Intracellular metabolism and pharmacokinetics of 5′-hydrogenphosphonate of 3′-azido-2′,3′-dideoxythymidine, a prodrug of 3′-azido-2′,3′-dideoxythymidine

Skoblov, Yurii S.; Karpenko, Inna L.; Shirokova, Elena A.; Попов, К. В.; Андронова, В. Л.; Галегов, Г. А.; Kukhanova, Marina K.

doi:10.1016/j.antiviral.2004.03.001

Cited by 29 publications

(22 citation statements)

References 23 publications

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“…These cells have also been used to screen methodologies or drugs that may inhibit HIV-1 infection or reduce transcriptional activation of the virus [117,[160][161][162][163][164][165][166][167][168][169][170][171][172][173]. These cell lines have also been used in studies of drug toxicity, permeability, and/or effects on cellular activation and differentiation to gain an understanding of what specific drugs might do to cells in the bone marrow [144,154,[174][175][176][177][178][179][180][181][182][183], as well as determining what signaling pathways may play a role or become dysregulated [184][185][186][187][188][189]. Additionally, other studies have been completed that utilize these cells to examine the role that distinct viral determinants as well as specific host factors have on cellular tropism, cellular differentiation, and cytopathology [190][191][192][193].…”

Section: Hl-60mentioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

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Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

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Section: Hl-60mentioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

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“…However 40-50 minutes after intragastric introduction to mice of tritium-labeled Nikavir both Nikavir and zidovudine were found in blood plasma. The peak radioactivity level of zidovudine was considerably higher than of Nikavir (Skoblov, 2004).…”

Section: Wwwintechopencommentioning

confidence: 98%

Nikavir in Chemoprevention Regimens of Vertical HIV Transmission

Иванова¹,

Shmagel²,

Vorobeva³

2011

Understanding HIV/AIDS Management and Care - Pandemic Approaches in the 21st Century

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“…Pharmacokinetic parameters of the latter were rather close to those of AZT H-phosphonate (2.5 times inferior to C max and less than two times to AUC and surpassing in T max and other parameters). Bioavailability of AZT after oral administration of 1 was 8%, which is only twice less than that of AZT H-phosphonate, which is an effective anti-HIV drug with considerably lower toxicity and a longer time of appearance of viral-resistant strains if compared with AZT (Machada et al, 1999;Skoblov et al, 2004;Kukhanova and Shirokova, 2005). Bioavailability of AZT after oral administration of AZT itself was six times as high as that of AZT from 1.…”

Section: Discussionmentioning

confidence: 99%

“…Many depot forms of anti-HIV drugs have been developed (Beaumont et al, 2003;Calogeropoulou et al, 2003), and some have resulted in new drugs (Kearney et al, 2004; LysengWilliamson et al, 2005;De Clercq and Field, 2006). In particular, the depot form of 3Ј-azido-3Ј-deoxythymidine (zidovudine, AZT), Nikavir (AZT H-phosphonate, phosphazide, AZT 5Ј-hydrogenphosphonate), proved to be highly effective and has been approved in Russia for the prevention and treatment of AIDS (Kravchenko, 2004;Skoblov et al, 2004;Kukhanova and Shirokova, 2005). In this work, we describe preliminary biological data for several new AZT depot Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.…”

mentioning

confidence: 99%

5′-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms: Antiviral Properties, Intracellular Transformations, and Pharmacokinetic Parameters

Khandazhinskaya¹,

Yanvarev²,

Jasko³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The main disadvantages of 3-azido-3-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short halflife in the organism. The introduction of an H-phosphonate group into the AZT 5 position resulted in significant improvement of its therapeutic properties and allowed a new anti-HIV drug, Nikavir (AZT H-phosphonate). In this work, we described a new group of AZT derivatives, namely, AZT 5-aminocarbonylphosphonates. The synthesized compounds displayed antiviral properties in cell cultures infected with HIV-1 and the capacity to release the active nucleoside in animals (rabbits and dogs) in a dose-dependent manner. The compounds were less toxic in MT-4 and HL-60 cell cultures and experimental animals compared with AZT. Major metabolites found in MT-4 cells after their incubation with AZT 5-aminocarbonylphosphonate 1 were AZT and AZT 5-phosphate (25 and 55%, respectively). Among the tested compounds, phosphonate 1 was the most effective AZT donor, and its longest t 1/2 and T max values in the line phosphonate 1 -AZT H-phosphonate -AZT imply that compound 1 is an extended depot form of AZT. Although bioavailability of AZT after oral administration of phosphonate 1 was lower than those of AZT H-phosphonate and AZT (8 against 14 and 49%), we expect that this reduction would not cause essential decrease of antiviral activity but noticeably decrease toxicity as a result of gradual accumulation of AZT in blood and the absence of sharp difference between C max and C min . Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT.The progress toward the treatment of HIV infections has steadily increased in the past 2 decades. At the end of the 1980s, the life expectancy of HIV-infected patients was only 2 to 5 years, whereas today many patients often survive between 10 and 15 years; however, once the infection progresses to full-blown AIDS, the mortality rate is 100%. Currently, more than 20 drugs have been approved for treatment of HIV; these include inhibitors of crucial viral enzymes such as reverse transcriptase, protease, and integrase. Despite significant progress in the design of anti-HIV drugs, many problems remain, such as toxicity and side effects, as well as rapid elimination from the body, resulting in more frequent dosing. More significantly, the development of drug-resistant strains has increased dramatically. As a result, there is a critical need for more effective and less toxic therapeutics.In that regard, HIV reverse transcriptase has proven to be an attractive target. HIV reverse transcriptase inhibitors are primarily modified nucleosides that are converted by way of an intracellular cascade of phosphorylations to the corresponding triphosphates. The triphosphates are then incorporated into the growing DNA chain, which results in termination of DNA synthesis. As the efficacy of the triphosphates is low, drug doses must therefore be high, which generally leads to significant toxicity. One solution ...

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Intracellular metabolism and pharmacokinetics of 5′-hydrogenphosphonate of 3′-azido-2′,3′-dideoxythymidine, a prodrug of 3′-azido-2′,3′-dideoxythymidine

Cited by 29 publications

References 23 publications

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nikavir in Chemoprevention Regimens of Vertical HIV Transmission

5′-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms: Antiviral Properties, Intracellular Transformations, and Pharmacokinetic Parameters

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