In this thesis, the efficiency of orally applied praziquantel (PQ) in two concentrations (Pramik 1 and Pramik 2) and mebendazole (MB) were tested on metacercaria of eye flukes (Diplostomum spathaceum, Rudolphi, 1819) in the grass carp (Ctenopharyngodon idella, Valenciennes, 1844). Naturally infected fish (average fish weight was 1.6 g and standard deviation was 0.1) were divided into four groups, for each tested group (Pramik 1, Pramik 2 and MB) belonged two aquariums of 100 liters each with 25 fish and for a control group belonged three aquariums of 100 liters each with 25 fish. The fish in the individual groups were fed with medicated feed containing praziquantel (Pramik 1 - 2.5 g PQ. kg-1 of feed, Pramik 2 - 1.25 g PQ. kg-1 of feed) and medicated feed mixture KP1 enriched with mebendazole (2.5 g MB. kg-1 of feed). The control group was fed with KP1 without drug addition. During the test the parasitological examinations of the ophthalmic lens were performed. The prevalence and intensity of infection were recorded. In the group of fish fed with medicated mixture containing MB, no statistically significant differences of the intensity of the infection indicating the MB potential in the fight against this fish infection were reported during the test. In the case of tested groups of fish fed with medicated feed mixture containing PQ (Pramik 1, Pramik 2), a statistically significant difference in the intensity of the infection was proved compared with the control group already after the first examination (estimated dose of consumed PQ. kg-1 of weight of fish = 500 and 250 mg). Near complete elimination of the eye flukes occurred in the group fed with feed mixture Pramik 1 after the expected consumption of 900 mg PQ. kg-1 of weight of fish. Statistically significant differences in the intensity of the infection in PQ treated fish groups compared to control groups indicate the usability of medicated feed containing PQ in the fight against fish diplostomosis.

Submitted by Mario BC (mario@bc.ufrpe.br) on 2017-08-04T13:38:25Z No. of bitstreams: 1 Vitor Hugo da Silva.pdf: 3831842 bytes, checksum: 10a85df0c7215ea8e7204701f45eb3c0 (MD5) / Made available in DSpace on 2017-08-04T13:38:25Z (GMT). No. of bitstreams: 1 Vitor Hugo da Silva.pdf: 3831842 bytes, checksum: 10a85df0c7215ea8e7204701f45eb3c0 (MD5) Previous issue date: 2015-02-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Mebendazole (MBZ) is a broad spectrum anthelmintic drug, often used as therapy against parasites from intestinal lumen. This substance has three different polymorphic forms, A, B and C. Among these forms, form A has no anthelmintic effect and renders the medication totally inactive when it exceeds 30% of mebendazole content in the formulation. Form B shows higher toxicity when ingested orally. Therefore, form C is the pharmaceutically preferred one because it does not have the drawbacks of forms A and B, and is stable at room temperature. All polymorphic forms of MBZ have been reported in pharmaceutical raw materials and commercial formulae. Thus, the aim of this work is to quantify the polymorphic forms of mebendazole in raw material using mid infrared (MIR), near infrared (NIR) and terahertz (THz) spectroscopies. For this, we built a ternary mixture design with 21 samples of polymorphic forms of MBZ. Models based on regression by Partial Least Squares (PLS) were developed using preprocessed MIR, NIR and THz spectra. All these techniques were efficient in discriminating among polymorphic forms of the drug, which have different spectral profiles with changes in intensities of bands and peaks, and displacements thereof. The multivariate calibration PLS models showed satisfactory results in the quantification of polymorphic forms of MBZ in the raw material. The best results for each spectral region showed values of determination coefficient (R²) above 0.95, correlation coefficient (R) above 0.97 and average RMSEP of 0.0294 w/w, 0.0132 w/w and 0.0282 w/w to polymorphic forms A, B and C, respectively. / O mebendazol (MBZ) é um medicamento anti-helmíntico de amplo espectro, frequentemente utilizado na terapia das parasitoses do lúmen intestinal. Tal substância possui três diferentes formas polimórficas, A, B e C. Dentre essas, a forma A não possui efeito anti-helmíntico e torna a medicação totalmente inativa quando excede 30% do seu teor na formulação, enquanto a forma B apresenta maior toxicidade por via oral. Portanto, a forma C é a farmaceuticamente preferida por não apresentar as desvantagens das formas A e B e ser estável à temperatura ambiente. No entanto, todas as formas polimórficas do MBZ são reportadas tanto na matéria prima quanto nos medicamentos comercializados. Diante disso, o objetivo deste trabalho é determinar quantitativamente as formas polimórficas do mebendazol na matéria prima utilizando as espectroscopias no Infravermelho Médio (MIR), Próximo (NIR) e Terahertz (THz). Para isso, foi construído um planejamento de misturas ternárias com 21 amostras das formas polimórficas do MBZ. Modelos baseados na regressão por Mínimos Quadrados Parciais (PLS) foram desenvolvidos utilizando os espectros MIR, NIR e THz pré-processados. Todas as técnicas estudadas apresentaram eficiência na diferenciação das formas polimórficas do fármaco, os quais apresentam perfis espectrais diferentes com mudanças nas intensidades das bandas e picos, além de deslocamentos dos mesmos.Os modelos de calibração multivariada PLS apresentaram resultados satisfatórios na quantificação das formas polimórficas do MBZ na matéria prima. Os melhores resultados para cada região espectral apresentaram valores de coeficiente de determinação (R²) acima de 0,95, coeficiente de correlação (R) acima de 0,97 e RMSEP médio de 0,0312 m/m, 0,0132 m/m e 0,0282 m/m para as formas polimórficas A, B e C, respectivamente.

Os Insumos farmacêuticos ativos (IFA) são em sua maioria produzidos e comercializados na forma de formulações sólidas. A eficácia terapêutica de cada IFA, no entanto, está diretamente relacionada com suas características no estado sólido. Desta forma, o controle e o entendimento da química das características físico-químicas de estado sólido dos IFAs, como produtos formulados ou substâncias puras, é uma importante parte do processo de desenvolvimento de novos medicamentos. Dentro deste marco, o presente trabalho tem o intuito de obter e caracterizar novas formas sólidas de dois compostos farmacêuticos, sendo eles, o fármaco anti-helmíntico Mebendazol e o hormônio Estradiol 17β Valerato. A caracterização destes compostos foi realizada por meio da técnica de difração de raios X de monocristais e complementada com dados provenientes de outras técnicas tais como espectroscopia Infravermelho e Raman e análise térmica. A partir da amostra de mebendazol obteve-se um novo sal, o mesilato de mebendazol monohidratado que cristaliza no grupo espacial triclínico P1. A unidade assimétrica deste composto apresenta uma molécula de MBZ, uma molécula de mesilato (metil sulfonato) e uma molécula de água. A análise estrutural mostrou que a molécula do principio ativo apresenta ligação de hidrogênio intramolecular assistida por ressonância. No que diz respeito às interações intermoleculares, a presença dos íons mesilato e da água fazem com que o empacotamento cristalino seja mais compacto que o apresentado pelas outras formas sólidas reportadas na literatura devido à presença de ligações de hidrogênio fortes. Estas ligações dão lugar à formação de cadeias infinitas nas quais as moléculas de MBZ estão unidas por interações fortes envolvendo os íons mesilato. Essas cadeias por sua vez se arranjam de maneira a formar estruturas bidimensionais unidas entre si por interações envolvendo as moléculas de água, o que estabiliza o empacotamento tridimensional. O Estradiol 17β Valerato, utilizado para tratamento de menopausa e em pílulas anticoncepcionais, não apresenta na literatura nenhuma caracterização de estado sólido. O mesmo cristalizou no grupo espacial não centrossimétrico P2₁ com duas moléculas por unidade assimétrica as quais mostram evidencias de desordem vibracional na cadeia terminal do grupo valerato. A análise térmica mostrou que este composto funde a 145°C sendo que o processo de decomposição da amostra acontece em 262°C. Analisando o comportamento térmico desse insumo a baixa temperatura constatou-se que ele apresenta uma transição de fase estrutural de primeira ordem em -22°C ao descer a temperatura e em -16°C ao subir. A caracterização estrutural deste sólido farmacêutico a 100K permitiu observar que a transição de fase está relacionada com uma forte mudança conformacional do grupo valerato. / The active pharmaceutical ingredients (API) are mostly produced and marketed in the form of solid formulations. The therapeutic efficacy of each API, however, is directly related to its characteristics in the solid state. Thus the control and understanding of the chemistry of the physicochemical characteristics of solid state APIs as pure substances or formulated products, is an important part of the process of developing new drugs. Within this framework, this paper aims to obtain and characterize new solid forms of two pharmaceutical compounds, among them, the anthelmintic drug Mebendazole and hormone 17β estradiol valerate. The characterization of these compounds was performed by means of diffraction X-ray single crystal and supplemented with data from other techniques such as infrared and Raman spectroscopy and thermal analysis. From the sample mebendazole obtained a new salt, mesylate monohydrate mebendazole which crystallizes triclinic space group P1. The asymmetric unit of this compound exhibits a MBZ molecule, a molecule of mesylate (methyl sulphonate) and one water molecule. Structural analysis showed that the molecule of the active principle presents intramolecular hydrogen bond assisted by resonance. In respect of intermolecular interactions, the presence of mesylate ion and the water cause the crystal packing is more compact than that shown by the solid forms reported in the literature by the presence of strong hydrogen bonding. These bonds give rise to the formation of endless chains in which molecules are joined by MBZ strong interactions involving ions mesylate. These chains in turn are arranged so as to form two-dimensional structures but joined by interactions between the molecules involving water which stabilizes the three-dimensional packaging. The 17β Estradiol valerate, used for treatment of menopause and in oral contraceptives, there has no literature characterization of the solid state. The same crystallized in the no centrosymmetric space group P2₁ with two molecules per asymmetric unit which show evidence of vibrational disorder in the chain terminal group valerate. Thermal analysis showed that this compound melting at 145°C and the process of decomposition of the sample occurs in 262°C. By analyzing the thermal behavior of this input at low temperature it was found that it presents a structural phase transition of first order in -22°C to lower the temperature and -16°C to rise. The structural characterization of this solid pharmacist 100K allowed observing the phase transition is related to a strong conformational change valerate group.

Os Insumos farmacêuticos ativos (IFA) são em sua maioria produzidos e comercializados na forma de formulações sólidas. A eficácia terapêutica de cada IFA, no entanto, está diretamente relacionada com suas características no estado sólido. Desta forma, o controle e o entendimento da química das características físico-químicas de estado sólido dos IFAs, como produtos formulados ou substâncias puras, é uma importante parte do processo de desenvolvimento de novos medicamentos. Dentro deste marco, o presente trabalho tem o intuito de obter e caracterizar novas formas sólidas de dois compostos farmacêuticos, sendo eles, o fármaco anti-helmíntico Mebendazol e o hormônio Estradiol 17β Valerato. A caracterização destes compostos foi realizada por meio da técnica de difração de raios X de monocristais e complementada com dados provenientes de outras técnicas tais como espectroscopia Infravermelho e Raman e análise térmica. A partir da amostra de mebendazol obteve-se um novo sal, o mesilato de mebendazol monohidratado que cristaliza no grupo espacial triclínico P1. A unidade assimétrica deste composto apresenta uma molécula de MBZ, uma molécula de mesilato (metil sulfonato) e uma molécula de água. A análise estrutural mostrou que a molécula do principio ativo apresenta ligação de hidrogênio intramolecular assistida por ressonância. No que diz respeito às interações intermoleculares, a presença dos íons mesilato e da água fazem com que o empacotamento cristalino seja mais compacto que o apresentado pelas outras formas sólidas reportadas na literatura devido à presença de ligações de hidrogênio fortes. Estas ligações dão lugar à formação de cadeias infinitas nas quais as moléculas de MBZ estão unidas por interações fortes envolvendo os íons mesilato. Essas cadeias por sua vez se arranjam de maneira a formar estruturas bidimensionais unidas entre si por interações envolvendo as moléculas de água, o que estabiliza o empacotamento tridimensional. O Estradiol 17β Valerato, utilizado para tratamento de menopausa e em pílulas anticoncepcionais, não apresenta na literatura nenhuma caracterização de estado sólido. O mesmo cristalizou no grupo espacial não centrossimétrico P2₁ com duas moléculas por unidade assimétrica as quais mostram evidencias de desordem vibracional na cadeia terminal do grupo valerato. A análise térmica mostrou que este composto funde a 145°C sendo que o processo de decomposição da amostra acontece em 262°C. Analisando o comportamento térmico desse insumo a baixa temperatura constatou-se que ele apresenta uma transição de fase estrutural de primeira ordem em -22°C ao descer a temperatura e em -16°C ao subir. A caracterização estrutural deste sólido farmacêutico a 100K permitiu observar que a transição de fase está relacionada com uma forte mudança conformacional do grupo valerato. / The active pharmaceutical ingredients (API) are mostly produced and marketed in the form of solid formulations. The therapeutic efficacy of each API, however, is directly related to its characteristics in the solid state. Thus the control and understanding of the chemistry of the physicochemical characteristics of solid state APIs as pure substances or formulated products, is an important part of the process of developing new drugs. Within this framework, this paper aims to obtain and characterize new solid forms of two pharmaceutical compounds, among them, the anthelmintic drug Mebendazole and hormone 17β estradiol valerate. The characterization of these compounds was performed by means of diffraction X-ray single crystal and supplemented with data from other techniques such as infrared and Raman spectroscopy and thermal analysis. From the sample mebendazole obtained a new salt, mesylate monohydrate mebendazole which crystallizes triclinic space group P1. The asymmetric unit of this compound exhibits a MBZ molecule, a molecule of mesylate (methyl sulphonate) and one water molecule. Structural analysis showed that the molecule of the active principle presents intramolecular hydrogen bond assisted by resonance. In respect of intermolecular interactions, the presence of mesylate ion and the water cause the crystal packing is more compact than that shown by the solid forms reported in the literature by the presence of strong hydrogen bonding. These bonds give rise to the formation of endless chains in which molecules are joined by MBZ strong interactions involving ions mesylate. These chains in turn are arranged so as to form two-dimensional structures but joined by interactions between the molecules involving water which stabilizes the three-dimensional packaging. The 17β Estradiol valerate, used for treatment of menopause and in oral contraceptives, there has no literature characterization of the solid state. The same crystallized in the no centrosymmetric space group P2₁ with two molecules per asymmetric unit which show evidence of vibrational disorder in the chain terminal group valerate. Thermal analysis showed that this compound melting at 145°C and the process of decomposition of the sample occurs in 262°C. By analyzing the thermal behavior of this input at low temperature it was found that it presents a structural phase transition of first order in -22°C to lower the temperature and -16°C to rise. The structural characterization of this solid pharmacist 100K allowed observing the phase transition is related to a strong conformational change valerate group.

Cancer remains one of the most pressing issues of contemporary science and medicine. Incidence of malignant diseases is rising worldwide and they represent a major problem for the society due to both economic and ethical issues they cause. Although the progress in cancer biology, therapy and immunology has led to the introduction of many novel therapeutic protocols, approaches and drugs with specificity defined on a molecular level into clinical practice, many malignancies retain their poor prognosis. Therefore, intense research into new ways to increase our therapeutic options is warranted. Unfortunately, bringing a completely novel drug into clinical use takes extremely high amounts of time and money and entails a high risk of failure. Therefore, a promising approach has been recently adopted which lies in repurposing compounds already used in human medicine for cancer treatment. This form of research can advance through clinical trials for a new indication much easier, faster and cheaper than researching completely new drugs. The aim of this study was to examine the anticancer potential of one such drug, mebendazole. An anthelminthic from the family of benzimidazoles, mebendazole has been in common clinical use from the 1970s and is marked by its low toxicity as well as its very low solubility....

<p>Mnogi lekovi registrovani za razne druge indikacije mogu da deluju selektivno na tumorske receptore, signalne puteve, metaboličke procese, bioenergetske faktore, enzime, proteine, gene koji reguli&scaron;u proliferaciju, apoptozu i neoangiogenezu tumora ne pogađajući ove procese kod zdravih ćelija. Uvođenje novih lekova je izrazito dug, složen i skup proces istraživanja. Kori&scaron;ćenjem principa otkrivanja antikancerskog efekta kod već registrovanih lekova za druge indikacije, direktno se utiče na skraćivanje vremena i tro&scaron;kova istraživanja. Eksperimentalno je ispitana efikasnost antitumorskog delovanja mebendazola, metformina, itrakonazola, diklofenaka, nitroglicerina i deoksiholne kiseline na fibrosarkom hrčka izazvan BHK21/C13 tumorskom ćelijskom linijom praćenjem veličine i histologije lečenih tumora. Eksperimentalno je ispitana mogućnost primene deoksiholne kiseline, nitroglicerina, kofeina i itrakonazola kao adjuvansa u kombinaciji sa pojedinim ispitivanim lekovima (metformin, itrakonazol, diklofenak) za lečenje fibrosarkoma hrčka. Kako je ispitivanje vr&scaron;eno na mladuncima imladim hrčkovima i kako su sarkomi najče&scaron;ći u dečijem uzrastu, definisanje potencijalne antikancerske uloge ispitivanih lekova se odnosi prvenstveno na njihovu primenu u pedijatriji. Pokazano je da metformin, kombinacije metformina sa kofeinom, metformina sa itrakonazolom i metformina sa nitroglicerinom deluju u pogledu svih ispitivanih parametara tumora antitumorski na fibrosarkom hrčka. Kofein, itrakonazol i nitroglicerin pojačavaju antitumorsko dejstvo metformina na fibrosarkom hrčka. Tokom svih eksperimenata realizovanih u okviru ove disertacije, pokazalo se da nije bilo delotvornog tretmana, koji ne sadrži metformin.</p> / <p>Many drugs registered for various other indications can act selectively to tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins, genes that regulate proliferation, apoptosis, and neoangiogenesis of the tumor without affecting these processes in the healthy cells. The introduction of new drugs is a very long, complex and expensive process of research. Using the principle of detecting the anticancer effect in already registered drugs for other indications, directly affects the reduction of time and cost of research. The efficacy of mebendazole, metformin, itraconazole, diclofenac, nitroglycerin and deoxycholic acid antitumor activity on hamster fibrosarcinoma induced experimentally by the BHK21/C13 tumor cell line was tested by monitoring the size and histology of the treated tumors. The possibility of using deoxycholic acid, nitroglycerin, caffeine and itraconazole as an adjuvant in combination with investigated drugs (metformin, itraconazole, diclofenac) for the treatment of hamster fibrosarcoma has been experimentally tested. As the examination was carried out on young cubs and young hamsters and that sarcomas are the most common in childhood, defining the potential anti-cancer role of the investigated drugs relates primarily to their application in pediatrics. Metformin, combinations of metformin with caffeine, metformin with itraconazole and metformin with nitroglycerin have shown antitumor action on the hamster fibrosarcoma in terms of all tested tumor parameters. Caffeine, itraconazole and nitroglycerin increase the antitumor effect of metformin on the hamster fibrosarcoma. During all the experiments carried out within this dissertation, there has been no effective treatment, which does not contain metformin.</p>