Development of novel active pharmaceutical ionic liquids and salts based on antibiotics and anti-fungal drugs

Ionic Liquids (ILs) are class of compounds, which have become popular since the mid-1990s. Despite the fact that ILs are defined by one physical property (melting point), many of the potential applications are now related to their biological properties. The use of a drug as a liquid can avoid some problems related to polymorphism which can influence a drug´s solubility and thus its dosages. Also, the arrangement of the anion or cation with a specific drug might be relevant in order to: a) change the correspondent biopharmaceutical drug classification system; b) for the drug formulation process and c) the change the Active Pharmaceutical Ingredients’ (APIs). The main goal of this Thesis is the synthesis and study of physicochemical and biological properties of ILs as APIs from beta-lactam antibiotics (ampicillin, penicillin G and amoxicillin) and from the anti-fungal Amphotericin B. All the APIs used here were neutralized in a buffer appropriate hydroxide cations. The cation hydroxide was obtained on Amberlite resin (in the OH form) in order to exchange halides. The biological studies of these new compounds were made using techniques like the micro dilution and colorimetric methods. Overall a total of 19 new ILs were synthesised (6 ILs based on ampicillin, 4 ILs, based on amoxicillin, 6 ILs based on penicillin G and 4 ILs based on amphotericin B) and characterized by spectroscopic and analytical methods in order to confirm their structure and purity. The study of the biological properties of the synthesised ILs showed that some have antimicrobial activity against bacteria and yeast cells, even in resistant bacteria. Also this work allowed to show that ILs based on ampicillin could be used as anti-tumour agents. This proves that with a careful selection of the organic cation, it is possible to provoke important physico-chemical and biological alteration in the properties of ILs-APIs with great impact, having in mind their applications.

Indexing and active fund management: International evidence

Author's pre-print

(Non) - Demand driven servitization: strategic implications for suppliers from incorporating their customers up front

Double Degree. A Work Project, presented as part of the requirements for the Award of a Master’s Degree in Management from NOVA – School of Business and Economics and a Masters Degree in International Business, Strategy and Innovation from Maastricht University

Nutritional assessment and lipid profile in HIV-infected children and adolescents treated with highly active antiretroviral therapy

INTRODUCTION: HIV-infected children and adolescents treated with highly active antiretroviral therapy (HAART) regimens that include a protease inhibitor (PI) can show significant improvements in clinical outcomes, nutritional status and quality of life. The study aimed to report nutritional and metabolic alterations for pediatric patients continuously exposed to HAART and for healthy controls for up to 1 year. METHODS: Clinical, anthropometric, lipid profile and food intake data were collected prospectively over approximately 12-months for each patient. RESULTS: Fifty-one individuals were studied, of these, 16 were healthy. After 12 months follow-up, HIV-positive individuals remained below the healthy control group parameters. No change was observed concerning food intake. Triglyceride serum levels were higher in patients using protease inhibitor at the onset of the study [PI groups: 114 (43 - 336), and 136 (63 - 271) versus control group: 54.5 (20 - 162); p = 0.003], but after twelve months follow-up, only the group using protease inhibitor for up to two months presented higher values [140 (73 - 273) versus 67.5 (33 - 117); p = 0.004]. HDL-cholesterol was lower in HIV-positive individuals [HIV-positive groups: 36 (27 - 58) and 36 (23 - 43); control 49.5 (34 - 69); p = 0.004]. CONCLUSIONS: HIV-infected children and adolescents treated with highly active antiretroviral therapy showed compromised nutritional parameters compared to a paired healthy control group. Individuals using protease inhibitor presented worse triglyceride serum levels compared to their healthy counterparts.

Enteric parasites in HIV-1/AIDS-infected patients from a Northwestern São Paulo reference unit in the highly active antiretroviral therapy era

INTRODUCTION: We describe the epidemiology of intestinal parasites in patients from an AIDS reference service in Northeastern São Paulo, Brazil. METHODS: Retrospective evaluation was done for all HIV-1/AIDS-positive patients whose Hospital de Base/São José do Rio Preto laboratorial analysis was positive for enteroparasites after diagnosis of HIV-1 infection, from January 1998 to December 2008. Statistical analysis was performed using the R statistical software version 2.4.1. The level of significance adopted was 5%. RESULTS: The most frequent protozoan was Isospora belli (4.2%), followed by Giardia lamblia (3.5%), Entamoeba coli (2.8%), and Cryptosporidium parvum (0.3%). Ancylostoma duodenale (1.4%) was the most frequently detected helminth, while Taenia saginata and Strongiloides stercoralis were found in 0.7% of the samples. The results showed that diarrhea was significantly associated with giardiasis and isosporiasis. However, no association was observed between CD4+ cell counts, viral load, and the characteristics of any particular parasite. CONCLUSIONS: Our data may be useful for further comparisons with other Brazilian regions and other developing countries. The data may also provide important clues toward improving the understanding, prevention, and control of enteric parasites around the world.

Active surveillance of American tegumentary leishmaniasis in endemic areas in rural Bolivia

INTRODUCTION: American tegumentary leishmaniasis (ATL), including mucocutaneous leishmaniasis (MCL) and localized cutaneous leishmaniasis (LCL), is endemic in Bolivia. We describe the results of active surveillance of ATL from 2001 to 2006 and assess demographic data related to ATL epidemiology in the Yungas valleys. METHODS: Community-based active ATL surveillance was performed by the institutions SERVIR, CÁRITAS, and the Health Services Department of La Paz, whose files were reviewed retrospectively. A cross-sectional survey was carried out to assess demographic data in two communities. RESULTS: Two thousand nine hundred nine cases of ATL were detected from 2001 to 2006: 2,488 (85.5%) corresponded to LCL and 421 (14.5%) to MCL. A reduction in the proportion of mucosal cases was observed between 2001 and 2006. The proportion of MCL cases increased with age and was higher among males (15.5% versus 12.1%, p=0.018). The rate of positivity via direct observation of the parasite in dermal scrapings and in parasite cultivation was significantly higher for LCL than for MCL (p<0.001 and p=0.009, respectively). The rate of reactivity in the leishmanin skin test was higher in the group with mucosal lesions (p=0.012). The cross-sectional survey showed that 40% of the families had emigrated from the Altiplano. CONCLUSIONS: It is necessary to undertake continuous case detection of ATL in the area, where the disease presents a high rate of mucosal cases. Increasing incidence seems to be associated with immigration and continuous deforestation to expand the crop-growing areas.

Leprosy in Buriticupu, state of Maranhão: active search in the general population

INTRODUCTION: This study was developed to evaluate the situation of leprosy in the general population of the municipality of Buriticupu, State of Maranhão, Brazil. METHODS: We used the method of active search to identify new cases from 2008 to 2010. Bacilloscopy of intradermal scrapings was performed in all patients with skin lesions compatible with leprosy, and histopathological examination in those who had doubts on the definition of the clinical form. RESULTS: The study included 19,104 individuals, with 42 patients diagnosed with leprosy after clinical examination, representing a detection rate of 219.84 per 100,000 inhabitants. The predominant clinical presentation was tuberculoid with 24 (57.1%) cases, followed by borderline with 11, indeterminate with four, and lepromatous with three cases. The study also allowed the identification of 81 patients with a history of leprosy and other skin diseases, such as pityriasis versicolor, dermatophytosis, scabies, vitiligo, and skin carcinoma. The binomial test showed that the proportion of cases in the headquarters was significantly higher than that in the villages (p = 0.04), and the generalized exact test showed that there was no association between age and clinical form (p = 0.438) and between age and gender (p = 0.083). CONCLUSIONS: The elevated detection rate defines the city as hyperendemic for leprosy; the active search for cases, as well as the organization of health services, is an important method for disease control.

Intervenção da fisioterapia após ligamentoplastia do LCA

RESUMO: Objectivo: Este estudo teve por objectivo descrever a prática clínica e os resultados da intervenção da fisioterapia, às 6, 12 e 24 semanas, em indivíduos após ligamentoplastia do LCA. Introdução: O sucesso da ligamentoplastia do LCA está directamente relacionado com a reabilitação após a realização da mesma, permitindo ao utente o retorno a um estilo de vida activo. Apesar de se saber que um programa de reabilitação estruturado e baseado na evidência tem um papel fulcral nos resultados após cirurgia, e de existir consenso sobre a efectividade destes programas após a cirurgia, o mesmo não se pode afirmar acerca de quais os melhores componentes que devem fazer parte desse programa. Tendo em conta a heterogeneidade encontrada na literatura, no que diz respeito à nomenclatura utilizada, às diferenças de duração dos protocolos e às variações significativas nas recomendações dos cuidados de reabilitação, torna-se primordial a realização duma caracterização da prática clínica da fisioterapia em indivíduos submetidos a ligamentoplastia em Portugal, e consequentemente, descrever quais os resultados obtidos ao nível da incapacidade funcional, intensidade de dor e percepção global de melhoria. Metodologia: Realizou-se um estudo de série de casos, com uma amostra de conveniência, do tipo não probabilístico, constituída por 14 utentes referidos para 4 clínicas de fisioterapia e para 3 hospitais, e que cumpriam os critérios de inclusão e exclusão estabelecidos. Os utentes foram avaliados em 4 momentos pré-definidos: na 1ª sessão de fisioterapia e às 6, 12 e 24 semanas após cirurgia. Os resultados obtidos após intervenção da fisioterapia foram descritos ao nível da incapacidade funcional, da intensidade da dor e da percepção global de melhoria. Paralelamente realizou-se uma caracterização da prática clínica relativamente às modalidades utilizadas, número de sessões de tratamento e duração do episódio de cuidados. Resultados: Observou-se uma tendência de melhoria ao longo das 24 semanas em todas as dimensões da Knee injury and Osteoarthritis Outcome Score (KOOS) e na Escala Numérica da Dor (END), assim como na percepção de melhoria pelo utente, medida através da Patient Global Impression of Change Scale (PGIC). Às 6 semanas, as melhorias nas variáveis de resultados foram superiores às encontradas às 12 e 24 semanas, ao nível da incapacidade funcional (à excepção das dimensões KOOS – actividades desportivas e de lazer e KOOS - qualidade de vida) e dor. Relativamente à intervenção da fisioterapia observou-se uma grande heterogeneidade nas modalidades e procedimentos utilizados. Em média realizaram-se 58,14 (±14,15) sessões, sendo que 71 foi o número de sessões mais utilizado. Conclusão: Os resultados deste estudo sugerem que apesar da heterogeneidade da prática clínica, a intervenção da fisioterapia proporciona melhorias ao nível da capacidade funcional e da dor, em indivíduos submetidos a ligamentoplastia do LCA e que essas melhorias são percepcionadas pelos participantes como clinicamente importantes. ---------ABSTRACT: Objective: The aim of this study was to describe the clinical practice and the results of physical therapy intervention, at 6, 12 and 24 weeks, in subjects after ACL reconstruction. Introduction: The success of ACL reconstruction is directly related with the rehabilitation after the surgery, allowing the patient to an active lifestyle return. Despite knowing that a rehabilitation program based on evidence and well designed has a key role in the results after surgery, the same cannot be said about what the best components that should make part of this program. Taking into account the heterogeneity found in the literature, whether at the level of the nomenclature used, whether at level of the differences in duration of the protocols, as well as the existence of recommendations of rehabilitative care that present significant variations at the international level, it becomes paramount to achieving a characterization of the clinical practice of physical therapy in subjects after ACL reconstruction in Portugal, and consequently describe the results obtained regarding to functional disability and pain intensity. Methodology: A case series design with a convenience sample of 14 patients referred to 7 different outpatients physical therapy settings, that fulfilled the pre- established inclusion and exclusion criteria. Patients were evaluated in four pre-defined moments: in the first session of physiotherapy and at 6, 12 and 24 weeks after surgery. The results obtained after physiotherapy intervention were described at the level of functional disability, pain and global perception of change. Subsequently, it was proceeded the characterization the practice of physical therapy regarding to the modalities used, the number of treatment sessions and duration of the episode of care. Results: It was found that there was a trend of improvement, clinically important, over the 24 weeks in all dimensions of Knee injury and Osteoarthritis Outcome Score (KOOS) and in the Numerical Pain Rating Scale (NPRS). At 6 weeks, improvements were superior to those found at 12 and 24 weeks, at the level of functional disability (with the exception of the KOOS-sports and recreation function and KOOS-knee related quality of life dimensions) and pain. As regards the intervention of physical therapy found that the heterogeneity encountered both at the level of clinical practice as evidence,are difficult to compare. On average 58,14 (±14,15) sessions were held, with 71 was the most commonly used sessions numbers. Conclusion: The results of this study suggest that in spite of the heterogeneity of clinical practice, physical therapy intervention provides improvements in terms of functional disability and pain in subjects after ACL reconstruction.

Efetividade de um programa de educação baseado na neurofisiologia da dor e exercício aquático em comparação com um programa de exercício aquático isolado em indivíduos com dor lombar crónica

RESUMO: Introdução e Objetivos: O exercício é uma das modalidades mais utilizadas no tratamento da Dor Lombar Crónica (DLC) mas também a mais recomendada pela literatura atual. Apesar de efetivo, o exercício não parece responder às características cognitivas e comportamentais identificadas nesta população. Assim, existem recomendações para que seja coadjuvado por educação de forma a minimizar a influência nos resultados de variáveis como o medo do movimento. Porém não é conhecido o real impacto nos resultados de um programa educacional quando acrescentado a um programa de exercício. O objetivo deste estudo foi investigar os efeitos de um programa de exercício aquático coadjuvado por educação baseada na neurofisiologia da dor (grupo experimental) comparado a um programa de exercício aquático isolado (grupo controlo), ao nível da intensidade da dor, incapacidade funcional e medo do movimento, em indivíduos com DLC. Metodologia: Sessenta e dois indivíduos com DLC foram aleatoriamente distribuídos pelo grupo experimental (n= 30) e pelo grupo controlo (n= 32). Os participantes de ambos os grupos realizaram um programa de 6 semanas constituído por 12 sessões de exercício aquático. No caso do grupo experimental foram realizadas duas sessões de educação baseada na neurofisiologia da dor (EBN) antes do programa de exercício aquático. As medidas de avaliação primárias foram a intensidade da dor (Escala Visual Análoga) e a incapacidade funcional (Quebec Back Pain Disability Scale). Secundariamente avaliou-se o medo do movimento através da Tampa Scale of Kinesiophobia. Os participantes foram avaliados antes da intervenção, 3 semanas após o início do programa de exercício aquático, no final da intervenção e 3 meses após o final da intervenção. Resultados: Foram encontradas melhorias significativas no final da intervenção ao nível da intensidade da dor e incapacidade funcional em ambos os grupos. Após 3 meses, apenas o grupo experimental apresentou melhorias significativas nas variáveis primárias. Na comparação entre grupos, os resultados foram favoráveis ao grupo experimental para a intensidade da dor nas avaliações após a intervenção (p= 0,032) e após 3 meses (p= 0,007). Quanto à incapacidade funcional e medo do movimento não se verificaram diferenças significativas entre grupos em nenhum momento. Também as medidas de relevância clínica utilizadas (tamanho do efeito; risco relativo; number needed to treat) favoreceram o grupo experimental. Conclusões: Os resultados mostram que um programa de exercício aquático e EBN foi mais efetivo na melhoria da intensidade da dor a curto e médio prazo do que um programa de exercício aquático isolado. Apesar de serem necessárias mais investigações sobre este tema, este estudo demonstra que a EBN pode otimizar os resultados quando associada a outras intervenções ativas como o exercício aquático.----------------ABSTRACT: Introduction and Objectives: Exercise is one of the most used modalities in the treatment of Chronic Low Back Pain (CLBP) but also the most recommended in current literature. Although it’s effective, exercise does not seem to respond to the cognitive and behavioural characteristics identified in this population. Thus, it is recommended to be assisted by education in order to minimize the influence of variables on the results such as the fear of movement. However, the real impact on the results of an educational program when added to an exercise program is not known. The aim of this study was to investigate the effects of a program of aquatic exercise and neurophysiology pain education (experimental group) compared to aquatic exercise program alone (control group), on the outcomes of pain intensity, functional disability and fear of movement in individuals with CLBP. Methodology: Sixty two individuals with CLBP were randomly distributed in the experimental group (n = 30) and in the control group (n = 32). Participants in both groups performed a 6-week program consisting of 12 sessions of aquatic exercise. In the case of the experimental group two sessions of neurophysiology pain education (NPE) were performed before the aquatic exercise program. The primary outcomes were pain intensity (Visual Analogue Scale) and functional disability (Quebec Back Pain Disability Scale). Secondarily, the fear of movement through the Tampa Scale of Kinesiophobia was assessed. Participants were assessed before the intervention, three weeks after the start of the aquatic exercise program, at the end of the intervention and 3 months after the end of the intervention. Results: Significant improvements were found at the end of the intervention in both groups in what intensity of pain and functional disability were concerned. After 3 months, only the experimental group showed significant improvements in the primary outcomes. Comparing both groups, the results favoured to the experimental group for intensity of pain scores after the intervention (p = 0.032) and after 3 months (p = 0.007). The functional disability and fear of movement had no significant differences between groups at any time. In addition, the measures of clinical relevance used (size effect; relative risk; number needed to treat) favoured the experimental group. Conclusions: The results show that a program of aquatic exercise and NPE were more effective in improving pain intensity at a short and medium term than an aquatic exercise program alone. Although more research on this topic is needed, this study demonstrates that the NPE can optimize results when combined with other active interventions such as aquatic exercise.

Evaluation of the therapeutic response of hepatitis C in coinfected patients (HIV/HCV): a study of cases from a hospital for chronic liver diseases in the Eastern Brazilian Amazon

INTRODUCTION: The aim of this study was to evaluate the therapeutic response of hepatitis C in patients coinfected with human immunodeficiency virus (HIV-1). METHODS: A retrospective study of 20 patients coinfected with HIV-1/HCV who were treated in the outpatient liver clinic at the Sacred House of Mercy Foundation Hospital of Pará (Fundação Santa Casa de Misericórdia do Pará - FSCMPA) from April 2004 to June 2009. Patients were treated with 180µg PEG interferon-α2a in combination with ribavirin (1,000 to 1,250mg/day) for 48 weeks. The end point was the sustained virological response (SVR) rate (HCV RNA negative 24 weeks after completing treatment). RESULTS: The mean age of the patients was 40±9.5 years, of which 89% (n=17) were male, and the HCV genotypes were genotype 1 (55%, n=11/20), genotype 2 (10%, n=2/20) and genotype 3 (35%, n=7/20). The mean CD4+ lymphocyte count was 507.8, and the liver fibrosis stages were (METAVIR) F1 (25%), F2 (55%), F3 (10%) and F4 (10%). The early virological response (EVR) was 60%, the end-of-treatment virological response (EOTVR) was 45% and the SVR was 45%. CONCLUSIONS: The median HCV viral load was high, and in 85% of cases in which highly active antiretroviral therapy (HAART) was used, none of the patients with F3-F4 fibrosis responded to treatment. Of the twenty patients treated, 45% achieved SVR and 45% achieved EOTVR. Studies that include cases from a wider region are needed to better evaluate these findings.

Momentum risk: An approach following the correlations between active stocks

The momentum anomaly has been widely documented in the literature. However, there are still many issues where there is no consensus and puzzles left unexplained. One is that strategies based on momentum present a level of risk that is inconsistent with the diversification that it offers. Moreover, recent studies indicate that this risk is variable over time and mostly strategy-specific. This work project hypothesises and proves that this evidence is explained by the portfolio constitution of the momentum strategy over time, namely the covariance and correlation between companies in the top and down deciles and across them.

Efficacy of voriconazole in experimental rat paracoccidioidomycosis

INTRODUCTION: Amphotericin B, azole or sulfamide drugs are used for treatment of patients with paracoccidioidomycosis. Among the azole drugs, voriconazole was active in vitro against Paracoccidioides brasiliensis and showed efficacy in the treatment of patients infected with this fungus.In the present study the antifungal activity of voriconazole and of other drugs was compared in a rat model of paracoccidioidomycosis. METHODS: Wistar rats were inoculated intravenously with the BOAS strain of P. brasiliensis and antifungal drugs were administered to the animals by gavage at the following doses (mg/kg weight/day): voriconazole (5 to 20), ketoconazole (12 to 15), fluconazole (6), itraconazole (4), and sulfamethoxazole-trimethoprim (120 to 150). The antifungal activity of the drugs was assessed by determining the P. brasiliensis colony forming units in the lungs and spleen of the animals at the end of treatment and by a survival study. RESULTS: Voriconazole reduced the total tissue fungal burden of P. brasiliensis, particularly at doses of ≥10mg/kg weight/day but its antifungal activity was less intense than that of fluconazole, itraconazole and sulfamethoxazole-trimethoprim. The mean survival of animals treated with the last three drugs, 29.1±10.7, 26.1± 10.1 and 28.4±9.6 days, respectively, was higher than that achieved with voriconazole 10mg/kg weight/day (18.5±8.3 days) and that observed in untreated animals (15.7±3.6 days). CONCLUSIONS: At doses similar to those used for clinical treatment, voriconazole showed lower antifungal activity in experimental rat paracoccidioidomycosis than that obtained with itraconazole and sulfamethoxazole-trimethoprim.

Students' choice of a master in management in Portugal: A means-end chain approach

In the increasingly competitive market of higher education introduced by the Bologna Declaration, understanding the decision-making of master in management students is at the center of institutional management and marketing efforts on its mission to attract prospective students in a less costly, more efficient manner. The means-end chain approach, applied to the choice of a Portuguese institution in which to pursue a master in management, points to the position in rankings and to the non-specificity of the program as the most important attributes. Additionally, results show that students with distinct demographic, household, or background characteristics choose in significantly different manners.

New focus of active transmission of Chagas disease in indigenous populations in the Peruvian Amazon basin

Introduction Several cases of acute Chagas disease (ACD) have been reported in the Peruvian Amazon basin. Methods The objective was to describe and investigate 6 ACD cases in children from indigenous Amazon communities in the province of Datem del Marañón in Loreto department (2006-2010). Results The mean age was 3.6 years. All patients had fever, 4/6 hepatomegaly, 2/6 splenomegaly, and 5/6 had trypomastigotes of Trypanosoma cruzi on thick smears. The fatality rate was 33.3%. Rhodnius pictipes and Rhodnius robustus adults were found inside the homes and in the peri-domiciles. Conclusions All cases reported were isolated cases. We report a new focus of ACD in indigenous populations.

Bloodstream infection in patients with end-stage renal disease in a teaching hospital in central-western Brazil

Introduction Vascular access in patients undergoing hemodialysis is considered a critical determinant of bloodstream infection (BSI) and is associated with high morbidity and mortality. The purpose of this study was to investigate the occurrence of BSI in patients with end-stage renal disease using central venous catheters for hemodialysis. Methods A cohort study was conducted in a public teaching hospital in central-western Brazil from April 2010 to December 2011. For every patient, we noted the presence of hyperemia/exudation upon catheter insertion, as well as fever, shivering, and chills during hemodialysis. Results Fifty-nine patients were evaluated. Thirty-five (59.3%) patients started dialysis due to urgency, 37 (62.7%) had BSI, and 12 (20%) died. Hyperemia at the catheter insertion site (64.9%) was a significant clinical manifestation in patients with BSI. Statistical analysis revealed 1.7 times more cases of BSI in patients with hypoalbuminemia compared with patients with normal albumin levels. The principal infective agents identified in blood cultures and catheter-tip cultures were Staphylococcus species (24 cases), non-fermentative Gram-negative bacilli (7 cases of Stenotrophomonas maltophilia and 5 cases of Chryseobacterium indologenes), and Candida species (6). Among the Staphylococci identified, 77.7% were methicillin-resistant, coagulase-negative Staphylococci. Of the bacteria isolated, the most resistant were Chryseobacterium indologenes and Acinetobacter baumannii. Conclusions Blood culture was demonstrated to be an important diagnostic test and identified over 50% of positive BSI cases. The high frequency of BSI and the isolation of multiresistant bacteria were disturbing findings. Staphylococcus aureus was the most frequently isolated microorganism, although Gram-negative bacteria predominated overall. These results highlight the importance of infection prevention and control measures in dialysis units.