Enabling Medicine Reuse Using a Digital Time Temperature Humidity Sensor in an Internet of Pharmaceutical Things Concept.

Medicinal waste due to improper handling of unwanted medicines creates health and environmental risks. However, the re-dispensing of unused prescribed medicines from patients seems to be accepted by stakeholders when quality and safety requirements are met. Reusing dispensed medicines may help reduce waste, but a comprehensive validation method is not generally available. The design of a novel digital time temperature and humidity indicator based on an Internet of Pharmaceutical Things concept is proposed to facilitate the validation, and a prototype is presented using smart sensors with cloud connectivity acting as the key technology for verifying and enabling the reuse of returned medicines. Deficiency of existing technologies is evaluated based on the results of this development, and recommendations for future research are suggested.

Stakeholder Views on the Idea of Medicines Reuse in the UK.

People's views about medicines reuse are being examined in a handful of qualitative studies and this commentary adds to that work by drawing on our own discussions with groups of stakeholders in the UK in the past two years. The reuse of medicines within the community pharmacy setting is not permitted in the UK but our multidisciplinary team anticipates that this position will change in the coming years as medication shortages and worries about environmental waste and financial losses from the destruction of unused medicines are brought to the fore. Indeed, for many stakeholders, the issue of waste is a strong feature of conversations about medicines reuse. In addition to this, stakeholders identify the numerous barriers to medicines reuse in the UK. This includes the current uncertainty about the quality of unused medicines returned to pharmacies, which could otherwise be reused. However, stakeholders have also been very willing to propose solutions to a range of existing barriers. Our commentary draws on stakeholder meetings to elaborate the range of views about medicines reuse within a UK context. The challenge is to move forward from these views to advance the technologies that will facilitate medicines reuse practically as well as legally.

Medicines as Common Commodities or Powerful Potions? What Makes Medicines Reusable in People's Eyes.

BACKGROUND: Medicines reuse involves dispensing quality-checked, unused medication returned by one patient for another, instead of disposal as waste. This is prohibited in UK community pharmacy because storage conditions in a patient's home could potentially impact on the quality, safety and efficacy of returned medicines. Our 2017 survey examining patients' intentions to reuse medicines found many favoured medicines reuse. Our aim was to analyse the qualitative comments to explore people's interpretations of what makes medicines (non-)reusable. METHODS: Thematic analysis was used to scrutinize 210 valid qualitative responses to the survey to delineate the themes and super-ordinate categories. RESULTS: Two categories were "medicines as common commodities" versus "medicines as powerful potions". People's ideas about medicines aligned closely with other common commodities, exchanged from manufacturers to consumers, with many seeing medicines as commercial goods with economic value sanctioning their reuse. Fewer of the comments aligned with the biomedical notion of medicines as powerful potions, regulated and with legal and ethical boundaries limiting their (re)use. CONCLUSION: People's pro-medicines-reuse beliefs align with perceptions of medicines as common commodities. This helps explain why patients returning their medicines to community pharmacies want these to be recycled. It could also explain why governments permit medicines reuse in emergencies.

The Effect of Quality Indicators on Beliefs about Medicines Reuse: An Experimental Study.

BACKGROUND: A number of studies have examined beliefs about medicines reuse. Although the practice is prohibited in UK community pharmacy, it does take place elsewhere in the world where it relies on visual checks of returned medicines as an indicator of their quality. One proposal is to integrate sensor technology onto medication packaging as a marker of their quality instead. Our aim was to gauge people's beliefs about medicines reuse, in an experiment, with or without sensor technology and with or without the promise of visual checks completed by a pharmacist, as experimental conditions, should the practice be sanctioned in the UK in the future. METHODS: A between participant study was designed with two independent factors testing the hypothesis that sensors and visual checks would increase pro-medicines-reuse beliefs. A questionnaire was used to measure medicines reuse beliefs and collect qualitative comments. RESULTS: Eighty-one participants took part. Attitudes toward medication offered for reuse, participants' perceived social pressure to accept the medication, and their intention to take part in medicines reuse all increased with the presence of sensors on packaging and with the promise of pharmacist visual checking, with the former causing a greater increase than the latter, and the combination of both making the greatest increase. People's qualitative comments explained their concerns about medicines reuse, validating the findings. The use of sensors on medication packaging warrants further investigation if regulators are to consider approving medicines reuse in the UK.

Identification of Suitable Biomarkers for Stress and Emotion Detection for Future Personal Affective Wearable Sensors.

Skin conductivity (i.e., sweat) forms the basis of many physiology-based emotion and stress detection systems. However, such systems typically do not detect the biomarkers present in sweat, and thus do not take advantage of the biological information in the sweat. Likewise, such systems do not detect the volatile organic components (VOC's) created under stressful conditions. This work presents a review into the current status of human emotional stress biomarkers and proposes the major potential biomarkers for future wearable sensors in affective systems. Emotional stress has been classified as a major contributor in several social problems, related to crime, health, the economy, and indeed quality of life. While blood cortisol tests, electroencephalography and physiological parameter methods are the gold standards for measuring stress; however, they are typically invasive or inconvenient and not suitable for wearable real-time stress monitoring. Alternatively, cortisol in biofluids and VOCs emitted from the skin appear to be practical and useful markers for sensors to detect emotional stress events. This work has identified antistress hormones and cortisol metabolites as the primary stress biomarkers that can be used in future sensors for wearable affective systems.

Enhancing Pharmaceutical Packaging through a Technology Ecosystem to Facilitate the Reuse of Medicines and Reduce Medicinal Waste.

Background: The idea of reusing dispensed medicines is appealing to the general public provided its benefits are illustrated, its risks minimized, and the logistics resolved. For example, medicine reuse could help reduce medicinal waste, protect the environment and improve public health. However, the associated technologies and legislation facilitating medicine reuse are generally not available. The availability of suitable technologies could arguably help shape stakeholders' beliefs and in turn, uptake of a future medicine reuse scheme by tackling the risks and facilitating the practicalities. A literature survey is undertaken to lay down the groundwork for implementing technologies on and around pharmaceutical packaging in order to meet stakeholders' previously expressed misgivings about medicine reuse ('stakeholder requirements'), and propose a novel ecosystem for, in effect, reusing returned medicines. Methods: A structured literature search examining the application of existing technologies on pharmaceutical packaging to enable medicine reuse was conducted and presented as a narrative review. Results: Reviewed technologies are classified according to different stakeholders' requirements, and a novel ecosystem from a technology perspective is suggested as a solution to reusing medicines. Conclusion: Active sensing technologies applying to pharmaceutical packaging using printed electronics enlist medicines to be part of the Internet of Things network. Validating the quality and safety of returned medicines through this network seems to be the most effective way for reusing medicines and the correct application of technologies may be the key enabler.

Coverage of Emotion Recognition for Common Wearable Biosensors.

The present research proposes a novel emotion recognition framework for the computer prediction of human emotions using common wearable biosensors. Emotional perception promotes specific patterns of biological responses in the human body, and this can be sensed and used to predict emotions using only biomedical measurements. Based on theoretical and empirical psychophysiological research, the foundation of autonomic specificity facilitates the establishment of a strong background for recognising human emotions using machine learning on physiological patterning. However, a systematic way of choosing the physiological data covering the elicited emotional responses for recognising the target emotions is not obvious. The current study demonstrates through experimental measurements the coverage of emotion recognition using common off-the-shelf wearable biosensors based on the synchronisation between audiovisual stimuli and the corresponding physiological responses. The work forms the basis of validating the hypothesis for emotional state recognition in the literature and presents coverage of the use of common wearable biosensors coupled with a novel preprocessing algorithm to demonstrate the practical prediction of the emotional states of wearers.

High-throughput kinetic screening of hybridomas to identify high-affinity antibodies using bio-layer interferometry.

Kinetic analysis of antibodies is crucial in both clone selection and characterization. Historically, antibodies in supernatants from hybridomas are selected based on a solid-phase enzyme-linked immunosorbent assay (ELISA) in which the antigen is immobilized on the assay plate. ELISA selects clones based on a combination of antibody concentration in the supernatant and affinity. The antibody concentration in the supernatant can vary significantly and is typically unknown. Using the ELISA method, clones that express high levels of a low-affinity antibody can give an equivalent signal as clones that express low levels of a high-affinity antibody. As a consequence, using the ELISA method, superior clones can be overshadowed by inferior clones. In this study, we have applied Bio-Layer Interferometry to screen hybridoma clones based on disassociation rates using the OctetRED 384 platform. Using the OctetRED platform, we were able to screen 2000 clones within 24 hours and select clones containing high-affinity antibodies for further expansion and subsequent characterization. Using this method, we were able to identify several clones producing high-affinity antibodies that were missed by ELISA.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2.

SU9516 is a 3-substituted indolinone compound with demonstrated potent and selective inhibition toward cyclin dependent kinases (cdks). Here, we describe the kinetic characterization of this inhibition with respect to cdk2, 1, and 4, along with the crystal structure in complex with cdk2. The molecule is competitive with respect to ATP for cdk2/cyclin A, with a K(i) value of 0.031 microM. Similarly, SU9516 inhibits cdk2/cyclin E and cdk1/cyclin B1 in an ATP-competitive manner, although at a 2- to 8-fold reduced potency. In contrast, the compound exhibited non-competitive inhibition with respect to ATP toward cdk4/cyclin D1, with a 45-fold reduced potency. The X-ray crystal structure of SU9516 bound to cdk2 revealed interactions between the molecule and Leu83 and Glu81 of the kinase. This study should aid in the development of more potent and selective cdk inhibitors for potential therapeutic agents.

The oxidative mechanism of action of ortho-quinone inhibitors of protein-tyrosine phosphatase alpha is mediated by hydrogen peroxide.

Here, we report the identification and characterization of five ortho-quinone inhibitors of PTPalpha. We observed that the potency of these compounds in biochemical assays was markedly enhanced by the presence of DTT. A kinetic analysis suggested that they were functioning as irreversible inhibitors and that the inhibition was targeted to the catalytic site of PTPalpha. The inhibition observed by these compounds was sensitive to superoxide dismutase and catalase, suggesting that reactive oxygen species may be mediators of their inhibition. We observed that in the presence of DTT, these compounds would produce up to 2.5mM hydrogen peroxide (H(2)O(2)). The levels of H(2)O(2) produced were sufficient to completely inactivate PTPalpha. In contrast, without a reducing agent the compounds did not generate H(2)O(2) and showed little activity towards PTPalpha. In addition, these compounds inhibited PTPalpha-dependent cell spreading in NIH 3T3 cells at concentrations that were similar to their activity in biochemical assays. The biological implications of these results are discussed as they support growing evidence that H(2)O(2) is a key regulator of PTPs.