Continuous Infusion of Flumazenil in the Management of Benzodiazepines Detoxification

An effective approach in the treatment of benzodiazepine (BZD) overdosing and detoxification is flumazenil (FLU). Studies in chronic users who discontinued BZD in a clinical setting suggested that multiple slow bolus infusions of FLU reduce BZD withdrawal symptoms. The aim of this study was to confirm FLU efficacy for reducing BZD withdrawal syndrome by means of continuous elastomeric infusion, correlated to drugs plasma level and patients\u2019 compliance. Methods: Seven-day FLU 1 mg/day subcutaneously injected through an elastomeric pump and BZDs lormetazepam, clonazepam, and lorazepam were assessed by HPLC-MS/MS in serum of patients before and after 4 and 7 days of FLU continuous infusion treatment. Changes in withdrawal severity were assessed by using the BZD Withdrawal Scale (BWS). Results: Fourteen patients (mean age \ub1 SD 42.5 \ub1 8.0 years, 5 male and 9 female), admitted to the hospital for high-dose BZD detoxification, were enrolled in the study. Serum FLU concentrations significantly decreased from 0.54 \ub1 0.33 ng/ml (mean \ub1 SD) after 4 days of treatment to 0.1 \ub1 0.2 ng/ml at the end of infusion. Lormetazepam concentrations were 502.5 \ub1 610.0 ng/ml at hospital admission, 26.2 \ub1 26.8 ng/ml after 4 days, and 0 at the end of treatment. BWS values decreased during FLU treatment temporal period. FLU was well-tolerated by patients. Conclusions: Elastomeric FLU infusion for BZD detoxification is a feasible administration device to maintain adequate, constant, and tolerated FLU concentrations for reducing BZD withdrawal symptoms

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Nuove tecniche di separazione in fase liquida (micro-HPLC ed Elettroforesi Capillare) accoppiate alla spettrometria di massa: applicazioni tossicologiche e biomediche

Nell\u2019ultimo decennio tecniche analitiche come l\u2019elettroforesi capillare (CE) e la micro-HPLC hanno assunto sempre maggiore interesse, in particolare nei settori dove l\u2019analita \ue8 presente in tracce nel campione, come nell\u2019analisi tossicologico-forense, nell\u2019analisi alimentare, nella chimica combinatoriale e nel drug discovery. In particolare in ambito forense per molti anni la gas-cromatografia \ue8 stata la tecnica di elezione, soprattutto per la robustezza analitica e l\u2019alta sensibilit\ue0. Questa tecnica \ue8 particolarmente adatta all\u2019analisi rapida di miscele di sostanze volatili,ma presenta tuttavia alcuni svantaggi tra cui l\u2019impossibilit\ue0 di analizzare sostanze non volatili e termolabili, e la necessit\ue0 di derivatizzazione nella determinazione di molte droghe e dei loro metaboliti. Questo se da un lato non ha limitato la diffusione di questa tecnica, dall\u2019altro ha orientato l\u2019interesse verso tecniche cromatografiche in fase liquida, principalmente l\u2019HPLC. La cromatografia liquida ad alte prestazioni si \ue8 subito imposta in tutti i settori analitici, principalmente perch\ue9 consente l\u2019utilizzo di rivelatori basati su principi chimico-fisici diversi il che la rende estremamente versatile. Questa tecnica viene utilizzata di routine per testare prodotti di impiego in campo farmaceutico, per applicazioni biomediche e biochimiche, nonch\ue9 per il controllo qualit\ue0. Pi\uf9 recentemente sono state sviluppate numerose geometrie di interfacciamento di questa tecnica con un rivelatore altamente sensibile quale lo spettrometro di massa. Il notevole incremento di sensibilit\ue0 e selettivit\ue0 cos\uec ottenuto spiega la vasta diffusione della strumentazione LC-MS nei laboratori di chimica analitica particolarmente nel settore farmaceutico, ambientale e alimentare, dove essendo gli analiti altamente polari, la gas-cromatografia non \ue8 applicabile se non previa derivatizzazione. Solo pi\uf9 recentemente questa tecnica si \ue8 diffusa anche nell\u2019analisi forense, costituendo una valida alternativa alla gas-cromatografia. L\u2019elettroforesi capillare (CE) \ue8 una tecnica analitica pi\uf9 recente che, originatasi dall\u2019ottimizzazione strumentale delle tradizionali tecniche elettroforetiche, \ue8 diventata una tecnologia indipendente con applicazioni nelle pi\uf9 diverse discipline chimico-analitiche. La CE si propone con alcune caratteristiche del tutto peculiari e di estremo interesse per le discipline analitiche sia farmaceutiche che forensi, quali grande versatilit\ue0 di applicazione (ioni organici e inorganici, droghe, farmaci, composti chirali ma anche macromolecole), elevata sensibilit\ue0 in termini di massa, possibilit\ue0 di applicazione secondo differenti modalit\ue0 separative impiegando diversi sistemi di rivelazione, bassi costi di gestione e robustezza sperimentale. Solo pi\uf9 recentemente su modello delle interfacce disponibili per LC-MS \ue8 stato realizzato l\u2019interfacciamento CE-MS, unendo l\u2019elevata efficienza separativa che caratterizza la CE con l\u2019alta sensibilit\ue0 e selettivit\ue0 portate dal rivelatore di massa. In ambito forense questa moderna tecnica non ha ancora avuto grande diffusione ma sembra gi\ue0 dare promettenti risultati bench\ue8 le geometrie di interfacciamento disponibili non siano ancora ottimizzate. Lo scopo del presente lavoro \ue8 stato quello di esplorare le possibilit\ue0 offerte da queste nuove metodiche di separazione in fase liquida (micro-HPLC e CE) al fine di mettere a punto nuovi metodi per la separazione di molecole di interesse medico-legale e biomedico.In the last decade, analytical techniques such as capillary electrophoresis (CE) and micro-HPLC have grown in interest, particularly in the areas where the analyte is present in traces in the sample, such as forensic toxicological analysis, food analysis, combinatorial chemistry and drug discovery. In particular, in the forensic field for many years gas chromatography has been the technique of choice, specifically for the robustness and high analytical sensitivity. This technique is particularly suitable for the rapid analysis of mixtures of volatile substances, but nevertheless is not suitable for highly polar, non volatile and thermally unstable substances, as many of the target drugs of forensic interest are. In most instances, these drawbacks can be overcome by introducing a derivatisation step, this however creates a new source of variability and complexity. High performance liquid chromatography (HPLC) was immediately utilized in all analytical areas, principally because it allows the use of detectors based on different physical-chemical principles which makes it extremely versatile. This technique is routinely used in the pharmaceutical field, in biochemical and biomedical applications, as well as for quality control. More recently the possibility to hyphenate HPLC with the mass spectrometer, significantly increased the sensitivity and selectivity obtained thus explaining the wide spread of LC-MS instrumentation in analytical chemistry laboratories particularly in the pharmaceutical, environmental, and food analysis fields. Only more recently, this technique has spread to forensic analysis, providing a viable alternative to gas chromatography. In recent years, capillary electrophoresis (CE) has been introduced as a new independent separation technique, showing original characteristics in terms of separation mechanisms, speed of analysis, separation efficiency and minimal sample requirements. The hyphenation of CE with MS has been successfully applied in many fields of analytical chemistry and biochemistry combining the high separative efficiency that characterizes the CE with high sensitivity and selectivity brought by the mass detector. Although the geometry of the interfaces are not yet optimized, CE-MS seems to give promising results. The purpose of this study was to explore the possibilities offered by these new liquid phase separation techniques (micro-HPLC and CE) in order to develop new methods for the separation of molecules of forensic and biomedical interest

Ricerca di composti farmacologicamente attivi e potenzialmente pericolosi in prodotti di libero commercio impiegando la spettrometria di massa ad elevata risoluzione

Negli ultimi anni a livello internazionale si \ue8 assistito alla crescente diffusione di prodotti estranei all\u2019ambito farmaceutico, pubblicizzati come integratori dietetici o prodotti naturali atti a migliorare il benessere psico-fisico, contenenti tuttavia sostanze illecite non dichiarate in etichetta. La commercializzazione di queste sostanze presenta una potenziale pericolosit\ue0 per la salute pubblica, sia per la dichiarata \uabnaturalit\ue0\ubb dei prodotti commerciali che induce l\u2019utilizzatore a sottostimarne gli eventuali effetti tossici, sia per la possibile interazione di tali composti con la terapia farmacologica eventualmente assunta in concomitanza. D\u2019altra parte, l\u2019estrema variet\ue0 dei principi attivi presenti in questi prodotti rende l\u2019identificazione degli stessi estremamente difficile, anche a causa della mancanza di standard di riferimento. In questo ambito, la spettrometria di massa ad alta risoluzione (HRMS) ha contribuito significativamente allo sviluppo della ricerca incognita di composti di interesse, introducendo un nuovo criterio di identificazione molecolare basato sull\u2019elevato potere discriminante della massa accurata, che, essendo direttamente calcolabile dalla formula chimica del composto, prescinde dalla necessit\ue0 di disporre di standard puri e dalla necessit\ue0 di frammentazione del composto. Nel presente lavoro, sono proposte e discusse applicazioni in questo ambito della spettrometria di massa ad alta risoluzione

Use of synthetic cannabinoids to cheat the toxicological screenings

Use of synthetic cannabinoids to cheat the toxicological screening

CE-MS in forensic sciences with focus on forensic toxicology

The present chapter reviews the literature on CE-MS applications in the main analytical fields of forensic science from the end of 1980s to current times. However, because of the number of papers and the variety of the subjects of potential forensic interest, no review can be comprehensive. Moreover, any ambition of completeness would be frustrated in the near future by the tide of publications of new research. Hence, the present work aims mainly at showing and discussing the different strategies adopted in the development and application of forensic CE-MS, with particular attention devoted to the peculiarities of this new technology

Chiral analysis of methorphan in opiate-overdose related deaths by using capillary electrophoresis

An enantioselective CE-based determination of methorphan and its main metabolites in blood is described. Enantiomeric separations were carried out in 50cm 750\u3bcm (ID) uncoated fused silica capillaries, using a background electrolyte composed of 150mM sodium phosphate pH 4.4 added with 5mM 2-(hydroxypropyl)-\u3b2-cyclodextrin and methanol 20% (v/v), at a constant voltage of 25kV. Sample injections were performed under field amplified sample stacking conditions. Detection was by recording UV absorbance at the wavelength of 200nm. Linearity of response was assessed within a concentration range from 25 to 500ng/mL for dextrometorhan, levomethorphan and their main metabolites (namely dextrorphan and levorphanol, respectively). Folcodine was used as internal standard. Under these conditions, the limit of quantification resulted 25ng/mL for each one of the analytes. The intra-day and inter-day precision, in terms of coefficient of variation (CV) were below 3.7% and 14.9 % for migration times and peak areas, respectively. The present method was successfully applied to the analysis of post-mortem blood samples from ten subjects died for heroin overdoses. Among the samples "positive" for methorphan (n=4), the d-enantiomer was found in concentrations ranging from 214 to 1282ng/mL. The concentration of its main metabolite dextrorphan in the same samples ranged from 49 to 389ng/mL

Drug screening by using the Toxtyper\u2122 LC-ion trap MS: Optimization of its application on serum samples in a DUID context

The toxicological approach for monitoring Driving Under Influence of Drugs (DUID) requires analytical techniques with a broad spectrum of identification coupled to a high analytical sensitivity. In this context immunological methods are generally used, while GC or LC-MS are applied for the confirmation step. A different approach for drug screening is represented by the Toxtyper\u2122 instrumentation, an LC-MS platform equipped with a high-speed ion trap mass analyzer, provided with ready-to-use protocols and a database of as many as 4500 therapeutic, toxic/illicit drugs and metabolites. The aim of the present work was to verify its performances in real conditions of drug screening of human serum in the context of DUID. To test and compare its analytical performances, four pooled serum samples were fortified with a selected panel of 47 drugs and metabolites. The agreement between the results from the ToxtyperTM and from the confirmatory techniques currently in use at the University of Verona (GC and LC-MS) was investigated by analyzing 90 real samples chosen from those routinely analyzed. The present study highlights the suitability of the ToxtyperTM for drug screening in serum with a sensitivity compatible with the needs of the DUID for all the tested compounds, with the only exception of cannabinoids