Dav id J. Cook, MD

• Professor
• Department of Anesthesiology
• Chair, Cardiovascular Anesthesiology
• Mayo Clinic
• College of Medicine
• Rochester, Minnesota

Some of the drugs reported to produce peripheral neuropathy are listed in Table 107 blood pressure 70 over 40 cheap zestoretic 17.5 mg overnight delivery. Many anecdotal reports of neuropathy possibly induced by other drugs may represent coincidental occurrences and remain to be substantiated arteria vesicalis superior discount zestoretic online. A more recent retrospective study pulse pressure is calculated by quizlet discount 17.5 mg zestoretic amex, however blood pressure vinegar order zestoretic 17.5 mg fast delivery, found that neurological complications are far less frequently encountered in the modern era than in the 1980s when amiodarone was introduced prehypertension 38 weeks buy 17.5 mg zestoretic mastercard, owing to differences in maintenance dosages. Sensorimotor polyneuropathy, either subacute or chronic, may develop in patients receiving long-term amiodarone (400 mg/day) therapy. Moderate sensory impairment and distal and sometimes proximal muscle weaknesses occur. Nerve biopsy demonstrates variable findings of loss of myelinated and unmyelinated fibers, axonal degeneration, and segmental demyelination. A distinctive feature is the presence of lysosomal lamellar inclusions in Schwann cells, fibroblasts, and endothelial cells resulting from inactivation of the lysosomal enzyme sphingomyelinase. There is up to 80 times greater concentration of amiodarone and desethylamiodarone in the peripheral nerve than in the serum. The long half-life also heightens the importance of correctly attributing the neuropathy to amiodarone and not other causes. Few equivalent antiarrhythmics exist for many patients, and a lengthy observation period is required to assess whether or not the progression has halted. Bortezomib Bortezomib (Velcade), used in the treatment of multiple myeloma, is a proteasome inhibitor that frequently causes a predominantly sensory reversible axonal neuropathy in a dose-dependent manner, which may rarely also affect the autonomic nervous system. The neuropathy of bortezomib is more pronounced in patients with a pre-existing neuropathy or other risk factors for neuropathy such as diabetes. As the scope of bortezomib has widened to include treatment of solid tumors, early observations have suggested that neuropathy may be significantly less common. This would suggest that multiple myeloma is a risk factor for bortezomib-induced neuropathy. The well-documented reversibility of neuropathic symptoms after stopping or reducing the dose, however, strongly suggests a primary causative role for bortezomib. Nerve biopsy reveals loss of large myelinated fibers and acute axonal degeneration. Most patients receiving cumulative doses below 500 mg/m2 improve following cessation of therapy, but the neuropathy may persist long after the cessation of medication (Strumberg et al. Vitamin E supplementation (-tocopherol 400 mg/day) has been shown to reduce the severity of neuropathy when administered along with and after cessation of cisplatin (Pace et al. There are other available and emerging platinum compounds including oxaliplatin, nedaplatin, and lobaplatin. Up to 90% of patients receiving a cumulative dose of 540 mg/ m2 or greater of oxaliplatin develop a predominantly sensory neuropathy (Cersosimo, 2005; Krishnan et al. During or shortly after the infusion of oxaliplatin, many patients experience transient sensory symptoms in the limbs, perioral region, and in the throat, possibly due to a temporary dysfunction of nodal voltage-gated sodium channels of peripheral nerve. Subacute proximal weakness and an associated mild distal axonal neuropathy may occur in patients with mild renal insufficiency receiving conventional doses of colchicine, or in patients receiving long-term colchicine for suppression of gout. Although the sural nerve biopsy shows only nonspecific changes, muscle biopsy reveals autophagic vacuoles and lysosomal accumulation. Colchicine probably causes neuropathy by interfering with axoplasmic transport and impairment of axonal microtubular assembly. Chloramphenicol Chloramphenicol can produce an often reversible peripheral and optic neuropathy following prolonged high-dose therapy. Chloroquine Chloroquine is an antimalarial drug that is also used in the treatment of connective tissue disorders. Typically, a painful vacuolar myopathy with increased serum muscle enzymes develops after prolonged therapy. Muscle and sural nerve biopsies show lamellar inclusions in muscle fibers and Schwann cells. Other antimalarial agents in the same chemical class may cause a similar neuropathy. The mechanism of toxicity is thought to be lysosomal enzyme inhibition similar to amiodarone. High doses may cause a predominantly motor neuropathy characterized by weakness and atrophy of distal muscles, particularly intrinsic hand muscles. The prototype of these is cisplatin, which is used widely in the treatment of ovarian, bladder, and testicular malignancies, as well as squamous cell carcinomas. The effect of cisplatin on tumor vasculature has also been implicated in its antineoplastic effect. Cisplatin causes a dose-dependent, predominantly sensory neuronopathy affecting large cells of long-fiber nerves, causing loss of large long myelinated fibers (Krarup-Hansen et al. Paresthesias, Lhermitte sign, loss of tendon reflexes, prominent proprioceptive loss, and sensory ataxia usually occur when cumulative doses exceed 400 mg/ m2. At the onset of symptoms, it may be difficult to distinguish this neuropathy from a paraneoplastic neuronopathy. Autonomic symptoms, especially gastroparesis and vomiting, are common and may reflect enteric ganglion cell loss. The neuropathy may develop as late as 4 months after the drug has been stopped (coasting). High doses of ddC produce an acute painful sensory neuropathy that may progress for 3 weeks, or even months, after treatment is stopped (coasting). Pre-existing neuropathy, diabetes mellitus, heavy alcohol consumption, and low serum cobalamin levels are risk factors that predispose to nucleoside neuropathy. Substantial evidence is now being accumulated on the role of mitochondrial dysfunction in the pathogenesis of nucleoside analog neuropathy. Distal "tingling asleep numbness" in the extremities, without overt clinical signs, may develop in 15% of patients on hydralazine. The neuropathy may be caused by pyridoxine deficiency by a mechanism similar to that associated with isoniazid. Symptoms improve after withdrawal of the drug or with low-dose vitamin B6 supplementation (50­100 mg/day). Disopyramide A few cases of reversible sensorimotor peripheral neuropathy have been associated with the cardiac antidysrhythmic agent, disopyramide (Briani et al. The incidence of neuropathy is dose related; most patients receiving daily doses of 500 mg or more develop nerve damage after 6 months. The clinical manifestations are initially distal sensory impairment and later progressive weakness. Encephalopathy or basal ganglia dysfunction may also be observed in patients receiving high doses of the drug. Acute axonal degeneration and loss of myelinated fibers, as well as accumulation of neurofilaments in the swollen axons, are seen in sural nerve biopsy specimens. The mechanism of neurotoxicity is unknown, but toxicity caused by carbon disulfide, a metabolite of disulfiram, and mitochondrial injury have been proposed. Typically, 6 months of treatment is needed before neuropathic symptoms of paresthesias, impaired distal lower extremity sensation, and weakness begin. The primary pathological process is axonal degeneration affecting both myelinated and unmyelinated fibers, often with prominent axonal regeneration. Ethambutol Ethambutol is an antituberculous drug that causes peripheral sensory and optic neuropathy after prolonged administration at doses above 20 mg/kg/day. Distal sensory axonal neuropathy develops in approximately 10% of patients after high-dose therapy with this agent. Leflunomide Leflunomide is an anti-inflammatory disease-modifying drug used in rheumatoid arthritis. A sensory, and sometimes motor, axonal neuropathy may develop a few months after initiation of therapy (Bonnel and Graham, 2004; Martin et al. Patients who stop the drug within 30 days of symptom onset are more likely to have improvement of symptoms or complete recovery than patients who continued to use drug for a longer time. Gold Organic gold salts are sometimes used in the treatment of rheumatoid arthritis. Toxic allergic reactions involving skin, kidneys, and blood are well known, whereas neurotoxic complications are uncommon. A dose-related distal axonal polyneuropathy may develop in patients receiving gold therapy. Many patients have the distinctive features of profound myokymia, muscle aches, insomnia, and autonomic dysfunction such as sweating and labile hypertension. In these cases, nerve conduction studies show evidence of demyelinating neuropathy. Linezolid Linezolid is an oxazolidinone used against methicillin- and vancomycin-resistant Gram-positive microorganisms. Its longterm use (>28 days) may result in a predominantly sensory and poorly reversible neuropathy with both large- and smallnerve fiber involvement. The mechanism of nerve toxicity is unknown but may be related to inhibition of nerve protein synthesis or mitochondrial dysfunction (Bressler et al. However, substantial controversy and doubt accompanies the true existence of such an association, its severity and extent, pathophysiology, and the benefits versus the risks of statins (Bays, 2006; Guyton, 2006; Leis et al. Even if statins do cause peripheral polyneuropathy, the Heroin Both nontraumatic brachial and lumbosacral plexopathies have been reported in heroin addicts. On resumption of heroin use after a period of abstinence, the symptoms recur in one-third of patients. Intense pain is a common clinical presentation, whereas weakness and sensory impairment are less prominent. The incidence of neuropathy is estimated at 12 per 100,000 person-years or a prevalence of 60 per 100,000 persons. The direct role of the underlying metabolic syndrome, hyperlipidemia, or an unrecognized impaired glucose tolerance (Hoffman-Snyder et al. Vitamin B12 supplementation appears to be of no benefit in treating N2O myeloneuropathy. Perhexiline Perhexiline maleate, now used infrequently in a few countries (but not the United States) for treatment of angina pectoris, causes a reversible demyelinating neuropathy mimicking an inflammatory demyelinating polyneuropathy. Metronidazole and Misonidazole Metronidazole is commonly used for the treatment of protozoal and anaerobic bacterial infections, as well as inflammatory bowel disease, peptic ulcers caused by Helicobacter pylori, and genitourinary tract infections. It may produce a painful, predominantly sensory polyneuropathy or sensory neuronopathy following the chronic use of cumulative doses of drug exceeding 30 g. Patients taking large doses in a short period for acute infections may also develop such neuropathies. Axonal degeneration of both myelinated and unmyelinated fibers can occur, with slow improvement after the agent is stopped. Misonidazole, a related compound used as an experimental radiation-sensitizing agent, causes a similar sensory neuropathy. Phenytoin Phenytoin, a widely used antiepileptic drug, may cause mild and largely reversible or asymptomatic polyneuropathy after many years of exposure. Typical manifestations are confined to lower-extremity areflexia, distal sensory loss, and mildly reduced motor conduction velocities. The degree of abnormality is generally proportional to the duration of phenytoin treatment. Folate deficiency, which may develop during phenytoin therapy, is unrelated to the onset of neuropathy. Pyridoxine High-dose pyridoxine (vitamin B6, 250­3000 mg/day) may cause a severe and remarkably uniform sensory polyganglionopathy. Painful paresthesias, sensory ataxia, perioral numbness, and Lhermitte sign are common features. Severe depletion of myelinated fibers and acute axonal degeneration are found in sural nerve biopsy specimens. In experimental studies, high-dose pyridoxine (300 mg/kg) produced widespread dorsal root ganglion degeneration. The vulnerability of dorsal root ganglia to circulating pyridoxine is thought to be due to weak blood­brain barrier in this region. It appears that the toxic effect is exerted by pyridoxine itself and not through its metabolites. The fact that most clinical cases gradually recover suggests that dysfunctional dorsal root ganglion neurons may regain their functional capacity despite severe sensory deficits early in the course of disease. Nitrofurantoin Nitrofurantoin is a broad-spectrum antibiotic used to treat urinary tract infections. A sensorimotor polyneuropathy of the distal axonal type may develop weeks to months after beginning therapy. Renal insufficiency, particularly in the elderly and females, predisposes patients to the development of neuropathy because of excessive tissue concentrations of nitrofurantoin, which is normally excreted by the kidneys. Patients with pre-existing diabetes are also at greater risk of developing neuropathy. The mechanism of toxicity is unclear but is thought to be inhibition of synthesis of acetyl-CoA by furan derivatives or accumulation of metabolites such as semicarbazide, known to cause neuropathy in experimental animals. Improvement occurs after the medication is discontinued, but it may be incomplete, especially if weakness is present. Suramin Originally introduced as an antiparasitic agent, suramin is used currently as an antineoplastic drug for refractory malignancies. Suramin neurotoxicity is the dose-limiting side effect leading to two distinct patterns of neuropathy: one a length-dependent axonal polyneuropathy and the other a subacute demyelinating polyradiculoneuropathy (Chaudhry et al. The distal sensorimotor neuropathy that occurs in 30% to 55% of patients manifests with paresthesias and mild distal leg weakness. About 15% of patients develop a subacutely evolving, demyelinating polyradiculoneuropathy. The severe neuropathy occurs predominantly at peak plasma suramin concentrations above 350 µg/mL. Suramin may induce Nitrous Oxide A predominantly sensory neuropathy and associated myelopathy develop in individuals repeatedly abusing or exposed to nitrous oxide (N2O), an inhalation anesthetic agent that is also used in the food industry as whipping cream propellant. Neurological symptoms occur following intentional abuse or, rarely, through contamination in operating rooms or pediatric dental offices with faulty N2O scrubbers.

The purpose of fasting is often thought to be avoidance of postprandial spikes in analytes like serum glucose blood pressure medication causing low blood pressure zestoretic 17.5 mg buy, but more importantly pulmonary hypertension xray discount 17.5 mg zestoretic with amex, fasting prior to sample collection standardizes conditions for all animals arteria glutea superior proven 17.5 mg zestoretic. If the test article affects food consumption or alters the eating pattern of treated animals compared with concurrent controls heart attack jarren benton purchase zestoretic pills in toronto, then clinical pathology testing of nonfasted animals has the potential to identify differences simply owing to eating patterns arterial network on the dorsum of the foot zestoretic 17.5 mg fast delivery. Fasting mice can be problematic as mice tend to become dehydrated quickly when not eating, and dehydration alters several test results, in addition to increasing the difficulty of blood collection. However, because blood collection from mice is usually a terminal procedure done just prior to necropsy, fasting is often desirable to reduce glycogen in hepatocytes and improve microscopic detection of subtle hepatocellular effects. If this is done, care must be taken to adjust or stagger the start time for fasting animals on the basis of their projected time of necropsy. Terminal necropsy for a large mouse study may take several hours, and animals at the end of the necropsy period should not be fasted significantly longer than those at the beginning. The length of necropsy procedures presents another source of variability, circadian effects. While circadian effects would be difficult to avoid in this situation, timing of multiple blood collections over the course of a study should be scheduled as uniformly as possible. Study-related procedures, including the act of blood collection, have the potential to increase variability as a result of endogenous catecholamine release due to excitement or fear (the fight or flight response). In addition to physical effects, such as increased heart rate and blood pressure, common clinical pathology changes include increased red cell mass due to splenic contraction, increased leukocyte counts due to movement from the marginal to circulating pool, and increased glucose due to glycogenolysis. The potential for misinterpreting changes from baseline results is greater when a monkey or dog study includes only a single baseline clinical pathology interval because this response is more common during the early part of a study before animals have become accustomed to handling or blood collection. Effects of stress, or endogenous corticosteroid release, can also increase variability, but these changes take longer to develop and last longer. In addition to stress associated with significant toxicity, study-related activities, such as shipping, surgery, and repeated anesthesia, can cause a stress response. The most common findings associated with stress are decreased absolute lymphocyte and eosinophil counts. If absolute lymphocyte counts are decreased but absolute eosinophil counts are not, the finding for absolute lymphocyte count is less likely stress-related because eosinophils are extremely sensitive to corticosteroids. Procedural sources of variation include blood collection technique/site, order of sample collection and analysis, and study design factors and events, such as vehicle characteristics, route of administration, surgical manipulations and other procedures requiring anesthesia, and toxicokinetics sample collection. The most important aspects of blood collection technique/site are proficiency and consistency. Several studies have been done comparing test results using different techniques and sites of collection, especially for rodents (Bennett et al. Although clear differences for some tests exist on the basis of technique/site. For example, it would unnecessarily complicate data interpretation to collect blood from anesthetized monkeys at some test intervals and conscious monkeys at others or to collect blood from the jugular vein of rats at an interim collection interval and the vena cava at the terminal collection. Requiring blood collection personnel to use a technique/site to which they are unaccustomed, for any reason, without proper training and sufficient, results-proven practice simply increases the likelihood of variability that can mask test article­related effects. The order of sample collection and analysis should always be planned to avoid effects of time bias. Collecting and analyzing samples in group order, beginning with the control group and ending with the high-dose group, is scientifically inappropriate because it can result in differences between control and treated groups that have no relationship to the test article. These differences can be reduced or eliminated by collecting samples in random order or round-robin order. This minimizes effects of preanalytical variables at the time of sample collection. If the size or complexity of a study requires a staggered start and staggered procedures over 2 days, effects of day-to-day variability can be minimized by starting and testing males on one day and females on the next. Certain vehicles or vehicle constituents, such as corn oil or polyethylene glycol, can increase variability of specific tests, and markers of inflammation in particular will be more variable when the route of administration is intravenous infusion via indwelling catheter. Attention should be paid to the composition of vehicle compound as some vehicles have been reported to cause toxicity making it difficult to distinguish test article-related effects from that of the vehicle (Aulbach et al. A few examples include pseudoallergic reactions sometimes caused by radiocontrast media, liposomal drugs (Doxil, Ambisome, and DaunoXome), and micellar solvents containing amphiphilic lipids. These agents trigger the reaction by producing anaphylatoxins by initiating classic and alternative pathways of complement activation. In addition to inducing anaphylactic reaction, these lipid-containing vehicles can also cause increased lipids or triglycerides concentration in blood. Some vehicles have relatively safe profiles at recommended dose but can exhibit toxicity at much higher doses, such as Transcutol, diethylene glycol monoethyl ether, that have been reported to cause renal toxicity at >1500 to 2000 mg/kg/day, mostly due to presence of ethylene glycol and diethylene glycol as impurities. A major procedural cause of increased variability is multiple blood sample collections for toxicokinetic analyses and, less frequently, antidrug antibody analysis and pharmacodynamic markers. Although the exact amount of blood taken can be calculated, that does not account for rebleeding that may occur when animals are returned to their cages. Animals bled six or eight times within 24 h on Day 1 of a study will often lose more blood than the calculated volume. Ultimately, some animals have much larger reductions in red cell mass and serum proteins than others, and a robust regenerative response occurs for some but not others. These differences can easily result in misinterpretation of data because of relatively Principles of Clinical Pathology 225 few animals in each group. If multiple toxicokinetic samples are collected on the final day of dosing in a repeat-dose study. Due to blood volume constraints, especially for rodent species, microsampling methods have been explored where small sample volume (100 L or less) can be collected at multiple successive time points from each animal (Niu et al. Such variability may be undesirable when hematotoxicity is expected as this can obscure minor test article­related effects and potentially limit the responsiveness or tolerability of animals to the hematotoxicity (Poitout-Belissent et al. Although it seems intuitive that all study-related procedures should be identical for control and treated animals, economic pressures and the desire to limit animal use can result in practices that ultimately reduce the power of studies to identify test article­related effects and lead to misinterpretation of test results. Some of these practices include collecting fewer blood samples from control animals than treated animals, collecting multiple toxicokinetic samples from rats used for toxicity endpoints, using different routes of administration or dosing regimens in a single study without an appropriate control for each route or dosing regimen, using different vehicle formulations in a single study without an appropriate control for each, and comparing animals that have been surgically manipulated. As some of these practices and others will no doubt continue, it is imperative that these compromises to optimal science be understood and considered during study design and data interpretation. If there are differences between control and treated animal test results, do those differences reflect true or real effects of the test article And if those differences do reflect real effects of the test article, are the effects toxicologically important or adverse These judgments require considering many factors and using a weight-of-evidence approach. Factors considered include all sources of variability previously described, species and number of animals tested, in-life observations, anatomic pathology findings, characteristics of each clinical pathology test, and the test article itself (Hall 2017). In such cases, baseline values (and/or historic control values) are used for interpretation, which generally enable identification of major toxicities that are expected in these early nonclinical studies. The first step is to identify differences between control and treated animal results at the intervals tested and differences between baseline and postdose results for large animal species. This can be done by subjectively examining the data for each group and for individuals within each group or with the aid of statistical analysis. Whether or not statistics are used, group and individual results must always be examined. Statistics are a tool and never the only interpretive consideration (Carakostas and Banerjee 1990; Chanter et al. When statistical comparisons are made 226 Toxicologic Pathology between multiple groups and sometimes at multiple testing intervals for 40+ clinical pathology tests, it is nearly certain that statistically significant differences between control and treated groups that do not represent real effects will be identified. Once a difference between control and treated animals has been identified, the decision concerning its relationship to the test article. For large animals, was there a similar difference present in baseline data before initiation of dosing Was the difference dose dependent, consistent over time, and consistent between sexes Dose dependency and consistency are not absolutely necessary for a difference to be real, especially with biologics, but they add to the weight of evidence. A difference 2 days postdose is more likely to be real than a difference 14 days postdose for the great majority of test articles. In other words, are questionable differences more or less reasonable given expected or suspected effects based on previous work Study design factors to consider include the test species, age, number of animals per group, and unique study conditions, such as route of administration, vehicle, multiple or excessive blood collections, and other study-related procedures. The same difference for a given test is more likely to be real in a study with 15 animals/group than a study with 5 animals/group. In general, clinical pathology data for mice and monkeys are more variable than those for rats and dogs. For mice, this is due, at least in part, to the difficulties associated with sample collection. For monkeys, this is partly due to their relatively small size compared with dogs and differences in their ages, the way they were raised, and their reaction to handling. A small difference for absolute neutrophil count or fibrinogen is more likely to be real in an oral gavage study than a chronic intravenous infusion study. A small difference for cholesterol is more likely to be real if the vehicle is reverse osmosis water and not corn oil. Small differences for red cell mass and absolute reticulocyte count at day 4 of a single-dose study are more likely to be real in a dog study than a monkey study because the effect of multiple toxicokinetic sample collections has less impact in dogs. Once a difference has been determined to be test article related, the decision concerning its toxicologic relevance is also based on many factors, but it is rare to consider a clinical pathology effect toxicologically important or adverse without correlative in-life observations or anatomic pathology findings that reflect the significance of the effect. Clinical pathology parameters can be divided into those that are critical to health and those that are simply markers for organ function, tissue integrity, or a process. Hemoglobin, glucose, calcium, and potassium are examples of analytes critical to health. Too little of these in blood will have serious negative consequences and be considered adverse. They would be accompanied by clinical observations, such as lethargy, weakness, muscle tremors, or arrhythmias. In contrast, creatinine, liver enzymes, and cardiac troponins are analytes in blood that have no intrinsic effect on health but can certainly be markers of adverse effects. Neutrophils and fibrinogen are examples of analytes that are both critical to health and markers for a process. Extremely low neutrophil count increases susceptibility to Principles of Clinical Pathology 227 infection, and too little fibrinogen increases the likelihood of hemorrhage. On the other hand, high absolute neutrophil count and fibrinogen concentration typically have no negative health effects, but they can certainly be markers for an adverse inflammatory process. Unfortunately, clinical pathology parameters have no well-defined critical values or "thresholds" to clearly indicate a toxicologically important or adverse effect. Were there correlative findings indicating that the clinical pathology effect was associated with a deleterious effect on organ function, tissue integrity, overall health, or survival A small increase in urea nitrogen concentration could reflect mild dehydration. If the test article is a chemotherapeutic agent, and the effect reverses when dosing is discontinued, then the corresponding dose level would normally be described as "not severely toxic," even though the effect on bone marrow integrity and function was clearly adverse. Determining whether a clinical pathology effect is adverse or a marker for an adverse effect is not a simple process and, as with many decisions concerning adverseness, is often subjective and open to debate with diverse interpretations each having merit. A recent publication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology and the Clinical Pathology Interest Group of the Society of Toxicologic Pathology described a similar approach for assessing adversity in clinical pathology data interpretation using pathophysiologic context and a weight-of-evidence approach (Ramaiah et al. The optimal means of assessing reversibility is to obtain and examine data for individual recovery animals at the end of the dosing and recovery phases. This is typically not possible for mice but recommended for rats and routine for larger species. If only group means are examined, relatively small clinical pathology effects often appear unchanged after the recovery phase because of the limited number of recovery animals evaluated. However, it is unrealistic to expect mean values for an affected group to exactly match or even closely approximate mean values for the control group after recovery. It is imperative that data for individual control and treated animals be assessed with respect to how they change from the end of dosing to the end of recovery. Do individual recovery animals in the affected group exhibit evidence that the effect is in the process of reversing Do individual recovery animals in the affected group even exhibit the effect at the end of the dosing phase Is it realistic to expect, on the basis of characteristics of the affected test, clear evidence of reversibility in the time allowed by the length of the recovery phase It is unlikely that results for recovery animals at the end of the dosing phase will perfectly represent the effect on their entire group, and it is not unusual for results of one or more recovery animals in an affected group to not exhibit the same evidence of reversibility present in the majority of recovery animals. The term "completely reversed" is often inappropriate for clinical pathology effects and should be avoided. In most studies, evidence of reversibility is frequently demonstrated, however, proving a complete reversal or recovery may be difficult because of individual variation in the data and influence from the above mentioned factors. Reference intervals, like statistics, can be used as a tool for data interpretation but should never be relied upon to determine whether differences between control and treated groups are real effects or whether real effects are adverse. Reference intervals can and do provide perspective but also have important limitations. Reference intervals are perhaps most valuable for assessing possible effects in early investigational or discovery-type studies that lack control animals or baseline data. In those situations, however, it is critical that animals and conditions used to establish the reference intervals match the animals and conditions of studies in question. Reference intervals provide perspective concerning expected interanimal variability for different analytes.

Relative to interpretation of clinical pathology data from an individual sick animal blood pressure 12080 buy zestoretic with paypal, interpretation of data from a nonclinical study has several advantages: multiple animals per group at increasing dose levels arrhythmia basics 17.5 mg zestoretic order visa, a concurrent control group blood pressure chart during pregnancy buy zestoretic 17.5 mg free shipping, baseline data for larger species blood pressure monitor costco best order for zestoretic, detailed clinical observations blood pressure guide zestoretic 17.5 mg purchase with mastercard, comprehensive anatomic pathology evaluations, and at least some knowledge of potential test article effects based on pharmacologic activity or drug class. However, these advantages can be a double-edged sword, and identification of subtle clinical pathology effects is common. Placing subtle effects into proper context may not only be challenging but also very important to the future development of the test article. New safety biomarkers have been investigated and approved (or qualified) by health authorities to address gaps for detection and monitoring of some toxicities with routine clinical pathology testing. Consortia of nonprofit organizations, academia, biopharmaceutical companies, and regulatory agencies have made significant progress during the last decade to promote the investigation and regulatory processes for qualification of new safety biomarkers. These new biomarkers are intended to detect toxicities earlier in drug development, with improved accuracy and translatability from nonclinical to clinical studies to enable a more effective safety monitoring strategy. A regulatory path has now been instituted that defines a staged approach to the qualification of biomarkers as drug development tools for regulatory decision-making (Amur et al. The new biomarkers or their panels that reproducibly outperform standard tests may gain regulatory endorsement. This article also addresses study design factors that influence clinical pathology test selection, timing, and frequency; sources of variability that confound data interpretation; general principles of data interpretation; and common patterns and correlative findings for standard hematology, coagulation, clinical chemistry, urinalysis, and urine chemistry tests. In these studies, selection of clinical pathology tests can be limited and targeted to specific needs or interests. On the other hand, if a study is part of the nonclinical package to support regulatory approval, several tests are required or recommended in guideline published by the various regulatory agencies. Unfortunately, guidelines are not uniform and are sometimes ambiguous; in a few instances, guidelines recommend or require inappropriate tests (Hall 1992). In 1996, an international committee composed of representatives from several professional organizations with scientific expertise in animal clinical pathology published "core" recommended tests for regulated safety assessment and toxicity studies in an effort to provide more standard recommendations (Weingand et al. Specific recommendations have been published for addressing clinical pathology testing recommendations to assess liver toxicity (Boone et al. The following paragraphs describe clinical pathology tests most commonly assessed in standard nonclinical studies. All these tests can be performed by hematology analyzers with species-specific software currently used in industry. State-of-the-art hematology analyzers can generate a great number of additional measurements about different cell populations that may be beneficial for very specific needs and investigational interests, but their value for standard toxicity screening is limited at this time by lack of experience with interpretation in various laboratory animal species under different conditions. Although it may be prudent to prepare bone marrow smears at necropsy for possible future use, indications for microscopic examination of bone marrow smears in standard toxicity studies are limited (Reagan et al. In contrast to a patient with unexplained nonregenerative anemia, leukopenia, thrombocytopenia, or pancytopenia, the cause of these findings in animals being administered a test article is not unexplained. The combination of serial peripheral blood findings that reflect bone marrow function and microscopic findings in bone marrow sections. Actual M:E ratios have little or no value and can usually be predicted by the peripheral blood findings or estimated by examination of bone marrow sections. Detailed examinations of bone marrow smears should only be undertaken to answer specific questions about bone marrow effects and may require a study designed specifically for that purpose. For example, bone marrow findings can vary greatly from one day to the next after an acute toxic insult, as reflected in peripheral blood counts that fall sharply and then rebound. Examination of bone marrow smears from a single point in time can result in incorrect assumptions about the nature of the toxic effect. Evaluation of different bone marrow cell populations by flow cytometry has the potential to provide better quantitative information than obtained manually, but technological challenges and practicality limit the use of flow cytometry to specific investigational work. Once mostly restricted to extended immunotoxicity assessment, these endpoints are now more commonly implemented for pharmacodynamic testing of immune cell-targeted therapy. Forethought must be given to the additional blood volume and sampling time points for this testing. Additionally, for leukocyte subsets already enumerated in the standard hematology panel. Toxicologically important effects on coagulation are relatively infrequent, and these tests are sometimes eliminated or delayed until terminal sacrifice if blood volume limitations are an issue because of animal size and the number of blood samples required for other assessments. Although part of the coagulation test profile, fibrinogen is an acute phase protein and useful as a marker of inflammation. These tests are typically performed on serum, but plasma is occasionally used for mice because the sample yield can be slightly better. Most routine clinical chemistry assays use enzymatic or chemical reactions that produce a colored product measured by spectrophotometry. These assays are mostly developed for human patients but the physicochemical similarity of analytes with animals also makes them applicable for animal species. In some cases, selection of specific methods or use of species-specific calibrators will improve accuracy. Urinalysis parameters routinely evaluated include volume (if collected over a period [e. Many other clinical pathology tests are available and may be indicated for assessment of specific test articles. Hematology tests, such as methemoglobin or enumeration of Heinz bodies, could be indicated for test articles causing oxidative injury. If exocrine pancreatic injury is a concern, measurement of amylase or lipase activity may be warranted. Various hormones can be measured to assess possible endocrine dysfunction, and urine chemistry tests. Cardiac troponin I or T may be indicated for test articles suspected of causing cardiac toxicity, and biomarkers to detect bone formation or resorption may be useful for test articles targeting bone. The list of possible tests is long and will continue to increase as the search for more specific and sensitive tests continues. Clinical laboratory tests in long-standing use for diagnosis of natural disease can also be applied to toxicity assessment. Implementation of these tests requires familiarity with the pathology of the natural disease, the mechanism and/or phenotype of the toxicity, and a thorough Principles of Clinical Pathology 219 knowledge of testing methodology and biomarker biology. To be successful, new safety biomarkers have to out-perform and/or complement existing tests to cover any gaps in safety monitoring. Some biomarkers that have obtained regulatory support, as well as exploratory biomarkers that are under active evaluation, are highlighted in this chapter. The test species influences test selection, most often because of sample volume limitations. Test selection for a mouse study must be carefully considered because an adult mouse has a blood volume of only approximately 2 mL, and collecting even half that volume cleanly is unlikely. However, it is usually possible to obtain enough blood from one mouse for standard hematology tests and a small subset of clinical chemistry tests that provides a broad screen of major organs and overall health status. Another option is to designate one subset of animals in each group for hematology tests and a second subset of animals for clinical chemistry tests. Coagulation tests are typically not performed in mouse studies, but if they are indicated by the test article and study objectives, coagulation test sample requirements necessitate inclusion of a subset of animals specifically for that purpose. Similar issues concerning sample volume and test selection can arise in a rat study, especially if interim clinical pathology intervals are desired. It may be necessary to limit the tests done at interim intervals or to perform terminal blood collections under anesthesia prior to sacrifice and necropsy. Blood volume limitations that affect test selection and frequency in monkey (nonhuman primate; refers to cynomolgus monkey unless otherwise stated) studies are due to the combination of their relatively small size, especially young females, and the use of each animal for other tests requiring blood. In addition to the obvious effect on test selection and frequency, these multiple blood collections can and do significantly affect the results of many clinical pathology tests. Dogs are much less affected by multiple blood collections because of their size and ease of handling. New biomarkers may still have limited availability of reagents and fully validated assays for some species. While commercial manufacturers are on a continual path to develop and release assays that are applicable to individual nonclinical species, testing laboratories should confirm species cross-reactivity and reagent conditions. Blood collection from mice for clinical pathology tests is usually a terminal procedure and can only be done at the time of sacrifice. While predose or baseline data are critical for interpretation of clinical pathology results in studies with larger species. First, data can be used to screen and remove animals with potential health concerns or outlier values that might complicate future data interpretation. Evidence of a potential health concern includes findings such as low hematocrit or albumin concentration and high absolute neutrophil count, fibrinogen concentration, or liver enzyme activity. Examples of outlier values that could complicate future data interpretation include a high cholesterol concentration in a study of a drug indicated for treating hypercholesterolemia or low absolute neutrophil count in a study of a chemotherapeutic agent. Because the number of animals used in a dog or monkey study is small and interanimal variability can be relatively large, especially for monkeys, baseline data provide essential perspectives 220 Toxicologic Pathology concerning apparent differences between control and treated animals after dosing. Many rangefinding studies in large animals have no control group, so each animal serves as its own control. The optimal number of predose or baseline intervals depends on a few factors, including species, number of animals in the study, and study duration. For monkey studies, two baseline collections, at least 5 days apart, are recommended. Not only do they provide more data for perspective concerning inter- and intra-animal variability and preexisting group differences, two collections also help animals become accustomed to the blood collection procedure, which serves to reduce variability caused by excitement or fear. For dog studies, two baseline collections are preferred, especially when relatively few animals are on study. However, if several animals are in each group and the study duration is relatively long. As a general rule, clinical pathology testing in a single-dose study is best done approximately 48 to 72 hours postdose. The objective is to allow enough time for important toxic effects to be manifested but not reverse. Testing 24 hours postdose is often too soon for many changes to occur or reach their peak after toxic injury. Serum liver enzyme activities, tests of kidney function, and peripheral blood cell counts typically are not clearly affected the day after a single significant toxic insult to the liver, kidneys, and bone marrow, respectively. Another reason to avoid an assessment only 24 hours postdose is variability caused by study-related procedures that occur on the day of dosing, such as multiple blood collections for toxicokinetics and handling for various procedures. The effects of these procedures, along with effects of transient test article­related events, such as vomiting, diarrhea, and anorexia, can result in variable data that are more difficult to interpret and that increase the likelihood of identifying transient changes. Conversely, early data collection is occasionally desirable for certain tests or study objectives. Peripheral blood effects of chemotherapeutic agents do not all occur simultaneously. In order to assess cell count nadirs and recovery of different blood cell types, it is necessary to collect blood for hematology tests on multiple days postdose. The need for an interim clinical pathology interval in a longer-duration rat study depends in large part on findings from previous studies with the test article. There may be no need to include an interim interval if prior studies provided relatively definitive answers at dose levels relevant to the longerduration study. Clinical pathology testing is not recommended for rodent toxicity studies longer than 52 weeks because of naturally occurring disease conditions that cause excessive variability in results (Weingand et al. Clinical pathology testing should be very limited in rodent carcinogenicity studies. The most current recommendation, based on a survey of many companies and clinical pathologists working in industry, is limited to preparation of blood smears from all sacrificed animals (scheduled or unscheduled). Blood smears are then available for examination if necessary as an adjunct for confirmation of potential hematopoietic neoplasia (Young et al. For example, if dosing occurs once weekly for 13 weeks, interim and terminal clinical pathology samples might be taken either 1 day or 3 days after the 6th and 13th doses as long as the interval between dosing and sample collection is the same. Similarly, if dosing occurs for Principles of Clinical Pathology 221 5 consecutive days once each month for 3 months, samples might be taken 1, 3, or 5 days after the first and last dosing cycle as long as the interval is the same. Timing and frequency of clinical pathology sample collection during a recovery phase depend on study needs. If the objective is to simply determine whether effects are reversible, collection at the end of the recovery phase should suffice. If the objective is to determine the speed of reversibility, then multiple recovery intervals would be necessary, and timing would depend on the nature of the test article. The recovery assessment should be performed from all animals (including those assigned to recover assessment) at the end of the dosing phase, which allows assessment of reversibility in individual animal. When permitted by blood volume, it should also be considered for rats, especially in studies of longer duration (1 month or more), where animals may grow enough to allow blood collection for clinical pathology testing from recovery cohort at the end of the dosing phase, as well as at the end of the recovery. It is usually not possible in mice because enough blood for routine clinical pathology testing is only obtained with terminal methods. Unlike traditional approach, the inclusion of recovery animals in nonclinical studies is becoming more strategic due to increasing awareness and focus on animal welfare and 3Rs (reduction, refinement, replacement). Recovery assessment can also be useful in certain other instances, such as when the ability of the organ to recover is uncertain based on the pathophysiologic assessment, for development programs that have unique concerns or a potential for delayed toxicity, or when recovery monitoring enhances the pharmacologic understanding of efficacy markers (Tomlinson et al. On the other hand, recovery evaluation for clinical pathology endpoints may have limited value when no test articlerelated alterations are identified at the end of the dosing phase. Although, timely evaluation of data may not be possible in some cases to make such determination result in default recovery assessment for clinical pathology. A similar approach for timing and frequency is applied for biomarker testing as described for standard clinical pathology. New biomarkers may have the advantage of improved sensitivity, early appearance, and a short half-life, which allows close monitoring of active injury and onset of resolution. The time points can usually be refined based on the evidence derived from pilot studies, which may rely on several factors including the pharmacologic drivers of toxicity, mechanism and time-course of toxicity, biomarker induction, regulation, and release mechanisms, biomarker halflife, and sensitivity of the assay. Many of the biomarkers that have been qualified through regulatory agencies have used a cross-sectional approach in small animals, using comparisons between vehicle group compared with test-article treated groups. For large animals, baseline measurements allow additional latitude in evaluating the performance of percent and absolute change from baseline for individuals, which may improve sensitivity when there is high inter-individual variability and low intra-individual variability.

Myasthenic symptoms recur on abrupt withdrawal of azathioprine despite a stable course blood pressure low bottom number zestoretic 17.5 mg order overnight delivery, even up to myasthenic crisis (Hohlfeld et al blood pressure medication for asthmatics 17.5 mg zestoretic free shipping. Several factors have been cited as possible explanations for these negative results arteria occipital order generic zestoretic from india, including the generally mild disease of the patients in the studies blood pressure juice cheap zestoretic 17.5 mg free shipping, the better-than-expected response to relatively low-dose daily prednisone helvetic nerds - blood pressure best 17.5 mg zestoretic, and the short duration of the studies (Sanders and Siddiqi, 2008). In general, side effects are relatively mild and most commonly consist of diarrhea, nausea, and abdominal pain. It also inhibits lymphokine production and interleukin release and leads to reduced function of effector T cells. Monitor blood pressure and serum creatinine monthly and adjust the dose to keep the creatinine below 150% of pretreatment values. Improvement begins within 2 to 3 months in most patients; maximum improvement requires 6 months or longer. So far, there are no results from well designed, controlled and randomized clinical trials. Increased potassium levels often occur and there are interactions with other drugs and food, particularly grapefruit juice. The cumulative dose and duration of therapy should be documented because of the increasing risk of infertility of both sexes after age 30 and late effects, including malignancies (about 1%, increasing in frequency with increasing dose and duration of therapy). It can be used as a reserve treatment in the way it is used in rheumatoid arthritis-a dose of 7. The goal of full or substantial remission is often obtained but few patients maintain improvement unless therapy is continued at effective doses indefinitely. Avoid abrupt withdrawal of immunosuppression, as it may lead to recurrent myasthenic symptoms, even myasthenic crisis (Hohlfeld et al. Anecdotal evidence suggests that some patients may not achieve previous levels of improvement after withdrawal and exacerbation. Opportunistic infections, lymphomas and other serious treatment-related morbidities may occur with increasing duration of immunosuppression. In addition to removing all tumor tissue, remove any residual normal thymus tissue via an extended complete thymectomy. Since most patients will require long-term immunosuppression, it is reasonable to begin treatment. However, the authors expressed uncertainty as to whether the observed improvement was due to thymectomy or explicable by differences in baseline characteristics. The response to thymectomy is unpredictable and impairment may continue for months or years after surgery, even in patients who do ultimately improve. The best responses are in young people, especially women, early in the disease, but improvement can occur even after many years of symptoms. The preferred surgical approach has traditionally been a transthoracic, sternal-splitting procedure that allows wide exploration of the anterior mediastinum. Transcervical and endoscopic approaches have less postoperative morbidity and shorter recovery times, but may not allow sufficient exposure for total thymic removal and are not recommended when there is a thymoma. Robotic video-assisted thorascopic thymectomy combines the advantages of minimally invasive techniques with added maneuverability and enhanced visualization, which reportedly permits an extended thymectomy similar to that using a transsternal approach. Without a prospective study comparing different techniques, the value of different surgical approaches remains unclear. The therapeutic goal is to return the patient to normal function as rapidly as possible while minimizing side effects of therapy. In the longterm management of patients treated with immunotherapies, the lowest effective dose should always be determined. Treatment of Associated Diseases and Medications to Avoid It is important to recognize the effect of concomitant diseases and their treatment on myasthenic symptoms. Thyroid disease requires vigorous treatment-both hypo- and hyperthyroidism adversely affect myasthenic weakness. Many antibiotics fall into this category, particularly aminoglycosides, fluoroquinolones and macrolides. Ophthalmic preparations of -blockers and aminoglycoside antibiotics may cause worsening of ocular symptoms. When using corticosteroids to treat concomitant illness, anticipate and explain the potential adverse and beneficial effects to the patient. Population-based studies have shown associations with Guillain­Barré syndrome, pemphigus, and dermatomyositis (Eaton et al. Vaccination against pneumococcus is a recommendation for at-risk patients before starting prednisone or other immunosuppressive drugs. The Centers for Disease Control and Prevention report that those taking less than 2 mg/kg per day of prednisone or every-other-day prednisone are not at risk. The tidal volume should exceed 5 cc/kg-this usually corresponds to a vital capacity of at least 1,000 cc. If the patient complains of fatigue or shortness of breath, defer extubation even if these values and blood gas measurements are normal. Prevention and aggressive treatment of medical complications offer the best opportunity to improve the outcome of myasthenic crisis. Avoid the use of neuromuscular blocking agents or use them sparingly- inhalation anesthetic agents alone usually provide adequate muscle relaxation. The required dose of depolarizing blocking agents may be greater than that needed in nonmyasthenic patients whereas low doses of nondepolarizng agents cause pronounced and long-lasting blockade that may require extended postoperative assisted respiration. SpecialSituations Myasthenic Crisis Myasthenic crisis is respiratory failure from myasthenic weakness. An identifiable precipitating event, such as infection, aspiration, surgery, or medication change, precedes most episodes of crisis. The safest approach is to admit the patient to an intensive care unit and observe closely for impending respiratory insufficiency. A volume-controlled respirator set to provide tidal volumes of 400 to 500 cc and automatic sighing every 10 to 15 minutes is preferred. Check the pressure of the tube cuff frequently and verify the tube position daily by chest radiographs. Use an oxygen-enriched atmosphere only when arterial blood oxygen values fall below 70 mm Hg. Humidify the inspired gas to at least 80% at 37°C to prevent drying of the tracheobronchial tree. Low-pressure, high-compliance endotracheal tubes may be tolerable for long periods and usually obviate the need for tracheostomy. Retrospective studies suggest that both are equally effective in disease stabilization (Murthy et al. This eliminates the possibility of cholinergic overdose and permits determination of disease severity. When respiratory strength improves, begin weaning from the respirator for 2 or 3 minutes at a time and increase as tolerated. The decision to initiate steroid therapy will depend upon the risk-benefit assessment, which is significantly different in patients considering treatment for purely cosmetic reasons vs. Start prednisone at an initial dose of 10­20 mg/day with gradual increases every 3­5 days until achieving a clinical response. There are no reported adverse effects on the immune system from removing the thymus even at this early age. The severity of symptoms in the newborn does not correlate with the severity of symptoms in the mother. Affected newborns are typically hypotonic and feed poorly during the first 3 days. Symptoms usually last less than 2 weeks but may persist for as long as 12 weeks, which correlates with the half-life of neonatal antibodies. It is not clear why some newborns develop weakness and others, with equally high antibody levels do not. D-Penicillamine-Induced Myasthenia Gravis D-Penicillamine is used in the treatment of rheumatoid arthritis, Wilson disease, and cystinuria. Rarely, patients treated with D-penicillamine for several months develop a myasthenic syndrome that resolves after stopping the drug. D-Penicillamineinduced myasthenia is usually mild and often restricted to the ocular muscles. Often, the diagnosis is unsuspected because severe arthritis may hide the weakness. It is likely that D-penicillamine stimulates or enhances an immunological reaction against the neuromuscular junction. The myasthenic response induced by D-penicillamine usually remits within a year after stopping the drug. First trimester worsening is more common in first pregnancies, whereas thirdtrimester worsening and postpartum exacerbations are more common in subsequent pregnancies. The clinical status at onset of pregnancy does not reliably predict the course during pregnancy. Magnesium sulfate has neuromuscular blocking effects and is not recommended to manage pre-eclampsia-barbiturates usually provide adequate treatment. In the second stage, voluntary muscles are at risk for easy fatigue and outlet forceps or vacuum extraction may be necessary. They are individually and collectively rare, but produce novel insights into the understanding of neuromuscular junction physiology. Symptoms are present at birth in most forms, but may go unrecognized until adolescence or adulthood, particularly when progression is gradual and clinical manifestations are mild. Autosomal recessive inheritance accounts for all genetic forms of myasthenia except for the slow-channel syndrome, which has autosomal dominant inheritance. Determination of the specific genetic or physiologic defect requires genetic studies or specialized morphological and electrophysiological studies on muscle tissue. Ophthalmoparesis and ptosis are present in most cases during infancy; mild facial paresis may be present as well. Some children develop generalized fatigue and weakness but limb weakness is usually mild compared to ophthalmoplegia. Skeletal deformities like high-arched palate, facial dysmorphism, arthrogryposis, and scoliosis are common. The symptoms are generalized weakness, ptosis, ophthalmoparesis, bulbar and limb weakness, underdevelopment of muscles and slowed pupillary responses to light. Skeletal deformities include lordosis or scoliosis that worsens with prolonged standing. Severe cases present in infancy or early childhood but mild cases may present in adulthood, as late as the seventh decade. Ptosis, ophthalmoparesis, dysarthria, dysphagia, proximal limb weakness and respiratory insufficiency also occur in some cases. Most commonly, an subunit mutation results in continued expression of the fetal subunit. Clinical manifestations include hypotonia, respiratory insufficiency, weakness of ocular and bulbar muscles and skeletal deformities. Electrodiagnostic findings are variable and depend on the severity and distribution of weakness. Generalized hypotonia, ptosis and feeding difficulties are present at birth, and the early course of the disease is punctuated by sudden episodes of severe bulbar and generalized weakness with life-threatening apnea triggered by infections or stress. Within weeks after birth, the child becomes stronger and ultimately breathes unassisted. However, episodes of life-threatening apnea occur repeatedly throughout infancy and childhood, even into adult life, and there may be a history of sudden infant death syndrome in siblings. The decrement may repair with brief exercise but becomes more marked with prolonged exercise or continuous repetitive stimulation at 3 Hz for 3­5 minutes (Stålberg et al. Jitter also becomes progressively worse during continuous nerve stimulation (Stålberg et al. Symptoms tend to lessen in adolescence and adulthood, when the disease resembles mild autoimmune myasthenia gravis or a congenital myopathy. Symptoms are usually present at birth and there is severe ptosis and ophthalmoplegia. Patients have a weak cry and poor feeding, severe acral weakness, and frequent respiratory crises. Treatment is primarily supportive with ventilator support, often from birth, and gastrostomy for feeding. Respiratory crises are common until about 7 years of age in the setting of stress, such as infections, and then become less frequent. Most patients report gradual onset of lower extremity weakness, sometimes with muscle tenderness. Dry mouth is a common symptom of autonomic dysfunction; other features are erectile dysfunction, postural hypotension, constipation, and dry eyes. Prolonged apnea and ventilator dependence may follow use of neuromuscular blocking agents for surgery (Anderson et al. Strength (and tendon reflexes) may facilitate briefly after exercise and then weaken with sustained activity but this is not a universal finding. Membrane leaflet shows active zones (arrows) and clusters of large intramembrane particles (arrowheads). In patients without cancer, treatment with immunosuppression produces improvement in many patients but most require substantial and continuing doses of immunosuppressive medications (Maddison et al. Weakness may improve after effective cancer therapy and some patients require no further treatment. Repeat the search for occult malignancy periodically, especially during the first 2 years after symptom onset.

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References

• Schechter MM. The superior vena cava syndrome. Am J Med Sci 1954;227(1):46-56.
• Izumi R, Shimizu K, Iyobe T, et al. Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology. 1994;20(2):295-301.
• Bar-Joseph G, Galvis AG: Perforation of the heart by central venous catheters in infants: Guidelines to diagnosis and management, J Pediatr Surg 18:284-287, 1983.
• Von Eiselberg A. Uber plastik bei ektropium des unterkeifers (progenie). Klin Wochenschr 1906;19:1505.
• Mustard CA, Mayer T. Case-control study of exposure to medication and the risk of injurious falls requiring hospitalization among nursing home residents. Am J Epidemiol 1997;145:738-45.