Stavudine

Hurst, Miriam; Noble, Stuart

doi:10.2165/00003495-199958050-00012

Cited by 54 publications

(6 citation statements)

References 94 publications

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“…The lack of antibacterial activities of several of these NAs, e.g., cytarabine, vidarabine, fludarabine, abacavir, emtricitabine, lamivudine and tenofovir, are in agreement with published data [35,36]. ≤0.9 [37] 64…”

Section: Nas Induce Mutagenesis In Bacteria At Concentrations That Do...supporting

confidence: 90%

Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis

et al. 2021

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Drugs targeting DNA and RNA in mammalian cells or viruses can also affect bacteria present in the host and thereby induce the bacterial SOS system. This has the potential to increase mutagenesis and the development of antimicrobial resistance (AMR). Here, we have examined nucleoside analogues (NAs) commonly used in anti-viral and anti-cancer therapies for potential effects on mutagenesis in Escherichia coli, using the rifampicin mutagenicity assay. To further explore the mode of action of the NAs, we applied E. coli deletion mutants, a peptide inhibiting Pol V (APIM-peptide) and metabolome and proteome analyses. Five out of the thirteen NAs examined, including three nucleoside reverse transcriptase inhibitors (NRTIs) and two anti-cancer drugs, increased the mutation frequency in E. coli by more than 25-fold at doses that were within reported plasma concentration range (Pl.CR), but that did not affect bacterial growth. We show that the SOS response is induced and that the increase in mutation frequency is mediated by the TLS polymerase Pol V. Quantitative mass spectrometry-based metabolite profiling did not reveal large changes in nucleoside phosphate or other central carbon metabolite pools, which suggests that the SOS induction is an effect of increased replicative stress. Our results suggest that NAs/NRTIs can contribute to the development of AMR and that drugs inhibiting Pol V can reverse this mutagenesis.

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Section: Nas Induce Mutagenesis In Bacteria At Concentrations That Do...supporting

confidence: 90%

Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis

et al. 2021

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“…RT with the M184V mutation was also found not to be resistant to D4GTP. While D4TTP has not been tested against RT M184V in a transient kinetic study, this mutation has never been associated with D4T resistance in vivo or in vitro (52). These results suggest that the 2′,3′-dideoxyribose ring of the analogue is an important factor in governing its incorporation and the base may play a less prominent role in determining incorporation efficiency or resistance.…”

Section: Discussionmentioning

confidence: 97%

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

et al. 2002

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Abacavir (1592U89, or Ziagen) is a powerful and selective inhibitor of HIV-1 viral replication that has been approved by the FDA for treatment of acquired immunodeficiency syndrome. Abacavir is metabolized to the active compound carbovir triphosphate (CBVTP). This compound is a guanosine analogue containing a 2',3'-unsaturation in its planar carbocyclic deoxyribose ring that acts on HIV-1 reverse transcriptase (RT(WT)) as a molecular target, resulting in chain termination of DNA synthesis. A single amino acid change from methionine 184 to valine in HIV-1 RT (RT(M184V)) has been observed clinically in response to abacavir treatment. The ability of the natural substrate, dGTP, or CBVTP to be utilized during DNA- and RNA-directed polymerization by RT(WT) and RT(M184V) was defined by pre-steady-state kinetic parameters. In the case of RT(WT), CBVTP was found to be a surprisingly poor substrate relative to dGTP. In both DNA- and RNA-directed polymerization, a decrease in the efficiency of CBVTP utilization with respect to dGTP was found with RT(M184V), suggesting that this mutation confers resistance at the level of CBVMP incorporation. The relatively low incorporation efficiency for RT(WT) was unanticipated considering earlier studies showing that the triphosphate form of a thymidine nucleoside analogue containing a planar 2',3'-unsaturated ribose ring, D4TTP, was incorporated with high efficiency relative to the natural substrate, dTTP. The difference may be related to the isosteric replacement of oxygen in the deoxyribose ring with carbon. This hypothesis was tested by synthesizing and evaluating D4GTP (the planar 2',3'-unsaturated deoxyribose guanosine analogue that is complementary to D4TTP). In contrast to CBVTP, D4GTP was found to be an excellent substrate for RT(WT) and no resistance was conferred by the M184V mutation, thus providing novel insight into structure-activity relationships for nucleoside-based inhibitors. In this work, we illustrate how an understanding of the molecular mechanism of inhibition and drug resistance led to the discovery of a novel prodrug of D4G. This compound shows promise as a potent antiviral especially with the drug resistant M184V HIV-1 RT that is so often encountered in a clinical setting.

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“…In pregnancy, drug changes have to be quickly implemented, which may not be compatible with the delay required for HLA typing. Finally, D4T has been associated with peripheral neuropathy, lactic acidosis and other metabolic abnormalities including lipodystrophy [37, 38]. Nevertheless, this drug continues to be widely used in resource-limited countries.…”

Section: Discussionmentioning

confidence: 99%

Safety and Tolerability of Antiretrovirals during Pregnancy

Weinberg

Forster-Harwood

Davies

et al. 2011

Infectious Diseases in Obstetrics and Gynecology

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Combination antiretroviral therapy (CART) dramatically decreases mother-to-child HIV-1 transmission (MTCT), but maternal adverse events are not infrequent. A review of 117 locally followed pregnancies revealed 7 grade ≥3 AEs possibly related to antiretrovirals, including 2 hematologic, 3 hepatic, and 2 obstetric cholestasis cases. A fetal demise was attributed to obstetric cholestasis, but no maternal deaths occurred. The drugs possibly associated with these AE were zidovudine, nelfinavir, lopinavir/ritonavir, and indinavir. AE or intolerability required discontinuation/substitution of nevirapine in 16% of the users, zidovudine in 10%, nelfinavir in 9%, lopinavir/ritonavir in 1%, but epivir and stavudine in none. In conclusion, nevirapine, zidovudine, and nelfinavir had the highest frequency of AE and/or the lowest tolerability during pregnancy. Although nevirapine and nelfinavir are infrequently used in pregnancy at present, zidovudine is included in most MTCT preventative regimens. Our data emphasize the need to revise the treatment recommendations for pregnant women to include safer and better-tolerated drugs.

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Stavudine

Cited by 54 publications

References 94 publications

Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis

Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis

Insights into the Molecular Mechanism of Inhibition and Drug Resistance for HIV-1 RT with Carbovir Triphosphate

Safety and Tolerability of Antiretrovirals during Pregnancy

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