53 research outputs found
Development and validation of a HPLC-UV method for the quantification of antiepileptic drugs in dried plasma spots
No full textBackground: Therapeutic drug monitoring (TDM) of antiepileptic drugs is widely used in clinical practice to optimise therapy, but it is limited by technical problems and cost considerations. The aim of the present study was: 1) to validate a chromatographic method for the concomitant determination of levetiracetam, lamotrigine, ethosuximide, felbamate, rufinamide, zonisamide and monohydroxycarbamazepine; 2) to develop it for dried plasma spot (DPS) assessing its reliability against the classical determination from plasma; and 3) test its clinical application.
Methods: Extraction of plasma samples and DPS was done by simple precipitation. Chromatographic analysis was performed using high performance liquid chromatography with ultraviolet detection. After validation, both methods were applied for the quantification of plasma samples from patients on antiepileptic therapy.
Results: Mean inter-and intra-day accuracy and precision were < 15% for all compounds both in plasma and in DPS samples. DPS samples were considered stable under tested conditions. Measurements between plasma and DPS samples appeared related (p < 0.0001). BlandAltman analysis revealed accordance in lamotrigine values with mean overestimation of concentration for DPS sample of 2.8%. Also for monohydroxycarbamazepine data the agreement was acceptable (mean overestimation of 9.2%). For levetiracetam mean difference was 7.6%, while for ethosuximide mean percentage difference was 20.6%.
Conclusions: The developed methods simplify TDM of antiepileptic drugs. This is particularly relevant for the method on dried spot sample devices because it facilitates further sample handling, stability and shipments making the management of therapies in epileptic patients easier also in hospitals devoid of a dedicated laboratory
Analytical aspects of sunitinib and its geometric isomerism towards therapeutic drug monitoring in clinical routine
No full textSunitinib malate, an oral multi-targeted tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumor, and well-differentiated pancreatic neuroendocrine tumors, has been identified as a potential candidate for therapeutic drug monitoring approach. Nevertheless, the development of an analytical assay suitable for clinical application for the quantification of the plasma concentration of sunitinib and its active metabolite, N-desethyl sunitinib, is limited by its Z/E isomerization when exposed to light. Several LC–MS/MS methods already published require protection from light during all sample handling procedures to avoid the formation of E-isomer, which makes them not suitable for clinical practice. In order to obtain a simple and fast procedure to reconvert the E-isomer, formed during sample collection and treatment without light protection, and, thus, to have only Z-isomer peak to quantify, we studied the Z/E photodegradation with special attention to the condition allowing the reverse reaction in plasma matrix. After 30 min of light exposure, the E-isomer maximum percentage of both the analytes was reached (44% of E-sunitinib and 20% of E-N-desethyl sunitinib; these percentages were calculated with respect to the sum of E + Z). Moreover, the formation of the E-isomer increased up to 20% after lowering the pH of the solution. Since the reverse reaction takes place when the pre-exposed solution is placed in dark, we followed the E to Z-isomer kinetics into the autosampler. The conversion rate was very slow when the autosampler was set at 4 °C (after 4 h the mean percentages of E-isomer were 50% for sunitinib and 22% for N-desethyl sunitinib). The reconversion rate was considerably accelerated with the increasing of the temperature: incubating the analytical solution in a heated water bath for 5 min at 70 °C we obtained the quantitative (99%) reconversion of the E- to the Z-isomer. No effect of concentration was observed, while the presence of acids inhibited the reconversion. Based on these results, a simple and fast procedure was setup to quantitatively reconvert the E-isomer formed during sample collection and processing without light protection into its Z-form thus leading to a single peak to quantify. The application of this additional step allows to develop a LC–MS/MS method suitable to clinical practice, due to its practicality and speed
A new high-performance liquid chromatography–tandem mass spectrometry method for the determination of sunitinib and N-desethyl sunitinib in human plasma: Light-induced isomerism overtaking towards therapeutic drug monitoring in clinical routine
No full textSunitinib is approved for advanced renal cell cancer, imatinib-resistant or -intolerant gastrointestinal stromal tumors and pancreatic neuroendocrine cancers. It is prescribed at a fixed dose but its plasma exposure shows large inter-individual variations. Taking into account the narrow therapeutic window and the positive exposure-efficacy relationship, there is a robust rationale for its therapeutic drug monitoring. In fact, a target plasma concentration of sunitinib plus its active metabolite, N-desethyl sunitinib, ≥50 ng/mL was suggested. In order to quantify sunitinib and N-desethyl sunitinib in patients' plasma, we developed and validated a new LC-MS/MS method applicable to clinical routine. In solution, sunitinib and N-desethyl sunitinib undergo to photo-isomerization and many published methods overcome this problem by conducting the entire procedures of samples collection and handling under strictly light-protection. Our method is based on a simple and fast procedure that quantitatively reconverts the E-isomer of both analytes, obtained during sample draw and processing without light-protection, into their Z-forms. Moreover, our method uses a small plasma volume (30 μL) and the analytes are extracted by a rapid protein precipitation. It was validated according to EMA-FDA guidelines. The calibration curves resulted linear (R2 always >0.993) over the concentration ranges (0.1-500 ng/mL for sunitinib, 0.1-250 ng/mL for N-desethyl sunitinib) with a good precision (within 7.7 % for sunitinib and 10.8% for N- desethyl sunitinib) and accuracy (range 95.8-102.9% for sunitinib and 92.3-106.2% for N-desethyl sunitinib). This method was applied to a pharmacokinetic study in one patient treated with sunitinib. Moreover, as incurred samples reanalysis is an established part of the bioanalytical process to support clinical studies, its assessment was performed early in order to assure that any reproducibility issues was detected as soon as possible. The percentage difference between the two runs resulted within ±20% in all the re-analysed samples for both sunitinib and N- desethyl sunitinib
Galaxy groups in the COSMOS survey: cosmic laboratories for galaxy evolution and feedback
No full textField-assisted paper spray mass spectrometry for therapeutic drug monitoring: 1. the case of imatinib in plasma
No full textThe field-assisted paper spray (FAPS) – mass spectrometric method has been employed to quantify the imatinib (IMT) plasma levels in treated patients. The quantitative measurements have been performed on the collisionally generated fragment at m/z 394 of the protonated molecules of IMT and deuterated IMT (d3-IMT), used as internal standard. The FAPS-tandem mass spectrometry (MS/MS) method exhibits some limitations, because of the high number of operative parameters that need to be carefully controlled. For this aim, papers of different geometry, thickness, and porosity were tested. To obtain a more focalized and intense electrical field, a stainless steel needle was mounted axially and placed at 4 kV voltage. The variability observed in the measurements was ascribed either to the inter-individual variability (e.g. the concomitant presence of other compounds such as proteins, lipids, drugs and/or salts in the plasma of different patients) or to the uncontrollable variables in the instrumental setup (e.g. sample deposition, changes in paper spray conditions). Furthermore, the manual sample deposition and solvent dripping strongly affects the measure reproducibility. Despite this, it is interesting to observe that, once applied in blind on 24 real plasma
samples, FAPS-MS/MS led to results analogous to those obtained by the well-consolidated liquid chromatography-MS/MS, even if the mean coefficient of variation % (CV%) values of 20.4% and 2.6% were observed for the two methods, respectively. In conclusion, despite CV values are relatively high, it is worth noting that the FAPS-MS/MS method is much more straightforward, rapid and economical than the liquid chromatography-MS/MS one, and it appears therefore very promising for applications where a high precision is not always a required task, as e.g. in some cases of therapeutic drug monitoring
Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines
No full textPre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD-rs1801159, DPYD-rs17376848) for association with Grade ≥3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade ≥3 toxicity after bootstrap validation and Bonferroni correction (p=0.003, p=0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade ≥3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade ≥3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade ≥3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice
Automated Building Damage Classification using Remotely Sensed Data: Case study: Hurricane Damage on St. Maarten
No full textIn the second half of the 20th and beginning of the 21st century the amount of natural disasters has increased rapidly. Due to this rise in occurrences, more people are affected. An important indicator for people affected is the amount of damage to buildings. To gather this information aid workers now have to go into the field to gather data on the amount of destruction. In response to the possible dangers these people encounter in the field, remote sensing and analysis techniques have been developed for automated damage detection. However, due to various limitations on the implementation, these techniques are not yet widely adopted in emergency response and humanitarian aid.This work compares two methods and two data sources for the detection of building damage. The methods are evaluated on their accuracy and implementability within humanitarian aid in disaster situations. The main methods considered are equalisation of histograms of pre-event and post-event imagery, followed by Univariate Image Differencing; and a convolutional neural network on features withdrawn from post-event imagery, using OpenStreetMap data. Remotely sensed data sources considered are synthetic aperture radar and very high resolution optical imagery. All results are analysed and compared to current standards in damage detection. From the results it can be concluded that more research is required for a practical implementation of deep learning techniques. The constraint posed by the requirement of large datasets, make these methods impracticable without sufficient preparation and resources. More simpler methods, like Univariate Image Differencing, can be validated on smaller ground-truth datasets, and are therefore easier in implementation when resources are limited. The possible accuracy increase of deep learning methods does, at this moment, not outweigh the ease of an elementary differencing approach.Geomatic
Self-Sovereign Identities for Scaling Up Cash Transfer Projects: Designing a blockchain based digital identity system
No full textSituation: Information management enables humanitarian organizations to make adequate interventions based on timely, appropriate and trustworthy information. A crucial type of information are identities, because they can be used to assess vulnerability and efficiently manage aid distribution. Vulnerability determines who receives aid first because resources are always limited. This information is increasingly being stored and processed in identity systems. Complication: Most identity systems are centralized and produce analogue proofs of identity such as passports or ID cards. These systems are susceptible to privacy and data breaches. Centralization leads to single-points-of-failure and could lead to fraudulent behavior resulting in people lacking formal proofs of identity. In general there is limited interoperability between identity systems and limited collaboration between the owners of these systems.Approach: To create an interoperable and shared digital identity system using a Design Science Research strategy and systems engineering approach. This system must be distributed, protect privacy and put the identity owner in control of his or her data. The foundation of the system consists of Humanitarian Information Management principles, Privacy-by-Design principles and Self-Sovereign Identity principles. This research creates a functional blockchain based system, that enables identities for the use-case of Cash Transfer Programs.Results: We present a validated set of ten design decisions that represent the trade-offs that have been made and prescribe a blueprint for a technical design.Next steps:Future research should be done on how such a system could be implemented and used. This would require a process design approach that has to be developed, Also, elaborate research into user experience and user interfaces should be conducted.Complex Systems Engineering and Management (CoSEM
Can I Communicate With My AUV? Performance and challenges is shallow water
No full textThe prospects for an increased future use of autonomous underwater vehicles (AUVs) in the Maritime & Offshore sector are high, mainly due to the search for cost effectiveness. AUVs reduce the need for large crews, divers and vessels in the operational area. AUVs are already operational for bathymetric and environmental mapping, pipeline tracking and mine hunting, and there is a trend towards their use for inspection and environmental monitoring
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