Ian S. Blagbrough

Novel psychoactive substances (NPS) pose one of the greatest challenges across the illicit drug landscape. They can be highly potent, and coupled with rapid changes in structure, tracking and identifying these drugs is difficult and presents users with a "Russian roulette" if used. Benzodiazepines, synthetic opioids, synthetic cannabinoids, and synthetic cathinones account for the majority of NPS-related deaths and harm. Detecting these drugs with existing field-portable technologies is challenging and has hampered the development of community harm reduction services and interventions. Herein, we demonstrate that hybridizing fluorescence and reflectance spectroscopies can accurately identify NPS and provide concentration information with a focus on benzodiazepines and nitazenes. The discrimination is achieved through a deep learning algorithm trained on a library of preprocessed spectral data. We demonstrate the potential for these measurements to be made using a low-cost, portable device that requires minimal user training. Using this device, we demonstrate the discrimination of 11 benzodiazepines from "street" tablets that include bulking agents and other excipients. We show the detection of complex mixtures of multiple drugs, with the key example of nitazene + benzodiazepine (metonitazene + bromazolam), fentanyl + xylazine, and heroin + nitazene (etonitazene) combinations. These samples represent current drug trends and are associated with drug-related deaths. When combined with the implementation of detection technology in a portable device, these data point to the immediate potential to support harm reduction work in community-based settings. Finally, we demonstrate that the approach may be generalized to other drug classes outside NPS discrimination.

This review covers the intramolecular through-space steric compression that may produce a significant deshielding effect and provides uncommon ¹H NMR chemical shift confusing NMR analysts.

Novel Psychoactive Substances (NPS) pose one of the greatest challenges across the illicit drug landscape. They can be highly potent, and coupled with rapid changes in structure, tracking and identifying these drugs is difficult, and presents users with a ‘Russian roulette’ if used. Benzodiazepines, synthetic opioids, synthetic cannabinoids and synthetic cathi-nones account for the majority of NPS related deaths and harm. Detecting these drugs with existing field-portable technol-ogies is challenging and has hampered the development of community harm reduction services and interventions. Herein, we demonstrate that hybridizing fluorescence and reflectance spectroscopies can accurately identify NPS and provide concentration information, with a focus on benzodiazepines and nitazenes. The discrimination is achieved through a deep learning algorithm trained on a library of pre-processed spectral data. We demonstrate the potential for these measure-ments to be made using a low-cost, portable device that requires minimal user training. Using this device, we demon-strate the discrimination of 11 benzodiazepines and from ‘street’ tablets that include bulking agents and other excipients. We show the detection of complex mixtures of multiple drugs, with the key example of nitazene + benzodiazepine (metonitazene + bromazolam), fentanyl + xylazine and heroin + nitazene (etonitazene) combinations. These samples represent current drug trends and associated with drug related deaths. When combined with the implementation of detection technology in a portable device, these data point to the immediate potential to support harm reduction work in community-based settings. Finally, we demonstrate that the approach may be more broadly generalized to other drug classes outside of NPS discrimination.

A general procedure to prepare gold nanourchins (GNUs) via a seed-mediated method was followed using dopamine hydrochloride as a reducing agent and silver nitrate salt (AgNO₃) as a shape-directing agent. The novelty of this study comes from the successful incorporation of the prepared gold urchins as an aqueous suspension in a nasal pressurized metered dose inhaler (pMDI) formulation and the investigation of their potential for olfactory targeting for direct nose-to-brain drug delivery (NTBDD). The developed pMDI formulation was composed of 0.025% w/w GNUs, 2% w/w Milli-Q water, and 2% w/w EtOH, with the balance of the formulation being HFA134a propellant. Particle integrity and aerosolization performance were examined using an aerosol exposure system, whereas the nasal deposition profile was tested in a sectioned anatomical replica of human nasal airways. The compatibility of the gold dispersion with the nasal epithelial cell line RPMI 2650 was also investigated in this study. Colloidal gold was found to be stable following six-month storage at 4 °C and during the lyophilization process utilizing a pectin matrix for complete re-dispersibility in water. The GNUs were intact and discrete following atomization via a pMDI, and 13% of the delivered particles were detected beyond the nasal valve, the narrowest region in the nasal cavity, out of which 5.6% was recovered from the olfactory region. Moreover, the formulation was found to be compatible with the human nasal epithelium cell line RPMI 2650 and excellent cell viability was observed. The formulated GNU-HFA-based pMDI is a promising approach for intranasal drug delivery, including deposition in the olfactory region, which could be employed for NTBDD applications.

The olfactory region of the nasal cavity directly links the brain to the external environment, presenting a potential direct route to the central nervous system (CNS). However, targeting drugs to the olfactory region is challenging and relies on a combination of drug formulation, delivery device, and administration technique to navigate human nasal anatomy. In addition, in vitro and in vivo models utilized to evaluate the performance of nasal formulations do not accurately reflect deposition and uptake in the human nasal cavity. The current study describes the development of a respirable poly(lactic-co-glycolic acid) nanoparticle (PLGA NP) formulation, delivered via a pressurized metered dose inhaler (pMDI), and a cell-containing three-dimensional (3D) human nasal cast model for deposition assessment of nasal formulations in the olfactory region. Fluorescent PLGA NPs (193 ± 3 nm by dynamic light scattering) were successfully formulated in an HFA134a-based pMDI and were collected intact following aerosolization. RPMI 2650 cells, widely employed as a nasal epithelial model, were grown at the air-liquid interface (ALI) for 14 days to develop a suitable barrier function prior to exposure to the aerosolized PLGA NPs in a glass deposition apparatus. Direct aerosol exposure was shown to have little effect on cell viability. Compared to an aqueous NP suspension, the transport rate of the aerosolized NPs across the RPMI 2650 barrier was higher at all time points indicating the potential advantages of delivery via aerosolization and the importance of employing ALI cellular models for testing respirable formulations. The PLGA NPs were then aerosolized into a 3D-printed human nasal cavity model with an insert of ALI RPMI 2650 cells positioned in the olfactory region. Cells remained highly viable, and there was significant deposition of the fluorescent NPs on the ALI cultures. This study is a proof of concept that pMDI delivery of NPs is a viable means of targeting the olfactory region for nose-to-brain drug delivery (NTBDD). The cell-based model allows not only maintenance under ALI culture conditions but also sampling from the basal chamber compartment; hence, this model could be adapted to assess drug deposition, uptake, and transport kinetics in parallel under real-life settings.

Synthetic cannabinoids (SCs) make up a class of novel psychoactive substances (NPS), used predominantly in prisons and homeless communities in the U.K. SCs can have severe side effects, including psychosis, stroke, and seizures, with numerous reported deaths associated with their use. The chemical diversity of SCs presents the major challenge to their detection since approaches relying on specific molecular recognition become outdated almost immediately. Ideally one would have a generic approach to detecting SCs in portable settings. The problem of SC detection is more challenging still because the majority of SCs enter the prison estate adsorbed onto physical matrices such as paper, fabric, or herb materials. That is, regardless of the detection modality used, the necessary extraction step reduces the effectiveness and ability to rapidly screen materials on-site. Herein, we demonstrate a truly instant generic test for SCs, tested against real-world drug seizures. The test is based on two advances. First, we identify a spectrally silent region in the emission spectrum of most physical matrices. Second, the finding that background signals (including from autofluorescence) can be accurately predicted is based on tracking the fraction of absorbed light from the irradiation source. Finally, we demonstrate that the intrinsic fluorescence of a large range of physical substrates can be leveraged to track the presence of other drugs of interest, including the most recent iterations of benzodiazepines and opioids. We demonstrate the implementation of our presumptive test in a portable, pocket-sized device that will find immediate utility in prisons and law enforcement agencies around the world.

With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting" approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.

Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL⁻¹.

Norditerpenoid alkaloids (NDA) are hexacydic highly oxygenated compounds, and the analysis of their 3D configuration is important as it helps to interpret their bioactive conformations. High-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry (LC/MS-APCI) is a promising technique to investigate NDA stereochemistry. The effect of the alpha (alpha)-substituent at carbon 1 and its configuration on the stability of NDA in the mass spectrometer was studied. It was observed that 1-OH NDA are more stable compared to 1-OMe NDA due to the intramolecular H-bonding that exists in 1-OH NDA. In addition, 1-epi-condelphine 9 was found to be less stable in the mass spectrometer compared to condelphine 7 as the nitrogen is no longer hydrogen-bonded to the beta-hydroxyl at position 1, which highlights the importance of the substituent configuration at carbon 1.