Therapeutic drug monitoring of clozapine in human serum by high-throughput paper spray mass spectrometry.

Introduction: Monitoring the atypical antipsychotic drug clozapine is crucial to ensure patient safety. This article showcases a high-throughput analytical method for measuring clozapine and its primary metabolite norclozapine (N-desmethylclozapine) in serum using paper spray mass spectrometry (PS-MS). Objectives: This study aimed to assess the viability of a PS-MS method for the rapid measurement of clozapine and norclozapine in human serum samples as an alternative to liquid chromatography mass spectrometry (LC-MS). Methods: Serum samples were processed by protein precipitation followed by deposition of the supernatant containing labelled internal standards onto paper spray substrates mounted in cartridges. Analytes were then analyzed using a triple quadrupole mass spectrometer equipped with a commercial paper spray ionization source. The results obtained from the patient samples were compared to those from a validated LC-MS assay. Results: PS-MS calibrations for clozapine and norclozapine were linear (R2 > 0.99) over five days. Between-run precision was below 8 %, and within-run precision did not exceed 10 %. When compared to a validated LC-MS method, the mean bias for 39 patient samples was -9% for clozapine and -1% for norclozapine, with no outliers. Mass spectrometry ion ratio comparisons indicated no interference for patient samples above the lower limit of quantification. There was less than 7 % change in the measured concentrations of both analytes over five days for samples dried on paper substrates. Notably, virtually no maintenance of the MS source was required during this study. Conclusion: This study illustrates the potential of PS-MS for serum drug monitoring in the clinical laboratory.

Discrimination and geo-spatial mapping of atmospheric VOC sources using full scan direct mass spectral data collected from a moving vehicle.

Volatile and semi-volatile organic compounds (S/VOCs) are ubiquitous in the environment, come from a wide variety of anthropogenic and biogenic sources, and are important determinants of environmental and human health due to their impacts on air quality. They can be continuously measured by direct mass spectrometry techniques without chromatographic separation by membrane introduction mass spectrometry (MIMS) and proton-transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). We report the operation of these instruments in a moving vehicle, producing full scan mass spectral data to fingerprint ambient S/VOC mixtures with high temporal and spatial resolution. We describe two field campaigns in which chemometric techniques are applied to the full scan MIMS and PTR-ToF-MS data collected with a mobile mass spectrometry lab. Principal Component Analysis (PCA) has been successfully employed in a supervised analysis to discriminate VOC samples collected near known VOC sources including internal combustion engines, sawmill operations, composting facilities, and pulp mills. A Gaussian mixture model and a density-based spatial clustering of application with noise (DBSCAN) algorithm have been used to identify sample clusters within the full time series dataset collected and we present geospatial maps to visualize the distribution of VOC sources measured by PTR-ToF-MS.

Discrimination of constructed air samples using multivariate analysis of full scan membrane introduction mass spectrometry (MIMS) data.

RATIONALE: Volatile and semi-volatile organic compounds (S/VOCs) are important atmospheric pollutants affecting both human and environmental health. They are directly measured as an unresolved mixture using membrane introduction mass spectrometry (MIMS). We apply chemometric techniques to discriminate, classify, and apportion air samples from a variety of sources. METHODS: Full scan mass spectra of lab-constructed air samples were obtained using a polydimethylsiloxane membrane interface and an electron ionization ion trap mass spectrometer. Normalized full scan spectra were analyzed using principal component analysis (PCA), cluster analysis, and k-nearest neighbours (kNN) for sample discrimination and classification. Multivariate curve resolution (MCR) was used to extract pure component contributions. Similar techniques were applied to VOC mixtures sampled from different woodsmoke emissions and from the headspace above aqueous hydrocarbon solutions. RESULTS: PCA successfully discriminated 32 constructed VOC mixtures from nearly 300 air samples, with cluster analysis showing similar results. Further, kNN classification (k = 1) correctly classified all but one test set sample, and MCR successfully identified the pure compounds used to construct the VOC mixtures. Real-world samples resulting from the combustion of different wood species and those associated with water contaminated with different commercial hydrocarbon products were similarly discriminated by PCA. CONCLUSIONS: Chemometric techniques have been evaluated using full scan MIMS spectra with a series of VOC mixtures of known composition containing known compounds, and successfully applied to samples with known sources, but unknown molecular composition. These techniques have application to source identification and apportionment in real-world environmental samples impacted by atmospheric pollutants.

Characterization of a condensed-phase membrane introduction mass spectrometry (CP-MIMS) interface using a methanol acceptor phase coupled with electrospray ionization for the continuous on-line quantitation of polar, low-volatility analytes at trace levels in complex aqueous samples.

We report the development and application of a capillary hollow fibre membrane interface using methanol as an acceptor phase to deliver target analytes to an electrospray ionization source and a triple quadrupole mass spectrometer. Superior fluid handling systems lead to greater signal stability and membrane integrity for the continuous on-line monitoring of polar and charged analytes in complex aqueous samples with detection limits in the parts-per-trillion to parts-per-billion range. The system can be operated in either a continuous flow or a stopped acceptor flow mode - the latter giving rise to greater sensitivity. We report detection limits, enrichment factors and signal response times for selected analytes with polydimethylsiloxane and Nafion® polymer membrane interfaces. In addition, we demonstrate the use of this interface to detect pharmaceuticals and other contaminants in natural water and artificial urine. The improved sensitivity and analytical response times of our CP-MIMS system make it possible to continuously monitor dynamic chemical systems with temporal resolutions on the order of minutes. Presented is a comparison of the performance of CP-MIMS versus direct infusion electrospray ionization, demonstrating the potential advantages over direct infusion for trace analyte measurements in complex, high ionic strength samples. Furthermore, by continuously flowing a reaction mixture in a closed loop over the interface, we demonstrate the use of the system as an in situ reaction-monitoring platform for the chlorination of a model organic compound in aqueous solution.

The Use of MIMS-MS-MS in field locations as an on-line quantitative environmental monitoring technique for trace contaminants in air and water.

Membrane introduction mass spectrometry (MIMS) is emerging as an important technique for on-line, real-time environmental monitoring. Because MIMS interfaces are simple and robust, they are ideally suited for operation in MS instrumentation used for in-field applications. We report the use of an on-line permeation tube to continuously infuse an isotopically labeled internal standard for continuous quantitative determinations in atmospheric and aqueous samples without the need for off-line calibration. This approach also provides important information on the operational performance of the analytical system during multi-day deployments. We report measured signal stability during on-line deployments in air and water of 7% based on variation of the internal standard response and have used this technique to quantify BTEX (benzene, toluene, ethylbenzenes, and xylenes), pinenes, naphthalene and 2-methoxyphenol (guaiacol) in urban air plumes at parts-per-billion by volume levels. Presented are several recent applications of MIMS-MS-MS for on-line environmental monitoring in atmospheric and aqueous environmental samples demonstrating laboratory, remote and mobile deployments. We also present the use of a thermally assisted MIMS interface for the direct measurement of polyaromatic hydrocarbons, alkylphenols, and other SVOCs in the low ppb range in aqueous environmental samples and discuss improvements in both the sensitivity and response times for selected SVOCs. The work presented in this paper represents significant improvements in field deployable mass spectrometric techniques, which can be applied to direct on-site analytical measurements of VOC and SVOCs in environmental samples.

Low-power resonant laser ablation of copper.

We emphasize two points: (l) the properties and mechanisms of very low-fluence ablation of copper surfaces and (2) the sensitivity and selectivity of resonant laser ablation (RLA). We present results for ablation of bulk copper and copper thin films; spot-size effects; the effects of surface-sample preparation and beam polarization; and an accurate measurement of material removal rates, typically ≤ 10(-3) Å at 35 mJ/cm(2). Velocity distributions were Maxwellian, with peak velocities ≈ 1-2 × 10(5) cm/s. In addition, we discuss the production of diffractionlike surface features, and the probable participation of nonthermal desorption mechanisms. RLA is shown to be a sensitive and useful diagnostic for studies of low-fluence laser-material interactions.

Resonant laser ablation as a selective metal ion source for gas-phase ion molecule reactions.

Resonant laser ablation (RLA) is used as a source to selectively generate multiple metal ion species from the same sample. The capability of rapidly changing metal ions for gas-phase ion chemistry studies is a significant advantage in ion-molecule chemistry. The simple experimental arrangement uses relatively modest laser pulse energies (≤ 25 µJ/pulse) from a tunable dye laser to desorb and selectively ionize different metal atoms from a multicomponent sample. In turn, this allows the chemistry of several components to be investigated without breaking vacuum or altering the experimental geometry. This work demonstrates the use of RLA as a selective source of several reagent metal ions for gas-phase ion chemistry investigations. In particular, the reactivity of acetone with Cr(+), Fe(+), Ni(+), and Cu(+) was examined for metal ions selectively created by RLA from a standard steel sample.

Blood conservation during myocardial revascularization.

A prospective study of blood utilization in 50 consecutive patients undergoing elective coronary artery bypass was undertaken. Blood was removed from all patients during induction of anesthesia and reinfused after bypass (mean, 675 ml). Intraoperatively, all discard suction was routed through a regionally heparinized collecting and processing system, and the resulting red cell concentrate was transfused. At the conclusion of bypass, all blood remaining in the pump oxygenator was retained for transfusion. After operation, shed mediastinal blood was collected in a sterile, filtered collection system and transfused. Normovolemic anemia was accepted in hemodynamically stable patients. The mean amount of patients' blood salvaged by the intraoperative system was 259 ml (range, 0 to 724 ml) and by the postoperative system, 194 ml (range, 0 to 564 ml). Ninety-four percent (47/50) of the patients received no bank blood or blood products during their hospital stay. No patients received bank blood intraoperatively or during the first 24 hours following operation. There were no complications attributable to blood salvage techniques.