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1. General Introductionmucosa, and then dissemination follows. In contrast to the immuno-compromised host, inwhich MAC disease is usually limited to the lungs, in patients with AIDS, bacteremia is byfar the most common syndrome. Before the 1980s, infections with these bacteria wereuncommon in humans and were recognized as a slowly progressing pneumonitis in elderlypatients with chronic pulmonary disorders, particularly in patients with silicosis (18) and,occasionally, immunocompromised leukemic patients (19). Since 1981, however, numerousmedical institutions began to report cases of MAC bacteremia in AIDS patients (20) whichwere responsible for significant morbidity and mortality in human immunodeficiency virus(HIV)-positive patients (21). Disseminated infections with MAC organisms are diagnosed inonly 3% of HIV-positive patients at the time of AIDS diagnosis (22). However, theseinfections are found in about half of the autopsied patients with AIDS (23). MAC isolates areintracellular pathogens resistant to many of the standard antituberculosis drugs. In many casesthis resistance is due to the low levels of drug permeation into macrophages, as manyantibiotics are unable to traverse the cell membranes, making it difficult to achieve sufficientconcentrations at the infection sites (24, 25).Nevertheless, it was not until the post-human immunodeficency virus (HIV) era, that renewedinterest became widespread in mycobacterial diseases in the immunocompromised host.Several reasons for such interest are the following. First, re-emergence of TB in countrieswhere this type of disease was in the way of eradication, was puzzling. Second, MOTT thatwere generally quite rarely isolated before the advent of AIDS, but represented before therecently used efficient antiretroviral therapies, have a considerable role in morbidity andmortality. This was particularly true for the M. avium complex (MAC) because theseorganisms are the single most important cause of disseminated bacterial infection in AIDSpatients (26). Third the number of cases of infection with multiply-drug-resistant (MDR) ofMT and MAC is increasing and this has compromised both treatment and control programmesworldwide. The rising prevalence of MDR strains has resulted in outbreaks and individualcases that are a problem to treat and are often fatal. Worldwide, TB and disseminated MACdisease, both contribute substantially to morbidity and mortality in this population.Among the mycobacterial genus, the vast majority of species are saprophytic belonging to theenvironmental microflora. They are present at different latitudes, and could be isolated fromsoil, and water. Mycobacteria are aerobic, Gram-positive, non-motile bacilli with a highmycolic acid content in their cell wall that enables intracellular survival within mononuclearphagocytes.12
1. General IntroductionABFigure 1.1:Mycobacterium Tuberculosis MT (A) and Mycobacterium Avium Complex MAC (B)Being intracellular survivors, Mycobacteria species evoke a granulomatous topyogranulomatous host response. Mycobacteria can be grouped conceptually into threecategories: (1) obligate parasites that behave as primary pathogens and require a mammalianhost to that comprise the tubercle bacilli (Mycobacterium tuberculosis (MTB),Mycobacterium bovis (MB) and Mycobacterium microti(MM)), (27, 28, 29, 30, 31); (2)saprophytes that can behave as facultative pathogens, causing localised or systemic diseasedepending on the degree of host compromise; these can be divided further into slow growers,such as the Mycobacterium avium intracellulare complex (MAC), Mycobacterium genavense(MG) and Mycobacterium xenopi (MX), or rapid growers, such as Mycobacterium fortuitum(MF), Mycobacterium chelonae (MC), Mycobacterium smegmatis (MS), Mycobacteriumphlei (MP) and Mycobacterium thermoresistible (MTH); and (3) Mycobacteria species sodifficult to culture that their environmental niche has not been determined with certainty,including Mycobacterium leprae (ML), Mycobacterium visibilis (MV),(31, 32, 33, 34, 35).The natural history of pathological and casual opportunist mycobacteria diseases differ due todifferent tissue tropisms: the MOTT opportunists appear to be more limited than M.tuberculosis in parallel with the experimental observations of more limited virulence. Forinstance, experimental infection with M. tuberculosis is often lethal in normal non-immunocompromisedmice, in contrast virulent strains of M. avium infection are only lethal inimmunodeficient mice (36).MTB was first described on 1882 by Robert Koch, and the M. Tuberculosis genome wassequenced (37, 38) in 1999. MTB divides every 15 to 20 hours, extremely slowly compared toother bacteria, which tend to have division times measured in minutes. It is a small, rod-likebacillus that can withstand weak disinfectants and can survive in a dry state for weeks but cangrow only within a host organism. An important consideration in the treatment of tuberculosis13
Page 1: European Union Ministero dell’Uni
Page 5 and 6: Table Of Contents1. GENERAL INTRODU
Page 7: 7.1.4. Release Studies/Stability St
Page 10 and 11: 1. General Introduction1.1. Pulmona
Page 14 and 15: 1. General Introductionis the fact
Page 16 and 17: 1.3. Lung Anatomy1. General Introdu
Page 18 and 19: 1. General Introductionhighly vascu
Page 20 and 21: 201. General Introductionliquid (84
Page 22 and 23: 1. General IntroductionAerosol size
Page 24 and 25: 1. General Introductionof numerous
Page 26 and 27: 1. General Introductionintermittent
Page 28 and 29: 1. General Introductionsphere prepa
Page 30 and 31: 1. General Introductionit, respecti
Page 32 and 33: 1. General Introductionthe subject
Page 34 and 35: 1. General IntroductionA. zahoor et
Page 36 and 37: 2. Chitosan And PLGA2.1. Chitosan a
Page 38 and 39: 2. Chitosan And PLGAfor the prepara
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Page 44 and 45: 2. Chitosan And PLGAneed to be a go
Page 46 and 47: 2. Chitosan And PLGAdichloromethane
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Page 51: 3. Aim of the WorkBiodegradable mic
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4. RFP Loaded Chitosan Microspheres
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5. Rifampicin Loaded ChitosanMicros
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8. Final Discussion and Conclusions
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9. References9. References1. Fred S
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9. References40. Wayne L.G., Good R
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1269. References88. Carpenter R.L.
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1289. References135. Fukushima S.;
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9. References173. Zeng X.M., Martin
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9. References219. Berthold A., Crem
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9. Referencesmediates target gene e
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