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173 Cards in this Set
- Front
- Back
What are 4 anti fungal classes?
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Polvenes, allyl aminies, azoles, eschinocandins
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At the cellular level, the greatest difference between fungal cells and mammalian cells is the what?
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that fungal cells have cell walls but that mammalian cells do not
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. Inhibitors of bacterial cell wall biosynthesis, such as ____ and ____ have provided many powerful antibacterial agents with little toxicity to humans.?
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penicllins and cephalosporins
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which would be expected to be potent antifungals yet have little human toxicity. Only recently, however, have a few potent inhibitors of ___ ___ ___ ___ have become avaliable for clinical use?
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of fungal cell wall biosynthesis
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The difference between fungal and mammalian cells that is most widely exploited, however, is that the cell membranes of fungi and mammals contain different what?
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sterols
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Sterols are important structural components of fungal and mammalian cell membranes and are critical to the proper functioning of many what?
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cell membrane enzymes and ion-transport proteins.
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Mammalian cell membranes contain what? whereas fungi contain ?
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cholesterol as the sterol component
ergosterol |
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Although the two sterols are quite similar, the side chains are slightly different, and when three-dimensional models are constructed, the ring system of ergosterol is slightly ____ because of the additional ___ ___ in the B ring
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flatter
double bonds |
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Most fungal infections are caused primarily by various what?
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yeasts and molds
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Yeasts typically grow as what?
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single oval cells and reproduce by budding
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Candida albicans and some other pathogenic yeasts also can grow in multicellular chains called what?
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hyphae
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. Infection sites may contain both yeast and hyphal forms of the microorganism. True or False
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True
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Molds, such as Trichophytonrubrum, one of the causative agents of ringworm, grow in clusters of hyphae called what?
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mycelium
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All fungi produce what?
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spores
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All fungi produce spores, which may be transported how?
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by direct contact or through the air
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Although most topical fungal infections are readily treated, the incidence of life threatening systemic fungal infections, including those caused by yeasts such as ____ and molds such as ___ ____ are increasing and mortality remains high
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Candida albicans
Aspergillusfumigan |
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The fungal kingdom includes what?
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yeasts, molds, rusts, and mushrooms
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Most fungi are what?
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saprophytic
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What does saprophytic mean?
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means that they live on dead organic matter in the soil or on decaying leaves or wood
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There are relatively few what among the fungi?
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obligate animal parasites
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what are obligate animal parasites
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microorganisms that can only live on mammalian hosts)
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The obligatory parasites are limited to what?
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dermatophytes
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The obligatory parasites are limited to dermatophytesthat have evolved to live on/in the ____ and___ of mammals?
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kertain-containing hair and skin
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The obligatory parasites are limited to dermatophytesthat have evolved to live on/in the keratin-containing hair and skin of mammals, where they cause diseases such as what 2?
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ringworm and athletes foot.
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IS Ringworm cause by a parasitic worm?
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No
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Dermatophytes are fungi causing infections of what 3?
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skin, hair, and nails
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The dermatophytes obtain nutrients from attacking what?
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from attacking the cross-linked structural protein keratin
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Dermatophytic infections, known as what?
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tinea
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Dermatophytic infections, known as tinea, are caused by various species of three genera which are what?
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Trichophyton, Microsporum, and Epidermophyton)
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Tineacapitis effects what?
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hair and scalp
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tineapedis ?
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feet
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tineamanuum?
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hands
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tineacruris?
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groin
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tineaunguium?
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fingernails
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The most common cause of yeast infections is what?
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Candida albicans
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The most common cause of yeast infections is Candida albicans, which is part of the normal flora in a significant portion of the population where it resides in the where?(4)
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oropharynx, gastrointestinal tract, vagina, and surrounding skin
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Yeast infections commonly occur in what?
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mucosal tissue when the normal population of flora has been disturbed by treatment of a bacterial infection with an antibiotic or when growth conditions are changed by hormonal fluctuations, such as occur in pregnancy.
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Thermally Dimorphic Fungi (Endemic Mycoses) are what?
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saphyophytes
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Thermally Dimorphic Fungi (Endemic Mycoses) are saprophytes that grow how?
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in one form at room temperature and in a different form in a human host at 37°C
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Thermally Dimorphic Fungi (Endemic Mycoses) live where? How do they cause disease?
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All these organisms live in soil and cause disease through inhalation of contaminated dust.
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What may transport the organims to different tissue? What can happen?
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The circulatory system may transport transport the organisms to other tissues, where the resulting systemic infection may be fatal.
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These fungi are endemic to dry areas of which areas in which countries?
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southern and southwestern United States and northern Mexico
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Where is thermally dimorphic fungi prevalent?
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It is particularly prevalent in the San Joaquin Valley of California, hence the name valley fever.
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________ is endemic to the Mississippi and Ohio River valleys of the United States, where nearly 90% of the population tests positive for exposure to the organism.
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Histoplasmacapsulatum
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What kind of mold species are found worldwide and are virtually ubiquitous in the environment.
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Aspergillu
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Because Aspergillus spores are everywhere what is the most common route? What others are possible?
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inhalation is the most common route of inoculation, but infection through wounds, burns, and implanted devices (e.g., catheters) also is possible
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_______ aspergillosis is a major source of infection in persons with leukemia and in those receiving organ or bone marrow transplants.
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Nosocomial(hospital-derived)
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What is Polyenes MOA?
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disruption of ergosterol-containing membranes
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What is Azoles (Imidazoles and Triazoles) MOA?
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inhibition of ergosterol biosynthesis (14α-demethylase enzyme)
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What is Allyl amines MOA?
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inhibition of ergosterol biosynthesis (squaleneepoxidase enzymes)
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What is Morpholines MOA?
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inhibition of ergosterol biosynthesis (Δ14-reductase and Δ8,Δ7-isomerase enzymes)
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What is Eschinocandins MOA?
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Inhibitors of cell wall biosynthesis (β-1,3-glucan synthase enzyme)
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Polyeneshave an affinity for what membranes?
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sterol-containing membranes
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The membranes of cells treated with polyenes become leaky, and eventually, the cells die because of the loss of what?
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essential cell constituents, such as ions and small organic molecules
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. Polyenes have a demonstrably higher affinity for membranes containing ___ over ____ containing membranes
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ergosterol over cholesterol
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The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon _____?
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squalene.
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Squalene is converted to ____ by th eenzyme ___?
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squaleneepoxideby the enzyme squaleneepoxidase (1).
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Squaleneepoxide is then cyclized to ___?
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lanosterol, the first steroid in the biosynthetic pathway
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Lanosterol is demethylated by what?
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14α-demethylase (2).
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Conversion of the side chain of lanosterol to the side chain of ___ involves action of ______ and _____
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ergosterol involves the acttion of Δ14-reductase (3) and Δ8,Δ7-isomerase (4) enzymes.
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All the azoles (imidazoles or triazoles) act by inhibiting what?
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ergosterol biosynthesis through inhibition of the 14α-demethylase enzyme (Site 2).
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The mechanism of action of the azoleagricultural antifungalsis identical to that of the agents used for what infections?
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for mammalian infections (inhibiting ergosterol biosynthesis)
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All of the allyl amines act by through the inhibition of the enzyme
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squaleneepoxidase (Site 1).
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What 3 drugs are not used to treat human disease but have wide utility in protecting crops from phytopathogenic fungi.
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he morpholines, fenpropimorph and tridemorph,
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_____ is the only drug in this class that is employed clinically in the treatment of human fungal infections?
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Amorolfine
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. Morpholine antifungals inhibit ergosterol biosynthesis by acting on the enzymes ____ and ____?
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Δ14-reductase and Δ8,Δ7-isomerase (Site 3 and 4).
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Fungal cells have a cell wall and mammalian cells do not. True or False
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True
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____ interfere with cell wall biosynthesis through inhibition of the enzyme ____ _____
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Echinocandins
β-1,3-glucan synthase |
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β-Glucan is an important polymer component of many what>
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fungal cell walls, and reduction in the glucan content severely weakens the cell wall, leading to rupture of the fungal cell.
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_____ is an iodinated acetylene active against dermatophytes
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Haloprogin
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Haloprogin is only used for what?
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topical applications
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Haloprogin has been demonstrated to interfere with what 2 components?
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with DNA biosynthesis and cell respiration
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______ is a hydroxylatedpyridinone that is employed for superficial dermatophytic infections, principally onychomycosis
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Ciclopirox
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Ciclopirox has a unique mechanism of action through what? What dose it cause?
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chelation of polyvalent cations, such as Fe3+, which causes inhibition of a number of metal-dependent enzymes within the fungal cell
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. Although ciclopirox has been available for more than 30 years, a new formulation of an 8% lacquer has been recently introduced for treating what?
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Nail Infections
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What are 3 antimycobacterial classes?
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Antituberculin drugs
MAC therapy Leprostatic drugs |
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What 2 drugs are under the MAC Therapy Class?
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Azithromycin
Clarithromycin |
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What 4 drugs are under the leprostatic drugs?
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Clofazimine
Dapsone Rifampin Thalidomide |
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what are AntimycobacterialsTherapeutic Options?
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Antituberculins (TB)
First Line Agents Second Line Agents MAC Drug Therapy (Mycobacterium Avium–Intracellulare Complex) Leprostatics (Leprosy) |
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Mycobacteria are a genus of acid-fast bacilli belonging to the what?
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Mycobacteriaceae
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Mycobacteria are a genus of acid-fast bacilli belonging to the Mycobacteriaceae, which include the organisms responsible for what?
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for uberculosis and leprosy as well as a number of other, less common diseases.
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Characteristic of mycobacteria is the fact that these organisms tend to be what 3 charateristics?
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slow-growing,
difficult to stain, and when they are stained with basic dye, can resist decolorization with acid alcohol. |
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Mycobacteria staining characteristics relate to the what?
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abnormally high lipid content of the cell wall
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what holds the secret to many of the characteristics of this genus of organisms?
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the cell wall or cell envelope of the mycobacterium
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The cell envelope is unique in both ___ and __?
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structure and complexity
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It has been suggested that the cell envelope is responsible for mycobacterium for what 5 components?
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pathogenicity or virulence, multiple drug resistance, cell permeability, immunoreactivity and inhibition of antigen responsiveness, as well as disease persistence and recrudescence
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The mycobacterial cell envelope contains, on the interior surface what?
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a plasma membrane similar to that found in most bacteria.
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The mycobacterial cell envelope contains, on the interior surface, a plasma membrane similar to that found in most bacteria. What appears next.
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A conventional peptidoglycan layer affording the organism rigidity
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The peptidoglycan layer is composed of what?
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alternating N-acetyl-D-glucosamines (Glu) linked to N-glycoyl-D-muramic acids (Mur) through 1–4 linkages that, in turn, is attached to the peptido chain of D-alanine (A), D-glutamine (G), meso-diaminopimelic acid (DP), and L-alanine (A).
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How is TB characterized?
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as a chronic bacterial infection caused by Mycobacterium tuberculosis, an acid-fast, aerobic bacillus with the previously discussed, unusual cell wall.
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The cell wall in TB has high what? What does this result in a high degree of?
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The cell wall has a high lipid content, resulting in a high degree of hydrophobicity and resistance to alcohol, acids, alkali, and some disinfectants.
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After staining with a dye, the M. tuberculosis cell wall cannot subsequently be what? What does this end up being?
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decolorized with acid wash
thus the characteristic of being an acid-fast bacillus. |
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It is estimated that today, one-third to one-half of the world population is infected with what?
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M. tuberculosis, leading to approximately 6% of all deaths worldwide (~2 million deaths).
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Mycobacterium tuberculosis is transmitted primarily via what route?
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respiratory
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Mycobacterium tuberculosis appears in what?
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in water droplets expelled during coughing, sneezing, or talking
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TB is a disease that mainly affects what?
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lungs (80-85% of cases)
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TB is a disease that mainly affects the lungs (80–85% of the cases), but M. tuberculosis can spread through the what?
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bloodstream and the lymphatic system to the brain, bones, eyes, and skin (extrapulmonary TB).
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___ or ___ may result from the infection and may lie dormant, encapsulated in a fibrotic lesion, for years and then reappear later.
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Granulomas or tubercles
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Patients with HIV infection and TB are ____ more likely of developing an active infection than noninfected patients.
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100-fold
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what are are atypical acid-fast bacilli that are ubiquitous in the environment and usually considered to be nonpathogenic in healthy individuals.?
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Mycobacterium Avium–Intracellulare Complex
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__ ___ ___ - ___ ___ is the most common bacterial opportunistic infection seen in patients with AIDS and the third most common opportunistic infection reported in patients with AIDS.
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Disseminated Mycobacterium avium–intracellulare complex (MAC)
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Today, approximately half of all patients with AIDS develop an infection caused by what?
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MAC
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The MAC organisms grow within what?
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macrophages
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____ is recognized as a chronic granulomatous infection caused by Mycobacterium leprae.
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Leprosy (Hansen's Disease)
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Leprosy may consist of what 3 components?
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lepromatous leprosy, tuberculoid leprosy, or a condition with characteristics between these two poles and referred to as borderline leprosy.
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Where is Leprosy more common?
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more common in tropical countries but is not limited to warm climate regions
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What is Leprosy's incubation period?
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The incubation period usually is three to five years.
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How is the Leprosy spread?
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Person-to-person contact appears to be the means by which the disease is spread, with entrance into the body occurring through the skin or the mucosa of the upper respiratory tract.
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What regions are the most susceptible to attack by leprosy?
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Skin and peripheral nerves
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_____ is generally considered to be the primary drug for treatment of M. tuberculosis
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Isoniazid (INH)
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It generally is recognized that INH is a pro-drug that is activated through what? By what kind of enzyme?
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an oxidation reaction catalyzed by an endogenous enzyme.
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Which enzyme exhibits catalase-peroxidase activity
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katG
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katG converts INH to a reactive species capable of what?
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acylationof an enzyme system found exclusively in M. tuberculosis.
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What are TB 1st line agents?
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Rifamycin Antibiotics
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The rifamycins inhibit bacterial____ by bidning to the __ subunit of the enzyme and are highly active against what?
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DNA-dependent RNA polymerase (DDRP) by binding to the β-subunit of the enzyme and are highly active against rapidly dividing intracellular and extracellular bacilli.
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With the introduction of Rifampin (RIF) in 1967, the duration of combination therapy for the treatment of TB was significantly ____?
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reduced (from 18 to 9 months).
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RIF is nearly always used how?
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in combination with one or more other antituberculin agents.
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Rif is a ____ _____
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P450 Inducer
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the CDC has recommended avoidance of RIF in treatment of what patients?
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HIV-infected
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What is another TB first-line agent
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Pyrazinamide(pyrazinecarboxamide)
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Pyrazinamide(pyrazinecarboxamide) was discovered while investigating analogues of _____?
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nicotinamide.
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Pyrazinamide is a ______ of nicotinamide
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bioisostere
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Pyrazinamide is a bioisostere of nicotinamide and possesses what?
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bactericidal action against Mycobacterium tuberculosis.
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Recent findings suggest that pyrazinamide may be active either totally or in part as a __-___?
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pro-drug
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Pyrazinamide has gained acceptance as an essential component in combination therapy for the treatment of TB. What is it a component of?
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(Rifaterwith INH and RIF).
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What is another 1st line TB agent?
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Ethambutol (EMB)
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Mycobacterium have a unique outer envelop consisting of ___ and ___?
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arabinofuranoseand galactose(AG)
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Mycobacterium have a unique outer envelop consisting of arabinofuranoseand galactose(AG), which is covalently attached to the peptidoglycan and an intercalated framework of ____
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lipoarabinomannan (LAM).
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The AG portion of the cell wall is highly branched and contains what?
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distinct segments of galactan and distinct segments of arabinan
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Ethambutol (EMB) mimics what?
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arabinan
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Ethambutol (EMB) mimics arabinan, resulting in a buildup of the arabinan precursor ____
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β-D-arabinofuranosyl-1-monophosphoryldecaprenol
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Ethambutol (EMB) mimics arabinan, resulting in a buildup of the arabinan precursor β-D-arabinofuranosyl-1-monophosphoryldecaprenol and, as a result, blockage of the synthesis of both ____ and __
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AG and LAM.
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What is another TB First Line agent?
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Streptomycin (STM)
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_____ was first isolated by Waksman and coworkers in 1944 and represented the first biologically active aminoglycoside.
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Streptomycin (STM)
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Streptomycin is able to diffuse across what of what?
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the outer membrane of Mycobacterium tuberculosis
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Streptomycin is able to diffuse across the outer membrane of Mycobacterium tuberculosis and, ultimately, to penetrate the ___ ___ and ___-____ process?
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cytoplasmic membrane through an electron-dependent process.
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What is a TB-Second-Line agent?
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Ethionamide
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The synthesis of analogues of isonicotinamide resulted in the discovery of ____ and a homologue in which the ethyl group is replaced with a ____?
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ethionamide
propyl (prothionamide). |
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Both ethionamide and propyl (prothionamide) compounds have proven to be bactericidal against
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Mycobacterium tuberculosis and Mycobacterium leprae.
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Evidence has been presented suggesting that the mechanism of action of ethionamide is similar to that of INH, where ethionamide is considered to be a pro-drug, which is converted via oxidation by catalase-peroxidase to an active acylating agent, _____, which in turn inactivates the ___?
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thionamidesulfoxide
inhAenoylreductase enzyme |
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What is another TB - Second-Line Agents?
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Cycloserine
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What is the active form of cycloserine?
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D-Cycloserine
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D-Cycloserineis considered to be the active form of the drug, having its action associated with the ability to inhibit two key enzymes, ____ and ____
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D-alanineracemase (1) and D-alanineligase (2).
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D-Alanine is an important component of the what?
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peptidoglycan portion of the mycobacterial cell wall.
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What is another TB - Second-Line Agents ?
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Capreomycin
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Capreomycinis a mixture of four what?
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four cyclic polypeptides,
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Capreomycinis a mixture of four cyclic polypeptides, of which ____ and ___ make up 90% of the mixture
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capreomycinIA and IB
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Capreomycin is produced by what? What antibiotic is it similar to?
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Streptomycescapreolusand is quite similar to the antibiotic viomycin
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Viomycin is a potent inhibitor of what?
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protein synthesis,
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Viomycin is a potent inhibitor of protein synthesis, particularly that which depends on ___ at the ___ ribosome?
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mRNA at the 70S ribosome.
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Viomycin blocks chain what?
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elongation
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Viomycin blocks chain elongation how?
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binding to either or both the 50S or 30S ribosomal subunits.
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What kind of drug is viomycin?
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a second-line bacteriostatic antituberculin drug, it is reserved for “resistant” infections and cases of treatment failure.
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Should the drug be given as a single agent?
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No
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What should capreomycin be used in combo with?
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EMB or INH.
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The 1997 guidelines for prophylaxis of MAC advise that all adults and adolescents with HIV infection and a CD4 lymphocyte count of less than 50 cells/mL receive what drugs and what dosing?
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clarithromycin, 500 mg b.i.d., or azithromycin, 1200 mg once a week.
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For treatment of MAC, it is recommended that a combination therapy be used that includes at least two drugs. Either ___ or ___ plus ___ for life
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either clarithromycin or azithromycin plus EMB for life).
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Other drugs that can be added to the combination consist of what 3?
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rifabutin, fluoroquinolones, and amikacin.
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What are ineffective in the treatment of disseminated MAC?
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that INH and pyrazinamide
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What is a Leprostatic?
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Sulfones
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The ___ represent the major class of agents used to treat leprosy.
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diarylsulfones
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The initial discovery of the sulfones came about as a result of studies directed at exploring what?
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the SAR of sulfonamides
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_____ was first introduced into the treatment of leprosy in 1943.
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Dapsone,
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Dapsone is what kind of agent?
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a bacteriostatic agent,
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Dapsone, a bacteriostatic agent, is thought to act in a manner similar to that of the sulfonamides—namely, through what kind of inhibition? Inhibition of what?
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competitive inhibition of p-aminobenzoic acid incorporation into folic acid (as with the sulfonamide antibiotics).
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Bacteria synthesize __ ___ but host cells do not?
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folic acid
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What co-administration will inactivate dapsone?
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coadministration of dapsone and p-aminobenzoic acid
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What is the final leprostatic?
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Thalidomide
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The development of painful, tender, inflamed, subcutaneous nodules that may last a week or two but may reappear and last for long periods is seen in a number of diseases. In the case of leprosy, the condition is referred to as ____?
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erythemanodosumleprosum (ENL).
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erythemanodosumleprosum (ENL) has been successfully treated with what?
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Thalidomide
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The mechanism whereby thalidomide produces relief is thought to be associated with the drug's ability to control ____ ____
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inflammatory cytokines.
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What kind of agent is thalidomide?
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very potent teratogenic agent
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Thalidomide can be safely used in what kind of women?
|
postmenopausal women, but strict controls are required for women of childbearing age.
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