Jennifer Hsing Choe

• Assistant Professor of Medicine
• Member of the Duke Cancer Institute

https://medicine.duke.edu/faculty/jennifer-hsing-choe

When used before surgery who diabetes definition 1999 buy cheap prandin 1mg online, chemotherapy can shrink large tumors test your diabetes risk 0.5 mg prandin with visa, thereby permitting lumpectomy in women who would otherwise require a mastectomy diabetes type 2 vs insulin resistance 1mg prandin for sale. When used after surgery diabetic diet kcal order 1mg prandin free shipping, chemotherapy can kill cancer cells that remain in the breast diabetic jamba juice buy prandin overnight, as well as cells that may have metastasized to distant sites diabetes symptoms numb toes prandin 1 mg with visa. A common regimen for breast cancer consists of doxorubicin (an anthracycline-type anticancer antibiotic) plus cyclophosphamide (an alkylating agent) followed by paclitaxel (a mitotic inhibitor). Zoledronate and Other Bisphosphonates In women with breast cancer, bisphosphonates can help preserve bone integrity, and can thereby decrease the risk of hypercalcemia and fractures. At this time, two bisphosphonates-zoledronate [Zometa] and pamidronate [Aredia]-are approved for hypercalcemia of malignancy, and one of them-pamidronate-is also approved for managing osteolytic bone metastases. However, although zoledronate is not approved for osteolytic bone metastases, it is just as effective as pamidronate. Furthermore, compared with pamidronate, zoledronate has three advantages: onset is faster, duration is longer, and infusion time is shorter (15 minutes vs. Principal adverse effects of the bisphosphonates are kidney damage and osteonecrosis of the jaw. In addition to reducing fractures and hypercalcemia, bisphosphonates may actually prevent metastases and prolong life. In women with breast cancer, bisphosphonates were originally employed to suppress bone resorption caused by metastases. While using bisphosphonates for this purpose, researchers noted something surprising: Bisphosphonates appeared to reduce the incidence of new bony metastases. Results of a follow-up study confirmed the original observation: In women with breast cancer, treatment with a bisphosphonate reduced metastases to bone and prolonged survival. These results were obtained using clodronate, an oral bisphosphonate available in Europe and Canada. When cancer cells spread to bone, they stimulate the activity of osteoclasts, the cells responsible for bone resorption. In turn, osteoclasts release growth factors that stimulate the cancer cells, thereby setting up a self-reinforcing cycle. Bisphosphonates interrupt the cycle by inhibiting osteoclast function and blocking tumor adhesion to bone. Efficacy was demonstrated in three double-blind trials that compared denosumab with zoledronate. Principal adverse effects of denosumab are hypocalcemia, serious infections, skin reactions, and osteonecrosis of the jaw. For men with localized prostate cancer, the preferred treatments are surgery and radiation, with or without adjunctive use of drugs. For men with metastatic prostate cancer, drug therapy and castration are the only options. The only other choices are cytotoxic drugs and a new immunotherapy known as sipuleucel-T [Provenge]. To minimize hypercalcemia and fractures caused by bone metastases, men may take zoledronate [Zometa] or denosumab [Xgeva] (see discussion of breast cancer above). The remaining 10% are produced by the adrenal glands and by the prostate cancer itself. Specifically, we can block testosterone receptors with drugs; we can lower testosterone production with drugs; and we can lower testosterone production by castration. Drug therapy is more effective than castration because castration only eliminates testicular androgens, leaving androgen synthesis by the adrenal glands and cancer cells intact. In contrast, by using drugs to block testosterone receptors and testosterone synthesis, we can reduce the influence of testosterone from all sources (testes, adrenal glands, prostate cancer). For patients with prostate cancer, leuprolide represents an alternative to orchiectomy (surgical castration). After several weeks of treatment, testosterone levels are equivalent to those seen after surgical castration. Because leuprolide therapy mimics the effects of orchiectomy, treatment is often referred to as chemical castration. It is important to note that leuprolide does not decrease production of androgens made by the adrenal glands or by the Therapeutic Use. As noted, these nontesticular sources account for about 10% of the androgens in circulation. Hence, even though production of testicular androgens is essentially eliminated, adrenal and prostatic androgens can still provide some support for prostate cancer cells. In patients receiving leuprolide, an androgen receptor blocker can help in two ways. The current trend is to use an androgen receptor blocker during the first weeks of leuprolide therapy (to prevent leuprolide-induced tumor flare), after which the drug is discontinued unless there is tumor progression despite continued leuprolide treatment. Hot flashes are the most common adverse effect, but these usually decline as treatment continues. Reduced testosterone may also lead to erectile dysfunction, loss of libido, gynecomastia, reduced muscle mass, new-onset diabetes, myocardial infarction, and stroke. During the initial weeks of treatment, elevation of testosterone levels may aggravate bone pain and urinary obstruction caused by prostate cancer. As a result, patients with vertebral metastases or preexisting obstruction of the urinary tract may find treatment intolerable. As noted, concurrent treatment with an androgen receptor blocker can minimize these problems. By suppressing testosterone production, leuprolide may increase the risk of osteoporosis and related fractures. Bone loss can be minimized by consuming adequate calcium and vitamin D, and by performing regular weight-bearing exercise. In addition, a bisphosphonate (eg, zoledronate [Zometa]) or denosumab [Xgeva] can be used to preserve bone and reduce fracture risk (see discussion of breast cancer above). Leuprolide implant, sold as Viadur, is formulated as a 65-mg pellet for subQ implantation in the inner aspect of the upper arm once every 12 months. Histrelin [Vantas] is formulated as a 50-mg pellet for subQ implantation in the inner aspect of the upper arm once every 12 months. In clinical trials, patients received an initial 240-mg dose followed by monthly maintenance 80-mg doses. Testosterone levels fell rapidly to those produced by castration, and then remained low for at least 12 months. Elimination is primarily by peptide bond hydrolysis, a process that occurs in the liver but does not involve cytochrome P450 enzymes. In addition, degarelix often causes injection-site reactions (pain, erythema, swelling), weight gain, and elevation of liver transaminases. After a year of treatment, about 10% of patients develop antibodies against degarelix. The regimen consists of an initial 240-mg dose (two 120-mg injections), followed by monthly 80-mg injections for maintenance. Nilutamide Like flutamide and bicalutamide, nilutamide [Nilandron, Anandron] blocks receptors for androgens. The drug is approved for metastatic prostate cancer in men who have undergone surgical castration. Benefits derive from blocking the actions of adrenal androgens, which are not reduced by castration. In clinical trials, nilutamide reduced bone pain, prolonged progression-free survival, and increased median survival time. Although nilutamide is structurally similar to flutamide, the drug is not as well tolerated. The most common adverse effects are hot flashes, delayed adaptation to darkness, nausea, constipation, insomnia, and gynecomastia. In addition, nilutamide can cause reduced libido, erectile dysfunction, decreased muscle mass, and decreased bone mass with associated increased risk of fractures. Currently, three androgen receptor blockers are available: flutamide, bicalutamide, and nilutamide. Benefits derive from blocking androgen receptors in tumor cells, thereby depriving them of needed androgenic support. The combination is not used continuously because it does not increase survival, but does increase toxicity. Most of each dose is converted to an active metabolite on the first pass through the liver. To reduce the risk of serious harm, liver function should be assessed at baseline, monthly during the first 4 months of treatment, and periodically thereafter. Of course, since flutamide is approved only for prostate cancer, use during pregnancy should not happen anyway. When bicalutamide is used alone, the most common side effects are breast pain and gynecomastia. When the drug is combined with leuprolide, the most common side effect is hot flashes. Also, like flutamide, bicalutamide poses a small risk of liver injury, and hence liver function should be monitored. Bicalutamide is just as effective as flutamide, and dosing is more convenient (50 mg once a day vs. Abiraterone [Zytiga] is indicated for combined use with prednisone to treat metastatic castrationresistant prostate cancer in men previously treated with docetaxel. Benefits derive from inhibiting production of androgens by the adrenal gland and by the prostate cancer itself. When tested in men with metastatic castration-resistant prostate cancer, the combination of abiraterone plus prednisone increased overall survival by nearly 4 months, and progression-free survival by 2 months. The most common adverse effects are hypokalemia, edema, joint swelling/discomfort, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, and hypertension. High levels of mineralocorticoids can cause retention of sodium and loss of potassium, leading to fluid retention, edema, hypertension, and hypokalemia. Low levels of glucocorticoids can increase the risk of death from traumatic events. Co-treatment with prednisone (a glucocorticoid) helps compensate for reduced production of glucocorticoids by the adrenal glands and, by suppressing release of adrenocorticotropic hormone from the pituitary, prednisone can reduce excessive production of mineralocorticoids. If these tests indicate significant liver injury, abiraterone should be discontinued or the dosage reduced. Of course, since abiraterone is approved only for prostate cancer, use during pregnancy should not be an issue. Abiraterone is supplied in 250-mg capsules, which should be swallowed with water on an empty stomach (1 hour before a meal or 2 hours after). Dosing should not be done with food, owing to greatly increased absorption, which could cause toxicity. The usual regimen is 1000 mg abiraterone once daily combined with 5 mg prednisone twice daily. Ketoconazole Ketoconazole [Nizoral], used primarily for fungal infections (see Chapter 92), can be used off-label for prostate cancer. As with abiraterone, benefits derive from inhibiting testicular, adrenal, and prostatic production of androgens. Dosages are higher than those used for antifungal therapy (400 mg 3 times a day compared with 200 mg once a day), and hence side effects are common. Among these are nausea, vomiting, fatigue, skin changes, liver damage, and gynecomastia. Because high-dose ketoconazole can suppress adrenal production of glucocorticoids, the drug is usually combined with hydrocortisone (to avoid adrenal insufficiency). Nonetheless, sipuleucel-This of great interest in that it represents an entirely new approach to cancer treatment. Sipuleucel-This indicated for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer. In clinical trials, sipuleucel-T prolonged life by about 4 months, compared with 2. Of note, although sipuleucel-T improves survival, it does not cause measurable tumor regression, nor does it delay the time to tumor progression- suggesting that the mechanism underlying prolonged survival may be something other than immune-mediated injury to cancer cells. Sipuleucel-This produced in two steps: collection of circulating immune cells (macrophages) from the patient, followed by modification of those cells in the laboratory. This process-cell collection plus modification-takes about 2 days, and must be done for each dose. Macrophage collection is done by leukapheresis, a process in which venous blood is circulated from the patient, through a machine, and then back into the patient. The machine separates out macrophages (along with some platelets and other blood cells), and then returns the remaining cells and serum to the patient. The most common are chills, fatigue, fever, back pain, nausea, joint ache, and headache. Other common reactions include paresthesias, vomiting, anemia, constipation, dizziness, weakness, and extremity pain. Symptoms include fever, chills, nausea, vomiting, fatigue, hypertension, tachycardia, and respiratory reactions (dyspnea, hypoxia, and bronchospasm). Infusion reactions can be reduced by premedication with acetaminophen plus an antihistamine, such as diphenhydramine [Benadryl]. Pretreatment with acetaminophen plus an antihistamine can reduce infusion reactions.

Acitretin Acitretin [Soriatane] is the principal active metabolite of etretinate diabetic diet on insulin purchase prandin 0.5mg line, a highly toxic drug that has been withdrawn diabetes test ziekenhuis buy discount prandin on line. The major difference between the two drugs is pharmacokinetic: Whereas etretinate has a very long half-life (120 days) diabetic needles prandin 1mg with visa, the half-life of acitretin is much shorter (only 49 hours) managing borderline diabetes generic prandin 2 mg without a prescription. Although acitretin is less dangerous than etretinate diabetes symptoms toddler cheap 0.5 mg prandin visa, it still can cause serious harm diabetes signs on neck buy prandin online, especially injury to the liver and to the developing fetus. Acitretin acts on epithelial cells to inhibit keratinization, proliferation, and differentiation. Acitretin is indicated for severe psoriasis, including erythrodermic and generalized pustular types. In clinical trials, the drug produced a 60% to 70% reduction in the severity and area of symptoms. Because side effects are very common and sometimes severe, acitretin should be reserved for patients who have not responded to safer drugs. These drugs are very effective and have become first-line treatments for moderate to severe psoriasis. Other dermatologic effects (dry skin, nail disorders, pruritus) occur in 25% to 50% of patients. Mucous membranes are affected, causing rhinitis (25% to 50%), inflammation of the lips (25% to 50%), dry mouth (10% to 25%), nosebleed (10% to 25%), and gingival bleeding, gingivitis, and stomatitis. Other common reactions include erythematous rash, bone and joint pain, spinal hyperostosis, dry eyes, and paresthesias. Signs of liver damage (elevation of aminotransferase activity) develop in one-third of patients, but normally resolve when treatment is stopped. Alcohol promotes conversion of acitretin to etretinate, and can thereby increase the risk of adverse effects and toxicity. Accordingly, women of child-bearing age should be warned against drinking alcohol. Because acitretin is a derivative of vitamin A, combining it with vitamin A supplements may pose a risk of vitamin A toxicity. Both acitretin and tetracycline can cause pseudotumor cerebri (intracranial hypertension); therefore, combining the drugs is not recommended. In addition, acitretin should not be combined with methotrexate and other drugs that can damage the liver. Acitretin is embryotoxic and teratogenic, and therefore must not be used during pregnancy. Major human fetal abnormalities that have been reported include encephalocele (herniation of the brain through a skull defect), reduced cranial volume, facial malformation, cardiovascular defects, absence of terminal phalanges, and malformations of the hips, ankles, and forearms. The manufacturer has developed a program for women of child-bearing age who will be prescribed acitretin. Before acitretin is given to women of reproductive age, pregnancy should be ruled out and two reliable methods of contraception implemented before beginning treatment. Contraception should be initiated at least 1 month before treatment and should continue for at least 3 years after treatment has ceased. If pregnancy occurs, acitretin should be discontinued immediately and the patient should contact the prescriber to discuss the effects on the fetus. The dosage for psoriasis is 25 or 50 mg once daily, taken with a meal to facilitate absorption. Ustekinumab [Stelara] is a first-in-class interleukin antagonist approved for adults with moderate to severe plaque psoriasis. Ustekinumab is very effective: About two-thirds of patients experience at least a 75% reduction in symptoms. Like the other biologic therapies for psoriasis, ustekinumab is administered by injection. However, since injections are made just once every 12 weeks, ustekinumab is more convenient than the other agents. In shortterm clinical trials, adverse effects were usually mild and self-limited, and their incidence was no greater than with placebo. Accordingly, patients should be checked for latent tuberculosis before starting treatment, and should be advised to report serious infections that develop during treatment. For adults who weigh 100 kg or less, dosing consists of 45 mg on days 1 and 28, followed by 45 mg every 12 weeks thereafter. For adults who weigh more than 100 kg, dosing consists of 90 mg on days 1 and 28, followed by 90 mg every 12 weeks thereafter. In the first step, affected regions are covered with 1% coal tar ointment for 8 to 10 hours, after which the coal tar is washed off. Unfortunately, treatment is expensive and time consuming (up to 30 treatments are needed), and patients dislike being coated with smelly coal tar. Cyclosporine Cyclosporine [Neoral, Sandimmune, Gengraf] is a powerful immunosuppressant that inhibits proliferation of B cells and T cells. Unfortunately, cyclosporine can cause kidney damage and other serious harm, and hence should be used only after treatment with other drugs has failed. Adverse effects associated with the procedure include pruritus, nausea, and erythema. In addition, the process may accelerate aging of the skin and may increase the risk of skin cancer. Photochemotherapy is indicated for patients with extensive, active psoriasis who have not responded adequately to more conventional therapy. Systemic Drugs for Psoriasis: Biologic Agents Like the conventional systemic drugs, the biologic agents are reserved for patients with moderate to severe psoriasis that has not responded to other treatments. All four drugs suppress immune function, and thereby increase the risk of serious infection. Of these options, cryotherapy (freezing with liquid nitrogen) is used most, owing to its speed, simplicity, and effectiveness. Because aminolevulinic acid is light sensitive, patients should protect treated areas from exposure to sunlight and bright indoor light before blue light exposure. The condition is characterized by dry, scaly skin and intense pruritus that often leads to scratching and rubbing, which in turn can lead to erythema, abrasions, rash, erosions with an exudate, and increased susceptibility to skin infection. Firstline therapy consists of moisturizers (eg, Cetaphil Moisturizing Cream, Eucerin Original Cream) and topical glucocorticoids. Unfortunately, the glucocorticoids can cause skin atrophy, hypopigmentation, telangiectasis (permanent focal red lesions), and, in high doses, possible systemic effects, including adrenal suppression. If topical glucocorticoids are insufficient, patients may be treated with a topical immunosuppressant (see below). A sedating antihistamine can help control itching and can facilitate sleeping at night. Fluorouracil the basic pharmacology of fluorouracil [Carac, Fluoroplex, Efudex] is discussed in Chapter 102. Fluorouracil is indicated for topical treatment of multiple actinic keratoses and superficial basal cell carcinoma. A course of topical treatment elicits the following sequence of responses: (1) mild inflammation; (2) severe inflammation, often with burning, stinging, and vesicle formation; (3) tissue disintegration, characterized by erosion, ulceration, and necrosis; and (4) healing. Although fluorouracil is only applied for 2 to 6 weeks, the events just described may require 3 or more months for completion. Among the more frequent reactions are itching, burning, rash, inflammation, and increased sensitivity to sunlight. Topical fluorouracil is available under three trade names: Carac (microspheres in a 0. Treatment should continue until a stage-three response (tissue disintegration) develops, usually within 2 to 6 weeks. Topical Immunosuppressants Two topical immunosuppressants-tacrolimus and pimecrolimus-are approved for atopic dermatitis. Although effective against atopic dermatitis, both drugs may pose a risk of skin cancer and lymphoma. Because of this potential for serious harm, tacrolimus and pimecrolimus are considered second-line drugs for atopic dermatitis, and should be reserved for patients who have not responded to glucocorticoids. Tacrolimus [Protopic], available as Prograf for preventing organ transplant rejection (see Chapter 69), is available as an ointment for moderate to severe atopic dermatitis. Specifically, the drug inhibits calcineurin, and thereby suppresses the activity of T cells and decreases the release of inflammatory mediators from cutaneous mast cells and basophils. Systemic absorption of topical tacrolimus is low, and gets even lower as the skin heals. The most common side effects are erythema, pruritus, and burning sensations at the application site. In children, tacrolimus may increase the risk of varicella-zoster virus infection. Adverse effects associated with systemic tacrolimus (nephrotoxicity, neurotoxicity, hypertension, diarrhea, nausea) have not occurred with topical therapy. There have been reports of skin cancer and lymphoma in humans, although a causal relationship has not been established. To reduce any risk of skin cancer, patients should protect treated areas from direct sunlight, and should avoid sunlamps and tanning beds. Pimecrolimus 1% cream [Elidel] is a topical immunosuppressant approved for mild to moderate atopic dermatitis. The drug is very similar to tacrolimus with regard to mechanism, therapeutic effects, and adverse effects. In clinical trials, twice-daily application for 3 weeks reduced signs and symptoms of eczema by 72%. Although studies comparing pimecrolimus directly with tacrolimus have not been done, clinical efficacy of the drugs appears similar. The most common adverse effects are erythema, pruritus, and burning sensations at the application site, especially during the first few days of treatment. As with tacrolimus, there have been reports of skin cancer and lymphoma, but a causal relationship has not been established. Systemic absorption of pimecrolimus is minimal; in clinical trials, blood levels were at or below the limit of detection. In clinical trials, twice-daily application for 60 to 90 days produced complete clearing in 50% of patients. The most common side effects are dry skin, itching, redness, and rash at the application site. Imiquimod is better tolerated than fluorouracil, but less effective, causing complete clearance in only 45% of patients, compared with 90% for fluorouracil. In clinical trials, 33% of patients experienced local reactions: redness, swelling, sores, blisters, itching, burning, scabbing, and crusting. Of note, lesion clearance correlated with the intensity of side effects, suggesting that an inflammatory reaction is needed to produce a clinical response. Fourteen to 18 hours later, the prescriber photoactivates the drug by exposing lesions to 1000 seconds of blue light, using the Blu-B Blue Light supplied by the manufacturer. In clinical trials, 66% of patients experienced complete clearing by 8 weeks after a single treatment, and 77% of patients experienced clearing of 75% or more. Local effects-burning, stinging, redness, and edema-occur in nearly all *Two other topical formulations of diclofenac, sold as Voltaren Gel and Flector, are available to relieve musculoskeletal pain (see Chapter 71). Most warts resolve spontaneously within a few months, but some can last for years. Podophyllin (podophyllum resin) [Podocon-25, Podofilm] is used primarily for perianal and venereal warts. Podophyllin is a mixture of resins from the May apple or mandrake (Podophyllum peltatum Linne). These preparations are highly caustic and should be applied only by a trained clinician. To minimize the risk of toxicity from systemic absorption, the resin should be washed off with alcohol or soap and water a few hours after application. Each treatment should be limited to a small surface area and to a small number of warts. Potential reactions include central and peripheral neuropathy, kidney damage, and blood dyscrasias. These effects are most likely when the drug is applied to large areas in excessive amounts. The drug should not be applied to moles or birthmarks, nor should it be applied to warts that are bleeding or friable (easily crumbled) or that have undergone recent biopsy. When used to remove venereal warts, podophyllin should be washed off 1 to 4 hours after application. Solutions of these acids are very watery, and hence can easily spread to and thereby injure surrounding tissue. To minimize spread, the solution should be allowed to dry before the patient sits or stands. If too much solution is applied, it should be neutralized with soap or sodium bicarbonate, or removed by applying talc. Venereal Warts Venereal warts form around the cervix, vulva, urethra, glans penis, and anus and anal canal. Individuals with anogenital warts should be warned that they can transmit the infection to sexual partners. Genital warts can be removed in two basic ways: with topical drugs or with physical measures such as cryotherapy (freezing), electrodesiccation (destruction with an electric current), laser surgery, and conventional surgery. Neither drugs nor physical measures can eradicate the virus because, even after successful wart removal, the virus remains. The drugs used to remove venereal warts can be divided into two groups: agents that must be administered by a healthcare provider and agents that can be applied at home.

The second category is Pharmacy Only Nonprescription Drugs metabolic disease associates erie pa purchase cheap prandin, and as the name implies diabetes insipidus osmolality buy prandin 0.5mg overnight delivery, these drugs are sold only at pharmacies diabetes insipidus review pdf buy discount prandin on-line. These medications are suitable for self-selection diabetes mellitus jurnal indonesia order prandin 0.5 mg otc, but may pose a risk to certain patient populations and therefore should be sold where the pharmacist is available to provide advice when requested diabetes type 2 celebrities buy 2mg prandin with mastercard. Examples include high-dose simple analgesics (ie diabetes type 1 uncontrolled icd 9 discount 2 mg prandin with mastercard, aspirin, nonsteroidal antiinflammatory drugs) and antihistamines. The third category includes nonprescription products that can be sold at any retail outlet and do not require professional supervision. In general, these products are provided with adequate information for the patient to make a safe and effective choice, and labeling is believed sufficient enough to permit appropriate use of the drug product. Examples are nicotine gum and patches, low-dose simple analgesics, and antiulcer therapy. National Drug Schedules As previously mentioned, individual provinces have enacted their own legislation controlling the sale of both prescription and nonprescription products. This has led to inconsistency and confusion for both the healthcare practitioner and the consumer. This model attempts to align the provincial drug schedules so that the conditions for the sale of drugs will be consistent across the country. Narcotics, controlled substances, and prescription medications are listed in Schedule I, while nonprescription medications are assigned to one of the three categories previously described. This new provision allowed generic drug companies to manufacture and distribute patented drugs in Canada, provided that a minimal 4% royalty fee was paid to the patent holder. Unfortunately, the system caused a decline in revenue to "innovative" pharmaceutical companies, with a resultant decline in research on new drug development. After much debate, and retroactive to June 1987, the Patent Act was amended to give patent holders market exclusivity either (1) for 7 to 10 years or (2) until the 17-year patent (from date of filing) expires, whichever comes first. This bill (1) eliminated compulsory licensing and (2) extended patent protection on brand-name drugs to 20 years, thereby making Canadian patent laws similar to those of the United States and other industrialized nations. A special committee reviewed the impact of Bill C-91 on such factors as drug prices, drug research and development, and job creation. In order to respond to concerns arising from changes in the Patent Act, a Patented Medicine Prices Review Board was created. There is, however, some pressure by the pharmaceutical industry to adopt worldwide patent laws for pharmaceutical products. These topics- presented in boxes throughout the text-highlight information that he found especially interesting. Gastroesophageal Reflux Disease the Increasingly Strong Case Against Antioxidants Antibiotics in Animal Feed: Dying for a Hamburger and Chicken Nuggets Methicillin-Resistant Staphylococcus aureus Clostridium difficile Infection. At the end of the gestational fourth week, branchial arches, branchial pouches and primitive gut make their appearance. This is when the embryo gets its first identifiable head and face with an orifice in its middle known as the stomodeum (primitive mouth). The stomodeum is surrounded bilaterally by mandibular and maxillary prominences, which are derivatives of the first arch. The stomodeum is limited superiorly by the presence of the frontonasal eminence and inferiorly by the mandibular arch. The primitive choana forms the point of development of the posterior pharyngeal wall and the various paranasal sinuses. The bucconasal membrane initially separates the primitive nasal cavity from the mouth, but it eventually breaks down, forming the primitive choanae. The palatal processes derived from the lateral maxillary mesoderm grow medially, fusing in the midline with each other and the septum to separate the nasal and oral cavities anteriorly. Posteriorly, this midline floor separates the nasopharynx and oral cavities and forms the soft palate. The nasal septum arises from a dorsal extending midline ridge from the posterior end of the frontonasal processes. The superior and posterior part of the primitive nasal septum ossifies to form the perpendicular plate and vomer, respectively. The anterior and inferior portions remain cartilaginous to form the quadrilateral cartilaginous septum. Development of the frontal sinus the frontal sinus starts developing at the fourth intrauterine month. The frontal sinus, the anterior ethmoidal complex and the complex array of the frontoethmoidal cells develop from five or so pits that lie between the first and second ethmoturbinates. The frontal bone is very poorly pneumatized at birth and the frontal sinuses not distinguishable from the anterior ethmoid complex. The fetal pits start to pneumatize the frontal bone and can be noted at the end of the first year of life. One of these fetal pits continues to pneumatize both plates of the frontal sinus such that by the twelfth year of life the frontal sinuses have largely developed. The bony structure is made of the nasal bones, which unite superiorly with the frontal bone at the nasion and laterally with the frontal processes of the maxilla. The distal two-thirds of the nose is formed by the upper and lower lateral cartilages, which overlap each other at the margins. The upper lateral cartilages fuse medially with the quadrilateral cartilage, forming the cartilaginous part of the nasal dorsum. The lower lateral cartilages, also called the alar cartilages, are each composed of the medial and lateral crus connected by the intermediate crus. The medial crus contributes to the columella attached posteriorly with the membranous septum. Branches of the facial artery supply the alar region, and branches of the ophthalmic and maxillary artery supply the dorsum and lateral walls. The venous drainage is to two units: the angular Development of the ethmoid sinus the fetus develops six to seven folds in the lateral nasal wall at the ninth and tenth weeks. These folds fuse, forming crests termed ethmoturbinates from which the permanent ethmoidal structures develop. The third crest is the basal lamella of the middle turbinate that divides the ethmoidal air cells in the anterior and posterior groups. The other structures that arise from these crests include the middle, superior and supreme turbinates, and all are seen to be attached to the lateral nasal wall by their basal lamella. Development of the sphenoid sinus the sphenoid sinus appears at the third intrauterine month as an evagination from the sphenoethmoidal Anatomy of the nose and paranasal sinuses / the nasal cavity and paranasal sinuses 5 vein and the ophthalmic veins. The latter interlinks with the anterior ethmoid system and thence into the cavernous sinus. The submandibular and submental nodes provide the main lymphatic drainage to the external nose. The medial crura of the lower lateral cartilages attach to the thin membranous septum anteriorly, forming one of the major tip support structures. At its upper margin, the quadrilateral cartilage is connected to the upper lateral cartilages, contributing to the projection and height of the mid-third of the nose. The keystone area represents the attachment of the quadrangular cartilage to the bony septum and nasal bones at the rhinion. Continuity and fixation at this point are important both aesthetically and functionally because it supports the projection of the upper third to mid-third of the nose. The nasal cavity is divided in the midline by the nasal septum, which forms the medial wall of the nasal passages. The roof is formed anteriorly by the undersurface of the upper lateral cartilages and nasal bones, and posteriorly by the cribriform plate, which houses the olfactory epithelium. The nasal floor is made up of the palatine process of the maxillary bone anteriorly, fused with the horizontal process of the palatal bones posteriorly. A, sphenoethmoidal recess; B, basal lamella; C, palatine bone; D, ethmoid bulla; E, uncinate process; F, hiatus semilunaris; G, aggar cell; H, maxillary process of inferior turbinate; I, lacrimal bone; J, frontal process of maxillary bone; 1a, posterior fontanel; 1b, anterior fontanels. The anterior aspect of the lateral wall has contributions from the nasal bones and upper lateral cartilage, the latter forming the internal nasal valve at its junction with the nasal septum. There are three prominences on the lateral nasal wall termed inferior, middle, and superior turbinates, respectively. The inferior turbinate develops as a separate bone whilst the middle, superior and supreme turbinates are medial projections of the ethmoid complex. Lateral to the inferior turbinate is a recess called the inferior meatus into which the nasolacrimal duct opens. Anterosuperiorly it is attached to the skull base, and posteriorly it curves laterally to attach to the lamina papyrecea forming a lamella termed the basal lamella. The basal lamella divides the ethmoidal complex into an anterior and a posterior group. The middle meatus is a recess into which drain the frontal, maxillary and anterior ethmoid sinuses. Two distinct bony prominences are seen laterally on removal of the vertical portion of the middle turbinate: the uncinate process and the ethmoid bulla. The uncinate process is a thin, boomerangshaped bone anterior to the ethmoid bulla. It attaches to the lacrimal bone anteriorly and to the inferior turbinate inferiorly. The posterior margin of the uncinate process is unattached and forms a sickle-shaped cleft between its free margin and the anterior face of the ethmoid bulla, called hiatus semilunaris. The hiatus semilunaris communicates laterally with a three-dimensional space, the ethmoidal infundibulum, bounded anteriorly by the aggar nasi and frontoethmoidal cells, medially by the uncinate process, posteriorly by the bulla ethmoidalis and laterally by the lamina papyracea. The blood supply to the lateral nasal wall and septum is mainly provided by the branches of the sphenopalatine artery with contribution from the anterior and posterior ethmoid artery, the greater palatine artery and the facial artery. Nerve supply is from the nasociliary branch of the anterior ethmoidal nerve, branches of the pterygopalatine ganglion and anterior palatine nerves. Lymphatic drainage is to the submandibular nodes anteriorly and to the retropharyngeal and upper deep cervical nodes posteriorly. The ethmoid sinuses are the most variable of the sinuses and develop from pneumatization of the ethmoid bone. When this pneumatization extends to the middle turbinate, it is termed a concha bullosa. Occasionally, the pneumatization of the ethmoid bone can extend beyond the ethmoid bone. A number of bony septa divide the ethmoidal sinus into up to 18 air cells, and these are grouped to form the anterior and posterior ethmoid air cells depending on their relationship to the basal lamella. The attachment of the basal lamella of the middle turbinate divides the anterior and posterior ethmoid systems. Suprabullar and retrobullar recesses may be formed when the ethmoid bulla does not extend to the skull base. The suprabullar recess is formed when there is a cleft between the roof of the ethmoid bulla and the fovea. The retrobullar space is formed when there is a cleft between the basal lamella and the bulla. The ostia of the anterior ethmoid cells open into the ethmoid infundibulum in the middle meatus. The face of the bulla attaches to the skull base immediately anterior to the anterior ethmoid artery. The anterior ethmoid artery exits the orbit through the lamina papyracae and courses horizontally across the roof of the ethmoid sinus in a thin bony mesentery (dehiscent inferiorly in 40 per cent of patients) to enter the cribriform plate and anterior cranial cavity through the fovea ethmoidalis. It then vertically penetrates the most anterior aspect of the cribriform plate to enter the nasal cavity to supply the septum and the anterosuperior nasal cavity as the terminal septal branch. The most posterior ethmoidal air cell may extend superiorly and laterally to the sphenoid in 10 per cent of cases (the onodi cell) and may have the optic nerve and internal carotid artery bulging into it. The blood supply to the ethmoid sinus is from branches of the anterior and posterior ethmoidal and sphenopalatine arteries. The innervation is from the supraorbital, anterior ethmoidal and orbital branches from the pterygopalatine ganglion. The maxillary sinus the maxillary sinus lies within the maxillary bone and is pyramidal in shape, with its base forming part of the lateral nasal wall and its apex pointing towards the zygomatic process. The roof of the sinus constitutes the orbital floor and contains the infraorbital nerve, which may be dehiscent in 14 per cent of cases. The alveolar process of the maxilla and the hard palate form the floor of the 8 Anatomy and physiology of the nose and paranasal sinuses maxillary sinus. The posterior wall separates the maxillary sinus from the pterygomaxillary fossa and its contents, i. At the superior aspect of the medial wall of the sinus, opening into the region of the inferior aspect of the ethmoid infundibulum, is the natural ostium. This is normally hidden from view by an intact uncinate process and therefore cannot be visualized endoscopically. The medial wall of the maxillary sinus has areas of bony dehiscence usually covered by mucosa called the anterior and posterior fontanels. In up to 30 per cent of cases these may be patent, usually at the posterior fontanel, to form an accessory ostium. The infraorbital, greater palatine and superior alveolar nerves provide the nerve supply to the maxillary sinus mucosa. Sphenoid sinus the sphenoid sinuses are the deepest of the paranasal sinuses pneumatizing the sphenoid bone. Like the frontal sinus, sphenoid sinuses are divided, often asymmetrically, by a septum in the paramedian position. Anteroinferiorly, the sphenoid rostrum articulates with the perpendicular plate and vomer of the nasal septum. The sphenoid sinus ostium lies in the anterior medial wall of the sinus and drains medial to the superior turbinate into the sphenoethmoidal recess. Several important vascular and neural structures lie in the walls of the sphenoid sinus and can indent the walls to a variable degree depending on the degree of pneumatization.

Isopropanol promotes local vasodilation and can thereby increase bleeding from needle punctures and incisions diabetes test zu hause purchase generic prandin canada. Aldehydes Glutaraldehyde Glutaraldehyde [Cidex Plus 28] is lethal to all microorganisms; the drug kills bacteria metabolic disease muscle order prandin 0.5 mg with mastercard, bacterial spores type 1 juvenile diabetes life expectancy discount 0.5 mg prandin, viruses diabetes medications bladder cancer prandin 0.5mg, and fungi diabetic diet webmd order 0.5mg prandin with amex. Glutaraldehyde is used to disinfect and sterilize surgical instruments and other medical supplies diabetes insipidus sodium purchase 1 mg prandin overnight delivery, including respiratory and anesthetic equipment, catheters, and thermometers. To completely eliminate bacterial spores, instruments and equipment must be immersed in glutaraldehyde for at least 10 hours. However, under alkaline conditions, glutaraldehyde eventually becomes inactive owing to gradual polymerization. Consequently, alkaline solutions of Alcohols Ethanol Ethanol (ethyl alcohol) is an effective virucide and kills most common pathogenic bacteria as well. However, the drug is inactive against bacterial spores, including those of Clostridium difficile, and has erratic activity against fungi. Bactericidal effects result from precipitating bacterial proteins and dissolving membranes. Ethanol can enhance the effects of several other antimicrobial preparations (eg, chlorhexidine, benzalkonium chloride). Glutaraldehyde should be used with adequate ventilation because fumes can irritate the respiratory tract. Accordingly, use is limited to disinfection and sterilization of equipment and instruments. First, formaldehyde acts slowly: Destruction of bacterial spores may take 2 to 4 days. Second, formaldehyde is more volatile than glutaraldehyde, and hence tends to cause more respiratory irritation. As with glutaraldehyde, blood should be removed before instruments and equipment are sterilized. In addition, povidone-iodine is employed to sterilize equipment, although superior disinfectants are available. The drug is supplied in a variety of formulations (ointments, solutions, aerosols, gels). Chlorine Compounds Chlorine is lethal to a wide variety of microbes, and is active both as elemental chlorine and as hypochlorous acid, which is formed by reaction of chlorine with water. However, because of physical properties that make working with chlorine difficult, chlorine itself is rarely used clinically. Instead, chlorine-containing compounds that release hypochlorous acid are employed. Iodine Compounds: Iodine Solution and Iodine Tincture Iodine was first employed as an antiseptic more than 160 years ago. Despite the introduction of numerous other drugs, iodine remains one of our most widely used germicidal agents. The drug is extremely effective, having the ability to kill all known bacteria, fungi, protozoa, viruses, and yeasts. Iodine tincture contains the same amounts of elemental iodine and sodium iodide and also contains 47% ethanol. The germicidal activity of iodine tincture and iodine solution is due only to free (dissolved) elemental iodine. In both the tincture and the solution, the concentration of free elemental iodine is very low-about 0. Because only free iodine is active, most of the elemental iodine and all of the sodium iodide present in both iodine tincture and iodine solution do not contribute directly to microbicidal activity. However, these components do contribute indirectly by serving as reservoirs from which free elemental iodine can be released. Iodine tincture and iodine solution are employed primarily for antisepsis of the skin, a use for which they are the most effective agents available. Povidone-iodine is an iodophor composed of elemental iodine plus povidone, an organic polymer that increases the solubility of the iodine. The concentration of free iodine achieved with application of povidone-iodine is lower than that produced with application of iodine tincture or iodine solution. The preparation is employed as a topical antiseptic and can be especially useful for treating localized infection caused by drug-resistant microbes. Oxychlorosene is also employed as an antiseptic for surgical prophylaxis and to irrigate and cleanse fistulas, sinus tracts, wounds, and empyemas (pus-filled cavities). Sodium Hypochlorite Sodium hypochlorite kills bacteria, bacterial spores, fungi, protozoa, and viruses. These preparations can be used to irrigate wounds and to cleanse and deodorize necrotic tissue. To minimize local irritation, solutions of sodium hypochlorite should be rinsed off promptly. Solutions of sodium hypochlorite are unstable and must be prepared fresh before each use. Phenols the family of phenolic compounds consists of phenol itself and several phenol derivatives. Following its introduction in 1867, phenol rapidly became both the antiseptic and disinfectant of choice. The drug is quite active against gram-positive bacteria-the bacteria found most frequently on the skin. In fact, when used on a regular basis, hexachlorophene encourages overgrowth with gram-negative organisms. However, the drug is no longer an accepted ingredient for hand disinfectants, and should not be used in the clinical setting. If absorbed in sufficient amounts, hexachlorophene causes central nervous system stimulation. To minimize systemic toxicity, hexachlorophene should not be applied extensively to burns, wounds, cuts, or mucous membranes. Healthcare Uses Hand cleansing Surgical scrub for hands and forearms Preoperative skin cleanser for surgical site or entire body Protection of central venous catheters Treatment of gingivitis Miscellaneous Agents Chlorhexidine Chlorhexidine is a fast-acting antiseptic lethal to most grampositive and gram-negative bacteria, but not to bacterial spores. At low concentrations, it disrupts the bacterial cell membrane, causing leakage of intracellular components. At higher concentrations, it precipitates intracellular proteins and nucleic acids. Antibacterial effects are reduced somewhat in the presence of soap, blood, and pus. Chlorhexidine that remains on the skin after rinsing is sufficient to exert continuing germicidal effects. The drug is used for preoperative preparation of the skin and as a surgical scrub, hand-wash preparation, and wound cleanser. It is also the preferred agent for preventing infection associated with central venous catheters. In patients with gingivitis and periodontitis, chlorhexidine is used as an oral rinse. Rarely, severe contact dermatitis has developed at the site of a central venous catheter. Hydrogen Peroxide Hydrogen peroxide is an excellent disinfectant and sterilizing agent, but is useless as an antiseptic. The entity in hydrogen peroxide solution responsible for antimicrobial effects is the hydroxyl free radical. These free radicals are destroyed when hydrogen peroxide is acted upon by catalase, an enzyme found in all tissues. The only benefit resulting from application of hydrogen peroxide to wounds derives from liberation of oxygen (by the reaction with catalase), which causes frothing that is sufficient to loosen debris and thereby facilitate cleansing. The principal use of hydrogen peroxide is disinfection and sterilization of instruments. However, owing to concerns about a possible (albeit unproved) link between thimerosal and autism, nearly all vaccines used by Americans are now devoid of this agent. Germicidal effects result from disruption of membranes, and are enhanced by ethanol. Recommended dilutions are 1: 750 (for application to intact skin and to minor wounds and abrasions); 1: 2000 to 1: 5000 (for application to mucous membranes and diseased or seriously damaged skin); and 1: 750 to 1: 5000 (for storage of instruments and supplies). Each year, an estimated 2 million patients in the United States acquire an infection while in a hospital; about 90,000 of them die as a result. Patients can also acquire infections in other settings, including clinics, dialysis centers, and long-term care facilities. Accordingly, the best way to reduce new infections in these settings is to improve hand hygiene. Unfortunately, this technique has several drawbacks: It Thimerosal Thimerosal is an organic compound that contains 49% mercury, the active antimicrobial factor. Thimerosal has only weak bacteriostatic and fungistatic properties, and hence does not kill bacteria or fungi. Use on large areas of denuded skin may yield systemic toxicity from absorption of mercury. Poisoning from thimerosal ingestion can be treated with dimercaprol (see Chapter 109). Thimerosal has been employed to irrigate wounds and prepare the skin before surgery. It has also been employed as an antiseptic for the eyes, nose, throat, and genitourinary tract. However, given that thimerosal has low efficacy and a significant potential for harm, and given that more effective and safer drugs are available, thimerosal has been withdrawn from the market. A central recommendation in the guidelines is the use of alcohol-based handrubs, rather than soap and water, for routine hand antisepsis. All you do is apply the handrub to the palm of one hand, and then rub your hands together until they are dry. Accordingly, when the hands are visibly soiled, soap and water must be used first. However, under certain conditions-including infectious disease outbreaks and performance of invasive procedures-an antiseptic that does have residual effects (eg, chlorhexidine) should be used. Each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and economic impact. Antimicrobial-impregnated wipes (ie, towelettes) may be considered as an alternative to washing hands with nonantimicrobial soap and water. Wash hands with non-antimicrobial soap and water, or with antimicrobial soap and water if exposure to spore-forming bacteria, such as Bacillus anthracis, is suspected or proven. Before applying the alcohol solution, prewash hands and forearms with a non-antimicrobial soap, and dry hands and forearms completely. Although antiseptics can help prevent development of a local infection, systemic antiinfective drugs are preferred for treating an established local infection. Washing with antiseptics by nurses, physicians, and others who contact patients will do more to protect patients from infection than will application of antiseptics to patients themselves. For routine hand antisepsis, alcohol-based handrubs are preferred to soap and water. Soap and water are preferred to alcohol-based handrubs following exposure to spore-forming bacteria, such as B. Their common names are giant roundworm, pinworm, hookworm, whipworm, and threadworm. Two types of nematodes invade tissues: (1) pork roundworms (responsible for trichinosis) and (2) filariae. Common names for these parasites are beef tapeworm, pork tapeworm, and fish tapeworm. These organisms fall into four groups having the following common names: blood fluke, liver fluke, intes tinal fluke, and lung fluke. Helminthiasis (worm infestation) is the most common affliction of humans, affecting more than 2 billion people worldwide. There fore, in the absence of reinfestation, many infections simply subside as adult worms die. In countries where providers and medication are readily available, drug therapy is definitely indicated. However, in less fortunate locales, several factors-cost of medication, limited medical facilities, and high probability of reinfestation-may render individual treatment impractical. In these places, preventative measures, such as improved hygiene and elimination of carriers, may be the most valuable interventions. In approaching the anthelmintic drugs, we begin by review ing classification of the parasitic worms. Next we briefly discuss the characteristics of the more common helminthic infestations. This section describes the major characteristics of infestation by specific helminths. These infestations can differ with respect to anatomic site and danger to the host. The name applied to an infestation is based on the official name of the invading organism. For example, infestation with the giant roundworm, whose official name is Ascaris lumbricoides, is referred to as ascariasis.

When handling or disposing of the drug diabetes mellitus y embarazo pdf purchase cheap prandin on-line, healthcare workers should follow the same guidelines established for cytotoxic anticancer drugs diabetes diet us discount 1mg prandin with amex. Probenecid competes with cidofovir for renal tubular secretion diabete 98 cheap prandin 0.5mg on-line, and thereby delays elimination diabetes mellitus oms buy prandin 0.5 mg with amex. Cidofovir has a prolonged intracellular half-life (17 to 65 hours) diabetes resources generic 2mg prandin, and hence a long interval (2 weeks) can separate doses diabetes mellitus low blood sugar cheap 0.5mg prandin with amex. The principal adverse effect is dose-dependent nephrotoxicity, manifesting as decreased renal function and symptoms of a Fanconi-like syndrome (proteinuria, glucosuria, bicarbonate wasting). Also, serum creatinine and urine protein should be checked within 48 hours before each dose and, if these values indicate kidney damage, cidofovir should be withheld or the dosage reduced. Cidofovir is contraindicated for patients taking other drugs that can injure the kidney, and for patients with proteinuria (2+ or greater) or baseline serum creatinine greater than 1. Neutropenia develops in about 20% of patients, so neutrophil counts should be monitored. Ocular disorders-iritis, uveitis, or ocular hypotony (low intraocular pressure)-can also occur. In animal studies, cidofovir was carcinogenic and teratogenic, and caused hypospermia. The dosage is 2 gm given 3 hours before the infusion, 1 gm given 1 hour after the infusion, and another 1 gm given 8 hours after that. Ingesting food before each dose can decrease probenecid-induced nausea and vomiting. For patients who can tolerate it, 1 L more can be infused over 1 to 3 hours, beginning when the cidofovir infusion begins or as soon as it is over. Compared with ganciclovir, foscarnet is more difficult to administer, less well tolerated, and much more expensive. Unlike many other antiviral drugs, which must undergo conversion to an active form, foscarnet is active as administered. Between 10% and 28% of each dose is deposited in bone; the remainder is excreted unchanged in the urine. Because foscarnet is eliminated by the kidneys, dosages must be reduced in patients with renal impairment. However, unlike ganciclovir, foscarnet does not cause granulocytopenia or thrombocytopenia. Renal injury, as evidenced by a rise in serum creatinine, is the most common dose-limiting toxicity. The risk of nephrotoxicity is increased by concurrent use of other nephrotoxic drugs, including amphotericin B, aminoglycosides (eg, gentamicin), and pentamidine. Renal function (creatinine clearance) should be monitored closely and the dosage should be reduced if renal impairment develops. Once inside cells, cidofovir is converted to cidofovir diphosphate, its active form. Foscarnet frequently causes hypocalcemia, hypokalemia, hypomagnesemia, and hypo- or hyperphosphatemia. Ionized serum calcium may be reduced despite normal levels of total serum calcium. Patients should be informed about symptoms of low ionized calcium (eg, paresthesias, numbness in the extremities, perioral tingling) and instructed to report these. Serum levels of calcium, magnesium, potassium, and phosphorus should be measured frequently. Special caution is required in patients with preexisting electrolyte, cardiac, or neurologic abnormalities. Common reactions (occurring in 25% to 50% of patients) include fever, nausea, anemia, diarrhea, vomiting, and headache. In addition, foscarnet can cause fatigue, tremor, irritability, genital ulceration, abnormal liver function tests, neutropenia, and seizures. Furthermore, if sexual transmission does occur, the risk of transmission between monogamous heterosexual partners is extremely low. For years, dual therapy with pegylated interferon alfa (peginterferon alfa) plus ribavirin has been the treatment of choice for chronic hepatitis C. However, adding a protease inhibitor-either boceprevir or telaprevir-greatly improves outcomes, and hence triple therapy-peginterferon alfa plus ribavirin plus either boceprevir or telaprevir-is likely to become the new standard of care. The disease can be caused by six different hepatitis viruses, labeled A, B, C, D, E, and G. All six can cause acute hepatitis, but only B, C, and D also cause chronic hepatitis. In most cases, acute hepatitis resolves spontaneously, so intervention is generally unnecessary. In contrast, chronic hepatitis can lead to cirrhosis, hepatocellular carcinoma, and lifethreatening liver failure, and hence treatment should be considered. Interferon Alfa Human interferons are naturally occurring compounds with complex antiviral, immunomodulatory, and antineoplastic actions. In the discussion below, these compounds are referred to collectively as interferon alfa. None of these agents can be used orally, and hence administration is parenteral-almost always subQ. The alfa interferons can be divided into two groups-conventional and long acting-based on their time course of action. The conventional preparations have short half-lives, so they must be administered frequently-at least 3 times a week. In contrast, the long-acting preparations are administered less frequently-just once a week-making them more convenient. In addition, with the long-acting preparations, blood levels remain high between doses, and hence clinical responses are better. Therapeutic effects of the pegylated product are due solely to its interferon component. Because of their convenience and superior efficacy, these products are preferred to conventional interferons. However, note that several side effects-injection-site reactions, dose-related neutropenia, and thrombocytopenia-are more common with pegylated interferons than with the conventional formulations. In patients with chronic hepatitis C, responses are equally modest with all forms of interferon alfa. Unfortunately, about half of these people relapse when treatment is stopped; sustained responses are maintained in only 5% to 15% of patients. As discussed below, combining interferon alfa with ribavirin, with or without a protease inhibitor, can improve response rates. All formulations of interferon alfa produce the same spectrum of adverse effects, some of which can be life threatening. The most common side effect is a flu-like syndrome characterized by fever, fatigue, myalgia, headache, and chills. Interferon alfa frequently causes neuropsychiatric effects- especially depression. If depression persists, a reduction in dosage or cessation of treatment is indicated. Prolonged or high-dose therapy can cause fatigue, thyroid dysfunction, heart damage, and bone marrow suppression, manifesting as neutropenia and thrombocytopenia. Injection-site reactions (inflammation, bruising, itching, irritation) are common, especially with long-acting formulations. Also, interferon may induce or exacerbate autoimmune diseases, such as thyroiditis and autoimmune chronic hepatitis. Ribavirin is a nucleoside analog with a broad spectrum of antiviral activity, but its mechanism of action remains unclear. Perhaps because of this cellular sequestration, ribavirin has a prolonged half-life, estimated at 6 to 12 days. As a result, when dosing stops, it can take weeks to clear the drug from the body. For example, in one trial, the response rate was 68% with peginterferon alfa plus ribavirin versus only 51% with conventional interferon alfa plus ribavirin. Although ribavirin and interferon alfa are generally well tolerated, both drugs can cause significant adverse effects. As noted above, interferon alfa frequently causes flu-like symptoms, and occasionally causes severe depression. Hemolytic anemia, characterized by a hemoglobin (Hb) level below 10 gm/dL, develops in 10% to 13% of patients receiving dual therapy with ribavirin/ interferon alfa. Hemolytic anemia can worsen heart disease, and may lead to nonfatal or fatal myocardial infarction. Owing to the risk of anemia, ribavirin should be avoided in patients with significant heart disease and in those with hemoglobinopathies, including sickle cell anemia and thalassemia major. Because anemia can develop rapidly, Hb determinations should be made before treatment, 2 weeks and 4 weeks into treatment, and periodically thereafter. Also, pregnancy testing must be done every month during treatment and for 6 months after treatment stops. To avoid pregnancy, couples should use two reliable forms of birth control during treatment and for 6 months after stopping. Furthermore, if ribavirin is used in conjunction with a protease inhibitor, hormonal contraceptives may not work, and hence two barrier contraceptives should be used, as discussed below under Protease Inhibitors. Until more is known, prudence dictates that couples avoid pregnancy if the male partner is receiving ribavirin. In addition to flu-like symptoms, depression, anemia, and birth defects, ribavirin/interferon alfa can cause many other adverse effects. Among these are autoimmune disorders, infections, pancreatitis, neutropenia, and injury to the eyes and lungs. For treatment of chronic hepatitis C, ribavirin must be combined with interferon alfa; the drug is not effective when used alone. For combined therapy, peginterferon alfa is preferred to conventional interferon alfa. Ribavirin is available (1) in 200-mg capsules marketed as Rebetol and Ribasphere; (2) in 200-mg tablets marketed as Copegus, or as 200-, 400-, and 600-mg tablets marketed as Ribasphere; and (3) as a 40-mg/mL oral solution marketed as Rebetol. The oral solution can be used if the patient is unable to swallow tablets or capsules. The doses that follow are representative examples only; they are not all-inclusive. For patients weighing 75 kg or less, the dosage is 1000 mg/day (400 mg in the morning and 600 mg in the evening). For patients weighing more than 75 kg, the dosage is 1200 mg/day (600 mg in the morning and 600 mg in the evening). Dosage depends on patient weight and the strain (genotype) of the hepatitis C virus. For all patients, regardless of weight, the dosage is 800 mg/day (400 mg in the morning and 400 mg in the evening). When combined with peginterferon alfa plus ribavirin, these drugs greatly enhance antiviral effects. However, despite their efficacy, the protease inhibitors do have drawbacks: Both drugs are expensive, and both can be difficult to use, owing to adverse effects and extensive drug interactions. The drug must always be used in conjunction with peginterferon alfa and ribavirin. Triple therapy with boceprevir/peginterferon alfa/ribavirin is much more effective than traditional dual therapy with interferon alfa/ribavirin. As discussed in Chapter 94, viral proteases act during the replication cycle to cleave large polypeptides into their smaller, functional forms. Boceprevir is administered orally, and plasma levels peak about 2 hours after dosing. Among patients receiving triple therapy with boceprevir/interferon alfa/ribavirin, the most common adverse effects, occurring in approximately 20% to 60% of patients, are fatigue, nausea, altered taste, chills, insomnia, vomiting, anemia, and neutropenia. Anemia and neutropenia are significantly more common than when peginterferon/ ribavirin are used without boceprevir. To monitor for hematologic effects, complete blood counts should be obtained at baseline, and then at weeks 4, 8, and 12 of treatment. Rather, it is always combined with ribavirin (a teratogenic, embryolethal drug) plus peginterferon. Accordingly, before women use the combination, pregnancy must be ruled out and two effective forms of contraception must be implemented. Furthermore, because the triple combination can render hormonal contraceptives ineffective, two nonhormonal contraceptives should be employed. Options include a copper-T intrauterine device, a diaphragm with spermicidal jelly, a cervical cap with spermicidal jelly, a male condom with spermicidal jelly, and a female condom with spermicidal jelly (but not a male condom combined with a female condom). Not only is the drug combination dangerous for women should they become pregnant while using it, it is dangerous for a pregnant woman whose male partner is using it. Accordingly, the combination is contraindicated for any man whose female partner is pregnant. Second, boceprevir inhibits P-glycoprotein, the transporter that pumps drugs out of cells in the intestine, liver, kidney, and other sites (see Chapter 4). By doing so, boceprevir can alter levels of drugs that are P-glycoprotein substrates. To list all the possible interactions would not be feasible, and it would be impossible to expect you to remember those. It is wise to always use a drug interaction checker (software application or online) before administering unfamiliar drugs, especially those, like this one, that have so many possible interactions.

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