Hussam Hamdalla, MD

• Gill Heart Institute and Division of Cardiovascular Medicine
• University of Kentucky
• Lexington, Kentucky

Over the next 24 h menstrual headaches symptoms purchase genuine fertomid line, neonates turn an ashen-gray color and become flaccid and hypothermic womens health 02 2013 chomikuj cheap fertomid 50 mg otc. A similar "gray syndrome" has been reported in adults who were accidentally overdosed with the drug menstruation unclean discount 50mg fertomid free shipping. Two mechanisms apparently are responsible for chloramphenicol toxicity in neonates: (1) a developmental deficiency of glucuronyl transferase women's health edmonton order fertomid 50 mg free shipping, the hepatic enzyme that metabolizes chloramphenicol; and (2) inadequate renal excretion of unconjugated drug zanaflex menstrual cramps 50 mg fertomid free shipping. At the onset of the clinical syndrome women's health center king of prussia pa order fertomid 50mg with mastercard, chloramphenicol concentrations in plasma usually exceed 100 g/mL and may be as low as 75 g/mL. Severe toxicity and death have occurred because of failure to recognize such effects. Four macrolides are available for clinical use: erythromycin, clarithromycin, azithromycin, and fidaxomicin. Erythromycin is the original agent in the class, discovered in 1952 by McGuire and coworkers in the metabolic products of a strain of Streptomyces erythreus. Adverse Effects Chloramphenicol inhibits the synthesis of proteins of the inner mitochondrial membrane, probably by inhibiting the ribosomal peptidyltransferase. These include subunits of cytochrome c oxidase, ubiquinone-cytochrome c reductase, and the proton-translocating 1054 Azithromycin and clarithromycin are semisynthetic derivatives of ery- thromycin that have largely replaced it in clinical use. Fidaxomicin is a nonsystemically absorbed macrolide used only for the treatment of Clostridium difficile colitis. Ketolides are semisynthetic derivatives of erythromycin with activity against some macrolide-resistant strains. Macrolide antibiotics contain a multimembered lactone ring (14membered rings for erythromycin and clarithromycin and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural modifications improve acid stability and tissue penetration and broaden the spectrum of activity. Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive organisms. Erythromycin appears to inhibit the translocation step such that the nascent peptide chain temporarily residing at the A site fails to move to the P, or donor, site. Alternatively, macrolides may bind and cause a conformational change that terminates protein synthesis by indirectly interfering with transpeptidation and translocation. Telithromycin differs from erythromycin in that a 3-keto group replaces the -L-cladinose of the 14-member macrolide ring, and there is a substituted carbamate at C11-C12. These modifications render ketolides less susceptible to methylase-mediated (erm) and effluxmediated (mef or msr) mechanisms of resistance. Ketolides therefore are active against many macrolide-resistant gram-positive strains; however, concerns about the safety of telithromycin have limited its use (Brinker et al. Staphylococci are not reliably sensitive to erythromycin, and macrolide-resistant strains of S. Gram-positive bacilli also are frequently sensitive to erythromycin, including Clostridium perfringens, Corynebacterium diphtheriae, and L. Azithromycin has similar activity as erythromycin against sensitive strains of streptococci and staphylococci, while clarithromycin is slightly more potent. Clarithromycin and azithromycin have good activity against Moraxella catarrhalis, Chlamydia spp. Gram-positive bacteria accumulate about 100 times more erythromycin than do gram-negative bacteria. Erythromycin has Erythromycin base is incompletely absorbed from the upper small intestine. Because it is inactivated by gastric acid, it is administered as enteric-coated tablets or as capsules containing enteric-coated pellets that dissolve in the duodenum; food may delay absorption. Although the t1/2 may be prolonged in patients with anuria, dosage reduction is not routinely recommended in patients in renal failure. The drug is not removed significantly by either peritoneal dialysis or hemodialysis. Clarithromycin may be given with or without food, but the extended-release form should be administered with food to improve bioavailability. Clarithromycin and its active metabolite, 14-hydroxyclarithromycin, achieve high intracellular concentrations throughout the body, including the middle ear. Clarithromycin is metabolized in the liver to several metabolites; the active 14-hydroxy metabolite is the most significant. Metabolism is saturable, resulting in nonlinear pharmacokinetics and longer half-lives with higher dosages. The amount of clarithromycin excreted unchanged in the urine ranges from 20% to 40%, depending on the dose administered and the formulation (tablet vs. Dose adjustment is not recommended unless the creatinine clearance is less than 30 mL/min. Azithromycin undergoes some hepatic metabolism to inactive metabolites, but biliary excretion is the major route of elimination. Telithromycin is formulated as a 400-mg tablet for oral administration; there is no parenteral form. Telithromycin penetrates well into most tissues and is concentrated in many tissues, in particular in macrophages and white blood cells, where concentrations of 40 g/mL (500 times the plasma concentration) are maintained even 24 h after dosing. No adjustment of the dose is required for those with hepatic failure or mild-tomoderate renal failure. Intravenous 1055 administration is generally reserved for the therapy of severe infections and is now used uncommonly; the usual dose is 0. Clarithromycin usually is given twice daily at a dose of 250 mg for adults with mild-to-moderate infections and 500 mg twice daily for more severe infections. The 500-mg extended-release formulation of clarithromycin is given as 2 tablets once daily. Clarithromycin (500 mg) is also packaged with lansoprazole (30 mg) and amoxicillin (1 g) as a combination regimen that is administered twice daily for 10 or 14 days to eradicate H. Azithromycin should be given 1 h before or 2 h after meals when administered orally. For outpatient therapy of community-acquired pneumonia, pharyngitis, or sinusitis, a loading dose of 500 mg is given on the first day, and then 250 mg per day is given for days 2 through 5. Azithromycin is useful in treatment of sexually transmitted diseases, especially during pregnancy when tetracyclines are contraindicated (Centers for Disease Control and Prevention, 2015). The treatment of uncomplicated nongonococcal urethritis presumed to be caused by C. In children, the recommended dose of azithromycin oral suspension for acute otitis media and pneumonia is 10 mg/kg on the first day (maximum 500 mg) and 5 mg/kg (maximum 250 mg/d) on days 2 through 5. Macrolides are suitable drugs for the treatment of a number of respiratory tract infections. Azithromycin and clarithromycin are suitable choices for treatment of mild-to-moderate community-acquired pneumonia among ambulatory patients. In hospitalized patients, a macrolide is commonly added to an antipneumococcal -lactam for coverage of atypical respiratory pathogens. Because of excellent in vitro activity, superior tissue concentration, the ease of administration as a single daily dose, and better tolerability compared to erythromycin, azithromycin (or a fluoroquinolone) has supplanted erythromycin as the first-line agent for treatment of legionellosis. Macrolides are also appropriate alternative agents for the treatment of acute exacerbations of chronic bronchitis, acute otitis media, acute streptococcal pharyngitis, and acute bacterial sinusitis. Azithromycin or clarithromycin are generally preferred to erythromycin due to their broader spectrum and superior tolerability. Telithromycin is effective in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis and has a potential advantage where macrolide-resistant strains are common. Macrolides are alternatives for treatment of erysipelas and cellulitis among patients who have a serious allergy to penicillin (Stevens et al. Erythromycin has been an alternative agent for the treatment of relatively minor skin and soft-tissue infections caused by either penicillin-sensitive or penicillin-resistant S. A single 1-g dose of azithromycin is recommended for patients with uncomplicated urethral, endocervical, rectal, or epididymal infections because of the ease of compliance. Erythromycin base is preferred for chlamydial pneumonia of infancy and ophthalmia neonatorum (50 mg/kg/d in four divided doses for 14 days). Azithromycin, 1 g/week for 3 weeks, may be effective for lymphogranuloma venereum. Erythromycin for 7 days is very effective for acute infections or for eradicating the diphtheria carrier state. Antibiotics do not alter the course of an acute infection with diphtheria or decrease the risk of complications. The usual oral dose of erythromycin (erythromycin base) for adults ranges from 1 to 2 g/d, in divided doses, usually given every 6 h. Food should not be taken concurrently, if possible, with erythromycin base or the stearate formulations, but this is not necessary with erythromycin estolate. If administered early in the course of whooping cough, erythromycin may shorten the duration of illness; it has little influence on the disease once the paroxysmal stage is reached. Nasopharyngeal cultures should be obtained from people with pertussis who do not improve with erythromycin therapy because resistance has been reported. Azithromycin is much less likely to be involved in these drug interactions; however, caution is advised when the consequences of interaction are severe. Clarithromycin (500 mg twice daily) plus ethambutol (15 mg/kg once daily) with or without rifabutin is an effective combination regimen. Lincosamides the class originator lincomycin and its congener clindamycin are approved in the U. Clindamycin has largely replaced lincomycin in clinical practice and is principally used to treat gram-positive aerobic and anaerobic infections, as well as some parasitic infections. Erythromycin is an effective alternative for the prophylaxis of recurrences of rheumatic fever in individuals who are allergic to penicillin. Azithromycin or clarithromycin is recommended for Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Oral or intravenous administration of erythromycin frequently is accompanied by moderate-to-severe epigastric distress. A large cohort study found a small but statistically significant increase in the risk of sudden cardiac death with azithromycin compared to no antibiotic treatment or to amoxicillin. These symptoms are followed shortly thereafter by jaundice, which may be accompanied by fever, leukocytosis, eosinophilia, and elevated transaminases in plasma. Hepatotoxicity has also been observed with clarithromycin and azithromycin, although at a lower rate than with erythromycin. Telithromycin may induce severe hepatotoxicity and should only be used if it represents a clear advantage over alternative agents (Brinker et al. Allergic reactions observed are fever, eosinophilia, and skin eruptions, which disappear shortly after therapy is stopped. Auditory impairment and tinnitus have been observed with macrolides, especially at higher doses. Visual disturbances due to slowed accommodation have been reported following telithromycin. Telithromycin is contraindicated in patients with myasthenia gravis due to exacerbation of neurological symptoms. Clindamycin generally is similar to erythromycin in its in vitro activity against susceptible strains of pneumococci, S. Clindamycin is more active than erythromycin or clarithromycin against anaerobic bacteria, especially B. Clindamycin plus primaquine and clindamycin plus pyrimethamine are second-line regimens for Pneumocystis jiroveci pneumonia and T. Antimicrobial Activity Resistance to Lincosamides Macrolide resistance due to ribosomal methylation also may produce resistance to clindamycin. Because clindamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced constitutively. However, selection for a subpopulation of constitutive methylase producers may occur among staphylococci and streptococci with a macrolide-inducible phenotype (Lewis and Jorgensen, 2005). Clindamycin is not a substrate for macrolide efflux pumps; thus, strains that are resistant to macrolides by this mechanism are susceptible to clindamycin. Clindamycin palmitate, an oral preparation for pediatric use, is an inactive prodrug that is hydrolyzed rapidly in vivo.

The appeal of these targeted therapies is that they specifically target the activities of T lymphocytes and cytokines that mediate inflammation pregnancy 4 weeks 2 days purchase 50 mg fertomid otc, whereas traditional systemic therapies are broadly immunosuppressive or cytotoxic women's health center of santa cruz purchase fertomid 50 mg. The pathogenesis of psoriasis and atopic dermatitis is discussed briefly next breast cancer xmas ornaments cheap 50 mg fertomid mastercard, followed by the relevant targeted therapies menopause relief without hormones discount 50 mg fertomid amex. Psoriasis is not limited to the skin breast cancer hats cheap 50 mg fertomid with mastercard, as there can be psoriatic arthritis and other systemic manifestations pregnancy x category drugs purchase 50 mg fertomid mastercard. No embryo-fetal toxicity in mice and non-human primates; no adequate, well controlled studies in pregnant women; use only if benefit justifies potential risk to fetus. Atopic dermatitis is a chronic skin disorder characterized by epidermal barrier dysfunction and immune-mediated inflammation. Topical corticosteroids and calcineurin inhibitors are common therapies, and several of the traditional immunosuppressants have been used for more severe or resistant cases (Eichenfield et al. Targeted therapies show promise for the future treatment of atopic dermatitis (Beck et al. Other adverse events include exacerbation of congestive heart failure and demyelinating disease in predisposed patients. All patients should be screened for tuberculosis, history of demyelinating disorder, cardiac failure, active infection, or malignancy prior to therapy. This may explain the increased efficacy of these agents in comparison to etanercept for treating granulomatous conditions as well as the higher risk of infection with their use. Studies have shown etanercept to be safe and efficacious for pediatric psoriasis at dosing of 0. Neutralizing antibodies to infliximab may develop and lead to decreased efficacy over time. Concomitant administration of methotrexate or glucocorticoids may suppress this neutralizing antibody formation. Adalimumab is approved for treatment of plaque psoriasis and psoriatic arthritis in adults. Safety of adalimumab in pediatric patients for psoriasis is supported by its use in other conditions, such as juvenile idiopathic arthritis (Bellodi Schmidt and Shah, 2015). Because certolizumab pegol lacks the Fc portion, it is not able to activate complement-mediated cytotoxicity. Ustekinumab is approved for treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. After initial doses at weeks 0 and 4, it is administered every 12 weeks for the maintenance phase of therapy, which may be ideal for some patients. Studies have shown ustekinumab to be safe and efficacious in adolescent patients at the same dosing as adults (Bellodi Schmidt and Shah, 2015). There is the potential for increased mucocutaneous candidiasis infections, although this was not common during clinical trials. Vismodegib and sonidegib are smoothened inhibitors, which block activation of the hedgehog pathway (Iwasaki et al. They are approved for use in patients with locally advanced, metastatic, or recurrent disease that cannot be adequately managed with surgery or radiation therapy. The most common side effects are muscle spasms, dysgeusia, alopecia, and diarrhea. The hedgehog pathway is vital to normal fetal development, so extreme caution is needed in women of reproductive potential, and men should be cautioned regarding potential for exposure and fetal harm through semen. Apremilast is approved for treatment of moderateto-severe plaque psoriasis and psoriatic arthritis in adults. Tofacitinib is an oral Jak inhibitor approved for use in rheumatoid arthritis in adults. It has demonstrated efficacy for psoriasis in clinical trials and for atopic dermatitis in a pilot study. Dupilumab has shown promising results in clinical trials, demonstrating significant improvement in disease severity and fewer skin infections compared to placebo (Beck et al. It is commonly associated with infusion reactions and causes prolonged immunosuppression. Early studies reported opportunistic infections, so antimicrobial prophylaxis is recommended. Intravenous Immunoglobulin Intravenous immunoglobulin is prepared from fractionated pooled human sera derived from thousands of donors with various antigenic exposures (see Chapter 36). These patients may possess antiIgA antibodies that place them at risk for severe anaphylactic reactions. Other relative contraindications include congestive heart failure and renal failure. Targeted Antineoplastic Agents Recent advances in understanding the molecular pathways and genetic alterations underlying cancer development have allowed for the rapid emergence of oncotherapeutic agents targeted against the specific molecules involved in tumor pathogenesis (Iwasaki et al. They are often better tolerated than conventional Targeted Therapies for Melanoma Until recently, therapies for metastatic melanoma had low response rates along with either high toxicity or no effect on long-term survival. There has been rapid development of several new therapeutic options for metastatic or unresectable melanoma, primarily geared toward inhibition of mutated, abnormally activated tyrosine kinases that drive growth or enhancing immune function to combat malignant cells by inhibiting immune checkpoints (John and Cowey, 2015). Drugs for Hyperkeratotic Disorders Keratolytic agents reduce hyperkeratosis through myriad mechanisms. Common disorders treated with keratolytics include psoriasis, seborrheic dermatitis, xerosis, ichthyoses, and verrucae. They also appear to increase glycosaminoglycans, collagen, and elastic fibers in the dermis and are used in various formulations to reverse photoaging. Salicylic acid functions through solubilization of intercellular "cement," reducing keratinocyte adhesion, and softening the stratum corneum. Salicylism may occur with widespread and prolonged use, especially in children and patients with renal or hepatic impairment. Salicylic acid, while chemically not a true -hydroxy acid, often is listed as such on cosmetic labels. Other -hydroxy acid ingredients in cosmetics include -hydroxybutanoic acid, -tropic acid, and trethocanic acid. Urea, at low concentrations, increases skin absorption and retention of water, leading to increased flexibility and softness of the skin. At concentrations greater than 40%, urea denatures and dissolves proteins and is used to dissolve calluses or avulse dystrophic nails. It exerts its keratolytic effect by reacting with cysteine within keratinocytes, producing cystine and hydrogen sulfide (H2S). Itching also may be a sign of internal disorders, including malignant neoplasms, chronic renal failure, and hepatobiliary disease. The frequency and severity increase with age and may begin during puberty in some patients. Treatment of androgenetic alopecia is aimed at reducing hair loss and maintaining existing hair (Varothai and Bergfeld, 2014). Minoxidil, originally developed as an antihypertensive agent (see Chapter 28), was noted to be associated with hypertrichosis in some patients. Minoxidil enhances follicular size, resulting in thicker hair shafts, and stimulates and prolongs the anagen phase of the hair cycle, resulting in longer and increased numbers of hair. Allergic and irritant contact dermatitis can occur, and care should be taken in applying the drug because hair growth may emerge in undesirable locations. Patients with increased sulfotransferase enzyme activity are most likely to respond to minoxidil treatment; this may be a useful predictive test in the future (Roberts et al. Orally administered finasteride (1 mg/d) variably increases hair growth in men over a 2-year period. Finasteride is approved for use only in men but has been used off label for female pattern hair loss (Varothai and Bergfeld, 2014). Pregnant women should not be exposed to the drug because of the potential for inducing genital abnormalities in male fetuses. Adverse effects of finasteride include decreased libido, erectile dysfunction, ejaculation disorder, and decreased ejaculate volume. There have been postmarketing surveillance reports of persistent sexual dysfunction after stopping the medication. Spironolactone is an aldosterone antagonist and K+-sparing diuretic; it also has antiandrogen activity. Women of reproductive potential should not receive spironolactone without reliable contraception because spironolactone can cause feminization of a male fetus. Monobenzone (monobenzyl ether of hydroquinone) causes permanent depigmentation and should not be used for routine hormonally induced or postinflammatory hyperpigmentation. A 20% cream is approved for final depigmentation therapy of extensive vitiligo affecting at least more than 50% body surface area; it is rarely used and not currently commercially available. Glycolic acid is an -hydroxy acid used in chemical peels for disorders of pigmentation. It is thought to work by inhibiting tyrosinase in a pH-independent manner and to cause exfoliation by decreasing keratinocyte adhesion. Potential side effects are erythema, desquamation, and postinflammatory hyperpigmentation. Glycolic acid peels are best used as adjunctive therapy along with other topical therapy in patients with refractory epidermal hyperpigmentation (Sheth and Pandya, 2011). Miscellaneous Agents Capsaicin is an alkaloid derived from plants of the Solanaceae family. Chronic exposure to capsaicin first stimulates and then desensitizes this channel to capsaicin and diverse other noxious stimuli. Capsaicin also causes local depletion of substance P, an endogenous neuropeptide involved in sensory perception and pain transmission. It is also approved in patch form by prescription for postherpetic neuralgia and is used for off-label treatment of painful diabetic neuropathy and some forms of pruritus. Bentoquatam (quaternium-18 bentonite) is a mixture of quaternium-18 (quaternary ammonium chloride salts made from the fatty acids of tallow) and bentonite clay. The 5% topical lotion must be applied prophylactically at least 15 min prior to potential risk for exposure to urushiol and reapplied every 4 h. It is used in dermatology primarily for the treatment of inflammatory skin conditions such as psoriasis, seborrheic dermatitis, and atopic dermatitis or other forms of eczematous dermatitis. Multiple formulations and products are available commercially or through compounding, including those containing crude coal tar, coal tar extracts, or coal tar solution (Sandhu and Schwartz, 2011). Coal tar products are often poorly tolerated by patients due to its unpleasant odor, messiness, and potential for staining of clothing. Though occupational exposures to coal tar have been associated with malignancies. Anthralin (dithranol), a synthetic version of chrysarobin, is derived from the bark of the Brazilian araroba tree and is used in the treatment of psoriasis and alopecia areata; its mechanisms of action are unclear (Menter et al. Use of anthralin has been limited by the potential to cause irritant contact dermatitis and to stain skin, hair, nails, fabrics, and household items. Bimatoprost is a prostaglandin analogue approved for topical treatment of hypotrichosis of the eyelashes by increasing their growth, including length, thickness, and darkness. The prostaglandin-mediated increase in eyelash growth was serendipitously noted during the use of intraocular prostaglandin analogues for glaucoma. The proposed mechanism of eyelash growth is by an increase in the fraction of hairs in, and the duration of, the anagen phase. Increased pigmentation of the hairs is thought to occur due to stimulation of melanin production without an increase in the number of melanocytes. Importantly, brown pigmentation of the iris and eyelid skin may occur, and the increased iris pigmentation may be permanent. Treatment of Hyperpigmentation the agents discussed are most effective on hormonally or light-induced pigmentation within the epidermis. Sun protection or avoidance is a vital component of any treatment regimen (Sheth and Pandya, 2011). Hydroquinone (1,4-dihydroxybenzene) decreases melanocyte pigment production by inhibiting tyrosinase, the initial enzyme in the melanin biosynthetic pathway. In addition, it causes degradation of melanosomes and destruction of melanocytes by production of reactive oxygen radicals. Azelaic acid, a dicarboxylic acid isolated from cultures of Malassezia furfur, inhibits tyrosinase activity but is less effective than hydroquinone. Because it has mild comedolytic, antimicrobial, and anti-inflammatory properties, it also is often used in acne and papulopustular rosacea, especially in patients with postinflammatory hyperpigmentation. Propranolol and timolol are nonselective adrenergic antagonists traditionally used for cardiovascular disease. These agents are also effective in treating infantile hemangiomas and become the preferred treatment of infantile hemangiomas requiring intervention (Chen et al. Topical 1291 timolol drops and gel-forming solution are available but do not adequately treat deeper lesions. Bickers, and Lowell Goldsmith have contributed to this chapter in earlier editions of this book. Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.

If the response after 2 more days still is unsatisfactory womens health center 90042 order fertomid 50 mg on-line, the dose may be increased to a maximum of 8 units/kg every 6 h women's health clinic vancouver bc purchase fertomid 50 mg with amex. Intravenous bisphosphonates (pamidronate menstrual questions and answers effective fertomid 50 mg, zoledronate) have proven very effective in the management of hypercalcemia (see further material for discussion of bisphosphonates) women's health clinic vernon bc discount fertomid line. With pamidronate women's health diet cleanse generic fertomid 50 mg overnight delivery, resolution of hypercalcemia occurs over several days women's health center bayonne nj fertomid 50 mg generic, and the effect usually persists for several weeks. Zoledronate has largely superseded pamidronate because of its more rapid normalization of serum Ca2+ and longer duration of action. Once the hypercalcemic crisis has resolved, or in patients with milder calcium elevations, long-term therapy is initiated. Parathyroidectomy remains the only definitive treatment of primary hyperparathyroidism. Therapy of hypercalcemia of malignancy ideally is directed at the underlying cancer. When this is not possible, parenteral bisphosphonates often will maintain Ca2+ levels within an acceptable range. Because the usual 10-mL vial of a 10% solution contains only 93 mg Ca2+, many vials are needed. The intramuscular route should not be employed because abscess formation at the injection site may result. For control of milder hypocalcemic symptoms, oral medication suffices, frequently in combination with vitamin D or one of its active metabolites. Calcium carbonate is relatively inexpensive and well tolerated, so it is prescribed most frequently. Bile is essential for adequate absorption of vitamin D and is also the primary route of vitamin D excretion. Patients who have intestinal bypass surgery or inflammation of the small intestine may fail to absorb vitamin D sufficiently to maintain normal levels; hepatic or biliary dysfunction also may seriously impair vitamin D absorption. Nutritional rickets results from inadequate expo- Hypocalcemia and Other Therapeutic Uses of Calcium Calcium is used in the treatment of calcium deficiency states and as a dietary supplement. Injections of calcium chloride are accompanied by peripheral vasodilation and a cutaneous burning sensation. The rate of injection should be slow (not more than 1 mL/min) to prevent cardiac arrhythmias from a high concentration of Ca2+. Because the fetus acquires more than 85% of its calcium stores during the third trimester, premature infants are especially susceptible to rickets and may require supplemental vitamin D. Treatment of fully developed rickets requires a larger dose of vitamin D than that used prophylactically. One thousand units daily will normalize plasma Ca2+ and phosphate concentrations in about 10 days, with radiographic evidence of healing in about 3 weeks. Osteomalacia, distin- bone mineralization that is due to decreased renal synthesis of calcitriol. In high-turnover (hyperparathyroid) or mixed high-turnover disease with deficient mineralization, dietary phosphate restriction, generally in combination with a phosphate binder, is recommended. Sevelamer hydrochloride is a nonabsorbable polymer that acts as a nonselective anion exchanger. Sevelamer not only effectively lowers serum phosphate concentration in hemodialysis patients but also binds bile acids, and to a lesser extent low-density lipoprotein cholesterol and fat-soluble vitamins. Side effects of sevelamer hydrochloride include vomiting, nausea, diarrhea, dyspepsia, and metabolic acidosis. Sevelamer carbonate is equivalent to sevelamer hydrochloride in terms of safety and tolerability, with a lower likelihood of inducing metabolic acidosis. The drug exhibits similar phosphate control efficacy as sevelamer with a lower daily pill burden. Ferric citrate also exhibits comparable phosphate control efficacy to sevelamer and to calcium acetate. In addition, ferric citrate delivers a significant amount of iron, resulting in increased erythropoietic parameters and the possibility of iron overload with chronic dosing. Diarrhea is a common side effect of both iron-based phosphate binders (Shah et al. Niacin and nicotinic acid lower serum phosphate and have been proposed as alternatives to the use of sevelamer. Recent studies suggested that extended-release niacin does not improve cardiovascular outcomes and is associated with greater all-cause mortality. Hypervitaminosis D is treated by immediate withdrawal of the vitamin, a low-calcium diet, administration of glucocorticoids, and vigorous fluid support; forced saline diuresis with loop diuretics is also useful. With this regimen, the plasma Ca2+ concentration falls to normal, and Ca2+ in soft tissue tends to be mobilized. Conspicuous improvement in renal function occurs unless kidney damage has been severe. Cholecalciferol (vitamin D3) and calcitriol (1,25-dihydroxycholecalciferol) are available for oral administration or injection. Doxercalciferol (1-hydroxyvitamin D2), a prodrug that first must be activated by hepatic 25-hydroxylation, is approved for use in treating secondary hyperparathyroidism. The hypercalcemic effects typically persist for 2 weeks but can last twice that long. It is equivalent to calcitriol in assays for stimulation of intestinal absorption of Ca2+ and bone mineralization; it does not require renal activation. Vitamin D and its analogues are the mainstay of the therapy of hypoparathyroidism. Although most hypoparathyroid patients respond to any form of vitamin D, calcitriol may be preferred for temporary treatment of hypocalcemia while awaiting effects of a slower-acting form of vitamin D. They therefore offer a safer and more effective means of controlling secondary hyperparathyroidism. Calcipotriol is less than 1% as active as calcitriol in regulating Ca2+ metabolism. Calcipotriol has been studied extensively as a treatment of psoriasis and is available for topical use (see Chapter 70). Paricalcitol (1,25-dihydroxy-19-norvitamin D2) is a synthetic calcitriol derivative that lacks the exocyclic C19 and has a vitamin D2 rather than vitamin D3 side chain. The primary toxicity associated with calcitriol reflects its potent effect to increase intestinal absorption of Ca2+ and phosphate, along with the potential to mobilize osseous Ca2+ and phosphate. The hypocalcemic and hypophosphatemic effects of calcitonin are caused predominantly by direct inhibition of osteoclastic bone resorption (Henriksen et al. Calcitonin lowers plasma Ca2+ and phosphate concentrations in patients with hypercalcemia. Although calcitonin is effective for up to 6 h in the initial treatment of hypercalcemia, patients become refractory after a few days. Use of calcitonin does not substitute for aggressive fluid resuscitation, and the bisphosphonates are the preferred agents. Calcitonin is effective in disorders of increased skeletal remodeling, such as Paget disease, and in some patients with osteoporosis. For Paget disease, calcitonin generally is administered by subcutaneous injection because intranasal delivery is relatively ineffective owing to limited bioavailability. After initial therapy at 100 units/d, the dose typically is reduced to 50 units three times a week. Side effects of calcitonin include nausea, hand swelling, urticaria, and, rarely, intestinal cramping. The antiresorptive activity apparently involves two primary mechanisms: osteoclast apoptosis and inhibition of components of the cholesterol biosynthetic pathway. They have remarkably limited bioavailability (<1% [alendronate, risedronate] to 6% [etidronate, tiludronate]), which is further reduced by food and medications containing divalent cations such as calcium supplements, antacids, and iron. Hence, these drugs should be administered with a full glass of water following an overnight fast and at least 30 min before breakfast. Bisphosphonates distribute extensively into bone, undergo negligible hepatic clearance, and are excreted unchanged by the kidneys. Renal excretion of bisphosphonates declines proportionally with kidney function, and they are not recommended for patients with a creatinine clearance of less than 30 mL/min (Cremers and Papapoulos, 2011; Ott, 2015). These agents form a three-dimensional structure capable of chelating divalent cations such as Ca2+ and have a strong affinity for bone, targeting especially bone surfaces undergoing remodeling. First-generation bisphosphonates (medronate, clodronate, and etidronate) contain minimally modified side chains or possess a chlorophenol group (tiludronate) and are the least-potent agents. Chemistry Bisphosphonates are used extensively in conditions characterized by osteoclast-mediated bone resorption, including Paget disease, tumorassociated osteolysis, and hypercalcemia. In particular, much interest is focused on the role of bisphosphonates in the treatment of osteoporosis, including postmenopausal osteoporosis and steroid-induced osteoporosis. Bisphosphonates may also have direct antitumor action by inhibiting oncogene activation through their antiangiogenic effects. Oral bisphosphonates have not been used widely in children or adolescents because of uncertainty of long-term effects of bisphosphonates on the growing skeleton. Adverse Effects Mechanism of Action Bisphosphonates act by direct inhibition of bone resorption. Bisphosphonates concentrate at sites of active remodeling, remain in the matrix until the bone is remodeled, and then are released in the acid environment of the resorption lacunae and induce apoptosis in osteoclasts. Symptoms often abate when patients take the medication after an overnight fast, with tap or filtered water (not mineral water), and remain upright. Initial parenteral infusion of pamidronate may cause skin flushing, flu-like symptoms, muscle and joint aches and pains, nausea and vomiting, abdominal discomfort, and diarrhea (or constipation) but mainly when given in higher concentrations or at faster rates than those recommended. These symptoms are short lived and generally do not recur with subsequent administration. Zoledronate can cause severe hypocalcemia and has been associated with renal toxicity, deterioration of kidney function, and potential kidney disease. Infusion of zoledronate, 4 mg, should be performed over at least 15 min; patients should have standard laboratory and clinical parameters of kidney function assessed prior to treatment and periodically thereafter to monitor for deterioration in kidney function. Bisphosphonate use also is associated with osteonecrosis of the jaw (a rare event, with an incidence of ~ 2 in 100,000 patient-years in which the precise causal role of bisphosphonates has not been elucidated) as well as stress fractures in the lateral cortex of the femoral shaft (most commonly associated with alendronate and rarely with zoledronate; Reid, 2015). The substituents (R1 and R2) on the central carbon of the bisphosphonate parent structure are shown in blue. Examples of a first-generation bisphosphonate (medronate), a secondgeneration aminobisphosphonate (alendronate), and a third-generation bisphosphonate (zoledronate) are shown. Etidronate sodium is used for treatment of Paget disease and may be used parenterally to treat hypercalcemia (although largely supplanted for this use by amidronate and zoledronate). Tiludronate in recommended doses does not interfere with bone mineralization, unlike etidronate. Zoledronate is approved for treating Paget disease; administered as a single 5-mg infusion, zoledronate decreases bone turnover markers for 6 months with no loss of therapeutic effect. Zoledronate is widely used for prevention of osteoporosis in patients with prostate and breast cancer receiving hormonal therapy. A 4-mg formulation is available for intravenous treatment of hypercalcemia of malignancy, multiple myeloma, or bone metastasis resulting from solid tumors. The potent bisphosphonate ibandronate is approved for the prevention and treatment of postmenopausal osteoporosis. For treatment of osteoporosis, ibandronate (3 mg) is given intravenously every 3 months. Zoledronate is the first bisphosphonate to be approved for once-yearly intravenous treatment of osteoporosis (5 mg annually). They are approved for use in treating severe osteoporosis in patients at a high risk for fracture. Candidates for treatment with teriparatide and abaloparatide include women who have a history of osteoporotic fracture, who have multiple risk factors for fracture, or who failed or are intolerant of previous osteoporosis therapy. Men with primary or hypogonadal osteoporosis are also candidates for treatment with these agents. These agents are peptides and are administered by subcutaneous injection (see Drugs Available). The elimination of teriparatide proceeds by nonspecific enzymatic mechanisms in the liver, followed by renal excretion.

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Biosynthesis of Thyroid Hormones the thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin breast cancer z11 buy fertomid online pills, a complex glycoprotein made up of two apparently identical subunits (330 kDa each) and constituting the vast majority of the thyroid follicular colloid womens health zeitschrift buy 50 mg fertomid overnight delivery. The thyroid gland is unique in storing great quantities of hormone precursor in this way womens health of blairsville order 50mg fertomid with mastercard, and extracellular thyroglobulin is proportional to the thyroid mass women's health center vanderbilt cheap fertomid 50 mg online. The gland was first recognized as an organ of importance when thyroid enlargement was observed to be associated with changes in the eyes and heart in the condition we now call hyperthyroidism pregnancy itching order genuine fertomid on line. Hypothyroidism was described later menstrual cycle 9 days late purchase fertomid with a visa, in 1874, when Gull associated atrophy of the gland with the symptoms characteristic of hypothyroidism. The term myxedema was applied to the clinical syndrome in 1878 by Ord, in the belief that the characteristic thickening of the subcutaneous tissues was due to excessive formation of mucus. In 1891, Murray first treated a case of hypothyroidism by injecting an extract of sheep thyroid gland, later shown to be fully effective when given by mouth. The successful treatment of thyroid deficiency by administering thyroid extract was an important step toward modern endocrinology. Extirpation experiments to elucidate the function of the thyroid were at first misinterpreted because of the simultaneous removal of the parathyroids. The structure of parathyroid hormone, however, was not reported until the early 1970s. Calcitonin was discovered in 1961, demonstrating that the thyroid gland produced a second hormone. As a result, the ratio of [I-]thyroid to [I-]plasma is usually between 20 and 50 and can exceed 100 when the gland is stimulated. Iodide transport is inhibited by a number of ions, such as thiocyanate and perchlorate. Oxidation and Iodination Transport of iodine from the thyroid follicular cell to the colloid is facilitated by the apical transporter pendrin. Iodine ingested in the diet reaches the circulation in the form of iodide ion (I-). The thyroid actively transports the ion via Uptake of Iodide Because T4 and T3 are synthesized and stored within thyroglobulin, proteolysis is an important part of the secretory process. This process is initiated by endocytosis of colloid from the follicular lumen at the apical surface of the cell, with the participation of a thyroglobulin receptor, megalin. This "ingested" thyroglobulin appears as intracellular colloid droplets, which apparently fuse with lysosomes containing the requisite proteolytic enzymes. The normal daily production of T4 is estimated to range between 80 and 100 g; that of T3 is between 30 and 40 g. Although T3 is secreted by the thyroid, metabolism of T4 by 5, or outer ring, deiodination in the peripheral tissues accounts for about 80% of circulating T3 (Gereben et al. Under normal conditions, about 40% of T4 is converted to each of T3 and rT3, and about 20% is metabolized via other pathways, such as glucuronidation in the liver and excretion in the bile. It is upregulated in hyperthyroidism, downregulated in hypothyroidism, and inhibited by the antithyroid drug propylthiouracil. D2 localizes to the endoplasmic reticulum, which facilitates access of D2-generated T3 to the nucleus. This results in suppressed levels of D2 in hyperthyroidism and elevated levels in hypothyroidism, thus helping to maintain T3 homeostasis. D3 catalyzes inner ring or 5-deiodination, the main inactivating pathway of T3 metabolism; D1 performs this function to some extent. D3 can be induced locally by inflammation and hypoxia and is highly expressed in certain tumors. Both D2 and D3 are expressed during development in time- and spatially-restricted patterns. The three deiodinases contain the rare amino acid selenocysteine in their active sites. Incorporation of selenocysteine into the growing peptide chain is a complex process involving multiple proteins. Transport of Thyroid Hormones in the Blood Iodine in the circulation is normally present in several forms, with 95% as organic iodine and about 5% as iodide. The thyroid hormones are transported in the blood in strong but noncovalent association with several plasma proteins. T4, but not T3, also is bound by transthyretin (thyroxine-binding prealbumin), a retinol-binding protein. Albumin also can bind T4 when the more avid carriers are saturated, but its physiological importance is unclear. Binding of thyroid hormones to plasma proteins protects the hormones from metabolism and excretion, resulting in their long half-lives in the circulation. The differential binding affinities for serum proteins also contribute to establishing the 10- to 100-fold differences in circulating hormone concentrations and half-lives of T4 and T3. Brain Pituitary Heart Brown fat Skeletal muscle Thyroid Essential to understanding the regulation of thyroid function is the "free hormone" concept: Only the unbound hormone has metabolic activity. Because of the high degree of binding of thyroid hormones to plasma proteins, changes in either the concentrations of these proteins or the affinities of the hormone-protein interactions have major effects on the total serum hormone levels. The liver is the major site of nondeiodinative degradation of thyroid hormones; T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the bile. Some thyroid hormone is liberated by hydrolysis of the conjugates in the intestine and reabsorbed. Factors Regulating Thyroid Hormone Secretion Thyrotropin is a glycoprotein hormone that consists of an subunit, common to pituitary glycoproteins such as gonadotropins, and a unique subunit. Thyroid-stimulating hormone increases the synthesis and secretion of thyroid hormone. Low levels of I- are required for T4 synthesis, but high levels inhibit T4 synthesis and release. In some areas of the world, simple or nontoxic goiter is prevalent because of insufficient dietary iodine. The addition of iodate to table salt (NaCl) provides a convenient iodine supplement. The recommended daily allowances for iodine range from 90 to 120 g for children, 150 g for adults, 220 g for pregnancy, and 290 g for lactation (Public Health Committee of the American Thyroid Association et al. Vegetables, meat, and poultry contain minimal amounts of iodine, whereas dairy products and fish are relatively high in iodine. Iodized Salt Iodine has been used empirically for the treatment of iodinedeficiency goiter for 150 years; however, its modern use evolved from extensive studies using iodine to prevent goiter in schoolchildren in Akron, Ohio, where endemic iodine-deficiency goiter was prevalent. The success of these experiments led to the adoption of iodine prophylaxis and therapy in many regions throughout the world where iodine-deficiency goiter was endemic. The most practical method for providing small supplements of iodine for large segments of the population is the addition of iodide or iodate to table salt; iodate is now preferred. The use of iodized salt is required by law in some countries, but in others, such as the U. The enlarged and stimulated thyroid becomes remarkably efficient at extracting the residual traces of iodide from the blood, developing an iodine gradient that may be 10 times normal; in mild-to-moderate iodine deficiency, the thyroid usually succeeds in producing sufficient hormone and preferentially secreting T3. The importance of nongenomic actions in thyroid hormone physiology and pathophysiology remains uncertain. This superfamily includes the receptors for steroid hormones, vitamin D, retinoic acid, a variety of small-molecule metabolites such as certain fatty acids and bile acids, and well as a number of "orphan receptors" (see Chapter 3). The binding of T3 causes replacement of the corepressor complex by a coactivator complex that includes histone acetyltransferases, methyltransferases, and other proteins. Not only does the animal grow limbs, lungs, and other terrestrial accoutrements, but also T3 causes the tail to regress. In humans, thyroid hormone plays a critical role in brain development by mechanisms that are incompletely understood (Abduljabbar and Afifi, 2012; Mayerl et al. The absence of thyroid hormone during the period of active neurogenesis (up to 6 months postpartum) leads to irreversible mental retardation (cretinism) and is accompanied by multiple morphological alterations in the brain. These severe morphological alterations result from disturbed neuronal migration, deranged axonal projections, and decreased synaptogenesis. Thyroid hormone supplementation begun during the first 2 weeks of postnatal life can prevent the development of these morphological changes. The actions of thyroid hormones are not limited to the brain; most tissues are affected by the administration of thyroid hormone or by its deficiency. The extensive defects in growth and development in cretins vividly illustrate the pervasive effects of thyroid hormones in normal individuals. Cretinism is usually classified as endemic (caused by extreme iodine deficiency) or sporadic (a consequence of abnormal thyroid development or a defect in the synthesis of thyroid hormone). The affected child is dwarfed, with short extremities, mentally retardation, and listlessness. Other manifestations include puffy face, enlarged tongue, dry and doughy skin, slow heart rate, constipation, and decreased body temperature. For treatment to be fully effective, the diagnosis must be made shortly after birth and T4 treatment initiated, long before these clinical manifestations are apparent. In regions of endemic iodine deficiency, iodine replacement is best instituted before pregnancy. Screening of newborn infants for deficient thyroid function is carried out in the U. Thermogenic Effects Thyroid hormone is necessary for both obligatory thermogenesis (the heat resulting from vital processes) and facultative or adaptive thermogenesis (Yehuda-Shnaidman et al. Only a few organs, including the brain, gonads, and spleen, are unresponsive to the thermogenic effects of T3. Obligatory thermogenesis is the result of T3 making most biological processes thermodynamically less efficient for the sake of producing heat. It is likely that multiple mechanisms contribute to this effect, such as the induction of futile cycling and changes in mitochondrial energetics, but the specific pathways involved and their quantitative contributions have yet to be fully defined. Although the induction by T3 of uncoupling protein 1 is an important thermogenic mechanism in rodent brown adipose tissue, there is no convincing evidence that induction of uncoupling proteins plays a significant role in T3-induced thermogenesis in other tissues (skeletal muscle, etc. Regardless of the mechanism, thermogenesis is highly sensitive to thyroid hormone around the physiological range: Small changes in levothyroxine replacement doses may significantly alter resting energy expenditure in the hypothyroid patient. There also is evidence for nongenomic actions of thyroid hormone T3 to stimulate thermogenesis has evolved along with ancillary effects to support this action, such as the stimulation of appetite and lipogenesis. Cardiovascular Effects Hyperthyroid patients have tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure (Grais and Sowers, 2014). Hypothyroid patients have bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, and elevation of mean arterial pressure. The chronotropic effect of T3 is mediated by increases in the pacemaker ion current If in the sinoatrial node (see Chapter 30). T3 also appears to have a direct nongenomic vasodilating effect on vascular smooth muscle, which may contribute to the decreased systemic vascular resistance and increased cardiac output of hyperthyroidism. Common signs include goiter (primary hypothyroidism only), bradycardia, delayed relaxation phase of the deep tendon reflexes, cool and dry skin, hypertension, nonpitting edema, and facial puffiness. Deficiency of thyroid hormone during the first few months of life causes feeding problems, failure to thrive, constipation, and sleepiness. Atrial arrhythmias, excess cardiac mortality, and excessive bone loss have been associated with this profile of thyroid function tests. As with most types of thyroid dysfunction, women are affected more than men, with a ratio ranging from 5:1 to 7:1. Graves disease is more common between the ages of 20 and 50 but may occur at any age. The characteristic exophthalmos associated with Graves disease is an infiltrative ophthalmopathy and is considered an autoimmune-mediated inflammation of the periorbital connective tissue and extraocular muscles. Most of the signs and symptoms of thyrotoxicosis stem from the excessive production of heat, increased motor activity, and increased sensitivity to catecholamines produced by the sympathetic nervous system. The skin is flushed, warm, and moist; the muscles are weak and tremulous; the heart rate is rapid, the heartbeat is forceful, and the arterial pulses are prominent and bounding. Increased expenditure of energy gives rise to increased appetite and, if intake is insufficient, to loss of weight. There also may be insomnia, difficulty in remaining still, anxiety and apprehension, intolerance to heat, and increased frequency of bowel movements. Older patients may experience less manifestations of sympathetic nervous system stimulation and reduced symptoms compared to younger individuals, sometimes referred to as "apathetic hyperthyroidism. The most severe form of hyperthyroidism is thyroid storm (see section that follows on therapeutic uses of antithyroid drugs). Postreceptor defects in the liver and peripheral tissues are manifested by depleted glycogen stores, enhanced gluconeogenesis, and an increase in the rate of glucose absorption from the gut. There may be impaired glucose tolerance or even diabetes, but the vast majority of hyperthyroid patients are euglycemic. Conversely, hypothyroidism results in decreased absorption of glucose from the gut, decreased insulin secretion, and a reduced rate of peripheral glucose uptake.

The transferable genetic material consists of two different sets of plasmid-encoded genes on the same or different plasmids: one encoding the actual resistance womens health birth control fertomid 50mg without prescription, and another encoding genes necessary for bacterial conjugation menstruation exhaustion order fertomid 50 mg line. The efficiency of transfer is low; however women's health urinary problems discount fertomid 50mg, antibiotics can exert a powerful selective pressure to allow emergence of the resistant strain women's health center in waco buy fertomid 50 mg low cost. Genetic transfer by conjugation is common among gram-negative bacilli women's health center voorhees fertomid 50mg free shipping, and resistance is conferred on a susceptible cell as a single event women's health partners boca raton buy cheap fertomid 50 mg on-line. Enterococci also contain a broad range of host-range conjugative plasmids that are involved in the transfer and spread of resistance genes among gram-positive organisms. Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Development and qualification of a pharmacodynamic model for the pronounced inoculum effect of ceftazidime against Pseudomonas aeruginosa. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Penetration of levofloxacin into skin tissue after oral administration of multiple 750 mg once-daily doses. Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects. Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation. Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis. Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. Isoniazid bactericidal activity and resistance emergence: Integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations. Clinical use of genotypic and phenotypic drug resistance testing to monitor antiretroviral chemotherapy. Selection of Plasmodium falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemetherlumefantrine in Nigerian children with uncomplicated falciparum malaria. Mechanisms of heteroresistance to isoniazid and rifampin of Mycobacterium tuberculosis in Tashkent, Uzbekistan. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy. Quinolone efflux pumps play a central role in emergence of fluoroquinolone resistance in Streptococcus pneumoniae. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Inducible azole resistance associated with a heterogeneous phenotype in Candida albicans. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type1. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. The antibiotic resistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug resistance. Association of a bundled intervention with surgical site infections among patients undergoing cardiac, hip, or knee surgery. Biofilm-associated infections: antibiotic resistance and novel therapeutic strategies. The relationship between quinolone exposures and resistance amplification is characterized by an inverted U: a new paradigm for optimizing pharmacodynamics to counterselect resistance. Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malariain Thailand. Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Prevention of infective endocarditis: guidelines from the American Heart Association. This disease is caused by infection with protozoan parasites of the genus Plasmodium. Plasmodium falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. Plasmodium vivax accounts for half of the malaria burden in South and East Asia and more than 80% of the malarial infections in the Americas and has been underappreciated as a cause of severe malaria (Baird, 2013). In response, new, multiprong international public-private partnerships as well as other funding agencies and sources have emerged to create new pipelines that advance drug candidates from discovery to clinical development (Hemingway et al. Biology of Malarial Infection Malarial infection is initiated when a female anopheline mosquito injects Plasmodium sporozoites during a blood meal (Miller et al. After entering the dermis, sporozoites enter the bloodstream and, within minutes, arrive at the liver, where they infect individual hepatocytes via cell surface receptor-mediated events (Sinnis et al. This process initiates the asymptomatic prepatent period, or exoerythrocytic stage of infection, which typically lasts about 1 week. During this period, the parasite undergoes asexual replication within hepatocytes, resulting in production of liver-stage schizonts. When an infected hepatocyte ruptures, tens of thousands of merozoites are released into the bloodstream and infect red blood cells. Transmission of human-infecting malarial parasites is maintained in human populations by the persistence of hypnozoites (several months to a few years for P. The asexual erythrocytic stages of malarial parasites are responsible for the clinical manifestations of malaria. This part of the Plasmodium life cycle is initiated by merozoite recognition of red blood cells and mediated by cell surface receptors that facilitate invasion of red blood cells. Once inside a red blood cell, the merozoite develops into a ring form, which becomes a hemoglobin-metabolizing trophozoite (feeding stage) that matures into an asexually dividing blood-stage schizont. Although most invading merozoites develop into schizonts, a small proportion becomes gametocytes, the form of the parasite infective to mosquitoes. Gametocytes are ingested by the mosquito during an infectious blood meal; on reaching the midgut of the mosquito, the gametocytes transform into gametes that fertilize to become zygotes. Zygotes mature into ookinetes that invade the mosquito midgut wall and transform into oocysts. Plasmodium falciparum has a family of binding proteins that recognize a variety of host cell molecules that this parasite species uses to invade all stages of erythrocytes (Lim et al. Plasmodium malariae generally causes an indolent infection with very low levels of parasitemia and often does not produce clinical symptoms. This parasite can be found in all malaria-endemic areas but is most common in sub-Saharan Africa and the southwest Pacific. This infection is distinguished by a shorter erythrocytic cycle (24 h compared with 72 h for P. Although different studies are not entirely consistent in the definition of asymptomatic, generally this state implies a lack of fever, headache, and other systemic complaints, within a defined time period prior to a positive test for malaria parasitemia. Migration of asymptomatic individuals to areas where malaria is not present but vector mosquitoes are. Novel approaches to preventing transmission from asymptomatic reservoirs-whether through new drugs or vaccines-will be essential for future malaria control, elimination, and eradication strategies. Thus, antimalarial drugs can be classified based on their activities during this life cycle as well as by their intended use for either chemoprophylaxis or treatment. The first relates to chemoprophylaxis: Because no antimalarial drug kills sporozoites, it is not truly possible to prevent infection; drugs can only prevent the development of symptomatic malaria caused by the asexual erythrocytic forms, either in the bloodstream or as produced within and released by hepatocytes prior to erythrocyte invasion. The second relates to the treatment of an established infection: No single antimalarial is effective against all hepatic and intraerythrocytic stages of the life cycle that may coexist in the same patient. Complete elimination of the parasite infection, therefore, may require more than one drug. Agents (artemisinins, chloroquine, mefloquine, quinine and quinidine, pyrimethamine, sulfadoxine, and tetracycline) that are not reliably effective against primary or latent liver stages. Instead, their action is directed against the asexual blood stages responsible for disease. Drugs (typified by atovaquone and proguanil) that target not only the asexual erythrocytic forms but also the primary liver stages of P. This additional activity shortens to several days the required period for postexposure chemoprophylaxis. Primaquine, an eight-amino quinoline that is effective against primary and latent liver stages as well as gametocytes. Tafenoquine, an eight-amino quinolone, is a long half-life analogue of primaquine, has a similar spectrum of action as primaquine, and is in advanced clinical trials (Llanos-Cuentas et al. Severe headache, a characteristic early symptom in malaria caused by all Plasmodium spp. Plasmodium falciparum causes the most severe disease and may lead to organ failure and death. New insights into malaria clinical presentations indicate that-in the endemic setting where nonsterilizing clinical immunity is the rule, not the exception- the cardinal symptoms of malaria may be atypical or absent (Chen et al. Plasmodium vivax malaria is characterized by relapses caused by the reactivation of latent tissue forms. These include neurological symptoms (diminished consciousness, seizure) and pulmonary edema. Rare but life-threatening complications can occur, including splenic rupture, acute lung injury, and profound anemia. Plasmodium ovale is more common in sub-Saharan Africa and some islands in Oceania. Quinine and primaquine, which have significant toxicity and relatively short half-lives, generally are reserved for the treatment of established infection and are not used for chemoprophylaxis in a healthy traveler. By contrast, chloroquine, which is relatively free from toxicity and has a long t1/2, is convenient for chemoprophylactic dosing (in those few areas still reporting chloroquine-sensitive malaria). For ease of reference, detailed information on the antimalarial drugs appears next in alphabetical order by drug name. Artemisinin and its three major semisynthetic derivatives in clinical use, dihydroartemisinin, artemether, and artesunate, are potent and fast-acting antimalarials. Moreover, in the presence of mutations that confer resistance to partner drugs. Both artesunate and artemether have modest levels of plasma protein binding, ranging from 43% to 82%. Drug bioavailability via rectal administration is highly variable among individual patients. The artemisinins generally are not used alone because of their limited ability to eradicate infection completely. Artemisinins are highly effective for the first-line treatment of malaria when combined with other antimalarials. Artemisinins should not be used for chemoprophylaxis because of their short t1/2 values. Preclinical toxicity studies have identified the brain (and brainstem), liver, and bone marrow as the principal target organs. However, no systematic neurological changes have been attributed to treatment in patients 5 years of age or older. Patients may develop dose-related and reversible decreases in reticulocyte and neutrophil counts and increases in transaminase levels. This combination is highly effective for the treatment of uncomplicated malaria and is the most widely used first-line antimalarial across Africa. Administration with a high-fat meal is recommended because it significantly increases absorption. A sweetened dispersible formulation of artemether-lumefantrine has been approved for treatment of children. By contrast, amodiaquine has a t1/2 of about 3 h, attaining a peak concentration of about 25 nM within 30 min of oral administration. Artemisinins cause a significant reduction of the parasite burden, with a 4-log10 reduction in the parasite population for each 48-h cycle of intraerythrocytic invasion, replication, and egress.