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 aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.
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PMID:Variability in the developmental toxicity of bropirimine with the day of administration. 239 79

We measured 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells and serum of 14 HBsAg- and HBeAg-positive patients with chronic hepatitis B with or without acute exacerbation. Elevated levels of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells and serum were found in seven chronic hepatitis B patients with acute exacerbation, whereas in the remaining seven chronic hepatitis B patients without acute exacerbation, both levels were similar to those of normal subjects despite active hepatitis B virus multiplication. 2',5'-Oligoadenylate synthetase levels in peripheral blood mononuclear cells and serum, which were not statistically different from those of normal subjects prior to acute exacerbation, increased during acute exacerbation from 3- to 23-fold over initial levels following elevations in ALT activity. 2',5'-Oligoadenylate synthetase levels fluctuated over a normal range while ALT levels were elevated, and they returned to a baseline with ALT normalization. This suggests that the in vivo interferon system may be activated during acute exacerbation, and that this activation may not be a result of hepatitis B virus multiplication alone, but also of a host-immune response to hepatitis B virus multiplication. Three patients were treated with interferon during acute exacerbation. All three had elevated levels of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells and serum just before treatment. 2',5'-Oligoadenylate synthetase levels increased only 1.1- to 2.2-fold over initial levels during treatment, with none of the patients clearing HBeAg during and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Elevated levels of 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells and serum during acute exacerbation of chronic hepatitis B. 246 93

Two years or more after 35 patients (29 men and six women) with chronic hepatitis B were treated by interferon, we studied relationships of age, ALT activity, activity of serum DNA polymerase associated with the hepatitis B virus, serum levels of hepatitis B e antigen and activity of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells when treatment started in comparison with treatment results. Seventeen patients were given human lymphoblastoid interferon-alpha; the other 18 patients were given interferon-beta. We measured the activity of 2',5'-oligoadenylate synthetase in these mononuclear cells and found the rate of increase in vivo and in vitro; the correlation between the two was r = 0.68. This enzyme activity in the patients who became negative for DNA polymerase after interferon treatment increased more both in vivo and in vitro than in patients who did not became negative. Also, both the in vivo and in vitro activity increased more in patients who became negative for the e antigen after interferon therapy than in those who remained positive. In the first group, interferon was considered to be effective; in the second, ineffective. Of the patients who became negative, some developed e antibodies and some did not; the increase in this enzyme activity in the two groups was not significantly different. The increase in the activity of 2',5'-oligoadenylate synthetase activity could be used to predict the results of interferon treatment and is an index that can be used before treatment to predict the response.
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PMID:Relationship of the effects of interferon on chronic hepatitis B and the induction of 2',5'-oligoadenylate synthetase. 247 40

Oral bropirimine (an immunomodulator shown to induce interferon) was administered to timed-pregnant Sprague-Dawley rats in five experiments utilizing several different dosing schedules. Concentrations of 100, 200, and 400 mg/kg of bropirimine were used. Interferon levels were determined in maternal serum, spleen, and whole embryo extracts and uterine contents were evaluated for survival of the embryos. Maternal toxicity occurred in all experiments as evidenced by dose-related decreases in body weight during the first 24 hr postdosing. Hematoxicology analyses of maternal serum revealed significant decreases in urea nitrogen, potassium, and albumin, along with increases in aspartate transaminase, alanine transaminase, and total bilirubin, in bropirimine-treated dams as compared to the vehicle controls. In addition, the means for maternal thymus weight decreased while the means for spleen weight increased with increasing concentration of bropirimine. As compared to the vehicle controls, interferon titers were high in maternal serum, maternal spleen, and, to a lesser extent, whole embryos, 2 hr postdosing, but had decreased or were below detectable levels 24 hr postdosing. Embryolethality was pronounced (increases in pre- and postimplantational loss) after a single dose (Gestation Day 3, 4, 5, 8, 9, or 10) of bropirimine, as well as after 7 or 8 consecutive days (Gestation Days 6-12 or 6-13) of treatment. Although embryotoxicity never occurred in these experiments in the absence of pronounced maternal toxicity, the pregnant dams never died as the result of bropirimine treatment, whereas the embryos frequently failed to survive.
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PMID:Bropirimine-induced embryolethality after oral administration to the pregnant rat. 247 83

The effect of interferon (IFN) treatment on serum levels of pre-S antigens [pre-S(1) antigen, pre-S(2) antigen, polymerized human serum albumin receptor (pAR)] which are coded by the pre-S region of hepatitis B virus DNA (HBV-DNA), and HBV-markers was analyzed in 23 patients with chronic hepatitis B. One year after IFN treatment, 4 patients (Group C) became HBeAg negative. Six patients (Group B) transiently became HBeAg-negative, but reverted to HBeAg positive. Thirteen patients (Group A) remained HBeAg positive. All of the patients remained HBsAg-positive. Initiation of IFN treatment was rapidly followed by reduction or loss of DNA-P in the serum whether the patients became HBeAg negative or remained positive, and whether serum transaminase (S-GPT) levels became normal or not after IFN treatment. Group C patients, in whom pre-S antigens decreased rapidly during IFN treatment and disappeared before S-GPT levels normalized, became HBeAg negative one year after IFN treatment. Anti-pAR was detected in three out of these 4 patients. In contrast, Group A and Group B patients, in whom pre-S antigens decreased slowly during IFN treatment and did not disappear in spite of those patients being transiently negative for HBeAg and DNA-P, remained HBeAg positive with elevated S-GPT levels one year after IFN treatment. Anti-pAR was almost undetectable. These results suggest that testing for pre-S antigens is more useful for determining the prognosis of patients with chronic hepatitis B treated with IFN than testing for HBsAg, HBeAg and DNA-P.
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PMID:Changes in serum levels of hepatitis B virus markers after interferon treatment. 248 99

33 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis (NANB PTH) were randomized 2:1 to treatment with interferon alpha-2b (Introna) or to controls. The treatment group received 3 MU interferon 3 times weekly subcutaneously for 36 weeks. 22/33 (67%) patients were reactive for antibodies against hepatitis C virus (anti-HCV). 11/19 (58%) treated patients versus none of the 12 controls had a complete response with normalization of serum alanine aminotransferase levels (p less than 0.001). Another 4/29 (21%) treated patients had a partial response which was also seen in 4/12 (33%) controls; 4 treated patients were nonresponders, all with chronic active hepatitis. Nonresponders had a significantly higher mean weight than responders (p less than 0.05) and tended to have a longer duration of their disease before therapy. During the 6-month follow-up period post treatment 4/11 (36%) complete responders had a sustained response and 7/11 (64%) relapsed. All who were retreated responded again. We conclude that a majority of patients with chronic NANB PTH will respond to 9 months interferon alpha-2b treatment, but that only 1 out of 3 will have a sustained response 6 months post treatment, and that the reactivity for anti-HCV was not correlated to the outcome of therapy.
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PMID:A randomized controlled open study of interferon alpha-2b treatment of chronic non-A, non-B posttransfusion hepatitis: no correlation of outcome to presence of hepatitis C virus antibodies. 248 36

We have treated 17 patients with non-A, non-B chronic hepatitis by recombinant interferon alpha (0.3-9 megaunits for 4-28 weeks). In six patients, serum aminotransferase levels fell to normal or near-normal range during treatment. The mean levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 17 patients fell from 156 +/- 80 (mean +/- SD) and 213 +/- 135 at the beginning of treatment to 94 +/- 49 and 112 +/- 71, respectively, at the end of treatment. In 12 patients, liver biopsies were performed before and after (or during) the treatment, and histological activity indices (HAI) were blindly examined by two independent observers. For comparison, we examined histological changes of pre- and posttreatment liver biopsies of 19 patients who were treated by recombinant interferon for chronic hepatitis B. Mean HAI scores improved from 10.0 to 5.4 after treatment in non-A, non-B chronic hepatitis. The most marked reduction was noted in scores of portal inflammation and hepatocellular degeneration and/or necrosis. No such reduction was observed in B-viral chronic hepatitis. These data indicated that rapid biochemical resolution by the treatment was related to histological improvement of the liver in our patients with non-A, non-B hepatitis.
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PMID:Histological changes of the liver by treatment of chronic non-A, non-B hepatitis with recombinant leukocyte interferon alpha. Comparison with histological changes in chronic hepatitis B. 249 64

32 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis and raised aminotransferase levels since more than 1 year were randomized 2:1 to treatment with interferon alpha-2b, Introna, or to controls. The interferon group received 3 MU interferon 3 times weekly subcutaneously. Interim results 12 weeks after randomization showed that 14/21 (67%) patients in the treatment group had normalized their serum alanine aminotransferase levels whereas none of 11 patients in the control group had (p less than 0.001). If interferon alpha-2b is only suppressive during ongoing therapy or curative will be shown later during continued follow-up.
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PMID:Interferon alpha-2b treatment of chronic posttransfusion non-A, non-B hepatitis: interim results of a randomized controlled open study. 249 37

We measured activities of alpha- and gamma-interferon simultaneously in 198 sera of 70 patients with acute and chronic viral hepatitis using specific and sensitive enzyme immunoassay and immunoradiometric assay. The results were compared with those in patients with influenza and in healthy controls. Twelve out of 28 patients with acute viral hepatitis showed positive alpha-IFN and/or gamma-IFN activities. alpha-IFN was detectable throughout the clinical course while gamma-IFN levels rose in the convalescent phase regardless of etiology. Conversely, in patients with influenza, both alpha-IFN and gamma-IFN levels of initial samples tended to be higher than those of late samples. Six out of 12 patients with chronic active type B hepatitis showed increased alpha-IFN and/or gamma-IFN values during acute deterioration with marked elevation of serum alanine aminotransferase. However, the two interferons did not always appear simultaneously, although either was detectable in both acute and chronic hepatitis. Enhanced alpha-IFN or gamma-IFN activity was not found in asymptomatic chronic hepatitis B carriers or in patients with chronic persistent hepatitis and liver cirrhosis with chronic hepatitis B virus infection, with the exception of 2 cases. Our results indicated that circulating multiple IFN species were present during the clinical course in some patients with acute and chronic viral hepatitis.
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PMID:Serum levels of alpha-interferon and gamma-interferon in patients with acute and chronic viral hepatitis. 249 28

Chronic hepatitis C (non-A, non-B hepatitis) is a common and often progressive viral liver disease. To assess the efficacy of therapy with the antiviral agent interferon alfa, we randomly assigned 166 patients with chronic hepatitis C to treatment with either 3 million or 1 million units of recombinant interferon alfa three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after six months of interferon therapy was 46 percent in patients treated with 3 million units of interferon (P less than 0.001) and 28 percent in those treated with 1 million units (P less than 0.02), but only 8 percent in untreated patients. The serum alanine aminotransferase level became completely normal in 22 of the 26 patients (85 percent) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56 percent) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histologic improvement because of the regression of lobular and periportal inflammation. Relapse within six months after the completion of treatment occurred in 51 percent of the patients treated with 3 million units of interferon and 44 percent of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.
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PMID:Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. 250 16


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