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 investigate the secular change in the incidence rate of drug-induced hepatitis (DIH) due to anti-tuberculosis chemotherapy including isoniazid (INH) and rifampicin (RFP), but not including pyrazinamide (PZA), we retrospectively studied the incidence rates of DIH in patients treated with chemotherapy including INH and RFP in four periods 1980-83, 87-88, 91-92, and 1998-2000. The criteria for selection of the patients were as follows. 1. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before, and one month (20-40 days) and 2 months (45-75 days) after starting anti-tuberculosis chemotherapy. When the serum AST and ALT were measured twice or more during period 20-40 days or 45-75 days after starting anti-tuberculosis chemotherapy, the data obtained nearest to 30 or 60 days after were chosen as those of one or two months after starting chemotherapy, respectively. 2. The serum AST and ALT were within normal range before starting anti-tuberculosis chemotherapy. The normal range of serum AST and ALT were < or = 40 K-A and < or = 35 K-A (in 1980-83) or < or = 31 IU/l and 34 IU/l (in 1987-2000), respectively. 3. Chronic active hepatitis and cirrhosis patients were excluded. 4. All alive after completion of anti-tuberculosis chemotherapy. The numbers of the subjects who fulfilled the above criteria were 113, 135, 128 and 154 in 1980-83, 1987-88, 1991-92 and 1998-2000, respectively. DIH was defined serologically by serum AST > or = 40 K-A and/or ALT > or = 35 K-A (in 1980-83), or AST > or = 40 IU/l and/or ALT > or = 40 IU/l (1987-2000). The DIH incidence rate of the subjects classified by the year of treatment and age were examined, and the contributions of the risk factors for DIH, such as age, sex, alcoholics, previous liver disease history, HBs ag positivity, anti-HCV ab positivity, and hypoalbuminenia were studied, and none except the age over 80 y.o. was found to be a risk factor to DIH, in our subjects. In patients with the age over 80 y.o., daily doses of antituberculosis drugs RFP, INH and ethambutol (EB) were significantly higher in patients with DIH than those without DIH, but body weight and serum albumin level were not significantly different between these two groups. There was no risk factor to DIH in our patients less than 80 y.o. and this could be explained by the above-mentioned criteria of study patients selection. To exclude the age dependence of the incidence rate of DIH in our subjects, the incidence rates of DIH were calculated in patients less than 80 y.o. by the period of treatment, and they were 10/111 (9.0%), 23/131 (17.6%), 26/123 (21.1%) and 32/117 (27.4%) in 1980-83, 87-88, 91-92, and 1998-2000, respectively. The secular increase of the incidence rate of DIH was statistically significant (p = 0.01). It is quite clear that this secular increase was not at all attributable to the above-mentioned risk factors. It is suspected that human liver has become more easily affected with INH and RFP in recent years. It is suggested that the new chemical compounds present in our increasingly complicated human milieu give heavier burdens on human liver, weaken the liver function, and enhance the capacity of INH and RFP to cause DIH.
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PMID:[Secular increase in the incidence rate of drug-induced hepatitis due to anti-tuberculosis chemotherapy including isoniazid and rifampicin]. 1273 93

We experienced 4 cases of agranulocytosis due to anti-tuberculosis drugs (rifampicin [RFP], isoniazid [INH], ethambutol [EB], streptomycin [SM] or pyrazinamide [PZA]) among some 6,400 tuberculosis patients who underwent chemotherapy over the past 20 years from 1981 to 2002 in our hospital, and the incidence rate of agranulocytosis was estimated at 0.06%. The 4 cases of agranulocytosis were as follows. CASE 1: A 51-year-old woman with right chest pain and fever was admitted to our hospital on Jan 4, 2001. The white blood cell (WBC) count was 5,200/microliter. The tubercle bacilli were cultured in her sputum. The treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, allopurinol and teprenone was started on Jan 13. Pyrazinamide and allopurinol were stopped because of hyper-uric acidemia on Feb 7. Agranulocytosis and eosinophilia (WBC 1,300 [Neut 1%, Ly 57%, Eos 35%]) developed on Feb 13. All drugs were withdrawn and G-CSF drug nartograstim 100 micrograms was injected subcutaneously for 3 days. The WBC recovered to normal level and she was thereafter treated with INH, EB and Levofloxacin (LVFX) without any further trouble. Agranulocytosis in this case was supposed to be due to RFP. CASE 2: A 66-year-old man who had had nephrotic syndrome and hypothyroidism and has been treated with prednisolone 10 mg/day was admitted to our hospital on Aug 9, 2000 because of miliary tuberculosis. The tubercle bacilli were cultured in his sputum and the treatment with INH 0.3, RFP 0.45, and EB 0.75 g/day were started on Aug 10, but it was withdrawn on Aug 17 because of general skin eruption. After re-starting treatment with EB and INH on Aug 24, RFP was added in small dosage (0.05 g) on Oct 12, but agranulomatosis (WBC 2,300/microliter [Neut 2%]) developed on Nov 21, and all drugs were withdrawn again. The G-CSF drug filgrastim was used once subcutaneously, and WBC recovered immediately. He was thereafter treated with INH, EB, LVFX successfully. Agranulocytosis was supposed to be due to RFP. CASE 3: A 60-year-old woman without symptoms had abnormal chest roentgenograph, and consulted with our hospital on Aug 26, 2002. The broncho-alveolar lavage fluid was smear and culture-negative, but PCR-TB positive, and the case was diagnosed as pulmonary tuberculosis. Treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, alloprinol 300 mg and rebamipide 300 mg/day was started on Sept. 5, 2002. Late in September, she complained of appetite loss. The laboratory data on Oct 3 revealed WBC 900/microliter (Neut 1%, Ly 94%), aspartate aminotransferase (AST) 199 IU/l, and alanine aminotransferase (ALT) 253 IU/l, showing agranulocytosis and drug-induced hepatitis. The chemotherapy was immediately withdrawn and she was admitted to our hospital on the next day. Glycyrrhizin derivative (SNMC) 40 ml was injected for 5 days, and WBC recovered, and AST and ALT also became normal. CASE 4: A 60-year-old man was admitted to our hospital on March 11, 1981 because pulmonary tuberculosis had recurred. He had been treated with SM, PAS and INH in 1973 for pulmonary tuberculosis. On admission examination of blood count and blood chemistry were normal. Treatment with RFP, INH and SM was started on March 11. He stopped out from the hospital on April 17, but in a few days he returned back with sore throat, lower lip swelling and gingival bleeding. Blood cell count on April 24 showed pancytopenia with RBC 226, Hb 7.5, WBC 800 (Ly 96%, Eos 4%) and Plt 10,000/microliter. The bone-marrow showed NCC (nuceated cell count) of 5,500, and megakaryocyte 0. Thereafter ground glass appearance shadows were seen on the whole lung field, and he died May 26. Autopsy showed generalized aspergillosis. It was strongly suspected that either of RFP, INH or SM was responsible for his pancytopenia. We collected another 10 cases of agranulocytosis due to anti-tuberculosis drugs in the world wide literature, and found men/women ratio 5/8 (in one case gender was not known), the duration of chemotherapy before appearance of agranulocytosis 1-3 months, no change in the lymphocyte count of the peripheral blood, and the accompanying of another allergic signs such as skin eruption, blood eosinophilia or drug-induced hepatitis in some cases, and these findings suggest that the mechanism of agranulocytosis due to anti-tuberculosis drugs was allergic in nature.
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PMID:[Agranulocytosis due to anti-tuberculosis drugs including isoniazid (INH) and rifampicin (RFP)--a report of four cases and review of the literature]. 1467 45

Besides the long-term effectiveness of a given compound, safety is a very important feature to consider when developing new compounds for chemotherapy against tuberculosis. Reports of fatal and severe liver injury associated with rifampicin-pyrazinamide (RIF-PZA) treatment regimens for latent tuberculosis infections prompted this study to evaluate whether a mouse model has any potential as a tool to assess liver injury following extensive exposure to tuberculosis drugs. Mice were administered high doses of existing drug regimens for latent tuberculosis over a relatively short time period. Alanine aminotransferase (ALT), aspartate aminotransferase and bilirubin levels were determined after 2 weeks and 4 weeks of treatment in serum samples collected from uninfected mice as well as mice infected with Mycobacterium tuberculosis. ALT levels increased significantly after a RIF-PZA treatment regimen for 4 weeks in uninfected mice and after 2 weeks in infected mice. Bilirubin serum levels were also significantly elevated in the M. tuberculosis-infected mice after 4 weeks of RIF-PZA treatment. The data obtained indicate that changes in serum enzyme levels in mice after extensive exposure to tuberculosis drugs could be useful as an initial indicator of drug-related hepatotoxicity.
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PMID:Significant increases in the levels of liver enzymes in mice treated with anti-tuberculosis drugs. 1595 8

Pyrazinamide (PZA) combined with either ethambutol (EMB) or a fluoroquinolone for 6-12 months is one of the treatments recommended for latent tuberculosis infection (LTBI) in contacts exposed to multidrug-resistant tuberculosis (MDR-TB). The aim of the present study was to describe the side effects related to combined PZA and EMB treatment given for LTBI, in contacts previously exposed to MDR-TB. In total, 12 consecutive contacts, all of African origin and aged 38+/-5 yrs, were treated with daily PZA (23+/-4 mg.kg(-1)) and EMB (17+/-4 mg.kg(-1)) at Geneva University Hospital outpatient clinic (Switzerland), as a result of contact-tracing procedures for two patients with contagious MDR-TB. Clinical status and liver function tests (aspartate aminotransferase (ALAT) and alanine aminotransferase (ASAT)) were monitored monthly. In seven cases (58%) treatment was discontinued after a median of 119 days, due to hepatic toxicity in six cases (ALAT or ASAT elevation more than four times the upper normal limit), and gastrointestinal symptoms in one case. In conclusion, combined pyrazinamide and ethambutol for latent tuberculosis infection may be associated with a high risk of hepatic toxicity, and warrants close monitoring. There is clearly a need for alternative preventive treatments for contacts exposed to multidrug-resistant tuberculosis.
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PMID:High hepatotoxicity of pyrazinamide and ethambutol for treatment of latent tuberculosis. 1613 29

Mycobacterium tuberculosis is a concern in patients with human immunodeficiency virus (HIV) infection. Rifampin (RIF), an agent used against M. tuberculosis, is contraindicated with most HIV protease inhibitors. Atazanavir (ATV) has clinical efficacy comparable to a standard of care regimen in naive patients and, when dosed with low-dose ritonavir (RTV), also in treatment-experienced patients. We evaluated here the safety and pharmacokinetics of ATV, resulting from three regimens of ATV, RTV, and RIF in 71 healthy subjects. The pharmacokinetics for ATV and RTV were assessed after 6 and 10 days of dosing with ATV 400 mg (n = 53) and with ATV-RTV at 300 and 100 mg (ATV/RTV 300/100; n = 52), respectively. Steady-state pharmacokinetics for ATV, RTV, RIF, and desacetyl-rifampin (des-RIF) were measured after 10 days of dosing of ATV/RTV/RIF 300/100/600 (n = 17), ATV/RTV/RIF 300/200/600 (n = 17), or ATV/RTV/RIF 400/200/600 (n = 14). An RIF 600-alone arm was enrolled as a control group (n = 18). With ATV/RTV/RIF 400/200/600, ATV area under the concentration-time curve values were comparable, but the C(min) values were lower relative to ATV 400 alone. ATV exposures were substantially reduced for the other RIF-containing regimens relative to ATV 400 alone and for all regimens relative to ATV/RTV 300/100 alone. RIF and des-RIF exposures were 1.6- to 2.5-fold higher than with RIF 600 alone. The incidence of grade 3/4 alanine aminotransferase/aspartate aminotransferase values was limited to 1 subject each in both the ATV/RTV/RIF 300/200/600 and the ATV/RTV/RIF 400/200/600 treatments. Coadministration of ATV with RIF was safe and generally well tolerated. Since ATV exposures were reduced in all regimens, ATV and RIF should not be coadministered at the dosing regimens studied.
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PMID:Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. 1700 14

Suppression of viral replication is followed by increases in CD4+ lymphocytes, and this has been shown to result in decreased susceptibility to opportunists after initiation of highly active antiretroviral therapy (HAART). However, clinical aggravations after the initiation of HAART have been thought to be due to the restored ability to mount an inflammatory response, or the immune reconstitution inflammatory syndrome (IRIS). The degree of IRIS observed in human immunodeficiency virus (HIV)-infected patients following initiation of HAART is variable. This prospective study was aimed at determining the proportion of IRIS and the pattern of opportunistic infections among 186 HIV/AIDS patients receiving HAART between December 2006 and July 2007 at Zewditu Memorial Hospital, Addis Ababa, Ethiopia. The proportion of IRIS was 17.2% (32/186). The mean number of days of IRIS occurrence for each disease ranged from 26 to 122 days with a mean of 80. Opportunistic diseases associated with IRIS were tuberculosis (68.8%, 22/32), herpes zoster rash (12.5%, 4/32), cryptococcosis (9.4%, 3/32), toxoplasmosis (6.3%, 2/32) and bacterial pneumonia (3.1%, 1/32). Compared to baseline readings there were significant increases in CD4 count, aspartate aminotransferase and alanine aminotransferase levels while hemoglobin values decreased during the development of IRIS. In summary, the proportion of IRIS and the pattern of opportunistic infections in HAART-treated patients in Ethiopia mirrored those reported in other countries. Further prospective surveys on epidemiological, immunological, microbial and clinical studies are imperative to assess the proportion and pattern of IRIS and effect of HAART in Ethiopia.
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PMID:Immune reconstitution inflammatory syndrome among HIV/AIDS patients during highly active antiretroviral therapy in Addis Ababa, Ethiopia. 1850 70

Rapid diagnosis is crucial for adequate treatment of disseminated mycobacteriosis. We conducted a retrospective cohort study to identify clinical and laboratorial features of disseminated mycobacteriosis in human immunodeficiency virus (HIV) infected patients that could help to differentiate tuberculosis (TB) from non-tuberculous mycobacteria (NTM) disease. All patients diagnosed from 1996 to 2006 were reviewed. TB was diagnosed in 65 patients and NTM in 31. Patients with TB had higher median levels of aspartate aminotransferase (AST) (69.0 vs. 45.0, P = 0.02) and lactate dehydrogenase (LDH) (725.0 vs. 569.0, P = 0.03). AST and LDH may be valuable tools in differentiating disseminated TB from NTM in HIV-infected patients.
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PMID:Laboratory features for presumptive diagnosis of disseminated tuberculosis in HIV-infected patients. 1892 48

An open-label, 60-day trial was conducted in 75 newly diagnosed tuberculosis (TB) patients to assess the adjunctive effect of the oral immunomodulator Dzherelo with standard anti-TB chemotherapy (ATT) consisting of izoniazid, rifampicin, pyrazinamide and streptomycin (HRZS) administered as directly observed therapy (DOT). Group 1 (n = 28) with cavitary TB and group 2 (n = 17) with infiltrating pulmonary TB received 50 drops of Dzherelo twice daily in addition to HRZS. Group 3 (n = 30), which served as a control, received ATT only. Liver damage indicators, bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased to normal levels in groups 1 and 2, but increased significantly in group 3. Kidney failure markers, urea and creatinine, normalized in Dzherelo recipients, but were unchanged or worsened in the ATT-only group. The changes in serum lactate dehydrogenase, catalase, malondialdehyde and diene conjugates suggested that Dzherelo downregulates TB-associated inflammation. The anti-inflammatory property of Dzherelo was further supported by a favourable haematology profile, reduced erythrocyte sedimentation rate and faster defervescence. Radiological recovery was significant in both Dzherelo groups, but not in the control group (p = 0.0085, p = 0.025 and p = 0.23, respectively). These findings correlated positively with sputum smear conversion and clinical findings (r = 0.94; p < 0.05). Mycobacterial clearance at day 30 was observed in 77%, 72% and 40% of patients in groups 1, 2 and 3, respectively. After 2 months sputum conversion rates in groups 1, 2 and 3 were 93%, 89% and 70%, respectively. Sixty-day treatment outcomes in groups 1, 2 and 3 as assessed by improvement in clinical features and respiratory function attained respective p-values of 0.008, 0.25 and 0.72, and 0.013, 0.48 and 0.0015. Dzherelo is thus useful as an immunotherapeutic adjunct in the management of TB.
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PMID:Treatment of cavitary and infiltrating pulmonary tuberculosis with and without the immunomodulator Dzherelo. 1945 29

Isoniazid is a widely used drug for the treatment of tuberculosis, but hepatotoxicity is a major concern during treatment. Thiopronin contains an SH-group and is generally considered an antioxidant. The aim of the present study was to investigate the effects of thiopronin during liver injury and DNA damage induced by isoniazid. Rats were injected daily with isoniazid (100 mg/kg, i.p.) for 21 days with or without thiopronin co-administration (60 mg/kg, i.p.) from day 11 to day 21. The influence of thiopronin on isoniazid-induced DNA oxidative damage was analyzed in precision-cut rat liver slices by HPLC-MS/MS. Thiopronin prevented isoniazid-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage (alanine aminotransferase and aspartate aminotransferase) and histopathological analysis. In vivo, thiopronin significantly inhibited isoniazid-induced CYP2E1 activity as assessed by both chlorzoxazone hydroxylase and aniline hydroxylase (p<0.001). Thiopronin concentration-dependently inhibited CYP2E1-dependent aniline hydroxylation, and the Dixon plots suggest that thiopronin is a competitive inhibitor of CYP2E1. Thiopronin markedly attenuated isoniazid-induced inhibition of the detoxification system through cytosolic glutathione S-transferases (GSTs), including mu GST and alpha GST. In precision-cut liver slices, the free radical scavenging activity of thiopronin reduced the generation of DNA adducts induced by isoniazid (p<0.05). Altogether, these results suggest that thiopronin exerts its hepatoprotective activity against isoniazid-induced hepatotoxicity by inhibiting the production of free radicals in addition to its role as a scavenger. Thiopronin may reduce free radical generation via inhibition of hepatic CYP2E1 and increase the removal of free radicals directly or through the induction of cytosolic GSTs.
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PMID:Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats. 1968 30

Blastocystis hominis and nonpathogenic enteric protozoa were diagnosed in 300 patients with pulmonary tuberculosis mainly of its infiltrative form and 500 with Stages II and III HIV infection; the patients received antituberculosis therapy (ATT) and antiretroviral therapy (ART), respectively. Control groups included 200 Tashkent dwellers and 350 patients with various noninfectious diseases of the gastrointestinal tract. Triple coproscopy was made. B. hominis was significantly more frequently detected in patients with pulmonary tuberculosis and those with HIV infection than in healthy individuals: in 53.6 +/- 2.9, 42.2 +/- 2.2, and 18.0 +/- 2.5, respectively (P < 0.01). Only did the tuberculosis or HIV-infected patients show a high intensity of B. hominis infection, which was accompanied by recurring diarrhea and nausea. The high activity of alanine aminotransferase and aspartate aminotransferase was observed in 20% of the patients with tuberculosis + blastocytosis; that of alkaline phosphatase was seen in 25%. The tuberculosis or HIV-infected patients were more frequently found to have Chylomastix mesnili, Jodamoeba butschlii, and Endolimax nana. The specific features of intestinal colonization seem to reflect changes in local immunity; the drugs included into ATT and ART have no substantial effects on the viability of protozoa.
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PMID:[Blastocystis hominis and nonpathogenic enteric protozoa in patients with pulmonary tuberculosis and those with HIV infection]. 2087 79


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