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Adrenoceptors also modulate the secretion of parathyroid hormone depression anatomical definition 15 mg abilify buy with visa, calcitonin depression symptoms cognitive abilify 20 mg buy overnight delivery, thyroxine mood disorder blood tests cheap 20 mg abilify with visa, and gastrin; however mood disorder dsm 4 discount 20 mg abilify otc, the physiologic significance of these control mechanisms is probably limited mood disorder 1 purchase abilify 15 mg with amex. In high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of sequestered white blood cells back into the general circulation. These effects have been described as ranging from “nervousness” to “an adrenaline rush” or “a feeling of impending disaster. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly β receptors) and the vasoconstriction induced in1 many vascular beds (α receptors). Epinephrine also activates β receptors in some vessels (eg, skeletal muscle blood2 vessels), leading to their dilation. Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection (Figure 9–6; Table 9–4). Under physiologic conditions, epinephrine functions largely as a hormone; it is released from the adrenal medulla and carried in the blood to distant sites of actions. Norepinephrine also activates1 2 β receptors with similar potency as epinephrine, but has relatively little effect on β receptors. Consequently,1 2 norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. Its deficiency in the basal ganglia leads to Parkinson’s disease, which is treated with its precursor levodopa. Direct-Acting Sympathomimetics Phenylephrine was discussed previously when describing the actions of a relatively pure α agonist (1 Table 9–2). It is an effective mydriatic and decongestant and can be used to raise the blood pressure (Figure 9–6). Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α -receptor agonist. The peak1 concentration of desglymidodrine is achieved about 1 hour after midodrine is administered orally. The primary indication for midodrine is the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function. Although the drug has efficacy in diminishing the fall of blood pressure when the patient is standing, it may cause hypertension when the subject is supine. Such drugs (eg, clonidine, methyldopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11. On the other hand, the primary indication of dexmedetomidine is for sedation in an intensive care setting or before anesthesia. Oxymetazoline is a direct-acting α agonist used as topical decongestant because of its ability to promote constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (see Chapter 11). Isoproterenol (isoprenaline) is a very potent β-receptor agonist and has little effect on α receptors. The drug has positive chronotropic and inotropic actions; because isoproterenol activates β receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9–4; Figure 9–6). Beta subtype-selective agonists are very important because the separation of β and β effects (1 2 Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications. Beta -selective agents (1 Figure 9–8) increase cardiac output with less reflex tachycardia than nonselective β agonists such as isoproterenol, because they are less effective in activating vasodilator β receptors. Its chemical structure resembles dopamine,1 but its actions are mediated mostly by activation of α and β receptors. Clinical formulations of dobutamine are a racemic mixture of (−) and (+) isomers, each with contrasting activity at α and α receptors. The (−) isomer is a potent α agonist, which is capable of causing significant1 1 vasoconstriction when given alone. Dobutamine has a positive inotropic action caused by the isomer with predominantly β-receptor activity. Activation of α receptors probably explains why1 peripheral resistance does not decrease significantly. Mixed-Acting Sympathomimetics Ephedrine occurs in various plants and has been used in China for over 2000 years; it was introduced into Western medicine in 1924 as the first orally active sympathomimetic drug. Because ephedrine is a noncatechol phenylisopropylamine (Figure 9–5), it has high bioavailability and a relatively long duration of action—hours rather than minutes. As with many other phenylisopropylamines, a significant fraction of the drug is excreted unchanged in the urine. Phenylpropanolamine, a common component in over-the-counter appetite suppressants, was also removed from the market because its use was associated with hemorrhagic strokes in young women. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale. Amphetamine’s actions are mediated through the release of norepinephrine and, to some extent, dopamine. Methamphetamine (N-methylamphetamine) is very similar to amphetamine with an even higher ratio of central to peripheral actions. Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in children with attention deficit hyperactivity disorder (see Therapeutic Uses of Sympathomimetic Drugs). Modafinil is a psychostimulant that differs from amphetamine in structure, neuro-chemical profile, and behavioral effects. It is often associated with increases in blood pressure and heart rate, though these are usually mild (see Therapeutic Uses of Sympathomimetic Drugs). Tyramine (see Figure 6–5) is a normal byproduct of tyrosine metabolism in the body and can be produced in high concentrations in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9–5). If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Catecholamine Reuptake Inhibitors Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Many antidepressants, particularly the older tricyclic antidepressants, can inhibit norepinephrine and serotonin reuptake to different degrees. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking α receptors, but the mechanism remains unclear. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. Norepinephrine reuptake is particularly important in the heart, especially during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors frequently cause orthostatic tachycardia. It has been taken off the market in the United States and several other countries because it has been associated with a small increase in cardiovascular events including strokes in patients with a history of cardiovascular disease, which outweighed the benefits gained by modest weight reduction. Duloxetine is a widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects (see Chapter 30). Duloxetine and milnacipran, another serotonin and norepinephrine transporter blocker, are approved for the treatment of pain in fibromyalgia (see Chapter 30). Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (Figure 9–3). These properties and the fact that a rapid onset of action can be obtained when smoked, snorted into the nose, or injected, has made cocaine a heavily abused drug (see Chapter 32). It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets. Dopamine Agonists Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson’s disease and prolactinemia. Fenoldopam is a D -receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The1 primary indication for fenoldopam is in the intravenous treatment of severe hypertension (see Chapter 11). Treatment of Acute Hypotension Acute hypotension may occur in a variety of settings such as severe hemorrhage, decreased blood volume, cardiac arrhythmias, neurologic disease or accidents, adverse reactions or overdose of medications such as antihypertensive drugs, and infection. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume while the primary problem is determined and treated is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity. On the other hand, sympathomimetics may be required in cases of sustained hypotension with evidence of tissue hypoperfusion. Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. Even though there is expert agreement that sympathomimetic drugs should be used in the treatment of virtually all forms of shock, their efficacy in improving outcomes has not been rigorously tested, and theoretically they can constrict the microcirculation and worsen tissue perfusion. There appears to be no difference in overall survival depending on which vasopressor is used, but norepinephrine appears to be associated with a lower incidence of arrhythmias than dopamine, even in cardiogenic shock. Chronic Orthostatic Hypotension On standing, gravitational forces induce venous pooling, resulting in decreased venous return. Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function (eg, imipramine and other tricyclic antidepressants, α blockers for the treatment of urinary retention, and diuretics), diabetes, and other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system, as in the case study described at the beginning of the chapter. Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating α receptors can be used for this purpose. It is a prodrug that is converted to norepinephrine by the aromatic L-amino acid decarboxylase (dopa-decarboxylase), the enzyme that converts L-dopa to dopamine. Current evidence indicates that it improves the chance of returning to spontaneous circulation, but it is less clear that it improves survival or long-term neurologic outcomes and this is an area of active investigation. These actions lead to increased heart rate and increased myocardial work and can reveal areas of ischemia in the myocardium that are detected by echocardiogram or nuclear medicine techniques. Inducing Local Vasoconstriction Reduction of local or regional blood flow is desirable for achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, α- receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of administration. Effective pharmacologic hemostasis, often necessary for facial, oral, and nasopharyngeal surgery, requires drugs of high efficacy that can be administered in high concentration by local application. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Combining α agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block; the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1:200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other α agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. Use of epinephrine with local anesthesia of acral vascular beds (digits, nose, and ears) has not been advised because of fear of ischemic necrosis. Mucous membrane decongestants are α agonists that reduce the discomfort of allergic rhinitis and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. Constriction of the latter vessels may involve activation of α receptors, and phenylephrine or the longer-acting2 oxymetazoline are often used in over-the-counter nasal decongestants. Pulmonary Applications One of the most important uses of sympathomimetic drugs is in the therapy of asthma. For chronic asthma treatment in adults, long-acting β agonists should only be used in2 combination with steroids because their use in monotherapy has been associated with increased mortality. There is less agreement about requiring the discontinuation of long-acting β agonists once asthma control is achieved. Nonselective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs. Anaphylaxis Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0. Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injection of epinephrine may be required. The use of epinephrine for anaphylaxis precedes the era of controlled clinical trials, but extensive experimental and clinical experience supports its use as the agent of choice. Epinephrine activates α, β , and β receptors, all of which may be important in reversing the1 2 pathophysiologic processes underlying anaphylaxis.

It also has some activity mechlorethamine depression facebook abilify 20 mg purchase free shipping, vincristine mood disorder teens discount abilify 20 mg, and prednisone in the against small cell lung cancer depression definition in sport order line abilify. Procarbazine is also used in suppression and a peripheral neuropathy also may various combination chemotherapy protocols for non- occur depression types generic abilify 10 mg with visa. Limited antitumor effects Cisplatin have been observed against multiple myeloma depression symptoms body pain 15 mg abilify order fast delivery, melanoma, and non–oat cell lung cancers. Cisplatin (Platinol) is an inorganic coordination com- The major side effects associated with procarbazine plex with a broad range of antitumor activity. It is espe- therapy are nausea and vomiting, leukopenia, and throm- cially useful in the treatment of testicular and ovarian bocytopenia. Cisplatin also orubicin in multidrug-resistant cells and in patients who binds extensively to proteins. Mitoxantrone is active against breast carcinomas, Cisplatin shows biphasic plasma decay with a distri- leukemias, and lymphomas. Its antitumor efficacy in pa- bution phase half-life of 25 to 49 minutes and an elimi- tients with breast cancer is slightly lower than that of nation half-life of 2 to 4 days. Its major toxicity is myelosuppression; mu- drug is bound to plasma proteins, and binding may ap- cositis and diarrhea also may occur. Cisplatin does duces less nausea, alopecia, and cardiac toxicity than not cross the blood-brain barrier. Cisplatin also shows some activity against carci- Levamisole nomas of the head and neck, bladder, cervix, prostate, and lung. Levamisole (Ergamisol) is an antiparasitic drug that has Renal toxicity is the major potential toxicity of been found to enhance T-cell function and cellular im- cisplatin. The drug improves survival of patients with re- pany cisplatin administration may necessitate hospital- sected colorectal cancers when combined with 5-fluo- ization. Cisplatin has mild bone marrow toxicity, yield- rouracil; the mechanism of this interaction is not ing both leukopenia and thrombocytopenia. Levamisole does not have antitumor activity common and may require transfusions of red blood against established or metastatic cancer and has not cells. Anaphylactic allergic reactions have been de- been found useful in the adjuvant therapy of cancers scribed. Other reported tox- The major adverse effects of levamisole are nausea icities include peripheral neuropathies with paresthe- and anorexia. Its product derived from the interferon alfa-2b gene of hu- plasma half-life is 3 to 5 hours, and it has no significant man white blood cells. Renal excretion is the major route of tion involves binding to a plasma membrane receptor drug elimination. Its serum half-life is Despite its lower chemical reactivity, carboplatin 2 to 3 hours after parenteral administration. How- are resistant to cisplatin are cross-resistant to carbo- ever, it has minimal antitumor activity in most human platin. Remissions lasting a few months have been ob- The major advantage of carboplatin over cisplatin is served in 10 to 20% of patients with lymphomas, multi- a markedly reduced risk of toxicity to the kidneys, pe- ple myeloma, melanoma, renal cell carcinoma, and ripheral nerves, and hearing; additionally, it produces ovarian carcinoma. It is, however, more myelo- The adverse effects of interferon alfa-2b include fever suppressive than cisplatin. Other adverse effects include and a flulike syndrome of muscle ache, fatigue, headache, anemia, abnormal liver function tests, and occasional al- anorexia, and nausea. Imantinib mesylate (Gleevec) is a rationally designed The drug produces remissions in 15% of patients inhibitor of the tumor-specific bcr-abl kinase. The with renal cell carcinoma, with median durations of re- Philadelphia chromosome, present in nearly all patients mission of 18 to 24 months. The bcr-able kinase is therefore a verse effect is severe hypotension in as many as 85% of unique drug target in leukemic cells, and imantinib se- patients, which may lead to myocardial infarctions, pul- lectively and potently inhibits this kinase. Extension of the use of imantinib to other tu- and vomiting, diarrhea, stomatitis, anorexia, altered mor types with overexpression of c-kit kinase or mental status, fevers, and fatigue. Therefore, a therapeutic agent Filgrastim is used to accelerate recovery of neu- selective for this target is particularly valuable. Herceptin use is associated with in- adverse reaction being mild to moderate bone pain sec- fusion- related hypotension, flushing and bronchocon- ondary to stimulation of bone marrow proliferation. Herceptin appears to sensitize patients to cardiotoxic- ity, an important concern in patients also receiving Sargramostim doxorubicin. Iressa is undergoing clinical chemotherapy, radiation therapy, and bone marrow trans- trials in the treatment of various solid tumors, including plantation. Adverse effects associated with sargramostim head and neck cancer, breast cancer and non-small cell use include bone pain (similar to that of filgrastim), fa- lung cancer. The major A summary of the principal clinical uses of most of side effects include diarrhea and skin rash. Bone mar- the drugs mentioned in this chapter can be found in row toxicity has not been a dose-limiting problem. The nitrogen mustard with the broadest spectrum account for the fact that differences in the spectrum of antitumor activity in its class is of antitumor activity and clinical indications differ (A) Ifosfamide for agents within the same class. Ifosfamide also has (B) Cyclophosphamide a broad spectrum of antitumor activity although it is (C) Mechlorethamine not as broad as that of cyclophosphamide. The effectiveness of chemotherapy in human cancer was the use of melphalan is limited because a substituted phenyl which agent in trophoblastic choriocarcinoma in ring in the molecule reduces its reactivity. The long-term complete remissions of tro- (A) Chlorambucil phoblastic choriocarcinoma in women was the first (B) Thiotepa demonstration of the curative potential of (C) Methotrexate chemotherapy in human cancer. Which class of drugs bind avidly to tubulin and mission in patients with primary brain tumor, the cause arrest of cells in metaphase? The patient man breast cancer cells that contain estrogen recep- inquires about her chances for remission. Interferon alfa-2b has been somewhat of a disap- known as interferons were capable of containing vi- pointment as an anticancer drug. However, it has ral infections led to the hope that they would have proved useful in the treatment of which of the fol- many beneficial results, including anticancer activity. Pharmacogenetic determinants of anti- tion, differences in the toxicity profile, duration of cancer drug activity and toxicity. Receptor tyrosine kinases as rational tar- Vinorelbine for treatment of advanced non-small cell gets for prostate cancer treatment: Platelet-derived lung cancer. She consider administering methotrexate 12 mg in- tells you that she has been doing well, but recently trathecally every day for 4 days. The principal applications are in the use of im- Myasthenia gravis is an example of an autoimmune munosuppressive agents. Phagocytic cells are in turn attracted to these react against normal endogenous proteins and thereby sites, where they release enzymes that destroy sur- effect a reaction against certain body tissues. For those with deficien- Wegener’s granulomatosis cies in humoral immunity, the only effective treatment available is antibody replacement (e. For those with deficiencies in cell-mediated immunity, there is no effective pharmacological treatment. In general, because suppressive therapy is commonly used can be found in of the role of antibodies in protection against bacterial Table 57. Since transplantation is usually per- Candida albicans, cytomegalovirus, and Pneumocystis formed in patients with a poor prognosis for survival, carinii, since cell-mediated immune responses are the the use of immunosuppressive agents has potentially primary defenses against these types of infection. In the past, immunosuppression could be achieved only through the use of nonspecific cytotoxic drugs (e. Consequently, serious side effects, including bone consider three principles of immunosuppressive therapy. Therefore, components of concurrent use of corticosteroids with the immunosup- the primary phase of the immune response, such as pro- pressants increased the risk of additional toxicity. With cessing, proliferation, and differentiation, will be the the development of the immunosuppressants cy- most sensitive to drug action. Drugs that are effective in closporine and tacrolimus it is now possible to avoid suppressing an immune response in an unsensitized per- much of this toxicity. Because of their relatively low tox- son generally will show much less effect, if any, in a sen- icity, these drugs have revolutionized the field of trans- sitized individual. It is now possible to successfully transplant has been established, immunosuppressive drugs show tissues to patients not previously considered as candi- little effectiveness. Peak plasma concentrations are reached in Additionally, the different classes of immune globulins 3 to 4 hours, and the plasma half-life is 10 to 27 hours. Metabolism results in inactiva- inflammatory properties of certain of these drugs may tion of the immunosuppressive activity. Agents that en- be valuable because inflammation often accompanies hance or inhibit the mixed-function oxidase enzymes the immune response. Cyclosporine has been approved for use in allogeneic The focus in the next section is on immunosuppres- kidney, liver, and heart transplant patients and is under sants that have been shown to be clinically useful. Cyclosporine Cyclosporine appears to have promise in the treat- Cyclosporine (Sandimmune) is a potent inhibitor of an- ment of autoimmune diseases. It has a beneficial effect tibody- and cell-mediated immune responses and is the on the course of rheumatoid arthritis, uveitis, insulin- immunosuppressant of choice for the prevention of dependent diabetes, systemic lupus erythematosus, and transplant rejection. Adverse Effects Compared with previously available therapy, the adverse Mechanism of Action effects associated with cyclosporine are much less severe Cyclosporine can bind to the cytosolic protein cy- but still worthy of concern. This drug–protein complex inhibits cal- cur in up to 75% of patients, ranges from severe tubular cineurin phosphatase activity, which leads to a de- necrosis to chronic interstitial nephropathy. This effect is creased synthesis and release of several cytokines, generally reversible with dosage reduction. Hypertension occurs in Cyclosporine exhibits a high degree of specificity in 25% of the patients and more frequently in patients with its actions on T cells without significantly impairing B- some degree of renal dysfunction; the concomitant use of cell activity. Hypergly- antibody production by lymphocytes by preventing the cemia, hyperlipidemia, transient liver dysfunction, and differentiation of B cells into antibody-secreting plasma unwanted hair growth are also observed. However, the toxicity as- Absorption, Metabolism, and Excretion sociated with their use necessitates prudent administra- After oral administration, cyclosporine is absorbed tion. Additional information on corticosteroids can be slowly and incompletely, with great variation among in- found in Chapter 60. Corticosteroid ther- Azathioprine is a phase-specific drug that is toxic to apy alone is successful in only a limited number of au- cells during nucleic acid synthesis. Phase-specific drugs toimmune diseases, such as idiopathic thrombocytope- are toxic during a specific phase of the mitotic cycle, nia, hemolytic anemia, and polymyalgia rheumatica. Azathioprine is converted in vivo to thioinosinic Tacrolimus (Prograf) is a second-generation immuno- acid, which competitively inhibits the synthesis of in- suppressive agent that has been approved for use in osinic acid, the precursor to adenylic acid and guanylic liver transplantation. This those of cyclosporine except that weight for weight it is effectively inhibits both humoral and cell-mediated im- 10 to 100 times more potent. Although the binding proteins (cytophilins) Azathioprine is well absorbed following oral adminis- for cyclosporine and tacrolimus are different, they share tration, with peak blood levels occurring within 1 to 2 similar functions in that the cytophilins are important hours. It is speculated mercaptopurine, which is further converted in the liver that these proteins are important in regulating gene ex- and erythrocytes to a variety of metabolites, including 6- pression in T lymphocytes and that both drugs some- thiouric acid. Although its beneficial effect in various condi- Sirolimus tions is principally attributable to its direct immunosup- pressive action, the antiinflammatory properties of the Sirolimus (Rapamune) is structurally related to drug play an important role in its overall therapeutic ef- tacrolimus. This mechanism of action is different it is usually reserved for patients who do not respond to from those of tacrolimus and cyclosporine. It has largely been replaced by cyclosporine in im- Azathioprine (Imuran) is a cytotoxic agent that prefer- munosuppressive therapy. Since im- agents, the better oral absorption of azathioprine is the munologically competent cells are generally rapidly di- reason for its more widespread clinical use. The therapeutic use of azathioprine has been limited by Azathioprine, in combination with corticosteroids, the number and severity of adverse effects associated has historically been used more widely than any other with its administration. It is classified as a sulting in leukopenia, thrombocytopenia, or both may 57 Immunomodulating Drugs 661 occur. Because of its immunosuppressive activity, been used successfully alone and in combination with azathioprine therapy can lead to serious infections. It azathioprine and corticosteroids to prevent renal allo- has been shown to be mutagenic in animals and humans graft rejection. Mycophenolate Mofetil Antithymocyte globulin binds to circulating T lym- phocytes in the blood, which are subsequently removed Mycophenolate mofetil (CellCept), in conjunction with from the circulation by the reticuloendothelial system. It is used steroids is a more effective regimen than azathioprine for the prevention of acute allograft rejection in kid- in preventing the acute rejection of transplanted organs. It is also used to deplete T cells in marrow from donors before bone marrow transplanta- Other Cytotoxic Drugs tion. See Chapter 56 for izing antibodies may develop over time and necessitate further details of these agents. Antibodies Antiserum can be raised against lymphocytes or thymo- Rho(D) Immune Globulin cytes by the repeated injection of human cells into an An Rh-negative mother can become sensitized to Rh appropriate recipient, usually a horse. This antiserum or the immune globulin fraction derived sensitization may lead to Rh hemolytic disease in future from it has been used to produce immunosuppression. Rho(D) graft systems, the responses are variable, particularly immune globulin functions to prevent the mother from from one batch of serum to another. It is generally given at 28 weeks of pregnancy Antithymocyte globulin (Atgam) is purified immune and within 72 hours after delivery. Rh incompatibility globulin obtained from hyperimmune serum of horses can be identified with routine blood tests. These conditions humoral immunodeficiency, congenital agammaglobu- include immunodeficiency diseases, cancer, some types linemias, common variable immunodeficiency, severe of viral and fungal infections, and certain autoimmune combined immunodeficiency, idiopathic thrombocy- disorders. Immunostimulating agents are nonspecific; they cause The principal side effects are possible anaphylactoid general stimulation of the immune system. In most cases, the pharmacol- Thymic factors are naturally occurring substances that ogy of these agents has not been well described. The most promote T-lymphocyte differentiation and differentia- commonly used agents are discussed next.

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One trunk is located of origin of the preganglionic fber on each side of the vertebral column (paravertebral) and positioned anterior to the anterior rami depression symptoms unemployment generic abilify 20 mg buy. Along the trunk Preganglionic sympathetic fbers may synapse with post­ is a series of segmentally arranged ganglia formed from ganglionic motor neurons in ganglia associated with the collections of postganglionic neuronal cell bodies where sympathetic trunk anxiety relief techniques buy abilify overnight, afer which postganglionic fbers enter the preganglionic neurons synapse with postganglionic the same anterior ramus and are distributed with periph­ neurons depression symptoms questions cheap abilify 10 mg without a prescription. Anterior rami of Tl to 12 are connected to the eral branches of the posterior and anterior rami of that sympathetic trunk or to a ganglion by a white ramus spinal nerve (Fig depression brochure abilify 20 mg buy on-line. The fbers innervate structures at communicans depression definition in accounting order abilify mastercard, which carries preganglionic sympathetic the periphery of the body in regions supplied by the spinal fbers and appears white because the fbers it contains are nerve. It appears bral ganglion or the sympathetic trunk through a white gray because postganglionic fbers are nonmyelinated. The ramus communicans may take the following four path­ gray ramus communicans is positioned medial to the white ways to target tissues: ramus communicans. Peripheral sympathetic innervation above or small region of the spinal cord (Tl to 12), to be distributed below the level of origin of the preganglionic fber to peripheral regions innervated by all spinal nerves. Preganglionic sympathetic fbers may ascend ordescend to White rami communicantes only occur in association other vertebral levels where they synapse in ganglia associ­ with spinal nerves Tl to 12, whereas gray rami communi­ ated with spinal nerves that may or may not have visceral cantes are associated with all spinal nerves. All sympathetics passing into the head have gray rami communicantes and are distributed along the preganglionic fbers that emerge from spinal cord level posterior and anterior rami of the spinal nerves. Tl and ascend in the sympathetic trunks to the highest The ascending and descending fbers, together with all ganglion in the neck (the superior cervical ganglion), the ganglia, form theparavertebral sympathetic trunk, where they synapse. Often, these nerves and cervical viscera join branches from the parasympathetic system to form Preganglionic sympathetic fbers may synapse with post­ plexuses on or near the surface of the target organ, for ganglionic motor neurons in ganglia and then leave the example, the cardiac and pulmonary plexuses. Branches ganglia medially to innervate thoracic or cervical viscera of the plexus innervate the organ. The preganglionic fbers in these regions and the adrenals nerves are derived from spinal cord levels T 5 to 12. Preganglionic sympathetic fbers may pass through the The splanchnic nerves generally connect with sympa­ sympathetic trunk and paravertebral ganglia without syn­ thetic ganglia around the roots of major arteries that apsing and, together with similar fbers from other levels, branch from the abdominal aorta. These ganglia are part form splanchnic nerves (greater, lesser, least, lumbar, of a large prevertebral plexus that also has input from the Greater splanchnic nerves Lesser splanchnic nerves Least splanchnic nerves Lumbar splanchnic nerves White ramus communicans Prevertebral plexus and ganglia Gray ramus communicans Paravertebral - sympathetic trunk Abdominal and pelvicviscera Sacral splanchnic nerves Fig. Postganglionic sympathetic fbers are distributed in ganglionic neurons and secrete adrenaline and noradrena­ extensions of this plexus, predominantly along arteries, to line into the vascular system. These branches contribute to plexuses associ­ the head and neck only, whereas X (the vagus ated with thoracic viscera or to the large prevertebral nerve) also innervates thoracic and most abdominal plexus in the abdomen and pelvis. Visceral sensory fbers generally accompany visceral Like the visceral motor nerves of the sympathetic part, motor fbers. Visceral sensory fbers follow the course of sympathetic fbers entering the spinal cord at similar spinal cord levels. Sacral preganglionic parasympathetic fbers However, visceral sensory fbers may also enter the spinal In the sacral region, the preganglionic parasympathetic cord at levels other than those associated with motor fbers form special visceral nerves (the pelvic splanchnic output. For example, visceral sensory fbers from the heart nerves), which originate from the anterior rami of S2 to may enter at levels higher than spinal cord level Tl. Vis­ S4 and enter pelvic extensions of the large prevertebral ceral sensory fbers that accompany sympathetic fbers are plexus formed around the abdominal aorta. The postganglionic motor neurons are Visceral sensory fbers accompany parasympathetic fbers in the walls of the viscera. The enteric system • bundles of nerve fbers, which pass between ganglia and The enteric nervous system consists of motor and sensory from the ganglia into surrounding tissues. Interestingly, more neurons are reported to be in the enteric system than in the spinal cord itself • ganglia, which house the nerve cell bodies and associ­ Sensory and motor neurons within the enteric system ated cells, and control reflex activity within and between parts of the 47 http://medical. These activities can occur independently of the brain and spinal cord, but Referred pain can also be modifed by input frompreganglionic parasym­ Referred pain occurs when sensory information comes pathetic and postganglionic sympathetic fbers. Usually, this happens when the pain information comes from a region, such Nerve plexuses as the gut, which has a low amount of sensory output. These aferents converge on neurons at the same spinal Nerve plexuses are either somatic or visceral and combine cord level that receive information from the skin, which fbers from different sources or levels to form new nerves is an area with a high amount of sensory output. Pain is most ofen referred from a region innervated Somatic plexuses by the visceral part of the nervous system to a region Major somatic plexuses formed from the anterior rami of innervated, at the same spinal cord level, by the somatic spinal nerves are the cervical (Cl to C4), brachial (C5 to side of the nervous system. Tl),lumbar (11 to 14), sacral (14 to S4), and coccygeal (S5 Pain can also be referred from one somatic region to another. Except for spinal nerve Tl, the anterior on the inferior surface ofthe diaphragm, which is rami of thoracic spinal nerves remain independent and do innervated by the phrenic nerve, can be referred to not participate in plexuses. Visceral nerve plexuses are formed in association with viscera and generally contain efferent (sympathetic and parasympathetic) and afferent components (Fig. The massive prevertebral plexus nents of the respiratory, gastrointestinal, and urogenital supplies input to and receives output from all abdominal systems will be discussed in each of the succeeding chap­ and pelvic viscera. Pain interpreted as When the appendix becomes infamed, the visceral originating in distribution sensory fbers are stimulated. These fbers enter the of somatic sensory nerves spinal cord with the sympathetic fbers at spinal cord level Tl 0. The pain is difuse, not focal; every time a peristaltic wave passes through the ileocecal region, the pain recurs. In the later stages of the disease, the appendix contacts and irritates the parietal peritoneum in the right iliac fossa, which is innervated by somatic sensory nerves. This produces a constant focal pain,which predominates over the colicky pain that the patient felt some hours previously. The appendix is situated in a retrocecal position in approximately 70% of patients; therefore it may never contact the parietal peritoneum nerve anteriorly in the right iliac fossa. The back Bony elements consist mainly of the vertebrae, although contains the spinal cord and proximal parts of the spinal proximal elements of the ribs, superior aspects of the pelvic nerves, which send and receive information to and from bones, and posterior basal regions of the skull contribute most of the body. Cervical curvature (secondary curvature) As stresses on the back increase from the cervical to lumbar regions, lower back problems are common. Thoracic curvature Movement (primary curvature) Muscles of the back consist of extrinsic and intrinsic groups: • The extrinsic muscles of the back move the upper limbs Lumbar curvature and the ribs. Although the amount of movement between any two vertebrae is limited, the effects between vertebrae are addi­ tive along the length of the vertebral column. Also,freedom of movement and extension are limited in the thoracic region relative to the lumbar part of the vertebral column. In the cervical region, the frst two vertebrae and associ­ ated muscles are specifcally modifed to support and posi­ tion the head. Protection ofthe nervous system The vertebral column and associated soft tissues of the back contain the spinal cord and proximal parts of the spinal nerves (Fig. The more distal parts of the spinal nerves pass into all other regions of the body, including certain regions of the head. There are seven cervical, twelve thoracic, fve lumbar, fve sacral, and three to four coccygeal verte­ Bones brae. The sacral vertebrae fuse into a single bony element, The major bones of the back are the 33 vertebrae (Fig. The number and specifc characteristics of the verte­ structure, vary in number from three to four, and often fuse brae vary depending on the body region with which they into a single coccyx. In all other regions, these rib elements are small and are The vertebral arch is frmly anchored to the posterior incorporated into the transverse processes. Occasionally, surface of the vertebral body by two pedicles, which form they develop into ribs in regions other than the thorax, the lateral pillars of the vertebral arch. The superf­ The vertebral arch of a typical vertebra has a number cial group of these muscles is related to the upper limbs, of characteristic projections, which serve as: while the intermediate layer of muscles is associated with the thoracic wall. One group A spinous process projects posteriorly and generally of intrinsic muscles also moves the ribs relative to the ver­ inferiorly from the roof of the vertebral arch. Anterior Superior aricular process Superior Transverse process Vertebral body Anterior Posterior Fused costal (rib) element Vertebral Lamina Inferior arch Verebral body Inferior articular process Inferior vertebral notch A Posterior B Fig. In the vertebral canal, the dura mater is separated Within the vertebral canal, the spinal cord issurrounded from surrounding bone by an extradural (epidural) space by a series of three connective tissue membranes (the containing loose connective tissue, fat, and a venous meninges): plexus. Spinal cord Anterior internal vertebral venous plexus Arachnoid mater Posterior longitudinal ligament Position of spinal ganglion Posterior ramus Extradural space Extradural fat Vertebral body Transverse Intervertebral disc process Spinous process Fig. Theanterior rami form themajor somatic plexuses (cer­ Each nerve is attached to the spinal cord by a posterior root vical, brachial, lumbar, and sacral) of the body. Prevertebral ganglion (sympathetic) Vertebral body Anterior root Sympathetic ganglion Visceral components Anterior ramus Arachnoid mater Spinal cord Spinous Fig. The paired vertebral arteries ascend, one on each Head side, through foramina in the transverse processes of cervi­ Cervical regions of the back constitute the skeletal and cal vertebrae and pass through the foramen magnum to much of the muscular framework of the neck, which in participate, with the internal carotid arteries, in supplying turn supports and moves the head (Fig. In addition to providing support for each of Cervical these parts of the body, the vertebrae provide attachments enlargement for muscles and fascia, and articulation sites for other (of spinal cord) bones. The anterior rami of spinal nerves associated with the thorax, abdomen, and pelvis pass into these parts of the body from the back. Limbs The bones of the back provide extensive attachments for muscles associated with anchoring and moving the upper limbs on the trunk. This is less true of the lower limbs, ganglion which are frmly anchored to thevertebral column through articulation of the pelvic bones with the sacrum. The upper and lower limbs are innervated by anterior rami of spinal nerves that emerge from cervical and lumbosacral levels, respectively, of the vertebral column. Their spinal cord level of origin therefore becomes increasingly dissociated from their vertebral column level of exit. The foramen is joint (the joint between the articular processes), can affect formed between adjacent vertebral arches and is closely the function of the associated spinal nerve. Posterior branches of spinal nerves innervate the intrinsic • The posterior margin is formed by the articular pro­ muscles of the back and adjacent skin. Superior articular process Superior vertebral notch Intervertebral Joint between Interverebral disc Inferior articular process Inferior vertebral notch Fig. The skull, scap­ • The seven cervical vertebrae between the thorax and ulae, pelvic bones, and ribs also contribute to the bony skull are characterized mainly by their small size and framework of the back and provide sites for muscle the presence of a foramen in each transverse process attachment. Anterior Fused costal Foramen (rib) element transversarium 7 Cervical vertebrae Cervical vertebra vertebrae Thoracic vertebra vertebrae Fused costal (rib) element Lumbar vertebra Posterior 64 Fig. In the embryo, the vertebrae are formed intersegmen­ • Inferior to the thoracic vertebrae are fve lumbar verte­ tally from cells called sclerotomes, which originate from brae, which form the skeletal support for the posterior adjacent somites (Fig. Each vertebra is derived from abdominal wall and are characterized by their large size the cranial parts of the two somites below, one on each (Figs. Extending from the verte­ • The two laminae are flat sheets of bone that extend bral arch are a number of processes for muscle attachment from each pedicle to meet in the midline and form the and articulation with adjacent bone. The vertebral body is the weight-bearing part of the vertebra and is linked to adjacent vertebral bodies by inter­ A spinous process projects posteriorly and inferiorly vertebral discs and ligaments. The size of vertebral bodies from the junction of the two laminae and is a site for increases inferiorly as the amount of weight supported muscle and ligament attachment. A transverse process extends posterolaterally from The vertebral arch forms the lateral and posterior the junction of the pedicle and lamina on each side and is parts of the vertebral foramen. The vertebral foramina of all the vertebrae together Also projecting from the region where the pedicles form the vertebral canal, which contains and protects join the laminae are superior and inferior articular the spinal cord. Superior aricular process Superior vertebral notch Vertebral arch Inferior articular process Inferior vertebral notch Superior view Superolateral oblque view Fig. The seven cervical vertebrae are characterized by their small size and by the presence of a foramen in each trans­ The frst and second cervical vertebrae-the atlas verse process. A typical cervical vertebra has the following and axis-are specialized to accommodate movement of features (Fig. Foramen transversarium Vertebral body Uncinate process process Vertebral canal Foramen transversarium Spinous process A Superior view Anterior view Fig. Its major distinguishing feature is that it lacks a connected by an anterior arch and a posterior arch. In fact, the vertebral body of Each lateral mass articulates above with an occipital er fuses onto the body of en during development to become condyle of the skull and below with the superior articular the dens of err. The superior articular surfaces are bean shaped and concave, whereas the infe­ rior articular surfaces are almost circular and flat. Inferior articular facet on lateral mass of Cl The atlanto-occipital joint allows the head to nod up and down on the vertebral column. The posterior surface of the anterior arch has an articu­ lar facet for the dens, which projects superiorly from the vertebral body of the axis. The dens is held in position by a strong transverse ligament of atlas posterior to it and spanning the distance between the oval attachment facets on the medial surfaces of the lateral masses of the atlas. The transverse processes of the atlas are large and pro­ trude furtherlaterally than those of the other cervical ver­ tebrae and act as levers for muscle action, particularly for muscles that move the head at the atlanto-axial joints. The axis is characterized by the large tooth-like dens, which extends superiorly from the vertebral body (Figs. The anterior surface of the dens has an oval facet for articulation with the anterior arch of the atlas. The two superolateral surfaces of the dens possess cir­ cular impressions that serve as attachment sites for strong alar ligaments, one on each side, which connect the dens to the medial surfaces of the occipital condyles. It has two large L-shaped The twelve thoracic vertebrae areallcharacterized by their facets, one on each lateral surface, for articulation with the articulation with ribs. Each transverse process also has a facet (transverse Theposterior wall of thevertebral canal may be incom­ costal facet) for articulation with the tubercle of its own plete near the inferior end of the sacrum. The vertebral body of the vertebra is somewhat heart shaped when viewed from above, and the vertebral foramen Coccyx is circular. The coccyx is a small triangular bone that articulates with the inferior end of the sacrum and represents three to four Lumbar vertebrae fused coccygeal vertebrae (Fig. It is characterized Thefve lumbar vertebrae are distinguished from vertebrae by its small size and by the absence of vertebral arches and in other regions by their large size (Fig. The foramina allow structures, such as drical and the vertebral foramen is triangular in shape and spinal nerves and blood vessels, to pass in and out of the larger than in the thoracic vertebrae. An intervertebral foramen is formed by the inferior ver­ Sacrum tebral notch on the pedicle of the vertebra above and the The sacrum is a single bone that represents the fve fused superior vertebral notch on the pedicle of the vertebra sacral vertebrae (Fig.

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The ciliary processes are longitudinal ridges project­ Dilator pupillae ing from the inner surface of the ciliary body (Fig anxiety medication for children generic 10 mg abilify with mastercard. Iris Extending from them are zonular fbers attached to the lens of the eyeball retarded depression definition order 15 mg abilify, which suspend the lens in its proper position and collectively form the suspensory ligament of the lens major depression definition and symptoms buy 20 mg abilify mastercard. Contraction of the ciliary muscle decreases the size of Cornea thering formed bytheciliary body This reduces tension on the suspensory ligament of the lens vegetative depression definition generic abilify 10 mg without prescription. The lens therefore becomes more rounded (relaxed) resulting in accommoda­ tion of the lens for near vision anxiety 4 year old symptoms order abilify 10 mg. Several obvious features are visible on the posterior Inner layer of the eyeball surface of the optic part of the retina. It is lighter than the surrounding retina and part of the retina, which is sensitive to light, and anteri­ branches of the central retinal artery spread from this orly is the nonvisual part, which covers the internal point outward to supply the retina. The junction sensitive receptor cells in the optic disc, it is referred to as between these parts is an irregular line (the ora serrata). Lateral to the optic disc a small area with a hint of yel­ Optic part of the retina lowish coloration is the macula lutea with its central The optic part of the retina consists of two layers, an outer depression, the fovea centralis (Fig. This is the pigmented layer and an inner neural layer: thinnest area of the retina and visual sensitivity here is higher than elsewhere in the retina because it has fewer • The pigmented layer is frmly attached to the choroid rods (light-sensitive receptor cells that function in dim and continues anteriorly over the internal surface of the light and are insensitive to color) and more cones (light­ ciliary body and iris. If ultrasound, except that it uses light instead of sound to the visual problems are signifcant, surgical removal of the produce high-resolution cross-sectional images. The internal ear also contains petrous part of the temporal bone bounded laterally, receptors that detect motion and position. The part projecting Numerous intrinsic and extrinsic muscles are associated from the side of the head is the auricle (pinna) and the with the auricle: canal leading inward is the external acoustic meatus. It consists of cartilage covered with skin and • The extrinsic muscles, the anterior, superior, and poste­ arranged in a pattern of various elevations and depressions rior auricular muscles, pass from the scalp or skull to (Fig. Just anterior to the opening of the external acoustic Sensory innervation of the auricle is from many sources meatus, in front of the concha, is an elevation (the tragus). A smaller curved rim, parallel • The outer more superfcial surfaces of the auricle are and anterior to the helix, is the antihelix. Throughout its length the external acoustic meatus is Vessels covered with skin, some of which contains hair and modi­ Thearterial supply totheauricle is from numerous sources. Its diam­ Theexternal carotid artery supplies theposterior auricular eter varies, being wider laterally and narrow medially. For examination purposes, Lymphatic drainage ofthe auricle passes anteriorly into observation of the external acoustic meatus and tympanic parotid nodes and posteriorly into mastoid nodes, and pos­ membrane can be improved by pulling the ear superiorly, sibly into the upper deep cervical nodes. The major sensory input travels through branches of the auriculotemporal nerve, a branch of the mandibular nerve [V3] (anterior and supe­ rior walls), and in the auricular branch of the vagus nerve [X] (posterior and inferior walls). Tympanic membrane The tympanic membrane separates the external acoustic meatus from the middle ear (Figs. It consists of a connective tissue core External acoustic meatus lined with skin on the outside and mucous membrane on the inside. Tympanic membrane Pharyngotympanic Around the periphery of the tympanic membrane a tube fbrocartilaginous ring attaches it to the tympanic part Fig. At its center, a concavity is produced Pars flaccida Lateral process malleolar fold (of malleus) malleolar fold Handle malleus Umbo of light A Fig. The ear comprises three components-the external, Anteroinferior to the umbo of the tympanic membrane middle, and internal ear. Superior to the umbo in an anterior direction is the Exteral ear attachment of the rest of the handle of the malleus (Fig. At the most superior extent of this line of attach­ acoustic meatus and the tympanic membrane require ment a small bulge in the membrane marks the position otoscopic examination (Fig. An otoscope is a of the lateral process of the malleus as it projects device through which light can be shone and the image against the internal surface of the tympanic membrane. The membrane is thin and slack (the pars faccida), whereas normal tympanic membrane is relatively translucent the rest of the membrane is thick and taut (the pars and has a gray-reddish tinge. The relationship ofthese bones to the middle ear cavity is determined • Sensory innervation of the skin on the outer surface of and any masses identifed. In the clinic Tympanic membrane perforation Although perforation of the tympanic membrane (eardrum) has many causes, trauma and infection are still the commonest causes today. Most ruptures of the tympanic membrane tend to heal spontaneously, but surgical intervention may be necessary if the rupture is large. As the chorda tympani runs in the upper one-third of the tympanic membrane, incisions are always belowthis level. The richer blood supply to the posterior aspect of the tympanic membrane determines the standard surgical approach in the posteroinferior aspect. Otitis media (infection of the middle ear) is common and can lead to perforation of the tympanic membrane. The middle ear communicates with the mastoid area posteriorly and the nasopharynx (via the pharyngotym­ panic tube) anteriorly Its basic function is to transmit Middle ear vibrations of the tympanic membrane across the cavity of The middle ear is an air-flled, mucous membrane-lined the middle ear to the internal ear. It accomplishes this space in the temporal bone between the tympanic mem­ through three interconnected but movable bones that brane laterally and the lateral wall of the internal ear medi­ bridge the space between the tympanic membrane and the ally. These bones are the malleus (connected to the tympanic membrane), the incus (connected to the malleus • the tympanic cavity immediately adjacent tothe tym­ by a synovial joint), and the stapes (connected to the incus panic membrane, and by a synovial joint, and attached to the lateral wall of the • the epitympanic recess superiorly. The middle ear has a roof and a floor, and anterior, poste­ Near the medial border of the floor is a small aperture, rior, medial, and lateral walls (Fig. Tegmental wall Membranous wall The tegmental wall (roof of the middle ear consists of a thin layer of bone, which separates the middle ear from the The membranous (lateral) wall of the middle ear consists middle cranial fossa. This layer of bone is the tegmen almost entirely of the tympanic membrane, but because tympani on the anterior surface of the petrous part of the the tympanic membrane does not extend superiorly into temporal bone. The lower part of this wall consists of a which the tendon of the stapedius muscle enters the bony partition between the tympanic cavity and mastoid middle ear; and air cells. Superiorly, the epitympanic recess is continuous • the opening through which the chorda tympani nerve, with the aditus to the mastoid antrum (Figs. The lower part consists of a thin layer of bone that separates the tympanic cavity from the internal carotid Mastoid antrum Aditus to mastoid antrum artery. Superiorly, the wall is defcient because of the presence of: • a large opening for the entrance of the pharyngotym­ panic tube into the middle ear, and • a smaller opening for the canal containing the tensor tympani muscle. The foramen for the exit of the chorda tympani Pharyngotympanic tube nerve from the middle ear is also associated with this wall (Fig. Middle ear A process Labyrinthine wall The labyrinthine (medial) wall of the middle ear is also the lateral wall of the internal ear. A prominent structure on this wall is a rounded bulge (the promontory) produced by the basal coil of the cochlea, which is an internal ear structure involved with hearing (Fig. Additionally, a branch of thetympanic plexus (thelesser petrosal nerve) leaves the promontory and the middle ear, travels across the anterior surface of the petrous part of the temporal bone, and leaves the middle cranial fossa through the foramen ovale to enter the otic ganglion. Other struc­ tures associated with the labyrinthine wall are two open­ ings, the oval and round windows, and two prominent elevations (Fig. Regional anatomy • Ear • The round window is posteroinferior to the External acoustic meatus promontory. Mastoid area Posterior to the epitympanic recess of the middle ear is the aditus to the mastoid antrum, which is the opening to the mastoid antrum (Fig. Tympanic membrane The mastoid antrum is a cavity continuous with col­ lections of air-flled spaces (the mastoid cells), through­ Caril out the mastoid part of the temporal bone, including the mastoid process. Pharyngotympanic tube The mucous membrane lining the mastoid air cells is continuous with the mucous membrane throughout the Nasopharynx middle ear. In the clinic • a bonypart (the one-third nearest the middle ear); and Mastoiditis • a cartilaginous part (the remaining two-thirds). Infection within the mastoid antrum and mastoid cells is usually secondary to infection in the middle ear. The The opening of the bony part is clearly visible on the mastoid cells provide an excellent culture medium for inferior surface of the skull at the junction of the squa­ infection. Infection of the bone (osteomyelitis) may also mous and petrous parts of the temporal bone immediately develop, spreading into the middle cranial fossa. Drainage of the pus within the mastoid air cells is necessary and there are numerous approaches for Vessels doing this. When undertaking this type of surgery, it is The arterial supply to the pharyngotympanic tube is from extremely important that care is taken not to damage several sources. Any breach of the inner table of and from two branches of the maxillary artery (the middle the cranial vault may allow bacteria to enter the cranial meningeal artery and the artery of the pterygoid canal). Venous drainage of the pharyngotympanic tube is to the pterygoid plexus of veins in the infratemporal fossa. Pharyngotympanic tube Innervation The pharyngotympanic tubeconnects the middle ear with Innervation of the mucous membrane lining the pharyn­ the nasopharynx (Fig. Its opening in because it is continuous with the mucous membrane lining the middle ear is on the anterior wall, and from here it the tympanic cavity, the internal surface of the tympanic extends forward, medially, and downward to enter the membrane, and the mastoid antrum and mastoid cells. They form an osseous chain across the middle ear from the tympanic membrane to the oval window of The malleus is the largest of the auditory ossicles and is the internal ear (Fig. Identifable parts include the head of the malleus, neck of the malleus, Incus articulation anterior and lateral processes, and handle of the Malleus articulation malleus (Fig. Inferior to the head of the malleus is the constricted neck of the malleus, and below this are the anterior and lateral processes: • The anterior process is attached to the anterior wall of the middle ear by a ligament. A The downward extension of the malleus, below the Posterior limb Anterior limb anterior and lateral processes, is the handle of the malleus, which is attached to the tympanic membrane. Tensor tympani muscle Tendon of stapedius muscle Pyramidal eminence Pharyngotympanic tube Tympanic membrane Fig. The second bone in the series of auditory ossicles is the Contraction of the tensor tympani pulls the handle of incus. The stapedius muscle isa very small muscle that originates • The long limb extends downward from the body, paral­ from inside the pyramidal eminence, which is a small pro­ leling the handle of the malleus, and ends by bending jection on the mastoid wall of the middle ear (Fig. Its tendon emerges from the apex of the pyramidal emi­ • The short limb extends posteriorly and is attached by a nence and passes forward to attach to the posterior surface ligament to the upper posterior wall of the middle ear. The stapes is the most medial bone in the osseous chain Contraction of the stapedius muscle, usually in response and is attached to the oval window. It consists of the head to loud noises, pulls the stapes posteriorly and prevents of the stapes, anterior and posterior limbs, and the excessive oscillation. Venous drainage of the middle ear returns to the ptery­ goid plexus of veins and the superior petrosal sinus. Tensor tympani The tensor tympani muscle lies in a bony canal above the Innervation pharyngotympanic tube. It originates from the cartilagi­ The tympanic plexus innervates the mucous membrane nous part of the pharyngotympanic tube, the greater wing lining the walls and contents of the middle ear, which of the sphenoid, and its own bony canal, and passes includes the mastoid area and the pharyngotympanic through its canal in a posterior direction, ending in a tube. Once in the middle ear, the tympanic nerve forms the tympanic plexus, along with branches from the plexus of nerves surrounding the internal carotid artery (caroticotympanic nerves). Branches from the tym­ panic plexus supply the mucous membranes of the middle ear, including the pharyngotympanic tube and the mastoid area. The tympanic plexus also gives off a major branch (the lesser petrosal nerve), which supplies preganglionic para­ sympathetic fbers to the otic ganglion (Fig. The lesser petrosal nerve leaves the area ofthe promon­ tory, exits the middle ear, travels through the petrous part Groove and hiatus for greater petrosal of the temporal bone, and exits onto the anterior surface nerve of the petrous part of the temporal bone through a hiatus just below the hiatus for the greater petrosal nerve (Fig. It continues diagonally across the anterior surface for lesser petrosal nerve of the temporal bone before exiting the middle cranial fossa through the foramen ovale. Regional anatomy • Ear Internal ear The internal ear consists of a series of bony cavities (the bony labyrinth) and membranous ducts and sacs (the membranous labyrinth) within these cavities. All these structures are in the petrous part of the temporal bone between the middle ear laterally and the internal acoustic meatus medially (Figs. The bony labyrinth consists of the vestibule, three Anterior semicircular canals, and the cochlea (Fig. Suspended within the perilymph but not flling all spaces of the bony labyrinth is the membranous labyrinth, which consists of the semicircular ducts, the cochlear duct, and two sacs (the utricle and the saccule). The structures in the internal ear convey information to the brain about balance and hearing: • The cochlear duct is the organ of hearing. Bony labyrinth Cochlea Thevestibule, which contains theoval window in itslateral Projecting in an anterior direction from the vestibule is the wall, is the central part of the bony labyrinth (Fig. This arrangement A narrow canal (the vestibular aqueduct) leaves produces a cone-shaped structure with a base of the the vestibule, and passes through the temporal bone to cochlea that faces posteromedially and an apex that faces open on the posterior surface of the petrous part of the anterolaterally (Fig. Projecting in a posterosuperior direction from the vestibule Extending laterally throughout the length of the modio­ are the anterior, posterior, and lateral semicircular lus is a thin lamina of bone (thelamina of the modiolus, Lateral semicircularcanal and duct Posterior semicircular canal and duct mater Ampulla Utricle Cochlea vestibuli Cochlear duct Scala tympani Round window Opening of cochlear canaliculus Pharyngotympanic tube Fig. Circling around the modiolus, and held cochlea and are continuous with each other at the apex in a central position by its attachment to the lamina of the through a narrow slit (the helicotrema): modiolus, is the cochlear duct, which is a component of the membranous labyrinth. Attached peripherally to the outer wall of the cochlea, • The scala tympani is separated fom the middle ear by the cochlear duct creates two canals {the scala vestibuli the secondary tympanic membrane covering the round and the scala tympani), which extend throughout the window {Fig. Finally, near the round window is a small channel (the cochlear canaliculus), which passes through the tempo­ ral bone and opens on its inferior surface into the posterior cranial fossa. Membranous labyrinth The membranous labyrinth is a continuous system of ducts and sacs within the bony labyrinth. It is flled with endolymph and separated from the periosteum that covers the walls of the bony labyrinth by perilymph. Consisting of two sacs (the utricle and the saccule) and four ducts (the three semicircular ducts and the cochlear duct), the membranous labyrinth has unique functions related to balance and hearing: Lamina of modiolus Cochlear nerve Spiral ganglion • The utricle, saccule, and three semicircular ducts are part of the vestibular apparatus {i. Lateral semicircular canal and duct Posterior semicircular canal and duct Endolymphatic sac and duct mater Utricosaccular duct Round window vestibuli Cochlear duct Opening cochlear canaliculus Fig. It is maintained in this lar canals of the bony labyrinth, posteriorly, and position by being attached centrally to the lamina of the • the saccule and utricle within the vestibule of the bony modiolus, which is a thin lamina of bone extending from labyrinth, in the middle. Thus, the triangular-shaped cochlear duct has: Organs of balance Five of the six components of the membranous labyrinth • an outer wall against the bony cochlea consisting of are concerned with balance.

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These are then Neuraminidase and haemagglutin are antigenic proteins expressed as converted into essential mature proteins (e anxiety vest for dogs order abilify with visa. Hydrogen ions then enter the endosome though maturation of virions depression pills abilify 10 mg order on-line, resulting in the production of non-infectious the M2 ion channel causing disassembly of the virus and leading to particles depression symptoms after giving birth purchase abilify 20 mg without a prescription. Adverse effects include nausea mood disorder group activities discount 10 mg abilify free shipping, vomiting anxiety uncontrollable shaking order abilify australia, budding from the cell membrane, a process that requires neuramini- diabetes and lipodystrophy. The neuraminidase inhibitors, zanamivir and oseltamivir, reduce the symptoms of infuenza by about one day and are most effective if Immunomodulators started within a few hours of the onset of symptoms. Levamisole (centre left) stimulates the nico- tozoa and helminths are generally referred to as parasites. They typi- tinic receptors at the neuromuscular junction and causes a spastic cally are eukaryotic and have complex life cycles. Drugs effective agent, induces muscular contraction and spastic paralysis play an important part in the treatment and control of parasitic dis- in these parasites by increasing calcium fuxes. The fatworms are divided into do to human tubulin, and block the transport of secretory granules tapeworms (cestodes, bottom right) and fukes (trematodes, top and other organelles. It is possible that diethylcarbamazine alters of the selective toxicity of most drugs used to treat infections with the parasite so that it becomes susceptible to the host immune worms (anthelmintics). Dead worms evoke Ascaris lumbricoides (common roundworm) infects the gut lumen in granuloma formation and may cause blindness. The worms, which are between diethylcarbamazine, which kills migrating worms, but cannot affect 10 and 30 cm in length, are common in the subtropics, especially in fbrosing lesions already present. Schistosomiasis (bilharziasis) is infection with fukes of the genus Hookworm is infection of the gut with either Ancylostoma duode- Schistosoma; these fukes affect the bladder and urinary tract (S. Children are Hookworm is a common cause of iron-defciency anaemia in tropical infected early in life by playing in infected water. Infection with Enterobius vermicularis Taenia saginata and Taenia solium infections occur after eating under- (about 1 cm in length) is very common, especially in children. Female worms deposit eggs on the perianal from the ingested cysticercus (larval stage) and fxes to the gut wall. Trichuris trichiura causes infection of the gut lumen, Praziquantel is effective in tapeworm infections. Both the adult and larval (microflariae) forms Mebendazole, tiabendazole and albendazole are benzimidazoles of the flariae occur in humans. It is given Lymphatic flariasis is infection, usually with Wuchereria ban- orally and paralyses the worms, which are then expelled in the faeces. However, more recent studies suggest that ivermectin activates a Onchocerciasis is infection with Onchocerca volvulus and occurs glutamate-gated chloride channel found only in invertebrates. Transmission is by and trematodes lack high-affnity binding sites for ivermectin and so blackfies of the genus Simulium. It is of the microflariae in the skin causes chronic pruritus, and in the also highly effective against ascariasis, enterobiasis, trichuriasis and cornea eventually causes scarring and blindness (river blindness). A single dose of the drug, given every 6–12 months, controls, but does Onchocerciasis was, for many years, treated with diethylcarbamazine, not cure, onchocerciasis. Unfortunately, killing the microflariae exacerbates the disease, It is highly effective against many trematodes and cestodes (but not often with severe reactions when there are lesions in the eyes. The drug is taken up by susceptible helminths and binds Ivermectin causes much less exacerbation of the disease and is now to the β-subunit of the schistosome voltage-gated Ca2+ channels. Eggs shed in the faeces of dogs and cats are ingested damages the tegmentum, causing activation of host defence mecha- (most often by children) and release larvae, which become nisms and destruction of the helminths. This has forced the use of com- Most antimalarials are toxic to the erythrocytic schizonts (blood bination antimalarial regimens. There is no prophylactic drug treat- schizonticides, top right) and the rapidly acting ones (chloroquine, ment for other protozoal infections (right bottom). When a Proguanil acts too slowly for this purpose and is used to provide mosquito bites a human, it injects sporozoites into a capillary (top left prophylaxis. Mefoquine, Malarone and chloroquine are used for both of fgure, ) and these are carried in the blood to the liver, where prophylaxis and treatment. After (left) is a tissue schizonticide used to eliminate the schizonts in the 15–16 days, the schizonts rupture and release ( ) thousands of liver (radical cure) once the clinical attack has been controlled. Blood schizonticides (slow-acting) mefoquine is widely used in areas of the world with multidrug- Proguanil and pyrimethamine are effective schizonticides, but their resistant P. However, it is of no value in treating clinical attacks because following the use of quinine to treat P. The mechanism of Sulfadoxine and dapsone act on the same pathway as pyrimethamine, action of primaquine is unknown. Pyrimethamine and the active metabolite of lysis of erythrocytes in persons with an inherited defciency of glu- proguanil (cycloguanil) are folate antagonists. Other protozoal diseases Amoebiasis is caused by infection with Entamoeba histolytica, a Blood schizonticides (rapid-acting) potent pathogen that is the second leading cause of death from para- Chloroquine is used to treat P. Metronidazole (and tinidazole) (Chapter 37) are highly has no action on the liver schizonts and must be followed by a course effective for amoebic colitis and liver absescess. Plasmodial haem polymerase converts haem to harmless haema- vaginal discharge and occasionally causes urethritis in both sexes. Chloroquine (and quinine) is concentrated in sensitive plasmodia Metronidazole is usually very effective. Pneumocystis carinii is a common organism that thought to kill the parasites by a membranolytic action. These are unusual with the low doses used immunosuppressed patients (steroids, immunosuppressive drugs, for prophylaxis. It is Prolonged administration of high doses may irreversibly damage the treated with co-trimoxazole (Chapter 37), atovaquone or pentamidine. The Combined therapy is not necessary with Riamet or Malarone, which organic pentavalent antimony compounds react with thiol groups and are more potent and less toxic than quinine. Miltefosine is the frst effective oral treatment for vis- nausea, tinnitus, headache, blindness and hypersensitivity reactions. African trypanosomiasis (sleeping sickness) is doxycycline is increasingly being used to provide prophylaxis in areas spread by the tsetse fy and is caused by infection with either of chloroquine-resistant P. Suramin and pentamidine Malarone is atovaquone, a hydroxynaphthoquinone that acts by are used before central nervous system involvement. Drug treat­ drugs, left), while others (cycle-specifc drugs, right) are cytotoxic ments (chemotherapy) may cure some cancers, especially those with throughout the cell cycle (lower fgure). One is a folic acid Drugs used to treat cancer inhibit the mechanisms of cell pro­ antagonist (methotrexate). They are therefore toxic to both tumour cells and prolif­ left) inhibit mitosis by binding to the microtubular proteins necessary erating normal cells, especially in the bone marrow, gastrointestinal for spindle formation. The selectivity of cytotoxic drugs newer drugs that react with antigen specifcally expressed on cancer occurs because, in malignant tumours, a higher proportion of the cells. The Fc portion of the antibody is left exposed and this activates component cells are undergoing division than in normal proliferating the host’s immune mechanism that kills the cancer cells. Resistance to anticancer drugs may be aquired along the synthetic pathway of cellular macromolecules (top). Some during treatment and combinations of cytotoxic drugs may be 94 Medical Pharmacology at a Glance, Seventh Edition. It causes more myelosuppression than vincristine, The administration of cytotoxic drugs is associated with unpleasant but is less neurotoxic. Pretreatment with dexametha­ Selectivity sone and antihistamines is necessary to prevent sensitivity reactions. Their benefcial effects depend on the bone marrow cells recovering faster than the Antimetabolites tumour cells after drug administration. Methotrexate competitively inhibits dihydro­ more drug can be given and, because a fxed proportion of tumour folate reductase and prevents the regeneration of tetrahydrofolic acid cells is killed during each period of drug administration, the tumour and the coenzyme methylene tetrahydrofolate, which is essential for may eventually be eradicated. Because colony­stimulating factor) may reduce the duration of drug­induced rapidly dividing cells require an abundant supply of deoxythymidylate neutropenia. Fluorouracil is converted to fuorodeoxyuridylic Adverse effects acid, which inhibits thymidylate synthetase, the enzyme responsible Individual drugs sometimes have specifc toxic effects, but general for converting deoxyuridylate to thymidylic acid. It is used in (reduced by antiemetics such as metoclopramide, dexamethasone and the treatment of solid tumours. Chapter 30), oral and intestinal ulceration, diarrhoea, alo­ pecia and bone marrow suppression, which can decrease the produc­ Monoclonal antibodies tion of any or all of the formed elements of blood. Vincristine and bleomycin are exceptions that do not cause Rituximab lyses B­cell lymphocytes by attaching to a surface protein myelosuppression. It improves sur­ Some cancers are resistant to drugs from the outset, but others may vival of patients with colorectal cancer when given with standard aquire resistance during treatment due to mutation of the tumour cells treatment, e. As susceptible cells are killed the tumour becomes populated by more Hormones and hormone antagonists resistant cells. The growth of some tumours, especially carcinoma of the breast Alkylating agents and prostate, is partly dependent on hormones. The drugs are associated with an increased incidence of acute tration of an antagonist may induce tumour regression. Cyclophosphamide is metabolized in are steroid hormone receptor­positive, tamoxifen, an oestrogen antag­ the liver, forming several active metabolites. One metabolite, acrolein, onist, is widely used for adjuvant therapy following breast cancer occasionally causes haemorrhagic cystitis, a serious complication. They should not be used in premenopausal women, but Cytotoxic antibiotics are less toxic than, and probably superior to , tamoxifen for the treat­ Doxorubicin is widely used in acute leukaemias, lymphomas and a ment of metastatic breast cancer in postmenopausal women. Vincristine is used in acute lymphoblastic leukaemia, lymphomas and Unfortunately, the effects of hormones are usually temporary, because some solid tumours. The Th2 cells cause B cells to proliferate and develop into with circulating autoantibodies to rheumatoid factors and extra- plasma cells that produce antibodies ( ). These drugs are expensive but result in remis- cant toxicity and may take at least 6 months to produce any beneft. Methotrexate is a cytotoxic folate antagonist used in the treatment of They act by inhibiting the action of transcription factors e. However, methotrexate is associated synthesis is an important action that reduces clonal proliferation of Th with bone marrow suppression, hepatotoxicity and pneumonitis. The many unwanted effects of corticosteroids are discussed in Sulfasalazine is split in the colon by bacteria to produce sulfapyri- Chapter 33. It is also used in the treatment Antiproliferative drugs of chronic infammatory bowel disease (Chapter 13). The mechanism Azathioprine is widely used to prevent tissue rejection in transplant of action of 5-aminosalicylic acid is uncertain. It is metabolized to mercaptopurine, an antimetabolite include rashes, gastrointestinal disorders and blood abnormalities. The resulting cytotoxic Gold as sodium aurothiomalate is given by intramuscular injec- action inhibits clonal proliferation in the induction phase of the tion. Adverse effects are common and include rashes, blood Mycophenolate mofetil is used for the prophylaxis of acute rejec- disorders and proteinuria. However, adverse effects cause 30–40% of the body to mycophenolic acid, which inhibits inosine monophosphate patients to give up gold therapy within a year. The drug is more specifc than azathioprine because T and B lym- Penicillamine has a similar action to gold. The mechanism of hydroxychloroquine cytosolic protein, cyclophilin, which is a member of a class of intracel- is unknown. They are also used in Crohn’s disease, Tacrolimus has similar actions to ciclosporin but is more potent. This agent works by which of the fol- 16 A medical student is doing a summer research project lowing mechanisms of action? Which of the following medication is dosed at 10 mg and causes improve- routes of administration would be most effcacious for ment in bradykinesia and cogwheel rigidity in 99% of medications to bring the blood sugar down? However, 100 mg of this medication causes toxicity manifested as seizures in 1% of the popula- (A) Intramuscular tion treated with this medication. What juice is known to interfere with the cytochrome P450 percentage of the original plasma load of ibuprofen system, disrupting levels of certain drugs. The cyto- will remain in his blood when afternoon practice chrome P450 system includes dozens of enzymes. Most of the phenytoin in her blood is plasma- chrome P450 enzyme wish to isolate the enzyme of protein bound, and only the free fraction is pharmaco- interest from the many other proteins in the cells. The free fraction must diffuse through of their initial steps is to lyse the cells and isolate the many barriers to reach its site of action. Which of the following describes a likely explanation for bicarbonate administration in step of metabolism? The procedure is done under general bicarbonate anesthetic and there are no postoperative complica- (D) Weak acids such as amitriptyline are chemically tions. Three days later, he contacts his physician and complains of diffculty moving his 27 An 80-year-old male nursing home resident is hospi- bowels. This type of adverse drug reaction is most talized on a morphine drip to control pain for his similar to which of the following? Which chloramphenicol of the following metabolic reactions is likely still (C) Dizziness in a 65-year-old man after taking intact in this patient? He accidently hits his thumb with the topical benzoyl peroxide preparation, but the patient hammer, which subsequently becomes swollen and is unsatisfed with the results. Many taking a vitamin A–based acne control product, and proteins are activated in response to injury leading to her friend often tells her how well it works. Which of the following proteins is a begins taking her friend’s pills and is pleased with the transcription factor? You suspect that her medication is 33 A 24-year-old primigravid female’s water breaks at causing her to feel sleepy.

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Asaru, 58 years: A hydroxyl group on controlled by glucocorticoid levels and by input from the hip- C11 is needed for glucocorticoid activity (cortico- pocampus.

Kaelin, 25 years: This is an important example of a cytotoxic chemotherapy for advanced colorectal, lung drug designed precisely to address the biological and breast cancers.

Eusebio, 62 years: This lage, whereas the more inferolateral wall is more fbrous hamulus is immediately behind the alveolar arch and infe­ and is known as the membranous lamina.

Ingvar, 42 years: Therefore, it is There is general agreement that drugs prescribed for dis- important to know how much disease drugs do cause ease are themselves the cause of a serious amount of disease and why they cause it, so that preventive measures can (adverse reactions), ranging from mere inconvenience to be taken.

Tuwas, 35 years: In cases of infected emboli, bacteria grow on the valve and are showered of into the peripheral circulation.

Daryl, 53 years: The apex of this triangle is directed anteriorly represents a “processus acuminis,” resulting from the and inferiorly and overhangs the falciform sulcus 140 Chapter 5 Fig.

Hengley, 54 years: These methotrexate polyglutamates are re- Methotrexate tained in the cell and are also potent inhibitors of dihy- Methotrexate competitively inhibits the binding of folic drofolate reductase.

Fraser, 37 years: Ideally, these individuals should have no questionably ethical practices committed in the past, medical problems other than the condition for which the most countries have established safeguards to protect new drug is intended.

Riordian, 60 years: One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of most antidepressants are not seen for many weeks.

Armon, 63 years: In some situations, it may be necessary or desirable to compute the valproic acid pharmacokinetic parameters for the patient and uti- lize these to calculate the best drug dose.

Sinikar, 31 years: Imipramine is a dibenzazepine with a structure that is very similar to the phenothiazines, whereas amitriptyline is a dibenzocyclohepta- diene that has a structure which resembles thioxanthenes.

Stan, 27 years: The five areas are serum albumin, total bilirubin, prothrombin time, ascites, and hepatic encephalopathy.

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Mine-Boss, 39 years: Considerable interest has focused on which α -receptor subtype is most important for1 smooth muscle contraction in the prostate: subtype-selective α1A-receptor antagonists like tamsulosin may have improved efficacy and safety in treating this disease.

Jack, 56 years: In the clinic Construction of a dialysis fstula Ulnar arery Fistula Radial artery Many patients throughout the world require renal dialysis for kidney failure.

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