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Capa Da Dissertação Universidade de Aveiro Departamento de Química 2007 Maria Suzel Costa de Métodos de análise de piperazinas em fluidos Sousa e Escada biológicos Universidade de Aveiro Departamento Química 2007 Maria Suzel Costa de Métodos de análise de piperazinas em fluidos Sousa e Escada biológicos Dissertação apresentada à Universidade de Aveiro para cumprimento dos requisitos necessários à obtenção do grau de Mestre, no Mestrado em Métodos Instrumentais e Controlo da Qualidade Analítica, realizada sob a orientação científica do Doutor Armando Jorge Domingues Silvestre, Professor Associado do Departamento de Química e do Doutor Armando da Costa Duarte , Professor Catedrático do Departamento de Química da Universidade de Aveiro. A parte experimental deste trabalho decorreu nas instalações do Serviço de Toxicologia Forense da Delegação de Lisboa do Instituto Nacional de Medicina Legal. Dedicada à memória da minha avó Firmina, raiz da minha vida pelo seu Amor, pelo nosso Amor o júri presidente Prof. Dr. João António Baptista Pereira de Oliveira professor Associado da Universidade de Aveiro Prof. Dr. Armando da Costa Duarte professor Catedrático da Universidade de Aveiro Prof. Dr. Fernando Jorge dos Ramos professor Associado da Faculdade de Farmácia da Universidade de Coimbra Prof. Dr. Armando Jorge Domingues Silvestre professor Associado da Universidade de Aveiro agradecimentos Ao Prof. Doutor Armando Silvestre, orientador desta dissertação, agradeço e louvo a atenção e o interesse dispensado, sobretudo nos momentos mais complicados, que não foram poucos, assim como a sua orientação e a confiança em mim depositada. Pelo seu incentivo constante e pela amizade demonstrada, obrigada! Ao Prof. Doutor Armando Duarte co-orientador desta dissertação, um especial agradecimento por todo o apoio, alento e ensinamentos durante a realização deste mestrado. Ao Prof. Doutor Jorge Costa Santos, Director da delegação de Lisboa do Instituto Nacional de Medicina Legal, agradeço a oportunidade de realizar este trabalho na Instituição e a disponibilização dos meios necessários à sua execução. Ao Mestre Mário João Dias, Director do Serviço de Toxicologia Forense da delegação de Lisboa do Instituto Nacional de Medicina Legal, quero deixar uma palavra de apreço pela possibilidade de realizar este trabalho no laboratório e utilizar os instrumentos indispensáveis à sua execução. Pela sua capacidade de ver mais longe e infinita tolerância. Ao Dr. Nuno Gonçalves pela partilha dos seus conhecimentos estatísticos e auxílio nas ilustrações, por saber ouvir e pelo seu bom humor. Ao Dr. Francisco Vale por me ter apoiado e acompanhado durante todo este trabalho. Ao Dr. António Castanheira agradeço todo o apoio dispensado nas incertezas relacionadas com a validação dos métodos. Ao Dr. Mário Barroso pela preciosa ajuda na revisão do texto. A todos os meus colegas do Serviço de Toxicologia pela sua boa disposição e infinita tolerância, Muito Obrigada a todos! Aos meus colegas de mestrado, pelo companheirismo e alegria. A todos os amigos que me acompanharam ao longo destes anos deixo uma palavra de gratidão. À Lurdes, ao meu irmão Henrique, à Neide, pela ajuda valiosa no arquivo e ordenação da bibliografia. Aos meus pais e família pela compreensão e ajuda, por estarem sempre ao meu lado mesmo nos momentos menos bons, por todas as vicissitudes que passámos ao longo destes anos e que souberam enfrentar com equilíbrio. Ao Jorge, por tudo! palavras-chave Piperazinas, triagem, quantificação, sangue total, urina, GC-MS, SPE, SPME, validação resumo Nas últimas décadas, é notório um acréscimo no consumo abusivo de drogas sintéticas nas sociedades contemporâneas. Estas adquirem uma expressão cada vez maior, na sociedade actual, graças à popularidade obtida como rave drugs e partypills. A partir da segunda metade dos anos 90, surgiram no mercado ilícito novas drogas de abuso sintéticas, em particular, as denominadas ‘‘piperazinas’’. Poderão distinguir-se, entre as drogas sintéticas derivadas das piperazinas: a 1-benzilpiperazina (BZP), 1-(3- trifluorometilfenil)piperazina (TFMPP), 1-(3-clorofenil)piperazina (mCPP) e 1- (4-metoxifenil)piperazina (MeOPP). Os efeitos psicoactivos da BZP e da TFMPP são comparados aos efeitos obtidos após o consumo de anfetamina e de ecstasy (MDMA), respectivamente, e apresentados como uma alternativa legal, barata e segura às anfetaminas e ao ecstasy. Indícios da oferta e da facilidade de aquisição são a existência na Internet de inúmeros sites especializados no comércio das piperazinas e as apreensões destas drogas registadas no mundo inteiro. Não obstante a sua reputação como droga segura, a BZP foi associada a óbitos, na Suíça e Suécia, e a alguns casos de intoxicação. A 22 de Março de 2007 o Conselho da União Europeia determinou uma avaliação de riscos relacionados com o consumo da BZP e poderá decidir (final de Julho) sujeitar esta droga a medidas de controlo na UE. Por estes motivos justifica-se o desenvolvimento de metodologia analítica que possibilite a triagem, a identificação e quantificação destas drogas em fluidos biológicos, sendo esse o principal objectivo da presente dissertação Foram desenvolvidos dois métodos de triagem, confirmação e quantificação simultânea de piperazinas em amostras de sangue total e urina. As amostras foram analisadas por GC-MS em modo SIM após extracção por SPE e derivatização nas amostras de sangue e após extracção por SPME e derivatização nas amostras de urina. Os métodos foram validados na sua totalidade, e ambos são apropriados para a triagem e identificação simultânea das piperazinas estudadas, sendo os limites de detecção inferiores a 5 ng/mL. O método de SPE-GC-MS é linear entre 10 e 1000 ng/mL para a BZP, TFMPP e mCPP. O método de SPME-GC-MS é linear entre 5 e 100 ng/mL apenas para a mCPP. Para estes compostos os resultados obtidos no estudo da precisão e exactidão dos métodos estão contidos nos intervalos considerados aceitáveis. keywords Piperazines, screening, quantification, whole blood, urine, GC-MS, SPE, SPME, validation abstract In the last decades an increase of synthetic drugs of abuse has been perceived in contemporary societies. These drugs have acquired a larger significance in actual society, due to their popularity as rave drugs and party pills. Several new ones have emerged in the black market during the 1990’s, particularly those derived from piperazine, such as 1-benzylpiperazine (BZP), 1-(3- trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP). BZP and TFMPP’s psychoactive effects are analogous to those induced by amphetamines and ecstasy (MDMA) respectively, and are introduced as a cheap, legal and safe substitutes of ecstasy and amphetamines. Several piperazine-specialized websites in the Internet, or the increase in seizures recorded throughout the world are traces of a wider offer and easiness to buy. Despite its reputation as safe drug, BZP was associated to fatalities in Switzerland and Sweden and some cases of intoxication. In the 22nd March 2007, European Union Council has decided to request an assessment on the associated risks of BZP use and may decide, by the end o f July, to subject them to measures of control in all the EU. For all these reasons, it is intended to develop analytical methods for the screening, confirmation and quantification of these drugs in biological fluids, which is the aim of the dissertation. Two methods for the screening, confirmation and simultaneous quantification of piperazines have been developed in whole blood and urine samples. The samples were analyzed by GC-MS in SIM mode after extraction by SPE and SPME in blood and urine samples, respectively, followed by derivatization. Both methods were fully validated, and can be used for the screening and confirmation of all piperazines. The detection limit was less than 5 ng/mL. The SPE-GC-MS method was linear between 10 and 1000 ng/mL for BZP, TFMPP and mCPP, and SPME-GC-MS was linear between 5 and 100 ng/mL, but only for mCPP. The precision and accuracy of the developed methods were within the required limits for these particular compounds compounds. Índice Abreviaturas e acrónimos.......................................................................................................................................v 1 Introdução ......................................................................................................................................................1 1.1 Drogas de abuso recreativas .....................................................................................................................................1 1.2 Novas drogas sintéticas relacionadas com a piperazina.......................................................................................3 1.3 Apreensões de drogas relacionadas com a piperazina .........................................................................................3 1.4 Contexto legislativo das drogas relacionadas com a piperazina .........................................................................4 1.5 Formas de apresentação das drogas relacionadas com a piperazina .................................................................5 2 Piperazinas: Aspectos gerais e farmacológicos.........................................................................................9 2.1 Estrutura química e classificação das piperazinas.................................................................................................9 2.2 Propriedades físico-químicas das piperazinas......................................................................................................11
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