Search

Aim: Determination of plasma protein binding ( PPB) is considered vital for better understanding of pharmacokinetic and pharmacodynamic activities of drugs due to the role of free concentration in pharmacological response. Methodology & results: Solid-phase microextraction (SPME) was investigated for measurement of PPB from biological matrices and compared with a gold standard approach (rapid equilibrium dialysis [RED]). Discussion & conclusion: SPME-derived values of PPB correlated well with literature values, and those determined by RED. Respectively, average protein binding across three concentrations by RED and SPME was 33.1 and 31.7% for metoprolol, 89.0 and 86.6% for propranolol and 99.2 and 99.0% for diclofenac. This study generates some evidence for SPME as an alternative platform for the determination of PPB.

Background: The hemaPEN is a liquid microsampling device for the reproducible collection and storage of blood samples as dried blood spots, for subsequent quantitative analysis. Materials & methods: We examined the device’s ability to collect accurate and precise blood volumes, at different hematocrit levels, via in vitro studies using acetaminophen in human blood. We also investigated the impact of different user training approaches on device performance. Results: The hemaPEN demonstrated acceptable volumetric accuracy and precision, regardless of the training medium used. Issues with apparent hematocrit-dependent bias were found to be associated with the extraction process, rather than the volumetric performance of the device. Conclusion: The hemaPEN is capable of readily producing high quality blood microsamples for reproducible and accurate quantitative bioanalysis.

There is growing interest in the implementation of microsampling approaches for the quantitation of circulating concentrations of analytes in biological samples derived from nonclinical and clinical studies involved in drug development. This interest is partly due to the ethical advantages of taking smaller blood volumes, particularly for studies in rodents, children and the critically ill. In addition, these technologies facilitate sampling to be performed in previously intractable locations and occasions. Further, they enable the collection of samples for additional purposes (extra time points, biomarkers, sampling during a clinical event, etc). This article gives a comprehensive insight to the utilization of these approaches in drug discovery and development, and provides recommendations for best practice for nonclinical, clinical and bioanalytical aspects.

A previous Senior Editor, and the present Senior Editor of Bioanalysis reflect on their journeys in the field of bioanalysis, and with the journal. They discuss the evolution and progress of journal since its launch 10 years ago, and where they would like to see it heading in the future.

There is continuing interest in the development and application of various microsampling technologies for drug development. The AAPS bioanalytical community microsampling subgroup and the European Bioanalysis Forum conducted a survey of their members (39 individual organizations). This gives a snapshot of current practices and demonstrates that implementation of microsampling approaches is becoming increasingly commonplace, but not universal. Greater adoption was observed for nonclinical studies, particularly nonregulatory. A number of respondents reported that they have included microsampling data in regulatory submissions. Another important observation was that where microsampling is employed for clinical studies, dried blood approaches predominate, reflecting the interest in their use where they enable sample collection which is not feasible with standard approaches or to derive richer data sets.

[ ]of writing, it is unclear whether this will result in a permanent change in how blood sampling for clinical trials and routine healthcare are performed, although it seems unlikely that the progression of these sampling technologies will be slowed by the current situation Many of the early publications in this area had a primary focus on the development of blood sampling technologies, validation of bioanalytical methods and were limited to applications supporting nonclinical and clinical studies for pharmaceutical drug development Bioanalysis 7(16) (2015) https://www future-science com/toc/bio/7/16 Neil Spooner: Spooner Bioanalytical Solutions Ltd, Hertford, UK and School of Life and Medical Sciences, University of Hertfordshire, UK Melanie Anderson: Merck and Co , Inc , West Point, PA 19486, USA Enaksha R Wickremsinhe: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA

Aim: Collection and quantitative analysis in dry blood using volumetric absorptive microsampling (VAMS™) potentially offers significant advantages over conventional wet whole blood analysis. This manuscript explores their use for pediatric sampling and explores additional considerations for the validation of the bioanalytical method. Results: HPLC–MS/MS methods for the determination of midazolam and its major metabolite 1-OH midazolam in both whole wet blood, and dry blood collected on VAMS were developed, validated, and used to support an observational clinical study to compare pharmacokinetic parameters in pediatric patients. Conclusion: Validation data met internationally accepted guideline criteria. A strong correlation was observed in calculated concentrations between wet and dry test samples, indicating that VAMS is a suitable technique for use in pediatric clinical studies.

A previous Senior Editor, and the present Senior Editor of

Aim: The quality of quantitative analytical measurements is dependent on the quality of the sample collected, and dried blood spots (DBS) are no exception. As the use of DBS has matured into late-stage clinical drug-development studies, it has become apparent that a simple and straightforward approach in a controlled single-site, first-time-into-human clinic, does not always translate into multicenter clinical studies. Using synthetic blood, a method of training and assessing clinical laboratory staff has been developed to ensure the quality of sampling. Methods: A test kit comprising of synthetic blood, a pipetting aid, blank blood spot card, drying rack and training manual was sent to each clinical site for each technician to assess and approve prior to spotting PK samples. Results: The development of a DBS training kit along with a step-by-step guide has been successfully implemented. Conclusion: The training kit has been 100% successful across three large multisite clinical studies.

Background: Control blood plasma is regularly used in bioanalysis, biomarkers and proteomics, and is often obtained from commercial sources. It has always been assumed that this plasma will be comparable to plasma drawn during a drug development study. Results: When compared using total protein concentrations, plasma from only one species (dog) demonstrated statistical comparability, plasma from all other species tested (human, rabbit, mouse and rat) shows a statistically significant difference. Conclusion: If endogenous components of blood plasma are being measured, or if an assay technique does not significantly limit matrix effects, any assay controls should be prepared using control plasma from the drug development site, or using commercial plasma that has been screened against drug development site plasma.

Background: Automated DBS direct elution systems are available that incorporate IS spray modules which, unlike conventional IS addition via the extraction solvent, apply IS prior to DBS samples prior to extraction, allowing analyte and IS to be coextracted. Results: IS spray system parameters were optimized to identify the conditions that produced the best analytical performance in quantitative bioanalytical assays, without interfering with the integrity of the DBS sample prior to extraction. Conclusion: LC–MS/MS method validations across four representative small molecule assays using the optimized IS spray conditions were demonstrated to produce analytical performance comparable to conventional methods of IS addition, demonstrating that the spray technique is a viable alternative.

Background: Automated DBS direct elution techniques eliminate the manual extraction burden of DBS bioanalysis, offer good quantitative performance, the ability to eliminate hematocrit-based assay bias, and, previous reports have demonstrated that significant increases in assay sensitivity compared with manual DBS extraction are possible. Results: An investigation into elucidating parameters for optimized generic DBS direct elution for high sample throughput quantitative bioanalytical applications is presented for the first time. Generic direct elution conditions were identified that enabled LC–MS/MS assay sensitivity to be maximized while retaining acceptable chromatographic performance. Conclusion: Compared with generic conventional DBS manual extraction, assay sensitivity was demonstrated to be increased up to 33-fold across four representative small molecule compounds, using the recommended direct elution conditions.

Aims: A cross-laboratory experiment has been performed on a novel dried blood sampler in order to investigate whether it overcomes issues associated with blood volume and hematocrit (HCT) that are observed when taking a subpunch from dried blood spot samples. Materials & methods: An average blood volume of 10.6 μl was absorbed by the samplers across the different HCTs investigated (20–65%). Results: No notable change of volume absorbed was noted across the HCT range. Furthermore, the variation in blood sample volumes across six different laboratories was within acceptable limits. Conclusion: The novel volumetric absorptive microsampling device has the potential to deliver the advantages of dried blood spot sampling while overcoming some of the issues associated with the technology.

The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years’ editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies’ input) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the upcoming issues of Bioanalysis.

The portfolios of pharmaceutical companies have diversified substantially over recent years in recognition that monotherapies and/or small molecules are less suitable for modulating many complex disease etiologies. Furthermore, there has been increased pressure on drug-development budgets over this same period. This has placed new challenges in the path of bioanalytical scientists, both within the industry and with contract research organizations (CROs). Large pharmaceutical, biotechnology and small-medium healthcare enterprises have had to make important decisions on what internal capabilities they wish to retain and where CROs offers a significant strategic benefit to their business model. Our journey has involved asking where we believe an internal bioanalytical facility offers the greatest benefit to progressing drug candidates through the drug-development cycle and where externalization can help free up internal resources, adding flexibility to our organization in order to deal with the inevitable peaks and troughs in workload.

Background: Dried blood spot (DBS) sampling is emerging as a valuable technique in a variety of fields, including clinical and preclinical testing of pharmaceuticals. Despite this popularity, current DBS sampling and analysis processes remain laborious and time consuming. Digital microfluidics, a microscale liquid-handling technique, characterized by the manipulation of discrete droplets on open electrode arrays, offers a potential solution to these problems. Results: We report a new digital microfluidic method for multiplexed extraction and analysis of pharmaceuticals in DBS samples. In the new method, four DBS samples are extracted in microliter-sized droplets containing internal standard, and the extract is delivered to dedicated nanoelectrospray ionization emitters for direct analysis by tandem mass spectometry and selected reaction monitoring. Conclusion: The new method allows for an order of magnitude reduction in processing time and approximately three-times reduction in extraction solvent relative to conventional techniques, while maintaining acceptable analytical performance for most drugs tested.

Background: The aim of the work was to evaluate the sensitivity and reproducibility of real-time reverse transcriptase PCR for quantitative analysis of an oligonucleotide in a biological matrix. A novel approach for the identification of outliers when assessing the suitability of calibration standards and QC samples is investigated. Results: A suitable assay was established for the determination of the oligonucleotide in human plasma over a range of 0.5–100 ng/ml. Conclusion: In these preliminary investigations, the precision and accuracy of the method was established for the quantification of the oligonucleotide in human plasma. It was established that the method was precise and accurate for quantification of the oligonucleotide in human plasma. The acceptability of the data was assessed using a novel three-step process to identify any outliers, involving the use of the Grubbs’ test. The analytical method only requires a small sample volume (

This article discusses the benefits of dried blood spot sampling and the recent issues that have emerged when this technique is used in the regulated quantitative bioanalytical environment. The author explores what the way forward might be for this important technique and what some of the unexpected benefits of this change in sampling methodologies have been.

Aims Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a ‘DBS/microvolume platform’ in preterm infants. Methods DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement. Results Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6–2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h−1 kg−1; V = 593 ml kg−1; t1/2 = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9–7.9 ml h−1 kg−1; V = 640–970 ml kg−1; t1/2 = 101–144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data. Conclusions This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.

Circulating drug concentrations (clinical or preclinical) underly many interactions between industry and regulators; expressing safety coverage, pharmacokinetic-pharmacodynamic relationships or defining bioequivalence and dosing regimens. Accurate and precise measurement of these circulating concentrations is pivotal to the evolution and validation of any bioanalytical method that supports regulatory interactions. Since the bioanalyst is presented with a sub-aliquot of sampled biological matrix, how do they ensure this aliquot reflects the concentration in the subject at the time of collection? Here we share experiences from project support (internal and at CROs) that suggests we need to be ever vigilant translating the needs of bioanalysis with those of project teams. The simple mantra is for bioanalytical measurements to be physiologically relevant to the patient.

21st International Reid Bioanalytical Forum, University of Surrey, Guildford, UK, 7–10 September 2015 The 21st International Reid Bioanalytical Forum held between 7 and 10 September 2015, brought together over 100 scientists from around the world, representing industry, academia and vendors, for 4 days of engaging science at the University of Surrey in Guildford, UK. The scientific program consisted of 43 podium and 23 poster presentations from key opinion leaders and those just setting out on their scientific career. The latter being the focus of the meeting. One of the highlights of the forum was the debate. An expert panel helped spark off an active discussion among a passionate audience on the topic of ‘The Current Skills Gaps in Analytical Sciences are Failing Industry.’

The Deep Underground Neutrino Experiment (DUNE) is a project to design, construct and operate a next-generation long-baseline neutrino detector with a liquid argon (LAr) target capable also of searching for proton decay and supernova neutrinos. It is a merger of previous efforts of the LBNE and LBNO collaborations, as well as other interested parties to pursue a broad programme with a staged 40 kt LAr detector at the Sanford Underground Research Facility (SURF) 1300 km from Fermilab. This programme includes studies of neutrino oscillations with a powerful neutrino beam from Fermilab, as well as proton decay and supernova neutrino burst searches. In this paper we will focus on the underground physics with DUNE., Comment: 5 pages, 3 figures, contribution to TAUP2015

Further to the discussions on the bioanalysis of samples generated using microsampling techniques [1–6] and more specifically the ongoing work of the European Bioanalysis Forum (EBF) Liquid Microsampling Consortium [7], this article seeks to highlight some of the ‘philosophical’ aspects around liquid microsampling and to introduce some of the experimental elements that will form part of future efforts by the Consortium. Discussion will be focused on three major areas: sample manipulation, homogeneity of samples and validation of assays. The scope of this manuscript will be liquid microsampling and will not focus on adsorption techniques such as dried blood spots (DBS) and solid phase microextraction. Different microsampling techniques have created great interest from toxicokinetic (TK) and pharmacokinetic (PK) scientists, since they offer the potential to reduce sample volumes for exposure assessment in biofluids. For preclinical studies microsampling can facilitate the generation of serial profiles in rodent exposure evaluation studies, rather than working with composite designs. Microsampling has facilitated the removal of satellite animal groups leading to substantial reductions in the number of animals required and the reduction or elimination of rodent warming. Benefits in the clinical environment include the ability to take reduced sample volumes from pediatric, elderly and critically ill patient populations. In a recent publication the NC3R group proposes the following definition of a blood microsample: the sample should ideally not contain more than 50 μl whole blood [8]. As a consequence the subsequent plasma volumes are 20 μl or lower. Another, more philosophical consideration would be the impact of sampling volume on the animal or subject; for example, 50 μl of blood may not be considered as a ‘microsample’ in the context of juvenile animals or newborn babies. Two major liquid microsampling approaches can be envisaged

Background: To ensure that PK data generated from DBS samples are of the highest quality, it is important that the paper substrate is uniform and does not unduly contribute to variability. This study investigated any within and between lot variations for four cellulose paper types: Whatman™ FTA®DMPK-A, -B and -C, and 903®(GE Healthcare, Buckinghamshire, UK). The substrates were tested to demonstrate manufacturing reproducibility (thickness, weight, chemical coating concentration) and its effect on the size of the DBS produced, and the quantitative data derived from the bioanalysis of human DBS samples containing six compounds of varying physicochemical properties. Results & discussion: Within and between lot variations in paper thickness, mass and chemical coating concentration were within acceptable manufacturing limits. No variation in the spot size or bioanalytical data was observed. Conclusion: Bioanalytical results obtained for DBS samples containing a number of analytes spanning a range of chemical space are not affected by the lot used or by the location within a lot.

Background: For shipping and storage, dried blood spot (DBS) samples must be sufficiently dry to protect the integrity of the sample. When the blood is spotted the humidity has the potential to affect the size of the spot created and the speed at which it dries. Results: The area of DBS produced on three types of substrates were not affected by the humidity under which they were generated. DBS samples reached a steady moisture content 150 min after spotting and 90 min for humidities less than 60% relative humidity. All packaging materials examined provided some degree of protection from external extreme conditions. However, none of the packaging examined provided a total moisture barrier to extreme environmental conditions. Conclusion: Humidity was shown not to affect the spot area and DBS samples were ready for shipping and storage 2 h after spotting. The packing solutions examined all provided good protection from external high humidity conditions.

Background: A novel device and procedure for the collection and isolation of microvolumes of plasma have been developed and two pilot rodent PK studies have been completed. Results: This method involves collection of blood into a plastic-wrapped, EDTA-coated capillary tube, containing a small amount of a thixotropic gel and a porous plug. Following blood collection, the capillary is placed into a secondary labeled container suitable for centrifugation and plasma is generated. During centrifugation, the thixotropic gel isolates the plasma from the red blood cells and creates a physical barrier between the two matrices. The plasma is then dispensed from the capillary tube into a separate container for storage or processing. Conclusion: A simple and robust novel approach for the collection of small plasma volumes from rodent TK studies has been demonstrated.

Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity. Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels. Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled. © 2013 Future Science Ltd.

Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants.DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement.Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h⁻¹ kg⁻¹; V = 593 ml kg⁻¹; t(½) = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h⁻¹ kg⁻¹; V = 640-970 ml kg⁻¹; t(½) = 101-144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data.This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques.

Dried bloodspot (DBS) technology has been available for many decades but only in the last five years has it been considered for routine bioanalysis of blood samples collected on preclinical and clinical studies as part of a drug development programme. Advantages of using DBS versus typical plasma samples include smaller blood volumes, less processing of the samples (e.g. no centrifugation) and no requirement for storing or shipping of the samples at frozen temperatures. The current study compared blood concentrations (AUC0− t and Cmax) from rats given an oral dose of acetaminophen (APAP) using two different sampling sites (caudal venepuncture versus tail snip), two different collection methods (3 separate 15 μL ethylenediaminetetraacetic acid [EDTA]-coated capillary tubes versus an EDTA integrated capillary blood collection system) and variability between blood spots on one card. There were no noteworthy differences (i.e. two-fold or greater) in blood concentrations of APAP using the different sites or methods. Furthermore, comparisons of the APAP blood concentrations in the original spot to a duplicate bloodspot from the same bloodspot card were within 12% of the original concentration.

ISSN 1757-6180 10.4155/BIO.10.153 © 2010 Future Science Ltd Bioanalysis (2010) 2(11), 1781 Well here we are again! Following hot on the heels of the special focus issue of Bioana lysis dedicated to dried blood spots in August 2010, we have another special issue concentrating on the same subject. The large volume of highquality contributions in these two editions and the numerous dedicated conference sessions and workshops on this subject in the last 2 years is rapidly contributing to a broader understanding and acceptance of this technique by the drug bioana lysis community. However, the work of this community is increasingly highly regulated, which naturally leads to a conservative approach and in-depth questioning of any new technologies. This is resulting in a number of members of the community holding back on implementing any real change, whilst they wait for others to trip up, or for the regulators to make a proclamation etched in stone about the suitability of the technique. Whilst this may at times be ‘irritating’ to the leaders who just want to get out there and do it – “isn’t it obvious?” – this is an understandable reaction that must be heard. We need to take the time to thoroughly understand the technique and to perform the best science possible. However, it is my belief that we should not let all the understandable questions and reservations bury the pure fact that there are real benefits to be had with this technique. Standing still is not an option. The pressure from society to deliver ethical and environmentally friendly solutions is ever present. Added to this is the need of the pharmaceutical industry and healthcare providers to get better value for their money. Dried blood spot sampling delivers on all these aspects in spades and so will become an accepted part of the drug-development landscape of the future. The revolution is here! Anyway, enough of my rant! I welcome you to this special focus issue of Bioana lysis dedicated to dried blood spot sampling. I would like to thank the authors for sharing with us their high-quality science and discussion. I would also like to thank the dedicated and hard work of the editorial staff for putting together this special issue.

In addition to free sterols, higher plants contain significant amounts of sterol in the form of steryl fatty acyl esters, steryl ferulates, steryl glycosides, and steryl acylglycosides. Methods have now been developed for the analysis of these various steryl conjugates employing high temperature capillary gas chromatography and mass spectrometry.

Delivering Neonatal Drugs Research: Acceptability of Dried Blood Spot Sampling for Pharmacokinetic Research in Premature Infants

Summary This article argues that it is important to differentiate between high value export crops traditionally grown in the estate sector and other crops more often associated with the smallholder sector, in terms of their economic and agricultural characteristics. High value export crops require that a specific set of input services be provided if they are to be successfully grown by smallholders. Typical rural development programmes in Africa have not provided these inputs and have locked smallholders into the production of food crops and lower value export crops which have been historically associated with the smallholder sector, with important consequences for equity and growth. Resume La Banque Mondiale presente‐t‐elle un Handicap pour la Production a l'Exportation dans les Petites Exploitations? Le Cas du Malawi Cet article insiste sur le fait qu'il est important de faire la difference, suivant leurs caracteristiques economiques et agricoles, entre les produits a l'exportation et de valeur elevee, traditionellement cultives dans le secteur des grandes exploitations, et la production associee plus generalement avec les petites exploitations. Les produits agricoles de valeur elevee, destines a l'exportation demandent la mise en oeuvre d'un nombre specifique de services afin d'obtenir des resultats satisfaisants lorsque la production est assuree par de petites exploitations. Les programmes typiques de developpement rural en Afrique n'ont pas offert la garantie de ces investissements et ont limite les petits exploitants a la production de produits agricoles de premiere necessite, traditionellement associes avec le secteur des petites exploitations; ceci a eu des conse quences importances en ce qui concerne l'equite et la croissance. Resumen ?Inhibe el banco mundial los cultivos comerciales? El caso de Malawi Este articulo destaca la importancia de distinguir los cultivos de exportacion de alto valor producidos tradicionalmente en el sector de haciendas de aquellos originados mas frecuentemente en el de pequenas granjas, en terminos de sus caracteristicas agricolas y economicas. Si se pretende que los primeros sean producidos exitosamente por pequenos agricultores, debe proporcionarse a estos el conjunto de servicios especificos requeridos. En Africa, los tipicos programas de desarrollo rural no proporcionaron estos servicios y encerraron a los pequenos agricultores en la produccion de alimentos y de cultivos de exportacion de bajo valor, historicamente asociados al sector de pequenos productores, con serias consecuencias para la equidad y el crecimiento.

Toxicokinetic analysis is an essential part of nonclinical drug development. Advances in bioanalytical techniques have opened up the potential to use smaller sample volumes (microsamples) to assess drug exposure in blood, plasma and/or serum. Microsampling can increase the amount of nonclinical safety information available, improve its validity by linking toxic effects to drug exposure in individual animals and represents the most significant opportunity to reduce animal use in toxicology studies in the short term. In May 2013, a workshop was held with 80 delegates from 33 companies with the aim of sharing information and knowledge on microsampling technologies. This article covers the discussions at the workshop, current practice in the industry, regulatory experiences and the future direction of microsampling across drug development.

Ultra-performance liquid chromatography (UPLC) combined with mass spectrometric detection (MS) is used successfully in the bioanalysis of small molecule drug candidates in plasma. UPLC-MS is shown to increase sample throughput by reducing run times over 3-fold, without compromising analytical sensitivity or analyte resolution. The technique is demonstrated to be practical and robust on a commercially available ultra-high pressure system when injecting extracts of plasma and has also shown to be a technique that can be used effectively on a conventional high-performance liquid chromatography system fitted with short columns (

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017., Comment: 102 pages + references