INTRODUCTION: Smoking is one of the single greatest causes of numerous preventable diseases. We were interested in developing an animal model of nicotine metabolism that can be used to examine the effects of potential CYP2A6 inhibitors on nicotine metabolism and nicotine-mediated behaviours. Pharmacogenetic studies have demonstrated that in humans, smoking behaviour is associated with rates of nicotine metabolism by the CYP2A6 enzyme. Mouse CYP2A5 shares structural and functional similarities to human CYP2A6 and has been implicated in nicotine self-administration behaviours in mice, therefore the mouse represents a potential animal model for studying nicotine metabolism. METHODS: We characterized nicotine and cotinine metabolism in two commonly used mouse strains (DBA/2 and C57Bl/6). We also examined the association between nicotine self-administration behaviours and nicotine metabolism, and the impact of direct manipulation (i.e. inhibition) of nicotine metabolism on nicotine pharmacodynamics (hot-plate and tail-flick tests) in mice. Finally, we studied the effect of selegiline (a known cytochrome P450 mechanism-based inhibitor) on nicotine metabolism in mice and in human CYP2A6. RESULTS: Nicotine metabolism in mice in vitro was mediated by CYP2A5, and this enzyme was responsible for over 70% and 90% of the metabolism of nicotine to cotinine and cotinine to 3-hydroxycotinine as shown by immuno-inhibition studies, respectively. A polymorphism in CYP2A5 between mouse strains, known to alter the probe substrate coumarin’s metabolism, did not affect nicotine metabolism but dramatically altered cotinine metabolism. Nicotine self-administration behaviour in mice was associated with level of hepatic CYP2A5 proteins and rates of nicotine metabolism in male mice. In inhibition studies, the CYP2A5/6 inhibitor methoxsalen inhibited both in vitro and in vivo nicotine metabolism in mice and substantially increased the anti-nociceptive effect of nicotine. Finally, selegiline was found to be an inhibitor of CYP2A5 decreasing nicotine metabolism in vitro and in vivo in mice. Moreover, we showed that selegiline is a mechanism-based inhibitor of CYP2A6 inhibiting nicotine metabolism irreversibly. CONCLUSION: The above data suggested that the mouse model may be suitable for examining the impact of inhibition (and genetic variation) on nicotine metabolism and nicotine-mediated behaviours and may potentially be used to screen for novel inhibitors of nicotine metabolism.

INTRODUCTION: Smoking is one of the single greatest causes of numerous preventable diseases. We were interested in developing an animal model of nicotine metabolism that can be used to examine the effects of potential CYP2A6 inhibitors on nicotine metabolism and nicotine-mediated behaviours. Pharmacogenetic studies have demonstrated that in humans, smoking behaviour is associated with rates of nicotine metabolism by the CYP2A6 enzyme. Mouse CYP2A5 shares structural and functional similarities to human CYP2A6 and has been implicated in nicotine self-administration behaviours in mice, therefore the mouse represents a potential animal model for studying nicotine metabolism. METHODS: We characterized nicotine and cotinine metabolism in two commonly used mouse strains (DBA/2 and C57Bl/6). We also examined the association between nicotine self-administration behaviours and nicotine metabolism, and the impact of direct manipulation (i.e. inhibition) of nicotine metabolism on nicotine pharmacodynamics (hot-plate and tail-flick tests) in mice. Finally, we studied the effect of selegiline (a known cytochrome P450 mechanism-based inhibitor) on nicotine metabolism in mice and in human CYP2A6. RESULTS: Nicotine metabolism in mice in vitro was mediated by CYP2A5, and this enzyme was responsible for over 70% and 90% of the metabolism of nicotine to cotinine and cotinine to 3-hydroxycotinine as shown by immuno-inhibition studies, respectively. A polymorphism in CYP2A5 between mouse strains, known to alter the probe substrate coumarin’s metabolism, did not affect nicotine metabolism but dramatically altered cotinine metabolism. Nicotine self-administration behaviour in mice was associated with level of hepatic CYP2A5 proteins and rates of nicotine metabolism in male mice. In inhibition studies, the CYP2A5/6 inhibitor methoxsalen inhibited both in vitro and in vivo nicotine metabolism in mice and substantially increased the anti-nociceptive effect of nicotine. Finally, selegiline was found to be an inhibitor of CYP2A5 decreasing nicotine metabolism in vitro and in vivo in mice. Moreover, we showed that selegiline is a mechanism-based inhibitor of CYP2A6 inhibiting nicotine metabolism irreversibly. CONCLUSION: The above data suggested that the mouse model may be suitable for examining the impact of inhibition (and genetic variation) on nicotine metabolism and nicotine-mediated behaviours and may potentially be used to screen for novel inhibitors of nicotine metabolism.

No description available.

O objetivo desta pesquisa é explicar os mecanismos sociais das decisões judiciais. Em particular, a investigação centra-se no processo de tomadas de decisões de operadores do Direito no sistema de justiça juvenil em São Paulo. Busca-se, assim, verificar quais são os fatores determinantes da aplicação da medida socioeducativa de internação para adolescentes acusados de cometimento de ato infracional e o modo pelo qual se dá esse processo decisório. Desde a promulgação do Estatuto da Criança e do Adolescente, em 1990, o sistema de justiça juvenil brasileiro passou a operar em um novo registro: as medidas socioeducativas passaram a se restringir a autores de infrações penais; e a medida de internação, em particular, a crimes cometidos com violência e/ou grave ameaça à pessoa. Mas a gravidade do ato infracional é de fato o principal preditor das decisões judiciais na justiça juvenil? Ou haveria outros fatores explicativos, como aqueles relacionados às características sociais dos adolescentes, às relações de poder inscritas nas interações sociais ou mesmo à estrutura organizacional dos tribunais? Na busca pela explicação dos mecanismos sociais dessas decisões judiciais, esta pesquisa propôs um desenho multimetodológico, integrando técnicas quantitativas e qualitativas para investigar os mecanismos das decisões e verificar os determinantes da aplicação da medida socioeducativa de internação em São Paulo. Assim, em um primeiro momento, as hipóteses citadas foram testadas por meio de modelos logísticos binomiais tendo a decisão sobre a internação como variável dependente em um cenário multivariado. Os resultados encontrados indicam um alto grau de proporcionalidade entre crime e pena, tendo os atos infracionais considerados mais graves os mais significativos efeitos sobre a probabilidade de internação; mas indicam, também, a reprodução de relações de poder - adolescentes usuários de drogas e que não trabalham nem estudam, mantidas as outras dimensões constantes, também têm maior chance de receber a medida socioeducativa de internação. Em seguida, a fim de explicar os mecanismos dos efeitos do tratamento estimados anteriormente, foram acompanhadas semanalmente as audiências de apresentação e de continuação e as oitivas informais no Fórum Brás, em São Paulo. Ao mesmo tempo em que se concluiu que as oitivas informais, centrais no processo decisório, ocorrem cerimonialmente e que as decisões são tomadas via documentos, o que explica o mecanismo de proporcionalidade encontrado anteriormente, pôde-se concluir que eventualmente os Promotores de Justiça \"voltam atrás\" de suas decisões quando há um rompimento na definição da situação, o que explica o mecanismo dos efeitos das características individuais dos adolescentes. / This research aims at investigating the social mechanisms of judicial decisions. It particularly focuses on the decision-making process of legal actors in the juvenile justice system in São Paulo. Thus, the research aims at verifying the determinants of the confinement disposition for juveniles who have been accused of a crime and the way which this decision is made by. Since the Child and Adolescent Statute was promulgated in 1990, the Brazilian juvenile justice system started working under new guidelines: dispositions are now restricted to offenders; and the confinement disposition is restricted to offenses committed with violence and/or with a threat to a person. But is the seriousness of the crime indeed the best predictor of judicial decisions? Or are there other explanatory factors, such as the ones related to the individual characteristics of the teenagers, to the power relations within social interactions, or even to the court organizational structure? Aiming at a mechanism-based explanation of these judicial decisions, this research has proposed a mixed-methods research design, integrating both quantitative and qualitative techniques to investigate mechanisms of the decision-making process and to verify the determinants of the confinement disposition in São Paulo. Thus, at first, the aforementioned hypotheses were tested with binary logistic models, presenting the decision concerning the confinement disposition as the dependent variable on a multivariable scenario. Results indicate a high degree of proportionality between crime and punishment, with the seriousness of the offenses having significant effects on the probability of confinement; but the results also indicate some reproduction of power relations - drug user youth and those who neither work nor study increase their odds of being more severely punished. After that, aiming at explaining the mechanisms of the treatment effects estimated beforehand, both judicial and informal hearings (at the State\'s Attorney office) were weekly observed at the juvenile court in São Paulo. While it was possible to conclude that the informal hearings are central to the decision-making process and occur ceremonially, with decisions being made by documents-consulting (which explains the proportionality mechanism), the research also found that the Attorneys often regret their decisions when there is a rupture of the definition of the situation. This explains the mechanism of the individual characteristics effects on juvenile sentencing.

O objetivo desta pesquisa é explicar os mecanismos sociais das decisões judiciais. Em particular, a investigação centra-se no processo de tomadas de decisões de operadores do Direito no sistema de justiça juvenil em São Paulo. Busca-se, assim, verificar quais são os fatores determinantes da aplicação da medida socioeducativa de internação para adolescentes acusados de cometimento de ato infracional e o modo pelo qual se dá esse processo decisório. Desde a promulgação do Estatuto da Criança e do Adolescente, em 1990, o sistema de justiça juvenil brasileiro passou a operar em um novo registro: as medidas socioeducativas passaram a se restringir a autores de infrações penais; e a medida de internação, em particular, a crimes cometidos com violência e/ou grave ameaça à pessoa. Mas a gravidade do ato infracional é de fato o principal preditor das decisões judiciais na justiça juvenil? Ou haveria outros fatores explicativos, como aqueles relacionados às características sociais dos adolescentes, às relações de poder inscritas nas interações sociais ou mesmo à estrutura organizacional dos tribunais? Na busca pela explicação dos mecanismos sociais dessas decisões judiciais, esta pesquisa propôs um desenho multimetodológico, integrando técnicas quantitativas e qualitativas para investigar os mecanismos das decisões e verificar os determinantes da aplicação da medida socioeducativa de internação em São Paulo. Assim, em um primeiro momento, as hipóteses citadas foram testadas por meio de modelos logísticos binomiais tendo a decisão sobre a internação como variável dependente em um cenário multivariado. Os resultados encontrados indicam um alto grau de proporcionalidade entre crime e pena, tendo os atos infracionais considerados mais graves os mais significativos efeitos sobre a probabilidade de internação; mas indicam, também, a reprodução de relações de poder - adolescentes usuários de drogas e que não trabalham nem estudam, mantidas as outras dimensões constantes, também têm maior chance de receber a medida socioeducativa de internação. Em seguida, a fim de explicar os mecanismos dos efeitos do tratamento estimados anteriormente, foram acompanhadas semanalmente as audiências de apresentação e de continuação e as oitivas informais no Fórum Brás, em São Paulo. Ao mesmo tempo em que se concluiu que as oitivas informais, centrais no processo decisório, ocorrem cerimonialmente e que as decisões são tomadas via documentos, o que explica o mecanismo de proporcionalidade encontrado anteriormente, pôde-se concluir que eventualmente os Promotores de Justiça \"voltam atrás\" de suas decisões quando há um rompimento na definição da situação, o que explica o mecanismo dos efeitos das características individuais dos adolescentes. / This research aims at investigating the social mechanisms of judicial decisions. It particularly focuses on the decision-making process of legal actors in the juvenile justice system in São Paulo. Thus, the research aims at verifying the determinants of the confinement disposition for juveniles who have been accused of a crime and the way which this decision is made by. Since the Child and Adolescent Statute was promulgated in 1990, the Brazilian juvenile justice system started working under new guidelines: dispositions are now restricted to offenders; and the confinement disposition is restricted to offenses committed with violence and/or with a threat to a person. But is the seriousness of the crime indeed the best predictor of judicial decisions? Or are there other explanatory factors, such as the ones related to the individual characteristics of the teenagers, to the power relations within social interactions, or even to the court organizational structure? Aiming at a mechanism-based explanation of these judicial decisions, this research has proposed a mixed-methods research design, integrating both quantitative and qualitative techniques to investigate mechanisms of the decision-making process and to verify the determinants of the confinement disposition in São Paulo. Thus, at first, the aforementioned hypotheses were tested with binary logistic models, presenting the decision concerning the confinement disposition as the dependent variable on a multivariable scenario. Results indicate a high degree of proportionality between crime and punishment, with the seriousness of the offenses having significant effects on the probability of confinement; but the results also indicate some reproduction of power relations - drug user youth and those who neither work nor study increase their odds of being more severely punished. After that, aiming at explaining the mechanisms of the treatment effects estimated beforehand, both judicial and informal hearings (at the State\'s Attorney office) were weekly observed at the juvenile court in São Paulo. While it was possible to conclude that the informal hearings are central to the decision-making process and occur ceremonially, with decisions being made by documents-consulting (which explains the proportionality mechanism), the research also found that the Attorneys often regret their decisions when there is a rupture of the definition of the situation. This explains the mechanism of the individual characteristics effects on juvenile sentencing.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.

No description available.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.