Desenvolvimento de organogel injetável subcutâneo de Pluronic®-F127 e lecitina de soja (OPL) contendo meloxicam para uso veterinário / Development of a veterinary organogel formulation containing soy lecithin, Pluronic® F-127 and meloxicam for the treatment of acute and chronic pain in small animals

O organogel é formado por uma matriz tridimensional composta de filamentos que se auto-organizam em uma rede entrelaçada e que, por seu tipo de estrutura, pode ser utilizado com o objetivo de atuar como um implante que se forma in situ, sendo capaz de se comportar como uma forma farmacêutica de liberação prolongada. Esse trabalho tem, por tanto, o objetivo desse trabalho foi desenvolver, caracterizar, quantificar e traçar perfis de dissolução para formulações de organogel contendo meloxicam como principio ativo. O material está dividido em quatro capítulos, sendo apresentada inicialmente (I) revisão da literatura a respeito da lecitina de origem vegetal, com suas principais fontes de obtenção, como soja, girassol e colza, e também seu uso farmacêutico na obtenção de formulações como organogéis, microemulsões e lipossomas. Os demais capítulos abordam (II) desenvolvimento e otimização de uma formulação de organogel contendo lecitina de soja e Pluronic® F-127 como formadores da matriz tridimensional e meloxicam como principio ativo. (III) Desenvolvimento e validação de um método de quantificação do teor de meloxicam por cromatografia líquida de alta eficiência (CLAE). (IV) Desenvolvimento de um método de dissolução para formulações de organogel, que fosse capaz de ser utilizado na caracterização do perfil de dissolução de diferentes formulações. Com os resultados obtidos, foi possível desenvolver formulações de organogel contendo lecitina de soja, Pluronic® F-127 e meloxicam, assim como um método analítico validado para as analises de teor. Por fim, foram obtidos também os perfis de dissolução de duas formulações mais promissoras

Organogels are formed by a three-dimensional matrix composed of filaments that selforganize in an interlaced network and that, due to its type of structure, can be used with the objective of acting as an implant that forms in situ, being able to behave as an extendedrelease dosage form. This work has, therefore, the objective of this work was to develop, characterize, quantify and trace dissolution profiles for organogel formulations containing meloxicam as active ingredient. The material is divided into four chapters, initially presented (I) review of the literature on lecithin of plant origin, with its main sources of production, such as soybean, sunflower and rapeseed, and also its pharmaceutical use in obtaining formulations such as organogels , microemulsions and liposomes. The remaining chapters address (II) development and optimization of an organogel formulation containing soy lecithin and Pluronic® F-127 as three-dimensional matrix formers and meloxicam as an active ingredient. (III) Development and validation of a method for quantification of meloxicam content by high performance liquid chromatography (HPLC). (IV) Development of a dissolution method for organogel formulations, capable of being used to characterize the dissolution profile of different formulations. With the results obtained, it was possible to develop organogel formulations containing soy lecithin, Pluronic® F-127 and meloxicam, as well as a validated analytical method for content analysis. Finally, the dissolution profiles of two more promising formulations were also obtained

Low back pain prevalence in Parkinson's disease / Prevalência da dor lombar na doença de Parkinson

ABSTRACT BACKGROUND AND OBJECTIVES: Low back pain is a non-motor symptom commonly reported by individuals with Parkinson's disease. The aim of this study was to identify the prevalence of low back pain and its characteristics in individuals with Parkinson disease from a specialized treatment center. METHODS: Individuals with idiopathic Parkinson's disease answered a questionnaire for the assessment of clinical parameters and associated pain symptoms. Pain intensity was assessed using the visual analog scale. RESULTS: One hundred and twenty-three patients with mean age 68.1±11.8 years, and disease duration of 7.0±4.9 years, answered the questionnaire. Pain was reported by 102 (82.9%) patients: 71 (57.7%) had low back pain and 31 (25.2%) had pain in other body segments. There was no difference in age, education, time of Parkinson's disease symptoms and diagnosis when comparing individuals with and without pain, as well as individuals with pain in other segments and low back pain. The group with low back pain had pain in a greater number of body segments in addition to the lumbar region, with longer duration of this symptom and more frequent use of analgesic drugs. In the low back pain group, women had greater pain intensity. CONCLUSION: The results show the high prevalence of pain in individuals with Parkinson's disease, specifically low back pain.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor lombar é um sintoma não motor comumente relatado por indivíduos com doença de Parkinson. O objetivo deste estudo foi identificar a prevalência de dor lombar e suas características em indivíduos com doença de Parkinson em um centro de tratamento especializado. MÉTODOS: Indivíduos com doença de Parkinson idiopática responderam a um questionário para a avaliação de parâmetros clínicos e sintomas de dor associados. A intensidade da dor foi avaliada utilizando a escala analógica visual. RESULTADOS: Cento e vinte e três pacientes com idade média de 68,1±11,8 anos e duração média da doença de 7,0±4,9 anos responderam o questionário. A dor foi relatada por 102 (82,9%) pacientes: 71 (57,7%) com dor lombar e 31 (25,2%) com dor em outros segmentos corporais. Não houve diferença quanto à idade, escolaridade, tempo de sintomas e de diagnóstico da doença de Parkinson ao comparar os indivíduos com e sem dor, assim como indivíduos com dor em outras regiões e dor lombar. O grupo com dor lombar queixava-se de dor em maior número de segmentos corporais além da região lombar, com maior tempo de duração desse sintoma e uso mais frequente de analgésicos. Dentre os indivíduos do grupo com dor lombar, as mulheres apresentavam maior intensidade da dor. CONCLUSÃO: Os resultados mostraram alta prevalência da dor em indivíduos com doença de Parkinson, especificamente da dor lombar.

Can fatigue predict walking capacity of patients with Parkinson's disease?

Although fatigue is an expressive symptom of Parkinson's disease (PD), few studies have investigated the association between fatigue, mobility and walking capacity of these patients. OBJECTIVE: To investigate whether fatigue is an independent factor associated with mobility and the walking capacity in patients with PD. METHODS: Forty-eight patients with PD (22 with fatigue) were tested for mobility and their walking capacity: Timed Up and Go (TUG), 10-Meter Walk Test (10MWT) at usual and fastest speed, and 6-Minute Walk Test (6MWT). Fatigue was measured with Parkinson's Fatigue Scale (PFS-16). Linear regression analysis was used to investigate if fatigue is an independent factor contributing to variance in mobility and walking capacity. RESULTS: There was a positive correlation between PFS-16 and TUG (rs=0.385; p=0.007). There was a negative correlation between PFS-16 and 10MWT at comfortable (r=-0.385; p=0.007) and fast speeds (r=-0.396; p=0.005), and 6MWT (r=-0.472; p=0.001). Linear regression analysis revealed that fatigue did not explain the variance of TUG and 10MWT. PFS-16, age and section III of UPDRS explained 49.6% (adjusted R2; p<0.001) variance in the 6MWT, and fatigue was the most significant predictor (F=-32.1; p=0.022). CONCLUSIONS: Fatigue is an independent factor contributing to the distance covered during 6MWT in patients with PD. Our results highlight the importance of recognition and management of this symptom.

Can fatigue predict walking capacity of patients with Parkinson's disease? / A fadiga pode predizer a mobilidade e a capacidade de marcha em pacientes com doença de Parkinson?

ABSTRACT Although fatigue is an expressive symptom of Parkinson's disease (PD), few studies have investigated the association between fatigue, mobility and walking capacity of these patients. Objective: To investigate whether fatigue is an independent factor associated with mobility and the walking capacity in patients with PD. Methods: Forty-eight patients with PD (22 with fatigue) were tested for mobility and their walking capacity: Timed Up and Go (TUG), 10-Meter Walk Test (10MWT) at usual and fastest speed, and 6-Minute Walk Test (6MWT). Fatigue was measured with Parkinson's Fatigue Scale (PFS-16). Linear regression analysis was used to investigate if fatigue is an independent factor contributing to variance in mobility and walking capacity. Results: There was a positive correlation between PFS-16 and TUG (rs=0.385; p=0.007). There was a negative correlation between PFS-16 and 10MWT at comfortable (r=-0.385; p=0.007) and fast speeds (r=-0.396; p=0.005), and 6MWT (r=-0.472; p=0.001). Linear regression analysis revealed that fatigue did not explain the variance of TUG and 10MWT. PFS-16, age and section III of UPDRS explained 49.6% (adjusted R2; p<0.001) variance in the 6MWT, and fatigue was the most significant predictor (F=-32.1; p=0.022). Conclusions: Fatigue is an independent factor contributing to the distance covered during 6MWT in patients with PD. Our results highlight the importance of recognition and management of this symptom.

RESUMO Embora a fadiga seja um sintoma importante na doença de Parkinson (DP), poucos estudos investigaram a associação entre fadiga, mobilidade e capacidade de marcha nesses pacientes. Objetivo: Investigar se a fadiga é um fator independente associado à mobilidade e à capacidade de marcha em pacientes com DP. Métodos: Quarenta e oito pacientes com DP (22 com fadiga) foram avaliados com testes de mobilidade e capacidade de marcha: Timed Up and Go (TUG), Teste de Caminhada de 10 metros (T10m) na velocidade usual e máxima, Teste de Caminhada de Seis Minutos (TC6m). A fadiga foi medida pela Escala de Fadiga no Parkinson (PFS-16). A análise de regressão linear foi utilizada para investigar se a fadiga é um fator independente que contribui para a variação na mobilidade e capacidade de marcha. Resultados: Houve correlação positiva entre PFS-16 e TUG (rs=0,385; p=0,007). Houve correlação negativa entre PFS-16 e T10m na velocidade usual (r=-0,385; p=0,007) e máxima (r=-0,396; p=0,005) e TC6m (r=-0,472; p=0,001). Análise de regressão linear revelou que a fadiga não explicava a variância do TUG e T10m. A PFS-16, a idade e a seção III da UPDRS explicaram 49,6% (R2 ajustado, p<0,001) da variância no TC6m e a fadiga foi o preditor mais significativo (F=-32,1; p=0,022). Conclusões: A fadiga é um fator independente que contribui para a distância percorrida durante o TC6m em pacientes com DP. Nossos resultados destacam a importância do reconhecimento e manejo desse sintoma.

Caracterização da dor em pacientes com doença de Parkinson / Pain characterization of Parkinson's disease patients

FUNDAMENTO: A dor é um sintoma não motor frequente em indivíduos com doença de Parkinson (DP). Pode estar associada aos sinais motores ou surgir no início da doença. Os mecanismos subjacentes à dor na DP ainda não são bem elucidados e muitos fatores podem influenciá-la, como o uso de levodopa e a presença de outros sintomas não motores, como depressão. OBJETIVOS: Descrever a prevalência e caracterizar a dor em pacientes com DP de um centro terciário referência em pesquisa e assistência clínica. MÉTODOS: Foram recrutados pacientes com diagnóstico de DP idiopática a partir do ambulatório de neurologia do Centro de Especialidades Médicas (CEM) da Santa Casa de Belo Horizonte/MG. Um questionário para coleta de dados sociodemográficos e clínicos foi aplicado. A função cognitiva, gravidade dos sinais e sintomas, depressão, distúrbios de sono e fadiga foram avaliados. A dor foi mensurada por meio do Questionário de McGill e Escala Visual Numérica. RESULTADOS: Participaram do estudo 45 pacientes, sendo que 19 (42,2%) apresentavam queixa de dor e, em sua maioria, após o diagnóstico de DP (74%). Não houve diferença entre os grupos com dor e sem dor para os parâmetros clínicos avaliados, com exceção da fadiga que foi mais prevalente (p=0,036) e mais grave (p=0,031) nos pacientes com dor. CONCLUSÃO: A dor é um sintoma prevalente em pacientes com DP atendidos no CEM. A partir dos resultados obtidos pelo McGill, observou-se que a dor crônica e profunda, acometendo principalmente os membros inferiores, com importantes aspectos sensoriais e afetivos, foi comum nos pacientes avaliados.

BACKGROUND: Pain is a common non-motor symptom in Parkinson´s Disease (PD). It can be associated to motor signs or can arise in the beginning of the disease. Mechanisms of pain in PD are not completely understood. Moreover, many factors can interfere, such as use of levodopa and presence of other non-motor symptoms as depression. OBJECTIVES: The aim of this study was to describe prevalence and characterization of pain in PD patients from a research and clinical terciary care center in Belo Horizonte, Minas Gerais, Brazil. METHODS: PD patients from the Neurology Center of Santa Casa Hospital (Belo Horizonte, MG, Brazil) were recruted. Socio-demographic and clinical data were collected. Cognitive function, severity of PD signs and symptoms, depression, sleep disturbance and fatigue were evaluated. Pain was measured by McGill Pain Questionnaire and Visual Numeric Scale (VNS). RESULTS: Forty-five PD patients participated in the study and 42,2% had pain complaints, mostly (74%) after PD diagnosis. No difference between group with pain or without pain for clinical parameters was detected, except for fatigue, which was more prevalent (p=0,036) and more severe (p=0.031) in patients with pain. CONCLUSION: Pain was very prevalent in PD patients from CEM. Results obtained from McGill showed that chronic and deep pain, mostly in lower limbs, with important physical and affective features was very common in this sample of PD patients.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease.

There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease / Os níveis circulantes de fatores neurotróficos não estão alterados em pacientes com doença de Parkinson

ABSTRACT There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

RESUMO Há evidências de que alteracões nas ações exercidas por fatores neurotróficos (FNs) estejam associadas à fisiopatologia da doença de Parkinson (DP). O presente estudo foi conduzido para avaliar os níveis plasmáticos de FNs e suas possíveis associações com sintomas clínicos na DP. Para este fim, 40 pacientes com DP e 25 controles foram submetidos à avaliação clínica e coleta de sangue periférico. Os níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF), pro-BDNF, neurotrofina 3, neurotrofina 4, fator de crescimento do nervo, fator neurotrófico derivado da glia e fator neurotrófico ciliar foram avaliados por ensaio de imunoadsorção enzimática. Não houve diferença significativa entre pacientes com DP e controles quanto aos níveis plasmáticos dos FNs avaliados. Além disso, não encontramos associação entre os níveis dos FNs e duração da doença, grau de comprometimento motor ou funcional, desempenho cognitivo e gravidade dos sintomas depressivos. Em conclusão, embora os FNs possam desempenhar papéis relevantes na fisiopatologia da DP, os níveis circulantes dessas moléculas não estão necessariamente alterados em pacientes com DP.

Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The cause of neurodegeneration in PD is not completely understood, and evidence has shown that inflammatory/immune changes may be involved in PD pathophysiology. Herein, we aimed to determine the profile of the peripheral immune system in patients with PD in comparison with controls. Forty patients with PD and 25 age- and gender-matched controls were enrolled in this study. From these, 23 PD patients and 21 controls were included in the immunophenotyping analyses. Peripheral blood was drawn on the same day of the clinical assessment and submitted to plasma separation for enzyme-linked immunosorbent assay or cytometric bead array. Immunophenotyping analyses of the peripheral blood were performed by flow cytometry. We found that patients with PD presented peripheral immune changes evidenced by decreased percentage of T lymphocytes (CD3+ cells), especially activated T lymphocytes (CD4+CD25+ cells), when compared with controls. In line with these results, we also found decreased plasma levels of the cytokines IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A in the PD group. In vitro experiments demonstrated that the production of cytokines by peripheral blood mononuclear cells harvested from healthy young donors was reduced after exposure to the anti-parkinsonian drugs levodopa and pramipexole. Our data corroborate the hypothesis that immunological mechanisms are involved in PD. It is not clear whether the differences that we have found are due to adaptive mechanisms or to changes associated with PD, including pharmacological treatment, or even directly related to the disease pathophysiology. Future studies are needed in this regard.

In vitro study activity proliferative fibroblast human submitted to treatment Zincummetallicum and Calendula officianlis in homeopathic ultra dilutions

Cicatrization can be divided into three phases: inflammation, fibroblastic, maturation and remodeling [1]. The extracellular matrix may be replaced by a stronger and more elastic connective tissue. In a scar collagen is the major component of the mature connective tissue [2]. In homeopathic area, the greater is the investigated segment ultra dilutions [6]. However, little research has been done to explore the effect of dynamized drugs in in vitro cell culture [4]. Using the Zincum metallicum 6CH and Calendula officinalis 6CH applied independently in different concentrations in fibroblast cultures sought to determine the increase in proliferative activity using techniques such as IC50, MTT, flow cytometry and quantification of collagen. As expected from the literature, ie both homeopathic according to the literature are used for treatments that Require skin healing, both showed increased proliferative activity, having Calendula most cellular response, presenting as cell cycle stimulating checked via flow cytometry.

In vitro study activity proliferative fibroblast human submitted to treatment zincum metallicum and calendula officinalis in ultra dilutions homeopathic

Cicatrization can be divided into three phases: inflammation, fibroblastic, maturation and remodeling [1]. The extracellular matrix may be replaced by a stronger and more elastic connective tissue. In a scar collagen is the major component of the mature connective tissue [2]. In homeopathic area, the greater is the investigated segment ultra dilutions [6]. However, little research has been done to explore the effect of dynamized drugs in in vitro cell culture [4]. Using the Zincum metallicum 6CH and Calendula officinalis 6CH applied independently in different concentrations in fibroblast cultures sought to determine the increase in proliferative activity using techniques such as IC50, MTT, flow cytometry and quantification of collagen. As expected from the literature, ie both homeopathic according to the literature are used for treatments that Require skin healing, both showed increased proliferative activity, having Calendula most cellular response, presenting as cell cycle stimulating checked via flow cytometry.(AU)

Peripheral levels of angiotensins are associated with depressive symptoms in Parkinson's disease.

BACKGROUND: The pathogenesis of PD remains elusive. The renin-angiotensin-system (RAS) has recently been implicated in the degeneration of dopaminergic neurons. This study aimed to compare plasma levels of components of the RAS of individuals with PD with controls. We also investigated the association between these circulating markers and motor, depressive and cognitive parameters. METHODS: Thirty PD patients and twenty controls were subjected to clinical evaluation, including cognitive and depressive symptoms assessment. Plasma levels of Angiotensin (Ang) I, Ang II, Ang- (1-7), angiotensin-converting enzyme (ACE) and ACE2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: PD patients presented lower plasma levels of Ang I, Ang II and Ang- (1-7) than control individuals. Among PD patients, lower circulating levels of angiotensins were associated with increased severity of depressive symptoms. CONCLUSIONS: This is the first study showing that peripheral levels of RAS components are changed in PD and associated with depressive symptoms.

Cognitive Status Correlates with CXCL10/IP-10 Levels in Parkinson's Disease.

Cognitive impairment and depressive symptoms are of great interest in Parkinson's disease (PD), since they are very common and lead to increased disability with poor quality of life. Inflammatory mechanisms have been implicated in PD and its nonmotor symptoms. In the current pilot study, we aimed to evaluate plasma levels of chemokines in PD patients and to analyze the putative association of chemokines with depressive symptoms and cognitive performance. We hypothesized that higher chemokines levels are associated with worse cognitive performance and increased depressive symptoms in PD. For this purpose, 40 PD patients and 25 age- and gender-matched controls were subjected to a clinical evaluation including cognitive and mood tests. Peripheral blood was drawn and plasma levels of CCL2/MCP-1, CCL11/eotaxin, CCL24/eotaxin-2, and CXCL10/IP-10 were measured by enzyme-linked immunosorbent assay. PD patients and control individuals presented comparable plasma concentrations of all the evaluated chemokines. In PD patients, CXCL10/IP-10 plasma levels correlated positively with Hoehn and Yahr staging scale. In addition, the higher CXCL10/IP-10 levels, the worse performance on cognitive tests. Although there was no significant difference between PD patients and control individuals regarding chemokines levels, our preliminary results showed that CXCL10/IP-10 may be associated with cognitive status in PD.