O glioblastoma multiforme (GBM) é um tipo de câncer grave que acomete o sistema nervoso central (SNC), e a sobrevida dos pacientes é de aproximadamente 12 meses. O tratamento com o quimioterápico paclitaxel (PTX) reduz o GBM experimental e humano. No entanto, sua utilização é limitada pelas reações adversas graves que acarreta. A nanoemulsão rica em colesterol (LDE), a qual mimetiza a lipoproteína de baixa densidade, tem sido empregada como um sistema de entrega de fármacos eficiente em alguns casos de tumores. No presente trabalho visou-se avaliar a eficácia do oleato de PTX (OPTX), um derivado mais lipofílico do que o PTX, associado a LDE (LDE-OPTX) em ensaios in vitro e in vivo. Inicialmente, células tumorais da linhagem de glioblastoma murino GL261 foram incubadas com PTX em solução ou com LDE-OPTX, nas concentrações de 1 ou 10 µM. Os resultados obtidos mostraram que o tratamento in vitro com PTX e o LDE-OPTX causa toxicidade in vitro em células GL261 pela redução da proliferação e indução de apoptose, e que ainda reduz a secreção de MCP-1 (proteína quimiotáxica de monócitos). Os ensaios in vivo mostraram a toxicidade intensa do PTX comercial, uma vez que os animais com GBM não sobreviveram ao tratamento com 75mg/Kg, i.p., a cada 3 dias, e foram a óbito a partir do oitavo dia de tratamento. Diferentemente, os animais tratados com a mesma dose de LDE-OPTX sobreviveram ao tratamento, sem sinais de toxicidade, mas os dados obtidos mostraram que este protocolo de tratamento não foi eficaz para redução do volume tumoral. Assim, os animais com GBM passaram a ser tratados com doses diárias, i.p., de 15 mg/kg de PTX ou de 75mg/Kg de LDE-OPTX. Os resultados obtidos mostraram a ineficácia e eficácia dos tratamentos com PTX e LDE-OPTX, respectivamente, em reduzir o GBM; no entanto os animais tratados com LDE-OPTX apresentaram redução no peso corporal e no número de linfócitos circulantes. Em conjunto, os dados obtidos mostram a habilidade de preparação LDE-OPTX causar toxicidade in vitro nas células GL261 e sua eficácia terapêutica em dose elevada, em reduzir o GBM em modelo murino. / Glioblastoma multiforme (GBM) is a type of severe cancer that affects the central nervous system, and patient survival is about12 months. The treatment with the chemotherapeutic paclitaxel (PTX) reduces the experimental and human GBM, however, their use is limited by side effects. The lipid nanoemulsion (LDE), that is mimetic to low density protein, has been employed as an efficient drug nanocarrier to treat cancer. Therefore, the present study aimed to assess the effectiveness of the oleate PTX (OPTX), a more lipophilic derivative of PTX, associated to (LDE), in in vitro and in vivo studies. Initially, glioblastoma murine strain GL261 was incubated with commercial PTX solution or LDE-OPTX at concentrations of 1 or 10 µM. Data obtained showed that treatment with PTX or LDE-OPTX caused in vitro toxicity to GL261 cells, by reducing the proliferation and inducing apoptosis. Moreover, both treatments reduced the secretion of monocyte chemotacticprotein-1 (MCP-1). In vivo experiments showed the severe toxicity of commercial PTX, as mice with GBM did not survive to the treatment with 75mg/kg, i.p., each 3 days, and died after 8 days of treatment. Conversely, animals treated with the same schedule of treatment with LDE-OPTX survived until the end of treatment, without any toxicity signal. Nevertheless, the treatment was not effective to reduce the GBM volume. Hence, other sets of animals with GBM were treated with daily i.p. dose of 15mg/kg of PTX or 75mg/kg of LDE-OPTX. Data obtained showed the inefficacy and efficacy of PTX and LDE-OPTX treatments, respectively, to reduce the volume of GBM. Nevertheless, mice treated with LDE-OPTX lost weight and lower number of circulating lymphocytes. Together, our data show the ability of LDE-OPTX treatment cause in vitro toxicity on GL261 cells e the in vivo therapeutic efficacy of higher doses on GBM murine model.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / O expectorante MelagriÃo à um fitoterÃpico composto de seis plantas medicinais com conhecida aÃÃo no trato respiratÃrio: Mikania glomerata, Cephaelis ipecacuanha, Aconitum napellus, Polygala senega, Myroxylon balsamum e Nasturtium officinale. O objetivo desse estudo foi avaliar a seguranÃa, o potencial genotÃxico do MelagriÃo em voluntÃrios sadios e sua eficÃcia terapÃutica em pacientes com diagnÃstico clÃnico de bronquite aguda. Este estudo contemplou dois protocolos clÃnicos: no protocolo A foi avaliado a Toxicologia ClÃnica e seguranÃa do MelagriÃo que consistiu de um estudo duplo-cego, controlado por placebo, randomizado e paralelo, com 46 voluntÃrios, adultos, que foram aleatoriamente distribuÃdos em dois grupos: MelagriÃo e Placebo ambos constituÃdos por 28 e 18 voluntÃrios, respectivamente. Os voluntÃrios foram tratados durante 28 dias ininterruptos com 120 mL de MelagriÃo ou Placebo dividido em 4 doses diÃrias. AvaliaÃÃes clÃnica e laboratorial foram realizadas no prÃ-estudo, durante o perÃodo de tratamento, bem como apÃs o encerramento do estudo. A genotoxicidade do MelagriÃoÂ, por sua vez, foi investigada mediante o emprego do teste do cometa. A idade mÃdia dos voluntÃrios foi de 19,37  17,36 anos para o grupo MelagriÃo e de 24,70  23,50, para o grupo Placebo. As funÃÃes hematolÃgica, hepÃtica, renal e metabÃlica foram analisadas, antes, durante (7o, 14o e 28o dia) e 7 dias apÃs o estudo atravÃs dos exames laboratoriais, os quais nÃo evidenciaram sinais de toxicidade. Cefaleia, vÃmito, dor abdominal, tosse seca, sonolÃncia, diarrÃia, flatulÃncia, pirose e insÃnia foram os eventos adversos atribuÃdos aos dois grupos. Pelo teste do cometa, nÃo foram observados danos (p>0,05) nos linfÃcitos perifÃricos dos voluntÃrios tratados com o MelagriÃoÂ. Os estudos de toxicologia clÃnica e genotoxicidade nÃo evidenciaram nenhuma toxicidade nos voluntÃrios tratados por 28 dias ininterruptos com o MelagriÃoÂ. Jà o protocolo B consistiu de um estudo duplo-cego, randomizado e paralelo, com 86 pacientes. Os quais foram aleatoriamente distribuÃdos em dois grupos: MelagriÃo ou Bromexina constituÃdos por 43 voluntÃrios em cada grupo. Os voluntÃrios foram tratados durante 7 dias consecutivos, utilizando posologia de acordo com grupo e idade. AvaliaÃÃes clÃnica foram realizadas no prÃ-estudo e no sÃtimo dia, e laboratorial somente no prÃ-estudo. A idade mÃdia dos voluntÃrios foi de 19,37  17,36 anos para o grupo MelagriÃo e de 24,70  23,50, para o grupo Bromexina. Resultados do Protocolo B mostram equivalÃncia entre as formulaÃÃes testadas, nÃo sendo evidenciadas diferenÃas clÃnicas e estatÃsticas dentro dos parÃmetros avaliados, sendo, portanto o fitomedicamento MelagriÃo eficaz no tratamento da bronquite aguda. VÃmito, dor abdominal e febre foram os eventos adversos atribuÃdos aos dois grupos. O MelagriÃo demonstrou seguranÃa na dose terapÃutica, carÃter genotÃxico negativo e eficaz na melhora dos sinais e sintomas da bronquite aguda. / The expectorant MelagriÃo is a phytotherapic medicine composed of six medicinal plants with known action in the respiratory tract: Mikania glomerata, Cephaelis ipecacuanha, Aconitum napellus, Polygala senega, Myroxylon balsamum and Nasturtium officinale. The aim of this study was to evaluate the safety, the genotoxic potential of MelagriÃo in healthy volunteers and its efficacy in patients with clinical diagnosis of acute bronchitis. This study contemplated two clinical protocols. Protocol A evaluated the Clinical Toxicology and safety of MelagriÃo and consisted of a double-blind, placebo-controlled, randomized, parallel, with 46 adults subjects, randomly divided into two groups: Placebo and MelagriÃoÂ, each consisting of 28 and 18 volunteers, respectively. The subjects were treated for 28 uninterrupted days with 120 mL of MelagriÃo or Placebo, divided into four daily doses. Clinical and laboratory evaluations were performed in the pre-study, during the treatment period and after the end of the study. The genotoxicity of MelagriÃoÂ, was investigated through the comet assay. The mean age of the subjects was 19.37  17.36 years for the MelagriÃo group and 24.70  23.50 for the placebo group. The hematological, hepatic, renal and metabolic functions were analyzed before, during (7th, 14th and 28th day) and 7 days after the study through laboratory findings, which did not evidence signs of toxicity. Headache, vomiting, abdominal pain, dry cough, drowsiness, diarrhea, flatulence, heartburn and insomnia were the found adverse events attributed to both groups. No damage was observed (p >0.05) in peripheral lymphocytes of the subjects treated with MelagriÃo by the comet assay. The clinical toxicology and genotoxicity studies showed no toxicity in the volunteers treated with MelagriÃo for 28 uninterrupted days. Protocol B consisted of a double-blind, randomized and parallel study with 86 patients, randomly divided into two groups: MelagriÃo (n = 43) or bromhexine (n = 43). They were all treated for 7 consecutive days using the recommended dosage according to the treatment group and age. Clinical and laboratory evaluations were performed in the pre-study and only clinical evaluation was performed on the seventh day. The mean age of the subjects was 19.37  17.36 years for the MelagriÃo group and 24.70  23.50 for bromhexine group. Results of Protocol B show equivalence between the formulations tested, not being evident clinical and statistical differences within the parameters evaluated, and therefore the phytomedication MelagriÃo effective in treating acute bronchitis. Abdominal pain and fever were the found adverse events attributed to both groups. The MelagriÃo demonstrated safety in therapeutic dose, genotoxic negative character and effective in improving the signs and symptoms of acute bronchitis.

O glioblastoma multiforme (GBM) é um tipo de câncer grave que acomete o sistema nervoso central (SNC), e a sobrevida dos pacientes é de aproximadamente 12 meses. O tratamento com o quimioterápico paclitaxel (PTX) reduz o GBM experimental e humano. No entanto, sua utilização é limitada pelas reações adversas graves que acarreta. A nanoemulsão rica em colesterol (LDE), a qual mimetiza a lipoproteína de baixa densidade, tem sido empregada como um sistema de entrega de fármacos eficiente em alguns casos de tumores. No presente trabalho visou-se avaliar a eficácia do oleato de PTX (OPTX), um derivado mais lipofílico do que o PTX, associado a LDE (LDE-OPTX) em ensaios in vitro e in vivo. Inicialmente, células tumorais da linhagem de glioblastoma murino GL261 foram incubadas com PTX em solução ou com LDE-OPTX, nas concentrações de 1 ou 10 µM. Os resultados obtidos mostraram que o tratamento in vitro com PTX e o LDE-OPTX causa toxicidade in vitro em células GL261 pela redução da proliferação e indução de apoptose, e que ainda reduz a secreção de MCP-1 (proteína quimiotáxica de monócitos). Os ensaios in vivo mostraram a toxicidade intensa do PTX comercial, uma vez que os animais com GBM não sobreviveram ao tratamento com 75mg/Kg, i.p., a cada 3 dias, e foram a óbito a partir do oitavo dia de tratamento. Diferentemente, os animais tratados com a mesma dose de LDE-OPTX sobreviveram ao tratamento, sem sinais de toxicidade, mas os dados obtidos mostraram que este protocolo de tratamento não foi eficaz para redução do volume tumoral. Assim, os animais com GBM passaram a ser tratados com doses diárias, i.p., de 15 mg/kg de PTX ou de 75mg/Kg de LDE-OPTX. Os resultados obtidos mostraram a ineficácia e eficácia dos tratamentos com PTX e LDE-OPTX, respectivamente, em reduzir o GBM; no entanto os animais tratados com LDE-OPTX apresentaram redução no peso corporal e no número de linfócitos circulantes. Em conjunto, os dados obtidos mostram a habilidade de preparação LDE-OPTX causar toxicidade in vitro nas células GL261 e sua eficácia terapêutica em dose elevada, em reduzir o GBM em modelo murino. / Glioblastoma multiforme (GBM) is a type of severe cancer that affects the central nervous system, and patient survival is about12 months. The treatment with the chemotherapeutic paclitaxel (PTX) reduces the experimental and human GBM, however, their use is limited by side effects. The lipid nanoemulsion (LDE), that is mimetic to low density protein, has been employed as an efficient drug nanocarrier to treat cancer. Therefore, the present study aimed to assess the effectiveness of the oleate PTX (OPTX), a more lipophilic derivative of PTX, associated to (LDE), in in vitro and in vivo studies. Initially, glioblastoma murine strain GL261 was incubated with commercial PTX solution or LDE-OPTX at concentrations of 1 or 10 µM. Data obtained showed that treatment with PTX or LDE-OPTX caused in vitro toxicity to GL261 cells, by reducing the proliferation and inducing apoptosis. Moreover, both treatments reduced the secretion of monocyte chemotacticprotein-1 (MCP-1). In vivo experiments showed the severe toxicity of commercial PTX, as mice with GBM did not survive to the treatment with 75mg/kg, i.p., each 3 days, and died after 8 days of treatment. Conversely, animals treated with the same schedule of treatment with LDE-OPTX survived until the end of treatment, without any toxicity signal. Nevertheless, the treatment was not effective to reduce the GBM volume. Hence, other sets of animals with GBM were treated with daily i.p. dose of 15mg/kg of PTX or 75mg/kg of LDE-OPTX. Data obtained showed the inefficacy and efficacy of PTX and LDE-OPTX treatments, respectively, to reduce the volume of GBM. Nevertheless, mice treated with LDE-OPTX lost weight and lower number of circulating lymphocytes. Together, our data show the ability of LDE-OPTX treatment cause in vitro toxicity on GL261 cells e the in vivo therapeutic efficacy of higher doses on GBM murine model.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: In traditional medicine, there is a long-standing culture of combining herbal drugs to increase the therapeutic efficacy. The improved medical action is thought to be due to synergistic interactions between different plant bioactive components. The aim of this study was to test the pharmacological interactions in a medicinal plant combination which consisted of Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus. The rationale for the analysis of this particular mixture is that it had noteworthy antibacterial activity and exhibited the highest activity out of seven medicinal plant mixtures previously investigated. Using chromatographic analysis, the phytochemistry of the plants was also assessed. The chloroform: methanol (1:1; v/v) extracts or hydo-distilled essential oils (A. crenulata and E. globulus) were screened individually and in combinations (double and triple plant combination) for activity against five respiratory pathogens using a microdilution assay. The antimicrobial interactions in combinations were assessed with the fractional inhibitory concentration (FIC) and the isobolograms. The organic extracts generally showed the highest antimicrobial activity with E. globulus having the highest activity with MIC values below 1 mg ml-1 representing noteworthy activity. The overall activity of the aqueous extracts was poor. The essential oil activity of E. globulus was mostly noteworthy (0.5 to 2 mg ml-1) while A. crenulata essential oil displayed moderate activity (1 to 4 mg ml-1). The ΣFIC values for double combinations (1:1) of A. crenulata with D. viscosa, A. crenulata with E. globulus and D. viscosa with E. globulus were calculated from the minimum inhibitory concentration (MIC) data and the interactions were classified as synergistic, additive, indifferent and antagonistic. The highest synergistic interactions observed were for a 1:1 combination of A. crenulata with E. globulus against K. pneumoniae, S. aureus and B. subtilis with ΣFIC values of 0.07. There was only one incident of antagonism noted in the study for D. viscosa with E. globulus (1:1) against C. neoformans with ΣFIC value of 4.25. The double combinations against selective pathogens (K. pneumoniae, S. aureus and E. coli) were further analysed for interactions using isobolograms. Mostly, the antimicrobial interactions as presented by the isobolograms were congruent with FIC results which further validated the occurrence of relevant antimicrobial interactions in those combinations. The ΣFIC values for triple combinations (1:1:1) revealed mostly synergistic interactions. When the triple combinations were analysed further against certain pathogens based on the predictions of the Design of Experiments software program (MODDE 9.1®), the MIC values remained the same despite the different combinations that were tested Thin layer chromatography (TLC) was used for a quick chemical fingerprinting of the plant extracts. This was followed by a bio-autographic assay. The chemical profiles of the organic extracts and essential oils from two of the study aromatic plants (A. crenulata and E. globulus) were further analysed with liquid chromatography mass spectrometry (LC-MS) and gas chromatography mass spectrometry (GC-MS) respectively. For combined plant extracts, a multivariate data analysis using principal component analysis (PCA) and hierarchical clustering analysis (HCA) was used to determine the relationship of the chemical make-up of combinations with that of individual plant extracts. According to the TLC analysis, E. globulus extracts had more compounds than the other two plants in the study. For the bio-autographic assay, E. globulus and combinations that included this plant showed greater inhibition zones than A. crenulata and D. viscosa. For the LC-MS analysis, PCA and HCA showed a close relationship between A. crenulata with D. viscosa, D. viscosa with E. globulus and the triple combination. Twenty one components were identified in the essential oil of A. crenulata representing 88.83% of the total oil composition. The oil was dominated by oxygen-containing monoterpenes (46.25%). In the essential oil of E. globulus, twenty six compounds were identified making up to 95.62% of the oil composition. Oxygen-containing monoterpenes (32.98%) also dominated the E. globulus essential oil. There was no great variation in essential oil metabolites of the individual plants and their combination as shown by both PCA and HCA. The enhanced in vitro antimicrobial activity and pharmacological interactions (synergy and additivity) in some of the combinations (double and triple) that were tested in this study adds scientific support to the use of medicinal plant combinations in Western Cape traditional medicine. The metabolic profiles of plants in combination might be unique due to interaction of the different plant bioactive molecules and thus result into defined antimicrobial activity. / AFRIKAANSE OPSOMMING: In tradisionele geneeskunde is dit ’n lank bestaande kultuur om kruiemiddels te kombineer om die terapeutiese werking daarvan te verhoog. Dié verbeterde mediese werking word toegeskryf aan die oënskynlik sinergistiese interaksies tussen verskillende bioaktiewe plantkomponente. Die doel van hierdie studie was om die farmakologiese interaksies in medisinale plantkombinasies van Agathosma crenulata, Dodonaea viscosa en Eucalyptus globulus te bestudeer. Daar is op die ontleding van hierdie spesifieke mengsel besluit omdat dit oor beduidende antibakteriese waarde beskik en omdat dit uit sewe medisinale plantmengsels wat voorheen bestudeer is, as die doeltreffendste een aangewys is. Die fitochemie van die plante is ook met behulp van chromatografiese ontleding beoordeel. Deur middel van ’n mikroverdunningstoets is die chloroform:metanol- (1:1; v/v-)ekstrakte of hidrogedistilleerde vlugtige olies (A. crenulata en E. globulus) individueel sowel as in kombinasie (dubbele en drievoudige plantkombinasies) nagegaan vir hul werking met betrekking tot vyf respiratoriese patogene. Die gekombineerde antimikrobiese interaksies is met behulp van fraksioneel stremmende konsentrasie (FIC) en isobologramme ondersoek. Die organiese ekstrakte het oor die algemeen die meeste antimikrobiese aktiwiteit by E. globulus getoon, met MIC-waardes onder 1 mg ml-1 wat as noemenswaardige aktiwiteit beskou is. Die algehele aktiwiteit van die waterekstrakte was swak. Die vlugtige-olieaktiwiteit van E. globulus was merendeels noemenswaardig (0,5 tot 2 mg ml-1), terwyl die vlugtige olie van A. crenulata matige aktiwiteit getoon het (1 tot 4 mg ml-1). Die ΣFIC-waardes vir dubbelkombinasies (1:1) van A. crenulata en D. viscosa, A. crenulata en E. globulus, en D. viscosa en E. globulus is uit die minimum stremmende konsentrasie (MIC) bereken en die interaksies is as sinergisties, additief, neutraal en antagonisties geklassifiseer. Die sterkste sinergistiese interaksies is by ’n 1:1-kombinasie van A. crenulata en E. globulus met betrekking tot K. pneumoniae, S. aureus en B. subtilis opgemerk, met ΣFIC-waardes van 0,07. Die studie het slegs een geval van antagonisme opgelewer, naamlik by D. viscosa en E. globulus (1:1) met betrekking tot C. neoformans, wat ’n ΣFIC-waarde van 4,25 geregistreer het. Die werking van die dubbelkombinasies met betrekking tot gekose patogene (K. pneumoniae, S. aureus en E. coli) is voorts met behulp van isobologramme vir interaksies nagegaan. Die antimikrobiese interaksies wat uit die isobologramme geblyk het, was meestal in pas met FIC-resultate, wat die bestaan van tersaaklike antimikrobiese interaksies in daardie kombinasies verder bevestig het. Die ΣFIC-waardes vir die drievoudige kombinasies (1:1:1) het meestal sinergistiese interaksies aan die lig gebring. Toe die drievoudige kombinasies verder op grond van die voorspellings van die sagteware Design of Experiments (MODDE 9.1®) met betrekking tot sekere patogene ontleed is, het die MIC-waardes onveranderd gebly, ondanks verskillende toetskombinasies. Dunlaagchromatografie (TLC) is vir ’n vinnige chemiese ontleding van die plantekstrakte gebruik en is gevolg deur ’n bio-outografiese toets. Die chemiese profiele van die organiese ekstrakte en vlugtige olies van twee van die aromatiese plante in die studie (A. crenulata en E. globulus) is verder met vloeistofchromatografie-massaspektrometrie (LC-MS) en gaschromatografie-massaspektrometrie (GC-MS) onderskeidelik ontleed. Vir gekombineerde plantekstrakte is veelveranderlike-ontleding in die vorm van hoofkomponentontleding (PCA) en hiërargiese groepsontleding (HCA) gebruik om die verhouding van die chemiese samestelling van kombinasies in vergelyking met dié van individuele plantekstrakte te bepaal. Volgens die TLC-ontleding beskik E. globulus-ekstrakte oor meer verbindings as die ander twee plante in die studie. Vir die bio-outografiese toets het E. globulus en kombinasies daarmee groter stremmingsones as A. crenulata en D. viscosa getoon. In die LC-MS-ontleding het PCA en HCA op ’n hegte verhouding tussen A. crenulata en D. viscosa, D. viscosa en E. globulus, en die drievoudige kombinasie daarvan gedui. Een-en-twintig komponente is in die vlugtige olie van A. crenulata gevind, wat 88,83% van die algehele oliesamestelling uitmaak. Die olie is deur suurstofhoudende monoterpene (46,25%) oorheers. Die vlugtige olie van E. globulus het 26 verbindings opgelewer, wat 95,62% van die oliesamestelling uitmaak. Suurstofhoudende monoterpene (32,98%) het ook die vlugtige olie van E. globulus oorheers. Nóg PCA nóg HCA het op enige beduidende variasie in die metaboliete van die vlugtige olies van die individuele plante en hul kombinasies gedui. Die verhoogde in vitro- antimikrobiese aktiwiteit en farmakologiese interaksies (sinergie en additiwiteit) in van die kombinasies (dubbel én drievoudig) wat in hierdie studie getoets is, bied wetenskaplike stawing vir die gebruik van medisinale plantkombinasies in Wes-Kaapse tradisionele geneeskunde. Die metaboliese profiele van plantkombinasies kan verander weens die interaksie van die verskillende bioaktiewe plantmolekules, en kan baie bepaalde antimikrobiese aktiwiteit tot gevolg hê.

Orientador: Rosangela Gonçalves Peccinini / Resumo: A Doxorrubicina (Dox) é uma antraciclina modelo amplamente utilizada em diversos tipos de neoplasias e, assim como a maioria dos quimioterápicos antineoplásicos, a Dox apresenta uma série de efeitos adversos, dentre eles os mais significativos são os efeitos cardiovasculares como hipotensão, taquicardia e insuficiência cardíaca congestiva (ICC), que limitam a terapia com este fármaco. A cardiotoxicidade é favorecida pela sua ampla distribuição no miocárdio, e a Dox tem sidoconsiderada a de maior efeito tóxico sobre o tecido cardíaco. A utilização de recursos em tecnologia farmacêutica que modifiquem o perfil farmacocinético e a toxicidade é uma importante ferramenta para a introdução de um novo produto no mercado cuja resulte em desfecho clínico mais favorável ao paciente. Pesquisadores da Universidade Federal do Rio Grande do Norte (UFRN) desenvolveram um sistema de nanopartículas (Np) para a veiculação de Dox com o intuito de modificar suas características farmacocinéticas e de toxicidade. No presente trabalho o objetivo foi avaliar a nova formulação proposta e compará-la às formulações comerciais de Dox (na forma de cloridrato e lipossomal) quanto a atividade antitumoral in vitro e in vivo e quanto às suas características farmacocinéticas. Foi abordada a atividade in vitro em ensaios de citotoxicidade como o ensaio de Resazurina (RSZ), sulforrubina B (SRB) e a determinação de Trisfosfato de Adenosina (ATP) realizados em cardiomiblasto (H9c2 (2-1), ATCC® CRL 1446™) e célula... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

O movimento \"Medicina baseada em evidências (EBM), surgido na década de 1990, encontrou rápida aceitação por parte da comunidade médica e dos sistemas de saúde. Entre suas principais características, encontram-se a exigência de que a prática clínica seja baseada na melhor evidência disponível, a hierarquização da evidência, a valorização dos ensaios clínicos e, sobretudo, o recurso extensivo a procedimentos de análise estatística. Neste trabalho, apresentamos a EBM, descrevemos seus conceitos e procedimentos centrais e indicamos alguns de seus antecedentes históricos. Damos especial atenção aos conceitos de randomização, significância estatística, evidência científica e eficácia terapêutica. Finalmente, desenvolvemos uma crítica às concepções de cientificidade e progresso defendidas pela EBM e a utilizamos como ponto de partida para tecermos considerações gerais acerca do estatuto epistemológico da medicina, do progresso médico e das funções que a estatística desempenha na medicina contemporânea. / Evidence-based medicine (EBM) is a medical movement whose first appearance dates back to the 1990s. Since then, it has received wide acceptance from the medical community and international health systems. Among its most important characteristics, it is possible to indicate the demand to base the clinical practice on the best current evidence, the hierarchies of evidence, the valorisation of the randomized-controlled trials, and, especially, the extensive recourse to procedures of statistical analysis. This Masters dissertation is intended to present the EBM movement, describe its main concepts and procedures, and identify some of its historical backgrounds. Special consideration is given to the concepts of randomization, statistical significance, scientific evidence, and therapeutic efficacy. Finally, we present some criticisms on the conceptions of medical science and medical progress defended by EBM proponents. We then use them as a starting point for the development of our own considerations about the epistemological status of medicine, the medical progress and the advancement of knowledge in the contemporary medical sciences.

A administração de medicamentos por via subcutânea é considerada segura, de manuseio simples e descrita como alternativa às vias intravenosa e intramuscular em pacientes em cuidados paliativos (CP) com difícil acesso venoso. A escassez de estudos e a pouca divulgação dessa via parenteral para administração de antibióticos restringem o seu uso. Portanto, realizou-se uma revisão integrativa da literatura, com objetivo de identificar e analisar as evidências disponíveis na literatura científica sobre o uso de antibióticos por via subcutânea em pacientes com difícil acesso venoso em CP quanto à tolerância local e à eficácia terapêutica, utilizando-se como referencial teórico a Prática Baseada em Evidências. Para a busca e seleção dos estudos, foram utilizadas 5 bases de dados: LILACS, CINAHL, PUBMED, EMBASE e Biblioteca Cochrane. A amostra foi de 17 estudos, sendo 4 com nível de evidência forte (nível II), 5 com nível de evidência moderada (nível III) e 8 com nível de evidência fraca (nível V e VI). Foram encontrados 10 antibióticos: Ertapenem, Ceftriaxona, Cefepime, Teicoplanina, Ampicilina, Tobramicina, Amicacina, Netilmicina, Gentamicina e Sisomicina, sendo Ceftriaxona o antibiótico mais estudado. A eficácia terapêutica foi satisfatória por via subcutânea a partir dos parâmetros farmacocinéticos, quando comparados às vias intravenosa e intramuscular, variando de um estudo para o outro de acordo com características da população estudada, dose e concentração do antibiótico. A confirmação da eficácia terapêutica por parâmetros clínicos foi avaliada em 1 estudo sobre Ceftriaxona com melhora dos sintomas clínicos dos pacientes. Sobre a tolerância local, constatou-se que, quanto maior a diluição do antibiótico, melhor a tolerância. Exceto a Tobramicina, todos os Aminoglicosídeos foram associados a lesões graves com evolução para necrose tecidual. A baixa tolerância reforça a restrição de uso apenas para essa classe de antibióticos. Para Ampicilina e Ertapenem não se observou intolerância local. Com Teicoplanina, a tolerância local foi boa: apenas 1 relato de dor e eritema quando se utilizou água para injeção como diluente. Com Cefepime, foram observados 2 casos de edema leve com eritema seguido de mínima dor, e 1 caso de prurido local. Para Ceftriaxona com 2 g associado a lidocaína a 1% observou-se dor e necrose tecidual; com 0,5 g não se observou intolerância alguma, e com 1 g observou-se boa tolerância, porém, em todos os casos com placebo salino ou hialuronidase prévios houve queixa de dor. As previsões de eficácia terapêutica e a boa tolerância constatadas para os antibióticos por via subcutânea sugerem uma possibilidade a ser considerada quando se deseja uma via de administração parenteral alternativa. Entretanto, recomenda-se cautela e avaliação criteriosa devido à lacuna existente sobre o uso de antibióticos por via subcutânea em pacientes em CP e suas necessidades e condições específicas. Embora os dados evidenciados fortaleçam o corpo de conhecimento de enfermagem na tomada de decisão para a implementação da assistência, faz-se necessária a realização de mais estudos com nível de evidência forte e de boa qualidade metodológica que comprovem ou refutem a efetividade desses antibióticos por via subcutânea para os pacientes em CP. / The administration of medication by subcutaneous route is considered safe, simple to handle and described as an alternative to intravenous and intramuscular routes in patients in palliative care (PC) with difficult venous access. The lack of studies and the little disclosure of this parenteral route to administer antibiotics restrict its use. Therefore, this integrative literature review aimed to identify and analyze the evidences available in scientific literature on the use of antibiotics by subcutaneous route in patients with difficult venous access in PC regarding the local tolerance and therapeutic efficacy, using as theoretical framework Evidence-Based Practice. The following five databases were used in the search and selection of studies: LILACS, CINAHL, PUBMED, EMBASE and Cochrane Library. The sample consisted of 17 studies, 4 with strong level of evidence (level II), 5 with moderate level of evidence (level III) and 8 with low level of evidence (level V and VI). Ten antibiotics were found: Ertapenem, Ceftriaxone, Cefepime, Teicoplanin, Ampicillin, Tobramycin, Amikacin, Netilmicin, Sisomicin and Gentamicin. The antibiotic Ceftriaxone was studied the most. The therapeutic efficacy was satisfactory via subcutaneous route, according to the pharmacokinetic parameters when compared to intravenous and intramuscular routes, varying from study to study according to characteristics of the studied population, dose and concentration of the antibiotics. Confirmation of the therapeutic efficacy by clinical parameters was evaluated in one study about Ceftriaxone with improvement of clinical symptoms of patients and cure of the infection. With regard to local tolerance, it was found that the higher the dilution of the antibiotic, the better the tolerance. Except for Tobramycin, all aminoglycosides have been associated with severe injury progressing to tissue necrosis. The low tolerance reinforces the restriction of use only to this class of antibiotics. No local intolerance was observed for Ampicillin and Ertapenem. Teicoplanin showed good local tolerance: there was only one report of pain and erythema when using water as diluent for injection. With Cefepime, the following was observed: 2 cases of mild edema with erythema followed by minimal pain, and 1 case of local itching. For Ceftriaxone 2 g associated with Lidocaine 1%, pain and tissue necrosis was observed, with 0.5 g no intolerance was observed, and with 1 g there was good tolerance, however, in all cases with previous saline placebo or Hyaluronidase there was complaint of pain. Predictions of therapeutic efficacy and good tolerability observed for antibiotics with subcutaneous route suggest a possibility to be considered when there is need of an alternative parenteral route for administration. However, there is for caution and careful evaluation as there is a gap on the use of antibiotics vie subcutaneous route in PC and their specific needs and conditions. Although the evidenced data strengthen the body of knowledge for nursing in decision making for the implementation of care, there is need of further studies with strong level of evidence and good methodological quality that can prove or refute the effectiveness of these antibiotics through subcutaneous route to patients in PC.

A administração de medicamentos por via subcutânea é considerada segura, de manuseio simples e descrita como alternativa às vias intravenosa e intramuscular em pacientes em cuidados paliativos (CP) com difícil acesso venoso. A escassez de estudos e a pouca divulgação dessa via parenteral para administração de antibióticos restringem o seu uso. Portanto, realizou-se uma revisão integrativa da literatura, com objetivo de identificar e analisar as evidências disponíveis na literatura científica sobre o uso de antibióticos por via subcutânea em pacientes com difícil acesso venoso em CP quanto à tolerância local e à eficácia terapêutica, utilizando-se como referencial teórico a Prática Baseada em Evidências. Para a busca e seleção dos estudos, foram utilizadas 5 bases de dados: LILACS, CINAHL, PUBMED, EMBASE e Biblioteca Cochrane. A amostra foi de 17 estudos, sendo 4 com nível de evidência forte (nível II), 5 com nível de evidência moderada (nível III) e 8 com nível de evidência fraca (nível V e VI). Foram encontrados 10 antibióticos: Ertapenem, Ceftriaxona, Cefepime, Teicoplanina, Ampicilina, Tobramicina, Amicacina, Netilmicina, Gentamicina e Sisomicina, sendo Ceftriaxona o antibiótico mais estudado. A eficácia terapêutica foi satisfatória por via subcutânea a partir dos parâmetros farmacocinéticos, quando comparados às vias intravenosa e intramuscular, variando de um estudo para o outro de acordo com características da população estudada, dose e concentração do antibiótico. A confirmação da eficácia terapêutica por parâmetros clínicos foi avaliada em 1 estudo sobre Ceftriaxona com melhora dos sintomas clínicos dos pacientes. Sobre a tolerância local, constatou-se que, quanto maior a diluição do antibiótico, melhor a tolerância. Exceto a Tobramicina, todos os Aminoglicosídeos foram associados a lesões graves com evolução para necrose tecidual. A baixa tolerância reforça a restrição de uso apenas para essa classe de antibióticos. Para Ampicilina e Ertapenem não se observou intolerância local. Com Teicoplanina, a tolerância local foi boa: apenas 1 relato de dor e eritema quando se utilizou água para injeção como diluente. Com Cefepime, foram observados 2 casos de edema leve com eritema seguido de mínima dor, e 1 caso de prurido local. Para Ceftriaxona com 2 g associado a lidocaína a 1% observou-se dor e necrose tecidual; com 0,5 g não se observou intolerância alguma, e com 1 g observou-se boa tolerância, porém, em todos os casos com placebo salino ou hialuronidase prévios houve queixa de dor. As previsões de eficácia terapêutica e a boa tolerância constatadas para os antibióticos por via subcutânea sugerem uma possibilidade a ser considerada quando se deseja uma via de administração parenteral alternativa. Entretanto, recomenda-se cautela e avaliação criteriosa devido à lacuna existente sobre o uso de antibióticos por via subcutânea em pacientes em CP e suas necessidades e condições específicas. Embora os dados evidenciados fortaleçam o corpo de conhecimento de enfermagem na tomada de decisão para a implementação da assistência, faz-se necessária a realização de mais estudos com nível de evidência forte e de boa qualidade metodológica que comprovem ou refutem a efetividade desses antibióticos por via subcutânea para os pacientes em CP. / The administration of medication by subcutaneous route is considered safe, simple to handle and described as an alternative to intravenous and intramuscular routes in patients in palliative care (PC) with difficult venous access. The lack of studies and the little disclosure of this parenteral route to administer antibiotics restrict its use. Therefore, this integrative literature review aimed to identify and analyze the evidences available in scientific literature on the use of antibiotics by subcutaneous route in patients with difficult venous access in PC regarding the local tolerance and therapeutic efficacy, using as theoretical framework Evidence-Based Practice. The following five databases were used in the search and selection of studies: LILACS, CINAHL, PUBMED, EMBASE and Cochrane Library. The sample consisted of 17 studies, 4 with strong level of evidence (level II), 5 with moderate level of evidence (level III) and 8 with low level of evidence (level V and VI). Ten antibiotics were found: Ertapenem, Ceftriaxone, Cefepime, Teicoplanin, Ampicillin, Tobramycin, Amikacin, Netilmicin, Sisomicin and Gentamicin. The antibiotic Ceftriaxone was studied the most. The therapeutic efficacy was satisfactory via subcutaneous route, according to the pharmacokinetic parameters when compared to intravenous and intramuscular routes, varying from study to study according to characteristics of the studied population, dose and concentration of the antibiotics. Confirmation of the therapeutic efficacy by clinical parameters was evaluated in one study about Ceftriaxone with improvement of clinical symptoms of patients and cure of the infection. With regard to local tolerance, it was found that the higher the dilution of the antibiotic, the better the tolerance. Except for Tobramycin, all aminoglycosides have been associated with severe injury progressing to tissue necrosis. The low tolerance reinforces the restriction of use only to this class of antibiotics. No local intolerance was observed for Ampicillin and Ertapenem. Teicoplanin showed good local tolerance: there was only one report of pain and erythema when using water as diluent for injection. With Cefepime, the following was observed: 2 cases of mild edema with erythema followed by minimal pain, and 1 case of local itching. For Ceftriaxone 2 g associated with Lidocaine 1%, pain and tissue necrosis was observed, with 0.5 g no intolerance was observed, and with 1 g there was good tolerance, however, in all cases with previous saline placebo or Hyaluronidase there was complaint of pain. Predictions of therapeutic efficacy and good tolerability observed for antibiotics with subcutaneous route suggest a possibility to be considered when there is need of an alternative parenteral route for administration. However, there is for caution and careful evaluation as there is a gap on the use of antibiotics vie subcutaneous route in PC and their specific needs and conditions. Although the evidenced data strengthen the body of knowledge for nursing in decision making for the implementation of care, there is need of further studies with strong level of evidence and good methodological quality that can prove or refute the effectiveness of these antibiotics through subcutaneous route to patients in PC.

No description available.

Introduction: Emergence of resistance to artemisinin-based combination therapy (ACT) is a major threat to combat Plasmodium falciparum malaria. Regular therapeutic studies to monitor treatment efficacy is essential, and genotyping of molecular makers is useful for mapping development and spread of resistance. Aims: The study aims are to assess efficacy of artesunate-amodiquine (ASAQ) and prevalence of molecular markers of drug resistance in Zanzibar in 2017. Methods: Treatment efficacy of the clinical trial conducted in 2017 was compared with efficacies in 2002 and 2005. A total of 142 samples were genotyped for single nucleotide polymorphisms (SNPs) in the P. falciparum chloroquine resistance transporter gene (pfcrt) gene, the P. falciparum multi drug resistance 1 (pfmdr1) gene, and in the P. falciparum Kelch 13 (PfK13) propeller region. Prevalence of SNPs were assessed during the period 2002-2017. Results: Cure rate was 100% in 2017, compared to 94% and 96%, in 2002-2003 and 2005, respectively. Day 3 fever clearance rate were also high 93% (2002-3), 99% (2005) and 98% (2017) in all studies. Prevalence of pfcrt 76T, pfmdr1 86Y, 184Y and 1246Y and pfmdr1 (86Y, 184Y and 1246Y) YYY haplotypes were significantly decreased between 2002-3 and 2017 (p &lt; 0.001). No SNP in the PfK13 gene related to artemisinin resistance was identified. Conclusion: Efficacy of ASAQ remains high after fourteen years as first-line treatment, despite the wide-scale use of ASAQ, and there is no evidence of selection of resistance markers in Zanzibar. Continuous monitoring of drug efficacy and resistance markers is recommended. / <p>This master thesis is a collaboration project between Institutionen för kvinnors och barns hälsa, Department of Women's and Children's Health, Uppsala Universtiy and Anders Björkman group, Department of Microbiology, Tumor and Cell Biology (MTC), C1, Karolinska Institutet. Laboratory examinations were mainly conducted at MTC house, Karolinska Institutet.</p>