Armando Diego Bedoya, MD

• Medical Instructor in the Department of Medicine

https://medicine.duke.edu/faculty/armando-diego-bedoya-md

The term sialorrhoea should be restricted to the symptom complex consisting of involuntary flow of saliva from the mouth; this is also known as drooling blood pressure chart free printable coumadin 1 mg fast delivery. The symptom of excessive salivation is very uncommon blood pressure chart systolic diastolic discount coumadin 2 mg amex, because usually the saliva is swallowed arrhythmia 200 bpm order coumadin cheap online. Occasionally arteria subclavia buy coumadin 5 mg amex, hypersalivation may be associated with heavy metal poisoning (lead blood pressure readings by age generic coumadin 2 mg on-line, mercury arterial ulcer buy cheapest coumadin and coumadin, arsenic) or iodine toxicity, may be temporary following the initiation of some medications (reserpine, clozapine, pilocarpine and isoproterenol) and may even follow a change of dentures. In such patients it may be necessary to follow a structured investigation process, more to exclude a serious diagnosis and to provide reassurance. When sialadenitis is suspected, an underlying ductal disease should first be considered. Because the majority of cases are associated with calculi, other causes may be due to ductal stenosis or mucus plugs. Salivary stones are located in the submandibular gland system in 60 per cent of cases and in the parotid gland in 40 per cent. Because the majority of salivary stones are composed of calcium carbonate and calcium phosphate and are thus radio-opaque, they will show up on a plain radiograph. Other stones are not radio-opaque; some may be multiple; and there may be a stricture present. However, the use of sialoendoscopy is indicated when the cause of salivary swellings is unclear, including swellings associated with stones, strictures, inflammation or tumours and other processes that might cause obstruction of the duct. Sialendoscopy is a technique for inspecting the salivary ductal system with a fibre-optic system, which allows for manipulation of instruments to remove, dilate and biopsy lesions within the salivary duct system. The salivary gland ductal system branches, without systematization, and has a decreasing diameter from the main duct to the terminal duct. It is not possible to enter the third- or fourth-level branches with the current sialendoscopes. Small salivary stones can be removed endoscopically, employing a scope and a retrieval basket, when they are less than 3 mm in the parotid duct and less than 4 mm in the submandibular duct. Stones of a larger size or stones located within the gland itself can be removed using a combined approach with the sialendscope and an external approach, creating a ductotomy and delivering the stone, then repairing the ductal opening using a vein graft, ensuring the creation of a widening plasty of the duct at the 248 Salivary gland disease level of impaction to minimize the possibility of duct stenosis. In the past, salivary gland excision surgery was performed for the removal of salivary stones on the assumption that the gland itself was diseased beyond repair. Clinicopathological studies have shown (1) that submandibular glands excised because of sialolithiasis did not demonstrate any correlation between the degree of gland alteration and the number of infectious episodes; (2) there is no correlation between the degree of gland alteration and the duration of evolution; and (3) despite appropriate indications for submandibular excision, close to 50 per cent of the removed glands were histopathologically normal or close to normal. Excisional gland surgery should be the exception rather than the rule for sialoadenitis, which has been associated with significant morbidity. There exists a non-specific bacterial sialadenitis, which is considered to be due to a retrograde contamination from the oral cavity. Penicillinresistant, coagulase-positive Staphylococcus is commonly encountered but is often mixed flora containing Streptococcus pneumoniae and betahaemolytic Streptococcus, Escherichia coli and Pseudomonas aeruginosa as well as anaerobic bacteria. These infections include bartonellosis (cat scratch disease), tuberculosis, actinomycosis and sarcoidosis. The most frequent scenario is that of an adult presenting with a swelling of the parotid or submandibular gland, with a diagnosis of obstructive sialadenitis associated with sialolithiasis. Bacterial sialadenitis may also present in an acute manner with a tender painful swelling, with the parotid gland being more frequently affected than the submandibular gland. The disease is found in all age groups but usually in patients between the ages of 40 and 60 years, and it is rarely seen in children and adolescents. There is often an interval of several years from the start of symptoms to confirmation of the diagnosis. Objective evidence of salivary gland involvement is defined by a positive result for at least one of the following diagnostic tests: (1) unstimulated whole salivary flow (>1. Reduced exocrine function or sicca symptoms may be caused by a variety of conditions and may also be age related. The most definitive test is a biopsy of the minor salivary glands from inside the lower lip, which should demonstrate a focus as defined as an accumulation of at least 50 inflammatory cells (lymphocytes) per 4 mm2 of glandular tissue. Treatment includes support of symptoms, reduction of mouth dryness, prevention of corneal dryness and minimization of fungal infections. It presents as a persistent enlarged or nodular parotid or submandibular gland with regional or generalized lymphadenopathy, pulmonary infiltrates, hepatomegaly, vasculitis and monoclonal gammopathy. The serum immunoglobulin G4 (IgG4) concentration is elevated, and IgG4 expressing plasmacytes infiltrates the salivary glands. Other benign non-epithelial lesions may present as slow-growing masses in the parotid or submandibular gland areas and include haemangioma, lymphangioma and lipomas. Before considering surgical excision, it is important that a firm diagnosis be made, because surgery may result in an angry and unhappy patient. Other lesions need to be considered in the differential diagnosis, such as lymph node disease, salivary cysts, inflammatory lesions and granulomatous lesions, many of which do not necessarily need excision surgery. In England, about 450 new cases of salivary gland malignancy are diagnosed every year, with the incidence increasing by 37 per cent between 1990 and 2006. Malignant salivary glands have been classified into 24 differing types of carcinoma. The proportion of malignant tumours increases as the gland size decreases, with malignancy accounting for 10 per cent of parotid gland cancers, 33 per cent of submandibular gland cancers and 67 per cent of minor salivary gland cancers. A diagnosis of a benign salivary gland neoplasm of the sublingual gland is exceedingly rare. There is reported to be a risk of malignant degeneration/transformation associated with the salivary pleomorphic adenoma of about 8 per cent, which is thought to increase the longer the tumour remains untreated. Malignant salivary gland tumours are many, but prognosis is associated with the presence of nerve weakness or paralysis, size of the tumour, presence of cervical adenopathy, histological grade of disease, ability to ensure complete excision and whether or not post-operative radiotherapy has been applied to the tumour bed. The most serious complication of major parotid surgery is facial or hypoglossal nerve paralysis, which might be partial or complete. The marginal mandibular branch of the facial nerve is the branch most likely to be traumatized during surgery on the parotid and submandibular glands. Other complications are related to local effects on wound healing, wound draining and local skin numbness. Fine-needle aspiration cytology: A reliable tool in the diagnosis of salivary gland lesions. Diagnosis and management of parotid carcinoma with special focus on recent advances on molecular biology. Symptoms of salivary gland diseases and disorders are limited in number and are generally non-specific. Pain as a dominant symptom may be associated with inflammation and neoplasms but is not itself diagnostic of malignancy. Sialadenitis most commonly presents in adults, associated with salivary ductal stenosis with salivary stones, duct stenosis or mucus plug. Primary salivary gland neoplasms require a confirmatory needle biopsy before proceeding to treatment, which is usually surgery but may be different if proven malignant. Recurrence of primary salivary gland neoplasms tends to manifest within 5 years of surgery, but some types of salivary malignant neoplasms recurrences have been reported 15 years or more after initial surgery. It has a discrete blood supply from the superior and inferior thyroid arteries and venous drainage via the superior, middle and inferior thyroid veins. T3 and T4 act on the body to increase metabolism, affect growth and development and increase the sensitivity to catecholamines. In addition to the metabolically active hormones, the thyrocytes also produce the protein thyroglobulin, which is stored as colloid in the follicles. The parafollicular or C cells produce calcitonin, which acts to reduce the circulating blood levels of calcium. In adults, the conditions that affect the thyroid gland can be classified as inflammatory and autoimmune, hyperplastic and metabolic abnormalities, cysts and neoplasms (Table 29. The important consideration when assessing these patients is whether the mass is part of a generalized process affecting the gland or a malignant tumour. A solitary thyroid nodule was assessed as if it were potentially malignant, whereas a diffuse enlargement was more likely to be benign. Whilst the assessment technology has changed with the advent of cross-sectional imaging and ultrasound assessment, the terminology has not. A radiological suspicious nodule in a more diffuse process such as a multinodular goitre 3. An incidentally found suspicious nodule in a patient scanned for other reasons Imaging Ultrasound is now central in the assessment of these patients. With ultrasound, it is possible to describe position, shape, size, margins, content, echogenic pattern and, whenever possible, the vascular pattern of the nodule. It is of less utility in diagnosing follicular thyroid cancer because the differentiation between a benign adenoma and a carcinoma is not cytological but is based on the presence of peri-vascular or peri-capsular invasion. The optimal results are likely to be achieved by a dedicated cytologist under ultrasound guidance. Known risk factors for thyroid cancer are radiation exposure, family history and pre-existing thyroid disease. Staging is then further defined according to tumour type and patient age (Table 29. I-131 can be used for diagnostic purposes to assess both the completeness of the excision and the presence of metastatic disease (iodine uptake) or the destruction of residual thyroid tissue and metastatic disease with high-dose radioiodine (iodine ablation). The use of radioiodine also requires any residual thyrocytes to be metabolically active. This increase has been noted throughout Europe and America, although the cause for this is not clear. Blood levels of thyroglobulin can be used as a tumour marker to assess both response to treatment and rising potential of recurrent disease. This needs to include an assessment of thyroglobuin antibodies as well; if present, they will give a false, low result. In this situation, however, the thyroglobulin antibody level itself can act as a tumour marker. These strategies are effective only in patients who have undergone total thyroidectomy. In clinical practice, this means that most patients undergo total thyroidectomy and post-operative radioiodine ablation. If the tumour is a small (<10 mm) papillary or follicular carcinoma, then hemithyroidectomy alone may be satisfactory. All patients with this diagnosis should be referred for genetic testing and counseling. Whilst medullary cancer cells do not take up iodine, they produce calcitonin; this can be used as a diagnostic blood test and also for post-operative monitoring. Therefore, the minimum Thyroid cancer / Surgery in the thyrotoxic patient 261 operation is total thyroidectomy with neck dissection and a low threshold for external beam radiotherapy. It responds poorly to chemotherapy or radiotherapy and is normally inoperable by the time of diagnosis. Historically, the only surgery advocated was biopsy or tracheotomy for airway obstruction, with or without isthmusectomy. If there is no involvement of the great vessels, then surgery in the form of total thyroidectomy and neck dissection can be performed, but this is unlikely to be curative and is aimed at reducing the chance of airway or swallowing problems. The role of a staging central compartment clearance, in the absence of known disease, is controversial. It is known that papillary thyroid cancer metastasizes early to lymph nodes in levels 6 and 7 and that pre-operative imaging of this area is difficult. Therefore, it is justified that in greater than 20 per cent of cases, such a clearance will be therapeutic. In the node-negative cases, it may reduce the need for post-operative radioiodine. Normally, those patients who cannot be rendered euthyroid by other means present for surgery. Surgically, these patients are a challenge, because the metabolically active gland has an increased blood supply, and global enlargement makes the surgery more complex and at higher risk of complications than do other indications for thyroid surgery. Historically, subtotal thyroidectomies, preserving part of the superior pole to reduce the chance of developing hypothyroidism, were performed, but with improvements in the use and monitoring of thyroxine treatment, total or near-total thyroidectomy is the standard. From the anaesthetic point of view, the toxic patient is prone to cardiac arrhythmias; with perioperative manipulation of the gland, this can be exacerbated. Post-operatively, toxic patients are at increased risk of developing Neck dissection in follicular thyroid cancer Most follicular cancer is diagnosed after diagnostic hemithyroidectomy. The presence of metastatic neck disease mandates therapeutic neck dissection of the involved levels to optimize the post-operative adjuvant treatments. Unlike in papillary thyroid cancer, there is no established benefit in doing a staging neck dissection because lymph node metastases are not frequently found. Neck dissection in medullary thyroid cancer Central compartment neck dissection with total thyroidecotomy is the minimum treatment for medullary thyroid cancer, and many would also do a lateral neck dissection (levels 2a, 3, 4 and 5b) on the ipsilateral side. The presence of disease in the lateral neck mandates a comprehensive dissection on that side.

Cancer cells are characterized by immortality blood pressure vinegar order coumadin 1mg on-line, persistent proliferation heart attack 80 damage discount 2mg coumadin overnight delivery, invasive growth blood pressure 90 over 60 order coumadin 2mg mastercard, and the ability to form metastases pulse pressure 120 order 5 mg coumadin otc. Cancer can be treated with three basic modalities: surgery hypertension prognosis buy coumadin us, radiation therapy blood pressure 30 over 50 buy coumadin 1 mg online, and drug therapy. Agents used for drug therapy fall into two main groups (1) cytotoxic agents and (2) noncytotoxic agents, such as hormones, immunomodulators, and targeted drugs. Drugs are the treatment of choice for disseminated cancers (leukemias, disseminated lymphomas, widespread metastases). Drugs are also used as adjuvants to surgery and irradiation to kill malignant cells that surgery and irradiation leave behind. Following mitosis, the resulting daughter cells may either enter G1 and repeat the cycle, or enter G0 and become mitotically dormant. The growth fraction of a tissue is defined as the ratio of proliferating cells to cells in G0. Tissues with a large percentage of proliferating cells and few cells in G0 have a high growth fraction. Cytotoxic anticancer drugs are more toxic to cancers that have a high growth fraction than to cancers that have a low growth fraction. Because cytotoxic anticancer drugs are more active against proliferating cells than against cells in G0. The most common cancers-solid tumors of the breast, lung, prostate, colon, and rectum-have a low growth fraction, so they respond poorly to cytotoxic drugs. To cure a patient of cancer, we must produce 100% cell kill, which is rare with chemotherapy alone. That is, at any given dose, drugs kill a constant percentage of malignant cells, regardless of how many cells are present. Over the course of chemotherapy, cancer cells often become drug resistant, thereby decreasing the chance of success. The purpose of intermittent chemotherapy is to allow normal cells to repopulate between rounds of treatment. However, if the cancer cells repopulate as fast as (or faster than) normal cells, there will be no reduction in tumor burden with each round of treatment, and hence treatment will fail. Because combination therapy can (1) suppress drug resistance, (2) increase cell kill, and (3) reduce injury to normal cells (at any given level of anticancer effect). Ideally, the drugs used in combination therapy should have (1) different mechanisms of action, (2) minimally overlapping toxicities, and (3) good efficacy when used alone. For drugs that act during a specific phase of the cell cycle, selecting the right dosing schedule is critical to success. Toxicity to normal tissues is the major obstacle to successful therapy with cytotoxic anticancer drugs. Cytotoxic anticancer drugs injure normal tissue because these drugs lack selective toxicity. Myelosuppression (toxicity to bone marrow) can reduce the number of neutrophils, platelets, and erythrocytes, thereby posing a risk of infection (from loss of neutrophils), bleeding (from loss of platelets), and anemia (from loss of erythrocytes). Loss of neutrophils and platelets during chemotherapy is common; significant loss of erythrocytes is relatively rare, but can happen with certain drugs (eg, cisplatin). If neutropenia is substantial (absolute neutrophil count below 500/mm3), the next round of chemotherapy should be delayed. When a neutropenic patient develops an infection, immediate and vigorous intervention is required. Neutropenia can be minimized by treatment with granulocyte colony-stimulating factor (short-acting and long-acting forms) and granulocyte-macrophage colonystimulating factor-drugs that act on bone marrow to increase neutrophil production. Anemia can be managed with erythropoietin, but only in patients who do not have myeloid malignancies (eg, leukemia), and then only when the goal is palliation (erythropoietin shortens life in all cancer patients, and hence must not be used when the goal is cure or prolongation of life). By injuring the epithelial lining of the Gl tract, anticancer drugs often cause stomatitis and diarrhea. Many anticancer drugs cause moderate to severe nausea and vomiting, in part by stimulating the chemoreceptor trigger zone. The combination of aprepitant, dexamethasone, and ondansetron is especially effective. Anticancer drugs often injure hair follicles, thereby causing alopecia (hair loss). Accordingly, men undergoing chemotherapy should be counseled about possible sperm banking. Renal injury from hyperuricemia can be minimized by giving (1) fluids, (2) prophylactic allopurinol (a drug that blocks uric acid formation), and (3) rasburicase (an enzyme that catalyzes uric acid degradation). Cancer chemotherapy has three possible benefits: cure, palliation, and prolongation of useful life. In addition, some agents (eg, vinblastine, vincristine) act specifically to block mitosis, and one drug- asparaginase-disrupts synthesis of proteins. Note that, with the exception of asparaginase, all of the cytotoxic drugs disrupt processes carried out exclusively by cells that are undergoing replication. As a result, these drugs are most toxic to tissues that have a high growth fraction (ie, a high proportion of proliferating cells). About half of the cytotoxic anticancer drugs are phase specific, and the other half are phase nonspecific. Phase-specific agents are toxic only to cells that are passing through a particular phase of the cell cycle. Vincristine, for example, acts by causing mitotic arrest, and hence is effective only during M phase. Because of their phase specificity, these drugs are toxic only to cells that are active participants in the cell cycle; cells that are "resting" in G0 will not be harmed. Obviously, if these drugs are to be effective, they must be present as neoplastic cells cycle through the specific phase in which they act. To accomplish this, phase-specific drugs are often administered by prolonged infusion. Alternatively, they can be given in multiple doses at short intervals over an extended time. Because the dosing schedule is so critical to therapeutic response, phase-specific drugs are also known as schedule-dependent drugs. The phasenonspecific drugs can act during any phase of the cell cycle, including G0. Among the phase-nonspecific drugs are the alkylating agents and most antitumor antibiotics. Because phase-nonspecific drugs can injure cells throughout the cell cycle, whereas phase-specific drugs cannot, phase-nonspecific drugs can increase cell kill when combined with phasespecific drugs. Although the phase-nonspecific drugs can cause biochemical lesions at any time during the cell cycle, as a rule these drugs are more toxic to proliferating cells than to cells in G0. As their name implies, these agents act directly on cancer cells to cause their death. The cytotoxic drugs can be subdivided into eight major groups: (1) alkylating agents, (2) platinum compounds, (3) antimetabolites, (4) hypomethylating agents, (5) antitumor antibiotics, (6) mitotic inhibitors, (7) topoisomerase inhibitors, and (8) miscellaneous cytotoxic drugs. First, cells in G0 have time to repair drug-induced damage before it can result in significant harm. This is much like inflicting a flat tire on an automobile: the tire can be deflated at any time; however, loss of air is consequential only if the car is moving. Specifically, cells that divide quickly are harmed more readily than cells that divide slowly. The common major toxicities of the cytotoxic anticancer drugs, together with management procedures, are discussed in Chapter 101. Therefore, as we consider individual anticancer agents in this chapter, discussion of most toxicities is brief. High-alert medications are those drugs that can cause devastating effects to patients in the event of a medication error. In addition, direct contact with the skin, eyes, and mucous membranes can result in local injury (and can increase cancer risk if enough drug is absorbed). Accordingly, it is imperative that healthcare personnel involved in preparing and administering these drugs follow safe handling procedures. Risk of injury from contact with parenteral chemotherapeutic drugs can be minimized by using biologic safety cabinets and by following approved procedures for compounding and administration. Drugs with strong vesicant properties include carmustine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, mechlorethamine, mitomycin, plicamycin, streptozocin, vinblastine, and vincristine. Before considering the properties of individual alkylating agents, we discuss the characteristics of the group as a whole. Dosage, Handling, and Administration Cancer chemotherapy is a highly specialized field. Accordingly, in a general text such as this, presentation of detailed information on dosage and administration of specific agents seems inappropriate. However, be aware that dosages for anticancer agents must be individualized and that timing of administration may vary with the particular protocol being followed. Also, because of the complex and hazardous nature of cancer chemotherapy, anticancer drugs should be Shared Properties Mechanism of Action. The alkylating agents are highly reactive compounds that can transfer an alkyl group to various cell constituents. Because alkylation reactions can take place at any time during the cell cycle, alkylating agents are considered cellcycle phase nonspecific. However, most of these drugs are more toxic to dividing cells-especially cells that divide rapidly-than they are to cells in G0. Accordingly, they can be administered by bolus dosing, rather than by prolonged infusion. Resistance may also result from decreased uptake of alkylating agents and from increased production of nucleophiles (compounds that act as decoy targets for alkylation). Blood dyscrasias-neutropenia, thrombocytopenia, and anemia-caused by bone marrow suppression are of greatest concern. Cyclophosphamide, formerly available as Cytoxan and Neosar, is a bifunctional alkylating agent active against a broad spectrum of neoplastic diseases. Cyclophosphamide is a prodrug that undergoes conversion to its active form in the liver. In addition, the drug can cause acute hemorrhagic cystitis; bladder injury and associated bleeding can be minimized by (1) maintaining adequate hydration and (2) giving a protective agent called mesna [Mesnex] when high-dose cyclophosphamide is employed. Other adverse effects include sterility, immunosuppression, and hypersensitivity reactions. Mechlorethamine [Mustargen], a bifunctional compound, was the first alkylating agent employed clinically. Caution must be exercised to avoid both extravasation and direct contact with the skin. Once in the bloodstream, mechlorethamine undergoes rapid conversion to active metabolites. Other major toxicities include severe nausea and vomiting, alopecia, diarrhea, stomatitis, amenorrhea, and sterility. Bendamustine [Treanda] is a derivative of mechlorethamine, and may be better tolerated. Some patients experience an infusion reaction, characterized by fever, hypotension, chills, rigors, and myalgias. There have been postmarketing reports of serious skin reactions, including bullous exanthema and toxic epidermal necrolysis. Nonetheless, if a severe skin reaction occurs, bendamustine should be withheld or discontinued. Other adverse effects include hepatotoxicity, sterility, and, rarely, pulmonary fibrosis. Chlorambucil is a drug of choice for palliative therapy of chronic lymphocytic leukemia. The drug can cause secondary malignancy and is mutagenic like other alkylating agents. Melphalan is a preferred drug for multiple myeloma, and is also active against lymphoma and carcinoma of the ovary and breast. If the analysis reveals microscopic hematuria, dosing should be postponed until hematuria resolves. Severe adverse effects are most likely in patients receiving high-dose therapy and in those with renal failure. Nitrosoureas the nitrosoureas are bifunctional alkylating agents, and are active against a broad spectrum of neoplastic diseases. Unlike many anticancer drugs, the nitrosoureas are highly lipophilic, and hence can readily penetrate the blood-brain barrier. Owing to its ability to cross the blood-brain barrier, carmustine is especially useful against primary and metastatic tumors of the brain. The principal dose-limiting toxicity is delayed bone marrow suppression; leukocyte and platelet nadirs occur 4 to 6 weeks after treatment. Accordingly, if pulmonary function begins to decline, glucocorticoids should be given to prevent fibrosis. Topical administration is done by implanting a biodegradable, carmustineimpregnated wafer [Gliadel] into the cavity created by surgical removal of a brain tumor. This technique has the obvious benefit of concentrating the drug where it is most needed.

Treatment consists of placing 1 drop on the cornea every 2 hours while the patient is awake hypertension united states purchase genuine coumadin line, for a maximum of 9 drops/day heart attack video 1mg coumadin free shipping. Once re-epithelialization of the cornea has occurred hypertension treatment guidelines 1mg coumadin with mastercard, the dosage is reduced to 1 drop every 4 hours and continues for an additional 7 days prehypertension hypothyroidism coumadin 2 mg discount. As discussed below (under Ganciclovir) pulmonary hypertension xanax order coumadin with amex, benefits derive from suppressing viral replication hypertension 39 weeks pregnant discount coumadin 2 mg with visa. The recommended dosage is 1 drop in the affected eye 5 times a day until symptoms abate, followed by 1 drop 3 times a day for 7 days. Instruct patients to apply drops directly to the affected eye, and to avoid contact lenses until lesions heal. Ganciclovir is converted to its active form, ganciclovir triphosphate, inside infected cells. Bioavailability of oral ganciclovir is low: only 5% under fasting conditions and 9% when taken with food. Since viral resistance can develop during treatment, this possibility should be considered if the patient responds poorly. The adverse effect of greatest concern is bone marrow suppression, which can result in granulocytopenia and thrombocytopenia. These hematologic responses can be exacerbated by concurrent therapy with zidovudine. Conversely, granulocytopenia can be reduced with granulocyte colony-stimulating factors (see Chapter 56). Because of the risk of adverse hematologic effects, blood cell counts must be monitored. Treatment should be interrupted if the absolute neutrophil count falls below 500/mm3 or if the platelet count falls below 25,000/mm3. Ganciclovir should be used with caution in patients with preexisting cytopenias, in those with a history of cytopenic reactions to other drugs, and in those taking other bone marrow suppressants (eg, zidovudine). Ganciclovir is teratogenic and embryotoxic in laboratory animals and probably in humans. Women should be advised to avoid pregnancy during therapy and for 90 days after ending treatment. At doses equivalent to those used therapeutically, ganciclovir inhibits spermatogenesis in mice; sterility is reversible with low doses and irreversible with high doses. Solutions are alkaline and must be infused into a freely flowing vein to avoid local injury. Infection can also be acquired by way of blood transfusion or organ transplantation. After the initial infection, which has minimal symptoms in healthy people, the virus remains dormant within cells for life, without causing detectable injury or clinical illness. Adequate hydration must be maintained in all patients to ensure renal excretion of ganciclovir. Surgical implantation, which takes about 1 hour, is performed under local anesthesia on an outpatient basis. As discussed above (under Topical Drugs for Ocular Herpes Infections), ganciclovir is available in a 0. Valganciclovir [Valcyte] is a prodrug version of ganciclovir [Cytovene] with greater oral bioavailability (60% vs. The principal concern is blood dyscrasias-granulocytopenia, anemia, and thrombocytopenia- secondary to bone marrow suppression. In addition, any of the following adverse effects typically occur in 20% to 40% of patients: diarrhea, nausea, vomiting, fever, and headache. Valganciclovir is presumed to pose the same risks of mutagenesis, aspermatogenesis, and carcinogenesis as ganciclovir. Valganciclovir [Valcyte] is available in (1) 450-mg tablets and (2) a powder that makes a 50-mg/mL oral solution when reconstituted with 91 mL of purified water. Because valganciclovir has the potential for mutagenesis and carcinogenesis, the powder and tablets should be handled carefully. When handling or disposing of the drug, healthcare workers should follow the same guidelines established for cytotoxic anticancer drugs. Probenecid competes with cidofovir for renal tubular secretion, and thereby delays elimination. Cidofovir has a prolonged intracellular half-life (17 to 65 hours), and hence a long interval (2 weeks) can separate doses. 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.

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Unfortunately arrhythmia heart rate monitor cheap 2mg coumadin, prolonged use of high-dose metronidazole poses a risk of peripheral neuropathy heart attack from weed buy cheap coumadin 2mg on line. In one study pulse pressure is order coumadin without a prescription, ciprofloxacin produced complete or partial remission in 72% of those treated blood pressure medication for elderly cheap 1mg coumadin free shipping. Cisapride [Propulsid] is a potentially dangerous drug that can cause fatal cardiac dysrhythmias blood pressure medication with c buy 2 mg coumadin with amex. Today heart attack jarren benton lyrics coumadin 2 mg cheap, it is once again available-but only through an investigational, limited-access program sponsored by Janssen Pharmaceutical. In all cases, cisapride is considered a drug of last resort, reserved for patients who have not responded to standard therapy. The risk is greatest among patients with disorders that predispose to dysrhythmias. Before receiving cisapride, patients should undergo electrocardiographic evaluation. Furthermore, the disease frequently develops soon after smoking cessation, and smoking resumption can help reduce symptoms. These observations in smokers have been reinforced by controlled experiments, which have shown that transdermal nicotine (nicotine patches) and a nicotine enema can reduce symptoms in patients with mild to moderate ulcerative colitis. However, until more information is available, nicotine cannot be recommended for routine treatment. Cisapride [Propulsid] is formulated in tablets (10 and 20 mg) and an oral suspension (10 mg/mL). To reduce the risk of adverse effects, the lowest effective dosage should be used. For reasons discussed below, palifermin is currently indicated only for patients with hematologic malignancies. Among these are rash, erythema, edema, pruritus, distortion of taste, thickening and/ or discoloration of the tongue, and oral or perioral dysesthesias (unpleasant sensations produced by ordinary stimuli). The most serious reaction is skin rash, which develops in less than 1% of patients. In some patients, serum levels of amylase and lipase rise, suggesting possible injury to the pancreas. Because palifermin can stimulate epithelial growth in the lens, there is concern that it might affect vision. Accordingly, dosing with palifermin should cease at least 24 hours before giving chemotherapy, and should not resume for at least 24 hours after. Preparations, Dosage, and Administration Palifermin [Kepivance] is supplied as a powder (6. Dosing is done once daily on 3 consecutive days before chemotherapy and on 3 consecutive days after, for a total of six doses. The first dose is given 3 to 4 days before chemotherapy (so that the third dose can be given 1 to 2 days before chemotherapy). The fourth is given at least 4 days after the third dose of palifermin, and at least 1 day after stem cell infusion. Palifermin should be stored under refrigeration, protected from light, and used immediately after reconstitution. Similarly, in healthy human volunteers, palifermin produced dosedependent proliferation of epithelial cells in the buccal mucosa. In both trials, palifermin reduced the need for pain relief with opioid analgesics, and the need for supplemental parenteral nutrition. As we learn more about the safety of palifermin in nonhematologic cancers, indications for the drug may expand. These enzymes are secreted into the duodenum, where they help digest fats, carbohydrates, and proteins. To protect the enzymes from stomach acid and pepsin, the pancreas secretes bicarbonate. The bicarbonate neutralizes acid in the duodenum, and the resulting elevation in pH inactivates pepsin. Deficiency of pancreatic enzymes can compromise digestion, especially digestion of fats. Causes of deficiency include cystic fibrosis, pancreatectomy, pancreatitis, and obstruction of the pancreatic duct. Pancreatic enzymes for clinical use are available as pancrelipase, a mixture of lipases, amylases, and proteases prepared from hog pancreas. All drugs, with the exception of Viokase, are supplied in delayed-release capsules designed to dissolve in the duodenum and upper jejunum. The capsules should not be crushed, chewed, or retained in the mouth, owing to a risk of irritating the oral mucosa. The most common adverse effects are abdominal discomfort, flatulence, headache, and cough. The most serious concern is fibrosing colonopathy, seen rarely during high-dose therapy in patients with cystic fibrosis. Porcine pancrelipase contains high levels of purines, and hence may pose a risk to patients with gout or hyperuricemia. Acid suppressants (eg, histamine2 receptor blockers, proton pump inhibitors) may be employed as adjuvants to pancreatic enzyme therapy. Determining factors include the extent of enzyme deficiency, dietary fat content, and enzyme activity of the preparation selected. The efficacy of therapy can be evaluated by measuring the reduction in 24-hour fat excretion. Because chenodiol is hepatotoxic, the drug is contraindicated for patients with preexisting liver disease. Following production in the liver, bile may be secreted directly into the small intestine or it may be transferred to the gallbladder, where it is concentrated and stored. Bile has two principal functions: It (1) aids in the digestion of fats, and (2) serves as the only medium by which cholesterol is excreted from the body. Cholelithiasis-development of gallstones-is the most common form of gallbladder disease. Stones made of cholesterol alone cannot be detected with x-rays, and hence are said to be radiolucent. In contrast, stones that contain calcium (in addition to cholesterol) are radiopaque (ie, they absorb x-rays and therefore can be seen in a radiograph). When symptoms do develop, they can be much like those of indigestion (bloating, abdominal discomfort, gassiness). Cholelithiasis may be treated by cholecystectomy (surgical removal of the gallbladder) or with drugs. In asymptomatic patients, more conservative measures (weight loss and reduced fat intake) may be indicated. Like chenodiol, ursodiol reduces the cholesterol content of bile, thereby facilitating the gradual dissolution of cholesterol gallstones. Like chenodiol, ursodiol promotes dissolution of radiolucent gallstones but not radiopaque gallstones. Ursodiol is indicated for dissolution of cholesterol gallstones in carefully selected patients. The usual adult dosage for dissolving gallstones is 4 to 5 mg/kg twice daily (1 capsule or tablet in the morning and 1 in the evening). These fissures afflict about 700,000 Americans every year, often causing unrelenting and debilitating pain. Topical nitroglycerin relieves pain and promotes healing by relaxing the internal anal sphincter. Nitroglycerin ointment has been used in other countries for years, and is considered by many experts to be a first-line therapy. Chenodiol [Chenodal, Chenix], is a naturally occurring bile acid that reduces hepatic production of cholesterol. Reduced cholesterol production lowers the cholesterol content of bile, which in turn facilitates the gradual dissolution of cholesterol gallstones. Chenodiol may also increase the amount of bile acid in bile, and may thereby enhance cholesterol solubility. It should be noted that chenodiol is useful only for dissolving radiolucent stones. Chenodiol is given to promote dissolution of cholesterol gallstones, but only in carefully selected patients. Success is most likely in women who have low cholesterol levels, stones of small size, and the ability to tolerate high doses of the drug. Complete disappearance of stones Other Anorectal Preparations Various preparations can help relieve discomfort from hemorrhoids and other anorectal disorders. Local anesthetics (eg, benzocaine, dibucaine) and hydrocortisone (a glucocorticoid) are common ingredients. Anorectal preparations may also contain emollients (eg, mineral oil, lanolin), whose lubricant properties reduce irritation, and astringents (eg, bismuth subgallate, witch hazel, zinc oxide), which reduce irritation and inflammation. Anorectal preparations are available in multiple formulations: suppositories, creams, ointments, lotions, foams, tissues, and pads. Serotonin antagonists, such as ondansetron [Zofran], are the most effective antiemetics available. Aprepitant (an antiemetic) is the first member of a new class of drugs: the substance P/neurokinin1 receptor antagonists. For patients receiving highly emetogenic chemotherapy, the preferred antiemetic regimen consists of three drugs: aprepitant, a glucocorticoid (eg, dexamethasone), and a serotonin antagonist (eg, ondansetron). Nausea and vomiting develop in about 75% of pregnant patients, especially during the first trimester. First-line therapy for pregnancy-related nausea and vomiting consists of two drugs: doxylamine plus vitamin B6 (pyridoxine). Opioids (eg, diphenoxylate) are the most effective antidiarrheal agents available. Colitis and complications of constipation have led to hospitalization, blood transfusion, surgery, and death. Palifermin is used to reduce the intensity and duration of oral mucositis in patients with hematologic malignancy undergoing intensive radiochemotherapy. In addition, they often differ for males and females, and typically increase for women who are pregnant or breast-feeding. Intake of a nutrient below the established range for that nutrient increases the risk of malnourishment. Intake of a nutrient above the established range for that nutrient increases the risk of chronic diseases. Several vitamins are inactive in their native form and must be converted to active compounds in the body. Collectively, Classification of Vitamins the vitamins are divided into two major groups: fat-soluble vitamins and water-soluble vitamins. Especially rich sources are carrots, cantaloupe, mangoes, spinach, tomatoes, pumpkins, and sweet potatoes. Because dietary carotenoids are poorly absorbed and incompletely converted into retinol. Hence, to produce the nutritional equivalent of retinol, we need to ingest much higher amounts of the carotenoids. Under normal conditions, dietary vitamin A is readily absorbed and then stored in the liver. As a rule, liver reserves of vitamin A are large and will last for months if intake of retinol ceases. In the absence of vitamin A intake, levels are maintained through mobilization of liver reserves. Except for vitamin B12, water-soluble vitamins undergo minimal storage in the body, and hence frequent ingestion is needed to replenish supplies. In contrast, fat-soluble vitamins can be stored in massive amounts, which is good news and bad news. The bad news is that extensive storage greatly increases the potential for toxicity if intake is excessive. They report that there is insufficient evidence to recommend either for or against the use of multivitamins by Americans to prevent chronic disease. For example, too much vitamin A increases the risk of osteoporosis in postmenopausal women and can cause birth defects when taken early in pregnancy. In people who smoke, too much beta-carotene (a precursor of vitamin A) increases the risk of lung cancer. And in older people with chronic health problems, too much vitamin E increases the risk of death. Because of these and other concerns, high-dose multivitamin supplements should be avoided. Although research supporting the use of multivitamin supplements is inconclusive, we do have solid data supporting the use of three individual vitamins-vitamin B12, folic acid, and vitamin D. Nutrition experts recommend vitamin B12 for all people over age 50, folic acid for all women of child-bearing age, and vitamin D (plus calcium) for postmenopausal women and other people at risk of fractures. Because vitamin A is needed for dark adaptation, night blindness is often the first indication of deficiency. With time, vitamin A deficiency may lead to xerophthalmia (a dry, thickened condition of the conjunctiva) and keratomalacia (degeneration of the cornea with keratinization of the corneal epithelium). In addition to effects on the eye, deficiency can produce skin lesions and dysfunction of mucous membranes.