Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the effects of acute pancreatitis on hepatic function and hepatic cellular and subcellular organellar fragility, we studied 1) the hepatic secretion of lysosomal enzymes (beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-glucosaminidase) into bile in the isolated perfused rat liver model; 2) the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and lysosomal enzyme levels in the effluent in an isolated liver model; 3) hepatic lysosomal fragility in an in vitro incubation study; and 4) protective effects of a new low molecular weight synthetic protease inhibitor, ONO 3307, against hepatic injury in doses of 2 and 5 mg/kg.h in acute pancreatitis induced by a supramaximal dose of cerulein in rats. Decreased hepatic secretion of lysosomal enzymes into bile and accelerated hepatic lysosomal fragility were observed in acute pancreatitis induced by cerulein. ONO 3307 showed a significant protective effect against this hepatic injury in acute pancreatitis, the dose of 5 mg/kg.h showing a more potent effect than the dose of 2 mg/kg.h. These results suggest that the impaired hepatic function, including depressed hepatic secretion of lysosomal enzymes, seems to be closely related to accelerated hepatic fragility and that some unknown protease, which is present in pancreatitis and is susceptible to inhibition by ONO 3307, plays a crucial pathologic role in the development of this liver injury during acute pancreatitis.
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PMID:Effects of acute pancreatitis on hepatic secretion of lysosomal enzymes into bile and hepatic lysosomal fragility: protective effects of a new synthetic protease inhibitor, ONO 3307. 150 86

It was shown in Wistar male rats that the development of tourniquet shock was followed by an increase of proteolytic activity in the blood by 3 times, activity of aspartate aminotransferase (AST) by 3 times, that of alanine aminotransferase (ALT) by 6 times, contents of urea and residual nitrogen by 2.5-3 times; level of alpha 1-protease inhibitor (alpha 1-PI) decreased by 4 times and that of alpha 2-macroglobulin (alpha 2MG) by 2.5 times. At administration of contrykal (10,000 U/kg) proteolytic activity increased only by 32.5%, content of alpha 1-PI decreased only by 10-20% and level of alpha 2-MG did not differ from that in healthy animals. Activity of AST and ALT remained high, and contents of urea and residual nitrogen were near-normal.
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PMID:[Effect of kontrikal on the dynamics of proteolytic system indices in postischemic toxemia]. 243 73

Glutamate is believed to be an excitatory amino acid neurotransmitter in the retina. Enzymes for glutamate metabolism, such as glutamate dehydrogenase, ornithine aminotransferase, glutaminase, and aspartate aminotransferase (AAT), exist mainly in the mitochondria. The abnormal increase of intracellular calcium ions in ischemic retinal cells may cause an influx of calcium ions into the mitochondria, subsequently affecting various mitochondrial enzyme activities through the activity of mitochondrial calpain. As AAT has the highest level of activity among enzymes involved in glutamate metabolism, we investigated the change of AAT activity in ischemic and hypoxic rat retinas and the protection against such activity by calpain inhibitors. We used normal RCS (rdy+/rdy+) rats. For the in vivo studies, we clamped the optic nerve of anesthetized rats to induce ischemia. In the in vitro studies, the eye cups were incubated with Locke's solution saturated with 95% N2/5% CO2. The activity of cytosolic AAT (cAAT) was about 20% of total activity, whereas mitochondrial AAT (mAAT) was about 75% in rat retina. Ninety minutes of ischemia or hypoxia caused a 20% decrease in mAAT activity, whereas cAAT activity remained unchanged. To examine the contribution of intracellular calcium ions to the degradation of mAAT, we used Ca2+-free Locke's solution containing 1 mM EGTA, ryanodine (Ca2+ channel blocker), and thapsigargin (Ca2+-ATPase inhibitor). In the present study, thapsigargin in Ca2+-free Locke's solution, but not ryanodine in this solution, was found to prevent AAT degradation. AAT degradation was also prevented by calpain inhibitors (Ca2+-dependent protease inhibitor) such as calpeptin at 1 nM, 10 nM, 0.1 microM, 1 microM and 10 microM, and by calpain inhibitor peptide, but not by other protease inhibitors (10 microM leupeptin, pepstatin, chymostatin). Additionally, we determined the subcellular localization of calpain activity and examined the change of calpain activity in ischemic rat retinas. Our results suggest that decreased activity of mAAT in ischemic and hypoxic rat retinas might be evoked by the degradation by calpain-catalyzed proteolysis in mitochondria.
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PMID:Possible mechanism for the decrease of mitochondrial aspartate aminotransferase activity in ischemic and hypoxic rat retinas. 1039 49

The relationship between ritonavir plasma concentration, efficacy, and tolerance was evaluated in 31 children with advanced HIV infection who were receiving a triple therapy with ritonavir as protease inhibitor. Median CD4+ lymphocyte count and median viral load before the initiation of ritonavir-containing combination therapy were 1320 cells/mL and 5 log10 copies/mL, respectively. Ritonavir was given at a dose ranging from 300 to 450 mg/m2 twice daily. The median follow-up of triple therapy was 19 months. Response was defined as a drop of viremia of more than 1 log. Plasma drug levels were determined twice during the observation period: after at least 4 weeks and after 3 months of combined treatment. Samples were collected before (residual) and 2 hours (T2) after drug intake. Cholesterol, triglycerides, alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase were assessed at the same time. The median values of ritonavir residual and T2 levels were 1.64 mg/L and 5.9 mg/L at observation 1 and 3.35 mg/L and 6.29 mg/L at observation 2, respectively. According to virologic response, median residual concentrations of ritonavir were 3.17, 2.52, and 1.04 mg/L for the complete, the partial, and the no-response groups. The authors observed a wide intersubject variability of ritonavir concentrations with an increase in residual levels between the two observation periods. Residual levels were correlated with virologic response whereas there was no direct association between T2 levels and long-term response. Patients with complete or partial response displayed statistically significantly higher residual concentrations than the no-response group. No correlation could be demonstrated between elevated plasma drug concentrations and abnormal cholesterol or triglycerides values. These results emphasize the importance of a sustained high ritonavir concentration to achieve optimal treatment efficacy. Furthermore, these results prove the clinical benefit of therapeutic drug monitoring and could potentially improve patient evaluation in terms of treatment efficacy, compliance, and viral resistance.
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PMID:Relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced HIV infection. 1094 79

S-Nitrosylated compounds (nitrosothiols; RS-NOs) function as nitric oxide (NO) reservoirs and preserve the antioxidant activities of NO. We found remarkable cytoprotection by an S-nitrosylated protease inhibitor from human plasma, S-nitroso-alpha(1)-protease inhibitor (S-NO-alpha(1)-PI) that possesses a completely nitrosylated SH group, in hepatic ischemia-reperfusion injuries in rats. Liver ischemia was induced in rats by occluding both the portal vein and hepatic artery for 30 min and was followed by reperfusion. S-NO-alpha(1)-PI and control compounds such as native alpha(1)-PI, an NO synthase (NOS) inhibitor, and standard RS-NOs were given via the portal vein just after reperfusion was initiated. Liver injury was evaluated by measuring the extracellular release of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). Infiltration of neutrophils and induction of apoptosis and heme oxygenase-1 (HO-1) in the liver were also examined. Maximal liver injury occurred at 3 h after reperfusion and then decreased gradually. Not only did S-NO-alpha(1)-PI treatment (0.1 micromol; 5.3 mg/rat) greatly reduce elevation of liver enzymes in plasma, as well as neutrophil accumulation and apoptotic change in liver, it also improved the impaired hepatic blood flow as assessed by laser Doppler flowmetry and potentiated the induction of HO-1 in the liver. Although native alpha(1)-PI moderately reduced liver injury, low molecular weight RS-NOs such as S-nitrosoglutathione and S-nitroso-N-acetyl penicillamine produced no obvious protective effect. An NOS inhibitor exacerbated the hepatic ischemia-reperfusion injuries. These results suggest that S-NO-alpha(1)-PI exerts a potent cytoprotective effect on ischemia-reperfusion liver injury by maintaining tissue blood flow, inducing HO-1, and suppressing neutrophil-induced liver damage and apoptosis.
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PMID:Protective effect of S-nitrosylated alpha(1)-protease inhibitor on hepatic ischemia-reperfusion injury. 1108 23

This study assessed the activity and tolerability of an HIV-protease inhibitor, saquinavir, alone or in combination with zidovudine. A total of 92 previously untreated HIV-infected patients with CD4 cell counts < 300 cells/mm3 participated in a parallel, randomized double-blind study. Patients were randomized to receive one of five treatments, each three times a day: 600 mg of saquinavir; 200 mg of zidovudine; 75, 200 or 600 mg of saquinavir in combination with 200 mg of zidovudine. The primary treatment period was 16 weeks, with monthly extensions in patients who did not show major disease progression or toxicity. The main measures of the efficacy of therapy used were changes in CD4 cell counts and in the concentration of HIV-1 RNA in the plasma (as determined by quantitative polymerase chain reaction). The 600 mg dose of saquinavir in combination with zidovudine induced a 1.6 log (after 4 weeks) and a 0.7 log (after 16 weeks) median reduction in plasma RNA concentration; this reduction was greater than those seen in the other four treatment groups. The combination of 600 mg of saquinavir with zidovudine also resulted in a larger and more sustained improvement in the CD4 cell count than either saquinavir or zidovudine monotherapy or the other combination therapies. In the group receiving 200 mg of saquinavir in combination with zidovudine, the maximal median change in CD4 cell count occurred at week 2 (85 cells/mm3), and by week 16 had fallen to 15 cells/mm3. In the group receiving 600 mg of saquinavir plus zidovudine, the median change in CD4 cell count remained high for the 16-week period (median change of 48 cells/mm3 at week 2 and 61 cells/mm3 at week 16). Saquinavir was safe and very well tolerated, either alone or in combination with zidovudine. The incidence of adverse events was greater in the four groups receiving zidovudine therapy, and all the most commonly reported adverse events have previously been associated with zidovudine therapy. Few changes in laboratory values occurred during the study, except for known zidovudine-associated toxicities. The most frequent abnormalities were raised aspartate aminotransferase and alanine aminotransferase levels, depressed calcium levels, and abnormally high or low phosphate levels. Despite the low oral bioavailability of saquinavir, combined virological and immunological data show definite antiviral activity in vivo for the combination of saquinavir at 600 mg plus zidovudine at 200 mg (each three times daily). The combination of drugs with different mechanisms of action represents an advance in the treatment of HIV infection.
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PMID:A randomized controlled trial of a protease inhibitor (saquinavir) in combination with zidovudine in previously untreated patients with advanced HIV infection. 1132 46

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.
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PMID:Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals. 1222 Sep 74

Risk factors associated with the occurrence of protease inhibitor (PI)-related severe and serious adverse drug reactions (SADRs) were analyzed in a prospective cohort of 1155 patients who initiated PI-containing therapy. During a total follow-up of 2037 patient-years, 169 SADRs were reported, yielding a rate of 8 incidents per 100 patient-years (95% confidence interval [CI], 6.8-8.6). The most frequent SADRs were elevated transaminase levels (in 49 events); renal colic (27); abnormal hematological findings (23); and metabolic (18), neuromuscular (7), pancreatic (6), cutaneous (6), cardiovascular (5), and psychiatric disorders (5). Among baseline characteristics, plasma human immunodeficiency virus RNA levels of >or=5 log(10) copies/mL (hazard ratio [HR], 1.5; 95% CI, 1.1-2.2), elevated aspartate aminotransferase levels (HR, 1.1 for each 20 IU of elevation; 95% CI, 1.1-1.2), creatinine clearance levels of <70 mL/min (HR, 2.1; 95% CI, 1.2-3.7), test results positive for hepatitis C virus antibodies or hepatitis B surface antigenemia (HR, 2.6; 95% CI, 1.8-3.7), and receipt of indinavir (HR, 1.7; 95% CI, 1.2-2.4) were independently predictive of a SADR. SADRs were frequent in the first 4 months after initiation of highly active antiretroviral therapy but continued to occur after that time period.
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PMID:Incidence of and risk factors for adverse drug reactions in a prospective cohort of HIV-infected adults initiating protease inhibitor-containing therapy. 1530 35

The objective of this study was to find predictive factors of lopinavir/ritonavir (LPV/r) discontinuation for drug-related toxicities in highly pre-treated human immunodeficiency virus (HIV)-infected subjects. The study was an observational study of HIV patients starting LPV/r with HIV RNA > 3log10 copies/mL and a follow-up > or = 6 months. Parameters studied were HIV RNA, CD4+ cell counts, metabolic parameters and drug-related adverse events. Acquired immune deficiency syndrome (AIDS) events and deaths were recorded. The Kaplan-Meier (KM) model was used to estimate time-dependent probability, and the multivariable Cox model to identify predictors of LPV/r discontinuation for adverse events. The study evaluated 416 HIV-infected patients. Seventy-seven patients (18.5%) discontinued LPV/r for toxicities. Adverse events leading to LPV/r discontinuation were gastrointestinal symptoms in 40 cases, hyperlipidaemia in 27 and increase of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in 10 patients. Nineteen patients (4.6%) developed an AIDS event during observation and 15 (3.6%) died. The KM probability of LPV/r discontinuation for toxicities was 5.3% (range 3.1-7.5%) at month 12 and 15.7% (range 12.1-19.3%) at month 24. Subjects with hepatitis C virus (HCV)-HIV co-infection (odds ratio (OR) 7.40; 95% confidence interval (CI) 3.73-14.66 versus HCV-negative; P = 0.001) and receiving LPV/r plus nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor (PI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) (OR 1.74; 95% CI 1.04-2.91 versus LPV/r plus only NRTIs; P = 0.04) showed a higher risk of LPV/r discontinuation by a Cox analysis, whereas non-intravenous drug abusers (IVDUs) (OR 0.40; 95% CI 0.24-0.67 versus IVDUs; P = 0.001) had a lower risk. The rate of discontinuation for toxicity decreased by 17% for each additional month of LPV/r exposure (OR 0.83; 95% CI 0.80-0.86 for each additional month; P < 0.001). LPV/r was substantially well tolerated. Diarrhoea was the most frequent adverse event leading to discontinuation. HCV-HIV co-infected patients and patients with a short exposure to LPV/r have a higher risk of discontinuing LPV/r and should be strictly monitored.
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PMID:Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals. 1587 62

Tipranavir is a recently approved nonpeptidic protease inhibitor specifically developed for the management of human immunodeficiency virus (HIV) infection in treatment-experienced patients with protease inhibitor-resistant infection. It is active against a wide range of drug-resistant laboratory- and patient-derived isolates. Tipranavir requires pharmacokinetic boosting by ritonavir (200 mg) to achieve therapeutic levels with twice-daily dosing and must be administered with food for optimal absorption. It is a potent protease inhibitor with a unique drug-resistance profile that offers advantages in the management of cases of multidrug-resistant HIV infection. Tipranavir (in combination with ritonavir) is both an inhibitor and inducer of cytochrome p450, with significant potential for drug-drug interactions, and therefore, it must be used cautiously when administered to patients who are receiving other drugs. Evolution of drug resistance after treatment failure with tipranavir is complex and is not yet fully understood. There is limited overlap in the resistance mutations that predict response to tipranavir and another new protease inhibitor, darunavir, which is active against drug-resistant isolates. Tipranavir is associated with elevations in alanine aminotransferase and aspartate aminotransferase levels, as well as elevated cholesterol and triglyceride levels, and can cause the typical gastrointestinal adverse effects associated with all protease inhibitors.
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PMID:Tipranavir: a new option for the treatment of drug-resistant HIV infection. 1771 62


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