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Cell Metabolism Apr 2019Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells...
Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
Topics: Age Factors; Animals; Dideoxynucleotides; Female; Inflammation; Male; Mice; Mice, Inbred Strains; Mice, Knockout; RNA-Binding Proteins; Sirtuins; Stavudine; Thymine Nucleotides; Zidovudine
PubMed: 30853213
DOI: 10.1016/j.cmet.2019.02.014 -
AIDS (London, England) Jul 2017There is inconsistent evidence that zidovudine use during pregnancy increases overall, cardiac, and male genital malformations. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
There is inconsistent evidence that zidovudine use during pregnancy increases overall, cardiac, and male genital malformations.
DESIGN
We conducted a systematic review and meta-analysis of zidovudine use and malformations and, using Bayesian methods, combined it with data from a cohort study of mother-infant pairs in the nationwide Medicaid Analytic eXtract (MAX).
METHODS
Using MAX data (2000-2010), we identified pregnant women with HIV treated with antiretroviral therapy (ART). Women with at least one zidovudine dispensing during the first trimester were compared to women receiving ART without zidovudine in the first trimester. Malformation outcomes were defined using diagnosis/procedure codes. To adjust for confounding, we performed 1 : 1 propensity score matching. Bayesian methods require specification of a prior, which we developed in the meta-analysis. Logistic regression models combined MAX data with the prior, estimating odds ratios (ORs) and 95% credible intervals.
RESULTS
Fourteen articles contributed information on overall malformations, seven on cardiac malformations, and five on male genital malformations. In MAX, matching led to a sample of 735 women each in the zidovudine and comparator groups. When comparing first trimester zidovudine use to other ART, the Bayesian procedure yielded OR estimates slightly above the null for overall [OR = 1.11, 95% credible interval (0.80-1.55)] and cardiac [OR = 1.30 (0.63-2.71)] malformations. There were no zidovudine-exposed cases of male genital malformations in MAX, but the meta-analysis yielded elevated OR estimates [OR = 2.57 (1.26-5.24)].
CONCLUSION
For most malformations, first-trimester zidovudine was not associated with increased risk. The potential increase in male genital malformations was small in absolute terms, and should be evaluated further.
Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Anti-HIV Agents; Child; Female; HIV Infections; Humans; Infant; Infant, Newborn; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Young Adult; Zidovudine
PubMed: 28537936
DOI: 10.1097/QAD.0000000000001549 -
Infectious Diseases in Obstetrics and... 1998Zidovudine was the first agent approved for treatment of HIV disease, and since its widespread availability in 1987, the pharmacokinetic disposition and clinical effects... (Review)
Review
Zidovudine was the first agent approved for treatment of HIV disease, and since its widespread availability in 1987, the pharmacokinetic disposition and clinical effects of ZDV have been extensively evaluated. In addition to its utility as a component of a multidrug combination regimen for the treatment of adult and pediatric HIV-1 infection, it is the only agent approved by the FDA for the prevention of mother-to-child HIV-1 transmission. The effectiveness of ZDV for the prevention of mother-to-child HIV-1 transmission has been demonstrated in several studies. The optimal time during gestation to initiate ZDV therapy and the relative importance of the intrapartum and newborn components is the focus of both current interventional and observational studies. Until more information is available from these trials, the combined maternal/newborn ZDV regimen studied in ACTG 076 remains the recommended treatment regimen of choice in the United States.
Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; National Institutes of Health (U.S.); Pregnancy; Pregnancy Complications, Infectious; United States; Zidovudine
PubMed: 9894173
DOI: 10.1002/(SICI)1098-0997(1998)6:5<197::AID-IDOG2>3.0.CO;2-1 -
Antiviral Research Sep 2017HIV and M. tuberculosis are two intersecting epidemics making the search for new dual action drugs against both pathogens extremely important. Here, we report on the...
HIV and M. tuberculosis are two intersecting epidemics making the search for new dual action drugs against both pathogens extremely important. Here, we report on the synthesis and suppressive activities of five dual-targeted HIV/TB compounds. These compounds are heterodimers of AZT, as anti-HIV molecules, and 5-substituted uracil derivatives, as anti-TB molecules. We found that these compounds inhibit the growth of M. tuberculosis and suppress the replication of HIV in human cell cultures and human lymphoid tissues ex vivo. We identified one particular heterodimer that inhibited both HIV and the drug-resistant TB strain MS-115 most potently. This compound demonstrated low toxicity and had no cytostatic effect on cells in culture, constituting an ideal candidate for future development and further in vivo testing.
Topics: Antitubercular Agents; Cell Culture Techniques; Cells, Cultured; Drug Design; Drug Resistance, Multiple, Bacterial; HIV Infections; HIV-1; Humans; Lymphocytes; Mycobacterium tuberculosis; Tuberculosis; Virus Replication; Zidovudine
PubMed: 28743447
DOI: 10.1016/j.antiviral.2017.07.011 -
CMAJ : Canadian Medical Association... Dec 1990Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled trial showing improved survival among patients with acquired immunodeficiency syndrome (AIDS) or symptomatic HIV infection (AIDS-related complex [ARC]) zidovudine has been evaluated in other stages of HIV infection. This review offers physicians who treat patients with HIV infection a comprehensive analysis of the current data on the clinical efficacy of zidovudine in various stages of HIV infection and on zidovudine's adverse effects. After a search of MEDLINE for pertinent articles published since 1985, controlled studies and studies of long-term zidovudine therapy, of zidovudine therapy for HIV-related conditions and of the incidence and management of adverse reactions were evaluated. In addition, abstracts from international meetings were reviewed. No significant difference in clinical outcome was found between high-dose and low-dose zidovudine therapy, but there were significantly fewer toxic effects in the low-dose group. In two other studies zidovudine was found to delay disease progression in patients with asymptomatic or mildly symptomatic HIV infection who had an absolute CD4 count of less than 0.5 x 10(9)/L; the low incidence of adverse reactions may have been due to either the early stage of the infection or the low dose used. The demonstration of zidovudine-resistant isolates after at least 6 months of therapy has yet to be correlated with clinical deterioration. When to begin zidovudine therapy among asymptomatic patients with a CD4 count of less than 0.5 x 10(9)/L remains unclear. Zidovudine can be used safely to delay progression to AIDS or ARC in certain patients with asymptomatic or mildly symptomatic HIV infection and can prolong survival in those with more severe infection. Further studies are necessary to identify indicators that could better define when to start treatment and how to alleviate toxic effects. Combination therapy with such agents as interferon alpha may become the preferred choice of therapy to prevent toxic effects and zidovudine resistance. Zidovudine prophylaxis has been used after HIV exposure. Although studies with animal models have had encouraging results infection has occurred despite immediate prophylaxis and thus further investigation is required.
Topics: Acquired Immunodeficiency Syndrome; Child; Humans; Zidovudine
PubMed: 2224694
DOI: No ID Found -
Cell Reports Jan 2023The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing...
The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
Topics: Animals; Humans; Zidovudine; Longevity; Activating Transcription Factor 4; Caenorhabditis elegans; Reverse Transcriptase Inhibitors; Retroviridae; HIV Infections
PubMed: 36640360
DOI: 10.1016/j.celrep.2022.111928 -
Lancet (London, England) Aug 1989The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment... (Clinical Trial)
Clinical Trial
The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment for human immunodeficiency virus infection. Zidovudine plasma concentrations were measured while subjects were receiving zidovudine alone, after 3 days of zidovudine plus 500 mg probenecid every 8 h, and after 3 days of zidovudine plus 500 mg probenecid plus 260 mg quinine sulphate every 8 h. A median increase of 80% in the area under the zidovudine plasma concentration/time curve occurred with the addition of probenecid. Quinine sulphate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal elimination of zidovudine. Probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs.
Topics: AIDS-Related Complex; Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Interactions; Drug Therapy, Combination; Humans; Male; Middle Aged; Patient Compliance; Probenecid; Quinine; Zidovudine
PubMed: 2570186
DOI: 10.1016/s0140-6736(89)92087-4 -
IARC Monographs on the Evaluation of... 2000
Review
Topics: Acyclovir; Animals; Antiviral Agents; Carcinogens; Didanosine; Disease Models, Animal; Evidence-Based Medicine; Humans; Intestinal Absorption; Neoplasms; Risk Factors; Tissue Distribution; Zalcitabine; Zidovudine
PubMed: 11000975
DOI: No ID Found -
The Journal of Antimicrobial... Aug 2021To investigate the efficacy of zidovudine in combination with carbapenems against NDM-1-producing Enterobacteriaceae.
OBJECTIVES
To investigate the efficacy of zidovudine in combination with carbapenems against NDM-1-producing Enterobacteriaceae.
METHODS
MICs were determined using the broth microdilution method. The combinatory effects of zidovudine and carbapenems were examined using the chequerboard method and time-kill analysis.
RESULTS
We found that the NDM-1-producing strains were resistant to all carbapenems tested. FIC index from chequerboard assay demonstrated that zidovudine synergized with carbapenems against all the NDM-1 strains. Time-kill analysis demonstrated significant synergistic activity when a low level of zidovudine was combined with meropenem.
CONCLUSIONS
Zidovudine in combination with carbapenems produced synergistic activity against NDM-1 Enterobacteriaceae strains in vitro.
Topics: Anti-Bacterial Agents; Carbapenems; Enterobacteriaceae; Microbial Sensitivity Tests; Zidovudine; beta-Lactamases
PubMed: 34120178
DOI: 10.1093/jac/dkab184 -
Molecules (Basel, Switzerland) Dec 2022The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single... (Review)
Review
The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3'-azido-2',3'-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.
Topics: Humans; Zidovudine; Acquired Immunodeficiency Syndrome; Pharmacophore; HIV-1; Viral Load; Anti-HIV Agents
PubMed: 36500608
DOI: 10.3390/molecules27238502