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Ketoconazole is an antifungal agent that blocks multiple P-450–dependent steps in steroidogenesis buy 50mg minocycline amex. Spironolactone antagonizes the binding of both androgen and aldosterone at their respec- tive receptors; it also decreases the activity of the steroidogenic enzyme 17-hydroxylase purchase 50mg minocycline mastercard. Spironolactone is used as a diuretic and to treat hirsutism in women (usually in combina- tion with estrogen) buy minocycline 50 mg low cost. The adrenals also synthesize various androgens order minocycline 50mg with mastercard, predominantly dehydroepiandrosterone and androstenedione. A wide array of steroid compounds with various ratios of mineralocorticoid to glucocorti- coid properties has been synthesized. Chapter 10 Drugs Acting on the Endocrine System 233 table 10-2 Properties of Adrenocortical Steroids Equivalent Metabolic Anti-Inflammatory Sodium-retaining Agent Dose (mg) Potency Potency Potency Oral Glucocorticoids Cortisol 20 20 1 1 Cortisone 25 20 1 1 Prednisone 5 5 4 0. Cortisone acetate and prednisone are 11-keto steroids that are converted to 11-hydroxyl groups by the liver to give cortisol and prednisolone, respectively. Methylation or hydroxylation at the 16a position abolishes mineralocorticoid activity with little effect on glucocorticoid potency. Natural and synthetic steroids enter cells rapidly and interact with these intracellular receptors. The resulting complexes modulate the transcription rate of specific genes and lead to an increase or decrease in the levels of specific proteins. Both natural and synthetic steroids are excreted by the kidney following reduction and for- mation of glucuronides or sulfates. All of the steroids listed in Table 10-2 (except aldosterone) may be administered orally. Various glucocorticoid preparations are available for otic, rectal, or topi- cal administration. As discussed in Chapter 9, glucocorticoids administered as inhalants are used to treat asthma. Drug administration attempts to pattern the circadian rhythm: A double dose is given in the morning, and a single dose is given in the afternoon. Alternate-day therapy relieves clinical manifestations of the disease state while causing less severe suppression of the adrenal–hypothalamic–pituitary axis. In this therapy, large doses of short-acting or intermediate-acting glucocorticoids are administered every other day. Patients removed from long-term glucocorticoid therapy must be weaned off the drug over several days, using progressively lower doses to allow recovery of adrenal responsiveness. Therapeutic actions and adverse effects are extensions of these physiologic effects. The anti-inflammatory effects of glucocorticoids are pro- duced by the inhibition of all of the classic signs of inflammation (erythema, swelling, soreness, and heat). Therapeutic uses (1) Glucocorticoids are used in replacement therapy for primary or secondary insufficiency (Addison disease); this therapy usually requires the use of both a mineralocorticoid and a glucocorticoid. Chapter 10 Drugs Acting on the Endocrine System 235 (b) These agents are also used in hypersensitivity and allergic reactions. Adverse effects and contraindications (1) Most of the adverse effects of glucocorticoids are exaggerated physiologic effects leading to a state of iatrogenic Cushing disease. Actions (1) Mineralocorticoids primarily affect the kidney, regulating salt and water balance and increasing sodium retention and potassium loss. Mineralocorticoids are used in replacement therapy to maintain electro- lyte and fluid balance in hypoadrenalism. Mitotane causes selective atrophy of the zona fasciculata and zona reticularis and can reduce plasma cortisol level in Cushing syndrome produced by adrenal carcinoma. Mitotane use is limited to adrenal carcinomas when other therapies are not feasible. Aminoglutethimide blocks the conversion of cholesterol to pregnenolone and reduces adre- nal production of aldosterone, cortisol, and androgens. Aminoglutethimide is useful in treating hyperadrenalism due to adrenal carcinoma or con- genital adrenal hyperplasia. Metyrapone blocks the activity of 11-hydroxylase, thereby reducing cortisol production. Ketoconazole is an antifungal agent that, at high doses, is a potent inhibitor of several of the P-450 enzymes involved in steroidogenesis in the adrenals and gonads. Natural thyroid hormones are formed by the iodination of tyrosine residues on the glyco- protein thyroglobulin. More than 99% of circulating T4 is bound to plasma proteins; only 5%–10% of T3 is protein bound. Levothyroxine sodium is preferred to liothyronine because it has better oral absorption, has a longer t1/2, and produces a favorable T4:T3 ratio. Thyroid hormones are essential for normal physical and mental development of the fetus.

Indeed quality minocycline 50 mg, in 1993 50mg minocycline otc, between 11 and 14% more children of all ages between 6 and 12 years had signs of gingivitis when compared with 1983 cheap minocycline 50 mg on-line. These differences were not maintained with increasing age order minocycline 50mg free shipping, however, as 52% of 15-year- olds had gingivitis in 1993 compared with 48% in 1983. Furthermore, there were no differences between 1983 and 1993, in the proportion of 15-year-olds with pockets between 3. These data suggest that the gingival condition of children in the United Kingdom has deteriorated over the 10 years between 1983 and 1993, whereas the periodontal status of 15-year-olds has not changed. Certainly, changes in gingival health do not mirror the dramatic improvement in the prevalence of caries over the same period. This trend was reversed by 1993 when between 10 and 20% more children of all ages had plaque deposits. The onset of puberty and the increase in circulating levels of sex hormones is one explanation for the increase in gingivitis seen in 11-year-olds. Oestrogen increases the cellularity of tissues and progesterone increases the permeability of the gingival vasculature. Oestradiol also provides suitable growth conditions for species of black pigmenting organisms which are associated with established gingivitis. Histopathology The inflammatory infiltrate associated with marginal gingivitis in children is analogous to that seen in adults during the early stages of gingival inflammation. The dominant cell is the lymphocyte, although small numbers of plasma cells, macrophages, and neutrophils are in evidence. Research findings have not yet determined unequivocally whether the lymphocyte population is one of unactivated B cells or is T-cell dominated. The relative absence of plasma cells, which are found in abundance in more established and advanced lesions in adults, confirms that gingivitis in children is quiescent and does not progress inexorably to involve the deeper periodontal tissues. Key Points Chronic gingivitis: • plaque-associated; • lymphocyte-dominated; • complex flora; • linked to the onset of puberty. Microbiology The first organisms to colonize clean tooth surfaces are the periodontally harmless, Gram-positive cocci that predominate in plaque after 4-7 days. After 2 weeks, a more complex flora of filamentous and fusiform organisms indicates a conversion to a Gram-negative infection, which, when established, comprises significant numbers of Capnocytophaga, Selenomonas, Leptotrichia, Porphyromonas, and Spirochaete spp. These species are cultivable from established and advanced periodontal lesions in cases of adult periodontitis. This suggests that the host response (rather than the subgingival flora) confers a degree of immunity to the development of periodontal disease in children, thus preventing spread of the contained gingivitis to deeper tissues. Manual versus powered toothbrushes The treatment and prevention of gingivitis are dependent on achieving and maintaining a standard of plaque control that, on an individual basis, is compatible with health. Toothbrushing is the principal method for removing dental plaque, and powered toothbrushes now provide a widely available alternative to the more conventional, manual toothbrushes for cleaning teeth. There is considerable evidence in the literature to suggest that powered toothbrushes are beneficial for specific groups: patients with fixed orthodontic appliances⎯for whom there is also evidence that powered toothbrushes are effective in reducing decalcification; children and adolescents; and children with special needs. It remains questionable whether children who are already highly motivated with respect to tooth cleaning will benefit from using a powered toothbrush. A systematic review evaluating manual and powered toothbrushes with respect to oral health has made some important conclusions. Compared to manual toothbrushes, rotating/oscillating designs of powered toothbrushes reduced plaque and gingivitis by 7-17% although the clinical significance of this could not be determined. Powered brushes, therefore, are at least as effective and equally as safe as their manual counterparts with no evidence of increased incidence of soft tissue abrasions or trauma. No clinical trials have looked at the durability, reliability, and relative cost of powered and manual brushes so it is not possible to make any recommendation regarding overall toothbrush superiority. Gingival enlargement occurs in about 50% of dentate subjects who are taking the drug, and is most severe in teenagers and those who are cared for in institutions. The gingival enlargement reflects an overproduction of collagen (rather than a decrease in degradation), and this may be brought about by the action of the drug on phenotypically distinct groups of fibroblasts that have the potential to synthesize large amounts of protein. Phenytoin-induced enlargement has been associated with a deficiency of folic acid, which may lead to impaired maturation of oral epithelia. Approximately 30% of patients taking the drug demonstrate gingival enlargement, with children being more susceptible than adults. There is evidence to suggest both a stimulatory effect on fibroblast proliferation and collagen production as well as an inhibitory effect on collagen breakdown by the enzyme collagenase. It is also given to post-transplant patients to reduce the nephrotoxic effects of cyclosporin. The incidence of gingival enlargement in dentate subjects taking nifedipine is 10-15%. The drug blocks the calcium channels in cell membranes⎯intracellular calcium ions are a prerequisite for the production of collagenases by fibroblasts.

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Identification of specific biomarker molecules in tumor tissue will permit prediction of clinical outcomes in response to drug treatment minocycline 50 mg lowest price. The cancer clinical trial toolkit order 50 mg minocycline fast delivery, including biomarkers that can detect antitumor activity of anticancer agents discount minocycline 50mg on-line, can guide selection of patients for specific drug treatments minocycline 50 mg on-line. Universal Free E-Book Store 258 10 Personalized Therapy of Cancer Personalized Therapy of Cancer Based on Cancer Stem Cells Cancers may rely on “cancer stem cells” that share the self-renewal feature of nor- mal stem cells. This has changed the perspective with regard to new approaches for treating cancer. Cancer stem cells are slow-dividing and inherently drug- resistant, and their eradication would be necessary for long-term success in cancer treatment. The cancer stem cell concept could be used to better tailor treatment strategies to individual patients. Most traditional anticancer agents affect primarily bulk tumor cells by disrupting their proliferation and/or survival. Cancer stem cells are less likely to be killed than bulk tumor cells by these approaches. Improved methods will be required to identify, isolate and genetically profile the stem cell population in cancers from individual patients. Cancer stem cells, amplified from individual clinical specimens, should be tested for gene expression profiles and sensitivity to a battery of agents, leading to indi- vidualized decisions on selection of the best therapeutic strategies. The antineoplas- tic agents of the future will have to target the ancient developmental molecular pathways on which stem cells depend on for replication and survival. Thus, an improved understanding of these pathways and their roles in cancer stem cells could lead to a new generation of more selective and effective antineoplastic treatments. Role of Epigenetics in Development of Personalized Cancer Therapies In addition to having genetic causes, cancer is also an epigenetic disease. Epigenetic regulation of gene transcription is emerged a key biological determinant of cellular differentiation and plays a significant patho- genic role in a number of human diseases, particularly cancer. Disruption of the activity of disease-associated epigenetic enzymes offers a mechanism-based opportunity for pharmacologic intervention in diseases such as cancer. When used in combination with conventional chemotherapeutic agents, epigenetic- based therapies may provide a means to sensitize drug-resistant tumors to estab- lished treatments. Universal Free E-Book Store Design of Future Personalized Cancer Therapies 259 Epizyme Inc is focused on discovering novel, small molecule drugs that act as selective inhibitors of key epigenetic enzymes. Once the methyl group has been deposited on the histone site, the affected genes continue to be regu- lated (turned on or off) until this chemical unit is removed by other enzymes, known as histone demethylases. Aberrant epigenetic modifications are frequently associated with distinct cancer types and have potential utility as biomarkers. Selective Destruction of Cancer Cells While Sparing Normal Cells A problem with conventional chemotherapy or radiotherapy is that damage is not limited to cancer cells but involves normal cells as well. It is easy to kill cells in vitro and many new anticancer drugs are being discovered. However, it is difficult to selectively kill cancer cells in vivo without harming normal cells. Even though some success is achieved in animal experiments, it is difficult to translate these findings into practical management of cancer patients. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from inter- nal sources when external nutrients are unavailable. In contrast, normal cells can adapt to the nutrient stress that kills cancer cells by becoming quiescent and cata- bolic. It is well recognized that hypoxia influences the response of cells and tissues to radiation and increases the resistance of cancer to radiother- apy requiring higher radiation doses that can normal tissues. Cancer cells adapt to this stress to survive, and may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Therefore, targeting this non-oncogene dependency may result in selective death of cancer cells. A cell-based small-molecule screening and quantitative pro- teomics approach led to the unbiased identification of piperlongumine, a small mol- ecule that selectively kills cancer cells but not normal cells (Raj et al. Significant antitu- mor effects were observed in mouse xenograft tumor models treated with piper- longumine, but no toxic effects were observed in normal mice. Moreover, piperlongumine inhibits the growth of spontaneous breast cancers in mice. These findings show that ability a small molecule can selectively induce apoptosis in cells that have a cancer genotype by targeting a non-oncogene dependency acquired through the expression of the cancer genotype in response to oxidative stress induced by malignant transformation. Initial trial with the drug will be a study in patients with breast or ovarian cancers to determine a safe dose. Role of Oncoproteomics in Personalized Therapy of Cancer Clinical proteomics is an exciting new subdiscipline of proteomics that involves the application of proteomic technologies at the bedside, and cancer, in particular, is a model disease for studying such applications. Oncoproteomics is the term used for application of proteomic technologies in oncology.

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Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy cheap 50mg minocycline fast delivery. Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem minocycline 50mg low price. Experience with a once-daily Aminoglycoside Program administered to 2 cheap 50 mg minocycline amex,184 adult patients minocycline 50mg lowest price. Clinical failures of linezolid and implications for the clinical microbiology laboratory. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylo- coccus aureus. Impact of a rotating empiric antibiotic schedule on infectious mortality in an intensive care unit. Rotating antibiotics in the intensive care unit: feasible, apparently beneficial, but questions` remain. Cunha Infectious Disease Division, Winthrop-University Hospital, Mineola, New York, and State University of New York School of Medicine, Stony Brook, New York, U. Group D streptococci may be further subdivided as enterococcal or non- enterococcal group D streptococci. The most important non-enterococcal group D streptococcus is Streptococcus gallolyticus (S. Group D enterococci, however, are the predominant streptococcal pathogens encountered in critical care. Because group D streptococci colonize the terminal colon, they are frequent colonizers of the urinary tract. Group D enterococci primarily colonize the hepatobiliary/gastrointestinal tract and are frequent secondary colonizers of bile, wounds, and urine (1). The two most important group D enterococcal pathogens are Enterococcus faecalis and Enterococcus faecium. Group D streptococci, occurring in blood cultures as part of a polymicrobial infection should suggest a gastrointestinal source. Excluding intravascular and intra-abdominal infections between the gallbladder and the urinary bladder, group D enterococci should be regarded as “permissive pathogens. Because group D enterococci are copathogens in intra-abdominal/pelvic abscesses, surgical drainage is the most important therapeutic intervention in these infections (1). Staphylococci are not usual hepatobiliary, gastrointestinal, or urinary tract pathogens (1). Non-enterococcal group D streptococci are differentiated from enterococcal group D streptococci microbiologically on the basis of penicillin suscep- tibility, bile esculin hydrolysis, and growth in 0. Non-enterococcal group D streptococci are penicillin sensitive and do not ferment bile esculin or grow in 0. The most important non-enterococcal group D streptococci encountered in clinical practice is S. Group D enterococci are also classified on the basis of their susceptibility to vancomycin. Isolates that are vancomycin susceptible are invariably ampicillin susceptible as well. Group D enterococci constitute a small part of the normal gastrointestinal tract flora in the colon, *75% of the bacteria are anaerobic, e. Fecal colonization contamination of skin is not uncommon in hospitalized patients from the mid-chest to the lower extremities. This is independent of inoculum size or location within the intra-abdominal cavity (1,2). The clinical expression of an “intermediate” and intensity of endocarditis with enterococcal group D streptococci also pertains to non-enterococcal group D streptococci, i. The route of administration of the antibiotic depends on the severity of the infection and gastrointestinal absorption. In general, all non-critically ill patients capable of gastrointestinal absorption may be treated equally. In compromised hosts, after urinary catheter change/removal, one week of therapy is usually sufficient. Since methicillin is no longer used for in vitro susceptibility testing, oxacillin is used in its place. Staphylococci do not colonize the urine, but urine cultures may be contaminated by staphylococci from the skin of distal urethra during urine specimen collection. As mentioned previously, staphylococcal infections originate from trauma or procedures done through the skin. Staphylococcal abscesses may complicate any invasive procedure done penetrating the skin. The presence of bilateral cavitary infiltrates some of which may be wedge- shaped/pleural-based with temperatures! Bilateral septic pulmonary emboli may be differentiated from bland pulmonary emboli by fever, i. Also, with bland pulmonary emboli, there are one or very few lesions, whereas in septic pulmonary emboli, there are multiple lesions that rapidly cavitate.

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For subsequent measurements of unknown samples discount minocycline 50 mg with amex, correction is made to compensate for the dead time loss giving true count rates discount minocycline 50mg otc. Another method uses two radioactive sources minocycline 50 mg sale, which are counted in the counter individually and together order minocycline 50 mg line. From these three mea- surements, one can calculate dead time using appropriate equations (see Cherry et al. Various techniques, such as use of buffers, in which overlapping events are held off during the dead time, use of pulse pileup rejection circuits, and use of high-speed electronics have been employed to improve the dead time correction. Placing a radioactive sample in the central hole of the detector increases the geometric efficiency (almost 99%) and hence the counting efficiency of the counter. The NaI(Tl) detectors have dimensions in the range of 5-cm diameter × 5-cm thick to 23-cm diameter × 23-cm thick. Smaller detectors are used for low-energy g -rays (less than 200keV), and larger detectors are used for high-energy g -rays. This calibration is called the high-voltage or energy cali- bration of the well counter. After placing a 137Cs source in the well counter, the lower and upper discriminator levels are set at 640 divisions 102 8. Starting from low values, the high voltage is increased in small increments for a given ampli- fier gain until the observed count rate reaches a maximum. The high voltage at the maximum count rate is kept as the operating voltage for subsequent counting of photons of different energies. The discriminator dials are then said to be energy calibrated; for example, each dial unit corresponds to 1keV at an amplifier gain of 1. Thus, the center of the 140-keV photopeak of 99mTc can be set at 140 divisions of the discriminator setting, with lower and upper values set as desired. After calibration, well counters should be checked regularly for any voltage drift using a long-lived source, such as 137Cs. Counting in Well Counters For relative comparison of count rates between samples, the well counter does not need to be calibrated, provided all samples for comparison have the same volume. In radioimmunoassays, ferrokinetics, blood volume, red cell mass measurements, a standard of the same geometry (volume) and with relatively the same activity is counted along with all samples, and then a comparison is made between each sample and the standard. However, when the absolute activity of a radioactive sample needs to be determined, then the detection efficiency of the counter must be measured for the g-ray energy of interest using a standard of the radioactive sample of known activity. The efficiency correction can then be applied to the count rates of samples of unknown radioactivity when counted at the same setting as the standard to give the absolute activity. For Gamma Well Counters 103 absolute activity, the photopeak efficiency must be determined for each photon energy. When multiple g-rays, either from a single radionuclide or from many radionuclides, are present in a radioactive sample, then the energy spectrum becomes complicated by the overlapping of different photopeaks and also by Compton contributions from the high-energy photons to the low-energy photopeaks. This is accomplished by counting a sample of pure 131I in both 140-keV and 364-keV discriminator settings and determining the percentage of spillover from the ratio of the counts in the 140-keV photopeak to those in the 364-keV photopeak. Effects of Sample Volume The sample volume affects the counting efficiency of well counters. As the sample volume for a given activity is increased, more radiations are lost through the opening of the well without interacting in the detector, and hence, the counting efficiency drops. Therefore, correction factors should be determined for different sample volumes and applied to the measured activity. The dotted line under the 140-keV photopeak is the spillover, or crosstalk, contribution from the 364-keV photon. Scintillation and Semiconductor Detectors Well counters are available with automatic sample changers having pro- visions of counting as many as 500 samples. Most counters are program- mable with computers and provide printouts with various information on counting. The major advantage of the well counter is its high detection efficiency due to increased geometric efficiency, which approaches almost 100% depending on the volume of the sample. The detection efficiency of a well counter decreases with increasing photon energy and decreasing detector size. Typically, the overall detection efficiency is close to 100% for 99m 131 140-keV photons of Tc and 30% to 90% for 364-keV photons of I, depending on the detector size. Thyroid Probe The thyroid probe is a counter commonly employed to measure the uptake of 131I or 123I in the thyroid gland after the oral administration of a 131I-NaI or 123I-NaI capsule. It consists of a NaI(Tl) detector, 5cm in diameter by 5cm in thickness, and other associated electronics, as in a well counter. One of the differences between the well counter and the thyroid probe is that the latter requires a collimator, which limits the field of view on the thyroid.

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