By H. Mojok. Trinity College, Washington DC. 2019.

Direct inoculation or local extension from adjacent soft tissue infection or osteomyelitis is less common buy zyban 150mg line. Prosthetic joints or damaged joints from rheumatoid or osteoarthritis are particularly susceptible to hematogenous seeding buy generic zyban on-line. Once an infection is established within a joint order 150mg zyban with visa, a complex cascade of physiologic responses occurs that leads to a severe inflammatory reaction, with subsequent cartilage degradation and bone destruction. The rapidity and severity of this process depend on the virulence of the organism and the length of delay before appropriate antibiotics are started. Clinical Features Clinically, septic arthritis may be indistinguishable from crystalline arthritis or other inflammatory joint diseases. The presentation is often acute and monoarticular, with physical findings of warmth, swelling, tenderness, erythema within the confines of the joint margins, and markedly limited joint motion. In the case of suspected cellulitis, appropriate antibiotics should be administered and arthrocentesis performed only if symptoms or findings do not improve within 48 hours. Synovial fluid analysis can confirm septic arthritis and identify organisms on Gram’s stain or in culture. The fluid should be transferred immediately to the laboratory, both anaerobic and aerobic cultures should be ordered routinely, and special requests for fungus or other organisms that require a special growth medium (e. A meta-analysis of various laboratory studies in septic arthritis suggests that the likelihood ratio of septic arthritis increases incrementally with higher synovial leukocyte counts [5]. Although initial radiographs of the infected joint are often normal, baseline x-rays are useful to identify preexisting joint abnormalities and for comparison to identify subsequent damage. Classic late radiographic findings include juxta-articular osteopenia, joint-space narrowing, or subchondral bone loss. Therapy Treatment of septic arthritis requires adequate drainage in addition to appropriate antibiotics. Gram-negative and anaerobic organisms occur less frequently, but must be suspected in patients at risk (elderly, immunocompromised, recent hospitalization or surgery, prior antibiotics, and possible urogenital or abdominal infections) [4]. For the critically ill patient with multiple risk factors, broad-spectrum antibiotic coverage against Staphylococcus and Streptococcus, Gram-negative bacteria, and Pseudomonas should be initiated until culture results are available. Fungal or mycobacterial septic arthritis is often subacute or chronic, but should be considered in patients failing broad-spectrum antibiotics. Candida organisms have caused acute arthritis and the Gram stain or fungal preparation may be positive before cultures are available. The duration of antibiotic therapy varies according to the clinical situation, but antibiotics should be continued intravenously for at least 2 weeks. Further route and duration of therapy depend on the specific type and sensitivity of the identified organism and the patient’s clinical response. Please refer to Chapter 73 for appropriate antibiotic treatment for presumptive or identified infectious organisms. Drainage of the infected joint with either serial percutaneous needle aspiration or surgical intervention is also crucial. Because there are no prospective studies comparing these options, controversy exists regarding the optimal approach. The physical removal of inflammatory cells, cellular debris, lysosomal enzymes, and bacterial by-products reduces the potential damage to the joint. Prosthetic joints and other native joints such as hip, shoulder, wrist, finger, sacroiliac, or sternoclavicular joints require immediate surgical intervention, whereas native septic knees may respond to serial percutaneous needle aspiration. Arthroscopy or arthrotomy has the advantage of more complete debridement of fibrin, infected synovium, and loculations. However, percutaneous drainage may be the only option for a critically ill patient who is too unstable for surgery. Thus, the ideal approach is to consult both an orthopedic surgeon and a rheumatologist at the time of diagnosis to decide on optimal management. Once antibiotics are given and drainage has been performed, early physical therapy with passive range of motion and graduation to active range of motion will improve outcomes. Because septic arthritis usually occurs as a consequence of bacteremia from a distant primary source of infection, investigation for these sites must be pursued. Unless an obvious site of local inoculation is present, cultures from blood, urine, sputum, indwelling lines, and catheters should be obtained before the institution of antibiotics. Risk factors are similar for native joint septic arthritis discussed previously and also include prior infection of a prosthetic joint at the same site or revision arthroplasty. If aspiration is not done before surgery, then intraoperative sampling of multiple periprosthetic tissue sites will increase the yield of an organism. If the patient is a surgical candidate, options include: (1) resection arthroplasty, (2) one- or two-stage surgery with prosthesis removal and reimplantation, or (3) surgical debridement with retention of prosthesis with or without long-term oral antibiotic suppression. The first option is rarely performed unless the patient has failed previous surgical attempts at eradicating the infection or is likely to have minimal functional improvement after replacement. The latter usually entails removal of the infected prosthesis, treatment with antibiotics with or without an antibiotic-loaded spacer for a period of 6 to 12 weeks, and then subsequent reimplantation. Debridement with retention of the infected prosthesis is an option only if (i) age of the prosthesis is less than 3 months; (ii) symptoms have been present for less than 3 weeks; (iii) absence of sinus tract communicating with joint space; (iv) no radiographic evidence of prosthetic loosening; (v) infection not involving S. Prolonged oral antibiotics (3 months for hips and 6 months for knees) are recommended in patients treated with debridement with implant retention [6]. Hemarthrosis In the absence of an underlying inherited disorder of coagulation, hemarthrosis in the intensive care setting is most likely a complication of anticoagulation therapy, most frequently described in patients receiving an oral anticoagulant. Because hemarthrosis may occur spontaneously in an anticoagulated patient, a history of trauma is often absent. Prolongation of coagulation parameters suggests the diagnosis, but diagnostic arthrocentesis is essential to confirm the diagnosis of hemarthrosis and exclude septic arthritis, crystalline disease, or other causes. When performed aseptically and carefully, arthrocentesis is safe and free of significant long-term morbidity. A precise definition of hemarthrosis has not been established, but the diagnosis is suggested by a synovial fluid hematocrit exceeding 3%. Despite the fact that hemophiliac patients with repeated hemarthrosis have significant joint abnormalities, an isolated episode of spontaneous hemarthrosis has a benign prognosis. Treatment of hemarthrosis from hemophilia or other bleeding diathesis is discussed elsewhere (see Chapters 88 and 89). Management of spontaneous hemarthrosis from anticoagulation consists of immobilization, analgesia, and, if possible, temporarily reducing or correcting clotting parameters with fresh frozen plasma or reversal agents when the patient is not at high risk of thrombotic complications. Involvement of the cervical spine, temporomandibular or cricoarytenoid joints, or oral aperture may limit adequate positioning, visualization, or successful endotracheal intubation with conventional direct laryngoscopy. Advanced airway techniques including fiberoptic intubation, video laryngoscopy, and nasotracheal intubation enable safe airway placement for most patients with difficult airways (see Chapter 8). Laryngeal mask airway is a possible rescue measure for patients who cannot be intubated but can be ventilated and is a good alternative to bag mask ventilation.

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It is Differential diagnosis includes: difficult to define a clear cut ‘end point’ for assessing the • Infections (viral order zyban on line, bacterial quality zyban 150 mg, fungal) efficacy of such extrapulmonary tuberculosis with delayed • Neoplasms (lymphoma) response to treatment buy zyban 150mg overnight delivery. Delayed response to treatment and • Collagen vascular disease and diseases of reticuloen- non-tuberculous mycobacterial infection usually requires a dothelial system. The presence of 10–100 bacilli per cubic millimeter of surgery the specimen is enough for a positive culture result. Several media can be used as described under pulmonary It provides a rapid tissue diagnosis and confirms the tuberculosis. Surgical techniques include aspiration, 281 incision and drainage, and curettage, complete excision of (<5 years) in whom neurotuberculosis occurs is significantly the affected lymph nodes. Hence practicing When lymph nodes are fluctuant and ready to drain, pediatricians have a greater responsibility in early diagnosis antigravity aspiration should be done. Infection usually occurs after inhalation of the bacilli in Paradoxical reaction can occur during antituberculous infected respiratory secretions. Affected nodes may enlarge or new nodes tuberculosis multiplies in alveolar macrophages. Within may appear representing an immune response to kill 2–4 weeks, through blood circulation, bacilli spread to mycobacteria. This can occur in 6–30% of patients extrapulmonary sites and produce small granulomas in within the first 2 months of tubercular lymphadenitis. These small lymphadenitis is best treated with antitubercular drugs and granulomas are known as ‘rich focus’. Decreased bibliography immunity is believed to play a role in the rupture of Rich foci. The bacilli enter the central nervous system by cytology as a diagnostic tool in pediatric lymphadenitis. Essentials of Tuberculosis in Children, 4th inflammation, dense basal exudates, vasculitis and hydro- edition. Diffuse tubercular encephalopathy is Introduction characterized by diffuse edema of the brain, perivascular In developing countries, tuberculous involvement of the myelin loss and hemorrhagic leukoencephalopathy. Even the latest guidelines – Radiculomyelitis/myelitis for diagnosis of neurotuberculosis laid down by Indian • Parenchymal: 282 Academy of Pediatrics (2010) fail to pick up any case of – Tuberculoma (tuberculous granuloma) neurotuberculosis. The other highlight is that the age group – Tuberculous abscess • secondary involvement of nervous system: based on clinical features, cerebrospinal fluid changes and – Spinal cord disease (compression) imaging characteristics. Bacteriological confirmation is not – Miliary tuberculosis of brain secondary to hemato- possible in all cases. It cannot discriminate between tuberculosis meningitis and partially • stage I (early): Conscious, nonspecific symptoms, with treated bacterial meningitis. The specificity of tuberculosis meningitis diagnosis can be the responsibility on practicing pediatricians is to send increased by molecular diagnostic tests. Because of its high specificity, a positive commercial • clinical entry criteria: Symptoms and signs of nuclear acid amplification test is regarded as a definite meningitis including one or more of the following: test in patients with suspected tuberculosis meningitis headache, irritability, vomiting, fever, neck stiffness, and offers particular value in patients who have previously convulsions, focal neurological deficits, altered consci- received tuberculous treatment. Hydrocephalus and • definite tuberculosis meningitis: Clinical entry criteria basal meningeal enhancements are the most common plus one or more of the laboratory criteria. Eighty percent of children have laboratory Investigations hydrocephalus and 75% basal meningeal enhancement. Tuberculosis meningitis is an important manifestation and Hydrocephalus is less common (45%) in adolescents and so is associated with high morbidity and mortality. Basal meningeal and gastric aspirate further increase the chance of a positive enhancement is most sensitive (89%). They have treatment higher frequency of infarcts, gyral enhancement and Appropriate chemotherapeutic regimens should be mass lesions compared with patients who do not have administered as early as possible. The patient’s clinical stage in other causes of meningitis, such as Cryptococcus, at presentation is the most important prognostic factor. Focal lesions, intracranial tuberculomas and Suggestive chest radiograph abnormalities are seen tuberculous abscess do not require surgical intervention in 33–60% of patients. The only way to reduce morbidity and mortality children with tuberculosis meningitis shows that they is by early diagnosis, timely recognition of complications significantly improve the survival rate and intellectual and institution of the appropriate treatment strategies. Corticosteroids do not affect the incidence of dual therapy with antibiotics and antitubercular therapy basal ganglia infarction significantly. Hepatotoxicity Antituberculosis Treatment Hepatotoxicity may be seen in malnourished and those A secured microbiological diagnosis is seldom, if ever, with disseminated disease. In case of overt toxicity there achieved in neurotuberculosis and the decision to is pain abdomen, vomiting and hepatic enlargement. This Mannitol (20%) is most frequently used in the emergency is because there is significant morbidity and mortality treatment of cerebral edema. The practicing pediatrician associated with late institution of therapy in advanced can safely give it in the dose of 5 mL/kg stat followed by 2 disease. Hyponatremia and raised intracranial pressure can cause drug regimens seizures in acute phase. Imaging Techniques Contrast enhanced computed tomography is utilized as the Surgical Management of Hydrocephalus initial imaging modality. Surgical wing three types of tuberculoma: intervention by shunt procedure depends upon the extent 1. Non-caseating granuloma of hydrocephalus and needs the attention of a pediatric 2. Usually respond to anti- Involvement of the spinal arachnoid lining secondary to tuberculosis treatment and resolves over 3–6 months. Prognosis Immature faintly enhancing tuberculomas have a more Parenchymal neurotuberculosis likely chance of resolution with antituberculous chemo- therapy and corticosteroids. In contrast, as well formed and tuberculoma or tuberculous Granuloma probably large-sized (>3 cm) granuloma may have a risk of Tuberculoma is a manifestation of tuberculosis which paradoxical enlargement. It usually occurs in an area of tuberculous cerebritis as a cluster of microgranuloma which spinal cord disease (compression) when coalesces forms a mature noncaseating granuloma. Pathogenesis Though Pott’s disease is the most common form of skeletal the center of the tuberculoma when becomes necrotic forms caseous debris, while the periphery tends to Table 5. Tuberculous abscess is due tuberculoma to the liquefaction of the caseous material. It is due to the Tuberculoma Neurocysticercosis presence of polymorphonuclear leukocytes. May present at any age Rare before the age of 3 years Progressive neurological deficit Generally no neurological deficit, clinical features post-ictal focal deficits of varying severity resolve with in a matter of the size and site of tuberculoma as well as the presence days to weeks of concurrent meningitis determines the clinical features. The common symptoms are seizures without associated Ring size is usually >20 mm, irregular Usually smaller, regular rounded meningeal signs or evidence of tuberculosis elsewhere in the outline with marked cerebral edema outline with less cerebral edema body. The other forms like resolution with antituberculosis chemotherapy and intramedullary tuberculoma, epidural abscess and spinal corticosteroids while a well formed and probably large arachnoiditis are rare in pediatric age group.

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Extracellular fluid If a drug has a low molecular weight but is hydrophilic order genuine zyban on-line, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid purchase zyban 150 mg. However order zyban 150 mg without a prescription, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid (about 20% of body weight or 14 L in a 70-kg individual). Total body water If a drug has a low molecular weight and has enough lipophilicity, it can move into the interstitium through the slit junctions and pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual. Determination of Vd the fact that drug clearance is usually a first-order process allows calculation of V. First order means that ad constant fraction of the drug is eliminated per unit of time. This process can be most easily analyzed by plotting the log of the plasma drug concentration (C ) versus time (p ure 1. For example, if 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C = 1 mg/L (from the graph in0 ure 1. Effect of V on drug half-lifed V has an important influence on the half-life of a drug, because drug elimination depends on the amount of drugd delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of drug in the plasma. If a drug has a large V, most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, anyd factor that increases V can increase the half-life and extend the duration of action of the drug. Drug Clearance Through Metabolism Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary excretion. That is, a constant fraction of the drug is eliminated in a given unit of time. Metabolism results in products with increased polarity, which allows the drug to be eliminated. First-order kinetics the metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics, where Km is Michaelis constant (the substrate concentration at half maximal velocity). In most clinical situations, the concentration of the drug, [C], is much less than the Michaelis constant, Km, and the Michaelis-Menten equation reduces to That is, the rate of drug metabolism and elimination is directly proportional to the concentration of free drug, and first-order kinetics is observed. This means that a constant fraction of drug is metabolized per unit of time (that is, with each half-life, the concentration decreases by 50%). Zero-order kinetics With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large. Therefore, [C] is much greater than Km, and the velocity equation becomes the enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time. The rate of elimination is constant and does not depend on the drug concentration. Reactions of drug metabolism the kidney cannot efficiently excrete lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Phase I2 metabolism may increase, decrease, or have no effect on pharmacologic activity. The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids) and for the biotransformation of exogenous substances (drugs, carcinogens, and environmental pollutants). These enzymes have the capacity to modify a large number of structurally diverse substrates. Variations in P450 activity may alter drug efficacy and the risk of adverse events. Some drugs, however, are capable of inhibiting reactions for which they are not substrates (for example, ketoconazole), leading to drug interactions. Phase I reactions not involving the P450 system These include amine oxidation (for example, oxidation of catecholamines or histamine), alcohol dehydrogenation (for example, ethanol oxidation), esterases (for example, metabolism of aspirin in the liver), and hydrolysis (for example, of procaine). If the metabolite from phase I is sufficiently polar, it can be excreted by the kidneys. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. A notable exception is morphine-6-glucuronide, which is more potent than morphine. Drug Clearance by the Kidney Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes; the most important is elimination through the kidney into the urine. Patients with renal dysfunction may be unable to excrete drugs and are at risk for drug accumulation and adverse effects. Renal elimination of a drug A drug passes through several processes in the kidney before elimination: glomerular filtration, active tubular secretion, and passive tubular reabsorption. Glomerular filtration Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. Proximal tubular secretion Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions (for example, deprotonated 61 forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. Distal tubular reabsorption As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. Generally, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. Excretion by Other Routes Drug excretion may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are excreted in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, desflurane).

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The patient is already on a long-acting insulin (detemir) for basal control zyban 150mg low price, and another insulin for basal control is not warranted effective zyban 150mg. Sulfonylureas work primarily by increasing insulin secretion through stimulation of the β cells in the pancreas zyban 150 mg visa. Metformin contains a boxed warning due to the potential for increased risk of myocardial infarction. The primary adverse effects associated with metformin are gastrointestinal and in rare cases, lactic acidosis. Metformin does not carry a warning for increased risk of myocardial infarction (this is the case for rosiglitazone). Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis. Which of the following medications would be a poor choice for controlling her diabetes? They should be used with caution and dose reduction, if at all, in patients with heart failure. Exenatide, glyburide, and insulin do not have precautions for use in heart failure patients. Glipizide, insulin lispro, and metformin have not been associated with an increased risk of pancreatitis. Sulfonylureas (glimepiride) are associated with weight gain and should be avoided in this obese patient. Because of the potential for bronchospasm associated with inhaled insulin, it should be avoided in patients with a history of chronic obstructive pulmonary disorder and asthma. Adverse effects of canagliflozin are genital mycotic infections, urinary tract infections, and urinary frequency. Nateglinide may cause hypoglycemia but has not been associated with heart failure. These hormones are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty. The sex hormones are used therapeutically for contraception, management of menopausal symptoms, and replacement therapy in hormone deficiency. Several antagonists are effective in the treatment or prevention of hormone- responsive cancers. Sex hormones are synthesized from the precursor, cholesterol, in a series of steps that includes shortening of the hydrocarbon side chain and hydroxylation of the steroid nucleus. It is present in significant amounts during pregnancy, because it is synthesized by the placenta. Mechanism of action After dissociation from their binding sites on sex hormone–binding globulin or albumin in the plasma, steroid hormones (for example, estradiol) diffuse across the cell membrane and bind with high affinity to specific nuclear receptor proteins (ure 25. This results in the synthesis of specific proteins that mediate a number of physiologic functions. In the past, estrogens were widely used for prevention of osteoporosis; however, due to risks associated with estrogen therapy, current guidelines recommend use of other therapies, such as bisphosphonates (see Chapter 27). A common oral preparation used for the treatment of menopausal symptoms is conjugated equine estrogens (obtained from urine of pregnant mares), which primarily contains sulfate esters of estrone and equilin. Transdermal preparations of estradiol are also effective in treating menopausal symptoms. For women with an intact uterus, a progestogen is always included with the estrogen therapy, because the combination reduces the risk of endometrial carcinoma associated with unopposed estrogen. Thus, the adverse effects of estrogen replacement therapy are usually less pronounced than those seen in women taking estrogen for contraceptive purposes. Women who only have urogenital symptoms, such as vaginal atrophy, should be treated with vaginal rather than systemic estrogen to minimize the risks of use. Contraception the combination of an estrogen and progestogen provides effective contraception via the oral, transdermal, or vaginal route. Other uses Estrogen therapy mimicking the natural cyclic pattern, and usually in combination with a progestogen, is instituted to stimulate development of secondary sex characteristics in young women with primary hypogonadism. Similarly, replacement therapy is used for women who have hormonal deficiencies due to surgical menopause or premature ovarian failure. Naturally occurring estrogens These agents and their esterified or conjugated derivatives are readily absorbed through the gastrointestinal tract, skin, and mucous membranes. Taken orally, estradiol is rapidly metabolized (and partially inactivated) by the microsomal enzymes of the liver. Although estradiol is subject to first-pass metabolism, it is still effective when taken orally. Synthetic estrogens These compounds, such as ethinyl estradiol and estradiol valerate are well absorbed after oral administration. Estradiol valerate is a prodrug of estradiol which is rapidly cleaved to estradiol and valeric acid. The synthetic estrogens are fat soluble, stored in adipose tissue, and slowly released. These compounds have a prolonged action and a higher potency compared to the natural estrogens. Metabolism Bioavailability of estradiol after oral administration is low due to first-pass metabolism. To reduce first-pass metabolism, estradiol may be administered via a transdermal patch, topical formulation (gel or spray), intravaginal preparation (tablet, cream, or ring), or injection. Estrogens are transported in the blood bound to serum albumin or sex hormone–binding globulin. Estradiol and its metabolites subsequently undergo glucuronide and sulfate conjugation. The glucuronide and sulfate metabolites are also subject to enterohepatic recirculation. These compounds are secreted into the bile, hydrolyzed by gut bacteria, and then reabsorbed. Adverse effects Nausea and breast tenderness are among the most common adverse effects of estrogen therapy. In addition, the risk of thromboembolic events, myocardial infarction, and breast and endometrial cancer is increased with the use of estrogen therapy. This category includes tamoxifen, raloxifene, bazedoxifene, clomiphene, and ospemifene. Therefore, some hormone- responsive breast tumors regress following treatment with these agents. Unlike estrogen and tamoxifen, raloxifene does not stimulate growth of the endometrium and, therefore, does not predispose to endometrial cancer. This effect increases the secretion of gonadotropin-releasing hormone and gonadotropins, thereby leading to stimulation of ovulation. Therapeutic uses Tamoxifen is currently used in the treatment of metastatic breast cancer, or as adjuvant therapy following mastectomy or radiation for breast cancer.

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