This research involved a rigorous implementation of the conceptual framework of Australia's National Strategy for Quality Use of Medicines through a planned sequence of studies across a large defined geographical region to test the hypothesis that: The National Strategy for Quality Use of Medicines can be used to design, implement and evaluate a research program to achieve sustained improvement in health care in a regional setting.

Nesse trabalho estudamos o impacto do uso de benzodiazepínicos prescritos como co-adjuvantes para o controle de crise nos níveis de ansiedade em pacientes com epilepsia do lobo temporal. Estudo de corte transversal com 99 epilépticos. Avaliamos o nível de ansiedade desses pacientes por meio do Inventário de Ansiedade de Beck (BAI) e da Escala de Ansiedade de Hamilton. Dos 99 pacientes, 15 (15.15%) usavam benzodiazepínico (Clobazam/Clonazepam) e 84 (84.84%) não usavam benzodiazepínico para o controle das crises. Em nossa amostra os pacientes que usavam benzodiazepínico eram mais jovens e iniciaram com as crises mais cedo. Além disso, o uso de benzodiazepínico foi mais comum em pacientes com epilepsia refratária (OR=5.6; 95% CI; 1.97-11.06; p=0.047). Esses dados demonstram que o benzodiazepínico foi utilizado para controle de crise em pacientes com epilepsia refratária do lobo temporal. Nesse estudo observamos que ser mulher, ter transtorno de ansiedade ou de humor detectado pela entrevista clínica estruturada para desordens do eixo I do DSM-IVTR (SCID) está associado com altos níveis de ansiedade tanto na escala de BAI quanto na de Hamiltom. No BAI foi detectado altos níveis de ansiedade em pacientes com crises não controladas (OR=4.67; 95% CI 1.97-11.06; p<0.001). Na escala de ansiedade de Hamiltom encontramos altos níveis de ansiedade em pacientes com história familiar psiquiátrica. Não houve diferença estatisticamente significante nos níveis de ansiedade de pacientes que usavam e que não usavam benzodiazepínico cronicamente para o controle da epilepsia, diferente do que esperávamos. É plausível que o uso crônico de benzodiazepínicos possa induzir tolerância ao efeito ansiolítico desses fármacos em epilepsia. Estudos adicionais são necessários para definir melhores estratégias para o tratamento de transtornos de ansiedade em epilepsia. / In this study we evaluate the anxiety levels in patients with temporal lobe epilepsy whether using or not a benzodiazepine for seizure control. We performed a cross-sectional study with 99 patients diagnosed with temporal lobe epilepsy that whether were using or not a benzodiazepine (clobazam or clonazepam) for seizure control. We evaluated the anxiety level of patients using as tools the Beck Anxiety Inventory (BAI) and the Hamilton Anxiety Scale (HAMA). Of the 99 patients, 15 (15.15%) used a benzodiazepine (Clobazam/Clonazepam) and 84 (84.84%) did not use a benzodiazepine for seizure control. In our sample, patients using a benzodiazepine were younger and had seizures early in life. Additionally, the use of a benzodiazepine was more frequent in patients with refractory epilepsy (OR =5.6, 95% CI 1.97-11.06; p=0.047). These data demonstrate the a benzodiazepine was utilized for seizure control in patients with temporal lobe refractory epilepsy. We identified that female sex patients with anxiety disorder or mood disorders detected by SCID demonstrate high anxiety levels measured both with BAI as well as with HAMA. High anxiety levels were detected with the use of BAI in patients with uncontrolled seizures (OR=4.67; 95% CI 1.97-11.06; p<0.001). With the use of Hamiltom we identified high anxiety levels in patients with a positive psychiatric family history. There was no statically significant difference in anxiety levels among patients utilizing or not not a benzodiazepine for seizure control, differently from what we expected. It is plausible that chronic use of benzodiazepines can induce tolerance to the anxiolytic effect of these drugs in epilepsy. Additional studies are needed to define better strategies for treatment of anxiety disorders in epilepsy.

Nesse trabalho estudamos o impacto do uso de benzodiazepínicos prescritos como co-adjuvantes para o controle de crise nos níveis de ansiedade em pacientes com epilepsia do lobo temporal. Estudo de corte transversal com 99 epilépticos. Avaliamos o nível de ansiedade desses pacientes por meio do Inventário de Ansiedade de Beck (BAI) e da Escala de Ansiedade de Hamilton. Dos 99 pacientes, 15 (15.15%) usavam benzodiazepínico (Clobazam/Clonazepam) e 84 (84.84%) não usavam benzodiazepínico para o controle das crises. Em nossa amostra os pacientes que usavam benzodiazepínico eram mais jovens e iniciaram com as crises mais cedo. Além disso, o uso de benzodiazepínico foi mais comum em pacientes com epilepsia refratária (OR=5.6; 95% CI; 1.97-11.06; p=0.047). Esses dados demonstram que o benzodiazepínico foi utilizado para controle de crise em pacientes com epilepsia refratária do lobo temporal. Nesse estudo observamos que ser mulher, ter transtorno de ansiedade ou de humor detectado pela entrevista clínica estruturada para desordens do eixo I do DSM-IVTR (SCID) está associado com altos níveis de ansiedade tanto na escala de BAI quanto na de Hamiltom. No BAI foi detectado altos níveis de ansiedade em pacientes com crises não controladas (OR=4.67; 95% CI 1.97-11.06; p<0.001). Na escala de ansiedade de Hamiltom encontramos altos níveis de ansiedade em pacientes com história familiar psiquiátrica. Não houve diferença estatisticamente significante nos níveis de ansiedade de pacientes que usavam e que não usavam benzodiazepínico cronicamente para o controle da epilepsia, diferente do que esperávamos. É plausível que o uso crônico de benzodiazepínicos possa induzir tolerância ao efeito ansiolítico desses fármacos em epilepsia. Estudos adicionais são necessários para definir melhores estratégias para o tratamento de transtornos de ansiedade em epilepsia. / In this study we evaluate the anxiety levels in patients with temporal lobe epilepsy whether using or not a benzodiazepine for seizure control. We performed a cross-sectional study with 99 patients diagnosed with temporal lobe epilepsy that whether were using or not a benzodiazepine (clobazam or clonazepam) for seizure control. We evaluated the anxiety level of patients using as tools the Beck Anxiety Inventory (BAI) and the Hamilton Anxiety Scale (HAMA). Of the 99 patients, 15 (15.15%) used a benzodiazepine (Clobazam/Clonazepam) and 84 (84.84%) did not use a benzodiazepine for seizure control. In our sample, patients using a benzodiazepine were younger and had seizures early in life. Additionally, the use of a benzodiazepine was more frequent in patients with refractory epilepsy (OR =5.6, 95% CI 1.97-11.06; p=0.047). These data demonstrate the a benzodiazepine was utilized for seizure control in patients with temporal lobe refractory epilepsy. We identified that female sex patients with anxiety disorder or mood disorders detected by SCID demonstrate high anxiety levels measured both with BAI as well as with HAMA. High anxiety levels were detected with the use of BAI in patients with uncontrolled seizures (OR=4.67; 95% CI 1.97-11.06; p<0.001). With the use of Hamiltom we identified high anxiety levels in patients with a positive psychiatric family history. There was no statically significant difference in anxiety levels among patients utilizing or not not a benzodiazepine for seizure control, differently from what we expected. It is plausible that chronic use of benzodiazepines can induce tolerance to the anxiolytic effect of these drugs in epilepsy. Additional studies are needed to define better strategies for treatment of anxiety disorders in epilepsy.

Nesse trabalho estudamos o impacto do uso de benzodiazepínicos prescritos como co-adjuvantes para o controle de crise nos níveis de ansiedade em pacientes com epilepsia do lobo temporal. Estudo de corte transversal com 99 epilépticos. Avaliamos o nível de ansiedade desses pacientes por meio do Inventário de Ansiedade de Beck (BAI) e da Escala de Ansiedade de Hamilton. Dos 99 pacientes, 15 (15.15%) usavam benzodiazepínico (Clobazam/Clonazepam) e 84 (84.84%) não usavam benzodiazepínico para o controle das crises. Em nossa amostra os pacientes que usavam benzodiazepínico eram mais jovens e iniciaram com as crises mais cedo. Além disso, o uso de benzodiazepínico foi mais comum em pacientes com epilepsia refratária (OR=5.6; 95% CI; 1.97-11.06; p=0.047). Esses dados demonstram que o benzodiazepínico foi utilizado para controle de crise em pacientes com epilepsia refratária do lobo temporal. Nesse estudo observamos que ser mulher, ter transtorno de ansiedade ou de humor detectado pela entrevista clínica estruturada para desordens do eixo I do DSM-IVTR (SCID) está associado com altos níveis de ansiedade tanto na escala de BAI quanto na de Hamiltom. No BAI foi detectado altos níveis de ansiedade em pacientes com crises não controladas (OR=4.67; 95% CI 1.97-11.06; p<0.001). Na escala de ansiedade de Hamiltom encontramos altos níveis de ansiedade em pacientes com história familiar psiquiátrica. Não houve diferença estatisticamente significante nos níveis de ansiedade de pacientes que usavam e que não usavam benzodiazepínico cronicamente para o controle da epilepsia, diferente do que esperávamos. É plausível que o uso crônico de benzodiazepínicos possa induzir tolerância ao efeito ansiolítico desses fármacos em epilepsia. Estudos adicionais são necessários para definir melhores estratégias para o tratamento de transtornos de ansiedade em epilepsia. / In this study we evaluate the anxiety levels in patients with temporal lobe epilepsy whether using or not a benzodiazepine for seizure control. We performed a cross-sectional study with 99 patients diagnosed with temporal lobe epilepsy that whether were using or not a benzodiazepine (clobazam or clonazepam) for seizure control. We evaluated the anxiety level of patients using as tools the Beck Anxiety Inventory (BAI) and the Hamilton Anxiety Scale (HAMA). Of the 99 patients, 15 (15.15%) used a benzodiazepine (Clobazam/Clonazepam) and 84 (84.84%) did not use a benzodiazepine for seizure control. In our sample, patients using a benzodiazepine were younger and had seizures early in life. Additionally, the use of a benzodiazepine was more frequent in patients with refractory epilepsy (OR =5.6, 95% CI 1.97-11.06; p=0.047). These data demonstrate the a benzodiazepine was utilized for seizure control in patients with temporal lobe refractory epilepsy. We identified that female sex patients with anxiety disorder or mood disorders detected by SCID demonstrate high anxiety levels measured both with BAI as well as with HAMA. High anxiety levels were detected with the use of BAI in patients with uncontrolled seizures (OR=4.67; 95% CI 1.97-11.06; p<0.001). With the use of Hamiltom we identified high anxiety levels in patients with a positive psychiatric family history. There was no statically significant difference in anxiety levels among patients utilizing or not not a benzodiazepine for seizure control, differently from what we expected. It is plausible that chronic use of benzodiazepines can induce tolerance to the anxiolytic effect of these drugs in epilepsy. Additional studies are needed to define better strategies for treatment of anxiety disorders in epilepsy.

La douleur neuropathique est un syndrome secondaire à une maladie ou à une lésion affectant le système nerveux somatosensoriel. Les causes biologiques de ces comorbidités ne sont pas clairement établies. En utilisant un modèle murin de douleur neuropathique, nous avons cherché à amplifier l'inhibition nerveuse médiée par les récepteurs GABAA afin de tenter de réduire les symptômes douloureux neuropathiques et les troubles émotionnels associés. Pour cela nous avons utilisé l’étifoxine, un anxiolytique non benzodiazépinique qui possède une action originale sur les récepteurs GABAA mais, surtout, semble avoir des effets secondaires limités comparativement à d'autres molécules comme les benzodiazépines par exemple. Son effet passe par la potentialisation directe du récepteur GABAA (site modulateur situé sur les sous-unités β2 et β3) mais aussi par une action indirecte : la stimulation de la production de neurostéroïdes 3α-réduits capables de potentialiser la fonction des récepteurs GABAA. Quelques rares études ont montré que les neurostéroïdes endogènes, surtout ceux réduits en position 3α comme l'allopregnanolone (THP, allotétrahydroprogestérone) ou le THDOC (tétrahydrodéoxycorticostérone), pouvaient réduire les symptômes douloureux. Les effets obtenus dans ces études sont similaires à ceux issus d’injections exogènes des mêmes composés. / Neuropathic pain is associated with significant co-morbidity, including anxiety and depression, which impact considerably on the overall patient experience. Several lines of evidence suggest that anxiolytics may be of interest to alleviate pain symptoms and the associated negative emotions in chronic pain states. Among them, the non-benzodiazepine anxiolytic etifoxine (EFX: stresam™) has an interesting pharmacological profile. In patients, it has a weak sedative action, with limited functional tolerance and dependence, and without cognitive declines. In this study, we aim at analyzing the preclinical therapeutic potential of etifoxine on the anxiodepressive consequences of neuropathic pain.

Nous avons évalué les conséquences sur un plan endocrinien et cognitif de l’administration d’un stress aigu chez la souris BalbC jeune (6 mois) ou d’âge moyen (16 mois). Le stress aigu a été appliqué 5, 60 ou 120 minutes avant la phase de rappel dans une épreuve de mémoire contextuelle. La concentration en corticostérone hippocampique a été mesurée avant et après le stress. Suite à l'administration du stress, elle augmente rapidement (dès 15 minutes post-stress) et est inversement liée au rappel mnésique. En effet, plus la concentration de corticostérone hippocampique est élevée, plus faible est la réponse hippocampe-dépendante. Les effets cognitif et endocrinien du stress ont été reproduits par l'administration de corticostérone dans l'hippocampe et ont été bloqués par la métyrapone. Le vieillissement accroit l’anxiété et induit des conséquences sur le plan mnésique comparable à celles du stress chez la souris jeune. De plus, la concentration de corticostérone hippocampique, basale ou en réponse au stress, est plus élevée et durable chez les animaux âgés, par rapport aux jeunes. Par ailleurs, l’administration de diazépam 30 minutes avant le rappel chez la souris d’âge-moyen atténue les effets délétères du stress sur la mémoire et la concentration hippocampique de corticostérone. Ces données suggèrent que la perturbation de l'axe HPA chez la souris âgée joue un rôle clef dans les troubles de mémoire hippocampe-dépendants induits par le vieillissement. / The cognitive and endocrinal consequences of an acute stress were studied in young (6 months) and middle-aged (16 months) BalbC mice. Acute stress was delivered 5, 60 or 120 minutes before the retrieval phase of a contextual memory task. Hippocampal corticosterone concentration was measured before and after stress delivery by microdialysis. The acute stress induces a rapid hippocampal corticosterone rise in relation with a cognitive impairment. Indeed, when the level of hippocampal corticosterone is high, the cognitive performance of hippocampal-dependent memory is impaired. Moreover, the cognitive and endocrinal effects of stress were mimicked using corticosterone microinjection in the hippocampus, whereas metyrapone (an inhibitor of corticosterone synthesis) blocked it. The consequences of aging on memory retrieval are similar to stress effects in young mice. Furthermore, pre and post-stress hippocampal corticosterone concentration is higher in middle-aged as compared to young mice. In addition, the increase in hippocampal corticosterone is longer in middle-aged in contrast to young mice. Finally, the administration of diazepam in middle-aged mice (30 minutes before the retrieval test phase) attenuates the deleterious effects of an acute stress on memory retrieval and the increase in hippocampal corticosterone concentration. In conclusion, our data suggest that HPA axis dysregulation, observed in middle-aged subjects, plays a key role in episodic-like memory impairments induced by aging.

Les substances pharmaceutiques et les produits de soin utilisés pour la protection de la santé humaine sont retrouvés dans tous les compartiments du milieu aquatique. Certaines de ces substances présentent des caractéristiques physico-chimiques ou pharmacologiques suggérant une capacité à se bioaccumuler comme les filtres UV EHMC et OC aux log Kow supérieurs à 5 ou les benzodiazépines diazépam et tétrazépam aux log de Kow de 2,82 et 3,20. L'objectif de ce travail de thèse a été d'évaluer la contamination des moules par 3 filtres UV et de 2 benzodiazépines. Pour cela, une méthode analytique a été mise au point et validée pour le dosage de ces substances dans les moules. Le dosage de l'EHMC et de l'OC a montré qu'en milieu côtier la contamination des moules in situ provient majoritairement des activités récréatives en période estivale et que cette contamination est augmentée dans des zones semi-fermées. Des expérimentations de bioaccumulation sur ces deux substances ont montré que les moules ne bioaccumulent pas ces filtres UV ; elles reflètent les niveaux de contamination en temps réel. Les niveaux de benzodiazépines dans les moules ne sont pas détectables en milieu côtier. Des expérimentations en conditions contrôlées ont montré que les moules absorbent les benzodiazépines. Cependant, elles les éliminent et probablement les métabolisent. L'utilisation de moules pour l'étude de la contamination par des substances émergentes permet l'identification de zones ou de périodes à risque élevé. / Pharmaceutical and personal care products used for human health protection are detected in all aquatic ecosystems. Among them, some compounds have physico-chemical or pharmacological properties that suggest a bioaccumulation capability. It’s the case of the UV filters, EHMC and OC, with log Kow higher than 5 or pharmaceuticals like diazepam and tetrazepam, with log Kow higher than 2.82. The aim of these Phd works was to assess marine mussels contamination for UV filters and benzodiazepines. So, a new analytical method was developed and validated for the determination of these compounds in mussels. EHMC and OC analysis realized in mussels sampled in French coastal waters showed that mainly contamination came from recreational activities in summer season, and that semi-closed areas were more contaminated. Moreover, laboratory experiments showed that mussels had clearly not bioaccumulate these 2 UV filters. Contamination levels in mussels are controlled by water concentrations. Conversely, benzodiazepines were not detected in coastal mussels. However, laboratory experiments showed an accumulation of benzodiazepines in mussels, suggesting elimination and metabolization means. Mussels are nevertheless usefull bioindicators of marine contamination by emerging compounds, allowing to characterize higher risk areas or periods.

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