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1
Fisher, Michael. "Clozapine-induced paroxysmal discharges". Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2190.
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The atypical antipsychotic clozapine is a widely prescribed and effective treatment for the positive and negative symptoms of schizophrenia, but reports of side effects are common. In one study EEG abnormalities were observed in 53% of patients treated with clozapine, and the absence or presence of EEG abnormalities correlated with the plasma clozapine concentration. Here, epileptiform activity was present in conventional EEG recordings from a 32 year old male patient with psychiatric illness taking clozapine for 3 weeks. Brief (ca.100ms), transient epileptiform spikes occurred at a frequency of approximately 2 per h and originated primarily in parietal cortex. One month after withdrawal of clozapine, epileptiform spikes were no longer present. An in vitro model was developed using the equivalent region of association cortex, namely 2⁰ somatosensory cortex, in normal rat brain slices to probe such activity with increased spatial and temporal resolution, and to investigate mechanisms underlying its generation. Wide band in vitro recordings revealed that clozapine (10-20µM) induced regular, frequent very fast oscillations (VFO, > 70Hz) in this region. These VFO comprised short transient high frequency discharges and were maximal in patches along layer V. The atypical antipsychotic olanzapine, but not the classical antipsychotic haloperidol, also induced prominent VFO in this region. Sharp electrode intracellular recordings revealed that there was almost no correlation between the somatic activity of layer V regular spiking (RS) pyramidal cells and field VFO, but layer V intrinsically bursting (IB) cells did correlate to some extent with the local field. Interestingly, IB cell spikelets were also weakly correlated with field VFO suggesting a role for axonal hyperexcitability in this cell type in the mechanism. Clozapine-induced VFO persisted following blockade of AMPA, NMDA, and GABAA chemical synaptic receptors, and the gap junction blockers carbenoxolone and quinine also failed to significantly attenuate the power of this activity. Although octanol abolished clozapine-induced VFO, it was not clear that this effect resulted from blockade of gap junctions as this drug also blocks spikes. In addition to VFO events, clozapine (10-20µM) also induced occasional, spontaneous transient paroxysmal discharges, similar to the EEG phenomena, in 33% (11/33 slices) of slices in vitro. Sharp electrode intracellular recordings revealed that clozapine- induced full paroxysmal discharges were associated with spikes, EPSPs and IPSPs in layer V RS and IB cells, suggesting that these events were mediated via chemical synaptic transmission in both of these cell types. Multi-electrode array recordings of local field potentials and units suggested that clozapine-induced paroxysmal events started superficially in association cortex, moved deeper and then propagated horizontally along these deep layers. The onset of clozapine-induced VFO was accompanied by a significant elevation in parvalbumin immunoreactivity, particularly in layer II-IV, where there was a greater than twofold increase in the signal, and this may be relevant to the therapeutic action of the drug.
2
Mourlot-Chabanon, Pascale. "Bilan d'utilisation de la clozapine". Montpellier 1, 1997. http://www.theses.fr/1997MON11031.
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3
DAHER, OSCAR. "Tolerance a la clozapine (leponex*)". Saint-Etienne, 1993. http://www.theses.fr/1993STET6205.
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4
Durão, Ana Maria Sertori. ""Grupo de acompanhamento de pacientes e familiares de portadores de esquizofrenia medicados com clozapina: o impacto sobre o cotidiano de suas vidas"". Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/22/22131/tde-08092004-165526/.
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Trata-se de uma pesquisa de avaliação, de natureza qualitativa,do tipo descritivo exploratório. Que teve como proposta descrever o cotidiano do portador de esquizofrenia em três momentos: antes do uso da clozapina; após o uso da clozapina; após o uso da mesma e o acompanhamento em grupo. A população foi constituída por todos os portadores de esquizofrenia que participaram do grupo de medicações atípicas (GRUMA) em uso de clozapina e um familiar que os acompanhavam com maior freqüência ao grupo. Para coleta dos dados foram realizadas entrevistas semi-estruturadas, com pacientes e familiares, guiadas por roteiros pré-elaborados. As mesmas foram gravadas e, posteriormente, transcritas na íntegra pelo próprio pesquisador.Foi utilizada a análise qualitativa a qual embasou-se nos passos propostos por Minayo (1996). Obteve-se como resultados que antes do uso da clozapina e acompanhamento em grupo, a imprevisibilidade de comportamento e a demonstração de agressividade eram constantes no cotidiano dos pacientes e seus familiares, gerando grande sofrimento psíquico para ambos, além do desconhecimento sobre a doença. A manifestação dos sintomas constituía causa de isolamento social, perdas de relações com as pessoas mais próximas, prejudicando de maneira significativa às atividades de trabalho, estudo e de convívio social. Após o uso da clozapina, antes de realizarem acompanhamento em grupo, os pacientes apresentaram expressiva melhora dos sintomas positivos da doença, principalmente no que se refere à agressividade. Entretanto, verificamos que as dificuldades nos relacionamentos, no trabalho, no estudo, nas atividades de convívio social e em outras atividades do cotidiano dos pacientes permaneceram. Foi possível verificar que após o uso da clozapina e acompanhamento em grupo houve melhora do relacionamento, antes difícil, diminuição da ansiedade e da agressividade, aumento da a auto-estima, da tolerância e força de vontade bem como fortalecimento dos vínculos familiares. O grupo em questão possibilitou que pacientes e familiares fossem orientados a reconhecer os sintomas da doença e os sinais prévios de efeitos colaterais concernentes ao tratamento. Evidencia-se, também, a importância do acolhimento, da amizade e do conforto encontrado no grupo, além do clima de solidariedade e segurança. Constatou-se, assim, que apesar das adversidades de um sistema de saúde ainda incipiente, profissionais parecem ainda investir nas possibilidades de encontro, buscando meios para a criação de novas realidades no cotidiano pacientes e seus familiares.This descriptive, exploratory, assessment study of a qualitative nature has as its aim, to describe the daily life of the schizophrenic sufferer in three moments: before the use of clozapine; after clozapine use and after clozapine use and group follow-up. The population was made up of all the schizophrenia sufferers using clozapine and the most frequently accompanying relative that participated in the atypical medication group (GRUMA).Data was collected through tape recorded, semi structured interviews with patients and relatives using a previously prepared guideline. Afterwards the recorded interview was hand written by the researcher and a qualitative analysis based on the steps proposed by Minayo (1996) was carried out. The results obtained, showed that before the use of clozapine and group followup, unpredictable behaviour and overt aggressiveness were constant in the daily lives of the patients and their families, causing, in both, great psychological suffering as well as lack of know ledge about the disease. The manifestation of symptoms constituted cause for isolation, loss of relationships with close people affecting in a significant manner work, study and social living. After the use of clozapine, before beginning the folowup group, the patients presented expressive improvement of the positive and negative symptoms of the disease, principally in as far as agressiveness was concerned. However, it was found that the difficulties continued in relationships at work, in study pursuits, in social living activities as well as in the patients other daily talks. It was possible to verify that after the use of clozapine with the support of the followup group, there was an improvement in relationships that were difficult before, reduction of anxiety and agressiveness, thus increasing self respect, tolerance, willpower, as well as, the strenghthening of family ties. The group in question allowed the patients and relatives to be guided to recognize the symptoms of the disease and the previous signs of the collateral effects of the treatment. The importance of acceptance, of friendship and the comfort encountered in the group was also verified, as well as solidarity and security. It was also ascertained that inspite of the adversities of the still incipient health system, professionals still seem to invest in the possibilities of finding, looking for and of creating new realities in the daily lives of patients and their families.
5
Wilkes, Susanna Jane Lawson. "An investigation into clozapine induced agranulocytosis". Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336629.
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6
Tschen, Alice C. "The in vitro metabolism of clozapine, implications for an in vitro predictive test for clozapine-induced agranulocytosis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ28678.pdf.
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Hsu, Pei-Chun (Lisa). "Capillary electrophoresis improving clinical measurement of clozapine". Thesis, University of Canterbury. School of Biological Sciences, 2008. http://hdl.handle.net/10092/2260.
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Schizophrenia is a mental disorder affecting approximately one percent of the population worldwide. The introduction of the second generation antipsychotic drug, atypical antipsychotic, clozapine, has demonstrated 80% reduction in suicide incident. This drug showed effectiveness in the treatment of resistant schizophrenia, however, high concentrations of clozapine and N-desmethylclozapine in plasma exhibit the development of agranulocytosis, a possible lethal blood disorder. Therefore, constant therapeutic drug monitoring is important for patients who receive clozapine. High performance liquid chromatography (HPLC) is the current assay for clinical clozapine measurement. A different assay, the capillary electrophoresis (CE) was explored in this study. It was found the use of a background electrolyte (BGE) concentration of 60 mM, pH at 2.5, temperature at 22 ℃, voltage applied at 10 kV and sample injection at 23 kV for 1.5 seconds is the optimal condition for clozapine separation using a fused-silica capillary 75 μm in internal diameter (i.d.). The use of 75 μm (i.d.) fused-silica capillary not only permits a larger sample size, but also provided longer detection pathlength which increased the limit of detection for CE. One hundred and eight patients’ samples were analysed by CE and compared with HPLC results obtained from the Canterbury Health Laboratory. A linear regression line of 1.100 was obtained. Seven External Quality Control (EQC) samples were also analysed and compared to the HPLC results gained from the EQC program world wide. A linear regression line of 1.008 and 1.043 were obtained from clozapine and N-desmethylclozapine separation respectively. The developed CE method has shown to be a valid assay for clozapine and N-desmethylclozapine separation and a more cost effective method compared to HPLC.
8
Salmi, Peter. "Clozapine as a dopamine D1 receptor agonist /". Stockolm : Universitet Stockholms, 1998. http://catalogue.bnf.fr/ark:/12148/cb401175060.
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9
Raaska, Kari. "Pharmacokinetic interactions of clozapine in hospitalized patients". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/raaska/.
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10
Jolivel, Céline. "Etude médico-économique de la clozapine (Leponex (R)), neuroleptique atypique, dans le traitement des schizophrénies résistantes". Bordeaux 2, 1997. http://www.theses.fr/1997BOR2P054.
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11
Souza, Juliano dos Santos. "Eficácia de antipsicóticos atípicos comparados à clozapina em pacientes com esquizofrenia refratária: revisão sistemática e metanálise". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-04112010-160946/.
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INTRODUÇÃO: Considera-se a clozapina como padrão-ouro para o tratamento de pacientes com esquizofrenia refratária, com base principalmente em sua eficácia comprovadamente superior em relação aos antipsicóticos típicos. No entanto, os dados acerca do uso de outros antipsicóticos atípicos ainda são escassos ou divergentes. Tendo em vista que o uso de clozapina está associado a várias limitações, existe uma necessidade não atendida de alternativas terapêuticas eficazes e seguras para a esquizofrenia refratária. MÉTODOS: Foi realizada uma revisão sistemática de estudos controlados e randomizados (ECRs), comparando clozapina aos outros antipsicóticos atípicos, em pacientes com esquizofrenia refratária. Foram realizadas metanálises avaliando a eficácia das intervenções, medida por meio de escalas de avaliação de sintomas psicóticos. A resposta ao tratamento foi medida por meio da porcentagem de respondedores ou pela mudança média ou valores finais dos escores das escalas. Quando possível, foram realizadas metanálises da comparação entre clozapina e outro antipsicótico atípico específico. Os tamanhos de efeito foram dados pelo risco relativo (RR) ou pela diferença entre médias (DM), ponderada ou padronizada, acompanhados dos respectivos intervalos de confiança de 95%. As metanálises foram realizadas utilizando-se o modelo de efeitos fixos, ou aleatórios, no caso de haver heterogeneidade entre os estudos. Foram realizadas análises de sensibilidade, excluindo-se estudos que haviam incluído pacientes intolerantes junto à população refratária. RESULTADOS: Onze ECRs foram incluídos, representando 1182 pacientes, com 12 comparações entre clozapina e antipsicóticos atípicos: quatro com risperidona, um com ziprasidona e sete com olanzapina. Considerados como um grupo, não foi possível determinar diferenças no tamanho de efeito entre a clozapina e os outros antipsicóticos atípicos em nenhum tipo de medida geral de sintomas psicóticos. A metanálise que combinou as mudanças médias e os valores finais da PANSS e da BPRS apresentou uma diferença de médias de 0,00 (IC95%= -0,12, 011). Foi observada superioridade marginal dos antipsicóticos atípicos para sintomas negativos, medidos pelos valores finais da PANSS (DM= -1,96, IC95%= -3,44, -0,48). Foi observado que os estudos que compararam a clozapina à olanzapina tiveram doses finais médias altas de olanzapina (médias de 17,2 mg/d a 33,6 mg/d), o que pode ter influenciado nos resultados.CONCLUSÕES: Os antipsicóticos atípicos, particularmente a olanzapina em doses altas, podem representar uma alternativa de tratamento para pacientes com esquizofrenia refratáriaBACKGROUND: Clozapine is considered as the gold standard for the treatment of patients with refractory schizophrenia, based upon its well established superior efficacy against typical antipsychotics. Nevertheless, data on other atypical antipsychotics are still scarce or divergent for this population. Considering that clozapine use is associated to several caveats, there is an unmet need for safe and efficacious alternative therapeutic approaches for refractory schizophrenia. METHODS: It was conducted a systematic review of randomized clinical trials (RCTs) comparing clozapine to other atypical antipsychotics in patients with refractory schizophrenia. Metanalyses assessing the efficacy of interventions were performed. Efficacy was measured by psychotic symptoms scales. Response to treatment was measured by the percentage of responders or by mean change or endpoints values of such scales. Whenever possible, metanalyses comparing clozapine to other specific atypical antipsychotic were performed. Effect sizes were shown as relative risks (RR) or weighted or standardized mean differences (MD), with 95% confidence intervals. The fixed effect model was used, unless studies were considered heterogeneous. Sensivity analyses were performed with the exclusion of studies which had included intolerant patients along with true refractory patients. RESULTS: Eleven RCTs were included, figuring 1182 patients, with 12 comparisons between clozapine and other atypical antipsychotics: four with risperidone, one with ziprasidone, and seven with olanzapine. Considered as a group, it was not possible to determine different effect sizes between atypical antipsychotics and clozapine for any general measure of psychotic symptoms. Pooled mean change and endpoint PANSS and BPRS scores metanalysis presented a zero mean difference (MD=0.00, CI95%= -0.12, 0.11). Atypical antipsychotics were shown to be marginally superior to clozapine for negative symptoms, measured by PANSS negative symptoms subscale endpoint scores (DM= 1.96, CI95%= -3.44, -0.48). Studies which compared clozapine to olanzapine had relatively high mean final olanzapine doses (means ranging from 17.2 mg/d to 33.6 mg/d), what might have influenced the results. CONCLUSIONS: Atypical antipsychotics, particularly high dose olanzapine, can represent an alternative therapeutic approach to patients with refractory schizophrenia
12
Legge, Sophie E. "Examining treatment response and adverse effects of clozapine". Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/91366/.
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The antipsychotic clozapine is uniquely effective in the management of treatmentresistant schizophrenia (TRS), but its use is limited by its potential to induce agranulocytosis. A substantial proportion of patients discontinue clozapine treatment, which carries a poor prognosis, and only 30-60% of patients with TRS will respond to clozapine. The causes of clozapine-associated agranulocytosis, and of its precursor neutropenia, are largely unknown although genetic factors contribute. To examine the genetic susceptibility to clozapine-associated neutropenia, I conducted a multifaceted genetic analysis in the largest combined sample studied to date. Using GWAS, I identified a novel genome-wide significant association with rs149104283 (OR = 4.32, P = 1.79x10-8), a SNP intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes involved in drug uptake. Furthermore, I replicated a previously reported association between neutropenia and a variant in HLA-DQB1 (OR = 15.6, P = 0.015). I investigated clozapine discontinuation and clinical response in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. By studying the reasons for discontinuations due to a patient decision, I found that adverse drug reactions accounted for over half of clozapine discontinuations. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30-3.47). Female gender (HR = 0.63, 95% CI 0.41-0.96) and clinical improvement after one month of treatment (HR = 0.56, 95% CI 0.44- 0.71) were significantly associated with a good response to clozapine. However, I found that up to six months of treatment may be required to determine non-response. This thesis implicates variants that may increase susceptibility to clozapine-associated neutropenia and contributes to our current understanding of the causes of clozapine discontinuation and treatment response.
13
Brown, Julia. "Making Health Agency: Clozapine, Schizophrenia, and Personal Power". Phd thesis, Canberra, ACT : The Australian National University, 2018. http://hdl.handle.net/1885/148757.
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This thesis demonstrates how experiences of agency and health
persist in spite of confining social and biological
circumstances. I take the case of clozapine-treated
schizophrenia, where patients are presented with both renewed
hope for an independent life at the same time as undertaking an
intensive physiological monitoring regimen that prioritises their
life in the most immediate sense only. Clozapine patients face a
high risk of chronic multi-morbidities that significantly lower
their life expectancy, and they are not quite ‘cured’ of
their mental disturbances pertaining to chronic schizophrenia. I
demonstrate, though, how patients are able to experience a sense
of what I term health agency, where we might otherwise imagine
their well-being to be significantly compromised. Health agency
is a feeling of control over one’s well-being, where well-being
is defined in one’s own terms. It was remarkable to find it in
the clinical contexts in which I was working, where very narrowly
constituted definitions of health were ostensibly endorsed and
imposed. But in the thick of life in the clozapine clinic,
patients and institution did not occupy strict polar positions.
My fine grained ethnographic work revealed how patients worked
creatively with the clinical circuitries, biomedical imaginaries
and temporal underpinnings of clozapine treatment to personalise
their experiences and to exert subtle, personal power over their
health and future prospects.
My fieldwork was based in the UK and Australia over an 18-month
period (2015-2016) between two clozapine clinics. Research
participants included 43 people diagnosed with schizophrenia
(termed patients, hereafter) and 16 clinical staff at the
clozapine clinics (termed clinical caregivers, hereafter). I
conducted participant observation and 130 interviews. Drawing on
my ethnographic data, this thesis explicates how health agency
was available to patients in four central ways. First, health
agency was part of a hopeful, personal persistence for holistic
health in spite of the ‘physical,’ ‘mental,’ and
‘social’ aspects of health appearing irreconcilable in terms
of clinical definitions. Second, patients were able to creatively
manipulate and complement the goals of clozapine clinic blood
monitoring to actively participate in the aspect of their
treatment that is otherwise the furthest from patient control.
Third, patients drew on the ambiguities of clozapine and other
‘health’ consumptions or behaviours to negotiate how
clozapine impacted their minds and bodies. Fourth, patients
utilised the temporalities of clozapine and clinical suspending
of non-biological concerns to abundantly “live in the
present” and harness focused energies that kept their futures
open, while ephemerally suspending clinical symptoms and
clozapine side effects. I suggest that patients’ self and
social labour, and their quiet everyday efficacies in making
their own health, problematise some previous anthropological and
clinical conceptions about living with chronic schizophrenia
under biomedical treatment models. I make the case for further
ethnographic consideration for quiet expressions of agency within
highly structured conditions.
14
O'Donnell, Charles John Lawrence. "Molecular consequences of drug bioactivation". Thesis, University of Liverpool, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269600.
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Ginies, Emmanuelle. "Mesure et surveillance de la clozapinémie : vers un dosage thérapeutique de routine". Montpellier 1, 1998. http://www.theses.fr/1998MON11097.
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Allender, David Vanelle Jean-Marie. "Actualité de la clozapine dans la prise en charge du patient schizophrène". [S.l.] : [s.n.], 2004. http://theses.univ-nantes.fr/thesemed/SPEallender.pdf.
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Taylor, Anita Margaret. "The discriminative stimulus properties of the atypical antipsychotic clozapine". Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367204.
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Mujanovic, Ajdin. "Physical health outcomes for young people commenced on clozapine". Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-73267.
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Abstract BACKGROUND: Psychotic disorders are associated with symptoms such as delusions and hallucinations as well as impaired functioning. Second generation antipsychotic medications are the first line treatment for psychotic disorders, however a proportion of individuals will not respond to the medication. Clozapine is the most effective second generation anti-psychotics, however it is only used as a third line treatment because of serious side-effects. It is associated with metabolic side-effects, which increase the risk of obesity and diabetes mellitus. AIM: Determine the changes in the weight, waist circumference and blood pressure as well as triglycerides, fasting glucose and cholesterol in young people commenced on clozapine after 18 weeks and 6 months of commencement. METHOD: This is a cohort study, including participants aged 15-24 commenced on clozapine between the time period 1st of April 2016 and 30th of September 2017. Data concerning measured outcomes was gathered from patient journals. RESULTS: A total of 36 young people were commenced on clozapine during the study period and the mean age was 19.8 (SD±3.1). At the time of commencing clozapine, the mean weight of the cohort was 86.30kg (±17.08) and after 18 weeks it was 88.90kg (±16.71), and this difference was statistically significant (n=27,df=26,p=0.02) and this weight gain was present for males (n=17,df=16,p=0.038) but not females (n=10,df=9,p=0.214). CONCLUSION: Clozapine may be associated with weight gain in the early stages of commencement and it appears that males are more susceptible to this side-effect. More interventions aimed at attenuating this weight gain is needed.
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Martin, Francis. "Schizophrénie, résistance et clozapine : étude rétrospective sur le devenir de dix patients". Bordeaux 2, 1993. http://www.theses.fr/1993BOR2M046.
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Murphy, Kate. "Clozapine, concomitant medications and consumers: Assessing the accuracy of medication records and the lived experience of people prescribed clozapine under shared care arrangements". Thesis, Griffith University, 2018. http://hdl.handle.net/10072/381000.
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Schizophrenia is a serious long-term mental illness associated with significant morbidity and mortality. Clozapine is the most effective antipsychotic medication for the treatment of schizophrenia, however, due to potentially life-threatening haematological adverse effects, its use is restricted to people who have not responded to an adequate trial of at least two other antipsychotic medications. The high risk of adverse effects, associated mandatory monitoring and prescribing restrictions all mean that clozapine consumers often continue to be managed in a secondary care public mental health (MH) service.
In people stabilised on maintenance treatment living in the community, a shared care model, involving collaboration between a psychiatrist in secondary care, a general practitioner (GP) and community pharmacy in primary care is a management option. The aim of shared care is to lessen the burden on the consumer and on the secondary care service by allowing the GP to undertake the majority of monitoring and reduce the frequency of secondary care appointments.
While this may appear to be an ideal arrangement, discrepancies in medication information at transitions of care from one health service to another are common and contribute to prescribing errors. Where clinicians do not have full medication information there is potential for inappropriate clinical decision-making and the consumer can be exposed to adverse drug events (ADEs), which are defined as any harm occurring during drug therapy.
The overall aim of the study was to generate information and form recommendations to optimise communication pathways and access to accurate medication information between and for stakeholders (secondary care, general practice and community pharmacy) and consumers of a clozapine shared care service. The study was designed to assess the completeness and accuracy of consumer medication records held by shared care stakeholders and to describe the experiences of the consumers.
This was an exploratory mixed methods study undertaken in two parts. Firstly, a quantitative approach was used to examine secondary and primary care medication records in a public MH service setting. Fifty-five consumers (aged 18–65 years) prescribed clozapine under shared care were eligible to participate. Information from medication and dispensing records was used by a pharmacist to compile a best possible medication history for each consumer. Discrepancies were identified through reconciliation of stakeholder records with the medication history. Discrepancies were defined as an omission, addition, or administration discrepancy (difference in dose, frequency, or clozapine brand).
Thirty-five consumers who had previously consented to review of their medication records were then eligible to participate in Part Two of the study. Participants completed a semi-structured interview that included a number of questionnaires. The questionnaires focused on beliefs about illness and medicines, adverse effects, medication adherence and treatment burden, while the interview focused on advantages and disadvantages of clozapine, shared care, and communication pathways. Analysis was descriptive and thematic.
In Part One, 35 (63.5%) consumers consented to review of their records. Overall, 32 of the 35 consumers had at least one discrepancy in their records, with a mean of 4.9 discrepancies per consumer. Of 172 discrepancies, 127 (73.8%) were omissions. Primarily, concomitant medicines were omitted in 19/35 (54%) of secondary care records, while clozapine was omitted in 13/32 (40.6%) of community pharmacy records. In Part Two, 10/35 (28.6%) consumers agreed to participate in an interview. Findings included a low level of treatment burden with minimal adverse effects and medium-to-good adherence. Four inter-related themes surrounding treatment in the clozapine shared care program were identified: (i) understanding of illness and recovery; (ii) positive outcomes of treatment; (iii) treatment burden and acceptance and (iv) communication pathways. All participants described a positive experience with treatment in the clozapine shared care program, citing the efficacy of clozapine and the GP relationship as major benefits. Other findings included the fact that consumers were mostly unaware of any communication that took place between their shared care clinicians and assumed that clinicians had access to accurate medication information.
In summary, discrepancies were highly prevalent in the shared care medication records of clozapine consumers in this service, however participants reported positive treatment outcomes. Improved documentation and timely access to accurate and complete medication records for shared care stakeholders is needed to reduce the risk for suboptimal clinical decision-making and ADEs. Expanding the pharmacist's role in this setting could improve timeliness and accuracy in medication-related documentation and communication and make shared care an option for a wider group of clozapine consumers.Thesis (Masters)
Master of Philosophy (MPhil)
School of Human Serv & Soc Wrk
Griffith Health
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Mateus, Luiza Silva. "Efeitos in vitro do antipsicótico clozapina sobre a reatividade da aorta torácica de ratos Wistar". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17137/tde-08112018-153716/.
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Introdução: Em pacientes deprimidos, a mortalidade cardíaca devido à doença cardíaca coronária (CHD) é duas vezes maior do que em pacientes coronarianos nãodeprimidos, possivelmente devido à presença de disfunção endotelial. Pode haver uma associação entre a utilização de drogas antipsicóticas e doenças cardiovasculares, que são associadas à disfunção endotelial vasotônica. Os estudos relacionados aos efeitos das drogas antipsicóticas sobre a função endotelial vascular são praticamente inexistentes. Objetivo: Esse estudo foi delineado para avaliar os mecanismos envolvidos na reatividade vascular dependente do endotélio sob ação da droga antipsicótica atípica clozapina. Materiais e método: As curvas concentraçãoresposta em anéis pré-contraídos com PE (1 ?M), foram registradas na presença e na ausência de inibidores dos inibidores L-NAME e indometacina, os quais foram incubados, isolados e/ou em associação, por 30 minutos. Para estudar a participação dos canais para K+ foram realizados experimentos com os bloqueadores Tetraetilamonio e Cloreto de potássio (Kcl). Para finalizar o protocolo foram realizados experimentos com bloqueadores da guanilato ciclase (ODQ e azul de metileno) e os inibidores dos canais de K+ (apamina, paxilina e glibenclamida). Resultados: A clozapina causou relaxamento dependente do endotélio envolvendo as três vias de relaxamento (GMPc/NO, AMPc/PGI2 e hiperpolarização). Essa observação foi embasada na ineficiência dos bloqueadores, L-NAME, Indometacina e Tetraetilamônio (TEA), respectivamente. O relaxamento dependente do endotélio foi atenuado pela associação L-NAME/Indometacina e abolido em vasos contraídos por cloreto de potássio e incubados com glibenclamida. Conclusão: Estes resultados sugerem que há participação sinérgica, provavelmente através de um mecanismo de cross-talk, dos sistemas cAMP, cGMP e hiperpolarização. Portanto, mais estudos sobre possíveis funções endoteliais relacionadas aos efeitos colaterais dos antipsicóticos cardiovasculares seriam uma direção de pesquisa adequada.Objective: In depressed patients, cardiac mortality due to coronary heart disease (CHD) is twice as high as in non-depressed coronary patients, possibly due to the presence of endothelial dysfunction. There may be an association between the use of antipsychotic drugs and cardiovascular diseases, which are associated with vasotonic endothelial dysfunction. Studies related to the effects of antipsychotic drugs on vascular endothelial function are practically non-existent. Aims: This study was designed to evaluate the mechanisms involved in endothelium-dependent vascular reactivity under the action of the atypical antipsychotic drug clozapine. Method: As concentration-response curves in pre-contracted rings with PE (1 ?M), they were recorded in the presence and absence of inhibitors of the L-NAME and indomethacin inhibitors, which were incubated, isolated and / or in association, for 30 minutes. To study the participation of the K + channels, experiments were performed with the tetraethylammonium and potassium chloride (Kcl) blockers. In order to obtain the protocol they were performed with guanylase cyclase blockers (ODQ and methylene blue) and K + channel inhibitors (apamina, paxilin and glibenclamide). Results: Clozapine caused endothelium-dependent relaxation as the three relaxation pathways (cGMP / NO, cAMP / PGI2 and hyperpolarization). This observation was based on the inefficiency of the blockers, L-NAME, Indomethacin and Tetraethylammonium (TEA), respectively. Endothelium-dependent relaxation was attenuated by the association LNAME / Indomethacin and abolished in vessels contracted by potassium chloride and incubated with glibenclamide. Conclusion: These results suggest that there is synergistic participation, probably through a cross-talk mechanism, of the cAMP, cGMP and hyperpolarization systems. Therefore, more studies of possible endothelium function related to cardiovascular antipsychotics side effects would be a proper research direction.
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Semedo, Agostinho Tavares. "Avaliação da influência dos polimorfismos CYP2C19*2 e CYP2C19*17 na resposta ao tratamento à clozapina na esquizofrenia". Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/6899.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Clozapine (CLZ) has been an antipsychotic of choice in treatment refractory schizophrenia (TRS). However, around 30% of the patients do not respond appropriately to this antipsychotic, being in this way, super-refractory schizophrenia (SRS). Genetic polymorphisms from cytochrome P450 enzymes can influence the metabolism of drugs and individual variability therapeutic response. Considering CYP2C19 a polymorphic enzyme with second major participation in the metabolism of CLZ, the aim of the present study was to analyse the influence of CYP2C19*2 and *17 polymorphisms in the response to the treatment to CLZ. The present study included 69 schizophrenic patients and 137 healthy individuals as a control group. Genotyping test and analysis of polymorphisms was done using sequencing technique and enzymatic restriction (RFLP) for patients and control’s group respectively. The results showed a major distribution of CYP2C19*17 polymorphism in patients’s group in comparison to control’s group. The CYP2C19*2 polymorphism was significantly higher in patients with TRS than to patients with SRS. The CYP2C19*17 polymorphism in heterozygous (CYP2C19*1/*17) was associated to higher clozapine’s doses in polytherapy and less efficient therapeutic response in SRS patients’s group, while the CYP2C19*2 was associated to lower clozapine’s doses in monotherapy and good therapeutic response in TRS patients’s group. In addition, parameters like daily mean clozapine dose, symptons severity according to Brief Psyquiatric Rating Scale (BPRS) and female individuals were also associated to super-refractoriness response to CLZ having a major distribution in SRS patients’s group. These findings suggest that new treatment strategies must be evaluated for the patients carriers of CYP2C19*17 polymorphism with SRS, above all the female individuals. Future studies with larger sample should be relevant to give more consistence to these findings.
A clozapina (CLZ) é um antipsicótico de escolha no tratamento de esquizofrenia refratária (ER). No entanto, cerca de 30% dos pacientes não respondem adequadamente à este antipsicótico, sendo considerados super-refratários ao tratamento (ESR). Sabe-se que polimorfismos genéticos nas enzimas do citocromo P450 podem influenciar o metabolismo das drogas, interferindo na variabilidade individual de resposta terapêutica. Sendo a CYP2C19 uma enzima altamente polimórfica e com a segunda maior participação no metabolismo da CLZ, o presente estudo visou analisar as influências dos polimorfismos CYP2C19*2 e *17 na resposta ao tratamento à este antipsicótico. O estudo incluiu 69 pacientes diagnosticados com esquizofrenia e 137 indivíduos saudáveis como controle. Utilizou-se a técnica de sequenciamento na genotipagem dos pacientes e a restrição enzimática (RFLP- Restrition Fragment Length Polymorphism) para o controle. Os resultados mostraram uma maior distribuição do polimorfismo CYP2C19*17 no grupo dos pacientes em comparação ao grupo controle. O polimorfismo CYP2C19*2 teve uma maior distribuição no grupo dos pacientes com ER em comparação aos pacientes com ESR. O polimorfismo CYP2C19*17 em heterozigose (CYP2C19*1/*17) estava associado à maior dose de CLZ em politerapia e resposta terapêutica menos eficiente no grupo dos pacientes com ESR, enquanto que a CYP2C19*2 em heterozigose estava associado à menor dose de CLZ em monoterapia e à boa resposta terapêutica nos pacientes com ER. Notou-se também uma associação da média da dose diária de CLZ, da gravidade sintomatológica (BPRS) e dos indivíduos do sexo feminino à super-refratariedade de resposta ao tratamento à clozapina tendo esses parâmetros uma maior distribuição no grupo dos pacientes com esquizofrenia super-refratária. Esses achados sugerem que outras estratégias de tratamento sejam avaliadas para os pacientes portadores do polimorfismo CYP2C19*17 diagnosticados com ESR, sobretudo os do sexo feminino. Futuros estudos com amostras mais alargadas seriam relevantes para dar uma maior consistência a esses achados.
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Sausen, Tiago Rafael. "Desenvolvimento de comprimidos de clozapina obtidos pelo método de compressão direta". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2007. http://hdl.handle.net/10183/10879.
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O presente trabalho teve como objetivo o desenvolvimento de formulação para produção de comprimidos contendo 25 mg de clozapina através do método de compressão direta. A clozapina é utilizada no tratamento da psicose e consta na lista do Programa de Medicamentos Distribuídos em Caráter Excepcional do Ministério da Saúde. Para o desenvolvimento proposto, foi utilizado um desenho experimental do tipo desenho composto central a fim de avaliar a influência dos adjuvantes estearato de magnésio e croscarmelose sódica nas características dos comprimidos obtidos a partir de formulações que continham, além destes dois adjuvantes, dióxido de silício coloidal, celulose microcristalina e lactose spray-dried. Os complexos farmacêuticos formados apresentaram boa capacidade de escoamento e compactação e geraram comprimidos com parâmetros de qualidade dentro dos limites estabelecidos pelos códigos oficiais. A dureza e a friabilidade dos comprimidos foram mais suscetíveis à concentração de estearato de magnésio, enquanto que o tempo de desintegração sofreu maior influência da concentração de croscarmelose sódica. A eficiência de dissolução dos comprimidos também foi influenciada pela croscarmelose sódica, sendo que os comprimidos apresentaram perfis de dissolução característicos de formas farmacêuticas de liberação imediata. Dessa forma, através da comprovação da rápida dissolução dos comprimidos e da comparação das curvas de dissolução do medicamento de referência e do teste, verificou-se que a formulação contendo 4,41 % de croscarmelose, 1,59 % de estearato de magnésio, além de 0,5 % de dióxido de silício coloidal e uma mistura de celulose microcristalina e lactose (70:30 m/m), apresentou equivalência farmacêutica em relação ao medicamento de referência.It was the aim of this work to develop tablets containing 25 mg of clozapine by direct compression. Clozapine is used in psychoses treatment and is included on Brazilian Healthy Ministry Program of drugs exceptionally distributed. To this purpose, a composite central design was used to estimate the influence of the excipients magnesium stearate and sodium croscarmelose on the characteristics of tablets containing additionally, colloidal silicon dioxide, microcrystalline cellulose and spraydried lactose. The pharmaceutical mixtures obtained demonstrated good flowing and compaction capacity. Additionally, the tablets produced quality parameters within the limits established by official codex. Hardness and friability were more susceptible to magnesium stearate concentration, while disintegration time was influenced by sodium croscarmelose concentration. The dissolution efficiency was also influenced by sodium croscarmelose. Additionally, the dissolution profiles of the tablets suggest an immediate release mechanism of clozapine. Our results demonstrated that the formulation containing 4,41 % of sodium croscarmelose, 1,59 % of magnesium stearate, 0,5 % of colloidal silicon dioxide and a mixture of microcrystalline cellulose and spray-dried lactose (70:30 w/w) is pharmaceutically equivalent to the reference product.
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Mariet, Yves. "Neuroleptiques classiques et atypiques : utilisation de la clozapine au centre hospitalier Charles Perrens de Bordeaux". Bordeaux 2, 1993. http://www.theses.fr/1993BOR23095.
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Heff, Brigitte. "Dosage de la clozapine (Leponex (R)) et de la déméthylclozapine dans le plasma : méthodologie et intérêt dans le suivi thérapeutique de 23 patients". Bordeaux 2, 1998. http://www.theses.fr/1998BOR2P028.
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WACQUIER, SOPHIE. "Clozapine - agranulocytose et effets indesirables : etude aux hopitaux universitaires de strasbourg". Strasbourg 1, 1993. http://www.theses.fr/1993STR15054.
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Smith, Judith Anne. "The discriminative stimulus properties of psychotomimetics and antipsychotics". Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367805.
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Llorca, Pierre-Michel. "Contribution des approches quantitatives et pharmacologiques a l'etude de la schizophrenie resistante (doctorat)". Clermont-Ferrand 1, 2001. http://www.theses.fr/2001CLF1MM23.
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Salamanca, Ayda Luz Malaver. "Análise da influência dos polimorfismos 1236C>T, 2677G>T/A E 3435C>T do gene ABCB1 na resposta ao tratamento com clozapina". Universidade Federal de Goiás, 2015. http://repositorio.bc.ufg.br/tede/handle/tede/5291.
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Clozapine (CLZ) is the antipsychotic drug of choice in treatment refractory schizophrenia (TRS), however 30% of the patients with TRS don’t have full response to treatment with CLZ, these patients are considered to have super refractory schizophrenia (SRS). The response variability to treatment with CLZ may be associated with alterations of the CLZ plasma levels promoted by 1236C>T, 2677G>T/A e 3435C>T ABCB1 gene polymorphisms. ABCB1 is a transmembrane glycoprotein of transport, which export drugs from the intracellular to the extracellular space. ABCB1 polymorphisms cause structurally and functional protein changes that influence the intracellular CLZ levels and, consequently, promoting therapy failure. This work had the aim to establish the relation between the 1236C>T, 2677G>T/A e 3435C>T ABCB1 polymorphisms and the CLZ treatment response. This study included a total of 68 patients, 34 of whom were classified as TRS (CLZ responders) and 34 as SRS (CLZ non-responders). All patients were in use of CLZ for at least one year. For the genotype test was extracted genomic DNA, following for PCR and sequencing techniques. It was not observed any differences in allelic and genotype distribution between 1236C>T, 2677G>T/A and 3435C>T polymorphisms between RS and SRS groups. The polymorphisms not influenced the CLZ dose level, and percentage of BPRS change. In the same way, the results not showed relation between age, coffee intake, smoking behaviors and ethnicity and the CLZ treatment response, however, was evidenced a higher proportion of female patients in the SRS group when compared with the TRS group. In opposite, a lower proportion of male patients was observed in the SRS than the TRS group. Taken together, the results here obtained showed no association between 12361236C>T, 2677G>T/A e 3435C>T polymorphisms of ABCB1 gene and failure to CLZ treatment.
Clozapina (CLZ) é um antipsicótico de segunda geração, indicada no tratamento de esquizofrenia refratária (ER). Apesar de ser o fármaco de escolha nestes pacientes, 30% deles não respondem satisfatoriamente à terapia com CLZ, constituindo o grupo de indivíduos portadores de esquizofrenia super-refratária (ESR). A variabilidade na resposta ao tratamento com CLZ pode estar relacionada a alterações na farmacocinética da CLZ influenciadas pelos polimorfismos 1236C>T, 2677G>T/A e 3435C>T do gene ABCB1 . ABCB1 é uma proteína transportadora de membrana, que promove a passagem de fármacos do meio intra ao extracelular. Os polimorfismos de ABCB1 podem causar mudanças estruturais ou na expressão proteica, influenciando nas concentrações intracelulares de CLZ e contribuindo para o sucesso ou o fracasso da terapia. O presente trabalho teve como objetivo avaliar a associação entre os polimorfismos 1236C>T, 2677G>T/A e 3435C>T de ABCB1 com a resposta ao tratamento à CLZ. Um total de 68 pacientes em uso de CLZ, 34 portadores de ER e 34 de ESR, foram incluídos no estudo. Os testes de genotipagem foram realizados através da extração do DNA genômico, PCR e sequenciamento. Não foi observada diferença na distribuição alélica e genotípica dos polimorfismos de ABCB1, entre os grupos ER e ESR, assim mesmo não foi observada relação entre os polimorfismos estudados com a dosagem de CLZ e a gravidade psicopatológica avaliados pela escala BPRS. Fatores como consumo de café, cigarro, idade e etnia não influenciam na resposta ao tratamento com a CLZ. Foi evidenciada maior presença de pacientes do gênero feminino no grupo ESR em relação ao grupo ER e maior presença de indivíduos do gênero masculino no grupo ER quando comparado com o grupo ESR. O conjunto dos resultados aqui obtidos demonstram que não há associação entre os polimorfismos 1236C>T, 2677G>T/A e 3435C>T do gene ABCB1 com a refratariedade ao tratamento com CLZ.
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Malesieux, Frédéric. "Schizophrénies résistantes et clozapine : étude rétrospective sur 24 malades de l'évolution des symptômes positifs et négatifs au travers des échelles S.A.P.S et S.A.N.S. d'Andreasen; facteurs pronostiques de la réponse au traitement". Bordeaux 2, 1993. http://www.theses.fr/1993BOR2M114.
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Wasley, Rachel A. "A longitudinal study : clozapine versus risperidone in the management of chronic schizophrenia /". Title page, contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09ARPS/09arpsw319.pdf.
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Matthiasson, Páll. "Dealing with treatment resistance to clozapine : characteristics of treatment response in schizophrenia". Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/dealing-with-treatment-resistance-to-clozapine--characteristics-of-treatment-response-in-schizophrenia(f43c968b-8789-44e7-9161-3cab811ee429).html.
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Background: Clozapine, the treatment of choice in treatment-resistant schizophrenia, is not effective in up to half of patients. Aims of this thesis were: to verify whether clozapine augmentation with amisulpride, an atypical antipsychotic with preferential affinity at doparninergic D2-like receptors, is clinically effective; to test the prediction that changes in D2-like receptor availability might explain that improvement; to explore clinical and receptor availability characteristics of good clozapine responders. Methods: Study 1: Thirty-three patients with schizophrenia, partially or non-responsive to clozapine, had augmentation with amisulpride using an open label design. Study 2: Ten patients recruited from study 1 underwent 123I_IBZM SPET scans at baseline and after 10-12 weeks on amisulpride augmentation, to assess striatal D2-like receptor binding potential. Ten matched controls had one 123I-IBZM scan. Scanning was carried out using a Picker Prism 3000XP triple headed SPET camera. Study 3: Ten "good" responders to clozapine monotherapy were matched to patients in study 2 and had one 123I-IBZM scan. Results: Study 1: Twenty-eight subjects (85%) completed 6 months' augmentation. There was a statistically significant improvement from baseline in clinical rating scales and no change in side-effects. 71% and 32% of patients showed a 20% and 50% reduction in BPRS respectively. Study 2: Patients had mean striatal D2-like receptor occupancy of 47% at baseline, which increased with amisulpride augmentation to 59%. Study 3: Clozapine responders were on much lower doses of clozapine (331 mg/day) with lower s-clozapine levels (0.26 ng/L). Their D2-like occupancy was 45%. Conclusion: The augmentation led to substantial improvement in both positive and negative symptoms and was well tolerated. It raised D2-like binding to likely "threshold levels" for response. Some patients require both the broad receptor occupancy profile of clozapine and a higher degree of D2-like receptor occupancy than can be provided by clozapine alone.
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AUDY, VERONIQUE. "Clozapine et prise de poids : etude prospective chez quinze patients schizophrenes resistants". Clermont-Ferrand 1, 1994. http://www.theses.fr/1994CLF1M033.
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MURSCHEL, ALAIN. "La clozapine : effets indesirables ; etude dans les chs de la region alsace". Strasbourg 1, 1993. http://www.theses.fr/1993STR15084.
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Gomes, Felipe Villela. "Tratamento repetido com canabidiol atenua alterações comportamentais e moleculares em um modelo de esquizofrenia baseado no antagonismo dos receptores NMDA". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17133/tde-05012016-224242/.
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Dados pré-clínicos e clínicos indicam que o canabidiol (CBD), um composto não-psicotomimético presente na planta Cannabis sativa, induz efeitos tipo-antipsicóticos. No entanto, poucos estudos em animais de laboratório investigaram as propriedades antipsicóticas do tratamento repetido com CBD. As alterações comportamentais induzidas pelo tratamento repetido com antagonistas dos receptores glutamatérgicos do tipo N-metil-D-aspartato (NMDA) têm sido propostas como um modelo animal de esquizofrenia. Evidências sugerem que uma hipofunção dos receptores NMDA estaria envolvida nos sintomas positivos, bem como nos sintomas negativos e cognitivos da esquizofrenia. Assim, no presente estudo, nós avaliamos se o tratamento repetido com CBD atenuaria as alterações comportamentais e moleculares induzidas pela administração crônica de um desses antagonistas, o MK-801. Camundongos C57BL/6J receberam injeções intraperitoneais diárias de MK-801 (0,1, 0,5 ou 1 mg/kg) durante 14, 21 ou 28 dias. Vinte e quatro horas após a última injeção, os animais foram submetidos ao teste de inibição pelo pré-pulso (PPI). Posteriormente, foi avaliado se o tratamento repetido com CBD (15, 30 e 60 mg/kg) atenuaria o prejuízo no teste de PPI induzido pelo MK-801 (1 mg/kg; por 28 dias). O tratamento com CBD iniciou-se no sexto dia após o início da administração de MK-801 e continuou até o final do tratamento. Nós também avaliamos se o tratamento com CBD atenuaria as alterações comportamentais induzidas pelo MK-801 nos testes de interação social e reconhecimento de objeto. Imediatamente após os testes comportamentais, os cérebros dos animais foram removidos e processados para posterior avaliação de alterações moleculares. Foram avaliadas as alterações na expressão das proteínas FosB/FosB e parvalbumina, um marcador de atividade neuronal e uma proteína de ligação ao cálcio expressa em uma subclasse de interneurônios GABAérgicos, respectivamente. Alterações na expressão do RNAm para o gene da subunidade obrigatória GluN1 do receptor NMDA (GRN1) também foram avaliadas. Adicionalmente, um número crescente de estudos indica que condições neuroinflamatórias e células gliais, como microglia e astrócitos, parecem estar envolvidas na patogênese da esquizofrenia. E, devido ao fato que o CBD, além de suas propriedades antipsicóticas, também induz efeitos anti-inflamatórios e neuroprotetores, nós também avaliamos possíveis alterações na expressão de NeuN (um marcador neuronal), Iba-1 (um marcador de microglia) e GFAP (um marcador de astrócitos) induzidas pelos tratamentos. Os efeitos do CBD foram comparados àqueles induzidos pelo antipsicótico atípico clozapina. A administração de MK-801, na dose de 1 mg/kg, por 28 dias induziu um prejuízo no teste de PPI, um efeito atenuado pelo tratamento repetido com CBD (30 e 60 mg/kg). Adicionalmente, o CBD também foi capaz de atenuar os prejuízos nos testes de interação social e reconhecimento de objeto induzidos pelo MK-801. Além das alterações comportamentais, o tratamento repetido com MK-801 aumentou a expressão da proteína FosB/FosB e diminuiu a expressão da parvalbumina no córtex pré-frontal medial (CPFm). Uma diminuição da expressão do mRNA para GRN1 no hipocampo também foi observada. O tratamento com MK-801 resultou ainda em aumento no número de astrócitos GFAP-positivos no CPFm e na porcentagem de células microgliais Iba-1-positivas apresentando um fenótipo reativo no CPFm e hipocampo dorsal, mas sem alterar o número total de células Iba-1-positivas. Nenhuma alteração no número de células NeuN-positivas foi observada. Assim como para as alterações comportamentais, as alterações moleculares induzidas pelo MK-801 também foram atenuadas pelo CBD. Entretanto, o CBD por si só não induziu qualquer efeito. Além disso, os efeitos do CBD foram semelhantes àqueles induzidos pelo tratamento repetido com clozapina. Estes resultados indicam que o tratamento repetido com o CBD, semelhante à clozapina, atenuou as alterações comportamentais tipo-esquizofrenia e as alterações moleculares observadas após a administração repetida de um antagonista dos receptores NMDA. Estes dados reforçam a proposta de que o CBD possui propriedades antipsicóticas. Embora os possíveis mecanismos de ação envolvidos nesses efeitos não estejam completamente elucidados, eles poderiam envolver as propriedades antiinflamatórias e neuroprotetoras do CBD. Além disso, nossos dados suportam a visão de que a inibição da microglia ativada pode ser benéfica para a melhora dos sintomas da esquizofreniaPreclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate NMDA receptor antagonists have been proposed as an animal model of schizophrenia-like symptoms. Evidence suggests that NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. In the present study we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular changes induced by chronic administration of one of these antagonists, MK-801. Male C57BL/6J mice received daily intraperitoneal injections of MK-801 (0.1, 0.5 or 1 mg/kg) for 14, 21 or 28 days. Twenty-four hours after the last injection animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30 and 60 mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1 mg/kg; 28 days). We also evaluate if the repeated CBD treatment would attenuate the MK-801-induced behavioral changes in social interaction and novel object recognition tests. CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the behavioral tests, the mice brains were removed and processed to evaluate molecular changes. We measured changes in FosB/FosB and parvalbumin expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in the mRNA expression of the NMDA receptor GluN1 subunit gene (GRN1) were also evaluated. Additionally, an increasing number of data has linked schizophrenia with neuroinflammatory conditions, and glial cells, such as microglia and astrocytes, have become increasingly attractive as candidates accounting for the pathogenesis of schizophrenia. And besides its antipsychotic properties, CBD also induces anti-inflammatory and neuroprotective effects. Thus, we also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. MK-801 administration at the dose of 1 mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60 mg/kg) attenuated MK801-induced PPI impairment. CBD treatment also attenuated the impairment in social interaction and NOR tests induced by MK-801 treatment. Besides behavioral disruption, MK-801 treatment increased FosB/FosB expression and decreased parvalbumin expression in the mPFC. A decreased mRNA level of GRN1 in the hippocampus was also observed. Repeated MK-801 treatment also increased the number of GFAP-positive astrocytes in the mPFC and increased the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. In addition, no change in the number of NeuN-positive cells was observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDA receptor antagonist. These data reinforce the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms
36
Mongeot, Alexandre. "Synthèse, réactivité et intérêts pharmacologiques de nouvelles imidazo[-x]azines et de nouveaux imidazoles". Strasbourg 1, 2006. http://www.theses.fr/2006STR13254.
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Naghmeh, Jabarizadekivi. "A Comparison of the Effect of Omeprazole and Rabeprazole on Clozapine Serum Concentrations". University of Sydney, 2008. http://hdl.handle.net/2123/2471.
Texto completo da fonteResumo:
Master of PhilosophyClozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.
38
Masellis, Mario. "Pharmacogenetic analysis of serotonin receptors and clinical response to clozapine in schizophrenia patients". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29323.pdf.
Texto completo da fonte
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Taylor, David Michael. "Pharmacoepidemiological and pharmacokinetic aspects of the use of clozapine and olanzapine - optimising therapy". Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404765.
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Frimat, Bruno. "Contribution a l'etude du metabolisme de la clozapine : consequences cliniques (doctorat : pharmacie clinique)". Lille 2, 2000. http://www.theses.fr/2000LIL2P260.
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Philibin, Scott D. "The Discriminative Stimulus Properties of the Atypical Antipsychotic Clozapine in C57BL/6 Mice". VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1318.
Texto completo da fonteResumo:
Serotonin and α1 adrenergic receptor antagonism may contribute to atypical antipsychotic drug effects. Clozapine (2.5 mg/kg) drug discrimination in C57BL/6 mice may selectively screen atypical antipsychotic drugs. Previous data show that the atypical antipsychotics olanzapine, risperidone, ziprasidone but not the typical antipsychotic haloperidol fully substitutes for clozapine. The present study demonstrated that the atypical antipsychotics quetiapine, sertindole, zotepine, iloperidone, melperone fully substituted for clozapine but aripiprazole did not. The typical antipsychotics fluphenazine and perphenazine failed to fully substitute for clozapine but chlorpromazine and thioridazine fully substituted for clozapine. This model does not differentiate between atypical and typical antipsychotic drugs but it may be useful in the detection of antipsychotics with potent serotonin and α1 adrenergic receptor antagonist actions.
42
Naghmeh, Jabarizadekivi. "A Comparison of the Effect of Omeprazole and Rabeprazole on Clozapine Serum Concentrations". Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2471.
Texto completo da fonteResumo:
Clozapine is a drug of choice for treatment of refractory schizophrenia, which is primarily metabolized by Cytochrome P450 1A2 (CYP1A2). Norclozapine is its main metabolite. There are reports of wide ranging gastrointestinal side effects associated with clozapine therapy, that result in concomitant administration of proton pump inhibitors to treat acid-related disorders. Omeprazole is an established CYP1A2 inducer, while an in vitro study has shown that rabeprazole is much less potent in this regard. There is no available information about the impact of rabeprazole on CYP1A2 activity in patients. Firstly, this information is essential when prescriptions are changed from omeprazole to rabeprazole to reduce medication costs. Therefore, the aim of this study was to compare the effects of rabeprazole and omeprazole on CYP1A2-mediated clearance (CL/F) of clozapine. Secondly, the effective dosage of clozapine varies widely among patients, making it necessary to individualize drug therapy with clozapine. The reason for dosage variation could be due to the influence of patient-related variables on clozapine plasma concentrations. Therefore, another aim of this study was to investigate the relationship between patient variables, such as age, gender, cigarette smoke, weight and body mass index and clozapine clearance (CL/F). A cross-over study design was used for this study. Twenty patients from Macquarie hospital who were receiving clozapine and rabeprazole (with no other interacting medications) were recruited in this study. Blood samples were taken at 30 min, 1 hr, 2 hr and 12 hr after a dose of clozapine. Rabeprazole was then replaced with omeprazole. After at least 1 month blood samples were again collected at the above corresponding intervals after clozapine. The plasma concentrations of clozapine and norclozapine were determined by high performance liquid chromatography. Abbottbase Pharmacokinetic Systems Software, which utilizes Bayesian forecasting, was used to estimate pharmacokinetic parameters of clozapine. The ratio of plasma norclozapine/clozapine concentrations at trough level was used to reflect CYP1A2 activity. No difference was observed in clozapine clearance (CL/F) and CYP1A2 activity during concurrent therapy with either rabeprazole or omeprazole. According to some studies CYP1A2 induction by omeprazole is dose dependent. Furthermore, since rabeprazole is a weak CYP1A2 inducer in vitro, we conclude that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40 mg/day). Hence, replacement of omeprazole with rabeprazole at conventional therapeutic dosages (20 or 40 mg daily) offers no advantages in the management of patients with schizophrenia on clozapine and no dose adjustment is required. Consistent with previous studies, clozapine concentrations were found to be significantly lower in cigarette smokers due to CYP1A2 induction. No relationship was found between age, gender, or weight and clozapine clearance (CL/F). However, body mass index showed a significant negative correlation with clozapine clearance (CL/F). Since weight gain and lipid accumulation are common side effects of clozapine they may be associated with a reduction of CYP1A2 activity and clozapine clearance (CL/F). Moreover, high lipoprotein levels may decrease the unbound fraction of clozapine and decrease the availability of clozapine for oxidation by cytochrome P450 enzymes. Therefore, it is concluded that omeprazole and rabeprazole may not induce CYP1A2 activity when used at conventional therapeutic dosage (<40mg/day). Hence, replacement of omeprazole with rabeprazole does not require the dose of clozapine to be adjusted. Moreover, the negative correlation between clozapine clearance (CL/F) and BMI is informative. Further studies are now required to clarify the relationship between BMI, lipoprotein levels and clozapine clearance in patients with schizophrenia.
43
Joly, Florence. "Inhibition de l'hyperlocomotion provoquée par l'amphétamine chez le rat : comparaison du profil d'activité des antipsychotiques typiques à celui des antipsychotiques atypiques". Paris 5, 1995. http://www.theses.fr/1995PA05P081.
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Teixeira, Eduardo Henrique 1969. "Clozapina no tratamento da agressividade patológica grave em crianças e adolescentes com transtorno de conduta ou com autismo". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311601.
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Orientador: Paulo DalgalarrondoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: Comportamento agressivo pode ser a principal manifestação clínica de Transtorno de Conduta (TC) e Autismo e deve ser cuidadosamente manejado na criança e adolescente, considerando os possíveis prejuízos e a evolução para transtornos psiquiátricos graves na idade adulta. A clozapina se mostrou eficaz no controle da agressividade em crianças e adolescentes com esquizofrenia. Objetivos: Fazer uma análise detalhada dos resultados do uso clínico naturalístico da clozapina no manejo da agressividade patológica grave em TC e Autismo e seu impacto no funcionamento global dos casos estudados. Método: Sete crianças/adolescentes com diagnóstico de TC e quatro com diagnóstico de Autismo foram acompanhados durante seguimento ambulatorial em uso de clozapina por um período de 26 semanas para controle de agressividade patológica grave. Foram avaliadas periodicamente através das escalas CGI e CBCL. Resultados: O resultado foi positivo com dose média de clozapina de 375,0 mg/dia (± 202,2) principalmente em relação à agressividade afetiva/impulsiva, independente do diagnóstico. Em apenas um caso de TC os níveis de agressividade se mantiveram inalterados. A agressividade predatória/pró-ativa teve diminuição apenas parcial. As alterações hematológicas ficaram dentro dos limites de segurança. Conclusões: A clozapina se mostrou eficaz, foi bem tolerada e não ocorreram reações adversas graves, podendo ser considerada um recurso terapêutico útil nos casos em que os níveis de agressividade são muito elevados ou foram esgotadas outras abordagens terapêuticas. Esse antipsicótico se mostrou mais eficiente nos padrões de agressividade do tipo impulsiva/afetiva, portanto, esse tipo de agressividade parece poder ser manejada farmacologicamente e a clozapina é uma opção viável
Abstract: Introduction: Aggressive behavior can be the main clinical manifestation of Conduct Disorder (CD) and Autism, and has to be carefully approached in children and adolescents, since it may lead to serious psychiatric disorders in adulthood. Clozapine has proved effective in controlling aggressive behavior in schizophrenic children and teenagers. Objectives: Make a detailed analysis of the results of the naturalistic clinical use of Clozapine to control serious aggressive behavior in CD and Autism and its the global impact on patients. Method: Seven adolescents diagnosed with CD and four with Autism treated with Clozapine were followed during a period of 26 weeks to control severe aggressive behavior. They were analyzed periodically on the CGI and CBCL scale. Results: The results were positive with a medium doze of clozapine of 375,0 mg/day (± 202,2), specially in the cases affective/impulsive aggressiveness, regardless the diagnosis. In just one case of CD the levels of aggressiveness didn't change. The predatory/pro-active kind of aggressiveness experienced only partial reduction. The hematological alterations remained within safe limits. Conclusion: Clozapine was helpful, easily accepted and there weren't important adverse reactions. It can be considered a useful resource in cases where the levels of aggressiveness are extreme or there are no other therapeutic ways. This antipsychotic drug has show to be more effective in the impulsive/affective type of aggressive disorder. Therefore, this kind of aggressiveness seems to be controllable by pharmaceutical means and Clozapine is a viable option
Doutorado
Saude Mental
Doutor em Ciências Médicas
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Júnior, Antônio Reis de Sá. "Caracterização dos sintomas obsessivo-compulsivos em pacientes com esquizofrenia em uso de clozapina ou haloperidol". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-29012009-135612/.
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Métodos: Foi utilizado o SCID-IP para o diagnóstico de esquizofrenia e do TOC. Sessenta pacientes responderam às escalas DY-BOCS, Y-BOCS, PANSS e CGI. Os testes Qui-quadrado com correção de Yates, Mann-Whitney U e Kruskal-Wallis foram usados na análise estatística. Resultados: Dentre os sessenta pacientes avaliados, dez (16,7%) apresentavam critérios diagnósticos pelo DSM-IV para esquizofrenia e TOC; treze (21,7%) tinham SOC, mas não TOC e trinta e sete (61,6%) não tinham TOC ou SOC. A prevalência de TOC ou SOC foi semelhante em pacientes tomando clozapina ou haloperidol (40% VS 35%, respectivamente). Contudo, pacientes tomando clozapina apresentaram maior gravidade dos SOC quando comparados aos pacientes tomando haloperidol. (P= 0.027). Pacientes com esquizofrenia e TOC apresentaram maior gravidade dos sintomas da esquizofrenia quando comparados aos pacientes com esquizofrenia sem SOC (P= 0.002). Conclusões: Apesar da presença de SOC ou TOC ter sido semelhante entre os grupos tomando clozapina ou haloperidol, pacientes em uso de clozapina apresentaram escores mais elevados na YBOCS. Estes resultados podem sugerir uma associação entre a exacerbação do fenômeno obsessivo-compulsivo e o uso de clozapina. Pacientes com esquizofrenia e TOC apresentaram uma maior gravidade dos sintomas da esquizofrenia comparativamente aos demais gruposObjective: We conducted a cross-sectional study to compare the prevalence and severity of obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) in patients with schizophrenia treated with clozapine or haloperidol. Methods: SCID-I/P was used for the diagnoses of schizophrenia and OCD. Sixty subjects completed Y-BOCS, PANSS and CGI scales. Chi-square with Yates correction, Mann-Whitney U and Kruskal-Wallis tests were used for the statistical analyses. Results: Among the sixty schizophrenia patients evaluated, ten (16,7 %) met DSM-IV criteria for both schizophrenia and OCD; thirteen (21,7 %) had OCS but not OCD and thirty-seven (61,6 %) had neither OCD nor OCS. The prevalence of OCD or OCS was similar in patients taking clozapine or haloperidol (40% vs 35%, respectively). However, patients using clozapine showed higher severity of OCS than patients using haloperidol (P= 0,027). Patients with schizophrenia and OCD also showed higher severity of schizophrenic symptoms when compared to patients with schizophrenia without OCS (P= 0,002). Conclusions: Although the presence of OCS or OCD was similar between the groups taking clozapine or haloperidol, patients using clozapine showed higher scores in the YBOCS. These results may support an association between the exacerbation of obsessive-compulsive phenomena and the use of clozapine. Patients with schizophrenia and OCD showed a higher severity on psychotic symptoms than the other groups
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Mortimer, Ann M. "The neuropsychology of chronic severe schizophrenic patients treated with clozapine versus treatment as usual". Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/29435.
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Introduction: The cognitive effects of antipsychotic drugs represent a potential exploratory tool with which to investigate theoretical models of schizophrenia. According to the `levels of explanation' model, the manipulation of cognition of drugs, reflecting prior changes in brain physiology, should result in symptomatic change. Clozapine is superior to other antipsychotic drugs in the treatment of the symptoms of schizophrenia, but there was little support for the proposition that this was because of superior improvements in cognition. This study aimed to investigate this question in severely ill patients with major cognitive deficits. Additionally since data collection commenced (1993) cognition had become established as the most important determinant of social function in schizophrenia. The methodology of the study allowed for a prospective appraisal of this tissue. Method: This was an open naturalistic study. 26 chronic schizophrenic long stay inpatients began clozapine or stayed on treatment as usual according to clinical decision. Symptoms, cognition (rated independently) and social function were comprehensively assessed at baseline, six months, one year and two years. Results: At baseline the groups were similar on most measures. Clinical response rates in the clozapine group were consistent with the literature, and were better than expected in the treatment as usual group. There were striking improvements in symptoms and social function on clozapine which overall appeared early into the two year period. By contrast, no aspects of cognition improved significantly on clozapine, although there were some between group differences which overall occurred later in the study. Comparing clinical responders with non-responders across both groups did not change the cognitive results. Analyses suggested that gains in personal function were related to negative symptoms, not to cognition. Conclusions: The `levels of explanation' model of schizophrenia was not supported. This is discussed in terms of the alternative `domains' model, and the possible impact of symptom severity on cognition in these patients. In conclusion symptomatic relief and control should remain, at least in severely ill schizophrenic patients, the primary focus of therapeutic effort.
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Freitas, Pedro Henrique Batista de. "Refractory Schizophrenia: Prevalence of Metabolic Syndrome and Quality of Life of Patients Using Clozapine". Instituto Nacional de Pesquisas da Amazônia, 2018. http://bdtd.inpa.gov.br/handle/tede/2640.
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Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP
Observou-se prevalência de SM em 47,2% da amos tra, com predomínio entre as mulheres (58,8%). Pacientes com SM apresentaram percentuais mais elevados de alterações, principalmente em relação à glicemia e triglicérides. O uso de quatro ou mais medicamentos e a presença de sobrepeso e obesidade estiveram associados à SM. Além disso, pacientes com a síndrome apresen taram um histórico de menos internações psiquiátricas, comparados àqueles que não a possui.
Observou-se prevalência de SM em 47,2% da amos tra, com predomínio entre as mulheres (58,8%). Pacientes com SM apresentaram percentuais mais elevados de alterações, principalmente em relação à glicemia e triglicérides. O uso de quatro ou mais medicamentos e a presença de sobrepeso e obesidade estiveram associados à SM. Além disso, pacientes com a síndrome apresen taram um histórico de menos internações psiquiátricas, comparados àqueles que não a possui.
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Humbert-Claude, Marie. "Relations histamine-dopamine : implication du récepteur H₃ en neuropsychiatrie". Université Paris XI, 2010. http://www.theses.fr/2010PA114864.
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Des interactions entre le système histaminergique et le système dopaminergique ont été rapportées dans de nombreuses études. Dans un premier travail, nous avons exploré les interactions entre le récepteur histaminergique H₃ et dopaminergique D₂ co-exprimés dans le striatum. Nos résultats suggèrent que ces deux récepteurs n'interagissent pas au travers de leur couplage aux protéines G, mais montrent que leur activation est additive. Dans la schizophrénie, l'hyperhistaminergie qui accompagne l'hyperdopaminergie pourrait donc coopérer avec cette dernière pour générer les symptômes psychotiques. Dans une seconde étude, nous nous sommes intéressés à la clozapine, un anti-psychotique dont le mécanisme d'action reste encore à préciser. Les récepteurs histaminergiques pourraient jouer un rôle dans les psychoses et/ou l'action des neuroleptiques, mais leur implication dans le profil atypique de la clozapine était inconnue. Nos résultats montrent que la clozapine et son métabolite actif, la N-desmethylclozapin, interagissent avec les quatre récepteurs histaminergiques aux doses thérapeutiques. Ces interactions pourraient rendre compte en partie du profil atypique de la clozapine, mais aussi du profil de ses effets indésirables comme la sédation, la prise de poids ou l'hématotoxicité. Dans une troisième étude, nous avons exploré les propriétés prokinétiques potentielles du ciproxifan, un agoniste inverse H₃ de référence, dans un modèle animaI de la maladie de Parkinson : Les rats lésés par 6-OHDA. Les effets prokinétiques que nous avons pu observer supportent des propriétés anti-parkinsoniennes des agonistes inverses H₃. Ce travail soutient donc l'utilisation des agonistes inverses H₃ en thérapeutique, d'autant plus qu'ils sont connus pour améliorer les déficits cognitifs, fréquemment rencontrés dans la maladie de Parkinson et dans la schizophrénieSeveral studies showed interactions between histaminergic and dopaminergic system. The first study explored the interactions between H₃ receptors (H₃Rs) and D₂ receptors (D₂Rs), two G-protein coupled receptors co-expressed in the striatum. Our results suggest that they do not interact through their coupling ta G-proteins, but their activations are addictive. A hyperactivity of histaminergic and dopaminergic neurons being observed in schizophrenia, their additive activations may cooperate to generate some schizophrenic symptoms. Ln a second study, we considered the unique clinical profile of the antipsychotic clozapine, not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown. Our results showed that clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation, weight gain and hemato-toxicity. Ln a third study, we explored the abillty of ciproxifan, a reference H₃-receptor inverse agonist, to improve akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, a reference animal model of Parkinson's disease. Prokinetics effects of ciproxifan support anti-parkinsonian properties of H₃R inverse agonists. This work on H₃R inverse agonists supports their therapeutic interest inasmuch as they are known to improve cognitive deficits, frequently encountered in Parkinson's disease or schizophrenia
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Guitton-Simon, Claire. "Pharmacocinétique de la clozapine et de ses métabolites après administrations réitérées chez le patient schizophrène". Montpellier 1, 2001. http://www.theses.fr/2001MON13506.
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La première partie de notre mémoire est consacrée à l'analyse des données actuellement disponibles sur la pharmacocinétique et la pharmacologie de la clozapine. La deuxième partie concerne la partie analytique de notre travail. Une méthode de dosage de la clozapine et de ses métabolites (norclozapine et clozapine N-oxyde), dans le plasma et les érythrocytes, par chromatographie liquide à haute performance et détection dans l'ultra-violet a été mise au point. La troisième partie de notre travail concerne l' étude pharmacocinétique de la clozapine et de ses métabolites chez le patient schizophrène ; c'est la première étude qui rapporte le profil pharmacocinétique de ces molécules dns les érythrocytes. Ils reçoivent 200 à 900 mg/jour de clozapine, en deux ou trois prises, par voie orale. La variabilité intra et inter-individuelle des paramètres pharmacocinétiques est importante. Les rapports moyens (concentrations érythocytaires / concentrations plasmatiques) sont respectivement de 23, 61. 4, et 81,3% pour la clozapine, la norclozapine et la clozapine N-oxyde. Les demi-vies d'élimination calculées à partir des données plasmatiques et érothrocytaires sont du même ordre de grandeur : 7-10 h pour la norclozapine, 13-19h por la norclozapine et 7-9h pour la clozapine N-oxyde. Pour la clozapine, le volume de distribution et la clairance totale, déterminés à partir des données plasmatiques et non corrigés de la biodisponibilité, sont respectivement de 6-7 L/kg et 38-40 L/h ; la clairance sanguine totale est en moyenne de 55L/h. Les relations entre concentrations de clozapine et de norclozapine d'une part et entre concentrations de clozapine et de clozapine N-oxyde d'autre part sont de type exponentiel. Entre 200 et 900 mg/jour, la pharmacocinétique de la clozapine est linéaire. La dernière partie de notre travail a consisté à développer un modèle pharmacocinétique permettant l'analyse simultanée des concentrations plasmatiques en clozapine et norclozapine.
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Freitas, Rosana Ramos de. "Avaliação das dimensões psicopatológicas da esquizofrenia resistente e não resistente ao tratamento: estudo transversal multicêntrico internacional". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-31102018-130536/.
Texto completo da fonteResumo:
A Escala das Síndromes Positiva e Negativa (PANSS) é a escala mais amplamente utilizada para a avaliação da gravidade dos sintomas de esquizofrenia. As revisões das análises fatoriais (AFs) da PANSS sugerem que a melhor solução é o modelo de cinco - fatores (em geral os fatores Positivo, Negativo, Desorganização/Cognitivo, Excitação/Hostilidade, Ansiedade/ Depressão). Estudos atuais consideram que seria útil caracterizar a esquizofrenia resistente ao tratamento (ERT) como um subtipo de esquizofrenia, porém não há estudos que comparam adequadamente as dimensões psicopatológicas da PANSS entre pacientes resistentes e não resitentes ao tratamento (ENRT). Há apenas um estudo de análise fatorial exploratória (AFE) da PANSS nesta população. Não há estudos de análise fatorial confirmatória (AFC) em pacientes portadores de esquizofrenia resistente ao tratamento (ERT), a despeito da superioridade deste método quando comparado a AFE. O objetivo do presente estudo foi investigar por meio de análises fatoriais exploratória e confirmatória se a estrutura fatorial da PANSS difere em pacientes com ERT em comparação com ENRT. Foram utilizados dados da PANSS de entrada de 1429 pacientes que participaram do estudo PATTERN (Um Estudo Prospectivo de Não Intervenção em Pacientes com Sintomas Persistentes de Esquizofrenia). Para a definição de ERT, utilizamos um critério pragmático baseado no uso atual de clozapina. A AFE se baseou na extração de componentes principais utilizando a rotação Varimax. O número de fatores foi escolhido de acordo com o critério de Kaiser-Meyer-Oklin (\"autovalor\" igual ou superior a 1). Para a intepretação de cada um dos fatores gerados utilizamos como válida a carga fatorial maior ou igual à 0,5. Para realização da AFC foram utilizados os os seguintes índices: NNFI (non-normed fit index), CFI (comparative fit index), RMEA (root-mean square error of approximation). As análises foram realizadas usando SPSS 23.0 e o programa R versão 3.2.2. Observou-se que pacientes portadores de ERT apresentam características sociodemográficas e clínicas diferentes de pacientes portadores de ENTR, condizente com dados da literatura. A análise fatorial exploratória encontrou um modelo de cinco fatores composto respectivamente pelas seguintes dimensões: Negativa, Positiva, Afetiva, Cognitiva e Excitação nos dois grupos. A Análise Fatorial Confirmatória indicou que o modelo VDGAAG forneceu o melhor ajuste aos dados de ambos os grupos. Apesar da limitação referente à definição de resistência ao tratamento pelo uso de clozapina, nossos resultados mostraram que não há diferença na estrutura fatorial da PANSS em paciente portadores de ERT e ENRT obtida através de AFE e AFC. Os resultados foram condizentes com o único estudo que avaliou a estrutura fatorial da PANSS em pacientes portadores de esquizofrenia resistente ao tratamentoThe Positive and Negative Syndrome Scale (PANSS) is the most widely used scale for assessing the severity of schizophrenia symptoms. The reviews of PANSS factor analyses (FAs) suggest that the best solution is the five-factor model (usually Positive, Negative, Disorganization/Cognitive, Excitement/ Hostility, Anxiety/Depression). Current studies consider that it is useful to characterize treatment resistant schizophrenia (TRS) as a subtype of schizophrenia, but there are no studies that adequately compared the psychopathological dimensions of PANSS among resistant (TRS) and nontreatment resistant patients (NTRS). There is only one exploratory factor analysis (EFA) study of the PANSS in this population. There are no confirmatory factor (CFA) studies in patients with treatment resistant schizophrenia (TRS), despite the superiority of this method when compared to EFA. The present study aimed to investigate by use of EFA and CFA if the factorial structure of PANSS differs between patients with TRS and NTRS. We used baseline PANSS data from 1429 patients who participated in the PATTERN study (A Non Intervention Prospective Study of Patients With Persistent Symptoms of Schizophrenia). For the definition of TRS we used a pragmatic criterion based on the current use of clozapine. The EFA was based on the principal component analysis using the Varimax rotation. The number of factors was chosen according to the Kaiser-Meyer-Oklin criterion (\"eigenvalue\" equal to or greater than 1). For the interpretation of each of the generated factors, we used as valid the factorial load greater or equal to 0.5. The following indexes were used to perform the confirmatory factorial analysis: NNFI (non-normed fit index), CFI (comparative fit index), RMEA (root-mean square error of approximation). The analyzes were performed using SPSS 23.0 and R program version 3.2.2. TRS and NTRS patients presented different sociodemographic and clinical characteristics, consistent with data from the literature. The exploratory factorial analysis found a five factor model composed respectively of the following dimensions: Negative, Positive, Affective, Cognitive and Excitation in both groups. The Confirmatory Factor Analysis indicated that the VDGAAG model provided the best fit to the data of both groups. Despite the limitation regarding the definition of resistance to treatment by the use of clozapine, our results showed that there is no difference in the factorial structure of PANSS in patients with ERT and ENRT obtained through AFE and AFC. The results were consistent with the only study that evaluated the factorial structure of PANSS in patients with treatment-resistant schizophrenia