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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied hepatic transaminases among rural Ugandans initiating highly active antiretroviral therapy (HAART) and assessed the impact of positive serology for hepatitis B surface antigen (HBsAg) and coadministration of therapy for tuberculosis. From July 2003 to December 2004, persons with symptomatic HIV disease or a CD4 count less than 250 cells/mm(3) and who had alanine transferase (ALT) or aspartate transferase (AST) less than 5 times the upper limit of normal were started on HAART including nevirapine (96%) or efavirenz (4%). Repository sera from a subset of 596 participants were analyzed for hepatic transaminase levels. A transaminase elevation was present before therapy for 249 (42%) of 596, at 3 months for 140 (25%) of 553, 12 months for 59 (11%) of 520, and 24 months for 67 (13%) of 508. In multivariate analyses, a transaminase elevation at 3 months was associated with male gender (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.02-2.35), body mass index less than 18 kg/m(2) (OR, 2.10; 95% CI, 1.34-3.30), transaminase elevation at baseline (OR, 1.97; 95% CI, 1.30-2.99), and treatment for tuberculosis (OR, 4.68; 95% CI, 2.28-9.59). HBsAg status was not associated with transaminase elevations at baseline or while on HAART. The prevalence of hepatic transaminase elevations decreased during non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in this cohort of HIV-infected persons in rural Uganda.
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PMID:Liver enzymes improve over twenty-four months of first-line non-nucleoside reverse transcriptase inhibitor-based therapy in rural Uganda. 1877 41

Lippia javanica and Hoslundia opposita are aromatic herbs that occur all over Mozambique and are well known for their medicinal properties. A Phytochemical investigation of L. javanica led to the isolation of eight compounds, 4-ethyl-nonacosane (1), (E)-2(3)-tagetenone epoxide (2), myrcenone (3), piperitenone (4), apigenin (5), cirsimaritin (6), 6-methoxyluteolin 4'-methyl ether (7), 6-methoxyluteolin and 3',4',7-trimethyl ether (8). Three known compounds, 5,7-dimethoxy-6-methylflavone (9), hoslunddiol (10) and euscaphic acid (11) were isolated from H. opposita. This is the first report of compounds 1, 2, 5-8 from L. javanica and of compound (9) from H. opposita. The compounds were tested against Mycobacterium tuberculosis and HIV-1 reverse transcriptase for bioactivity. It was found that compounds 2, 4 and 9 inhibited the HIV-1 reverse transcriptase enzyme by 91, 53 and 52%, respectively, at 100 microg mL(-1). Of all the compounds tested against a drug-sensitive strain of M. tuberculosis, euscaphic acid (11) was found to exhibit a minimum inhibitory concentration of 50 microg mL(-1) against this strain.
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PMID:Bioactive compounds from Lippia javanica and Hoslundia opposita. 1878 Feb 45

Heat shock promoters of mycobacteria are strong promoters that become rapidly upregulated during macrophage infection and thus serve as valuable candidates for expressing foreign antigens in recombinant BCG vaccine. In the present study, a new heat shock promoter controlling the expression of the groESL1 operon was identified and characterized. Mycobacterium tuberculosis groESL1 operon codes for the immunodominant 10 kDa (Rv3418c, GroES/Cpn10/Hsp10) and 60 kDa (Rv3417c, GroEL1/Cpn60.1/Hsp60) heat shock proteins. The basal promoter region was 115 bp, while enhanced activity was seen only with a 277-bp fragment. No promoter element was seen in the groES-groEL1 intergenic region. This operon codes for a bicistronic mRNA transcript as determined by reverse transcriptase-PCR and Northern blot analysis. Primer extension analysis identified two transcriptional start sites (TSSs) TSS1 (-236) and TSS2 (-171), out of which one (TSS2) was heat inducible. The groE promoter was more active than the groEL2 promoter in Mycobacterium smegmatis. Further, it was found to be differentially regulated under stress conditions, while the groEL2 promoter was constitutive.
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PMID:Mycobacterium tuberculosis groE promoter controls the expression of the bicistronic groESL1 operon and shows differential regulation under stress conditions. 1922 81

HIV-tuberculosis coinfection is complex partly because rifamycins reduce therapeutic levels of protease inhibitors and nonnucleoside reverse transcriptase inhibitors, leading to potential virological failure. One therapeutic option is to use nucleos(t)ide-only regimens that have minimal interactions with antituberculous therapy. We report the largest published series of HIV-tuberculosis coinfected patients successfully treated with nucleos(t)ide regimens and antituberculous therapy. This group achieved similar virological and immunological outcomes when compared with tuberculosis patients on nonnucleoside reverse transcriptase inhibitor or protease inhibitor-based HAART, demonstrating the utility of this approach.
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PMID:The utility of nucleos(t)ide-only regimens in the treatment of Mycobacterium tuberculosis-HIV-1 coinfection. 1930 40

The emergence of highly active antiretroviral therapy using combinations of reverse transcriptase and protease inhibitors ushered the dawn of a new era in management of human immunodeficiency virus infection. Immune reconstitution inflammatory syndrome is an adverse consequence of the restoration of pathogen-specific immune responses during the early phase of antiretroviral therapy. Pre-existing subclinical or opportunistic infections become apparent or even "worse" as host immunological inflammatory responses are "switched on". Major reductions in plasma viral load were associated with substantial increases in circulating CD4 T-cell lymphocyte counts and restoration of immune function. The rapid reversal in immune function gives rise to paradoxical therapeutic reaction by rebuilding host immune responses. Herein, a hidden culprit responsible for tuberculosis-associated immune reconstitution characterized by severe hypercalcemia and acute renal failure is reported, illustrating the compounded therapeutic strategy in AIDS patients.
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PMID:Immune reconstitution associated hypercalcemia. 1949 80

Anaemia accelerates disease progression and increases mortality among HIV-infected individuals. Few studies have characterized this problem in developing countries. Haemoglobin values of adults presenting to an HIV tertiary care center in India between 1996 and 2007 were collected (n = 6996). Multivariate logistic regression analysis was performed to examine associations among anaemia, HIV progression and co-morbidities. Overall, anaemia prevalence was 41%. Twenty percent of patients with CD4 counts >500 cells/microL were anaemic, compared with 64% of those with CD4 counts <100 cells/microL (P < 0.001). In multivariate analysis, CD4 count <100 cells/microL (odds ratio [OR]:5.0, confidence interval [CI]:4.0-6.3), underweight body mass index (OR:4.8, CI:3.6-6.5), female gender (OR:3.1, CI:2.8-3.6) and tuberculosis (TB) (OR:1.6, CI:1.4-1.8) were significantly associated with anaemia. In this setting, management of anaemia should focus on antiretroviral therapy, nutritional supplementation and TB control. The high anaemia prevalence among patients meeting criteria for antiretroviral therapy highlights the need for increased access to non-zidovudine nucleoside reverse transcriptase inhibitors in developing countries.
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PMID:Factors associated with anaemia in HIV-infected individuals in southern India. 1954 92

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)-coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean +/- SD [% coefficient of variation [CV]) were 7.3 +/- 2.8 (39%), 31.9 +/- 33.6 (106%), and 16.4 +/- 5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2 +/- 1.9 (46%), 8.1 +/- 7.9 (98%), and 1.5 +/- 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein in UGT2B7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB-coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance.
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PMID:Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation. 1962 28

Coadministration of antitubercular and antiretroviral therapy is common in high-burden countries where tuberculosis is the commonest opportunistic infection. Concomitant use of rifampicin and many antiretroviral drugs is complicated by drug-drug interactions caused by the potent induction by rifampicin of genes involved in drug metabolism and transport, which could result in subtherapeutic antiretroviral drug concentrations. This review focuses on drug-drug interactions involving antiretrovirals used in resource-limited settings: the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz or nevirapine, and ritonavir-boosted protease inhibitors. The reduction of nevirapine concentrations with concomitant rifampicin is greater than with efavirenz, particularly during the lead-in dose period when subtherapeutic concentrations occur in the majority of patients. There is reassuring data on the effectiveness of standard doses of efavirenz with concomitant rifampicin, but the largest cohort study found a higher risk of virological failure with nevirapine. The drug-drug interaction between rifampicin and ritonavir-boosted protease inhibitors is more marked than with the NNRTIs, and therapeutic concentrations have only been achieved with adjusted doses of lopinavir/ritonavir or with saquinavir/ritonavir (400/400 mg every 12 h). The major barrier to using adjusted dose protease inhibitors with rifampicin is the high rates of hepatotoxicity seen in healthy volunteers. The alternative strategy followed in resource-rich settings is to replace rifampicin with rifabutin, but even if the price of rifabutin were to be dramatically reduced it would be difficult to implement in high-burden countries where standardized antitubercular regimens with fixed-dose combinations are used.
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PMID:Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries. 2003 33

The aim of this study was to evaluate the antimycobacterial, antigonorrheal and reverse transcriptase activities of five flavonoids: isobachalcone (IBC); kanzanol C (KAN); 4-hydroxylonchocarpin (4-LCP); stipulin (SPL) and amentoflavone (AMF) from Dortenia barteri, together with the crude extract from this plant. The Agar disc diffusion, broth microdilution, microplate alamar blue assay (MABA), radiometric respiratory technique using BACTEC 460 system and the reverse transcriptase (RT) assay were used for the investigations. The results of the antimycobacterial assay showed that the crude extract and compounds were able to prevent the growth of Mycobacteria with MIC<10 microg/ml being recorded with IBC on M. tuberculosis. Results of the killing rate experiment revealed that total inhibition effect on M. tuberculosis H37Rv strain was noted with IBC and SPL at day 9 when tested at 4x MIC. The results of the antigonorrheal assay indicated that MIC values below 10 microg/ml were also recorded with IBC on all the tested N. gonorrhoeae strains, meanwhile good activities (MIC<10 microg/ml) were also noted with the extract, KAN, 4-LCP and SPL on some of these strains. The anti-reverse transcriptase activities of extract and compounds also demonstrated that all samples were able to inhibit at various extents the reverse transcriptase activity, with IBC and 4-LCP showing the best effects. The overall results of this work provided evidence that the crude extract as well as some flavonoids from D. barteri could be potential sources of new antimicrobial drug against tuberculosis (TB), gonorrhea and probably the acquired immunodeficiency syndrome.
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PMID:Evaluation of flavonoids from Dorstenia barteri for their antimycobacterial, antigonorrheal and anti-reverse transcriptase activities. 2059 32

Mycobacterium tuberculosis is known to reside latently in a significant fraction of the human population. Although the bacterium possesses an aerobic mode of metabolism, it adapts to persistence under hypoxic conditions such as those encountered in granulomas. While in mammalian systems hypoxia is a recognized DNA-damaging stress, aspects of DNA repair in mycobacteria under such conditions have not been studied. We subjected Mycobacterium smegmatis, a model organism, to the Wayne's protocol of hypoxia. Analysis of the mRNA of a key DNA repair enzyme, uracil DNA glycosylase (Ung), by real-time reverse transcriptase PCR (RT-PCR) revealed its downregulation during hypoxia. However, within an hour of recovery of the culture under normal oxygen levels, the Ung mRNA was restored. Analysis of Ung by immunoblotting and enzyme assays supported the RNA analysis results. To understand its physiological significance, we misexpressed Ung in M. smegmatis by using a hypoxia-responsive promoter of narK2 from M. tuberculosis. Although the misexpression of Ung during hypoxia decreased C-to-T mutations, it compromised bacterial survival upon recovery at normal oxygen levels. RT-PCR analysis of other base excision repair gene transcripts (UdgB and Fpg) suggested that these DNA repair functions also share with Ung the phenomenon of downregulation during hypoxia and recovery with return to normal oxygen conditions. We discuss the potential utility of this phenomenon in developing attenuated strains of mycobacteria.
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PMID:Detrimental effects of hypoxia-specific expression of uracil DNA glycosylase (Ung) in Mycobacterium smegmatis. 2097 17


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