Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
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The pathophysiology, symptoms and treatment of paraquat intoxication, primarily from oral ingestion, and the pharmacology and pharmacokinetics of paraquat are reviewed. Toxicity has occurred after topical application, oral ingestion or inhalation of paraquat. Systemic toxicity has not been reported from smoking of paraquat-contaminated marijuana but heavy abusers of contaminated marijuana may experience coughing, hemoptysis and mouth irritation. Following ingestion of 30 mg/kg or 50 ml of a 21% (w/w) solution of paraquat (as the base), hepatic, cardiac or renal failure or death may occur. Smaller doses (greater than or equal to 4 mg/kg of paraquat base) may cause respiratory distress, renal dysfunction or, occasionally, jaundice or adrenal cortical necrosis. When paraquat ingestion is suspected, the drug should be removed immediately from the gastrointestinal tract by gastric lavage or by whole-gut irrigation. Adsorbents such as Fuller's earth, bentonite or activated charcoal may be used during gastric lavage. Combined use of forced diuresis (with furosemide, mannitol and i.v. dextrose in water or normal saline), hemodialysis or hemoperfusion is recommended until the compound cannot be detected in body fluids or the dialysate. Immediate and effective treatment is necessary to prevent systemic toxicity or death from paraquat intoxication.
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PMID:Paraquat poisoning: a review. 36 Aug 33

Biliary excretion is an important route for the elimination of some drugs and drug metabolites in man. The factors which determine elimination via the biliary tract include characteristics of the drug such as chemical structure, polarity and molecular size as well as characteristics of the liver such as specific active transport sites within the liver cell membranes. A drug excreted in bile may be reabsorbed from the gastrointestinal tract or a drug conjugate may be hydrolysed by gut bacteria, liberating original drug which can be returned to the general circulation. Enterohepatic circulation may prolong the pharmacological effect of certain drugs and drug metabolites, but the quantitative importance of this in man appears to be less than in animals. Biliary elimination may play a role in the interindividual differences in drug response observed in healthy subjects and in patients with certain diseases. Cholestatic disease states, in which normal bile flow is reduced, will influence drug elimination by this route resulting in increased risk of drug toxicity. Bile may serve as an alternate route of elimination in renal failure, but this has not been determined in man. Lack of reliable information regarding the biliary excretion of drugs in man is partly due to the relative inaccessibility of the human biliary tract. Most studies of drug excretion in human bile have been performed in post-surgical patients with T-tube drainage. This method of bile collection is not ideal because bile flow and composition are often severely altered during the period of study, not all bile is collected and enterohepatic circulation is partially interrupted. Recent advances in the methods of collection of bile may improve future studies of drug excretion in human bile.
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PMID:Biliary excretion of drugs in man. 38 28

99Tcm-pyridoxylidene glutamate (99Tcm-PG) scans have been carried out in 24 jaundiced adults (mean total bilirubin 255 mumol/l and 11 infants with prolonged obstructive jaundice (mean total bilirubin 165 mumol/l). Absence of radioactivity in the gut was interpreted as complete biliary obstruction which was the cause of jaundice in ten adults and six infants. Using this criterion occlusion or patency of the bile ducts was correctly determined in 21 adults and eight infants. False-negative gut images were found in one adult and two infants, and three scans were inconclusive (two adults, one infant). The scan was unable to show details of the site of obstruction or pathology but the technique was simple and atraumatic and was safely performed in patients with serious complications, e.g. renal failure, coagulation defects, septicaemia. In infants the 99Tcm-PG scan compared well with the 131I rose bengal faecal excretion test and with liver biopsy in the investigation of prolonged obstructive jaundice. Repeat scans in infants with biliary atresia were used to assess postoperative bile drainage. It is suggested that 99Tcm-PG scanning is useful screening test in difficult cases of jaundice. It is especially useful in frail patients, and patients with complications.
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PMID:Hepatobiliary imaging: the use of 99Tcm-pyridoxylidene glutamate scanning in jaundiced adults and infants. 70 36

Disseminated intravascular coagulation (DIC) may cause multiple organ failure. Although DIC may cause capillary occlusion in any and all organs, the lungs, liver, kidneys, gut, heart and brain are particularly affected. Focal brain necrosis can also be caused by DIC. Fibrinolytic therapy will often restore significant blood flow to the capillaries of the lungs. This results in significant increase in lung function because the lung is more resistant to actual necrosis and will resume function once circulation is restored. Administration of fibrinolytic therapy will also prevent liver and kidney failure if started within four hours after trauma. This therapy, when given in low doses intravenously over a twenty-four hour period, has little effect on the coagulation mechanism, and abnormal bleeding, therefore, has not been a concern. It is speculated that if plasminogen activators are effective and safe for treating the intravascular clots of DIC, then perhaps they would be effective in treating other types of intravascular coagulation in the brain, such as various types and degrees of stroke.
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PMID:Organ damage in shock, disseminated intravascular coagulation, and stroke. 147 53

Mucormycosis is an opportunistic infection that has been mainly described in adults with preexisting disease affecting immune status, eg, diabetes, leukemia, lymphoma, and renal failure on peritoneal dialysis. Few cases have been described in neonates. The presentation of mucormycosis as a cause of neonatal necrotizing enterocolitis is an unusual phenomenon. Three fatal cases of mucormycosis of the gut in premature infants in the period 1990 to 1991 are described. It is not clear whether this should be considered a separate disease or a variant of necrotizing enterocolitis. All three patients died soon after laparotomy from septic shock and the histological diagnosis of mucormycosis was made too late for effective chemotherapy.
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PMID:Mucormycosis of the neonatal gut: a "new" disease or a variant of necrotizing enterocolitis? 150 Oct 34

Prevention of bone disease associated with impairment of the renal function is desirable. Attempts at such prevention inevitably also embrace prevention of the extraosseous consequences of autonomous hyperparathyroidism, such as the effects of hypercalcaemia, need for parathyroid surgery, and, perhaps, toxic effects of the parathyroid hormone. Strategies for prevention in early, moderate, and end-stage renal failure are reviewed and discussed with particular reference to dietary phosphorus restriction, use of gut phosphorus binders, control of acidosis, calcium supplementation, use of oral and intravenous calcitriol, and use of synthetic analogues of 1,25-dihydroxyvitamin D3. The onset of severe renal osteodystrophy can be delayed. Early attempts at prevention are logical, but we do not know whether these will reduce the need for parathyroid surgery or will make patients feel better or live longer. The costs of prophylaxis--both financial and in terms of incidence and severity of complications--remain to be defined. An individual approach to each patient with renal impairment seems at present appropriate.
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PMID:Prevention of renal osteodystrophy. 181 86

Antineutrophil cytoplasmic autoantibodies (ANCA) are specific for constituents of neutrophil primary granules and monocyte lysosomes. There are different types of ANCA with different specificities. By indirect immunofluorescence microscopy using alcohol-fixed neutrophils as substrate, two major categories of ANCA can be recognized, one with cytoplasmic staining (C-ANCA) and the other with artifactual perinuclear staining (P-ANCA). Some C-ANCA have specificity for proteinase 3 (PR3-ANCA) and some P-ANCA have specificity for myeloperoxidase (MPO-ANCA), but there are additional C-ANCA and P-ANCA specificities. ANCA are found in the blood of patients with necrotizing systemic vasculitis, such as Wegener's granulomatosis and polyarteritis nodosa, and patients with idiopathic crescentic glomerulonephritis. The glomerular lesion in patients with systemic and renal-limited ANCA-associated diseases is the same, ie, a pauci-immune necrotizing and crescentic glomerulonephritis. No matter where the vascular lesions of ANCA-associated disease are (eg, kidney, lung, gut, muscle, skin), they are characterized by necrotizing inflammation and a paucity of immune deposits. The distribution of disease correlates to a degree with the ANCA specificity, although there is substantial overlap. For example, patients with Wegener's granulomatosis most often have C-ANCA and patients with renal-limited disease most often have P-ANCA. In patients with P-ANCA-associated glomerulonephritis, approximately 90% of the P-ANCA have specificity for MPO. The clinical manifestations of ANCA-associated diseases often begin following a flu-like illness. The onset is most often in the winter and least often in the summer. The renal disease usually presents as rapidly progressive renal failure with nephritis. One of the most life-threatening components of the systemic involvement is pulmonary hemorrhage caused by a necrotizing alveolar capillaritis. Intravenous cyclophosphamide plus steroids is as effective as oral cyclophosphamide plus steroids for controlling ANCA-associated diseases. Using life-table analysis, the 2-year patient and renal survival rate in both patients with renal-limited and systemic disease is greater than 70%. There is evidence that in addition to being a useful serologic marker, ANCA are directly involved in the pathogenesis of the vascular injury in patients with ANCA-associated diseases. Although ANCA antigens are normally in the cytoplasm of neutrophils and monocytes, priming of these cells, as occurs following exposure to certain cytokines, results in the release of small amounts of ANCA antigens at the cell surface. In vitro, ANCA-IgG causes cytokine-primed neutrophils to undergo a respiratory burst and degranulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antineutrophil cytoplasmic autoantibodies and associated diseases: a review. 197 31

Quinidine, procainamide and disopyramide are antiarrhythmic drugs in the class 1A category. These drugs have a low toxic to therapeutic ratio, and their use is associated with a number of serious adverse effects during long term therapy and life-threatening sequelae following acute overdose. Class 1A agents inhibit the fast inward sodium current and decrease the maximum rate of rise and amplitude of the cardiac action potential. Prolonged Q-T interval and, to a lesser extent, QRS duration may be observed at therapeutic concentrations of quinidine. With increasing plasma concentrations, progressive depression of automaticity and conduction velocity occur. 'Quinidine syncope' (a transient loss of consciousness due to paroxysmal ventricular tachycardia, frequently of the torsade de pointes type) occurs with therapeutic dosing, often in the first few days of therapy. Extracardiac adverse effects of quinidine include potentially intolerable gastrointestinal effects and hypersensitivity reactions such as fever, rash, blood dyscrasias and hepatitis. Procainamide produces electrophysiological changes that are similar to those of quinidine, although Q-T interval prolongation with the former is less pronounced at therapeutic concentrations. Hypersensitivity reactions including fever, rash and (more seriously) agranulocytosis are associated with procainamide, and a frequent adverse effect requiring cessation of therapy is the development of systemic lupus erythematosus. Of the 3 drugs, disopyramide has the most pronounced negative inotropic effects, which are especially significant in patients with pre-existing left ventricular dysfunction. As with quinidine, unexpected 'disopyramide syncope' at therapeutic concentrations has been described. Anticholinergic side effects are common with this drug and may require cessation of therapy. Disopyramide therapy may unpredictably induce severe hypoglycaemia. Severe intoxication with the class 1A agents may result from acute accidental or intentional overdose, or from accumulation of the drugs during long term therapy. Acute overdose can result in severe disturbances of cardiac conduction and hypotension, frequently accompanied by central nervous system toxicity. Decreased renal function can cause significant accumulation of procainamide and its active metabolite acecainide (N-acetyl-procainamide), resulting in severe intoxication. Mild to moderate renal dysfunction is less likely to lead to quinidine or disopyramide intoxication, unless renal failure is severe or concurrent hepatic dysfunction is present. Management of acute intoxication with class 1A drugs includes gut decontamination with provision of respiratory support and treatment of seizures as needed. Hypertonic sodium bicarbonate, by antagonising the inhibitory effect of quinidine on sodium conductance, may reverse many or all manifestations of cardiovascular toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and disopyramide. 228 95

Since most of the toxicity associated with class 1B antiarrhythmic drugs is dose-related, this review examines adverse effects seen in both therapeutic practice and accidental or premeditated overdose. Toxicity is very common with these agents and can be life-threatening. A high percentage of patients must discontinue therapy because of adverse effects. Mexiletine and tocainide are structural analogues of lignocaine (lidocaine) and toxicity is similar with all 3 drugs. With gradual intoxication (the most common form) central nervous system effects such as lightheadedness, dizziness, drowsiness and confusion are seen first. Seizures and respiratory arrest can occur. Cardiovascular toxicity is manifested by progressive heart block, reduced cardiac contraction, hypotension and asystole. Both mexiletine and tocainide may have proarrhythmic effects. Gastrointestinal toxicity is also common. Shock, hypotension, cardiac failure and beta-blocker therapy reduce lignocaine clearance and enhance the risk of intoxication during routine therapy. Both lignocaine and mexiletine elimination is impaired in severe liver disease while tocainide clearance is reduced in renal failure. Management of toxicity is largely supportive and symptomatic. Lignocaine infusion must be discontinued and decontamination of the gut in the case of oral preparations is recommended. Serious intoxication requires intensive care unit admission. Haemodialysis or haemoperfusion may be helpful in serious lignocaine and tocainide poisoning. In institutions where extracorporeal circulatory assistance is available, massive lignocaine poisoning has been successfully treated with this intervention. In the therapeutic setting serious toxicity can be prevented by close clinical surveillance and appropriate dose reduction in patients with reduced drug clearance. Because of the large interindividual variation in lignocaine pharmacokinetic parameters, therapeutic drug monitoring is recommended if results can be reported quickly. Mexiletine and tocainide have stereoselective metabolism and assays do not distinguish the more active isomers. Therapeutic drug monitoring is less useful in this situation.
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PMID:Poisoning due to class 1B antiarrhythmic drugs. Lignocaine, mexiletine and tocainide. 251 64

Bacterial infection is a serious and often fatal complication of patients with liver disease and can prove fatal either directly or by precipitation of gastrointestinal bleeding, renal failure, or hepatic encephalopathy. At greatest risk are patients with alcoholic cirrhosis or decompensated chronic liver disease, or cases of acute liver disease who progress to fulminant hepatic failure or subacute hepatic necrosis. Infection appears to be unusual in patients with primary biliary cirrhosis. The site and type of infection is unrelated to the aetiology of the liver disease. Bacteraemia, pneumonia, urinary tract infection and spontaneous bacterial peritonitis are most common but infective endocarditis and meningitis, especially with pneumococci, are easily overlooked. Clinical suspicion of infection must be high as the only indication may be a general deterioration in the patients' clinical state, increasing encephalopathy or renal impairment. In the case of patients with fulminant hepatic failure, infection may precipitate the initial or recurrent encephalopathy and contributes to death in 10% of fatal cases. Spontaneous bacterial peritonitis is now recognized to occur in the absence of clinical features of peritonitis. The PMN content of the ascitic fluid may provide the only indication of infection and is the most readily available screening test. The most common types of organism responsible for all types of infection are Gram-negative enteric and streptococci, especially pneumococci, while infection with anaerobes is rare. Risk factors for infection include decompensated alcoholic liver disease, fulminant hepatic failure, gastrointestinal bleeding, invasive practical procedures and impaired host defence mechanisms against infection. Of the host defence mechanisms, impaired function of the reticuloendothelial system, complement, and PMNs represent the most common and serious defects. Defects of humoral immunity are present in ascitic fluid from patients with cirrhosis and are probably a major reason for development of spontaneous bacterial peritonitis. Diuresis improves these functions and reduces the risk of peritonitis. Treatment of infections even with the appropriate antibiotic is still associated with a high mortality but the use of adjuvant gut sterilization is promising, particularly in cases infected with Gram-negative enteric organisms. Infusions of fresh frozen plasma, blood and cryoprecipitate improve some systemic host defences and may be beneficial in the treatment and reduction of risk of infection.
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PMID:Bacterial infections complicating liver disease. 265 49


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