Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer's disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via pi-pi interactions and (c) possible CH/pi interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme

Contribution of sociodemographic, clinical, and psychological variables to quality of life in women with cervical cancer in the follow-up phase

This study evaluates the contribution of sociodemographic, clinical, and psychological variables to quality of life (QoL) of women with cervical cancer in the follow-up phase. This cross-sectional study, conducted at the Portuguese Oncology Institute of Lisbon, included 200 women with cervical cancer during follow-up. Patients were assessed on QoL (EORTC QLQ-C30), body image and specific symptoms (EORTC QLQ-CX24), psychological morbidity (HADS), social support (SSSS), emotional expression (CECS), and spirituality (SpREUK). Education and social support contributed positively to QoL, whereas body image and symptoms contributed negatively. Body image played a moderating role in the relationship between depression and QoL, but not between anxiety and QoL. Spirituality and emotional expression did not moderate the relationship between anxiety/depression and QoL. Health professionals should reference and monitor women with cervical cancer, providing support at the diagnosis and follow-up phase since physical and psychological symptoms, resulting from the disease, remain after the end of treatment and contribute negatively to their QoL. Interventions should focus on these particular outcomes to promote patients' QoL.(undefined

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark

In silico, NMR and pharmacological evaluation of an hydroxyoxindole cholinesterase inhibitor

From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1 (4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl) methyl) piperidin-1-ium chloride) showed an IC50 of 18 μM for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer’s disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies. Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 µmol.min−1.mg−1) than donepezil (0.112 µmol.min−1.mg−1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min−1.mg−1)

Quality of life in caregivers of patients with multiple myeloma

Objectives: This study aimed to assess the relationship between sociodemographic, clinical, and psychological variables with quality of life (QoL) and the moderating role of caregivers' age and caregiving duration in caregivers of patients with Multiple Myeloma.Method: The sample included 118 caregivers who completed questionnaires that assessed psychological morbidity, satisfaction with social support, coping, burden, unmet needs, and QoL.Results: High psychological morbidity, burden and information, financial and emotional unmet needs were associated with lower QoL, while higher satisfaction with social support and more effective use of coping strategies were associated with better QoL. Women caregivers reported more satisfaction with social support and those who did not choose to care reported greater financial unmet needs and more use of coping strategies. The relationship between caregivers' psychological morbidity/social support and QoL was mediated by emotional needs and double mediated by coping and burden. The caregivers' age moderated the relationship between psychological morbidity/social support and emotional needs.Conclusion: Interventions to support the caregiver's emotional needs to promote their QoL are needed. These should be particularly tailored for older caregivers reporting greater psychological morbidity and younger caregivers less satisfied with their social support, as they have a negative indirect impact on their QoL.Portuguese Associations of Portuguese Association against Leukemia and the PortugueseAssociation of Leukemias and Lymphoma

Indicadores psicossociais da qualidade de vida no cancro de colo do útero

Tese de Doutoramento em Psicologia AplicadaO cancro de colo do útero (CCU) é a quarta patologia oncológica mais comum na mulher portuguesa, com uma incidência de 14.8 por cada 100 mil habitantes, acima da taxa europeia, 13.6/100 000 representando cerca de 33% das mortes anuais por cancro. Este é um tipo de cancro que atinge mulheres muito jovens, 1/3 dos diagnósticos ocorrerem em mulheres com idades abaixo dos 45 anos. Sendo uma patologia de elevada prevalência justifica-se o estudo dos fenómenos físicos, psicológicos e sociais associados de modo a promover um melhor ajustamento à doença. Foi nosso objetivo obter um maior conhecimento sobre esta população, explorar e identificar os fatores que contribuem para a qualidade de vida e ajustamento à doença. A amostra foi constituída por 140 mulheres com idades compreendidas entre os 23 e os 79 anos, com escolaridade média e maioritariamente residentes em meio urbano. Em termos clínicos, a maioria foi diagnosticada em idade fértil nos estádios iniciais do cancro de colo do útero, as mulheres encontram-se em follow-up, na Consulta de Ginecologia do Instituto Português de Oncologia de Lisboa. Os estudos apresentados permitiram-nos determinar quais as variáveis preditoras, mediadoras e moderadoras na qualidade de vida das doentes. Assim, os estudos 1 e 3 enfatizaram a importância da morbilidade psicológica, suporte social e imagem corporal na qualidade de vida, em mulheres sobreviventes de CCU. Por sua vez, os estudos 2 e 4 permitem-nos concluir que as relações diádicas são críticas quer para a satisfação sexual quer para a qualidade de vida. Do ponto de vista das políticas de saúde será importante averiguar o que pode ser implementado para minimizar o impacto financeiro do CCU, uma vez que as questões financeiras podem condicionar os próprios cuidados de saúde ou mesmo a adesão às recomendações médicas. Do ponto de vista psicológico, os programas de suporte e intervenção psicológica com o objetivo de promover a qualidade de vida devem focar-se na redução da morbilidade psicológica, no aumento do suporte social e, em particular, na imagem corporal e estilos de vinculação. Além disso, os resultados revelaram a importâncias das variáveis conjugais indicando a importância de tratar estas mulheres, no contexto da diada.Cervical cancer (CC) is the fourth most common cancer pathology among Portuguese women, with an incidence of 14.8 per 100,000 inhabitants, above the European rate, 13.6 / 100 000 representing about 33% of annual cancer deaths. This is a type of cancer that affects very young women, one third of diagnoses occur in women under the age of 45 years. Being a condition of high prevalence it is justified the study of physical, psychological and social phenomena associated to the promotion of a better adjustment to the disease. This study is aimed to describe the psychosocial effects of the diagnosis of cervical cancer. It was our goal to get a better understanding of this population, explore and identify the factors that contribute to the quality of life and adjustment to illness. It was intended therefore, in addition to a socio-demographic and clinical description, describe and assess sexual satisfaction, physical and psychological morbidity, emotional expression, marital adjustment, attachment, social support, spirituality and quality of life of patients undergoing various therapeutic modalities for the treatment of cervical cancer. The sample of 140 women aged between 23 and 79 years, with an average education and mainly living in an urban environment. Clinically, most were diagnosed in childbearing age in the early stages of cervical cancer, women are in follow-up in Gynecology Consultation of the Portuguese Institute of Oncology of Lisbon, the elapsed time since the end of the treatment is on average higher than 18 months, 68% of patients underwent surgery, and in 23.6% the surgical treatment was combined with radiotherapy or chemoradiotherapy. When comparing the results with the European reference data, we have disclosed that, with the exception of cognitive functioning scale, there are no differences between the two groups. However, symptoms such as neuropathy and breathlessness show statistically significant differences (more neuropathy complaints and fewer complaints of breathlessness in this study). An important point regards the economic impact that the disease has on the lives of these women, being significantly higher in the present study. The presented studies have allowed us to determine which are the predictor mediating and moderating variables, in the quality of live of the patients. Thus, Study 1 focused on the predictors of the quality of life, having anxiety and social support emerged as important predictors. Study 2 intended to find an adjusted model to allow to know the role of the predictor and mediator of different variables in the quality of life of women, having shown that marital adjustment and anxiety are important mediators. Without visible changes in the body image, we assess to what extent the changes caused by the treatments had impact on women and, thus, Study 3 focused on moderating role of body image, factor that has demonstrated being a moderator in relation to the experience of symptoms / depression and quality of life. Being sexuality such an important area in these women, it was also possible to establish an explanatory model of sexual satisfaction. Thus, Study 4 sought to find an adjusted model to the data that revealed the role of attachment styles as a predictor variable as well as the mediating role of marital adjustment in sexual satisfaction. In short, studies 2 and 4 allow us to conclude that the dyadic relationships are critical both for sexual satisfaction and for the quality of life. On the other hand, studies 1 and 3 emphasize the importance of psychological morbidity, social support and body image in the quality of life in women survivors of cervical cancer. From the point of view of health policies it will be important to find out what can be done to minimize the financial impact of the cervical cancer, since financial issues can condition their own health care or even the adherence to medical recommendations. From a psychological point of view, support programs and psychological intervention in order to promote quality of life, should focus on reducing psychological morbidity, increasing social support and, in particular, on body image and attachment styles. In addition, the results have disclosed the importance of marital variables indicating the importance of treating these women, in the context of dyad

Promoção da qualidade de vida em doentes oncológicos

Tese de mestrado em Psicoterapia e Psicologia da Saúde apresentada à F.P.C.E.U.L., 1997Na presente investigação pretende-se conhecer as significações/crenças dos indivíduos acerca dos seus problemas de saúde; as estratégias de confronto utilizadas para fazer face aos constrangimentos que esses mesmos problemas de saúde impõem; qual o sistemas de significações/crenças que contribuem para a avaliação que o indivíduo faz da sua qualidade de vida. E ainda, promover a qualidade de vida dos doentes portadores de doença oncológica. Facilitando-lhes o uso de modos de confronto mais adaptativos com os problemas de saúde e as limitações/incapacidades por eles impostas. Tal como foi referido no Capítulo II, existem vários aspectos fisiológicos e psicológicos da doença oncológica e seus tratamentos, que condicionam a qualidade de vida do doente. Um dos primeiros problemas que se coloca ao investigador é a definição dos conceitos. Como se viu no Capítulo III existem várias definições do construto "qualidade de vida", e nem todas são possíveis de ser operacionalizáveis. Neste trabalho optou-se pela definição proposta por Cella e Tuisky (1988): qualidade de vida é "a apreciação e satisfação que o doente tem com o seu funcionamento actual quando comparado com aquele que ele considera possível ou ideal". Tendo-se partido da premissa de que a variável qualidade de vida é multidimensional. Assim, a avaliação do funcionamento do indivíduo deverá contemplar as várias vertentes da sua vida. Ao longo dos últimos anos têm surgido vários estudos sobre qualidade de vida, e tal como se salienta no Capitulo III, todos eles revelam ser eficazes. A diferença entre o presente estudo e os seus antecessores prende-se com os modelos teóricos que o sustentam. Tal como foi discutido no Capítulo IV, a presente investigação insere-se no modelo construtivista e desenvolvimentista de Joyce-Moniz. Assim, considera-se o indivíduo como construtor activo das suas crenças/significações. E numa lógica desenvolvimentista considera-se ainda que as significações individuais se ordenam por niveis. Sendo a manutenção das significações ou a sua mudança feita à custa de operações dialéticas. Ao proceder a uma leitura desenvolvimentista das significações de qualidade de vida, pretende-se encontrar o nível desenvolvimentista global do indivíduo, ou seja, qual é o nível preferencial de funcionamento de cada indivíduo e quais os movimentos dialécticos utilizados para a manutenção das significações perturbadoras. Esta leitura desenvolvimentista foi feita com base na análise de entrevistas individuais. Tendo sido abordados cinco temas: Sintomas físicos e/ou psicológicos e efeitos secundários; Adesão ao tratamento; Estado de funcionamento físico; Estado de funcionamento psicológico; e Estado de funcionamento social. O modelo de intervenção utilizado neste trabalho foi explicitado no Capítulo V. Recorrendo ao modelo de "grupos temáticos" e ao Construtivismo pretendia-se promover no indivíduo competências para o confronto efícaz com os seus problemas, através do ensino de estratégias de resolução de problemas, diálogo assertivo e técnicas para o controlo da dor. A intervenção, descrita no Capítulo V, foi programada de modo a ser realizada simultaneamente à avaliação obtida através da entrevista. Pretendia-se com este estudo atingir os seguintes objectivos específicos: 1. Avaliar a eficácia do programa de intervenção no que respeita à redução de reacções emocionais e à melhoria da qualidade de vida, comparando para o efeito, os resultados obtidos pelos indivíduos na pré-avaliação, (momento de avaliação dos indicadores clínicos antes de se iniciar o programa interventivo), pós-avaliação (momento de avaliação dos indicadores clínicos uma semana após o termino do programa interventivo) e follow-up, (momento de avaliação três meses após o termino do programa). 2. Avaliar a eficácia do programa de intervenção no que respeita à redução de reacções emocionais e à melhoria da qualidade de vida, procedendo a uma comparação entre os resultados obtidos pelos indivíduos do grupo de intervenção e os do grupo de controlo, não submetido a qualquer tipo de intervenção psicoterapêutica, mas submetido a avaliação dos mesmos indicadores clínicos. 3. Proceder a uma caracterização desenvolvimentista das significações individuais da amostra em estudo, quanto ao nível de desenvolvimento socio-cognitivo e acções dialécticas utilizadas e sua relação com a eficácia do programa de intervenção. 4. Pretende-se a partir da leitura desenvolvimentista efectuada estabelecer a relação entre o nível desenvolvimentista dos indivíduos e o tipo de operações dialécticas utilizadas por estes. Os resultados obtidos foram apresentados no Capítulo VI. A discussão dos objectivos e das hipóteses que lhe estão subjacentes, apresentadas no Capítulo VII, levam-nos a concluir que o programa de intervenção implementado não atingiu os objectivos clínicos a que se propunha. No final deste trabalho são feitas sugestões para que no futuro se possa colmatar alguns dos problemas que se verificaram existir. Assim, propõe-se a criação de um programa de intervenção alongado no tempo, que acompanhe a vida do doente

Validation of the Short‐Form Survivor Unmet Needs Survey in older patients with myeloma

Background: Multiple myeloma (MM) affects mainly the older population and is the second most prevalent haematologic cancer. MM patients’ unmet needs are diverse, arise at different stages, and are associated with greater psychological distress. This study examined the psychometric properties of the Short-Form Survivor Unmet Needs Survey (SF-SUNS) in Portuguese MM patients. Methods: This cross-sectional study included 213 MM patients. The internal consistency of the scale was analyzed with Cronbach’s α. Principal component analysis and confirmatory factor analysis were used to assess construct validity. Convergent validity was examined by using correlations with quality of life, satisfaction with social support, and psychological morbidity. Multiple regression analyses were conducted to explore the contribution of sociodemographic and clinical variables to unmet needs. Results: The Portuguese SF-SUNS’s factor structure follows the original’s structure, although it includes fewer items. For each domain, Cronbach’s α was ≤0.70, the minimum acceptable criterion. For construct validity, only unmet relationship and emotional needs had significant correlations (r ≥ 0.40)—specifically negative associations with quality of life and social support and positive associations with psychological morbidity. Regarding patient variables and SF-SUNS results, only cancer stage contributed significantly to unmet information needs, with patients at stage I reporting more needs than patients at stage III. Conclusions: The SF-SUNS represents a valid and reliable tool to assess unmet needs among Portuguese MM patients. It may be useful in designing and monitoring interventions to improve well-being in cancer survivors.This study was supportedby a grant from the Portuguese Association againstLeukaemia and the Portuguese Association of Leu-kaemias and Lymphomas.info:eu-repo/semantics/publishedVersio