Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.
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PMID:Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. 51 12

As a basis for establishing dosing guidelines in order to avoid side effects due to overdosage, the concentrations of total and free non-protein bound clofibrinic acid (CA) were determined before and after the administration of a single clofibrate dose (0, 2, 6, 12, 24, 48, 72, 96h) in patients with various degrees of impaired renal function and in a control group (n = 56). The clofibrate doses administered to the five groups were: group 0 = control group without renal impairment: 1,000 mg; group 1 = serum creatinine up to 354 mumol/l: 1,000 mg; group 2a = creatinine levels greater than 354 mumol/l up to levels requiring dialysis: 1,000 mg; group 2b = creatinine levels like 2a, but only 500 mg; group 3 = patients requiring dialysis: 500 mg. In addition, serum albumin, CK, GOT and GPT were controlled. Total CA was determined by gas chromatography, the unbound fraction by equilibrium dialysis. Increasing serum creatinine levels were correlated with a decrease of total CA but with a statistically significant increase in free CA concentrations. The levels of non-protein bound CA of groups 1 and 2a were significantly different from control group 0 (same dosing). In addition, a significantly negative correlation between free CA and serum albumin levels was demonstrated. Determination of free CA as a control parameter of clofibrate therapy in patients with impaired renal function allows clofibrate dosing to be closer related to the individual subject than the determination of total CA only.
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PMID:Serum levels of free non-protein bound clofibrinic acid after single dosing to patients with impaired renal function of various degrees--a multicenter study. 355 32

The overfed rat served as the animal model for examining the influence of obesity on the hepatotoxic and nephrotoxic potential of metabolically activated drugs, and acetaminophen served as the prototype drug. Weanling Sprague-Dawley rats were given a standard pellet diet or semisynthetic, energy-dense diet designed to produce obesity. After 24 weeks, when overfed rats outweighed controls by more than 50%, animals received 710 mg/kg of acetaminophen i.p., based on total body weight. Toxicity evaluation included biochemical signs of organ injury over the first 24 hr and histopathologic changes in tissue morphology at 48 hr. Both enzyme release (alanine aminotransferase into plasma, alkaline phosphatase into urine) and frank cellular necrosis in liver and kidney of obese rats greatly exceeded that in pellet-fed controls. Contributing to the potentiation of injury were higher peak plasma concentrations of acetaminophen in obese animals resulting from total body weight dosing. However, liver and kidney injury and mortality remained elevated when peak plasma concentrations were matched by fat-free mass dosing, indicating that increased toxicity also was related to obesity. Incomplete recovery of acetaminophen and metabolites from obese animals (45 vs. 71% in control rats) caused by a functional renal impairment made it impossible to determine the metabolic fate of acetaminophen in overfed animals from the analysis of urine collections. Drug products measured in urine were summed with amounts remaining in carcass at sacrifice, computed as terminal plasma concentrations times respective distribution volumes. These results showed obese rats to form more glucuronide and less sulfate conjugate than did pellet-fed controls, coinciding with clinical evidence for enhanced glucuronidation in obese humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Obesity as a risk factor in drug-induced organ injury: increased liver and kidney damage by acetaminophen in the obese overfed rat. 359 8

The kidney is probably the major site of production of the plasma enzyme glutathione peroxidase (GSHPx-P). For this study, GSHPx-P activity was determined in 40 healthy people, in 34 patients with differing degrees of renal impairment, and in hemodialysis patients from whom blood samples were withdrawn either before or after each session (18 patients) or throughout the dialysis session (27 patients). Hemodialysis patients were treated by means of different techniques (bicarbonate hemodialysis, hemodiafiltration, and acetate free biofiltration), and different membranes (cuprophane, polyacrylonitrite, and polymethylmethacrylate). The following results were obtained: 1) GSHPx-P activity was significantly decreased in renal impairment patients; 2) GSHPx-P activity negatively correlated with serum creatinine values in renal impairment patients (r = -0.55; p < 0.001); and 3) the enzyme activity slightly increased after the session in hemodialysis patients. The following conclusions can be drawn: GSHPx-P activity could be new index of renal function, because it was decreased in patients with renal failure; the decrease in GSHPx-P activity paralleled the severity of renal impairment, and was maximal in hemodialysis patients; GSHPx-P activity was slightly raised at the end of the hemodialysis session, concomitant with other enzyme activities (aspartate transaminase, alanine transaminase, and alkaline phosphatase) and total protein concentration. This seems to be attributable to the process of water loss rather than other hypothetical mechanisms, such as A) enzyme activation by either peroxide generation during blood-membrane contact, or by the removal of a hypothetical inhibitor; and B) de novo synthesis in the residual renal mass or in other sites of production.
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PMID:The plasma glutathione peroxidase enzyme in hemodialyzed subjects. 785 33

We studied the pharmacokinetics of a new cephem antibiotic, S-1108, in patients with impaired kidney functions. Serum and urinary levels of S-1006 were determined after oral administration of S-1108 at 150 mg to 9 patients with renal dysfunction. In patients with severe renal impairment, high serum levels were maintained over long periods of time. Urinary excretion rates of S-1006 were lower as degrees of kidney failure were severer. S-1108 was administered to treat 27 patients with respiratory tract infections, and its clinical efficacy and safety were evaluated. The clinical efficacies were good in 26 patients, but poor in 1, yielding an efficacy rate of 96.3%. As to adverse reactions; diarrhea was observed in one case. Laboratory tests revealed elevated GOT and GPT in 1, and elevated gamma-GTP in another. These abnormalities, however, were slight and no severe side effects were caused by the drug.
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PMID:[Clinical pharmacology and efficacy of S-1108]. 810 69

An eight-week old infant with alcohol embryopathy, weighing 3,700 g, was found to have abnormal liver functions (GPT 312 U/l, Quick value 25%) after surgical repair of a stenosis of the left ureter at its origin. The hospital notes indicated that the infant had been given a total of 1.6 g paracetamol over 60 hours for postoperative restlessness and pain. The serum paracetamol level was 60 mg/l 8 hours after the last dose of the drug. Blood exchange transfusion lowered the paracetamol level to 11 mg/l within 14 hours. After the exchange transfusion further signs of poisoning, namely renal impairment and a severe encephalopathy were noted, and Candida was demonstrated in urine, tracheal secretion and ascites. The renal and hepatic damage proved reversible under symptomatic treatment. But the child, now 1 year old, is severely retarded mentally and in its motor functions. These sequelae may be a residue of the paracetamol poisoning, complications of the clinical course or a combination of the two.
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PMID:[Paracetamol poisoning in infancy]. 851 7

With improvements in surgical techniques and management of postoperative complications, heart transplantation can now be performed with donors and recipients who were previously considered unsuitable. In this study, we report the results of heart transplantation with marginal donors and recipients in our hospital. From June 1993 through June 1998, we performed 79 heart transplantations. Marginal recipients were defined as those with high pulmonary vascular resistance (> 6 Wood units), severe renal impairment (serum creatinine > 2 mg/dL and creatinine clearance < 50 mL/min), or severe hepatic dysfunction (ALT and AST > 100 IU/L or serum bilirubin > 2.5 mg/dL). Marginal donors were those with any of the following conditions: old age (> 40 years), size mismatch (donor/recipient body weight ratio < 0.8), history of chronic alcohol use, previous cardiopulmonary resuscitation and hypotension, hepatitis B or C virus positivity, coronary artery disease, high-dose dopamine (> 10 micrograms.kg-1.min-1), or prolonged allograft ischemic time (> 4 hours). Of the 79 transplantations performed, 45 (58%) involved marginal recipients or donors. The 30-day mortality rate was 5%, and the 1-year and 5-year survival rates were 87% and 83%, respectively. The survival rates did not differ significantly between cases involving marginal donors or recipients and those involving nonmarginal donors and recipients. There were 27 marginal recipients (34%), only one of whom died during surgery. Five of six recipients with severe renal impairment needed short-term hemodialysis after transplantation. Recipients with high pulmonary vascular resistance had a higher incidence of early acute rejection (5/10 vs 22/69). Thirty-three (42%) of the patients received transplants from marginal donors, four of whom died during surgery; two died of acute vascular rejection, one of allograft failure caused by prolonged ischemic time, and one of bleeding secondary to preoperative sepsis and coagulopathy. These results show that heart transplantation may be performed in marginal recipients and donors, with acceptable operative mortality.
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PMID:Heart transplantation with marginal recipients and donors. 1057 34

Allopurinol is widely used and generally well-tolerated. However, when used in patients with renal insufficiency it may have life-threatening toxic effects known as allopurinol hypersensitivity syndrome (AHS). We previously found that allopurinol increased ear swelling and mortality in a DNFB-induced contact hypersensitivity mouse model. In the present study, we investigated the toxic effect of allopurinol on DNFB-sensitized mice in order to clarify the mechanism responsible for the lethal effect of allopurinol. Allopurinol increased plasma GPT and GOT in DNFB-sensitized mice and markedly increased plasma creatinine and BUN. The increase in plasma GPT and GOT was moderate and declined time-dependently. In contrast, the increase in plasma creatinine and BUN was striking and continued until 18 hr after administration of allopurinol at 100 mg/kg/day. Although allopurinol increased GOT and GPT in DNFB-sensitized mice, no effect was observed in non-sensitized mice even at 100 mg/kg/day, indicating that allopurinol essentially has no toxic effect on the liver. A high dose of allopurinol induced renal impairment even in non-sensitized mice. These observations indicate that there is some biological interaction between allopurinol and DNFB, and suggest that allopurinol may modulate or enhance the inflammatory reactions induced by DNFB, and/or that DNFB may cause metabolic changes via inflammation, leading to the enhanced toxicity of allopurinol. In contrast, TEI-6720, a newly synthesized XOD/XDH inhibitor, had almost no effect on DNFB-sensitized mice. TEI-6720 at 1 mg/kg, in terms of hypouricemic effect, appeared to be more potent than allopurinol at 3 mg/kg. Therefore, the nephrotoxic effect of allopurinol observed in the present study may not be related to XOD/XDH inhibitory activity.
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PMID:Nephrotoxic effects of allopurinol in dinitrofluorobenzene-sensitized mice: comparative studies on TEI-6720. 1074 80

In a study of the influence of malaria-associated renal impairment on plasma concentrations of bilirubin, 111 Indian cases of Plasmodium falciparum malaria who had >34.2 microM total bilirubin/litre plasma were investigated. As the aim was to exclude those cases who had concomitant hepatic or (non-malarial) renal dysfunction, 19 cases who had serum concentrations of alanine aminotransferase (ALT) or alkaline phosphatase (AP) that were at least double the normal mean values were withdrawn. Of the remaining 92 patients, 47 showed evidence of renal impairment, the other 45 having plasma concentrations of creatinine that were <177 microM/litre. Plasma concentrations of the liver enzymes ALT and AP were similar for those with and without renal impairment. The plasma concentration of conjugated bilirubin (P<0.02), that of total bilirubin (P<0.05) and the ratio between the two (P<0.01) were, however, all significantly higher in the 47 patients with renal impairment than in the 45 with apparently normal renal function. The plasma concentration of creatinine was found to be not only positively correlated with the plasma concentrations of total (r=0.34; P<0.01) and conjugated (r=0.41; P<0.001) bilirubin but also negatively correlated with the urinary excretion rate for conjugated bilirubin (r=-0.34; P<0.001). The malaria-associated mortality was significantly higher among the patients with renal impairment than among those with apparently normal renal function, with 12 and three deaths, respectively (P<0.001). With increasing renal impairment there therefore appears to be a fall in the renal excretion of conjugated bilirubin. This leads to a disproportionate rise in the plasma concentration of conjugated bilirubin and this, since bilirubin can be toxic to renal tissue, may further worsen the renal impairment.
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PMID:Influence of renal impairment on plasma concentrations of conjugated bilirubin in cases of Plasmodium falciparum malaria. 1451 56

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.
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PMID:Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus. 1526 63


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