Introduction : Le trouble dépressif majeur (TDM) représente un enjeu de Santé Publique. Aujourd’hui, il existe différents médicaments antidépresseurs (AD), mais 60% des patients déprimés ne répondent pas suffisamment à ce type de traitement. La pharmacogénétique (PG) se définit comme l’étude de la variabilité de la réponse aux médicaments associée à des variations génétiques des gènes de la pharmacodynamie ou de la pharmacocinétique. La médecine personnalisée utilise la PG pour améliorer la prise en charge des patients. La venlafaxine (VEN), AD fréquemment utilisé en psychiatrie, est métabolisée par les enzymes du Cytochrome P450 (CYP) 2D6 et 2C19. Elle augmente le turnover des monoamines cérébrales, qui sont catabolisées par la catechol-O-méthyltransférase (COMT). L'objectif de ce travail est d'identifier des biomarqueurs génétiques de réponse à la VEN qui pourraient être utilisés dans la pratique clinique psychiatrique. Ce travail présente deux études de gènes candidats, et une étude de panel de gènes basée sur une revue de la littérature. Méthodes : Deux cent six patients caucasiens souffrant d’un épisode dépressif majeur unipolaire (DSM-IVTR), nécessitant un nouveau traitement AD, issus de la cohorte METADAP et traités par VEN ont été étudiés. METADAP est une cohorte prospective d’une durée de 6 mois, multicentrique, naturaliste, en conditions réelles de prescription en psychiatrie. La dépression a été mesurée avec l’échelle de dépression de Hamilton à l’inclusion et après 1, 3 et 6 mois de traitement antidépresseur, permettant d’évaluer le pourcentage d’amélioration, la réponse et la rémission. Les patients ont été génotypés pour les polymorphismes génétiques ou Single Nucleotide Polymorphisms (SNP) majeurs du CYP2D6 et du CYP2C19 : allèles défectueux entraînant une déficience enzymatique complète (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, délétion du gène *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013), allèles entraînant une diminution de l'activité enzymatique (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725), allèles associés à un métabolisme accéléré (duplication du gène CYP2D6*2xN) ; (CYP2C19 *17 rs12248560) et pour le polymorphisme de la COMT Val(108/158)Met, rs4680. La technique de discrimination allélique TaqMan a été utilisée. Les patients ont été classés selon le phénotype CYP2D6 et CYP2C19 en métaboliseurs lents, normaux, rapides, intermédiaires et ultrarapides et en 3 génotypes COMT Val(108/158)Met: Val/Val, Val/Met, Met/Met. Par ailleurs, 70 patients ont été séquencés en utilisant les technologies de séquençage à haut débit ou Next Generation Sequencing (NGS) MiSeq Illumina pour un panel de 70 gènes. Résultats : Dans cet échantillon, il n’existe pas d’association entre l’évolution de la dépression sous VEN et les SNPs que nous avons étudiés du CYP2D6, du CYP2C19 et de la COMT. Les données NGS sont en cours d’analyse. D’ores et déjà, la qualité des données a été validée par comparaison aux résultats de la discrimination allélique TaqMan des CYP. Suite à une revue de la littérature mettant en évidence l’importance des transporteurs OCTs (Organic Cation Transporter) et PMATs (Plasma Membrane Monoamine Transporter) dans le transport des monoamines et leur rôle dans la réponse aux AD, ces gènes seront intégrés dans la sélection du panel de gènes pour le NGS. Conclusion : Ce travail ne permet pas de recommander le génotypage des SNPs du CYP2D6, du CYP2C19 et de la COMT Val(108/158)Met en routine clinique psychiatrique chez les patients déprimés traités par VEN. Ce travail se poursuivra par l’analyse NGS qui tentera d’identifier des variants rares ou ultra-rares et pertinents, notamment pour des gènes qui n'ont pas été étudiés dans le TDM comme ceux des OCTs et PMATs. / Introduction: Major Depressive Disorder (MDD) represents an issue of Public Health. Currently, different antidepressant (AD) treatments exist, but 60% of depressed patients do not respond sufficiently to this type of treatment. Pharmacogenetics (PG) represents the study of the variability of response to a treatment associated to genetic variations identified in pharmacokinetic and pharmacodynamic genes. Personalized medicine is using PG to make the best therapeutic choice for a depressed patient. Venlafaxine (VEN), AD frequently used in psychiatry, is metabolized by the enzymes of Cytochromes P450 (CYP) 2D6 and 2C19. VEN increases the turnover of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The aim of this study is to identify genetic biomarkers of response to VEN that may be used in clinical practice in psychiatry. This work presents two candidate gene studies and a study of panel of genes based on a review of the literature. Methods : Two hundred and six Caucasian patients suffering from a unipolar major depressive episode (DSM-IVTR), requiring a new AD treatment, selected from METADAP cohort, treated by VEN have been studied. The METADAP cohort is a 6-month prospective, multicenter, real-world setting, treatment study in psychiatry. Depression was assessed by the Hamilton scale at the baseline and after 1, 3 and 6 months of AD treatment allowing the evaluation of the percentage of improvement, the response and the remission. Patients were genotyped for the major SNPs (Single Nucleotide Polymorphisms) of CYP2D6 and CYP2C19: loss of function alleles (CYP2D6 *3 rs35742686, *4 rs3892097, *6 rs5030655, the complete gene deletion *5); (CYP2C19 *2 rs4244285, *3 rs4986893, *4 rs28399504, *5 rs56337013); increased function alleles (gene duplication CYP2D6*2xN); (CYP2C19 *17 rs12248560); decreased function alleles (CYP2D6 *10 rs1065852, CYP2D6*41 rs28371725) and COMT Val(108/158)Met, rs4680. The TaqMan allelic discrimination technology was used. Accordingly to the CYP2D6 and CYP2C19 phenotype, the patients were classified in: poor, normal, extensive, intermediate, and ultra-rapid metabolizers and respectively 3 COMT Val(108/158)Met genotypes : Val/Val, Val/Met, Met/Met. Furthermore, 70 patients were sequenced using Next Generation Sequencing (NGS) technologies of MiSeq Illumina for a panel of 70 genes. Results : No association between the evolution of depression of patients treated by VEN and the SNPs of CYP2D6, of CYP2C19 and of COMT was showed in this sample. The NGS data is being analyzed. Le quality of the NGS data has been validated by comparing the results to the TaqMan allelic discrimination of the CYP. Following the review of the literature showing the importance of the OCTs (Organic Cation Transporter) and PMATs (Plasma Membrane Monoamine Transporter) transporters in the transport of monoamines and their role in the AD response, these genes will be integrated in the selection of the panel of genes for the NGS study. Conclusion: This work shows that routine genotyping of the SNPs of CYP2D6, of CYP2C19 and of COMT Val(108/158) Met cannot be recommended in clinical practice in psychiatry for depressed patients treated by VEN. This work will continue with the NGS analyses that will attempt to identify relevant, rare and very rare variants, in particular for genes that have not been studied in a context of MDD such as OCTs and PMATs.

The use of anti-depressants has become common in the past 20 years with users now taking them for longer periods than initially intended. There is concern about the cognitive effects chronic use may have. Previous research has shown cognitive deficits in depressed patients taking medications but is complicated by depressive symptoms. This study sets out to examine the effects of these drugs, without the influence of depressive symptoms, on short term memory and anxiety. 140 rats (70 male, 70 female) were given either high or low doses of three antidepressants (fluoxetine, reboxetine and venlafaxine) or placebo over a three week period, representing chronic use. The y-maze, open field test and emergence test were used to test short term memory and anxiety. Although memory deficits were found for male rats taking low doses of reboxetine and high doses of venlafaxine, a more notable result was a deficit in initial attention across all drugs and in both sexes. This finding provides evidence for the need to re-examine the cognitive effects of antidepressants in greater detail.

Over the recent years, venlafaxine has become the predominant antidepressant drug detected in municipal wastewater effluents (MWWE) and aquatic systems. However, very little is known about the effect of this drug in the aquatic environment on non-target organisms, including fish. Venlafaxine is a pharmaceutical compound designed to inhibit serotonin and norepinephrine reuptake, thereby increasing the synaptic availability of these neurotransmitters. In teleosts, the key aspect of stress adaptation involves the activation of the hypothalamus-pituitary-interrenal (HPI) axis, leading to the production of cortisol. Given that monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are involved in the regulation of a wide range of neuroendocrine responses, including stress axis function, my primary hypothesis was that venlafaxine acts as a neuroendocrine disruptor impacting the functioning of the corticosteroid stress axis in rainbow trout (Oncorhynchus mykiss). This hypothesis was tested through a series of in vivo exposure studies, as well as in vitro experiments, using environmentally relevant levels of venlafaxine, in order to tease out potential mode of action of this drug on target tissues involved in HPI axis functioning. The results suggest that venlafaxine alters monoamine neurotransmitter levels and their turnover rates in a region-specific manner in trout brain, and that the midbrain is the prime target. The monoamine changes may be responsible for the downstream effects on neuroendocrine responses coordinated in the hypothalamus, as this region receives monoaminergic inputs from the midbrain. The functional relevance of the above finding was confirmed by showing that venlafaxine exposure disrupted the neuroendocrine responses associated with social stress and appetite regulation. Functional downstream effects of HPI axis dysfunction were further confirmed by subjecting the fish to a handling disturbance, which revealed that the highly conserved cortisol and glucose responses to stressors were disrupted by venlafaxine. Also, there were tissue-specific effects of venlafaxine exposure on metabolic capacities, including enhanced gluconeogenesis and amino acid catabolism in the liver (a key glucose producing tissue), and alterations in the glycolytic capacity and sodium potassium ATPase activity in the gill (a key glucose utilizing tissue). The results suggest that the mode of action of venlafaxine may involve disruption of each target tissue involved in the HPI axis functioning. In vitro mechanistic studies indicated that hypothalamus functioning is disrupted by venlafaxine and this may involve effects mediated by serotonergic pathways. The reduced phosphorylation of cAMP response element binding protein (CREB) suggests that venlafaxine may impact downstream signalling cascades that are CREB-dependent. The transcript changes observed with venlafaxine in the hypothalamus include changes in mRNA levels of key genes involved in appetite regulation and stress response, including corticotropin releasing factor (CRF) and neuropeptide Y (NPY). At the pituitary level, venlafaxine impaired adrenocorticotropic hormone (ACTH) production, and this involved disruption of corticotropin releasing factor-receptor type 1 (CRF-R1), which is a key sensor for CRF stimulation. At the interrenal tissue level, the responsiveness of steroidogenic cells to ACTH stimulation was altered by venlafaxine and the mode of action appears to involve pathways upstream of the intracellular cAMP production. Also, cortisol biosynthetic capacity was disrupted by venlafaxine and this was accompanied by changes in transcript abundances of steroidogenic acute regulatory protein and cytochrome P450 side chain cleavage in the interrenal tissue. Taken together, the results demonstrate for the first time that the antidepressant venlafaxine, a human pharmaceutical contaminating aquatic systems, disrupts neuroendocrine responses and affects stress, feeding and metabolic responses in rainbow trout. The mode of action may include disruptions in brain monoamine levels and pathways involved in CREB signalling, while the exact mechanism of action remains to be elucidated. Exposure of fish to this pharmaceutical drug adversely affects the highly conserved adaptive responses that are essential to cope with subsequent stressors, and may translate into reduced fitness over the long-term. The findings underscore the necessity to understand the mechanisms of action of chemicals present in MWWE, and develop and utilize effective risk management strategies aimed at minimizing discharge of pharmaceuticals into the aquatic environment.

A venlafaxina é um fármaco usado no tratamento da depressão e dos transtornos de ansiedade generalizada. É disponível na clínica na forma de mistura racêmica dos enantiômeros S-(+) e R-(-) em formulação de liberação controlada. O enantiômero S-(+) inibe a recaptação da serotonina, enquanto o enantiômero R-(-) inibe a recaptação da serotonina e da norepinefrina. A venlafaxina é biotransformada pelo CYP2D6 e CYP2C19 em seu principal metabólito, O-desmetilvenlafaxina, o qual apresenta atividade farmacológica semelhante à venlafaxina. Outros metabólitos da venlafaxina, dependentes do CYP3A4, incluem a N-desmetilvenlafaxina e a N,O-di-desmetilvenlafaxina. A absorção e a distribuição da venlafaxina são moduladas pela ação da glicoproteina-P. O nifedipino, um fármaco da classe dos inibidores dos canais de cálcio, é descrito como inibidor da glicoproteina-P. O presente estudo investiga a influência do nifedipino na disposição cinética e no metabolismo da venlafaxina em voluntários sadios caracterizados como portadores de atividade normal do CYP3A (omeprazol como fármaco marcador) e fenotipados como metabolizadores rápidos do CYP2C19 (omeprazol como fármaco marcador) e do CYP2D6 (metoprolol como fármaco marcador). Os voluntários investigados receberam, em estudo cruzado e randomizado, dose única oral de 150 mg de venlafaxina racêmica (Fase 1) e 40 mg de nifedipino associada com dose única oral de 150 mg de venlafaxina racêmica (Fase 2). Foram coletadas amostras seriadas de sangue até 72 horas após a administração dos fármacos para o estudo farmacocinético. As concentrações plasmáticas dos enantiômeros da venlafaxina e de seus metabólitos foram determinadas por LC-MS/MS utilizando a coluna Chirobiotic V com fase móvel constituída de mistura de metanol: solução aquosa de acetato de amônio 15 mmol/L pH 6,0 (80:20, v/v). A farmacocinética da venlafaxina mostrou-se enantiosseletiva com acúmulo plasmático (AUC 526,0 vs 195,7 ng.h/mL) e menores valores de clearance (Cl/f 142,67 vs 408,01 L/h) para o enantiômero S-(+). A disposição cinética do metabólito ativo O-desmetilvenlafaxina apresentou enantiosseletividade apenas no parâmetro concentração plasmática máxima com observação de maiores valores para o enantiômero R-(-) (Cmax 69,33 vs 56,94 ng/mL). A disposição cinética da N,O-di-desmetilvenlafaxina também mostrou-se enantiosseletiva apenas para o parâmetro concentração plasmática máxima, mas com observação de maiores valores para o enantiômero S-(+) (Cmax 7,08 vs 4,61 ng/mL). A administração de dose única oral de 40 mg de nifedipino não alterou a farmacocinética de ambos os enantiômeros da venlafaxina e de seus metabólitos O-desmetilvenlafaxina e N,O-di-desmetilvenlafaxina, seja utilizando teste estatístico não paramétrico (teste de Wilcoxon para dados pareados, p < 0,05), seja avaliando o IC 90% das razões das médias geométricas de AUC e Cmax (Fase 2/Fase 1). Os dados obtidos evidenciam que o nifedipino na dose de 40 mg não age como um inibidor da P-gp / Venlafaxine is a drug used to treat depression and generalized anxiety disorders. It is available in clinical practice in the form of a racemic mixture of S-(+) and R-(-) enantiomers, in controlled release formulation. The S-(+) enantiomer inhibits the reuptake of serotonin, while the R-(-) enantiomer inhibits the reuptake of both serotonin and norepinephrine. Venlafaxine is biotransformed by CYP2D6 and CYP2C19 in its major metabolite, O-desmethylvenlafaxine, which has similar pharmacological activity when compared to venlafaxine. Other metabolites of venlafaxine, dependent of CYP3A4, include N-desmethylvenlafaxine and N, O-di-desmethylvenlafaxine. The absorption and distribution of venlafaxine are modulated by the action of P-glycoprotein. Nifedipine, a calcium channel blocker drug, is described as an inhibitor of P-glycoprotein. The present study investigates the influence of nifedipine on the kinetic disposition of venlafaxine enantiomers and its metabolites in healthy volunteers characterized as having normal activity of CYP3A (omeprazole as a probe drug) and phenotyped as rapid metabolizers of CYP2C19 (omeprazole as a probe drug) and CYP2D6 (metoprolol as a probe drug). The enrolled volunteers received, in a randomized, two-way study, a single 150 mg oral dose of racemic venlafaxine (Phase 1) and 40 mg oral dose of nifedipine associated with a single 150 mg oral dose of racemic venlafaxine (Phase 2). Serial blood samples were collected until 72 hours after drug administration to the pharmacokinetic study. Plasma concentrations of venlafaxine enantiomers and its metabolites were determined by LC-MS/MS using a Chirobiotic V column and a mobile phase constituted of methanol: aqueous 15 mmol/L ammonium acetate solution pH 6.0 (80:20, v/v). The venlafaxine pharmacokinetics is enantioselective with plasma accumulation (AUC 526.0 vs 195.7 ng h/mL) and lower clearance values (CL/f 142.67 vs 408.01 L/h) for the S-(+) enantiomer. The kinetic disposition of the active metabolite O-desmethylvenlafaxine exhibits enantioselectivity only in the maximum plasma concentration parameter with higher values for the R-(-) enantiomer (Cmax 69.33 vs 56.94 ng/mL). The kinetic disposition of N,O-di-desmethylvenlafaxine is also enantioselective only for the maximum plasma concentration parameter, but with higher values for the S-(+) enantiomer (Cmax 7.08 vs 4.61 ng/ml). Administration of a 40 mg single oral dose of nifedipine do not alter the pharmacokinetics of both enantiomers of venlafaxine and its metabolites O-desmethylvenlafaxine and N,O-di-desmethylvenlafaxine, using non-parametric statistical test (Wilcoxon test for paired data, p <0.05), or evaluating the 90% CI of the AUC and Cmax geometric mean ratios (Phase 2/Phase 1). The obtained data show that nifedipine in a 40 mg oral dose does not act as a P-gp inhibitor.

A venlafaxina é um fármaco usado no tratamento da depressão e dos transtornos de ansiedade generalizada. É disponível na clínica na forma de mistura racêmica dos enantiômeros S-(+) e R-(-) em formulação de liberação controlada. O enantiômero S-(+) inibe a recaptação da serotonina, enquanto o enantiômero R-(-) inibe a recaptação da serotonina e da norepinefrina. A venlafaxina é biotransformada pelo CYP2D6 e CYP2C19 em seu principal metabólito, O-desmetilvenlafaxina, o qual apresenta atividade farmacológica semelhante à venlafaxina. Outros metabólitos da venlafaxina, dependentes do CYP3A4, incluem a N-desmetilvenlafaxina e a N,O-di-desmetilvenlafaxina. A absorção e a distribuição da venlafaxina são moduladas pela ação da glicoproteina-P. O nifedipino, um fármaco da classe dos inibidores dos canais de cálcio, é descrito como inibidor da glicoproteina-P. O presente estudo investiga a influência do nifedipino na disposição cinética e no metabolismo da venlafaxina em voluntários sadios caracterizados como portadores de atividade normal do CYP3A (omeprazol como fármaco marcador) e fenotipados como metabolizadores rápidos do CYP2C19 (omeprazol como fármaco marcador) e do CYP2D6 (metoprolol como fármaco marcador). Os voluntários investigados receberam, em estudo cruzado e randomizado, dose única oral de 150 mg de venlafaxina racêmica (Fase 1) e 40 mg de nifedipino associada com dose única oral de 150 mg de venlafaxina racêmica (Fase 2). Foram coletadas amostras seriadas de sangue até 72 horas após a administração dos fármacos para o estudo farmacocinético. As concentrações plasmáticas dos enantiômeros da venlafaxina e de seus metabólitos foram determinadas por LC-MS/MS utilizando a coluna Chirobiotic V com fase móvel constituída de mistura de metanol: solução aquosa de acetato de amônio 15 mmol/L pH 6,0 (80:20, v/v). A farmacocinética da venlafaxina mostrou-se enantiosseletiva com acúmulo plasmático (AUC 526,0 vs 195,7 ng.h/mL) e menores valores de clearance (Cl/f 142,67 vs 408,01 L/h) para o enantiômero S-(+). A disposição cinética do metabólito ativo O-desmetilvenlafaxina apresentou enantiosseletividade apenas no parâmetro concentração plasmática máxima com observação de maiores valores para o enantiômero R-(-) (Cmax 69,33 vs 56,94 ng/mL). A disposição cinética da N,O-di-desmetilvenlafaxina também mostrou-se enantiosseletiva apenas para o parâmetro concentração plasmática máxima, mas com observação de maiores valores para o enantiômero S-(+) (Cmax 7,08 vs 4,61 ng/mL). A administração de dose única oral de 40 mg de nifedipino não alterou a farmacocinética de ambos os enantiômeros da venlafaxina e de seus metabólitos O-desmetilvenlafaxina e N,O-di-desmetilvenlafaxina, seja utilizando teste estatístico não paramétrico (teste de Wilcoxon para dados pareados, p < 0,05), seja avaliando o IC 90% das razões das médias geométricas de AUC e Cmax (Fase 2/Fase 1). Os dados obtidos evidenciam que o nifedipino na dose de 40 mg não age como um inibidor da P-gp / Venlafaxine is a drug used to treat depression and generalized anxiety disorders. It is available in clinical practice in the form of a racemic mixture of S-(+) and R-(-) enantiomers, in controlled release formulation. The S-(+) enantiomer inhibits the reuptake of serotonin, while the R-(-) enantiomer inhibits the reuptake of both serotonin and norepinephrine. Venlafaxine is biotransformed by CYP2D6 and CYP2C19 in its major metabolite, O-desmethylvenlafaxine, which has similar pharmacological activity when compared to venlafaxine. Other metabolites of venlafaxine, dependent of CYP3A4, include N-desmethylvenlafaxine and N, O-di-desmethylvenlafaxine. The absorption and distribution of venlafaxine are modulated by the action of P-glycoprotein. Nifedipine, a calcium channel blocker drug, is described as an inhibitor of P-glycoprotein. The present study investigates the influence of nifedipine on the kinetic disposition of venlafaxine enantiomers and its metabolites in healthy volunteers characterized as having normal activity of CYP3A (omeprazole as a probe drug) and phenotyped as rapid metabolizers of CYP2C19 (omeprazole as a probe drug) and CYP2D6 (metoprolol as a probe drug). The enrolled volunteers received, in a randomized, two-way study, a single 150 mg oral dose of racemic venlafaxine (Phase 1) and 40 mg oral dose of nifedipine associated with a single 150 mg oral dose of racemic venlafaxine (Phase 2). Serial blood samples were collected until 72 hours after drug administration to the pharmacokinetic study. Plasma concentrations of venlafaxine enantiomers and its metabolites were determined by LC-MS/MS using a Chirobiotic V column and a mobile phase constituted of methanol: aqueous 15 mmol/L ammonium acetate solution pH 6.0 (80:20, v/v). The venlafaxine pharmacokinetics is enantioselective with plasma accumulation (AUC 526.0 vs 195.7 ng h/mL) and lower clearance values (CL/f 142.67 vs 408.01 L/h) for the S-(+) enantiomer. The kinetic disposition of the active metabolite O-desmethylvenlafaxine exhibits enantioselectivity only in the maximum plasma concentration parameter with higher values for the R-(-) enantiomer (Cmax 69.33 vs 56.94 ng/mL). The kinetic disposition of N,O-di-desmethylvenlafaxine is also enantioselective only for the maximum plasma concentration parameter, but with higher values for the S-(+) enantiomer (Cmax 7.08 vs 4.61 ng/ml). Administration of a 40 mg single oral dose of nifedipine do not alter the pharmacokinetics of both enantiomers of venlafaxine and its metabolites O-desmethylvenlafaxine and N,O-di-desmethylvenlafaxine, using non-parametric statistical test (Wilcoxon test for paired data, p <0.05), or evaluating the 90% CI of the AUC and Cmax geometric mean ratios (Phase 2/Phase 1). The obtained data show that nifedipine in a 40 mg oral dose does not act as a P-gp inhibitor.

L’excès de glucocorticoïdes lors d’un stress prolongé perturbe la neurotransmission monoaminergique et mène à des troubles de l’humeur et de la mémoire. La Venlafaxine (Vlx) et l’Agomelatine (Ago) sont utilisés pour traiter ces troubles. L’exercice physique volontaire est aussi bénéfique pour la santé mentale. Nous avons analysé 1. les changements de l’humeur induits par le stress en fonction du temps, 2. l’effet de l’exercice volontaire sur l’axe hypothalamo-pituitaire, 3. l’efficacité de l’Ago, de la Vlx et de l’exercice à prévenir les perturbations liées au stress et 4. la localisation des récepteurs MT1 et MT2 chez des souris rapportrices transgéniques. Nous démontrons que le stress induit des dérèglements physiques, émotionnels et comportementaux chez des rats stressés. Le prétraitement par l’Ago, la Vlx et l’exercice préviennent l’anxiété, la dépression et les déficits de mémoire. La cartographie des récepteurs MT1 et MT2 a identifié des sites d’action potentiels de l’Ago. / In long-term stress exposure, excess glucocorticoids disturb the balance of monoamine neurotransmitters leading to mood disorders and memory impairment. Venlafaxine and Agomelatin are currently used to treat these disorders. Voluntary exercise also has beneficial effects on mental health. In this work, we analyzed 1. the time-dependent changes in stress-induced mood disorders, 2. the modulating effect of voluntary exercise on the hypothalamic pituitary adrenal axis, 3. the effectiveness of Agomelatin, Venlafaxine and exercise to prevent stress-related behaviors and 4. the localization of MT1 and MT2 receptors in transgenic reporter mice. We demonstrate that stress caused physical, emotional and behavioral abnormalities in stressed rats. Pre-treatment with Agomelatin, Venlafaxine and exercise reduced the chronic stress-related behaviors and prevented anxiety, depression and memory deficits. The mapping of MT1 and MT2 receptors identified potential sites of action of Agomelatin.

Nos últimos anos, a prescrição e o consumo de medicamentos psicotrópicos vêm aumentando ao redor do mundo, crescendo assim a presença destes compostos em efluentes. Embora os esgotos domésticos e hospitalares em geral sejam encaminhados para as Estações de Tratamento de Esgotos (ETEs), o tratamento convencional aplicado não é eficiente na remoção da maioria dos fármacos e, consequentemente, estes poluentes alcançam os corpos hídricos. Frente a essas informações, é importante entender os possíveis danos causados tanto para seres humanos, como para o ecossistema como um todo, após a exposição a esses fármacos, por meio da água contaminada. Desta maneira, nossa hipótese é que os fármacos psicotrópicos presentes em amostras de água possam induzir a danos neuronais e no desenvolvimento de organismos não alvo, como peixes. Para responder a esta hipótese, avaliamos os efeitos teratogêncios e neurotóxicos de fármacos psicotrópicos como venlafaxina, haloperidol, carbamazepina e fluoxetina, por meio da análise de parâmetros de letalidade e sub-letalidade nos em Danio rerio, visando a determinação dos possíveis efeitos teratogênicos. Adicionalmente, utilizamos a determinação da atividade da enzima acetilcolinesterase como biomarcador de neurotoxicidade em larvas, após a exposição dos embriões e a avaliação do padrão de movimentação. Os fármacos foram testados individualmente e em misturas, para avaliar os efeitos da co-exposição, simulando um cenário mais real de contaminação aquática. Os resultados mostraram que os fármacos carbamazepina e venlafaxina não apresentaram nenhum dos efeitos analizados de forma estatisticamente significativa. Já os fármacos haloperidol e fluoxetina, mesmo não apresentando efeito sobre a teratogenicidade e movimentação, provocaram um aumento na atividade enzimática, em doses consideradas bastante baixas. Considerando que esta estimulação inicial voltou a níveis próximos ao controle negativo e, no caso da fluoxetina, um estudo inibição da atividade em doses mais altas, sugerimos a manifestação de hormesis. A mistura dos fármacos não apresentou efeito significativo nas avaliações realizadas, mostrando que o aumento da atividade enzimática dfoi antagonizado na quando em mistura. Nosso trabalho mostra a importância do estudo de toxicidade em doses baixas, para que uma correta avaliação do risco seja possível. / In the last years, the prescription and use of psychotropic drugs have being increasing around the world, consequently the discharge of these drugs and their metabolites have also increased in wastewater. Considering the presence in the environment and the toxic effects to target and non target species, these compounds were classified as emerging water contaminants. The main sources of these compounds are the domestic and hospital treated effluents, because the conventional treatment applied by effluent treatment plants is not efficient to remove most of drugs, and consequently these pollutants reach the water bodies. In this context, it is important to understand the possible damages to humans and ecosystems after exposure to these drugs through contaminated water. In that way, the hypothesis of this research is that psychotropic drugs present in water samples could induce neurologic and development damages in non-target organisms, such as fish. Therefore, we propose the evaluation of teratogenic and neurotoxic effects of the psychotropic drugs Fluoxetine, Carbamazepine, Venlafaxine and Haloperidol using the determination of the activity of cholinesterase enzyme as biomarker of neurotoxicity in larvae, after the exposure of Danio rerio eggs. Lethality and sub-lethality parameters will be also analyzed in the same organisms to establish the potential of teratogenic effects, the movement analysis was also performed. These drugs will be tested individually and in mixtures to evaluate the effects of coexposure simulating a real scenario of water pollution. Carbamazepine and venlafaxine don\'t responde with significant results in any of these evaluations. Haloperidol and Fluoxetine presented negative results in teratogenic and moviment effects, but they incresed the activity of acetylcholinesterase enzime, this result was different from another study, that these drugs in highest concentrations decrease this activity, so it can indicate the presence of hormesis effect. However, the mixtures of drugs don\'t present any significant effect on all evaluations, this result can suggest that these effects caused by haloperidol and fluoxetine on the enzime activity were canceled, it can be a interaction of antagonist effects on the mixtures.

A venlafaxina é um fármaco quiral utilizado no tratamento da depressão e da ansiedade associada à depressão. A ação farmacológica desse fármaco está associada principalmente ao enantiômero (+)-(S)-venlafaxina, que inibe a recaptação da serotonina enantiosseletivamente. Quando metabolizada pelas enzimas da citocromo P450 dois metabólitos são produzidos, também quirais, a O-desmetilvenlafaxina (ODV) e a N-desmetilvenlafaxina (NDV). O estudos mostram que o metabólito ODV é farmacologicamente ativo, apresentando ação farmacológica semelhante a venlafaxina. Fungos são micro-organismos capazes de mimetizar o metabolismo de mamíferos, produzindo, muitas vezes, os mesmos metabólitos. Além disso, esse processo pode ser enantiosseletivo. Dessa forma, o objetivo desse trabalho foi avaliar a capacidade de fungos em biotransformar a venlafaxina em seus metabólitos ODV e NDV de uma maneira enantiosseletiva. A separação quiral dos analitos foi realizada por cromatografia liquida de alta eficiência (CLAE) e eletroforese capilar (CE). Como técnica de preparação de amostra foi empregada a microextração liquido-liquido dispersiva (DLLME). Essa técnica recente de preparação de amostra possui alta eficiência na extração, permitindo a obtenção de altos valores de recuperação e um consumo mínimo de solvente orgânico. Anterior aos estudos de biotransformação, o método foi validado para análise por CLAE e CE, empregando, em ambos os casos, a DLLME como técnica de preparação de amostras. A validação foi realizada de acordo com as recomendações da ANVISA para análise de fármacos em material biológico. Todos os parâmetros avaliados (linearidade, precisão, exatidão, estabilidade, seletividade e limite de quantificação) apresentaram valores dentro das exigências da ANVISA. Os estudos de biotransformação foram realizados empregando os seguintes fungos: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) e Glomerela cingulata (VA1). Entre esses, o fungo Cunninghamella elegans mostrou-se promissor na biotransformação da venlafaxina. Dessa forma, diversos fatores foram avaliados na tentativa de melhorar a biotransformação, sendo esses: troca de fonte de carbono do meio de cultura, alteração de meios de biotransformação e adição de cofatores ao meio de cultura. Os resultados mostraram fortes indícios de biotransformação enantiosseletiva da venlafaxina em seu metabólito (+)-(S)-N-desmetilvenlafaxina. / Venlafaxine is a chiral drug used in the treatment of depression and anxiety associated with depression. The pharmacological activity of this drug is mainly associated to the enantiomer (+)-(S)-venlafaxine, which inhibits the reuptake of serotonin with enantioselectivity. When metabolized by the cytochrome P450 enzymes, two metabolites, also chiral, are produced, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV). The studies have demonstrated that the ODV metabolite is pharmacologically active, with similar pharmacological activity of venlafaxine. Fungal are microorganisms capable of mimicking the mammalian metabolism, often producing the same metabolites. Moreover, this process can be enantioselective. Thus, the aim of this study was to evaluate the ability of fungi to biotransform, with enantioselectivity, the venlafaxine in its metabolites ODV and NDV. The chiral separation of the analytes was performed by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). As sample preparation was employed the dispersive liquid-liquid microextraction (DLLME). This recent technique of sample preparation has high extraction efficiency, allowing obtaining high values of recovery and minimal consumption of organic solvent. Before the biotransformation studies, the method was validated employing CE and HPLC with the DLLME technique as sample preparation. The validation was performed according to ANVISA recommendations. All parameters (linearity, precision, accuracy, stability, selectivity and limit of quantification) were acceptable as required by ANVISA. The biotransformation studies were conducted using the following fungal: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) and Glomerela cingulata (VA1). Among these, the fungus Cunninghamella elegans was promising in the biotransformation of venlafaxine. Thus, several factors were evaluated in an attempt to improve the biotransformation: carbon source exchange in the liquid culture medium, changes of the biotransformation medium and addition of cofators in the culture medium. The results provides strong evidences of enantioselective biotransformation of venlafaxine in its metabolite (+)-(S)-N-desmethylvenlafaxine.

A venlafaxina é um fármaco quiral utilizado no tratamento da depressão e da ansiedade associada à depressão. A ação farmacológica desse fármaco está associada principalmente ao enantiômero (+)-(S)-venlafaxina, que inibe a recaptação da serotonina enantiosseletivamente. Quando metabolizada pelas enzimas da citocromo P450 dois metabólitos são produzidos, também quirais, a O-desmetilvenlafaxina (ODV) e a N-desmetilvenlafaxina (NDV). O estudos mostram que o metabólito ODV é farmacologicamente ativo, apresentando ação farmacológica semelhante a venlafaxina. Fungos são micro-organismos capazes de mimetizar o metabolismo de mamíferos, produzindo, muitas vezes, os mesmos metabólitos. Além disso, esse processo pode ser enantiosseletivo. Dessa forma, o objetivo desse trabalho foi avaliar a capacidade de fungos em biotransformar a venlafaxina em seus metabólitos ODV e NDV de uma maneira enantiosseletiva. A separação quiral dos analitos foi realizada por cromatografia liquida de alta eficiência (CLAE) e eletroforese capilar (CE). Como técnica de preparação de amostra foi empregada a microextração liquido-liquido dispersiva (DLLME). Essa técnica recente de preparação de amostra possui alta eficiência na extração, permitindo a obtenção de altos valores de recuperação e um consumo mínimo de solvente orgânico. Anterior aos estudos de biotransformação, o método foi validado para análise por CLAE e CE, empregando, em ambos os casos, a DLLME como técnica de preparação de amostras. A validação foi realizada de acordo com as recomendações da ANVISA para análise de fármacos em material biológico. Todos os parâmetros avaliados (linearidade, precisão, exatidão, estabilidade, seletividade e limite de quantificação) apresentaram valores dentro das exigências da ANVISA. Os estudos de biotransformação foram realizados empregando os seguintes fungos: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) e Glomerela cingulata (VA1). Entre esses, o fungo Cunninghamella elegans mostrou-se promissor na biotransformação da venlafaxina. Dessa forma, diversos fatores foram avaliados na tentativa de melhorar a biotransformação, sendo esses: troca de fonte de carbono do meio de cultura, alteração de meios de biotransformação e adição de cofatores ao meio de cultura. Os resultados mostraram fortes indícios de biotransformação enantiosseletiva da venlafaxina em seu metabólito (+)-(S)-N-desmetilvenlafaxina. / Venlafaxine is a chiral drug used in the treatment of depression and anxiety associated with depression. The pharmacological activity of this drug is mainly associated to the enantiomer (+)-(S)-venlafaxine, which inhibits the reuptake of serotonin with enantioselectivity. When metabolized by the cytochrome P450 enzymes, two metabolites, also chiral, are produced, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV). The studies have demonstrated that the ODV metabolite is pharmacologically active, with similar pharmacological activity of venlafaxine. Fungal are microorganisms capable of mimicking the mammalian metabolism, often producing the same metabolites. Moreover, this process can be enantioselective. Thus, the aim of this study was to evaluate the ability of fungi to biotransform, with enantioselectivity, the venlafaxine in its metabolites ODV and NDV. The chiral separation of the analytes was performed by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). As sample preparation was employed the dispersive liquid-liquid microextraction (DLLME). This recent technique of sample preparation has high extraction efficiency, allowing obtaining high values of recovery and minimal consumption of organic solvent. Before the biotransformation studies, the method was validated employing CE and HPLC with the DLLME technique as sample preparation. The validation was performed according to ANVISA recommendations. All parameters (linearity, precision, accuracy, stability, selectivity and limit of quantification) were acceptable as required by ANVISA. The biotransformation studies were conducted using the following fungal: Mucor rouxii, Cunninghamella echinulata ATCC 8688A, Cunninghamella elegans 10028B, Beuveria bassiana ATCC 7159, Phomopsis sp (TD2), Chaetomiun globosun (VR10) and Glomerela cingulata (VA1). Among these, the fungus Cunninghamella elegans was promising in the biotransformation of venlafaxine. Thus, several factors were evaluated in an attempt to improve the biotransformation: carbon source exchange in the liquid culture medium, changes of the biotransformation medium and addition of cofators in the culture medium. The results provides strong evidences of enantioselective biotransformation of venlafaxine in its metabolite (+)-(S)-N-desmethylvenlafaxine.

Women undergoing endocrine therapy for breast cancer often experience hot flashes. As part of a performance improvement project, 14 patients were surveyed to determine who is at risk for hot flashes during endocrine therapy. This information encourages the education of patients, increases compliance with therapy, and improves quality of life.