New Psychoactive substances(NPS) are a heterogeneous group of substances, in pure form or in preparation, synthetized to mimic the effects of the classic drugs of abuse. Since they are not listed under the Presidential Decree (309/90), they are not considered illegal, thus representing a public health threat. One The most represented NPS class, are Synthetic Opioids (SO), narcotic analgesics with effect similar to that of the natural opioids. Recently, Benzimidazole Opiois (BO), a New SO subclass emerged onto the market raising concern for the public health. They have been first synthetized by a Swiss Company (CIBA) in the late 50s ad potential analgesic drugs, but due to its several side effects, they were never approved for marketing. In the 2019, after Fentanyl and its analogues have been listed under the Schedule I of the United Nations Single Convention on Narcotic Drugs of 1961, BO started to be illegally synthetized and sold onto the black market. So far, pharmacological study on BOs, reported etonitazene as the most potent nitazene (1000 fold more potent than morphine), followed by several analogues, such as isotonitazene, protonitazene, metonitazene and etodesnitazene. Currently, little is known about their metabolism, posing a significant challenge for drug policy aiming to contrast this health threat. The aim of this thesis was to study the metabolic profile of isotonitazene and etodesnitazene, to identify biomarkers of exposure to assist forensic toxicological analysis, health care system and researcher. In vitro incubation with human pooled hepatocyte, in silico prediction, analysis with liquid chromatography coupled to high resolution mass spectrometry tandem(LC-HRMS/MS and data mining with a specialized software were performed to study isotonitazene and etodesnitazene metabolism. A total of 11 and 17 metabolites were identified for isotonitazene and etodesnitazene, respectively, after 3h incubation. The main transformation occurred were N-dealkilation and N-deisopropilation. N-deethylated Isotonitazene(A11) and N-deethylation Etodesnitazene (B12), the most abundant metabolites, are suggested as specific biomarker of exposure.
Le nuove sostanze psicoattive (NPS) sono un gruppo molto ampio ed eterogeneo di molecole, principalmente di natura sintetica ma anche di origine naturale, che vengono principalmente sintetizzate per mimare gli effetti delle classiche sostanze d’abuso. Le NPS rappresentano un problema per la salute pubblica perché essendo nuove non sono inserite nelle Tabelle Ministeriali (legge 309/90), non risultano quindi illegali. Uno dei gruppi più rappresentati fra le NPS sono gli oppioidi sintetici, narcotici analgesici con effetti simili agli oppioidi naturali. Negli ultimi anni una nuova classe di oppioidi sintetici chiamati Benzimidazoli (BO) ha destato particolare preoccupazione per la salute pubblica. Sintetizzati per la prima volta nel 1957 come potenziali farmaci analgesici, a causa dei numerosi effetti collaterali non sono mai stati commercializzati. Nel 2019, dopo l’inclusione del Fentanil e dei suoi derivati nella tabella I delle sostanze stupefacenti e psicotrope, i BO hanno iniziato a comparire nel mercato illegale delle droghe. Studi relativi alla loro farmacologia riportano l’etonitazene, come il più potente fra i BO (fino a 1000 volte più potente della morfina), seguito da isotonitazene, protonitazene, metonitazene ed etodesnitazene. Nonostante sia ormai nota la loro potenza e pericolosità, il metabolismo dei BO più recentemente segnalati rimane tutt’ora poco studiato, rendendo difficile da parte delle autorità attuare misure di contrasto adeguate. Lo scopo di questo studio è stato quindi quello di indagare il profilo metabolico dell'isotonitazene e dell'etodesnitazene al fine di poter individuare i metaboliti più abbondanti ed essere utilizzati come marcatori di esposizione nelle analisi tossicologiche. Attraverso l’incubazione in vitro di epatociti umani, predizione in silico seguita da analisi in cromatografia liquida accoppiata alla spettrometria di massa ad alta risoluzione (LC-HRMS/MS) ed elaborazione dei dati attraverso un software è stato quindi studiato il metabolismo di isotonitazene ed etodesnitazene. Sono stati identificati 11 metaboliti per l'isotonitazene e 17 per l'etodesnitazene, dopo 3 ore di incubazione. Le principali reazioni coinvolte erano N-dealchilazione e N-deisoproprilazione. Il metabolita N-deetilato dell'isotonitazene (A11) e il metabolita N-deetilato dell'etodesnitazene (B12) sono stati suggeriti come biomarcatori specifici di esposizione.
Identificazione dei biomarker metabolici di esposizione ai nitazeni, una nuova sottoclasse letale di narcotici sintetici: Focus su isotonitazene ed etodesnitazene
TAOUSSI, OMAYEMA
2021/2022
Abstract
New Psychoactive substances(NPS) are a heterogeneous group of substances, in pure form or in preparation, synthetized to mimic the effects of the classic drugs of abuse. Since they are not listed under the Presidential Decree (309/90), they are not considered illegal, thus representing a public health threat. One The most represented NPS class, are Synthetic Opioids (SO), narcotic analgesics with effect similar to that of the natural opioids. Recently, Benzimidazole Opiois (BO), a New SO subclass emerged onto the market raising concern for the public health. They have been first synthetized by a Swiss Company (CIBA) in the late 50s ad potential analgesic drugs, but due to its several side effects, they were never approved for marketing. In the 2019, after Fentanyl and its analogues have been listed under the Schedule I of the United Nations Single Convention on Narcotic Drugs of 1961, BO started to be illegally synthetized and sold onto the black market. So far, pharmacological study on BOs, reported etonitazene as the most potent nitazene (1000 fold more potent than morphine), followed by several analogues, such as isotonitazene, protonitazene, metonitazene and etodesnitazene. Currently, little is known about their metabolism, posing a significant challenge for drug policy aiming to contrast this health threat. The aim of this thesis was to study the metabolic profile of isotonitazene and etodesnitazene, to identify biomarkers of exposure to assist forensic toxicological analysis, health care system and researcher. In vitro incubation with human pooled hepatocyte, in silico prediction, analysis with liquid chromatography coupled to high resolution mass spectrometry tandem(LC-HRMS/MS and data mining with a specialized software were performed to study isotonitazene and etodesnitazene metabolism. A total of 11 and 17 metabolites were identified for isotonitazene and etodesnitazene, respectively, after 3h incubation. The main transformation occurred were N-dealkilation and N-deisopropilation. N-deethylated Isotonitazene(A11) and N-deethylation Etodesnitazene (B12), the most abundant metabolites, are suggested as specific biomarker of exposure.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12075/12448