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- Toxicologia Forense: métodos analíticos para a determinação de Α-PHP e Α-PIHPPublication . Dinis, Pedro; Franco, João; Margalho, CláudiaA análise mais recente do Observatório Europeu da Droga e da Toxicodependência (EMCDDA), o Relatório Europeu sobre Drogas de 2024, revela um mercado resiliente e influenciado pelos desenvolvimentos globais. Os problemas persistentes de saúde e segurança colocados tanto por drogas ilícitas tradicionais quanto por substâncias mais recentes criam um ambiente desafiador para a elaboração e implementação de respostas eficazes. O termo de Novas Substâncias Psicoativas (NSPs) abrange substâncias não controladas por convenções internacionais, sendo o seu mercado caracterizado pelo constante surgimento de um grande número de substâncias. Entre destas, incluem-se o α- pyrrolidinohexanophenone (α-PHP) e o seu isómero posicional α- pyrrolidinoisohexanophenone (α-PiHP), duas catinonas sintéticas pertencentes ao subgrupo dos derivados da pirovalerona que, em Portugal, apresentam níveis de consumo mais expressivos nos arquipélagos da Madeira e dos Açores. O principal objetivo deste trabalho é compilar os mais recentes dados, internacionalmente publicados, relativos aos métodos analíticos para a determinação das duas catinonas sintéticas, α-PHP e α-PiHP, em amostras biológicas com interesse forense. Foi realizada uma pesquisa bibliográfica nas bases de dados PubMed e b-on entre os anos de 1967 e 2024 com as seguintes palavras-chave: α-PHP, α-PiHP, catinonas sintéticas, NPS e toxicologia forense. Seguidamente, foi feita uma compilação das metodologias analíticas publicadas para a determinação de α-PHP e α-PiHP em amostras biológicas. Nos artigos encontrados e analisados, o α-PHP e o α-PiHP foram detetados tanto em amostras biológicas convencionais (sangue periférico e cardíaco, soro e urina) como em amostras biológicas não convencionais (humor vítreo, bílis, conteúdo gástrico e tecidos sólidos). Na etapa de preparação das matrizes biológicas, as técnicas mais descritas foram a extração líquido-líquido e a extração em fase sólida. Relativamente à análise instrumental, o método mais utilizado foi a cromatografia líquida associada à espetrometria de massa em tandem (LC-MSMS), embora a cromatografia de gases associada à espetrometria de massa (GC /MS) também tenha sido aplicada em estudos recentes. Considerando o impacto que o consumo destas substâncias tem na saúde pública e segurança internacional, é necessário e fundamental continuar a investir no desenvolvimento de metodologias analíticas sensíveis e abrangentes para a deteção de NSPs em diversas matrizes biológicas.
- Α-Pyrrolidinoisohexanophenone (Α-PIHP) in three fatalPublication . Dinis, Pedro; Machado, Francisca; Franco, João; Margalho, CláudiaBackground & Aims The New Psychoactive Substances (NPSs) are widely spread worldwide through the illicit markets and are increasingly the cause of intoxication deaths. Alpha-pyrrolidinoisohexanophenone (α-PiHP) is a positional isomer of α-pyrrolidinohexanophenone (α-PHP) and has been reported for the first time in 2016 at seized materials in China. Both substances are pyrovalerone derivatives from the synthetic cathinones group, and mainly exert cardiovascular, psychological, and neurologic effects. In addition, as published in literature and regardless of their isomerism, both cathinones can appear separately or together in a mixture. This work presents three forensic fatal cases associated with the consumption of α-PiHP and/or α-PHP: case 1 involves a 41-year-old man, drug user, mostly of “bloom”, who committed suicide by hanging; case 2 reports to a 32-year-old man, addicted to synthetic drugs, associated with a sample of “weed” collected next to the corpse; case 3 concerns to a 58-year-old male drug addict, who died after being admitted to the emergency department in a state of coma. Methods The toxicological analyses were carried out in peripheral blood in the three cases and, in case 2, the sample of “weed” was also analysed. Samples (500µL) were prepared with 0.1 M phosphate buffer, extracted by solid-phase extraction and analysed through gas chromatography coupled with mass spectrometry (GC-MS) in full-Scan monitoring mode to search for unknown substances. Subsequently, the samples were analysed in single-ion monitoring mode to confirm the substances detected in full-Scan. The ions 140, 98 and 77 were monitored for α-PiHP; 140, 105 and 77 for α-PHP; and 185 for cocaine-d3 (internal standard). Results & Discussion In case 1 was detected and confirmed α-PiHP. Other substances were also detected and confirmed such as tramadol, fluoxetine, diazepam, nordiazepam, cyamemazine, olanzapine, paliperidone and risperidone. Regarding case 2, in the “weed” we were able to detect several cannabinoids (cannabicyclol, cannabichromene, cannabidiol, cannabidivarol, cannabigerol, cannabinol, delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol and tetrahydrocannabivarin), nicotine and α-PiHP. In peripheral blood was confirmed α-PiHP, cocaine and its metabolites (benzoylecgonine and ecgonine methyl ester), delta-9-tetrahydrocannabinol and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, phenacetine (a cocaine cutting agent), morphine, paracetamol, alprazolam, nordiazepam, sertraline and mirtazapine. In case 3, both α-PHP and α-PiHP were detected and confirmed in peripheral blood, such as paracetamol. Therefore, the toxicological results of the three cases are relevant to complement the case histories since the presence of α-PiHP in the peripheral blood can be related with the death of individuals. Conclusion With the three cases presented in this work, we can conclude that the search for NPS in biological and non-biological specimens plays an important role, especially in cases of drug-related deaths. The concomitant use of traditional drugs of abuse, prescription medication, α-PHP and α-PiHP, either separately or in combination, increases the possibility of a fatal intoxication since both substances have a high toxic potential.
- Comprehensive toxicological analysis in a case of unexpected fatal codeine intoxicationPublication . Margalho, Cláudia; Emanuel Santos Pinheiro, João; Dinis, Pedro; Mendonça, Ricardo; Castanheira, Alice; Franco, JoãoBackground and Aims: Codeine, a commonly prescribed opioid analgesic and antitussive, is widely used either alone or in combination with other medications. This substance is typically administered orally and is well absorbed from the gastrointestinal tract. After being absorbed, it is distributed throughout the body and crosses the blood-brain barrier to reach the central nervous system, where it exerts its pharmacological effects. Metabolized extensively by the liver enzyme CYP2D6, codeine is converted to its active metabolite, morphine, along with other metabolites such as norcodeine, codeine-6-glucuronide, and morphine-3-glucuronide. Despite its therapeutic benefits, codeine can induce adverse effects such as drowsiness, constipation, nausea, and respiratory depression, particularly at higher doses or in susceptible individuals. We present an unusual case concerning a 60-year-old woman that was found dead at home by his husband, when he came back home for lunch. In that morning, he left her sleeping in the bed. She had diarrhoea in the previous 48h, was obese, and suffer of asthma and psychiatric illness. Her usual prescribed medications included the antidepressants escitalopram and triticum, the anticonvulsant oxcarbazepine (used primarily to treat epilepsy and bipolar disorder), the anxiolytic lorazepam, the antipsychotic quetiapine, the asthma control montelukast and the atorvastatin used to treat hypercholesterolemia. There was no history of ingestion of any formulation containing codeine. Autopsy showed no evidence of trauma. A slight cardiac hypertrophy related with a hypertensive cardiopathy was observed macro and microscopically. Fragments of white pills were found in stomach and a dark liquid content until the jejune. Methods: Validated analytical procedures, routinely used in our casework, were applied to analyze peripheral and cardiac blood, urine, gastric content, and liver specimens. Initially, drugs of abuse and benzodiazepines were screened using immunoassay methodology, while ethanol screening was conducted by gas chromatography-flame ionization detector with headspace injection (GC-FID-HS). Subsequently, systematic toxicological analyses were performed using gas chromatography-mass spectrometry (GC-MS) for drugs of abuse and unknown substances, and ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS-MS) for prescription substances. Results and Discussion: No ethanol or drugs of abuse were detected in blood samples. However, codeine was confirmed, in all analyzed specimens, in significantly high concentrations: peripheral (5309 ng/mL) and cardiac (7545 ng/mL) blood, suggesting recent consumption; liver (9935 ng/mL), confirming extensive metabolism; urine (205918 ng/mL), indicating substantial drug excretion before death; and gastric content (197428 ng/mL), confirming ingestion prior to death. Additionally, morphine, a codeine metabolite, was present in peripheral and cardiac blood at concentrations of 190 and 616 ng/mL, respectively. Furthermore, therapeutic levels of various prescription medications were detected in peripheral blood, including atorvastatin, citalopram, oxcarbazepine, paracetamol, quetiapine, norquetiapine, trazodone and its metabolite mCPP, lorazepam and its metabolite desalkylflurazepam. Conclusion: The autopsy was negative except for a hypertensive cardiopathy, that was not severe enough to justify the death. On the other hand, toxicological results showed unexpectedly codeine in the blood, stomach, liver, and urine, in high concentrations. The pills fragments found in the gastric content reinforce its ingestion before death. Taking into account all these facts, the cause of death was attributed to codeine ingestion, although in an unknown formulation. The manner of death remains unascertained, as suicide could be a possibility according to her psychiatric antecedents, as well as an accident, if codeine had been taken to treat the diarrhoea she had.
- α-Pyrrolidinohexanophenone (α-PHP) and α-Pyrrolidinoisohexanophenone (α-PiHP): A ReviewPublication . Dinis, Pedro; Franco, João; Margalho, CláudiaNew Psychoactive Substances are currently a serious and growing problem affecting public health worldwide. By 2022, 1184 of these substances had been identified over a period of 16 years. Within these, α-pyrrolidinohexanophenone (α-PHP) and α-pyrrolidinoisohexanophenone (α-PiHP) have emerged, two synthetic cathinones from the pyrovalerone derivates subgroup that are positional isomers of each other. Alpha-PHP appeared on the Japanese illicit drug market in 2014 and, two years later, α-PiHP was identified for the first time in China. They were placed in schedule II on the list of Psychotropic Substances under International Control in 2020 and in March 2023, respectively. Both cathinones have no therapeutic potential for medical use and therefore are abused for recreational habits, which can lead to fatalities. The most frequent adverse effects reported are cardiac, psychiatric, and neurologic, and fatal intoxications have already been described. In Portugal, their consumption and consequent seizures are more prevalent on the archipelagos, which has been aggravating the health situation. In conclusion, these types of substances are a challenge for forensic toxicology since they are easily synthesized, modified, and placed on the market. Therefore, more studies to develop analytical methods to detect them and more comprehensive legislation should be applied. Thus, this review aimed to address the legislative, physicochemical, toxicological, and analytical aspects of both substances.