Introdução: A barreira hematoencefálica limita a penetração de compostos farmacologicamente ativos para o cérebro devido à presença de zônulas de oclusão no endotélio cerebral e a expressão de transportadores de influxo e efluxo que modulam o acesso de fármacos para o parênquima cerebral. Nanocápsulas de núcleo lipídico (LNC) tem sido estudadas como carreadores de fármacos para o tecido cerebral devido à capacidade de modulação da farmacocinética desses compostos. Entretanto, ainda pouco se sabe sobre os processos envolvidos nas alterações farmacocinéticas e na distribuição tecidual promovidas por esses transportadores. Objetivo: Pretendeu-se investigar as alterações na farmacocinética plasmática e penetração cerebral da quetiapina (QTP) nanoencapsulada em ratos Wistar. Materiais e Métodos: QLNC (1mg/mL) foram obtidas através da metodologia de nanoprecipitação e apresentaram reduzido tamanho de partícula (143 ± 6 nm), baixo indicie de polidispersão (PI < 0.1), alta eficiência de encapsulação (96%), potencial zeta negativo (-7.65 ± 0.815 mV) e pH ácido. QLNC quando visualizadas por MET apresentaram tamanho esférico, homogêneo com ausência de agregados. Os estudos in vivo desse trabalho foram aprovados pelo CEUA/UFRGS. Análise do plasma total e a utilização da microdiálise para determinação das concentrações plasmáticas e cerebrais livres foram realizadas após administração intravenosa da formulação de nanocápsulas de QTP (5 mg /kg ) (QLCN) ou do fármaco em solução (FQ) (5 mg /kg e 10 mg /kg) na presença e na ausência de 30 mg /kg de probenecida (PB), um inibidor de transportadores de membrana. Métodos validados foram utilizados para a quantificação do fármaco em diferentes matrizes. As concentrações cerebral e hepática totais foram investigadas através da técnica de homogeneizado de tecido. Além disso, a fração livre no plasma (fu) e a penetração nos eritrócitos também foi realizada. Resultados: QTP apresentou farmacocinética linear na faixa de doses investigadas, é um substrato para transportadores de efluxo na BHE. Diferenças foram observadas na fu da QTP até 2 h após administração de QLNC indicando que LNC do tipo III promove uma liberação sustentada do fármaco do carreador. QLNC não foi capaz de alterar o coeficiente de partição nos eritrócitos determinado in vitro. As concentrações cerebrais e hepáticas totais foram aumentadas após administração da formulação de nanocápsulas, porém, as concentrações cerebrais livres não foram alteradas em comparação com o QTP em solução. Após administração de PB o fator de penetração da QTP livre no cérebro foi reduzido de 1,55 ± 0.17 para 0,94 ± 0,15. Porém, essa inibição pela probenecida não teve efeito na penetração cerebral de QLNC (0,88 ± 0,21 – 0,92 ± 0.13) provavelmente devido ao fato da QTP ser carreada pela LNC e não estar disponível para interagir com transportadores. Conclusão: Considerando todos os resultados sugere-se que as LNC do tipo III carreiam a QTP através da circulação sistêmica até o parênquima cerebral. / Introduction: Blood-brain barrier (BBB) hinders the delivery of therapeutics to central nervous system due to the endothelial cells tight junctions, which restrict paracellular transport of substances, and the expression of influx and efflux transporters, which modulate drugs access to the brain. Lipid-core nanocapsules (LNC) have been proposed as drug carriers to improve brain delivery by modulating drug pharmacokinetics (PK). However, little in know about this modulation process and it is not clear whether the LCN carry the drug through the BBB or increase free drug penetration due to changes in the barrier permeability. Objective: The work aimed to investigate the alterations in the model drug quetiapine (QTP) plasma PK and brain penetration following nanoencapsulation into LNC (QLNC) using microdialysis. Methods: QLNC (1 mg.mL-1) were obtained by nanoprecipitation and presented small particle size (143 ± 6 nm), low polidispersion index (PI < 0.1), high incorporation efficiency (96%), negative zeta potential (–7.65 ± 0.815 mV) and acidic pH. TEM photomicrography showed spherically shaped particles and absence of aggregation. Animal studies approved by CEUA/UFRGS. Total plasma and free plasma and brain concentrations, last two determined by microdialysis, were analyzed after QLNC (5 mg/kg) and free drug (FQ – 5 and 10 mg/gk) i.v. dosing to Wistar rats alone or following probenecid (PB), an influx transporter inhibitor, i.v. administration (30 mg/kg). Drug was quantified in all matrices by validate LC/UV methods. Total brain and liver concentration after FQ and QLNC dosing were investigated in tissues homogenate. Furthermore, QTP free fraction (fu) in plasma and erythrocyte penetration were determined. Results: QTP presented linear PK in the dose range investigated and is substrate to influx transporters at the BBB. Differences observed on QTP fu up to 2 h after QLNC dosing indicate a drug slow release in the blood stream loaded into the LNC type III nanocarrier for this period of time. The LNC did not altered QTP erythrocytes partition coefficient. Total brain and liver concentrations were increased after QLNC dosing but free brain concentrations were not altered in comparison with FQ dosing. After PB dosing, QTP brain penetration was reduced from 1.55 ± 0.17 to 0.94 ± 0.15 when FQ was administered but the inhibition of influx transporters had no effect on QLNC brain penetration (0.88 ± 0.21 to 0.92 ± 0.13) probably because QTP is loaded into the LNC and not available to interact with transporters. Conclusions: Taking together these results suggested that LNC type III carries QTP in the blood stream and delivers the drug to the brain.

No description available.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Class of 2007 Abstract / Objectives: This 12-month retrospective, naturalistic study determined medication adherence, psychiatric hospitalizations, cost of services, cost of prescriptions, and rates of polypharmacy (less than 4 versus greater than or equal to 4 concomitant psychotropic medications) for patients receiving clozapine versus quetiapine therapy for the treatment of schizophrenia in an outpatient mental health facility. Methods: The clozapine and quetiapine groups were compared for gender, age, medication adherence rates, hospitalizations, cost of care, polypharmacy, and types of concomitant psychotropic medications over 12-months. The polypharmacy groups for clozapine and quetiapine (e.g., greater than or equal to 4 psychotropic medications versus less than 4 psychotropic medications) were compared for medication adherence. Results: A total of 71 patients met the entry criteria (44 = clozapine and 27 = quetiapine). The two groups were similar for age, gender, court order, average daily dose, and hospitalization rates. The clozapine group had a higher medication adherence rate of 0.901 (e.g., 329 days supply) compared to the quetiapine group’s adherence rate of 0.723 (e.g., 264 days supply) (p=0.007). The clozapine group had higher costs for medication, labs, and other services compared to the quetiapine group, as well as total costs of services (p=0.004). The clozapine group was on fewer concomitant psychotropic medications compared to the quetiapine group based on the rates of polypharmacy. Conclusions: Patient on clozapine therapy had improved medication adherence and lower rates of polypharmacy, but higher costs of care compared to quetiapine. The frequent monitoring required with clozapine may result in medication adherence that results in improved efficacy, less polypharmacy, and lower hospitalization rates. Further studies in larger populations are needed to compare different frequency rates of monitoring patients on outcome measures over a longer period of treatment.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit und ohne Zusatz der Antipsychotika gemessen. Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung von IL-17 unter allen getesteten Antipsychotika kam. Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.

The aetiology of bipolar disorder remains unclear and investigation to date has focussed largely on bipolar patients. Whilst ultimately of huge value, such studies may also be confounded by current mood or experience of repeated illness episodes or current or past medication; using at-risk samples may bypass some of these problems. The current research therefore assessed the efficacy of the Mood Disorder Questionnaire (MDQ) as a screening tool for vulnerability to bipolar disorder. The MDQ was used with two sets of criteria to identify two sub-groups of medication-naïve young bipolar phenotype subjects who were at risk for bipolar disorder by virtue of experience of mood elevation. Analysis of data from the Student Stress Survey was carried out to characterise the bipolar phenotype. Compared to a control group with no experience of mood elevation, the two bipolar phenotype sub-groups showed a gradient of prevalence of bipolar diagnosis and associated co-morbidity. Behavioural and functional magnetic resonance imaging (fMRI) techniques were employed to investigate emotional processing, decision-making, and sleep and circadian rhythmicity in bipolar phenotype students. Analyses revealed that positive emotional processing biases, disrupted decision-making, and increased activity during sleep were associated with the bipolar phenotype and, therefore, may represent vulnerability markers for bipolar disorder. Finally, a psychopharmacological investigation of quetiapine, which stabilises mood, was carried out in healthy volunteers. One-week quetiapine administration resulted in biases away from both positive and negative emotional stimuli (i.e. a mood-stabilising effect), reduced discrimination between different magnitudes of gains and losses during risky decision-making (consistent with an antidepressant effect), and increased sleep duration. In sum, this research has developed our understanding of vulnerability markers associated with the bipolar phenotype and provided a first step towards uncovering the psychological mechanisms through which quetiapine’s clinical effects may be mediated.

Contexte: L’anhédonie, un état caractérisé par une capacité réduite d’éprouver du plaisir. Des études cliniques récentes montrent qu’un médicament antipsychotique atypique, la quétiapine, est bénéfique pour le traitement de la toxicomanie qui est supposé d’atténuer les symptômes de sevrage associés à l’usage abusif des drogues psychotropes. Le but de la présente étude était d’étudier les effets de l'administration aiguë de quétiapine sur la récompense chez des animaux en état de sevrage après un traitement chronique avec l’amphétamine. Notre hypothese est que la quetiapine va diminuer l’anhedonie causer par le sevrage. Méthodes: Les expériences ont été effectuées avec des rats mâles de la souche Sprague-Dawley entraînés à produire une réponse opérante pour obtenir une courte stimulation électrique au niveau de l'hypothalamus latéral. Des mesures du seuil de récompense ont été déterminées chez différents groupes de rats avant et pendant quatre jours après le traitement avec des doses croissantes (1 à 10 mg/kg, ip toutes les 8 heures) de d-amphétamine sulfate, ou de son véhicule, au moyen de la méthode du déplacement de la courbe. L’effet de deux doses de quétiapine a été testé 24 h après le sevrage chez des animaux traités avec l’amphétamine ou le véhicule. Résultats: Les animaux traités avec l’amphétamine ont montré une augmentation de 25% du seuil de récompense 24 h après la dernière injection, un effet qui a diminué progressivement entre le jour 1 et le jour 4, mais qui est resté significativement plus élevé en comparaison de celui du groupe contrôle. La quétiapine administrée à 2 et 10 mg/kg pendant la phase de sevrage (à 24 h) a produit une augmentation respective de 10 % et 25 % du seuil de recompense; le meme augmentation du seuil a été observe chez les animaux traitées avec le véhicule. Un augmentation de 25 % du seuil de recompense a aussi été observés chez les animaux en état de sevrage à l'amphétamine. Un test avec une faible dose d’amphétamine (1 mg/kg) avant et après le sevrage a révélé une légère tolérance à l’effet amplificateur de cette drogue sur la récompense, un phénomène qui pourrait expliquer l’effet différent de la quétiapine chez les animaux traités avec le véhicule et ceux traités avec l’amphétamine. Conclusions: Ces résultats reproduisent ceux des études précédentes montrant que la quétiapine produit une légère atténuation de la récompense. Ils montrent également que le sevrage à l’amphétamine engendre un léger état d'anhédonie et que dans cet état, une dose élevée de quetiapine et non pas une dose faible accentue l’état émotionnel négatif. Ils suggèrent qu’un traitement à faibles doses de quétiapine des symptômes de sevrage chez le toxicomane devrait ni aggraver ni améliorer son état émotionnel. / Background: Anhedonia, a condition in which the capacity of experiencing pleasure is reduced, is observed in patients that are under withdrawal from drugs of abuse. Recent clinical studies show that quetiapine may be beneficial in the treatment of substance abuse by alleviating the withdrawal-negative affect stage of addiction. This study investigated the effects of acute quetiapine on reward in animals under withdrawal from d-amphetamine. Methods: Experiments were performed on male Sprague-Dawley rats trained for intracranial self-stimulation. Measures of reward threshold were determined with the curve-shift method in different groups of rats before, and during four days after treatment with escalating doses (1 to 10 mg/kg, i.p) of d-amphetamine sulphate or its vehicle. At 24h after withdrawal, the effects of two doses of quetiapine (2 and 10 mg/kg ip) were tested in all the animals. Results: Animals treated with d-amphetamine showed 25% reward attenuation at 24h of withdrawal, an effect that decreased over the next three days. Quetiapine administered acutely at 2mg/kg and 10mg/kg on the first day of withdrawal produced 10% and 25% reward attenuation, respectively, in the vehicle-control animals, an effect also observed in the animals under withdrawal from d-amphetamine but only at the high dose. Conclusions: These results show that quetiapine produced a mild attenuation of reward in normohedonic and in anhedonic animals. They suggest that quetiapine should be used at low doses for the treatment of substance abusers under withdrawal from psychostimulant drugs to avoid enhancement of the anhedonic state.

Contexte: L’anhédonie, un état caractérisé par une capacité réduite d’éprouver du plaisir. Des études cliniques récentes montrent qu’un médicament antipsychotique atypique, la quétiapine, est bénéfique pour le traitement de la toxicomanie qui est supposé d’atténuer les symptômes de sevrage associés à l’usage abusif des drogues psychotropes. Le but de la présente étude était d’étudier les effets de l'administration aiguë de quétiapine sur la récompense chez des animaux en état de sevrage après un traitement chronique avec l’amphétamine. Notre hypothese est que la quetiapine va diminuer l’anhedonie causer par le sevrage. Méthodes: Les expériences ont été effectuées avec des rats mâles de la souche Sprague-Dawley entraînés à produire une réponse opérante pour obtenir une courte stimulation électrique au niveau de l'hypothalamus latéral. Des mesures du seuil de récompense ont été déterminées chez différents groupes de rats avant et pendant quatre jours après le traitement avec des doses croissantes (1 à 10 mg/kg, ip toutes les 8 heures) de d-amphétamine sulfate, ou de son véhicule, au moyen de la méthode du déplacement de la courbe. L’effet de deux doses de quétiapine a été testé 24 h après le sevrage chez des animaux traités avec l’amphétamine ou le véhicule. Résultats: Les animaux traités avec l’amphétamine ont montré une augmentation de 25% du seuil de récompense 24 h après la dernière injection, un effet qui a diminué progressivement entre le jour 1 et le jour 4, mais qui est resté significativement plus élevé en comparaison de celui du groupe contrôle. La quétiapine administrée à 2 et 10 mg/kg pendant la phase de sevrage (à 24 h) a produit une augmentation respective de 10 % et 25 % du seuil de recompense; le meme augmentation du seuil a été observe chez les animaux traitées avec le véhicule. Un augmentation de 25 % du seuil de recompense a aussi été observés chez les animaux en état de sevrage à l'amphétamine. Un test avec une faible dose d’amphétamine (1 mg/kg) avant et après le sevrage a révélé une légère tolérance à l’effet amplificateur de cette drogue sur la récompense, un phénomène qui pourrait expliquer l’effet différent de la quétiapine chez les animaux traités avec le véhicule et ceux traités avec l’amphétamine. Conclusions: Ces résultats reproduisent ceux des études précédentes montrant que la quétiapine produit une légère atténuation de la récompense. Ils montrent également que le sevrage à l’amphétamine engendre un léger état d'anhédonie et que dans cet état, une dose élevée de quetiapine et non pas une dose faible accentue l’état émotionnel négatif. Ils suggèrent qu’un traitement à faibles doses de quétiapine des symptômes de sevrage chez le toxicomane devrait ni aggraver ni améliorer son état émotionnel. / Background: Anhedonia, a condition in which the capacity of experiencing pleasure is reduced, is observed in patients that are under withdrawal from drugs of abuse. Recent clinical studies show that quetiapine may be beneficial in the treatment of substance abuse by alleviating the withdrawal-negative affect stage of addiction. This study investigated the effects of acute quetiapine on reward in animals under withdrawal from d-amphetamine. Methods: Experiments were performed on male Sprague-Dawley rats trained for intracranial self-stimulation. Measures of reward threshold were determined with the curve-shift method in different groups of rats before, and during four days after treatment with escalating doses (1 to 10 mg/kg, i.p) of d-amphetamine sulphate or its vehicle. At 24h after withdrawal, the effects of two doses of quetiapine (2 and 10 mg/kg ip) were tested in all the animals. Results: Animals treated with d-amphetamine showed 25% reward attenuation at 24h of withdrawal, an effect that decreased over the next three days. Quetiapine administered acutely at 2mg/kg and 10mg/kg on the first day of withdrawal produced 10% and 25% reward attenuation, respectively, in the vehicle-control animals, an effect also observed in the animals under withdrawal from d-amphetamine but only at the high dose. Conclusions: These results show that quetiapine produced a mild attenuation of reward in normohedonic and in anhedonic animals. They suggest that quetiapine should be used at low doses for the treatment of substance abusers under withdrawal from psychostimulant drugs to avoid enhancement of the anhedonic state.