Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00216 (ABC)
 8,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Development of anti-retroviral regimens with enhanced efficacy against brain HIV-1 is essential if viral eradication is to be achieved. To address this, a severe combined immune deficiency mouse model of HIV-1 encephalitis was used to assay the effect of protease-containing and protease-sparing drug regimens on viral replication in brain macrophages. Here, HIV-1-infected human monocyte-derived macrophages (MDM) are inoculated into basal ganglia, causing a multinucleated giant cell encephalitis reminiscent of human disease. Drugs were administered at the time of MDM inoculation and continued until sacrifice. Immunohistochemical tests evaluated ongoing viral replication, glial immunity, and neuronal survival. Treatment with ddI/d4T decreased the numbers of infected cells by 75%, while ddI/d4T/amprenavir or ZDV/3TC/ABC diminished infection by 98%. Triple drug regimens decreased astrogliosis by > or = 25%. This small-animal model may be used to screen drug regimens that affect ongoing HIV-1 replication within its brain sanctuary.
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PMID:The efficacy of potent anti-retroviral drug combinations tested in a murine model of HIV-1 encephalitis. 1122 92

An advisory committee of the Food and Drug Administration (FDA) has recommended accelerated approval for abacavir (ABC, Ziagen). The approval decision was not unanimous due to concerns of drug toxicity. Three percent of those taking the drug have developed severe allergic reactions, and at least eight people have died of complications related to the allergic reaction. Abacavir works by attacking the viral enzyme reverse transcriptase (RT), and it is related to other drugs such as AZT, 3TC, d4T, ddI, and ddC. Abacavir should be taken twice daily, in combination with other anti-HIV medications.
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PMID:Abacavir gets green light from FDA advisory board. Food and Drug Administration. 1136 24

Information on dosage, cost, side effects, and interactions is provided for each of the seven nucleoside analog drugs available currently: Retrovir (AZT, ZDV), Videx (ddI), Hivid (ddC), Zerit (d4T), Epivir (3TC), Combivir (AZT/3TC), and Ziagen (abacavir sulfate). Most nucleoside analogs (with the exception of ddI) do not have food restrictions, but do have potential side effects such as nausea and fatigue. An activist, a doctor, and the drug's manufacturer offer comments. Contact information is provided.
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PMID:What they say about nucleoside drugs. 1136 20

Laboratory studies indicate that mycophenylate (CellCept) may increase the anti-HIV activity of abacavir (Ziagen). Mycophenylate suppresses the production of guanosine, which is critical to the replication of HIV. Although the combination of mycophenylate and abacavir has been shown to have a similar effect to that of the combination of Hydroxyurea and ddI, it may be more powerful and less toxic. These results are preliminary and must be confirmed by human studies, which are currently under way.
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PMID:Mycophenylate - a potential new option. 1136 67

The FDA approved FTC (emtricitabine, Emtriva) in July 2003 for use by adults in combination with other anti-HIV drugs. FTC is a nucleoside analog reverse transcriptase inhibitor (NRTI). Other drugs in this class include 3TC, abacavir, AZT, Combivir, d4T, d4T XR, ddC, ddI, ddI EC and Trizivir.
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PMID:FTC (emtricitabine, Emtriva). 1469 67

An immunological comparison of three different third companions (abacavir [ABC], efavirenz [EFV], ritonavir-boosted indinavir [IDVr]) on a backbone of either zidovudine plus didanosine (AZT/ddI) or zidovudine plus lamivudine (AZT/3TC) was performed in 76 HIV-infected, advanced-naive patients. Baseline median CD4 count and viremia were 217/microL and 238,301 copies/mL, respectively. Immunologic parameters were measured at baseline and after months of therapy. By the end of the study, 36 patients (mostly in the protease inhibitor [PI]-containing arms) had dropped out of the study; 22/36 cases of drop out were due to tolerability issues. All regimens resulted in increases in CD4 counts, with the most solid changes seen in patients using ABC as a third companion. Median HIV plasma viremia at month 12 was <50 copies/mL, and viremia was undetectable in 26/38 patients (68%). At the end of the study period, HIV antigen- and mitogen-stimulated proliferation overall was better in patients using either of the PI-boosted third companions. In these patients, the strongest down-modulation of activation marker-bearing cells was also observed. Finally, CD8+/28-/CD45RA+ lymphocytes (effector cells) were increased in all groups of patients with the exception of individuals receiving PI-boosted therapies. Results of this pilot study, although very preliminary, suggest that different combinations of antivirals result in a range of effects on immune cell functions. The clinical implications of these results need to be further analyzed in follow-up studies and in larger cohorts of patients.
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PMID:An immunological comparison of third companion in advanced drug-naive HIV-infected patients. 1716 15

Tenofovir disoproxil fumarate (TDF) has become an important component of HIV combination therapy because of its potency and once-daily dosing. Key mutation associated with resistance to TDF is a K65R in the reverse transcriptase (RT) gene. According to occurrence of K70E mutation after failure to TDF regimen, this mutation was recently reported as a mutation associated with TDF resistance in most resistance genotypic algorithms. The aim of this study was to analyze, retrospectively, the prevalence and conditions of selection of HIV-1 RT K70E mutation from a national clinical survey. Absence of selection of K70E in 850 HIV-1-infected naive patients suggests its role in NRTI drug resistance. Prevalence of K70E RT was low (99/41601, 0.24%) in patients treated between 1999 and 2005. Conversely with K65R mutation, thymidine analog mutations (TAMs) can be concomitantly observed with K70E mutation but its frequency decreased as the number of TAM increases. Concomitant association of K65R and K70E was possible but infrequent (11%). At the time of K70E selection, 60% of patients had received or received TDF-containing regimen and one-third received exclusive NRTI regimen. In conclusion, the K70E mutation could be an alternative pathway of TDF resistance, but as the K65R mutation, other NRTI as ABC, ddI, and 3TC could be also associated with the K70E selection.
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PMID:National survey of the prevalence and conditions of selection of HIV-1 reverse transcriptase K70E mutation. 1836 Sep 11

In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T-cell lines. PBMCs were infected with a full-length HIV-1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV + d4T), lamivudine + abacavir (3TC + ABC), lamivudine + didanosine (3TC + ddI), lamivudine + stavudine (3TC + d4T), tenofovir + stavudine (TDF + d4T), tenofovir + didanosine (TDF + ddI), tenofovir + abacavir (TDF + ABC), tenofovir + lamivudine (TDF + 3TC), tenofovir + zidovudine (TDF + ZDV), stavudine + didanosine (d4T + ddI), zidovudine + lamivudine (ZDV + 3TC), abacavir + didanosine (ABC + ddI), zidovudine + didanosine (ZDV + ddI), and abacavir + stavudine (ABC + d4T). The effect of combining two drugs was evaluated with a quantitative method based on the median-effect principle of Chou and Talalay. A synergistic effect was observed with combinations containing TDF and ZDV or d4T, d4T and ddI and ZDV plus 3TC. In contrast, combinations including TDF + ddI, 3TC + ddI, ABC + ddI, and ZDV + ddI showed an antagonistic effect on the inhibition of viral replication at all levels of inhibition tested. Lower antagonistic effect was also found in drug combinations that included 3TC + ABC, 3TC + TDF, 3TC + d4T, and TDF + ABC. In conclusion, the method developed allows to measure in vitro the effect of different combinations of two NRTIs on HIV replication. The results suggest that combined therapy including TDF with thymidine analogues may be considered for future therapeutic options in contrast to clearly antagonistic combinations such us TDF plus ddI or 3TC plus ddI, that would explain virological failure in clinical studies when these combinations were used.
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PMID:In vitro analysis of synergism and antagonism of different nucleoside/nucleotide analogue combinations on the inhibition of human immunodeficiency virus type 1 replication. 1910 82

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-gamma hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-gamma) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-gamma with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication.
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PMID:An analysis of enzyme kinetics data for mitochondrial DNA strand termination by nucleoside reverse transcription inhibitors. 1913 79

The objective of this study was to assess the patterns of genotypic and phenotypic resistance in a population of blood donor patients infected with HIV-1 subtype B' (Thai B', a clade of HIV-1 B) from central China, previously treated and harboring NRTI and NNRTI resistance mutations, with the purpose of designing effective therapeutic regimens. The HIV-1 pol genes from 65 patients were sequenced and estimated for drug resistance while the viruses isolated from the patients were used to analyze the phenotype based on the TZM-bl cell line. All the HIV-1 strains harboring one or more drug resistance mutations to HIV-1 RTIs possessed high cross-resistance to EFV (100%) and DLV (92%), as well as to ABC (84%) and TDF (77%), which are much higher than both FTC and 3TC (42%). There were more thymidine analog mutation (TAM)-associated mutations in the AZT/ddI/NVP group (62.5%) than in the d4T/ddI/NVP group (32.65%). A phenotypic assay showed high concordance between genotypic and phenotypic cross-resistance. This study showed there was a high level of cross-drug resistance to HIV-1 RTIs among Chinese AIDS patients harboring resistant strains, and there is also a high prevalence of primary resistance to 3TC, suggesting that one important recommendation should be the realization of genotypes in all naive patients due to the high prevalence of NRTI and NNRTI mutations.
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PMID:Genotypic and phenotypic cross-drug resistance of harboring drug-resistant HIV type 1 subtype B' strains from former blood donors in central Chinese provinces. 2071 29


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