Predicting drug penetration across the blood-brain barrier: comparison of different stationary phases for immobilized artificial membrane liquid chromatography

Several in vitro methods have been tested for their ability to predict drug penetration across the blood-brain barrier into the central nervous system. In this article, the performance of three stationary phases for immobilized artificial membrane (IAM) liquid chromatographic approaches were compared on a set of 49 compounds. IAM liquid chromatography measurements were performed with Dulbecco’s phosphate-buffered saline and methanol as organic modifier in the mobile phase. Transport across the blood-brain barrier (log BB) was predicted using computed descriptor data and the retention factor of all compounds. All data were correlated with experimental log BB values and the relative performance of the approaches was studied. The IAM.PC.DD2 column proved to be the best suited for prediction of log BB values, although all three columns performed very good

Exploration of the selectivity and retention behavior of alternative polyacrylamides in temperature responsive liquid chromatography

Temperature responsive liquid chromatography (TRLC) allows for separation of organic solutes in purely aqueous mobile phases whereby retention is controlled through temperature. The vast majority of the work has thus far been performed on poly[N-isopropylacrylamide] (PNIPAAm)-based columns, while the performance of other temperature responsive polymers has rarely been compared under identical conditions. Therefore, in this work, two novel TRLC phases based on poly[N-n-propylacrylamide] (PNNPAAm) and poly[N,N-diethylacrylamide] (PDEAAm) are reported and compared to the state of the art PNIPAAm based column. Optimal comparison is thereby obtained by the use of controlled radical polymerizations, identical molecular weights, and by maximizing carbon loads on the silica supporting material. Analysis of identical test mixtures of homologue series and pharmaceutical samples revealed that PNNPAAm performs in a similar way as PNIPAAm while offering enhanced retention and a shift of the useable temperature range toward lower temperatures. PDEAAm offers a range of novel possibilities as it depicts a different selectivity, allowing for enhanced resolution in TRLC in, for example, coupled column systems. Reduced plate heights of 3 could be obtained on the homemade columns, offering the promise for reasonable column efficiencies in TRLC despite the use of bulky polymers as stationary phases in HPLC

Arrival angles of teleseismic fundamental mode Rayleigh waves across the AlpArray

The dense AlpArray network allows studying seismic wave propagation with high spatial resolution. Here we introduce an array approach to measure arrival angles of teleseismic Rayleigh waves. The approach combines the advantages of phase correlation as in the two-station method with array beamforming to obtain the phase-velocity vector. 20 earthquakes from the first two years of the AlpArray project are selected, and spatial patterns of arrival-angle deviations across the AlpArray are shown in maps, depending on period and earthquake location. The cause of these intriguing spatial patterns is discussed. A simple wave-propagation modelling example using an isolated anomaly and a Gaussian beam solution suggests that much of the complexity can be explained as a result of wave interference after passing a structural anomaly along the wave paths. This indicates that arrival-angle information constitutes useful additional information on the Earth structure, beyond what is currently used in inversions

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Evaluation of electron capture detection in reversed-phase HPLC for pharmaceutical analysis

The coupling of RP-LC to electron capture detection (ECDNi63) is described. To reduce the amount of mobile phase entering into the detector, interfacing was performed via a Scott-type spray chamber. The performance of RP-LC/ECDNi63 was evaluated for pharmaceutical analysis and the results show that the system is able to work ill a routine environment using columns with 2 mm id and common amounts of the organic modifiers methanol or ACN in the mobile phase. Because of the high sensitivity and selectivity toward electrophilic compounds, the use of this detector opens possibilities for the analysis of impurities down to the 0.05% level of active pharmaceutical ingredients (API)

Advantages and Pitfalls of Capillary Electrophoresis of Pharmaceutical Compounds and Their Enantiomers in Complex Samples: Comparison of Hydrodynamically Opened and Closed Systems

Several research disciplines require fast, reliable and highly automated determination of pharmaceutically active compounds and their enantiomers in complex biological matrices. To address some of the challenges of Capillary Electrophoresis (CE), such as low concentration sensitivity and performance degradation linked to the adsorption and interference of matrix components, CE in a hydrodynamically closed system was evaluated using the model compounds Pindolol and Propranolol. Some established validation parameters such as repeatability of injection efficiency, resolution and sensitivity were used to assess its performance, and it was found to be broadly identical to that of hydrodynamically opened systems. While some reduction in separation efficiency was observed, this was mainly due to dispersion caused by injection and it had no impact on the ability to resolve enantiomers of model compounds even when spiked into complex biological matrix such as blood serum. An approximately 18- to 23-fold increase in concentration sensitivity due to the employment of wide bore capillaries was observed. This brings the sensitivity of CE to a level similar to that of liquid chromatography techniques. In addition to this benefit and unlike in hydrodynamically opened systems, suppression of electroosmotic flow, which is essential for hydrodynamically closed systems practically eliminates the matrix effects that are linked to protein adsorption

Screening therapeutics according to their uptake across the blood-brain barrier: A high throughput method based on immobilized artificial membrane liquid chromatography-diode-array-detection coupled to electrospray-time-of-flight mass spectrometry

The Blood-Brain Barrier (BBB) plays an essential role in protecting the brain tissues against possible injurious substances. In the present work, 79 neutral, basic, acidic and amphoteric structurally unrelated analytes were considered and their chromatographic retention coefficients on immobilized artificial membrane (IAM) stationary phase were determined employing a mass spectrometry (MS)-compatible buffer based on ammonium acetate. Their BBB passage predictive strength was evaluated and the statistical models based on IAM indexes and in silico physico-chemical descriptors showed solid statistics (r² (n − 1) = 0.78). The predictive strength of the indexes achieved by the MS-compatible method was comparable to that achieved by employing the more “biomimetic” Dulbecco’s phosphate buffered saline, even if some differences in the elution order were observed. The method was transferred to the MS, employing a diode-array-detection coupled to an electrospray ionization source and a time-of-flight analyzer. This setup allowed the simultaneous analysis of up to eight analytes, yielding a remarkable acceleration of the analysis time