Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic hepatitis C is a common cause of viral liver disease in kidney transplant recipients. To assess the efficacy and the safety of therapy with interferon alpha (IFN alpha) in such a population we conducted a prospective study where 16 kidney transplant recipients with chronic hepatitis C received recombinant IFN alpha 3 million units three times weekly scheduled for 24 consecutive weeks. All the patients had stable renal function for at least 1 year (mean serum creatinine 125.4 +/- 41 mumol/l). Fifteen patients had a positive HCV viraemia at the beginning of the study. In 15 patients serum alanine aminotransferase (ALT) levels decreased rapidly and normalized (48 +/- 44 vs 98.5 +/- 46 IU/l; P = 0.0044). ALT remained in the normal range as long as IFN alpha was continued. Serum levels of gamma glutamyl transpeptidase decreased from 129.75 +/- 111.2 to 88 +/- 85 IU/l; P = 0.012). After discontinuation of IFN alpha therapy seven responders relapsed within 1-9 weeks. HCV viraemia assessed 1 month after the end of IFN alpha therapy remained positive in all the patients who scored positive at the beginning, i.e. 15. Side effects of IFN alpha (fatigue, anorexia, weight loss) were frequent leading to four patients dropping out of the study. The haematological tolerance was moderate. The major concern was the increase in serum creatinine (162.5 +/- 57.6 vs 125.4 +/- 41 mumol/l; P < 0.05). In fact only six patients experienced renal failure occurring 45-168 days after the beginning of IFN alpha. Kidney transplant biopsies showed oedema, scarce scattered interstitial inflammatory cellular infiltration and moderate mesangial hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preliminary results of treatment of chronic hepatitis C with recombinant interferon alpha in renal transplant patients. 852 7

A 60-year-old man complained of severe general fatigue on October 11, 1992. Pertinent laboratory findings were: aspantate aminotransferase (AST) 1920 IU, alanine aminotransferase (ALT) 2050 IU, and total bilirubin (T. Bil) 124 micromol/l (normal range, 0-17 micromol/l). Virological assay revealed that hepatitis B surface antigen (HBsAg), anti-hepatitis B e (HBe), anti-HBc, and immunoglobulin M (IgM) anti-HBc were positive, and anti-HBs, HBeAg, and anti-delta antibody were negative. A diagnosis of acute hepatitis due to hepatitis B virus was made. Despite a decrease in transaminase, jaundice worsened and prothrombin time was prolonged. On the 60th day of hospitalization, massive ascites developed, but the patient's consciousness was not impaired. Although, albumin and diuretics were given, the ascites further increased. Paracentesis of 2000 ml of ascitic fluid was performed twice a week. On the 120th day of hospitalization, the patient passed black stools and he exhibited renal failure 3 weeks later. Although severe jaundice persisted, he was still alert. On the 150th day of hospitalization, massive gastrointestinal bleeding occurred, due to hemorrhagic gastritis. Despite receiving intensive care, the patient died. Determination of the HBV DNA sequence revealed two point mutations in the pre-core region; these have not been reported elsewhere.
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PMID:Late onset hepatic failure due to hepatitis B virus with mutations in the pre-core region. 857 43

1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.
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PMID:The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. 868 Jul 15

1. This study investigates the effects of the non-selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid-base balance and survival in a rat model of endotoxic shock. 2. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.) resulted in increases in the serum levels of tumour necrosis factor-alpha (TNF-alpha, maximum 60 min after LPS), endothelin-1, (ET-1; maximum 120 min after LPS), and interferon-gamma (IFN-gamma, maximum 180 min after LPS). 3. Injection of LPS also resulted in a fall in blood pressure from 113 +/- 3 mmHg (time = 0) to 84 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg-1, i.v. bolus + 100 micrograms kg-1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia. 4. Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h-survival from 71% (control) to 30% and 13%, respectively. 5. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilation (fall in PaCO2). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS. 6. Thus, the non-selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS-rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET-1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.
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PMID:Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. 873 96

This paper reviews the toxicity profile of gemcitabine, a novel anticancer drug. Gemcitabine has been administered using two different treatment schedules: once weekly or twice weekly for 3 weeks followed by a week of rest (one cycle). It was well tolerated and alopecia was not a problem. Toxicity was greater in the twice-weekly schedule. Comparing the once-weekly with the twice-weekly schedule, WHO grade 3 or 4 thrombocytopenia was reported in 4.7 and 25.6% of patients, respectively. Other hematological toxicity was minimal. Transient WHO grade 3 or 4 elevations of ALT and AST occurred in 9.2 and 7.2% of patients, respectively, in the once-weekly schedule. For the twice-weekly schedule the corresponding percentages were 12.2 and 13.8%. Symptomatic toxicity was greater in patients who received twice-weekly gemcitabine. Nausea and vomiting was mild and generally well controlled without 5HT3 antagonists. However, there was a greater incidence of nausea and vomiting on the twice-weekly schedule. Flu-like symptoms were documented in 19.8% of patients receiving once-weekly and 63.3% of patients receiving twice-weekly gemcitabine. Peripheral edema, not related to cardiac, hepatic or renal failure, was seen more often in patients on twice-weekly treatment. As the efficacy of gemcitabine in non-small cell lung cancer was equivalent when using both regimens, the better tolerated and more easily administered once-weekly schedule is recommended.
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PMID:Gemcitabine: once-weekly schedule active and better tolerated than twice-weekly schedule. 879 11

1 Here we compared the effects of various inhibitors of the activity of protein tyrosine kinase on (i) the expression of the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) caused by endotoxin (lipopolysaccharide, LPS) in cultured macrophages, (ii) the induction of iNOS and cyclooxygenase 2 (COX-2) protein and activity in rats with endotoxaemia, and (iii) the circulatory failure and organ dysfunction caused by LPS in the anesthetized rat. 2 Activation of murine cultured macrophages with LPS (1 microgram ml-1) resulted, within 24 h, in a significant increase in nitrite (an indicator of the formation of NO) in the cell supernatant. This increase in nitrate was attenuated by the tyrphostins AG126, AG556, AG490 or AG1641 or by genistein in a dose-dependent fashion (IC50: approximately 15 microM). In contrast, tyrphostin A1 (an analogue of tyrphostin AG126) or daidzein (an analogue of genistein) had no effect on the rise in nitrite caused by LPS. 3 Administration of LPS (E. coli, 10 mg kg-1, i.v.) caused hypotension and a reduction of the pressor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with the tyrphostins AG126, AG490, AG556, AG1641 or A1 attenuated the circulatory failure caused by LPS. Although genistein attenuated the vascular hyporeactivity to NA, it did not affect the hypotension caused by LPS. Daidzein did not affect the circulatory failure caused by LPS. 4 Endotoxaemia for 360 min resulted in rises in the serum levels of (i) urea and creatinine (indicators of renal failure), (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and gamma-glutamyl transferase (gamma GT) (indicators of liver injury/dysfunction), lipase (an indicator of pancreatic injury) as well as lactate (an indicator of tissue hypoxia). None of the tyrosine kinase inhibitors tested had a significant effect on the rise i the serum levels of urea, but the tyrphostins AG126, AG556 or A1 significantly attenuated the rises in the serum level of creatinine caused by LPS. In addition, all tyrphostins and genistein attenuated the liver injury/failure, the pancreatic injury, the hypoglycaemia and the lactic acidosis caused by LPS. In contrast, daidzein did not reduce the organ injury/dysfunction or the lactic acidosis caused by LPS. 5 Injection of LPS resulted (within 90 min) in a substantial increase in the serum level of tumor necrosis factor alpha (TNF alpha), which was attenuated by pretreatment of LPS-rats with any of the tyrphostins used. Genistein, but not daidzein, also reduced the rise in the serum levels of TNF alpha caused by LPS. Endotoxaemia for 6 h also resulted in a substantial increase in the expression of iNOS and COX-2 protein and activity in the lung, which was attenuated by pretreatment of LPS-rats with the tyrphostins AG126, AG556 or genistein, but not by daidzein. 6 Thus, tyrphostins (AG126, AG556, AG1641 or A1) and genistein, but not daidzein (inactive analogue of genistein), prevent the (i) circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury lactacidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock.
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PMID:Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: a possible role for protein tyrosine kinase. 929 29

Hepatitis C virus (HCV) infection is common in haemodialysis units, yet little information is available about the clinical feature of acute hepatitis C among renal failure patients. The present study is based on 49 cases of acute hepatitis C seen at a haemodialysis centre where sporadic nosocomial infection was occurring up to June 1993. Liver function tests were done at 4 weekly intervals on all dialysis patients, anti-HCV antibodies were tested by the C-100 and second generation tests and serum HCV-RNA was determined by the branched DNA and Amplicore tests. Diagnosis of acute hepatitis C was made on the basis of an acute rise in alanine aminotransferase (ALT) and seroconversion to positive anti-HCV antibodies. Clinical presentation of acute hepatitis was generally mild with rare overt jaundice and the diagnosis was possible only from increased ALT, which was generally low. Spontaneous resolution of acute hepatitis within 8 months with clearance of viral RNA occurred in only four cases, 91.8% of patients developing chronic hepatitis. Biopsy in 12 cases with high ALT levels showed mild to moderate inflammatory activities. In conclusion, the clinical presentation of acute hepatitis C is generally mild in chronic haemodialysis patients, but spontaneous resolution is infrequent. A longer follow-up period is required for defining the long-term prognosis.
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PMID:Acute hepatitis C among renal failure patients on chronic haemodialysis. 973 74

We report a 74-year-old woman with parkinsonism and dementia, who died 4 years after the onset of the disease. She was well until 70 years of the age (1993) when she noted slowness in the movement in her left hand. She also developed gait disturbance and the similar symptoms spread to the right upper and lower extremities. Two years after the onset, she had difficulty in walk, and was admitted to our hospital on March 9, 1995. Her daughter had the onset of hand tremor at 50 years of the age and gait disturbance at 52. Her gait improved after levodopa treatment, but her MRI revealed a liner T2-high signal lesion along the outer surface of each putamen. On admission, the patient was alert but slighted demented. Higher cerebral functions were normal. She had a masked face and small voice. Her gait was of small step without arm swing. Retropulsion was present. Rigidity was noted in the neck but not in the limbs. She was bradykinetic but tremor was absent. She was treated with levodopa/carbidopa, dops, and bromocriptine with considerable improvement and was discharged on March 30, 1995. On January 19, 1996, she developed fever and hallucination; she became more akinetic and admitted again. She showed marked dementia and stage IV parkinsonism. She was treated by supportive measures with improvement in the general condition, but she was found to have a gastric cancer for which a subtotal gastrectomy was performed on March 11, 1996. Post-operative course was uneventful, but her parkinsonism progressed to stage V. She was transferred to another hospital on May 13, 1996. In July 21, 1996, she developed dyspnea and fever and was admitted to our hospital again. She was somnolent. Rigidity was moderate to marked and she was unable to stand or walk. By supportive cares, her general condition improved and was discharged to home on November 4, 1996. She developed fever on June 13, 1997 and admitted to our service again. Her BP was 150/90 mmHg. She was alert but markedly demented. Laboratory examination revealed increases in liver enzymes (GOT 75 IU/l, GPT 101 IU/l) and renal dysfunction (BUN 68 mg/dl, creatinine 3.27 mg/dl). Subsequent hospital course was complicated by renal failure and thrombocytopenia (33,000/ml). She expired on July 1, 1997. The patient was discussed in a neurologic CPC, and a chief discussant arrived at the conclusion that the patient had diffuse Lewy body disease and her daughter striatonigral degeneration. Some participants thought both the patient and her daughter had diffuse Lewy body disease. Post-mortem examination revealed marked degeneration of the substania nigra and the locus coeruleus. The medial part of the nigra also showed marked cell loss. Lewy bodies were found in the remaining nigral and coeruleus neurons. Cortical Lewy bodies were very few and the striatum was intact. Pathologic diagnosis was Parkinson's disease. Dementia was in part attributed to the marked degeneration of the medial part of the substantia nigra.
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PMID:[A 74-year-old woman with parkinsonism and dementia who died four years after the onset]. 973 28

Rhabdomyolysis is a condition affecting body homeostasis that results from impaired supply of muscles with energy, nutritional factors and blood. Complex pathophysiological mechanism causes that extended myolysis may complicate different clinical conditions, such as: crush syndrome, excessive physical effort (work, seizures), toxic effect of drugs and toxins, water-electrolyte disturbances, congenital enzymatic deficiencies etc. It seems that on the cellular level, essential role is played by excessively high intracytoplasmatic calcium level, which affects metabolic processes. So high calcium level is a consequence of muscular cell injury irrespective to its reason. It manifests clinically as muscular weakness, pal and oedema and laboratory tests reveal elevated CK, GOT, GPT, aldolase and LDH levels as well as dark brown urine colour. Demonstration of elevated serum myoglobin level or its presence in urine directly confirms development of rhabdomyolysis. In unfavorable conditions, rhabdomyolysis may result in acute renal failure. Appropriately early and adequate water supply and alkalization plays an essential role in prevention of impairment in renal function. In advanced phase of renal failure, hemodialysis is a standard treatment.
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PMID:[Rhabdomyolysis: clinical features, causes, complications and treatment]. 974 Nov 96

Kidney failure is a contraindication to interferon therapy, and active chronic hepatitis is incompatible with kidney transplantation. Our study was aimed at investigating the activity and tolerability of leukocyte interferon-alpha in patients undergoing pre-transplant dialysis and suffering from chronic active hepatitis due to Hepatitis C virus infection. Ten patients, with persistently high ALT levels, were treated with leukocyte interferon-alpha, at a dose of 1 MU three times weekly for one year. Viraemia, ALT levels and other blood and urine tests, hepatitis stage and drug tolerance were all monitored throughout the study and the six-month follow-up period. After six months of treatment, two patients had continuing normalisation of ALT, negative HCV-RNA tests and normalisation of histological features ('long-term responders'). Four patients relapsed; three did not respond to treatment; and one patient discontinued it because of intolerance. The four relapsing patients received a second cycle with the same interferon, at a dose of 3 MU three times weekly, with attainment, in one patient, of complete remittance after six months of follow-up. Leukocyte interferon-alpha yielded an overall 30% therapeutic response in dialysed patients with chronic hepatitis C. Its use is helpful in enabling dialysed patients to undergo transplantation.
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PMID:Low-dose leukocyte interferon-alpha therapy in dialysed patients with chronic hepatitis C. 978 79


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