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)

The compound 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent inhibitor of a number of viruses in vitro such as human immunodeficiency virus types 1 and 2, herpes simplex virus types 1 and 2, hepatitis B virus, cytomegalovirus, and Epstein-Barr virus. PMEA also proved to be effective in vivo against feline immunodeficiency virus in cats and simian immunodeficiency virus in rhesus monkeys. In an open, non-placebo-controlled trial, the safety of weekly doses of PMEA in 10 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex was studied for a period of 11 weeks. CD4+ T-cell counts at baseline were between 10 and 450/mm(3). The drug was administered intravenously at a dose of 1000 mg. No serious side-effects were seen. On one occasion one patient showed alanine aminotransferase and aspartate aminotransferase levels 5 times higher than the upper limit of normal and another patient showed on one occasion aspartate aminotransferase levels 5 times higher than the upper limit of normal. In another patient serum amalyse levels increased, on one occasion 1.5 times above the upper limit of normal. An improvement in general well-being was reported by all patients. For patients with a CD4+ T-cell count > 100/mm(3) at baseline, the CD4+ T-cell count increased from a mean of 283/mm(3) at baseline to a mean of 448/mm(3) at the end of the study. Repeat infusions of PMEA at a dose of 1000 mg were safe and well tolerated. Our results suggest that PMEA, administrated according to this treatment schedule, may be effective in treating patients with human immunodeficiency virus infection.
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PMID:Safety of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in patients with human immunodeficiency virus infection: a pilot study. 886 29

The feasibility of noninvasive imaging of adenoviral-mediated herpes virus type one thymidine kinase (HSV1-tk) gene transfer and expression was assessed in a well-studied animal model of metastatic colon carcinoma of the liver. Tumors were produced in syngeneic BALB/c mice by intrahepatic injection of colon carcinoma cells (MCA-26). Seven days later, three different doses (3 x 10(8), 1 x 10(8), and 3 x 10(7) plaque-forming units (pfu) of the recombinant adenoviral vector ADV. Rous sarcoma virus (RSV)-tk bearing the HSV1-tk gene were administered by intratumoral injection in separate groups of mice. Two control groups of tumor-bearing mice received intratumoral injections of the control adenoviral vector dl-312 or buffer alone, respectively. T2-weighted magnetic resonance (MR) images of mice were obtained before administering the virus and provided an anatomical reference of hepatic tumor localization. Eighteen h after the virus injection, one group of animals was given i.v. injections of 300 microCi of no-carrier-added 5-[131I]-2'-fluoro-1-beta-D-arabinofuranosyluracil (FIAU) and imaged 24 h later with a gamma camera. In some animals, the tumors were sampled and processed for histology and quantitative autoradiography (QAR). The gamma camera images demonstrated highly specific localization of [131I]FIAU-derived radioactivity to the area of ADV.RSV-tk-injected tumors in the liver, which was confirmed by coregistering the gamma camera and T2-weighted MR images. There was no accumulation of [131I]FIAU-derived radioactivity in tumors that were injected with the control vector or injection solution alone. A more precise distribution of radioactivity in the area of transfected tumor was obtained by histological and QAR comparisons. A heterogeneous pattern of radioactivity distribution in transfected tumors was observed. A punctate pattern of radioactivity distribution was observed in peritumoral liver tissue in animals given injections of 3 x 10(8) and 1 x 10(8) pfu of ADV.RSV-tk but not in animals given injections of 3 x 10(7) pfu nor in control animals. A QAR-microscopic comparison showed that the punctate areas of radioactivity colocalized with cholangial ducts. The level of [131I]FIAU-derived radioactivity accumulation (HSV1-tk expression) in the transfected tumors was viral dose-dependent. The viral dose-dependency of radioactivity accumulation was more pronounced in peritumoral liver, which was confirmed by reverse transcription-PCR analysis. A separate group of tumor-bearing animals received different doses of ADV.RSV-tk vector followed by treatment with ganciclovir (GCV), 10 mg/kg i.p. b.i.d. for 6 days. The ADV.RSV-tk transfected tumors significantly regressed with GCV treatment; the control tumors continued to grow. During the GCV treatment, the levels of liver transaminases (ALT and AST) were significantly increased in animals that received injections of 3 x 10(8) and 1 x 10(8) pfu of ADV.RSV-tk but not in animals that received injections of 3 x 10(7) pfu and in control animals. The observed liver toxicity confirms the results of gamma camera and QAR imaging, which demonstrated an unwanted spread of ADV.RSV-tk vector and HSV1-tk expression in peritumoral and remote liver tissue at higher doses. These and our previous results indicate that noninvasive imaging of adenoviral-mediated HSV1-tk gene expression is feasible for monitoring cancer gene therapy in patients.
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PMID:Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo. 1053 96

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 - 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in approximately 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-alpha. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 - 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.
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PMID:Current pharmacotherapy for the treatment of chronic hepatitis B. 1452 91

Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an antiviral agent that suppresses hepatitis B virus (HBV) replication through inhibition of DNA polymerase and by chain termination. To determine the effectiveness of adefovir, three populations of patients with chronic hepatitis B patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg-negative patients, and patients with lamivudine-resistant tyrosine-methionine-asparate-aspartate (YMDD) mutants. All three groups of patients were treated for 48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and normalization of serum alanine aminotransferase (ALT) were noted. Significant improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in HBeAg-positive patients and in lamivudine-resistant patients. No major drug-related side effects were noted. Adefovir 10 mg/d orally is safe and effective for treatment of chronic hepatitis B.
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PMID:Treatment of patients with chronic hepatitis B with adefovir dipivoxil. 1519

Chronic hepatitis B infection continues to be a major public health concern worldwide. The natural history of the disease can be divided into 4 different phases: immune tolerance, immune clearance, inactive carrier, and reactivation. The goals of treatment are sustained viral suppression, normalization of ALT, and improvement in liver histology. Antiviral agents in current use include standard interferon-alpha, lamivudine, and adefovir. With an improved understanding of the natural history of the disease and a growing repertoire of antiviral drugs, the important questions are: who should receive treatment, what is the best agent to use, and what is the optimal duration of therapy? Treatment is indicated for patients in the immune clearance and reactivation phases. Patients with high pretreatment ALT level, detectable HBV DNA in the serum, and active inflammation on liver biopsy are predicted to have the highest chance of response to treatment. The choice of a particular agent must balance long-term benefits such as the likelihood of a sustained response against long-term risks such as drug resistance. Interferon treatment leads to a more durable response but is associated with unpleasant side effects. Lamivudine is effective and well tolerated but requires long-term therapy and is associated with drug resistance. Adefovir has proven efficacy and a very low rate of drug resistance but is associated with a small risk of reversible nephrotoxicity. For HBeAG-positive chronic hepatitis B and HBeAG-negative chronic hepatitis B, the duration of interferon therapy is 4-6 months and 12 months, respectively. Duration of treatment is at least 1 year with lamivudine and adefovir; longer duration of treatment is needed in most patients, but the optimal duration of treatment and the criteria for stopping treatment have not been established.
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PMID:Treatment of chronic hepatitis B: who to treat, what to use, and for how long? 1547 46

Adefovir dipivoxil, an acyclic nucleotide analogue, is effective for the treatment of chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and -negative patients, with improvement in liver histology, hepatitis B virus (HBV) DNA levels, alanine aminotransferase levels, and HBeAg seroconversion (for HBeAg-positive patients). It is also effective against lamivudine-resistant strains of hepatitis B mutations. It has been studied in pre- and post-liver transplant patients. Compared to lamivudine, adefovir dipivoxil is associated with a much lower risk of emergence of drug-resistant HBV. Adefovir-associated resistant virus is susceptible to lamivudine therapy. The recommended dose of adefovir dipivoxil 10 mg is associated with low risk of nephrotoxicity. Adefovir dipivoxil can be recommended as a first-line treatment but can also be used in patients with chronic hepatitis B infection who are failing lamivudine therapy.
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PMID:Adefovir dipivoxil in chronic hepatitis B infection. 1550 Mar 83

Adefovir is classified as a nucleotide reverse transcriptase inhibitor because it acts by inhibiting hepatitis B virus DNA polymerase (reverse transcriptase) and causing DNA chain termination after its incorporation into the viral DNA. Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine [ALT] or aspartate [AST]) or histologically active disease. It is useful in the treatment of patients with either hepatitis B e antigen-positive or -negative chronic hepatitis B. The recommended adefovir dipivoxil dose in the treatment of chronic hepatitis B in patients with adequate renal function is 10 mg once daily. Adefovir dipivoxil therapy can reduce viral load, improve ALT, and produce histologic improvement in patients with chronic hepatitis B. Improvements are generally seen within the first few weeks of therapy and have shown persistence up to at least 3 years with continued therapy. Therapy with adefovir dipivoxil is generally well tolerated. However, nephrotoxicity is a risk with adefovir therapy, especially in patients receiving higher doses (30-120 mg/d). Patients should have their renal function monitored closely throughout therapy and may require an adjustment in dose relative to changes in the creatinine clearance. Lactic acidosis and severe hepatomegaly with steatosis may also occur during therapy.
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PMID:Adefovir dipivoxil: focus on its use in the treatment of chronic hepatitis B. 1597 40

Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB) as safe oral therapy. FDA approved lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005. Lamivudine is effective in viral suppression, ALT normalization, and improvement in histology in both HBeAg positive and HBeAg negative / HBV DNA positive patients. HBeAg seroconversion rates correlate directly with pretreatment ALT levels at 18-30% after one year of therapy. Hepatitis flares may occur if lamivudine is stopped before HBeAg seroconversion. Lamivudine resistant YMDD mutants emerge at a rate of 15-20% per year of therapy; often associated with the rebound viraemia, relapse of hepatitis or even hepatic decompensation. Durability of response off lamivudine therapy is not satisfactory and may be dependent on duration of therapy post-seroconversion. Lamivudine is well tolerated with few serious adverse events, even in patients with decompensated cirrhosis. Long term therapy in viraemic patients with advanced fibrosis or cirrhosis delays clinical progression. Adefovir dipivoxil is an oral prodrug of adefovir. 10 mg daily is effective in suppressing both wild-type HBV and YMDD mutants, normalising ALT and improving histology. Adefovir dipivoxil has been shown to be well tolerated in longterm therapy. Renal toxicity reported in higher dosages is rarely seen except among patients with creatinine clearance less than 50 ml/min. Adefovir resistance may emerge and the overall rate is much lower than lamivudine, reaching 18% after 4 years of therapy. Adefovir-resistant mutants (rt N236T) are susceptible to lamivudine and entecavir. Little data is available for durability of response off therapy. Entecavir is an oral nucleoside analogue with a recommended dosage of 0.5 mg daily for nucleoside-naive patients, and 1 mg daily for lamivudine-refractory patients. It is a potent antiviral and may also reduced intrahepatitic cccDNA. Entecavir resistance so far has only been detected in lamivudine resistant patients in the one-year studies. Patient counseling is very important to decide on the choice among available therapeutic options. The assessment of the risks/benefits of each option should be carefully explained to individual patient.
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PMID:Chronic hepatitis B--treatment with nucleoside analogues. 1610 69

Adefovir dipivoxil (ADV), a new nucleotide analogue, has demonstrated activity against lamivudine-resistant HBV both in vivo and in vitro. Herein, we present eight lamivudine-resistant patients with chronic anti-HBe positive hepatitis B treated orally with adefovir dipivoxil at 10 mg/die to evaluate the efficacy and safety of this drug and to determine the possible development of clinical ADV resistance. After 48 weeks of therapy, 4/8 (50%) patients demonstrated a complete response with normalization of alaninoaminotransferase levels (ALT, normal value < 40 IU/L) and undetectable serum HBV- DNA (< 100 copies/ml tested by a PCR assay). In 3/8 subjects (37.5%), we observed a partial response with a > 50% reduction of both ALT and HBV DNA levels. Only one patient did not respond. Adefovir was well-tolerated and no patient presented adverse events related to treatment; there were no changes in renal parameters. We conclude that in patients with anti-HBe positive chronic hepatitis B resistant to lamivudine, a 48-week ADV treatment resulted in significant biochemical and virological improvement without major adverse effects.
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PMID:Clinical and virological response to adefovir dipovixil for lamivudine-resistant HBeAg-negative hepatitis B. 1624 Jun 90

The available evidence on interferon-alpha (IFN) treatment for chronic hepatitis B is sufficient to conclude that in patients with HBeAg positive chronic hepatitis, standard IFN therapy significantly improves clearance of HBeAg (number needed to treat [NNT] = 4), loss of HBV-DNA (NNT = 4) and clearance of HBsAg (NNT = 18). HBeAg positive patients with normal or slightly raised ALT should be treated only if there is histological evidence of progressive disease. In patients with HBeAg negative chronic hepatitis, less than 20% of subjects who have achieved an end-of-treatment virological response after a course of standard IFN maintain a sustained virological response in the long-term. IFN treatment could help to delay or prevent disease decompensation and liver-related deaths but further large studies are needed. Lamivudine is effective at reducing, and sometimes clearing, HBV replication in heavily immunosuppressed patients and can be safely administered to patients with advanced liver disease. Lamivudine should be continued over an undefined extended period of time, with a switch from lamivudine to adefovir if there is an HBV-DNA breakthrough under therapy. Adefovir, excluding cost, is preferable to lamivudine as a first-choice because there is less chance of inducing resistance. The long-term benefit of lamivudine and adefovir and the role of combinations is under investigation.
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PMID:Treatment options in HBV. 1635 81


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