Disease relevance of Azidothymidine

• SETTING: Seventeen ambulatory HIV clinics in Australia and London. SUBJECTS: Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43) [1].
• CONCLUSIONS: Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations [2].
• Trimeric TRAIL (in place of IFN-alpha) similarly synergized with AZT to induce apoptosis in HHV-8 positive PEL cells [3].
• Resistance to ZDV or to ddI could be induced in vitro in Salmonella isolates, but cross-resistance was not observed [4].
• Nine Escherichia coli blood isolates were inhibited by ZDV (MIC50, 0.125 microgram/ml; MIC range, 0.031 to 1 microgram/ml) to a greater degree than they were by ddI (MIC50, 62.5 micrograms/ml; MIC range, 31 to > 62.5 micrograms/ml) [4].

High impact information on Azidothymidine

• CONCLUSIONS: Uridine supplementation protects adipocytes from the adverse effects of d4T, ZDV and ddC on lipid accumulation, cell survival and mitochondrial functions, suggesting that the toxic effects could be linked to intracellular depletion of uridine or its metabolites [5].
• Resistance to zidovudine (ZDV) results from thymidine analog resistance mutations (TAMs) at human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) codons 41, 67, 70, 210, 215, and 219 [6].
• Viral replication kinetics, relative fitness, and infectivity were tested in the absence or presence of ZDV [6].
• While the viral burden was significantly reduced by ZDV monotherapy in peripheral blood lymphocytes, plasma, and thymus, thymic lesions were similar for the treated and untreated FIV-infected cats [7].
• To evaluate the anti-Salmonella activity of the antiviral agents ZDV, ddI, ddC, and acyclovir (ACV), we determined MICs for 39 nontyphoidal Salmonella blood isolates [4].

Chemical compound and disease context of Azidothymidine

• Acyclovir (ACV) triphosphate and azidothymidine (AZT) triphosphate inhibit the DNA polymerase of human hepatitis B virus (HBV) by 50% at submicromolar concentrations, but no effects of ACV or AZT treatment have been noted on the clinical manifestations of hepatitis B [8].
• DATA SYNTHESIS: Didanosine has been approved for the treatment of HIV infection in patients who are unable to tolerate ZDV because of adverse effects (e.g., anemia and neutropenia) or who experience clinical or immunologic deterioration while receiving ZDV [9].
• We conclude that oxandrolone can be used for the promotion of weight gain in patients with AIDS-related wasting without interference with the antiviral effects of ZDV, ddI, or ddC [10].
• MYA-1 cells (feline T-lymphoblastoid cells) were infected with FIV and were cultured in the presence of various concentrations of anti-human immunodeficiency virus agents such as azidothymidine (AZT) or dextran sulfate [11].
• Tumor necrosis factor-alpha (TNF)-cachectin increases the expression of the human immunodeficiency virus (HIV), reverses the therapeutic efficacy of zidovudine (ZDV), and may contribute to the wasting syndrome [12].

Biological context of Azidothymidine

• Enrolled were 1047 HIV-positive patients intolerant of and/or unresponsive to zidovudine (ZDV) therapy, with CD4+ cell counts of < 200/microliter or AIDS [13].
• At entry, the median CD41 cell count was 47/microliter and the median duration of prior ZDV treatment 19 months; 446 patients (43%) were classified as having AIDS [13].
• In the second study, 40 black, male homosexuals with CD4+ count between 350 and 500/mm3 were enrolled in groups of 10 to receive either nHuIFN-alpha or AZT, or both nHuIFN-alpha and AZT, or nothing (untreated controls) [14].
• Sequential quantitative lymphocyte cultures for HIV and ZDV pharmacokinetics were performed in a subset of patients [15].
• Primary and secondary transfectants of tr5 cells using total human DNA and pSV2neo plasmid were selected by sequential incubations in AZT (20-50 microM), G418 (400 micrograms/ml active dose), and medium containing hypoxanthine, aminopterin, and thymidine (HAT) [16].

Anatomical context of Azidothymidine

• Tocopherol equally ameliorates the growth of BFU-E and CFU-GM from the HIV-positive cohort in the presence of AZT (10-100 mumol/l) [17].
• Compared with ZDV, ddI has a long intracellular half-life and negligible bone-marrow toxicity [9].
• This cell line was used for this study for its elevated sensitivity to 5 microM AZT [16].
• Recently, 500 mg/day of ddI in sachet form demonstrated clinical effectiveness compared with zidovudine (ZDV) for delaying HIV disease progression in patients with AIDS or AIDS related complex (ARC) and less than 300 CD4+ T-lymphocytes, or asymptomatic individuals with less than 200 CD4+ T-lymphocytes [18].

Associations of Azidothymidine with other chemical compounds

• Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies [19].
• Applying this new method to HIV-infected MT-4 cell cultures treated with differing concentrations of the potent anti-HIV agent azidothymidine (AZT), we obtained a virus-inhibitory dose-response comparable to those obtained by the conventional (labour-intensive and time-consuming) methods [20].
• Combined treatments of AZT plus DDCTP result in a reduction in erythroid precursors compared to that resulting from DDCTP administration, while DDC plus DDCTP results in a differential cell count similar to that found in uninfected mice [21].
• The mean baseline CD4 counts were 165 and 147/microl in the placebo and acemannan groups, respectively; 90 percent of the patients were receiving ZDV at entry [15].

Gene context of Azidothymidine

• Eligible patients of either sex had CD4 counts of 50-300/microl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry [15].
• The majority of patients with progressive HIV infection develop a severe hematopoietic failure which is aggravated by the hematotoxic effect of azidothymidine (AZT) treatment [17].
• These results as well as the decrease of p24 antigenemia do indicate that ZDV indeed inhibits HIV replication in vivo [22].
• The data suggested that the genetic basis for AZT sensitivity may be related to the expression of alpha-type DNA polymerase, and the result indicated that AZT cytotoxicity could be reversed by transfection of appropriate human DNA into tr5 cells [16].
• DESIGN: Serum levels of cICAM-1 and TNF-alpha, determined by enzyme immunoassays, were evaluated in 52 HIV-1-infected children, aged between 1 month and 13 years; 35 children were not treated with ZDV and 17 were treated with ZDV [23].

Analytical, diagnostic and therapeutic context of Azidothymidine

• Over the next four months the drug therapy was altered from ddI to ZDV and ZDV to ddI because of increasing fatigue and gastrointestinal symptomatology; all of the other chronic medications were maintained at the same dosages and frequency [24].
• Although clinical trials have demonstrated early improvement in CD4 lymphocyte number with ZDV, long-term effects of ZDV on CD4 in advanced and asymptomatic disease are not well known [25].

References