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Chemical Compound Review

S1398_Selleck     1-[5-(hydroxymethyl)-2,5- dihydrofuran-2...

Synonyms: AG-J-03009, SureCN9999805, ACMC-209hh0, CHEBI:104320, NSC-163661, ...
 
 
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Disease relevance of d4T

 

Psychiatry related information on d4T

  • Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex [6].
 

High impact information on d4T

  • The complex with d4T triphosphate displayed an intramolecular CH.O bond contributing to catalysis, and the R(p) diastereoisomer of thymidine alpha-boranotriphosphate bound like a normal substrate [7].
  • So324 has anti-HIV activity in human CEM, MT4, and monocyte/macrophage cells that is superior to that of d4T [8].
  • The risk of virological failure at 6 months after d4T/TDF starting was 22% [2].
  • RESULTS: Whereas ddl had no effects, d4T, ZDV and ddC significantly decreased cellular lipid accumulation (by 32%, 46% and 24%, respectively), increased apoptosis and induced mitochondrial depolarization. d4T, ZDV and ddC decreased adipocyte mtDNA (by 64%, 53% and 46%, respectively) and reduced the mtDNA encoded COX II subunit [3].
  • Uridine (200 microM) had no intrinsic effect, but prevented all adverse effects of d4T, ZDV and ddC on adipocyte morphology, lipid staining, apoptosis, mtDNA depletion (partial prevention with ZDV), mitochondrial mass and membrane potential [3].
 

Chemical compound and disease context of d4T

  • In contrast to d4T, So324 is also able to inhibit HIV replication in thymidine kinase-deficient CEM cells [8].
  • Stavudine (d4T) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase [9].
  • Notably, the higher toxicities of d4T, ddC, and ddA arose from their 13-36-fold tighter binding relative to the normal dNTP even though their rates of incorporation were comparable with PMPA and AZT [10].
  • OBJECTIVE: To analyse 6861 patients in a large observational cohort from 21 Médecins Sans Frontieres (MSF) HIV/AIDS programmes taking 3TC/d4T/NVP, with subcohort analyses of patients at 12 and 18 months of treatment [11].
  • OBJECTIVE: To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC) [12].
 

Biological context of d4T

  • CONCLUSIONS: d4T and AZT can enhance hepatic fat oxidation and cause fat wasting, without decreasing adipose tissue mtDNA and without causing insulin resistance in mice [13].
  • V75T reverse transcriptase discriminates 3.6-fold d4T 5'-triphosphate relative to dTTP, as judged by pre-steady state kinetics of incorporation of a single nucleotide into DNA [14].
  • Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042] [15].
  • A small reduction in zidovudine phosphorylation was seen with d4T but only at d4T:zidovudine ratios of 100 and 1,000 [16].
  • Mean maternal antenatal d4T pharmacokinetics (terminal plasma half-life [T1/2], 83.5+/-16.8 min; area under the plasma-concentration time curve [AUC0-infinity), 81.6+/-22.0 microg.min/mL; n=6) were not significantly different from those during labor (T(1/2), 87.3+/-24.7 min; AUC0-infinity, 88.1+/-16.6 microg.min/mL; n=6) [17].
 

Anatomical context of d4T

 

Associations of d4T with other chemical compounds

  • OBJECTIVES: To evaluate antiviral efficacy of stavudine/tenofovir (d4T/TDF) backbone combination in late-line antiretroviral therapy, and to assess clinical and virological determinants of treatment success [2].
  • RESULTS: Whereas ddC or ddI did not change plasma beta-hydroxybutyrate and body fat mass, d4T, AZT and BAIBA increased plasma beta-hydroxybutyrate in lean mice suggesting increased hepatic fatty acid oxidation and ketogenesis [13].
  • The effectiveness of once-daily administration of ddI will be evaluated further in a new multinational clinical trial, AI454-148, in which it will be combined with d4T and the protease inhibitor, nelfinavir [20].
  • Virologic response was associated with a higher CD4 cell count, no prior exposure to d4T and 3TC, and no previous AIDS-defining illness [21].
  • Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite [22].
 

Gene context of d4T

  • The results showed that HIV-specific (but not mitogen-stimulated) IL-2 and IFN-gamma production was augmented and IL-10 production was reduced in patients who received EFV, NFV, and d4T [23].
  • METHODS: Lean or obese ob/ob mice were treated for 6 weeks with d4T, AZT or BAIBA, and lean mice with ddC or ddI [13].
  • The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months. d4T is a promising drug for patients with AIDS or ARC [24].
  • Since fat oxidation in non-adipose tissue can influence body adiposity, we sought to determine whether d4T, AZT and BAIBA can cause lipoatrophy in mice by this catabolic mechanism [13].
  • After 6 months of therapy, 7 ml of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddI, respectively [25].
 

Analytical, diagnostic and therapeutic context of d4T

References

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  2. Antiviral efficacy and genotypic resistance patterns of combination therapy with stavudine/tenofovir in highly active antiretroviral therapy experienced patients. Antinori, A., Trotta, M.P., Nastao, P., Bini, T., Bonora, S., Castagnas, A., Zaccarelli, M., Quirino, T., Landonio, S., Merli, S., Tozzi, V., Di Perri, G., Andreoni, M., Perno, C.F., Carosi, G. Antivir. Ther. (Lond.) (2006) [Pubmed]
  3. Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Walker, U.A., Auclair, M., Lebrecht, D., Kornprobst, M., Capeau, J., Caron, M. Antivir. Ther. (Lond.) (2006) [Pubmed]
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  10. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. Johnson, A.A., Ray, A.S., Hanes, J., Suo, Z., Colacino, J.M., Anderson, K.S., Johnson, K.A. J. Biol. Chem. (2001) [Pubmed]
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  12. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. Martin, A., Smith, D.E., Carr, A., Ringland, C., Amin, J., Emery, S., Hoy, J., Workman, C., Doong, N., Freund, J., Cooper, D.A. AIDS (2004) [Pubmed]
  13. Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting. Maisonneuve, C., Igoudjil, A., Begriche, K., Lettéron, P., Guimont, M.C., Bastin, J., Laigneau, J.P., Pessayre, D., Fromenty, B. Antivir. Ther. (Lond.) (2004) [Pubmed]
  14. The valine-to-threonine 75 substitution in human immunodeficiency virus type 1 reverse transcriptase and its relation with stavudine resistance. Selmi, B., Boretto, J., Navarro, J.M., Sire, J., Longhi, S., Guerreiro, C., Mulard, L., Sarfati, S., Canard, B. J. Biol. Chem. (2001) [Pubmed]
  15. Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy. Kallianpur, A.R., Hulgan, T., Canter, J.A., Ritchie, M.D., Haines, J.L., Robbins, G.K., Shafer, R.W., Clifford, D.B., Haas, D.W. AIDS (2006) [Pubmed]
  16. Effects of drugs on 2',3'-dideoxy-2',3'-didehydrothymidine phosphorylation in vitro. Hoggard, P.G., Kewn, S., Barry, M.G., Khoo, S.H., Back, D.J. Antimicrob. Agents Chemother. (1997) [Pubmed]
  17. Pharmacokinetics and safety of stavudine in HIV-infected pregnant women and their infants: Pediatric AIDS Clinical Trials Group protocol 332. Wade, N.A., Unadkat, J.D., Huang, S., Shapiro, D.E., Mathias, A., Yasin, S., Ciupak, G., Watts, D.H., Delke, I., Rathore, M., Hitti, J., Frenkel, L., Samelson, R., Smith, M.E., Mofenson, L., Burchett, S.K. J. Infect. Dis. (2004) [Pubmed]
  18. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. Walker, U.A., Setzer, B., Venhoff, N. AIDS (2002) [Pubmed]
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  21. Stavudine plus lamivudine in advanced human immunodeficiency virus disease: a short-term pilot study. Rouleau, D., Conway, B., Raboud, J., Rae, S., Fransen, S., Shillington, A., Zala, C., O'Shaughnessy, M.V., Montaner, J.S. J. Infect. Dis. (1997) [Pubmed]
  22. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. McGuigan, C., Cahard, D., Sheeka, H.M., De Clercq, E., Balzarini, J. J. Med. Chem. (1996) [Pubmed]
  23. Modulation of human immunodeficiency virus (HIV)-specific immune response by using efavirenz, nelfinavir, and stavudine in a rescue therapy regimen for HIV-infected, drug-experienced patients. Trabattoni, D., Lo Caputo, S., Biasin, M., Seminari, E., Di Pietro, M., Ravasi, G., Mazzotta, F., Maserati, R., Clerici, M. Clin. Diagn. Lab. Immunol. (2002) [Pubmed]
  24. 2',3'-didehydro-3'-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. Browne, M.J., Mayer, K.H., Chafee, S.B., Dudley, M.N., Posner, M.R., Steinberg, S.M., Graham, K.K., Geletko, S.M., Zinner, S.H., Denman, S.L. J. Infect. Dis. (1993) [Pubmed]
  25. Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. Becher, F., Landman, R., Mboup, S., Kane, C.N., Canestri, A., Liegeois, F., Vray, M., Prevot, M.H., Leleu, G., Benech, H. AIDS (2004) [Pubmed]
  26. Mitochondrial effects of a 24-week course of pegylated-interferon plus ribavirin in asymptomatic HCV/HIV co-infected patients on long-term treatment with didanosine, stavudine or both. Ballesteros, A.L., Miró, O., López, S., Fuster, D., Videla, S., Martínez, E., Garrabou, G., Salas, A., Côté, H., Tor, J., Rey-Joly, C., Planas, R., Clotet, B., Tural, C. Antivir. Ther. (Lond.) (2004) [Pubmed]
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