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By Y. Tukash. Salisbury State University. 2019.

The and determine the alcohol-insoluble cone has an inside bottom diameter of solids as prescribed in paragraph 7 order avanafil in united states online. As soon as the (4) Determine compliance as specified cone is filled avanafil 50mg, lift it vertically trusted avanafil 100mg. Dry and weigh each substandard quality specified in empty container and subtract the §130. Add enough water to new line as specified after the cor- bring the level within 9. Gently the canned corn fails to meet: wash the material on the sieve by com- (i)(a) or (ii)(a) "Excessive discolored ker- bined up-and-down and circular motion nels". Spread weight of the corn ingredient, deter- the husk flat and measure its aggre- mined by the procedure set forth in gate area and calculate the area per 600 §155. Take the standard of fill of container prescribed increase in volume as the aggregate in paragraphs (c)(1) and (2) of this sec- volume of the cob and calculate the tion, the label shall bear the general volume of cob per 600 g. Canned cream- ceeding in total 15 percent of the style field corn conforms to the stand- drained weight of the finished food. When butter, margarine, or frozen succulent seeds of the pea plant other vegetable or animal fats or oils of the species Pisum sativum L. Such food is sealed in a container or follow the name in the case of and, before or after sealing, is so proc- smooth-skin peas or substantially essed by heat as to prevent spoilage. In addition to peas or hybrids having similar charac- the optional packing media provided teristics. Where the peas are of sweet for in paragraph (a)(1) of this section, green wrinkled varieties or hybrids the following safe and suitable optional having similar characteristics, the ingredients may be used: name may include the designation (i) Salt. I (4–1–10 Edition) through a circular opening of a diame- weight is extraneous vegetable mate- ter of 7. The alco- (ii) The following shall be included as hol-insoluble solids of smooth-skin or part of the name or in close proximity substantially smooth-skin peas, such to the name of the food: as Alaska-type peas or hybrids having (a) A declaration of any flavoring similar characteristics, may not be that characterizes the food, as specified more than 23. The sum of the pea clared on the label as required by the material described in paragraphs (b)(1) applicable sections of parts 101 and 130 (i), (ii), (iii), (iv), and (v) of this section of this chapter. Not more (3) If the quality of canned peas falls than 2 percent of the drained weight is below the standard prescribed in para- blond and/or yellow peas, i. Not more than 5 substandard quality specified in percent of the drained weight is blem- §130. Not standard quality when the quality of more than 1 percent of the drained canned peas falls below the standard in weight is seriously blemished peas, i. Not more than 10 under paragraph (b)(1) of this section percent of the drained weight is pea which such canned peas fail to meet, as fragments, i. A container percent by count of the peas in the con- with lid attached by double seam shall tainer are ruptured to a width of 1. Canned dry peas con- acteristics of the fruit Lycopersicum forms to the definition and standard of esculentum P. The tomatoes may or may not ments for label declaration of ingredi- be peeled, but shall have had the stems ents, prescribed for canned peas by and calicies removed and shall have §155. Such that characterizes the product as speci- food is sealed in a container and before fied in §101. The name of onion, peppers, and celery, that may be the packing medium shall be preceded fresh or preserved by physical means, by the word "with". The meshes of such on the label as required by the applica- sieve are made by so weaving wire of ble sections of parts 101 and 130 of this 1. Without shift- ity for canned tomatoes is as follows: ing the tomatoes, so incline the sieve (i) The drained weight, as determined as to facilitate drainage of the liquid. The weight so found, less the quired to fill the container, as deter- weight of the sieve, shall be considered mined by the general method for water to be the drained weight. Fill the mixture od in which one-third the area of disc 1, into a black container to a depth of at and not more than one-third the area least 25. Free the mix- of disc 2, is exposed; ture from air bubbles, and skim off or (iii) Peel per kilogram (2. I (4–1–10 Edition) tomatoes fail to meet, to read as fol- soluble solids as defined in §155. One or any the total capacity of the container, as combination of two or more of the fol- determined by the general method for lowing safe and suitable ingredients fill of containers prescribed in may be used in the foods: §130. Prior to straining, food-grade as set forth in paragraph (a)(3)(iii) of hydrochloric acid may be added to the this section, the diluted article will tomato material in an amount to ob- contain not less than 5. Water may be added to adjust (a) The statement "Made from" or the final composition. Deter- and redness of color as prescribed in mine compliance as specified in §155. A lot shall be deemed to be in (ii) Whole seeds—Weigh out 600 grams compliance for tomato soluble solids as (21 ounces) of the well-mixed, diluted follows: concentrate; place a U. Deter- adjust the pH, and in compliance with mine compliance as specified in §155. Prior to corresponding paragraph(s) under para- straining, food-grade hydrochloric acid graph (b)(1) of this section which such may be added to the tomato material tomato concentrate fails to meet, as in an amount to obtain a pH no lower follows: than 2. Such acid is then neutralized with food-grade sodium hydroxide so (i) "Poor color. The food is preserved by heat than 90 percent of the total capacity, sterilization (canning), refrigeration, except when the food is frozen. When sealed in a container (2) Determine compliance as specified to be held at ambient temperatures, it in §155. One or any combina- paragraph (c) (1) and (2) of this section, tion of two or more of the following the label shall bear the general state- safe and suitable ingredients in each of ment of substandard fill specified in the following categories is added to the §130. Catsup, (iii) Spices, flavoring, onions, or gar- ketchup, or catchup is the food pre- lic. Report the average of two or tional tomato ingredient specified in more readings, excluding any that ap- paragraph (a)(1)(iv) of this section or pear to be abnormal. Each of the in- the standard prescribed in paragraphs gredients used in the food shall be de- (b) (1) and (2) of this section, the label clared on the label as required by the shall bear the general statement of applicable sections of parts 101 and 130 substandard quality specified in of this chapter; except that the name §130. The (ii) When the food is packaged in in- trough must also be at a temperature dividual serving-size packages con- close to 20 °C. Side-to-side level may be ad- (3) If the catsup falls below the stand- justed by means of the built-in spirit ard of fill prescribed in paragraphs (c) level. Transfer sample to the dry sam- (1) and (2) of this section, the label ple chamber of the Bostwick shall bear the general statement of Consistometer. Fill the chamber substandard fill as specified in slightly more than level full, avoiding §130.

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The economies of scale provided by industrial-scale sequencing have hastened progress to the point where at least two companies now have the majority of expressed human genes in their freezers order genuine avanafil on-line. This has certainly had the effect of restricting access to key therapeutic genes avanafil 50 mg line, but on the other hand subscribers to these proprietary databases have early access to information which would not otherwise be available order avanafil 50 mg amex. At the moment, the main beneficiaries of this commercial effort are pharmaceutical and biotech companies who see such access as conferring a significant competitive advantage on their research and development activities. Although there are as yet no methodologies for real-time gene expression observations, the attempt by companies such as Incyte and Affymetrix to place whole genomes on silicon chips, together with the advent of continuous flow hybridization approaches, promises a much greater depth to temporal analysis of complex biological processes than hitherto possible, bringing with it new opportunities for defining appropriate therapeutic intervention points in complex biological cascades. This information can now be complemented by hybridization array approaches, in which the expression of defined subsets of genes (or indeed the expression of entire genomes) can be carefully monitored at high volume across specific time courses and dose regimens, providing a degree of accuracy and reproducibility in determining the level of gene expression which sequencing alone cannot achieve. Together, sequencing and arraying techniques can be used to provide information on both the biology of disease and the behavior of compounds as they impact a biological system. The scientific basis of hybridization arraying as a technique for the determination of gene expression levels is shown in Figures 15. A full description of these hybridization arraying approaches has been published and is also available on the Web (see Table 15. Access to comprehensive sequence databases and the bioinformatics tools to analyze them plays a central role in these gene expression monitoring approaches, illustrating their “reach-through” impact in genomics in general. A further technique which holds considerable promise for evaluating individual gene expression at the histological or cellular level is in situ hybridization. This provides a cellular level of resolution to gene expression analysis which complements that of microarray analyses. All the above techniques have major potential applications in drug delivery, from defining new members of key transporter and receptor gene families and their expression, to providing experimental systems for evaluating the efficacy of new delivery systems. Similar databases will undoubtedly emerge from mammalian systems as mammalian cell genome closure and proteomics advance. Systematic approaches to biological function are encompassed within the broad area of “functional genomics”. For most of this century, our knowledge of cell biology has been primarily descriptive, reproducible in vitro work dating only from the 1960s. From the ability to induce neuronal cell differentiation to the observation of cellular apoptosis, cell culture is now offering radically new insights into the way in which genetic programs are executed at a functional level. The advent of genomic biology places cell structure and structural biology in a new context. Processes fundamental to cell biology, such as protein translocation and apoptosis, can now be seen as variations on an evolutionarily conserved theme. For drug discovery and delivery, this growing knowledge of cell biology is extremely useful. Not only has an intimate appreciation of cellular processes behind disease revealed new therapeutic targets, the inner workings of the cell have now become accessible to exploitation. The development of cell-based screening technologies, ranging from yeast-based screening to reporter gene assays, underlies the increasing trend towards directly harnessing cell biology to drug discovery. Cell-based systems are biology’s way of dividing the expressed genome into functional units. In drug discovery, a focus on specific cell systems, such as T-cells and fibroblasts for assembly of human immunodeficiency virus or herpes simplex virus particles and endothelial cells for demonstrating adhesion- dependent processes, often provides convenient primary drug screening systems. Other single cell systems, such as yeast, and even entire organisms, such as Caenorhabditis elegans, have themselves been positioned as cell-based screening systems, capable of relatively high-throughput screening using appropriate reporters, or even visual analysis. The value of such systems for functional genomics and genetic engineering has been greatly enhanced by access to genome sequences of both organisms, and they may provide new and sensitive ways of examining the potential of new delivery mechanisms. Proteomics may therefore be more useful than genomics for identifying therapeutic targets within the cell. Until recently the development of proteomics was limited by the availability of technology to reproducibly separate protein components from the cellular pool and to specifically identify the protein sequence of small amounts of protein products. The development of 2 D polyacrylamide gels which separate proteins according to molecular weight in one dimension and charge in the other direction has provided a high- resolution quantitative method for separation of low levels of expressed proteins. Tissue extracts are pooled and initial protein purification undertaken using ion-exchange and affinity chromatography. The resultant protein fractions are further separated by reverse-phase high performance liquid chromatography. The bands are identified using standard techniques such as silver or fluorescent dyes and the expression profile may be used to compare expression of proteins in normal and diseased tissue or to examine changes in expression under stress conditions or following drug administration. In this way proteins associated with different diseased or stress conditions can be identified and the changes in protein expressions, for example, due to drug metabolism may be identified. The specific proteins may be identified by in situ digestion and analysis by mass spectrometry. Recent developments in this technology have resulted in the technique being accepted as the primary tool for high- throughput, high-sensitivity protein analysis. The identification of the mass of individual peptide fragments allows the analyst to search genomic and protein sequence databases in order to find genes and/or proteins which would be expected to give the same fragmentation patterns. A highly matched database sequence will provide the full sequence and identify the protein. Although reliable, this technique may lead to false positive results in some cases. To overcome this problem many proteomic companies are now adopting the technique of tandem mass spectrometry to unambiguously identify protein sequences. This technique subjects proteins to successive routines of fragmentation and mass analysis in order to provide the actual amino acid sequence. Mode of drug action 372 By probing drug treated cells for expression of genes and proteins it may be possible to more precisely identify the specific mode of action of a drug of known therapeutic value, for example natural herbal remedies, thereby offering opportunities to develop new drugs for such therapeutic conditions. Toxicology The monitoring of expression of certain genes and proteins in, for example, hepatic cells offers a means of detecting upregulation of metabolic enzymes such as P450 isoenzymes. Similarly, such profiling may also provide opportunities to identify the mechanisms of drug toxicity of therapeutic agents in order to design new drugs to overcome these problems. Clinical applications These technologies will also allow the screening of patients for particular diseases or metabolic polymorphisms, which may dictate whether a patient is a rapid or slow metabolizer of certain drugs. Such response markers will allow more stringent selection criteria to be applied to clinical trials selection and could also be used to more specifically adjust a drug dosing regimen to a particular patient’s metabolic profile. Such diagnostic screens allow more effective patient treatment and the development of therapeutic agents specifically designed for the treatment of specific patient subpopulations. In the future these screening techniques will allow us to more readily identify upregulated enzymes in diseased tissues which will facilitate the development of prodrug-based technologies for the site-specific chemical delivery of drugs to these diseased cells. The identification of surface-expressed disease-specific ligands will allow targeting of polymeric and microparticulate drug delivery systems to these particular diseased cells through the use of molecular entities specifically targeted against these ligands. It is clear that genomics and proteomics are complementary in that genomics has an important role in providing data for elucidating amino acid sequences identified through proteomics, and proteomics provides a means of identifying those genes which have functional importance. The identification of future therapeutic targets will be driven by cross-fertilization between these two disciplines through bioinformatics. A perfect prodrug is a molecule which has no intrinsic pharmacological activity until it is converted enzymatically to a new molecular form which displays pharmacological activity. In principle, prodrug activation simply mirrors activation processes which are used widely in biological systems to regulate important enzymatic cascades.

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Desmosomes provide strong points of cohesion between cells and act as anchorage points for the cytoskeleton of each cell cheap avanafil 100mg overnight delivery. Gap junctions (nexus) are broad areas of closely opposed plasma membranes avanafil 100 mg generic, but there is no fusion of the plasma membranes and a narrow gap order avanafil line, of about 2 to 3 nm wide, remains. The “gap” is crossed by cytoplasmic filaments, which allow intracellular cytoplasm to transfer between cells. This type of cell junction not only functions as an adherent zone, but also permits the passage of ions and other small molecules (sugars, amino acids, nucleotides and vitamins). Junctional complexes comprise intercellular membrane specializations which encircle the cells, preventing access of luminal contents to the intercellular spaces. They are found between the cells of simple cuboidal (for example in the lungs) and simple columnar (for example in the gastrointestinal tract) epithelia, and lie immediately below the luminal surface. They are made up of three components: (i) tight junctions (zonula occludentes), which consist of small areas where the outer lamina of opposing plasma membranes are fused with one another, via specific proteins which make direct contact across the intercellular space. A fine mat of filamentous material is present on the cytoplasmic aspect of these junctions. Biochemical barriers 9 In addition to a physical barrier, the epithelia also present a biochemical barrier to drug absorption, in the form of degradative enzymes. For example, the gastrointestinal tract contains a wide array of enzymes, which are present in a variety of locations: • the lumen; • adsorbed to the mucus layer; • the brush-border (microvilli) of the enterocytes; • intra-cellular (free within the cell cytoplasm and within cellular lysosomes); • the colon (colonic microflora). Enzymes in the gut lumen include proteases, glycosidases and lipases, which are highly efficient at breaking down proteins, carbohydrates and fats from foodstuffs, so that they can be absorbed to make energy available to the body. However, these enzymes (and the enzymes present in the other locations in the gastrointestinal tract) can also degrade drug molecules, deactivating them prior to absorption. For example, the metabolizing enzyme cytochrome P450 on the microvillus tip is associated with a significant loss of drugs. Drugs that are orally absorbed must also first pass through the liver, via the portal circulation, prior to reaching the systemic circulation. The loss of drug activity due to metabolism in the gut wall and liver prior to reaching systemic circulation is termed the “first-pass” effect. In some cases this pre-systemic metabolism accounts for a significant, or even total, loss of drug activity. Thus the gastrointestinal tract poses a formidable challenge to the delivery of enzymatically labile drugs, such as therapeutic peptides and proteins. The extremely high metabolic activity of the gastrointestinal tract has been a major impetus in the exploration of alternative routes for systemic drug delivery. In comparison to the oral route, much less is known about the nature of the enzymatic barrier presented by the buccal, nasal, pulmonary, dermal and vaginal routes. However, it is generally accepted that such routes have a lower enzymatic activity, particularly towards drugs such as peptides and proteins. Furthermore, such routes also offer the advantage of avoiding first-pass metabolism by the liver. Efflux systems In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i. Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. Some of these efflux systems seem to involve P-glycoprotein, the principal component of multidrug resistance in a variety of cell types. As these efflux systems are located on the apical surface of the plasma membrane, it can be assumed that their physiological role is to restrict transcellular flux of some molecules. The rate of passive diffusion follows Fick’s Law, which is described in detail below. Passive diffusion is driven by a concentration gradient and is inversely related to molecular weight. This route is therefore not suitable for large molecular weight drugs, which are too large to cross between cell junctions. One approach to enhancing drug absorption via this route is to temporarily damage the integrity of the tight junctions using certain types of penetration enhancers. Obviously this approach has considerable toxicological implications, both directly, by damaging the epithelial interface and also indirectly, by increasing the permeability of the epithelium, thereby increasing the possibility of entry of potentially harmful substances. Transcellular passive diffusion Low molecular weight and lipophilic drug molecules are usually absorbed transcellularly, by passive diffusion across the epithelial cells. With respect to passive diffusion, the outer membrane of the epithelial cell may be regarded as a layer of lipid, surrounded on both sides by water (Figure 1. Thus for transport through the apical membrane, there are three barriers to be circumvented: • the external water-lipid interface; • the lipid membrane; • the internal lipid-water interface. In the process of passive diffusion: • lipid-soluble substances move into the lipid membrane according to their lipid/water partition coefficient; • molecules then diffuse across the lipid phase according to the concentration gradient established between the apical and basolateral sides of the membrane; • the molecules distribute out at the other side of the membrane, according to their lipid/water partition coefficient. The rate of diffusion through the membrane follows Fick’s Law, which states that the rate of diffusion across a membrane is proportional to the difference in concentration on each side of the membrane: (Equation 1. C –C where C and C denote the drug concentrations on the outsideo i o i and the inside of themembrane, respectively. Thus a drug molecule, driven by the concentration gradient, diffuses through the apical cell membrane and gains access to the inside of the cell. The molecule then diffuses through the epithelial cell and subsequently diffuses out through the basolateral membrane, to be absorbed by the underlying blood capillaries (Figure 1. Another possibility is that certain drugs, of appropriate partition coefficients, would preferentially remain within the lipid bilayer of the plasma membrane, rather than partitioning out into the cell cytoplasm. Such moieties could thus diffuse along the lipid bilayer of the membrane, down the side of the cell (rather than through it), emerging finally at the basolateral surface of the cell. However this scenario is limited by the fact that the lipid membrane constitutes a minute proportion of the available surface area of the cell; also cell junctions can act as diffusion barriers within the lipid bilayer of the plasma membrane. In some cases, for example in stratified epithelia such as that found in the skin and buccal mucosa, the epithelial barrier comprises a number of cell layers rather than a single epithelial cell. Thus the effective barrier to drug absorption is not diffusion across a single membrane as described above, but diffusion across the entire epithelial and endothelial barrier, which may comprise several membranes and cells in series. The driving force for absorption is, again, the concentration gradient and the process is governed by Fick’s Law. However, in this case, the concentration gradient driving absorption comprises the gradient established across the entire effective barrier, from the epithelial surface to the circulating blood. It should be noted, however, that even though the barrier to drug absorption may actually comprise several membranes and cells in series, it would appear that, generally, it is ultimately the apical plasma membrane which is rate-limiting for drug absorption. Thus in transcellular passive diffusion, the epithelium is assumed to act as a simple lipophilic barrier through which drugs diffuse and the rate of diffusion correlates with the lipid solubility of the drug. The circulating concentration of the drug is reduced by one or more of the following factors: • distribution into body tissue and other fluids of distribution; • binding to plasma proteins; • metabolism and excretion. As a consequence, the concentration of drug in systemic circulation is negligible in comparison to the drug concentration at the absorption surface. When sink conditions occur, it ensures that a large concentration gradient is maintained throughout the absorption phase, thereby enhancing the driving-force for absorption. In active absorption, carriers may transport substrates against a concentration gradient, in an energy- consuming process.

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She is a fellow in the Infectious Diseases Society of America and the American College of Physicians buy cheap avanafil line. Centers for Disease Con- trol and Prevention cheap avanafil, the Academic Advisory Committee for the National Institute of Public Health in Mexico cheap 50mg avanafil overnight delivery, and on four committees for the Insti- tute of Medicine of the National Academies, including the Committee on Emerging Microbial Threats to Health in the 21st Century. She has worked in Haiti at the Albert Schweitzer Hospital and leads the Harvard–Brazil Collaborative Course on Infectious Diseases, which is taught in Brazil. In 1996 she was a resident scholar at the Bellagio Study Center, Italy, and in 2002 she was a fellow at the Center for Advanced Study in the Behavioral Sciences in Stanford, California. Wilson was member of the Pew Na- tional Commission on Industrial Farm Animal Production whose report, Putting Meat on the Table: Industrial Farm Animal Production in America, was released in the spring of 2008. A former GeoSentinel site director, she now serves as a special advisor to the global GeoSentinel Surveillance Network. She has lectured and published widely, serves on several editorial boards, and is an associate editor for Journal Watch Infectious Diseases. She is the author of A World Guide to Infections: Diseases, Distribution, Diagnosis; senior editor, with Richard Levins and Andrew Spielman, of Dis- ease in Evolution: Global Changes and Emergence of Infectious Diseases; and editor of the volume New and Emerging Infectious Diseases, published Copyright © National Academy of Sciences. Yadav’s research explores the func- tioning of pharmaceutical supply chains using a combination of empirical, analytical, and qualitative approaches. His more recent work involves sup- ply chains for medicines in sub-Saharan Africa and other poor countries. In this work he collaborates closely with leading policy organizations and philanthropic foundations. He is the author of many scientifc publications and his work has been featured in prominent print and broadcast media. Yadav obtained his bachelor’s degree in engineering from the Indian Institute of Technology, his M. Before academia, he worked for many years in the area of pharmaceutical strategy, analytics, and supply chain consulting. Government Work Against Pharmaceutical Fraud Catherine Hill-Herndon, Director, Offce of International Health and Biodefense, U. Department of Justice Jeffery Gren, Director, Offce of Health and Consumer Goods, U. Manager of the Campaign for Access to Essential Medicines, Doctors Without Borders Ann Marie Kimball, Moderator Copyright © National Academy of Sciences. Committee members discussed the report and potential conclusions and recommendations. Goyal, Additional Secretary and Director General, Central Government Scheme, Ministry of Health and Family Welfare Arun Panda, Joint Secretary, Ministry of Health and Family Welfare 12:30-1:30 Lunch Copyright © National Academy of Sciences. Appaji, Director General, Pharmexcil India Meghana Inamdar, General Counsel and Managing Consultant, Sidvim Lifesciences Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs Copyright © National Academy of Sciences. Structure function analysis of Leishmania sirtuin: an ensemble of in silico and biochemical studies. Characterization of the anti-Leishmania effect induced by cisplatin, an anticancer drug. The synthesis and the in vitro cytotoxicity studies of bisnaphthalimidopropyl polyamine derivatives against colon cancer cells and parasite Leishmania infantum. Differential effects of polyamine derivative compounds against Leishmania infantum promastigotes and axenic amastigotes. A Leishmania infantum cytosolic tryparedoxin activates B cells to secrete interleukin-10 and specific immunoglobulin. Leishmania cytosolic silent information regulatory protein 2 deacetylase induces murine B-cell differentiation and in vivo production of specific antibodies. Flurazepam inhibits the P-glycoprotein transport function: an insight to revert multidrug-resistance phenotype. Evaluation of the immune response following a short oral vaccination schedule with hepatitis B antigen encapsulated into alginate-coated chitosan nanoparticles. The Faculty of Pharmacy of the University of Porto (Portugal), the Institute for Molecular and Cell Biology of the University of Porto (Portugal) and the Institut de Recherche pour le Développement, Montpellier (France) provided the facilities and logistical supports. Anabela, thank you for the opportunity to give my first steps in the research under your supervision, when I was still a university th student in the 4 year of the course. Thanks also, for your guidance, demand, encouragement, trust and of course, your unconditional support during all of these years. To Dr Ali Ouaissi, I would like to thank you for the advices, guidance and support. Thank you also for the interesting discussions and for the opportunity to work with you. I would like to thank the former head of the Biochemistry department of the Faculty Pharmacy of Porto University, Prof. Fernando Sena Esteves, not only for the facilities provided to perform my work during these years, but also for his support. Of course, to all members of the Parasite Disease group, with whose, I have shared physic and intellectual space, thanks for your friendship and motivation. A special thank for all the help and support (by seniority reasons…), goes to Marta Silva, Ricardo Silvestre, Nuno Santarem and Sofia Lima. Salette Reis of the Physic Chemistry department, and also to all the members of Toxicology department of the Faculty Pharmacy of Porto University for their prompt contribution in providing the facilities and/or the means in several situations of my research, without which it would be impossible to perform some experiments. To Madalena Pinto (Madazinha…), Lucilia Saraiva, Helena Castro and Helena Vasconcelos thank you so much for your friendship, support and motivation. I thank also all the members of the Biochemistry department of the Faculty Pharmacy of Porto University. To my dear Alexandra Ferreira I acknowledge her valuable help in the English revision of this dissertation (Is it correct? Esta tese é dedicada a vocês, uma vez que reflecte toda a educação, apoio incondicional, e amor que sempre me deram, e me permitiu atingir este ponto. Como os últimos sao sempre os primeiros, para ti, meu Germano, não existem palavras que me permitam agradecer-te por tudo. Sem a tua constante presença, ajuda, apoio, compreensão, paciência, conselhos, força e confiança esta tese não teria sido possível, de modo que a dedico também a ti. Disease control is dependent on drug therapy, since no approved human vaccine is available. However, the existing therapy is far from satisfactory owing to the emergence of resistances, toxicity and its limited efficacy due to disease exacerbation, mainly associated with compromised immune capability. Even though this strategy was effective in identifying N-(2- xiii fluorophenyl) nicotinamide, which can be used for lead designing, it failed to identify a truly potent and selective lead compound. En effet, les techniques de génétique inverse ont permis de démontrer que le gène était essentiel pour la survie des formes amastigotes. Ces observations peuvent avoir une implication dans le remodelage du cytosquelette au cours de la différenciation du parasite. Cependant, d’autres modifications sont nécessaires pour améliorer la performance de ce composé.