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)

We performed two courses of interferon-beta (IFN-beta) to a child with chronic hepatitis C. A complete response was not obtained by the first interferon treatment, however, the results of the second treatment differed from those of the first. Hepatitis C virus (HCV)-RNA remained negative and both aspartate aminotransferase and alanine aminotransferase levels remained normal after completion of the second course. From these results we estimated that HCV-RNA levels before IFN therapy could be significantly associated with the efficacy of this treatment. The serum level of HCV-RNA was 10(6) copies/50 microL before the first treatment, but was 10(3) copies/50 microL before the second course. We conclude that IFN therapy to children with hepatitis C should always be directed at providing a cure. Even if the clinical effects of the first course are minimal decreasing quantities of HCV-RNA still offer hope for cure by subsequent readministration.
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PMID:Relation between serum hepatitis C virus-RNA levels and efficacy of interferon-beta therapy. 757 60

In about 30% to 40% of patients with chronic hepatitis C, treatment with recombinant interferon alfa (r-IFN alpha) causes a decrease of serum aminotransferases and hepatitis C virus (HCV) RNA. The antiviral mechanism of interferon alfa (IFN alpha) in vivo is unknown. From serial measurements of serum HCV-RNA concentrations following IFN alpha induced perturbation of the balance between virus production and clearance, we obtained kinetic information on the pretreatment steady-state of HCV. In patients with chronic hepatitis C responding to IFN alpha, HCV-RNA declined exponentially with a half life of approximately 2 days. Modeling of the data predicts that in patients with chronic hepatitis C responding to IFN alpha this cytokine predominantly acts as an inhibitor of de novo infection of susceptible cells. HCV is released from infected cells with a mean half life of 2.7 +/- 1.3 days, whereas the clearance rate from serum is faster (mean half life, 0.7 +/- 0.4 days). The minimum virus production and clearance per day in patients with chronic hepatitis C was calculated to be 6.7 x 10(10) virions/d (range, 0.2 to 43.8 x 10(10) virions/d). These values showed no correlation with the HCV genotype, aminotransferase levels, or the histological activity as assessed before the administration of r-IFN alpha. Simultaneous kinetic analysis of serum aminotransferases as surrogate markers of hepatocyte integrity revealed half lifes for the release of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from hepatocytes of 4.7 +/- 3.8 and 3.0 +/- 3.5 days, respectively. The half life data for HCV in chronically infected patients are remarkably similar to recently published data on human immunodeficiency virus type 1 (HIV-1) suggesting that both RNA viruses replicate continuously and highly productive in vivo. The turnover rates explain the rapid generation of viral diversity and the opportunity for viral escape phenomena from the host immune surveillance.
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PMID:Effect of interferon alfa on the dynamics of hepatitis C virus turnover in vivo. 859 65

The comparative efficacy of prednisolone followed by interferon alfa (IFN-alpha) versus IFN-alpha alone in enhancing the rate of antibody to hepatitis B e antigen (anti-HBe) seroconversion has not been evaluated in a large cohort of white children. To determine this, a multicenter-controlled trial was conducted in 95 hepatitis B virus (HBV)-DNA/hepatitis B e antigen (HBeAg)-positive children (median age, 9 years [range, 2-16 years]; 56 boys; 84 [89 percent] white), all having inflammatory changes on liver biopsy. Patients were randomized to receive either prednisolone followed by IFN-alpha (n = 34); placebo followed by IFN-alpha (n = 30); or no treatment (n = 31). The prednisolone/placebo was given on a double-blind basis. Lymphoblastoid IFN-alpha was given at 5 MU/m(2) three times a week for 12 weeks. Baseline clinical, biochemical, and histological features were similar for the three groups. The majority (85 percent) had a baseline aspartate aminotransferase (AST) level < or = 100 IU/L. On follow-up between 12 and 18 months (median, 15 months) after treatment, the loss of HBeAg with anti-HBe seroconversion was more common in patients pretreated with steroids (12 of 34 [35 percent]) or placebo [12 of 30 (40 percent)] as against controls (4 of 31 [13 percent], P< .05). Factors predictive of anti-HBe seroconversion were baseline HBV-DNA concentration of < or = 1,000 pg/mL and a greater degree of portal tract inflammation on pretrial biopsy. Our results show that in white children treatment with IFN-alpha, at the dose and duration used in this study, improves the rate of anti-HBe seroconversion. Steroid priming does not potentiate the effect of IFN-alpha.
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PMID:Lymphoblastoid interferon alfa with or without steroid pretreatment in children with chronic hepatitis B: a multicenter controlled trial. 866 20

Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-alpha) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-alpha (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-treated patients (21%; P=.05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P=.43) or the ribavirin (P=.96) group. Posttreatment viremia levels were significantly reduced in IFN-alpha-treated (P=.05) but not in ribavirin-treated (P=.88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to < 10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P=.02 and P=.004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-alpha retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.
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PMID:A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. 958 98

Interferon alpha (IFN alpha) has been widely used as therapy for chronic hepatitis C. However, changes in glucose metabolism during IFN alpha therapy in patients with chronic hepatitis C remain unknown. To study the effects of IFN alpha on glucose tolerance in patients with chronic hepatitis C, we prospectively examined glucose tolerance in 15 patients with chronic hepatitis C before and four weeks after the start of IFN alpha therapy. Serum bilirubin, albumin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) improved after the therapy compared with before (p < 0.05, respectively), while levels of fasting blood sugar, blood sugar at 30 min in 75 g-oral glucose tolerance test (OGGT) and fasting immunoreactive insulin (IRI) decreased (p < 0.05, respectively); insulinogenic index (II) also increased (p < 0.05). Response patterns in 75 g OGGT before therapy were: four patients in normal pattern, five in a borderline pattern and four in a diabetic pattern, whereas those after therapy were changed to four in a normal pattern, and eight in a borderline pattern. Changes in AST between before and after therapy were correlated with those in blood glucose at 30 min in a 75 g-OGGT (r = +0.648, p = 0.042). Although interferons have been reported to impair glucose tolerance in viral infection, the results of the present study indicate that hepatic functional recovery may be associated with improved glucose tolerance in patients with chronic hepatitis C treated with IFN alpha.
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PMID:Changes in glucose tolerance after interferon-alpha therapy in patients with chronic hepatitis C. 960 92

To evaluate the safety, toxicity, and maximum tolerated dose (MTD) of IFN beta-1a (Rebif, Serono Laboratories, Inc.) in patients with malignant diseases unresponsive to standard therapies and to assess the pharmacodynamics and pharmacokinetics associated with IFN beta-1a administration, an open-label, single-center phase I study was designed. Thirty-four patients were enrolled and treated with IFN beta-1a. All had measurable solid neoplasms or evaluable hematological malignancies. All patients received a single i.v. bolus dose of IFN-beta-1a on day 1, followed 7 days later by daily s.c. injections for 28 consecutive days. Successive groups of three patients received increasingly higher doses (in geometric progression from 1.5 million international units (MIU)/m2 to 24 MIU/m2) until dose-limiting toxicities were noted. Pharmacokinetic and biological studies, including measurement of the activity of 2',5'-oligoadenylate synthetase (2',5'-OAS) in peripheral blood mononuclear cells and serum levels of soluble Tac (CD 25) and beta-2 microglobulin, were performed on patients who agreed to participate. i.v. and s.c. doses of IFN beta-1a up to 24 MIU/m2 were administered. The most frequent adverse events (AEs) were constitutional symptoms. Grade III AEs during i.v. dosing included fever, elevation of bilirubin, and infection unrelated to therapy. No grade IV events were seen. AEs noted during continuous s.c. therapy included fever, liver transaminase increase, albuminuria, fatigue, nausea, myalgia, and rigors. Dose-limiting toxicities were encountered during s.c. dosing at the 24-MIU/m2 and 18-MIU/m2 dose levels and included gastrointestinal toxicity, elevations of aspartate aminotransferase and alanine aminotransferase, and albuminuria. The s.c. MTD was determined to be 12 MIU/m2, although there was great variability in the individual patient's ability to tolerate IFN beta-1a. 2',5'-OAS activity, thought to be indicative of IFN activity, increased within hours after i.v. and s.c. dosing, with the level remaining persistently elevated during the s.c. daily injections. The highest peak level was attained in the 6-MIU/m2 group. There was no evidence that the increase in 2',5'-OAS activity decayed with repetitive dosing, nor was there evidence of accumulation in this pharmacodynamic marker. Serum beta-2-microglobulin levels showed a modest time- and dose-dependent increase after s.c. administration of IFN beta-1a, with the largest increase seen at the 24-MIU/m2 dose level. There were no clear dose-dependent responses noted in soluble Tac serum levels. IFN beta-1a was well-tolerated when administered by a single i.v. bolus injection at doses up to and including 24 MIU/m2. Daily s.c. injections for at least 28 days were well-tolerated at doses up to and including 12 MIU/m2, with some patients tolerating doses twice as high as this. The MTD for the i.v. route could not be clearly determined according to the guidelines of the protocol. However, i.v. bolus doses up to 24 MIU/m2 were relatively well-tolerated. For the s.c. route, the MTD was determined to be 12 MIU/m2, but there was great interpatient variability, with some patients able to tolerate higher doses.
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PMID:A phase I study of recombinant interferon-beta in patients with advanced malignant disease. 1063 30

To develop prognostic models for identifying children with hepatitis B who are likely to respond to interferon-alpha (IFN-alpha) or to spontaneously seroconvert, we evaluated results of a multinational controlled trial comprising 70 children with chronic hepatitis B who received IFN-alpha and 74 children who did not receive therapy. Prognostic models were developed using SMILES (similarity of least squares), which is a data analysis network that incorporates multidimensional relationships in the clinical data of complex diseases. Commonly collected clinical data included age, gender, serum aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus (HBV) DNA levels, and IFN-alpha dose. Additional data included pretreatment directional information (e.g. increases or decreases in serum aminotransferase and HBV DNA levels), liver biopsy results, race and transmission mode. Using data available prior to initiation of treatment, the SMILES models achieved prospective predictions of 89% for responders, 96% for non-responders, 100% for seroconverters and 93% for non-seroconverters. Although not predictive by themselves, the variables that had the greatest impact on predictions for IFN-alpha response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-alpha dose and gender. The variables that had the greatest impact on predictions for spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA level, age and AST pretreatment direction. Therefore, these models may be useful in determining, in children with hepatitis B, the likelihood of response to IFN-alpha and spontaneous seroconversion.
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PMID:Statistical models for predicting response to interferon-alpha and spontaneous seroconversion in children with chronic hepatitis B. 1076 45

Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic syndromes. The principal types of renal disorders associated with chronic HCV infection are cryoglobulinemia or noncryoglobulinemic membranoproliferative glomerulonephritis (MPGN). Interferon-alpha (IFN-alpha) may precipitate or exacerbate the occurrence of MPGN. Our patient was a 32-year-old man who tested positive for HCV in July 1997. The patient was treated with IFN-alpha in another medical center for 6 months because his liver biopsy showed chronic active hepatitis. In December 1998, he applied to our clinic for a follow-up examination. The level of aspartate aminotransferase (AST) was 44 U/L, and that of alanine aminotransferase (ALT) was 69 U/L. HCV RNA was positive in serum, and chronic HCV infection was detected by liver biopsy. IFN-alpha therapy (5 million U/day) was administered for 6 months longer. In May 1999, the patient came to our polyclinic with edema of the feet and legs. We detected proteinuria, serum cholesterol of 269 mg/dl, AST of 50 U/L, ALT of 41 U/L, serum total protein of 3.4 g/dl, serum albumin of 1.2 g/dl, positive cryoglobulin, and urine protein of 9.84 g/day. Cryoglobulinemic MPGN was suspected and kidney biopsy was performed, resulting in a diagnosis of minimal change disease (MCD).
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PMID:Minimal change disease in a patient receiving IFN-alpha therapy for chronic hepatitis C virus infection. 1263 99

Fumonisin (FB1), a mycotoxin, is produced by Fusarium moniliforme and F. proliferatum. A prevalence survey in Taiwan by our laboratory showed that there was a contamination rate of 40% in domestic animal feeds, and the average contaminated level was 4.5 mg/kg. Ninety-six birds were allotted into four treatments fed with diets containing 0 (control), 5, 10, or 15 mg/kg of FB1 for three weeks. The results showed that the growth performance was not influenced by the FB1 challenge, but relative bursa weight was significantly decreased. The activity of serum aspartate aminotransferase, and the serum levels of albumin and cholesterol were significantly elevated by the FB1 challenges. When broilers were stimulated with injection of lipopolysaccharides, mRNA abundance (determined by semi-quantitative RT-PCR) interleukin-1beta (IL-1beta), IL-2, interferon-alpha (IFN-alpha), IFN-gamma, and inducible nitric oxide synthase (iNOS) reached a plateau at 3 h, and declined at 6 h. A FB1 challenge for three weeks increased cytokine mRNA abundance in broilers. The results also showed that 15 mg FB1 per kg feed significantly inhibited the expression of IL-1beta, IL-2, IFN-alpha, IFN-gamma, but had no effect on iNOS. The macrophage functional profile was significantly changed under an exposure of 15 mg FB1 per kg for three weeks. Taken together, our results suggest that FB1 up to 15 mg/kg does not affect growth performance, but impairs some parameters of blood biochemistry and the immunocompetence in broilers.
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PMID:Effect of fumonisins on macrophage immune functions and gene expression of cytokines in broilers. 1692 24

Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c(+) cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.
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PMID:Fiber-modified adenovirus vectors decrease liver toxicity through reduced IL-6 production. 1723 26


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