruce [Picea abies (L.) H. Karst.] needles and European beech (Fagus sylvatica L.) leaves and roots. The same chaotrope mixture (7 M urea, 2 M thiourea) was found to be suitable for the extraction and separation of proteins from all samples. Nonetheless, the efficiency of the surfactants tested varied between samples so that optimal extraction and separation was achieved with different detergents or combination of detergents for each sample. The 2-DE separation of spruce needle proteins was optimal in a mixture of two zwitterionic detergents (2% CHAPS and 2% decyl dimethylammonio propanesulfonate). Beech proteins were best separated in buffers containing sugar-based detergents (2% n-octyl beta-D-glucopiranoside in the case of leaf samples and 2% dodecyl maltoside for the root samples). IEF was performed in buffers with the same composition as the extraction buffer except for the root proteins that were better focused in a buffer containing 2% CHAPS.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2004

A portable automated system for trace gas sampling in the field and stable isotope analysis in the laboratory.

A computer-controllable mobile system is presented which enables the automatic collection of 33 air samples in the field and the subsequent analysis for delta13C and delta18O stable isotope ratios of a carbon-containing trace gas in the laboratory, e.g. CO2, CO or CH4. The system includes a manifold gas source input for profile sampling and an infrared gas analyzer for in situ CO2 concentration measurements. Measurements of delta13C and delta18O of all 33 samples can run unattended and take less than six hours for CO2. Laboratory tests with three gases (compressed air with different pCO2 and stable isotope compositions) showed a measurement precision of 0.03 per thousand for delta13C and 0.02 per thousand for delta18O of CO2 (standard error (SE), n = 11). A field test of our system, in which 66 air samples were collected within a 24-hour period above grassland, showed a correlation of 0.99 (r2) between the inverse of pCO2 and delta13C of CO2. Storage of samples until analysis is possible for about 1 week; this can be an important factor for sampling in remote areas. A wider range of applications in the field is open with our system, since sampling and analysis of CO and CH4 for stable isotope composition is also possible. Samples of compressed air had a measurement precision (SE, n = 33) of 0.03 per thousand for delta13C and of 0.04 per thousand for delta18O on CO and of 0.07 per thousand for delta13C on CH4. Our system should therefore further facilitate research of trace gases in the context of the carbon cycle in the field, and opens many other possible applications with carbon- and possibly non-carbon-containing trace gases.

Carbon Dioxide↗

PubMed2006

Flushing time and storage effects on the accuracy and precision of carbon and oxygen isotope ratios of sample using the Gasbench II technique.

Continuous-flow isotope ratio mass spectrometry interfaced with a Gasbench II is used for automated and faster analyses of delta(13)C and delta(18)O in water, carbonate, and air samples that are accurate and highly precise. Prior to online chemistry and measurement using the Gasbench technique, rubber septa-capped glass vials are routinely flushed to remove air. Due to the small amounts of sample gas required for isotope analyses using current techniques, care should be taken to properly flush these vials to avoid contamination of sample gas with air. Our results indicate that isotopic composition of sample CO(2) gas remains constant when 10 mL vials are flushed (rate of 100 mL/min) for > or =600 s, whereas for vials flushed <600 s, the isotopic composition becomes substantially lighter with decreasing time of flushing, which affects the accuracy of analyses. This largely depends on the isotopic composition (and volume) of air that still remains after flushing. This effect is more pronounced on delta(18)O than on delta(13)C of sample CO(2) gas because there is very little carbon in the air. After 24 h storage in vials with punctured septa, both delta(13)C and delta(18)O of CO(2) become isotopically heavier compared with first day analyses, suggesting time-dependent changes in isotopic composition. The magnitude of shift depends on the concentration and the isotopic composition of CO(2) in laboratory air as well as on fractionation due to outflow of sample gas or inflow of air via punctured septa. Contamination of sample gas with air can be observed as a secondary peak on chromatograms that precedes sample peaks, and the intensity of these peaks depends on the amount of air. Such peaks are always present with short flushing times. For accuracy and better precision, irrespective of the magnitude of the secondary peaks, the analyses should be discarded if these appear in the chromatograms.

Journal Article↗

PubMed2006

Control of confounding through secondary samples.

The control of confounding is essential in many statistical problems, especially in those that attempt to estimate exposure effects. In some cases, in addition to the 'primary' sample, there is another 'secondary' sample which, though having no direct information about the exposure effect, contains information about the confounding factors. The purpose of this article is to study the influence of the secondary sample on likelihood inference for the exposure effect. In particular, we investigate the interplay between the efficiency improvement and the possible bias introduced by the secondary sample as a function of the degree of confounding in the primary sample and the sizes of the primary and secondary samples. In the case of weak confounding, the secondary sample can only little improve estimation of the exposure effect, whereas with strong confounding the secondary sample can be much more useful. On the other hand, it will be more important to consider possible biasing effects in the latter case. For illustration, we use a formal example of a generalized linear model and a real example with sparse data from a case-control study of the association between gastric cancer and HM-CAP/Band 120.

Case-Control Studies↗

PubMed1992

Optimum sample size determination in stratified case-control studies with cost considerations.

We investigate sample size determination for Cochran's test for stratified case-control studies when samples of cases and controls are allocated to maximize the asymptotic efficiency of Cochran's test subject to fixed total cost with cost per control varying by strata. We consider two situations typical of strata-matched case-control studies: when one samples both cases and controls and when cases are given and one samples controls. In each situation we develop and study an asymptotic method for finding the sample size required for a specific power under the optimum allocation proposed by Nam and Fears. Also, for the second situation, we investigate an asymptotic method for determining the common ratio, k, in one-to-k strata-matched case-control studies without cost consideration for a given power. When cases are given, neither the optimum nor the standard control sample sizes appear in a closed form; we present numerical methods for calculating these sample sizes and illustrate them with examples. We find the reduction in total cost obtained under the optimum allocation compared to standard allocation more pronounced as the differences in stratum-specific costs of sampling controls increase.

Adult↗

PubMed2002

Overview of results from the WaterTox intercalibration and environmental testing phase II program: Part 1, statistical analysis of blind sample testing.

There is an urgent need to evaluate the presence of toxicants in waters used for human consumption and to develop strategies to reduce and prevent their contamination. The International Development Research Centre undertook an intercalibration project to develop and validate a battery of bioassays for toxicity testing of water samples. The project was carried out in two phases by research institutions from eight countries that formed the WaterTox network. Results for the first phase were reported in the special September 2000 issue of Environmental Toxicology. Phase II involved toxicity screening tests of environmental and blind samples (chemical solutions of unknown composition to participating laboratories) using the following battery: Daphnia magna, Hydra attenuata, seed root inhibition with Lactuca sativa, and Selenastrum capricornutum. This battery was also used to assess potential toxicity in concentrated (10x) water samples. Results are presented for a set of six blind samples sent to the participating laboratories over a 1-year period. Analyses were performed for each bioassay to evaluate variations among laboratories of responses to negative controls, violations of test quality control criteria, false positive responses induced by sample concentration, and variability within and between labs of responses to toxic samples. Analyses of the data from all bioassays and labs provided comparisons of false positive rates (based on blind negative samples), test sensitivities to a metal or organic toxicant, and interlaboratory test variability. Results indicate that the battery was reliable in detecting toxicity when present. However, some false positives were identified with a concentrated soft-water sample and with the Lactuca and Hydra (sublethal end-point) tests. Probabilities of detecting false positives for individual and combined toxic responses of the four bioassays are presented. Overall, interlaboratory comparisons indicate a good reliability of the battery.

Animals↗

PubMed2005

Analysis of endosulfan and its metabolites in rat plasma and selected tissue samples by gas chromatography-mass spectrometry.

A method has been developed for the determination of trace levels of alpha-endosulfan, beta-endosulfan, endosulfan sulfate, and endosulfan diol in rat plasma and tissue samples. Endosulfan and its metabolites in the plasma samples were extracted with solid-phase extraction Chromabond-end-capped C18 cartridges and analyzed by a Shimadzu QP-5050A gas chromatograph-mass spectrometer (GCMS) with quadrupole detector in selected-ion-monitoring mode. The analysis of endosulfan and its metabolites in liver and kidney samples involved solvent extraction, Florisil solid-phase-extraction cleanup, and quantitation by GCMS. Recovery experiments for the plasma and tissue samples were conducted over concentration ranges of 10-100 ng mL(-1) and 100-1000 ng mL(-1), respectively. The method was applied to the analysis of trace levels of endosulfan and its metabolites in plasma and tissue samples collected from an animal study. Trace levels of alpha-endosulfan and beta-endosulfan in the ranges of undetectable to 3.11 microg g(-1) and undetectable to 1.19 microg g(-1), respectively, were detected in the kidney samples, whereas trace levels of endosulfan sulfate in the range of 0.02-0.22 microg g(-1) were detected in the liver samples of rats. Neither endosulfan nor its metabolites was detected in any of the plasma samples.

Animals↗

PubMed1996

On-the-probe sample cleanup strategies for glycoprotein-released carbohydrates prior to matrix-assisted laser desorption-ionization time-of-flight mass spectrometry.

On-the-probe sample cleanup strategies were developed for matrix-assisted laser desorption-ionization (MALDI) time-of-flight mass spectrometry to improve the mass spectral characteristics of glycoprotein-released carbohydrate samples, including those fractionated by high pH anion exchange (HPAE) chromatography or treated with glycosidases. Small in situ amounts of chromatographic media are codeposited with matrix onto a probe containing a carbohydrate sample to minimize interferences from cations, anions, and/or detergents introduced from the sample and/or matrix. On-the-probe sample cleanup is fast (a few minutes) and operates best on picomole quantities of analyte in sample volumes less than 5 microliter containing nanomole quantities or less of impurities. This in situ cleanup dramatically increases the mass spectral signal-to-background, improves mass accuracies, better equalizes the sensitivities for diverse carbohydrate structures, and has the potential to remove contaminants that bypassed previous purification schemes. Direct MALDI mass profiling of digest aliquots containing low picomole amounts of carbohydrate structures either enzymatically released from a glycoprotein or sequentially degraded with multiple glycosidases was performed using only microscale digest conditions with reduced buffer amounts and on-the-probe sample cleanup to minimize the digest impurities. Membrane microdialysis was compared to on-the-probe sample cleanup and found to more completely remove the nano- to micromole amounts of anions (and cations) in HPAE fractions in one step as opposed to multiple on-the-probe steps.

Carbohydrate Conformation↗

PubMed1996

IgG subclass antibodies to human cytomegalovirus (CMV) in normal human plasma samples and immune globulins and their neutralizing activities.

An enzyme-linked immunoabsorbent assay (ELISA) was developed for quantitation of IgG subclass antibodies to human cytomegalovirus (CMV) in human serum or plasma samples and in immune globulin (IG) preparations. The assay was based on the parallel titration of known concentrations of purified IgG subclass myeloma proteins and a specific CMV antiserum. The purified IgG subclass myeloma proteins were captured on an ELISA plate pre-coated with anti-human kappa, anti-human lambda or a mixture of anti-human kappa and lambda antibodies and the specific antiserum was titrated against CMV antigen coated on the plate. IgG subclass antibodies, captured or bound to antigen, were quantitated with IGG subclass heavy chain specific monoclonal antibodies. The method was highly reproducible, specific and sensitive. Using this method, 257 human plasma samples and 50 IG preparations were assayed for CMV specific IgG subclass and IgM antibodies. The major IgG subclass antibody to CMV was IgG1 which represented more than 96% of CMV IgG antibodies, followed by IgG3 (mean CMV IgG3 antibody content was 3% of IgG antibodies in IG preparations and 1.8% in plasma samples). A majority of the samples had low levels of IgG2 antibodies and a few samples exhibited low levels of IgG4 antibodies. IG preparations showed very low levels of CMV IgM antibodies whereas plasma samples had 14.2% of CMV antibodies (IgG and IgM) as IgM antibodies. Virus neutralizing (Nt) activity of these samples showed a significant correlation with CMV IgG1 antibodies. Nine samples of plasma and IGs were further evaluated for Nt activity of IgG1 and IgG3 antibodies by separating IgG3 from the rest of the antibodies with protein A agarose. IgG3 antibodies showed much higher Nt activity than IgG1 antibodies suggesting that enrichment of IgG3 antibodies in IG preparations may be useful in preparing CMV specific IG.

Antibodies, Viral↗

PubMed1997

Sample-Induced RF Perturbations in High-Field, High-Resolution NMR Spectroscopy

Conducting dielectric samples are often used in high-resolution experiments at high field. It is shown that significant amplitude and phase distortions of the RF magnetic field may result from perturbations caused by such samples. Theoretical analyses demonstrate the spatial variation of the RF field amplitude and phase across the sample, and comparisons of the effect are made for a variety of sample properties and operating field strengths. Although the effect is highly nonlinear, it tends to increase with increasing field strength, permittivity, conductivity, and sample size. There are cases, however, in which increasing the conductivity of the sample improves the homogeneity of the amplitude of the RF field across the sample at the expense of distorted RF phase. It is important that the perturbation effects be calculated for the experimental conditions used, as they have the potential to reduce the signal-to-noise ratio of NMR experiments and may increase the generation of spurious coherences. The effect of RF-coil geometry on the coherences is also modeled, with the use of homogeneous resonators such as the birdcage design being preferred. Recommendations are made concerning methods of reducing sample-induced perturbations. Experimental high-field imaging and high-resolution studies demonstrate the effect.

Journal Article↗

PubMed1996

Detection and molecular typing of Campylobacter jejuni in fecal samples by polymerase chain reaction.

In order to determine whether polymerase chain reaction (PCR) could be used to detect Campylobacter jejuni directly in stool samples, DNA from 66 frozen culture positive and negative fecal samples was purified by column chromatography. The flaA gene was amplified using primers directed against the conserved 5' and 3' regions and produced a 1.7 kb amplicon. Fifteen of 18 (83%) C. jejuni culture positive samples were detected by agarose gel electrophoresis and ethidium bromide staining. The test was negative in one sample containing C. coli. Twelve samples containing other enteric pathogens were negative as were 34 of 35 culture negative samples. Flagellin gene typing (see reference 14) of the flaA gene product from two stool samples in which the patients' stool isolate was also available showed the identical flagellin gene types suggesting that molecular typing of Campylobacter could potentially be performed on stool samples without the need for culture.

Bacterial Typing Techniques↗

PubMed1997

An explanation for failure to predict cyclosporine area under the curve using a limited sampling strategy: a beginner's second note.

Recently, limited sampling strategies have been developed to predict the area under a blood drug concentration-time curve (AUC). Multiple stepwise linear regression is the method used to develop limited sampling strategies. Several limited sampling strategies are used to predict cyclosporine AUC. However, recent findings demonstrated that, of all the developed limited sampling strategies, none can predict cyclosporine AUC correctly. Although several explanations have been given for this, the possible mathematical reason has not yet been fully explored. In the present study, we demonstrated that: (i) a steady-state blood drug concentration can be decomposed into the linear and non-linear components using the Fourier series; (ii) the non-linear component of the steady-state blood drug concentration leads to an AUC with a non-linear component, which affects the validation of limited sampling strategies; (iii) the correlation coefficient in a limited sampling strategy can only account for the linear association of linear components between a steady-state blood drug concentration and the AUC; (iv) the average steady-state blood drug concentration is a linear component of the steady-state blood drug concentration; and (v) when developing a limited sampling strategy, the non-linear component can be effectively ignored by: (a) choosing the sampling time around the middle point between the peak and the trough steady-state blood drug concentrations; and (b) increasing the trough steady-state blood drug concentration. However, the latter is restricted by clinical considerations.

Animals↗

PubMed1996

Microcalorimetric measurements carried out on isolated tumorous and nontumorous tissue samples from organs in the urogenital tract in comparison to histological and impulse-cytophotometric investigations.

In this comparative study, microcalorimetric measurements were carried out on a total of 96 tumorous and nontumorous tissue samples taken from organs of the urogenital tract using a thermal activity monitor (TAM). Changes in the heat emission of the tissue samples were measured at 1-min intervals and graphically displayed as a function of time. The aim of the study was to compare the microcalorimetric results with impulse-cytophotometric and histological findings and provide evidence for the metabolic activity of tumorous and nontumorous tissue. In order to obtain the variation in metabolic activity, the maxima (Pmax) of the curves were determined as a value of the maximum thermal power of a tissue sample, the mean values (P) were determined by the mean thermal power and the contour integrals (W) were defined by the behavior of the energy reserves and their mobilization. The first part of the study was carried out to investigate whether tumorous and nontumorous tissue samples differ in general according to their metabolic activity. We discovered, using the parameters described above, that in general tumorous tissue exhibited a higher metabolic activity than nontumorous tissue samples. For example, both W and P in tumorous prostate tissue samples were eightfold higher and the (Pmax) value was 8.4-fold higher than in normal tissue. Additional investigations on testicle and kidney tissues were performed to find a possible correlation between microcalorimetric results and histological grading. We found that an increasing malignancy correlated with a higher metabolic activity of the tissue. Based upon these results we were able to differentiate the various histological gradings of these tumorous tissues by microcalorimetric measurements. The results show it is possible to differentiate between normal and tumorous tissue samples by microcalorimetric measurement based on the distinctly higher metabolic activity of malignant tissue. Furthermore, microcalorimetry allows a differentiation and classification of tissue samples into their histological grading. With the help of microcalorimetry, it might be possible in future to detect and record the metabolic processes of isolated tissue structures and changes in these activities as a result of medical intervention such as cytostatic treatment.

Aged↗

PubMed1993

A limited sampling method for estimation of the etoposide area under the curve.

A limited sampling method for estimation of the etoposide area under the curve (AUC) is presented. The method was developed and validated in 23 patients (42 pharmacokinetic studies) with small-cell lung cancer (SCLC), limited disease. The patients received 100 mg/m2 etoposide as a 90-min intravenous infusion in combination with carboplatin, allowing for etoposide dose modification at a following course (25% increase or decrease) due to high or low nadir values for leukocytes or thrombocytes. Of the 42 pharmacokinetic studies, 27 were used in the model development and 15 were used in the model validation. Single regression analyses of the AUC versus the fitted concentrations for the model data set were performed at several time points. The analyses demonstrated high and essentially identical correlation coefficients in the interval between 2 and 21 h, with a maximal value of 0.96 being recorded at 4 h. Multiple regression analysis was then performed using fitted concentrations corresponding to 0.08-21 h. The best model for one sample was AUC = 1.01 x (dose level divided by 100 mg/m2) + 799 x C4 h, that for two samples was AUC = 1.43 x (dose level divided by 100 mg/m2) + 544 x C4 h + 1756 x C21 h, and that for three samples was AUC = 0.07 x (dose level divided by 100 mg/m2) + 110 x C5 min + 474 x C4 h + 1759 x C21 h. Not unexpectedly, the model validation revealed that the one-sample model was less precise than the two- or three-sample model [percentage of root mean squared error (RMSE%) = 11.6%, 7.1%, and 5.4%, respectively]. All models proved to be unbiased in the validation [percentage of mean predictive error (MPE%) +/- SE = 4.2% +/- 11.0%, 7.9% +/- 6.1%, and 6.3% +/- 5.3%, respectively]. The models were subsequently validated in 14 pharmacokinetic studies of patients with metastatic germ-cell tumours who were receiving combination chemotherapy with cisplatin and bleomycin plus 100 mg/m2 etoposide as a 90-min infusion. The RMSE% was 13.4%, 10.8%, and 9.0% and the MPE% +/- SE was -1.0% +/- 11.9%, 1.7% +/- 10.5%, and 2.7% +/- 7.9% for the one-, two-, and three-sample models, respectively. The limited sampling methods presented herein may prove to be a most valuable tool for therapeutic drug monitoring in regimens in which etoposide is given in combination with carboplatin or with cisplatin and bleomycin.

Antineoplastic Combined Chemotherapy Protocols↗