Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Murphy, Robert L.; Kivel, Nancy M.; Zala, Carlos; Ochoa, Claudia; Tharnish, Phillip M.; Mathew, Judy; Pascual, Maria Luz G.; Schinazi, Raymond F.

doi:10.3851/imp1514

Cited by 13 publications

(17 citation statements)

References 26 publications

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“…DXG was evaluated in the presence of AZT in macrophages (42,43). The cellular accumulation of DXG-TP and AZT-TP were unaffected by coincubation (Table 2), supporting similar findings in activated lymphocytes and lending further incentive for the development of this drug combination (44).…”

Section: Discussionmentioning

confidence: 57%

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Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Gavegnano

Detorio

Bassit

et al. 2013

Antimicrob Agents Chemother

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Understanding the cellular pharmacology of antiretroviral agents in macrophages and subsequent correlation with antiviral potency provides a sentinel foundation for definition of the dynamics between antiretroviral agents and viral reservoirs across multiple cell types, with the goal of eradication of HIV-1 from these cells. Various clinically relevant nucleoside antiviral agents, and the integrase inhibitor raltegravir, were selected for this study. The intracellular concentrations of the active metabolites of the nucleoside analogs were found to be 5-to 140-fold lower in macrophages than in lymphocytes, and their antiviral potency was significantly lower in macrophages constitutively activated with macrophage colony-stimulating factor (M-CSF) during acute infection than in resting macrophages (EC 50 , 0.4 to 9.42 M versus 0.03 to 0.4 M, respectively). Although tenofovirtreated cells displayed significantly lower intracellular drug levels than cells treated with its prodrug, tenofovir disoproxil fumarate, the levels of tenofovir-diphosphate for tenofovir-treated cells were similar in lymphocytes and macrophages. Raltegravir also displayed significantly lower intracellular concentrations in macrophages than in lymphocytes, independent of the activation state, but had similar potencies in resting and activated macrophages. These data underscore the importance of delivering adequate levels of drug to macrophages to reduce and eradicate HIV-1 infection.

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Section: Discussionmentioning

confidence: 57%

“…Since AZT and DXG are not cross-resistant, AZT can prevent the emergence of the K65R mutation, and in combination, the two drugs are synergistic in vitro and in humans (42). DXG was evaluated in the presence of AZT in macrophages (42,43).…”

Section: Discussionmentioning

confidence: 99%

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Gavegnano

Detorio

Bassit

et al. 2013

Antimicrob Agents Chemother

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“…The feasibility of developing an AMDX and ZDV coformulation is currently being explored, since this combination demonstrates synergy in vitro and at least additivity in vivo (36) against HIV-1 and prevents the selection of K65R mutation/ TAMs in primary human lymphocytes (40). A previous simulation study suggested that the ZDV dose may be reduced from 300 mg b.i.d.…”

Section: Discussionmentioning

confidence: 99%

“…Amdoxovir [(Ϫ)-␤-D-2,6-diaminopurine dioxolane (AMDX or DAPD)] is a guanosine nucleoside analogue being developed for the treatment of HIV-1 infections (23,31,47). AMDX is in advanced phase 2 clinical development under a U.S. Food and Drug Administration Investigational New Drug Application and has been administered safely to over 200 persons in seven human phase I/II trials (23,31,36,47,50). AMDX is a prodrug which undergoes rapid oral absorption in humans and other species and is deaminated by the ubiquitous enzyme adenosine deaminase to 9-(␤-D-1,3-dioxolan-4-yl)guanine (DXG) (4,16,35).…”

mentioning

confidence: 99%

“…Blood samples were centrifuged and stored at Ϫ80°C before being assayed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Safety was evaluated by determining the proportion of grade 3 or greater adverse events per treatment, using the AIDS Clinical Trials Group (ACTG) toxicity grading scale, and antiviral activity (change in plasma HIV-1 RNA [log 10 VL]) was determined daily (36).…”

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confidence: 99%

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Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

Hurwitz

Asif

Fromentin

et al. 2010

Antimicrob Agents Chemother

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Stereo‐Defined Ferrocenyl Glycol Nucleic Acid (Fc‐GNA) Constituents: Synthesis, Electrochemistry, Mechanism of Formation, and Anticancer Activity Studies

et al. 2021

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In this paper, we report the Yb(OTf) 3 -mediated etherification reaction that allowed obtaining R,R and S,R isomers of ferrocenyl glycol nucleic acid (Fc-GNA) nucleosides from their corresponding stereo-defined (S,R) precursor. The R,R absolute configuration of the chiral carbon atoms in one of the Fcnucleoside isomers was assigned by single-crystal X-ray diffraction. Density functional theory calculations showed that the stereochemical outcome of the reaction can be explained by an exo attack of ethylene glycol on the pro-R-or pro-S-configured α-ferrocenyl carbenium ion intermediate. The R,R isomer was transformed into the corresponding nucleotide diethyl ester which is, to the best of our knowledge, the first Fc-GNA nucleotide ever reported. The obtained compounds feature reversible one-electron oxidation of the ferrocenyl portion of their molecular structures. Anticancer activity studies showed that the (S,R) nucleoside was the most active against HeLa and Ishikawa cancer cells, while it did not show any activity against nontumorigenic L929 cells. The compound induced apoptosis in HeLa cells at IC 50 = 66.0 μM concentration upon 72 h of treatment.

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Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Abstract: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Cited by 13 publications

References 26 publications

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

Stereo‐Defined Ferrocenyl Glycol Nucleic Acid (Fc‐GNA) Constituents: Synthesis, Electrochemistry, Mechanism of Formation, and Anticancer Activity Studies

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