The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure-activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones' pharmacology and potential implications.

The coronavirus (CoV) disease 2019 (COVID-19) is expected to become endemic in the coming years, meaning that the worldwide society shall be prepared to routinely manage the highly contagious respiratory SARS-CoV-2. A rapid and early diagnosis of the SARS-CoV-2 infection is crucial for controlling the spread of the disease, interrupting the transmission chain, and providing timely medical attention to patients. We introduce an innovative nanophotonic biosensor for the quantitative detection of viral particles in less than 20 minutes total assay time. The nanosensor, based on the bimodal waveguide (BiMW) interferometric technology, has been functionalized with novel bioengineered nanobodies (Nb) targeting the SARS-CoV-2 receptor-binding domain (RBD). Our approach relies on the direct capture of the viral particles, and the optimized methodology allows the detection of the SARS-CoV-2 virus with outstanding sensitivity, below 200 TCID50 per mL, being able to provide accurate viral load determination within a broad dynamic range (10²–10⁶ TCID50 per mL). Both the nanobodies and the sensor nanotechnology can be produced at a large scale with highly-efficient cost-effective procedures, and they are being integrated into a user-friendly point-of-care device for multiplexed and decentralized operation. The implementation of this unique biosensor in primary care assistance, hospitals, pharmacies, or private laboratories could greatly aid in the relief and descongestion of the sanitary systems and the clinical and social management of COVID-19.

The persistence of traditional tattoo inks presents an advantage for continuous and long‐term health monitoring in point of care devices. The replacement of tattoo pigments with optical biosensors aims a promising alternative for monitoring blood biomarkers. Tattoo inks functionalization enables the control of interstitial biomarkers with correlated concentrations in plasma, to diagnose diseases, evaluate progression, and prevent complications associated with physio pathological disorders or medication mismatches. The specific biomarkers in interstitial fluid provide a new source of information, especially for skin diseases. The study of tattoo inks displays insufficient regulation in their composition, a lack of reports of the related complications, and a need for further studies on their degradation kinetics. This review focuses on tattoo optical biosensors for monitoring dermal interstitial biomarkers and discusses the clinical advantages and main challenges for in vivo implantation. Tattoo functionalization provides a minimally invasive, reversible, biocompatible, real‐time sensing with long‐term permanence and multiplexing capabilities for the control, diagnosis, and prevention of illness; it enables self‐controlling management by the patient, but also the possibility of sending the records to the doctor.

The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a multiparametric New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, and 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity using high-speed video microscopy and dynamic pixel analysis. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀/locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions, particularly para-chlorination, are associated with comparatively reduced functional separation between these endpoints within the assay. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with comparatively higher cardiac liability within this experimental framework.

The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a high-resolution New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, as well as 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity in zebrafish embryos using high-speed video microscopy and dynamic pixel analysis.. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀ / locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions—particularly para-chlorination—are associated with comparatively reduced safety margins. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with disproportionate cardiac risk.

Background/Objectives: Synthetic cathinones are a rapidly evolving class of new psychoactive substances whose structural diversity complicates toxicological risk assessment. Methylenedioxy cathinones occupy a pharmacological space between MDMA-like entactogens and more dopaminergic stimulant cathinones, but their direct cardiac liabilities remain poorly characterized. This study aimed to compare the cardiotoxic and neurobehavioral profiles of methylone, butylone, pentylone and their N,N-dimethyl analogues, and to determine how alkyl-chain extension and terminal amine substitution shape functional toxicity. Methods: Wild-type short-fin zebrafish (Danio rerio) embryos were used as a multiparametric New Approach Methodology. Cardiac rhythmicity was assessed in 3 days post-fertilization embryos after acute exposure to methylone, butylone, pentylone, dimethylone, dibutylone, dipentylone, dihexylone and diheptylone by high-speed video microscopy and dynamic pixel-based analysis, focusing on atrial chronotropy and atrioventricular conduction. Basal locomotor activity was evaluated in 5 days post-fertilization eleutheroembryos over 120 min using automated video tracking. Results: Negative chronotropy increased with alkyl-chain extension, with the monoalkyl subset following the rank order methylone < butylone < pentylone. Among dialkyl analogues, dihexylone and, especially, diheptylone produced the strongest atrial-rate inhibition. AV conduction impairment was more heterogeneous but became prominent among higher-liability analogues, with diheptylone showing the lowest AV-block midpoint descriptor and complete lethality at 1000 µM. Locomotor profiling revealed predominantly hypoactive phenotypes, with sustained late-phase inhibition especially for dipentylone, dihexylone and diheptylone. Conclusions: Alkyl-chain extension and terminal amine substitution shaped cardiac and neurobehavioral toxicity in a structure-dependent manner. The zebrafish workflow provides a structure-oriented framework for prioritizing emerging methylenedioxy cathinones with comparatively higher functional cardiac liability.