Stavudine


Stavudine
Stavudine
Systematic (IUPAC) name
1-((2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a694033
Pregnancy cat. C (USA)
B3 (Aus)
Legal status  ?
Pharmacokinetic data
Protein binding Negligible
Metabolism Renal elimination (ca.40%)
Half-life 0.8-1.5 hours (in adults)
Identifiers
CAS number 3056-17-5
ATC code J05AF04
PubChem CID 18283
DrugBank APRD00440
ChemSpider 17270 YesY
NIAID ChemDB 000005
UNII BO9LE4QFZF YesY
KEGG D00445 YesY
ChEMBL CHEMBL991 YesY
Chemical data
Formula C10H12N2O4 
Mol. mass 224.213 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Stavudine (2'-3'-didehydro-2'-3'-dideoxythymidine, d4T, brand name Zerit) is a nucleoside analog reverse transcriptase inhibitor (NARTI) active against HIV.

Contents

History

Stavudine was first synthetized in the sixties by Jerome Horwitz.[1][2] It was subsequently reconsidered as an anti-HIV agent by the Rega Institute for Medical Research in Belgium. Stavudine was approved by the U.S. Food and Drug Administration (FDA) on June 24, 1994 for adults and on September 6, 1996 for pediatric use and again as an extended-release version for once-a-day dosing in 2001. The fourth antiretroviral drug on the market, its patent expired in the United States on 2008-06-25.

Mechanism of action

Stavudine is an analog of thymidine. It is phosphorylated by cellular kinases into active triphosphate. Stavudine triphosphate inhibits the HIV reverse transcriptase by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis by incorporating into it.

Simultaneous use of zidovudine is not recommended, as it can inhibit the intracellular phosphorylation of stavudine. Other anti-HIV drugs do not possess this property.

Pharmacokinetics

The oral absorption rate of stavudine is over 80%. Approximately half of stavudine is actively secreted unchanged into the urine and the other half is eliminated through endogenic pathways.

Adverse events

The main severe adverse effect is peripheral neuropathy, which can be corrected by reducing dosage. Stavudine has been shown in laboratory test to be genotoxic, but with clinical doses its carcinogenic effects are non-existent. It is also one of the most likely antiviral drugs to cause lipodystrophy, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.

It is still used as first choice in first line therapy in resource poor settings such as in India. Only in case of development of peripheral neuropathy or pregnancy is it changed to the next choice - Zidovudine.

On Monday 30 November 2009, the World Health Organisation stated that "[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine (AZT) or Tenofovir (TDF) are recommended as less toxic and equally effective alternatives."[3]

Sources

  1. ^ J.P. Horwitz et al.. J. Org. Chem. 31. 205 (1966).
  2. ^ Oral account of the history of AZT, d4T and ddC by Jerome Horwitz and Hiroaki Mitsuya in the documentary film I am alive today - History of an AIDS drug.
  3. ^ World Health Organisation news release, New HIV recommendations to improve health, reduce infections and save lives.

References

  • De Clercq E., Perspectives for the chemotherapy of AIDS, Chemioterapia. 1988 Dec;7(6):357-64.

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