Objectifs : Comparer l’efficacité et l'aspect sécuritaire de la rivastigmine sous forme orale et transdermique destinée au traitement des symptômes liés aux instabilités posturales de patients atteints de la démence de la maladie de Parkinson (PDD) et qui sont des candidats pour un inhibiteur de l’acétylcholinestérase. La principale variable de l'étude était le changement de vitesse moyenne du centre de pression (CoP) en position debout après 6 mois de traitement. Les variables secondaires étaient les paramètres structuraux de posturographie dynamique, des échelles d’évaluation cliniques et les effets secondaires nécessitant une réduction de la dose. Méthodes: Des patients avec PDD ont été randomisé dans un ratio de 1 :1 impliquant une prise de rivastigmine orale ou transdermique avec des doses cibles de 6 mg deux fois par jour et 9,5 mg/10 cm2 par jour, respectivement. Les variables dépendantes ont été comparées au départ de l’étude et après 6 mois (comparaisons intra-groupes), de même qu'entre les groupes. Résultats: Dix-neuf patients ont complété l’étude (n=8 orale; n=11 transdermique). Des doses quotidiennes moyennes de 9,4 mg (± 1,5 mg) et 16,4 mg (± 3,6 mg) ont été administrées aux groupes oral et transdermique, respectivement. Le groupe transdermique a démontré une réduction significative de la vitesse moyenne du CoP de 15.8% (timbre: p=0,02; orale: réduction de 10,0%, p=0,16) lors de la condition d'équilibre la plus difficile (yeux fermés en maintenant l'équilibre sur une plateforme mobile synchronisée avec les déplacements du corps). Aucune différence n’a été trouvée entre les groupes (p=0,27). Concernant les paramètres structuraux, des améliorations significatives ont été observées au niveau de la durée moyenne des pics de stabilité de l'équilibre (timbre) et de la distance entre les pics de stabilité (orale) dans la condition d'équilibre la plus difficile. Aucun changement n’a été observé par rapport aux échelles cliniques. Six patients ont eu des effets secondaires mineurs nécessitant une réduction de dose (n=5 orale; n=1 transdermique). Conclusions: La rivastigmine pourrait améliorer certains éléments du contrôle postural de patients atteints de PDD, notamment la vitesse moyenne du CoP en position debout. Les bienfaits sont plus évidents sous les conditions qui challengent davantage l'équilibre. / Objectives: To compare the efficacy and safety of oral and transdermal rivastigmine for postural instability in patients with Parkinson’s disease dementia (PDD) who were candidates for a cholinesterase inhibitor. The primary outcome was the change in mean velocity of the centre of pressure (CoP) after 6 months. Secondary outcomes included structural parameters of dynamic posturography, clinical rating scales and adverse events requiring dose reduction. Methods: Patients with PDD were randomized in a 1:1 ratio to oral or transdermal rivastigmine with target doses of 6 mg twice daily and 9.5 mg/10 cm2 daily, respectively. Outcomes were assessed at baseline and 6 months. Results were compared within and between groups. Results: Nineteen patients completed the study (n=8 oral, n=11 transdermal). Mean daily doses of 9.4 mg (± 1.5 mg) and 16.4 mg (± 3.6 mg) were achieved in the oral and transdermal groups, respectively. The transdermal group demonstrated a significant 15.8% decrease in mean velocity of CoP (patch: p <0.05; oral: 10.0% decrease, p=0.16) in the most difficult scenario (eyes closed with sway-referenced support). There was no difference between groups (p=0.27). For structural parameters, significant improvements were seen in the mean duration of peaks (patch) and inter-peak distance (oral) in the most difficult condition. No changes were observed in clinical rating scales. Six patients experienced non-serious adverse events requiring dose reduction (n= 5 oral; n=1 transdermal). Conclusions: Rivastigmine may improve certain elements of postural control, notably the mean velocity of CoP. Benefits appear to be more obvious under more taxing sensory conditions.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

La schizophrénie est une psychopathologie caractérisée par une perturbation du fonctionnement cognitif. Malgré l'efficacité de certains traitements antipsychotiques en regard de certains symptômes négatifs et positifs, il n'en demeure pas moins que les troubles cognitifs demeurent présents. Ce travail doctoral a pour but d'examiner l'effet des inhibiteurs d'acétylcholinestérase sur le fonctionnement cognitif dans la schizophrénie, afin d'en vérifier l'efficacité. Il s'agit d'une famille de médicaments utilisés pour d'autres pathologies où des problèmes cognitifs, en particulier mnésiques, apparaissent liés à un neurotransmetteur particulier, l'acétylcholine. Après une introduction sur les troubles cognitifs en tant qu'éléments importants du tableau clinique de la schizophrénie, nous présentons les diverses avenues de recherche en pharmacologie visant l'amélioration du fonctionnement cognitif dans la schizophrénie. Cette présentation, sous la forme d'un article intitulé « On the trail of a cognitive enhancer for the treatment of schizophrenia » met en évidence l'implication du système cholinergique dans les troubles cognitifs de la schizophrénie. Sur la base de cette littérature, nous avons effectué une étude sur les effets de la rivastigmine, un inhibiteur d'acétylcholinestérase, chez des patients atteints de schizophrénie et présentant des troubles cognitifs. Les résultats de cette étude clinique menée auprès de patients sous médication neuroleptique et rivastigmine de manière concomitante n'ont pas révélé d'effet particulier de la rivastigmine sur le fonctionnement cognitif dans la schizophrénie. Les données contradictoires entre les études récentes sur l'effet des inhibiteurs d'acétylcholinestérase sur le fonctionnement cognitif dans la schizophrénie, et la nôtre nous ont incité à effectuer une méta-analyse. Le but de cette méta-analyse était de statuer sur les effets des différents inhibiteurs d'acétylcholinestérase sur le dysfonctionnement cognitif dans la schizophrénie. Les résultats de cette méta-analyse ont montré une faible contribution des inhibiteurs d'acétylcholinestérase dans l'amélioration des fonctions mnésiques chez les patients atteints de schizophrénie. Nos résultats expérimentaux et méta-analytiques ne permettent pas de confirmer notre hypothèse initiale stipulant que les inhibiteurs d'acétylcholinestérase puissent être efficaces pour le traitement des troubles cognitifs dans la schizophrénie. En fait, les faibles résultats obtenus apparaissent liés à des facteurs méthodologiques et un effet de pratique. En outre, plusieurs études récentes mieux contrôlées ne révèlent pas d'effet du traitement. Il ne semble donc pas prometteur de poursuivre des études dans ce domaine de recherche. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Schizophrénie, Fonctionnement Cognitif, Mémoire, Inhibiteur d'Acétylcholinestérase, Rivastigmine.

La maladie d’Alzheimer (MA) est une maladie neurodégénérative complexe caractérisée par une perte progressive de la mémoire et de la cognition. C’est la première cause de démence chez le sujet âgé et affecte environs 4.6 millions de personnes par an, selon un rapport de l’association « Alzheimer’s disease International », le nombre de patients pourrait s’élever à 135.5 millions en 2050. Du fait de sa complexité, la MA reste incurable et seuls 4 médicaments aux vertus palliatives dont 3 visant à inhiber l’acétylcholinestérase (AChE) ont reçu une autorisation de mise sur le marché à ce jour. L’approche multi-cible parait particulièrement adaptée du fait du grand nombre de cibles potentielles de la pathologie, et du caractère multifactoriel de la maladie. Cette approche consiste à associer sur une seule molécule, plusieurs pharmacophores afin qu’ils puissent agir simultanément sur différentes cibles impliquées dans le processus neurodégénératif. Dans ce contexte, en parallèle de la resynthèse d’un ligand multi-cible conjugué alliant un inhibiteur d’AChE (IAChE) et un antioxydant, deux nouvelles familles de ligands multi-cibles conjuguées, combinant un IAChE et un agoniste des récepteurs nicotiniques α7 (α7 nAChR) ont été conçues et leur synthèse abordée. Dans le cas de la première famille, le fragment ivastigmine a été choisi pour sa capacité à inhiber de manière pseudo-irréversible l’AChE et a été conjugué à un motif quinuclidine, un puissant agoniste des α7 nAChRs impliqués dans la MA. En combinant ces deux fragments, il a été observé que les propriétés biologiques in vitro de chaque pharmacophore étaient améliorées. La structure de la seconde famille est basée sur le Donepezil, un IAChE réversible de plus forte affinité, combiné au même motif quinuclidine que dans la série précédente. Si des intermédiaires avancés ont été obtenus, un ou deux étapes restent à finaliser pour finaliser la synthèse de cette troisième famille de MTDL. / Alzheimer’s disease (AD) is a complex neurodegenerative disease characterised by a progressive loss of memory and cognition. Nowadays, 4.6 million new patients are identified every year and according to the “Alzheimer’s diseases International” association, the number of patients could reach 135.5 million in 2050. Due to its complexity, AD remains uncurable and only 4 palliative drugs, of which 3 are acetylcholinesterase (AChE) inhibitors (AChEI), have been approved by FDA to date. AD being a multifactorial illness, with many potential targets involved in the pathology, the MTDL approach seems promising. This strategy associates in one single molecule, different pharmacophores (at least) acting on different targets involved in this CNS-related disorder. In this context, in parallel with the upscaled synthesis of a conjugated MTDL combining an AChEI inhibitor and an antioxidant, two new families of conjugated MTDLs associating an AChEI and a α7 nicotinic receptor (α7 nAChR) agonist have been investigated. The structure of the first family was based on a Rivastigmine scaffold, known to be a pseudo-irreversible AChE inhibitor, and a quinuclidine fragment, a potent α7 nAChR agonist. By combining these two fragments, it was brought to light that the in vitro biological properties were improved on both targets. The second family was based on a donepezil fragment, a more potent AChEI, and the same quinuclidine fragment than in the first family. Advanced intermediates have been obtained, and two last steps remain to be achieved for the completion of this third MTDL series.

A doença de Alzheimer (DA) é a principal causa de demência na população idosa mundial. O tratamento de primeira escolha em pacientes com DA de grau leve a moderado é com anticolinesterásicos, que promovem modesta melhora cognitiva. Trabalhos mostram que o lítio também possui efeito benéfico para o tratamento da DA e que é ainda mais eficaz se utilizado como prevenção dos sintomas de demência, mesmo em doses mais baixas que as terapêuticas. O objetivo desse trabalho foi avaliar o efeito de uma microdose de lítio em associação com um anticolinesterásico, para a memória e neuroproteção em modelos in vitro e in vivo de neurodegeneração induzida com o peptídeo <font face = \"symbol\">bA1-40. Em culturas organotípicas de hipocampo de camundongos c57Bl/6 de 12 meses de idade, foi observado aumento significativo da morte neuronal após incubação de <font face = \"symbol\">bA (10 <font face = \"symbol\">mg/mL). O tratamento com 10 <font face = \"symbol\">mM de lítio protegeu as fatias de hipocampo da morte celular, independente do tratamento com rivastigmina. O tratamento das fatias com lítio não alterou a atividade da acetilcolinesterase, diferente do observado com rivastigmina, porém, houve aumento não significativo da densidade de BDNF, em relação às fatias não tratadas. Para os estudos in vivo, camundongos C57Bl/6 machos de 10 meses de idade foram submetidos a três sessões de aquisição de memória em esquiva ativa (EA) e, em seguida, à cirurgia estereotáxica para implante de minibomba osmótica contendo veículo ou <font face = \"symbol\">bA (0,46 nmol). No dia seguinte, iniciou-se o tratamento com rivastigmina (Riv; 0,3 mg/kg/dia). Formaram-se 5 grupos: veículo, <font face = \"symbol\">bA, Li, Riv e Li+Riv. Os grupos tratados com lítio receberam o fármaco (0,3 mg/kg/dia) desde os 2 meses de idade e o tratamento foi mantido até o final dos experimentos. Todos os grupos tratados com Li e/ou Riv foram infundidos com <font face = \"symbol\">bA. O grupo veículo foi tratado com água. Os animais passaram por dois testes em EA, aos 7 e 35 dias após a cirurgia; a partir do 28º dia, foram realizadas avaliações de atividade motora e de memória de curta duração, utilizando-se caixa de atividade motora e teste de reconhecimento de objeto novo, respectivamente. Observou-se que o grupo <font face = \"symbol\">bA apresentou perda de memória em EA e no teste de reconhecimento de objeto novo, quando comparado ao grupo veículo. Nenhum dos tratamentos, no entanto, foi eficaz em prevenir esse prejuízo ou promover melhora no desempenho dos animais nos testes de memória. Não houve formação de placas amiloides em nenhum dos grupos, avaliada por meio da coloração com tioflavina S, sugerindo que o prejuízo cognitivo observado foi devido à forma solúvel do peptídeo. O peptídeo <font face = \"symbol\">bA induziu o processo autofágico no grupo <font face = \"symbol\">bA, verificado pelo aumento da formação de autofagossomos (avaliados por LC3-II) e níveis inalterados de p62 em relação ao veículo. Os tratamentos promoveram uma diminuição não significativa de autofagia, em relação ao grupo <font face = \"symbol\">bA. Dados os resultados in vivo e in vitro, concluiu-se que ambos os fármacos, em monoterapia, promovem efeitos benéficos, porém, quando associados, os efeitos são perdidos. / Alzheimer\'s disease (AD) is the leading cause of dementia in the elderly. The first- choice treatment for patients with mild to moderate AD is a cholinesterase inhibitor, which leads to a modest cognitive improvement. Previous studies have shown that lithium also has a beneficial effect for the treatment of AD, but more effective if used to prevent the symptoms of dementia, even at lower doses than the therapeutic ones. The objective of this work was to evaluate the effect of a lithium microdose in association with a cholinesterase inhibitor on memory and neuroprotection in both in vivo and in vitro models of neurodegeneration induced by <font face = \"symbol\">bA1-40 peptide. By using organotypic culture of hippocampus of 12-month-old c57Bl/6 mice, it was verified a significant increase in neuronal death after incubation with <font face = \"symbol\">bA (10 <font face = \"symbol\">mg/ml). Treatment with 10 <font face = \"symbol\">bM lithium protected the hippocampal slices from cell death, independently of rivastigmine. Treatment with lithium in slices did not alter acetylcholinesterase activity, different from that observed with rivastigmine, however, there was a non-significant increase in BDNF density, in relation to untreated slices. For the in vivo evaluation, 10- month-old male C57Bl/6 mice underwent three sessions of active avoidance memory acquisition (AA) and then, stereotactic surgery for the implant of an osmotic minipump containing vehicle or <font face = \"symbol\">bA (0.46 nmol). At the next day, the treatment with rivastigmine (Riv, 0.3 mg/kg/day) was started. Five groups were formed: vehicle, <font face = \"symbol\">bA, Li, Riv and Li+iv. The lithium-treated groups received the drug (0.3 mg/kg/day) from 2 months of age and the treatment was kept until the end of the experiments. All drug-treated groups were infused with <font face = \"symbol\">bA. Vehicle group was treated with water. The animals underwent two tests in AA: at 7 and 35 days after surgery; from the 28th day, motor activity and short-term memory evaluations were performed, using a motor activity cage and the novel object recognition test, respectively. <font face = \"symbol\">bA group presented memory loss in AA and in the novel object recognition test when compared to vehicle group. None of the treatments, however, was effective in preventing this injury or promoting improvement in the performance of the animals in memory tests. There was no amyloid plaque formation in any of the groups, which was evaluated by thioflavin S staining, suggesting that the observed cognitive impairment was due to the soluble forms of the peptide. <font face = \"symbol\">bA peptide induced autophagic process in <font face = \"symbol\">bA group, as evidenced by an increase in formation of autophagosomes (assessed by LC3-II) and unaltered levels of p62 when compared to vehicle group. The treatment with Li and Riv promoted a non-significant decrease of autophagy, in relation to <font face = \"symbol\">bA group. Together, the results suggest that the drugs promote beneficial effects when used in monotherapy, however, when associated, the effects are no longer observed.

Cholinesterase inhibitors (ChEIs) are the first line pharmacotherapy for the symptoms of Alzheimer’s disease (AD). Though ChEIs offer modest cognitive benefits in early AD, literature addressing their continued use in severe AD is scarce. This study assessed the safety of discontinuing ChEIs in institutionalized moderate-severe AD patients. Twenty-six patients were randomized, double-blind to ChEI continuation or placebo for 8-weeks. Vitals, weight (kg) and adverse events (AEs) were monitored biweekly. Chi-square test revealed no significant association between semi-blinded treatment allocation and AE occurrence (χ²=(1,26)=0.99, p=0.32). Groups showed no differences on clinically significant weight loss (χ²=(1,26) =1.9, p=0.17), mean weight loss (F=.531, p= .473), pulse rate (F=.624, p=.437), or side effects (F=.224, p=.640). Preliminary results suggest that either ChEIs are well tolerated or that these drugs are no longer providing therapeutic benefit. Study completion (recruitment of 60 patients and unblinding) will generate more comprehensive data for determination of safe ChEI discontinuation guidelines.

Cholinesterase inhibitors (ChEIs) are the first line pharmacotherapy for the symptoms of Alzheimer’s disease (AD). Though ChEIs offer modest cognitive benefits in early AD, literature addressing their continued use in severe AD is scarce. This study assessed the safety of discontinuing ChEIs in institutionalized moderate-severe AD patients. Twenty-six patients were randomized, double-blind to ChEI continuation or placebo for 8-weeks. Vitals, weight (kg) and adverse events (AEs) were monitored biweekly. Chi-square test revealed no significant association between semi-blinded treatment allocation and AE occurrence (χ²=(1,26)=0.99, p=0.32). Groups showed no differences on clinically significant weight loss (χ²=(1,26) =1.9, p=0.17), mean weight loss (F=.531, p= .473), pulse rate (F=.624, p=.437), or side effects (F=.224, p=.640). Preliminary results suggest that either ChEIs are well tolerated or that these drugs are no longer providing therapeutic benefit. Study completion (recruitment of 60 patients and unblinding) will generate more comprehensive data for determination of safe ChEI discontinuation guidelines.

Background: Dementia leads to progressive cognitive and functional decline. Population aging is a concern, and the healthcare system must refocus its limited resources to keep up with service demands. Three cholinesterase inhibitors (ChEIs) – donepezil, galantamine and rivastigmine – have been approved for the treatment of dementia and are covered under Ontario’s formulary plan, but there has been little research regarding their economic impact. Methods: The purpose of this study was to describe the patterns of use of ChEIs, and to assess associated health resource utilization and costs to Ontario’s healthcare system. Anonymized patient-level data from seven provincial administrative databases were linked at the Institute for Clinical and Evaluative Sciences at Queen’s University. First-time users of ChEIs aged 66 years and older were identified between April 1st, 2004 and March 31st, 2009, and were followed until treatment discontinuation or up to one year following their index date. Health resource use was classified into six care categories: prescription drugs, physicians, long-term care, home care nursing, emergency department, and hospitalizations. Chi-square, Kruskal-Wallis ANOVA and linear regression were employed to compare resource use between users of the three ChEIs. Results: In the cohort (N=40,057), the majority were prescribed donepezil (n=24,347), were female (60.5%) and had at least one other co-morbid disease. The odds of discontinuation were 1.47 (1.36, 1.60) and 1.26 (1.17, 136), higher for rivastigmine users than galantamine and donepezil users, respectively. Between 2005 and 2008, overall healthcare costs increased from $95.2 million to $106.1 million. Prescription drugs comprised 33% of all healthcare costs. ChEIs accounted for half of all prescription drug costs. Overall mean annual healthcare system cost per patient was $12,679.47 ($12,510.86, $12,848.08). Predictors of overall healthcare costs included long-term care, co-morbidity status, hospitalization and hip fractures. Conclusions: Prescription drugs account for a substantial proportion of healthcare costs for patients with dementia, and the amount attributable to ChEIs alone is significant. Knowing the health service utilization patterns for dementia patients can help healthcare professionals and decision-makers plan patient care and timely resource allocation. The results stress the utility of administrative databases and the need for further research for this disease. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2011-11-01 15:49:58.417

No description available.

Introdução: O traumatismo cranioencefálico (TCE) caracteriza-se por ser uma lesão não degenerativa e não congênita e que é provocado por uma força mecânica externa. Espera-se um prejuízo, permanente ou temporário, nas funções cognitiva, física e psicossocial, com diminuição ou alteração do estado de consciência. As consequências residuais pós-TCE acometem de forma diferente cada paciente. A maioria das pessoas que sofrem traumas leves tem um processo de recuperação sem grandes complicações, e são capazes de retornar às suas atividades pré-trauma. Entretanto, a maioria dos pacientes que sofrem de TCE moderado e grave apresentam sequelas e limitações. Uma das opções medicamentosas vigentes e descritas em relatos de casos são os inibidores de acetilcolinesterase que mostram benefícios significativos quanto a melhora atencional e principalmente da memória quando utilizados em paciente na fase crônica pós TCE. Objetivo: Investigar a eficácia da rivastigmina em pacientes com comprometimento cognitivo crônico após o TCE. Métodos: Foi realizado um estudo duplo-cego, controlado com placebo em pacientes com TCE. Catorze pacientes com TCE (sete que tomaram o remédio ativo e sete que tomaram placebo) entre 18 e 70 anos completaram o estudo. Os pacientes foram randomizados em dois grupos, para receber rivastgmina ou placebo. Utilizou-se para análise dos dados comparativos entre grupo medicamento e placebo, análise estatística Z escore, teste T, qui-quadrado, correlação com o EEG e teste de correlação. Resultados: Observou-se que os pacientes que receberam a rivastigmina apresentaram melhora nos testes Cubos, BAI e memória visual de evocação imediata. No entanto, estas diferenças não foram estatisticamente significativas pelos padrões usualmente utilizados em trabalhos da área médica (alfa de 5%). Conclusão: Os resultados obtidos em pacientes com TCE apontam uma tendência que o tratamento medicamentoso com rivastigmina (medicação anti-colinesterásica) pode favorecer a estabilização ou resultar até mesmo em melhora dos déficits cognitivos, emocionais e funcionais. São necessários mais estudos com número maior de pacientes para aprofundarmos os achados aqui encontrados / Introduction: Traumatic brain injury (TBI) is characterized by a nondegenerative and non-congenital injury and is caused by an external mechanical force. Permanent or temporary impairment is expected in cognitive, physical and psychosocial functions, with a decrease or alteration of the state of consciousness. The residual consequences after TBI affect each patient differently. Most people who suffer mild trauma have a recovery process without major complications and are able to return to their pre-trauma activities. However, most patients suffering from moderate and severe TBI have sequelae and limitations. One of the current and described drug options in case reports are acetylcholinesterase inhibitors that show significant benefits in terms of attentional and especially memory improvement when used in patients in the chronic phase after TBI. Objective: To investigate the efficacy of rivastigmine in patients with chronic cognitive impairment after TBI. Methods: A double-blind, placebo-controlled study was performed in patients with TBI. Fourteen patients with TBI (seven who took the active drug and seven who took placebo) between 18 and 70 years completed the study. Patients were randomized into two groups to receive rivastgmin or placebo. To analyze the comparative data between drug group and placebo, statistical analysis Z score, T test, chi-square, correlation with the EEG and correlation test were used. Results: It was observed that the patients who received rivastigmine presented improvement in the Cubus, BAI and visual memory of immediate recall. However, these differences were not statistically significant by the standards commonly used in medical papers (5% alpha). Conclusion: The results obtained in patients with TBI point to a tendency that drug therapy with rivastigmine (anti-cholinesterase medication) may favor stabilization or even result in improvement of cognitive, emotional and functional deficits. Further studies with a larger number of patients are needed to deepen the findings found here