Classification of highly similar crude oils using data sets from comprehensive two-dimensional gas chromatography and multivariate techniques.

Comprehensive two-dimensional gas chromatography (GCxGC) has proven to be an extremely powerful separation technique for the analysis of complex volatile mixtures. This separation power can be used to discriminate between highly similar samples. In this article we will describe the use of GCxGC for the discrimination of crude oils from different reservoirs within one oil field. These highly complex chromatograms contain about 6000 individual, quantified components. Unfortunately, small differences in most of these 6000 components characterize the difference between these reservoirs. For this reason, multivariate-analysis (MVA) techniques are required for finding chemical profiles describing the differences between the reservoirs. Unfortunately, such methods cannot discern between 'informative variables', or peaks describing differences between samples, and 'uninformative variables', or peaks not describing relevant differences. For this reason, variable selection techniques are required. A selection based on information between duplicate measurements was used. With this information, 292 peaks were used for building a discrimination model. Validation was performed using the ratio of the sum of distances between groups and the sum of distances within groups. This step resulted in the detection of an outlier, which could be traced to a production problem, which could be explained retrospectively.

Development of a laboratory robotic system for automated bioanalytical methods--I. The determination of theophylline in human plasma: a comparison between the robotized and manual method.

The quality of bioanalytical methods is often determined by the quality of sample preparation. Using a robot for sample treatment may give better results than manual sample preparation, since the robot lacks human behaviour and incidental errors that are part of it. The use of a laboratory robot has the additional advantage of giving each sample the same analytical history, resulting in better reproducibility. An automated method has been developed for the analysis of drugs in plasma using a laboratory robot. Theophylline was used as a probe drug. Sample preparation was automated with a Zymate II robot, followed by separation and quantitation on an HPLC-system. The robotic method showed a good correlation with the manual method, while sample throughput was doubled.

Theophylline-terbutaline, a steady state study on possible pharmacokinetic interactions with special reference to chronopharmacokinetic aspects.

1. The pharmacokinetic interaction of terbutaline and theophylline and chronopharmacokinetics of both drugs were studied in a three-way crossover study with repeated administration of terbutaline (Bricanyl Depot) 7.5 mg twice daily, theophylline (Theo-Dur) 300 mg twice daily alone or the combination of both for 7 days to 12 healthy volunteers (six male and six female). 2. After the morning dose on day 7, blood and urine were sampled for 12 h, and after the evening dose on day 7, blood and urine were sampled for 48 h. Theophylline concentrations in plasma and concentrations of unchanged drug and metabolites in urine were determined by two selective high performance liquid chromatography methods. Terbutaline concentrations in plasma and urine were measured with a gas chromatography-mass spectrometry method. Area under the plasma concentration-time curve, fluctuations in plasma concentration, mean residence time, elimination half-life, renal clearance as well as maximal, minimal and average plasma concentration at steady state were evaluated. 3. The addition of terbutaline to the repeated administration of theophylline lowered the relative bioavailability of theophylline by approximately 11% during the night interval. The rate of elimination of theophylline and mean residence time were influenced accordingly. No significant changes in excretion of the theophylline metabolites were observed, but the excretion of 3-methylxanthine was slightly reduced by the concomitant terbutaline administration. None of the observed changes should be of any clinical importance. 4. The addition of theophylline did not influence any of the calculated pharmacokinetic parameters of terbutaline. 5. It can be concluded that no dosage adjustment is necessary when terbutaline and theophylline are given together.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of the sources of variation affecting near-infrared spectroscopy using chemometric methods.

A rapid assessment of product quality can often be made using a combination of near-infrared spectroscopy (NIR) and multivariate calibration. The robustness of such a method is determined by the sensitivity of the multivariate calibration model to variations in the spectral data. An approach is described that uses a combination of experimental design methodology and principal component analysis to identify the main sources of variation in the spectra and to estimate their influence on the quantitative predictions. This is accomplished by comparing variations in a set of measured, replicate spectra to spectra with simulated variations. The approach was applied to the hydroxyl number determination of polyols by NIR spectroscopy and partial least-squares calibration. The results indicated that the most significant sources of variation were due to a variable cell path length and a variable curved background. Correction for these errors resulted in a 58% reduction in the standard deviation of the hydroxyl number predictions, indicating that a substantial improvement in the method precision is possible.

Elimination of uninformative variables for multivariate calibration.

A new method for the elimination of uninformative variables in multivariate data sets is proposed. To achieve this, artificial (noise) variables are added and a closed form of the PLS or PCR model is obtained for the data set containing the experimental and the artificial variables. The experimental variables that do not have more importance than the artificial variables, as judged from a criterion based on the b coefficients, are eliminated. The performance of the method is evaluated on simulated data. Practical aspects are discussed on experimentally obtained near-IR data sets. It is concluded that the elimination of uninformative variables can improve predictive ability.

Application of wavelet transform to extract the relevant component from spectral data for multivariate calibration.

An approach aiming at extracting the relevant component for multivariate calibration is introduced, and its performance is compared with the "uninformative variable elimination" approach and with the standard PLS method for the modeling of near-infrared data. The extraction of the relevant component is carried out in the wavelet domain. The PLS results on these relevant features are better, and therefore, it seems that this approach can successfully be used to remove noise and irrelevant information from spectra for multivariate calibration.

Creation of four consecutive instantaneous steady-state plasma concentration plateaus of theophylline and enprofylline by repeated infusions with exponentially decreasing delivery rates.

Repeated exponentially decreasing infusions have been used to administer theophylline and enprofylline to show whether it would be feasible to create consecutive plasma concentration plateaus within a few hours. The infusions were carried out on two separate days in 8 stable asthmatics. Before the infusion experiments, the pharmacokinetics of the substances in the individual subjects were determined on a separate day. Plasma concentration rose to the desired level within 5 min after the start of the infusion at each dose level and a stable plasma concentration plateau was maintained during the following 90 min of the infusion. It was possible to achieve 4 subsequent concentration plateaus within a 6 h period. Use of this infusion method resulted in predictable plasma concentrations at all levels and so the method appears safe when the required plasma concentrations are below the toxic level. Apart from clinical situations where effective dosages of drugs must be administered rapidly, the method showed be useful in pharmacological dose-response studies.

Effects of alpha-interferon on theophylline pharmacokinetics and metabolism.

1. The influence of alpha-interferon (Roferon-A) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intra-muscular injection (3 x 10(6) iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-1) was given. 2. Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3. Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4. After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P less than 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P less than 0.05). There was no systematic shift in the metabolic pattern of theophylline. 5. Additional investigations of the influence of the duration of alpha-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.

Dosing time and sex-related differences in the pharmacokinetics of cefodizime and in the circadian cortisol rhythm.

Two g cefodizime i.v. administration at 00:00, 06:00, 12:00 and 18:00 respectively, to 8 male and 8 female, young healthy volunteers, has shown: 1. a sex-related difference in both plasma (AUC) and total cumulative excretion of the agent with larger values in females than in males; 2. a dosing time-related difference in plasma (AUC) with the largest values for Rx at 00:00 and lowest for Rx at 18:00 in both males and females; 3. a dosing time-related difference in urinary concentration of cefodizime with largest values for Rx at 06:00 and lowest for Rx at 12:00. These urinary changes were highly correlated with changes in AUC for each dosing time; 4. no dosing time-related changes were observed for plasma T1/2 as well as cumulative urinary excretion of cefodizime; 5. curve patterns of plasma cortisol had similar aspects for both control and Rx at 00:00 with no sex-related differences. Curve patterns differed from control for other dosing times (p less than 0.005 to p less than 0.001 with ANOVA tests).