Stavudine

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Stavudine
Stavudin.svg
Stavudine ball-and-stick.png
Systematic (IUPAC) name
1-[(2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
Clinical data
Trade names Zerit
AHFS/Drugs.com Monograph
MedlinePlus a694033
Pregnancy
category
Routes of
administration
Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability >80%
Protein binding Negligible
Metabolism Renal elimination (~40%)
Biological half-life 0.8–1.5 hours (in adults)
Identifiers
CAS Number 3056-17-5 YesY
ATC code J05AF04 (WHO)
PubChem CID 18283
DrugBank DB00649 YesY
ChemSpider 17270 YesY
UNII BO9LE4QFZF YesY
KEGG D00445 YesY
ChEMBL CHEMBL991 YesY
NIAID ChemDB 000005
Synonyms 2′,3′-didehydro-2′,3′-dideoxythymidine
Chemical data
Formula C10H12N2O4
Molar mass 224.213 g/mol
  (verify)

Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS.[1] It is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class. It is used in combination antiretroviral therapy (ART) in resource-constrained countries due to its low cost.

Stavudine is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[2] WHO now recommends it be phased out to due to high toxicity levels. Until an affordable alternative is available it is recommended that the dosage be lowered to reduce serious side effects. A 2015 Cochrane review found no clear advantage between high and low dosage regimens.[3]

Adverse events[edit]

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. Hyperlactatemia, bone mineral density (BMD) loss, reduction in limb fat and an increase in triglycerides were found when administered in high dosages. 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.

HLA-B*4001 may be used as a genetic marker to predict which patients will develop stavudine-associated lipodystrophy, to avoid or shorten the duration of stavudine according to a study in Thailand.[4]

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. Safety and effectiveness of dosage titration was not reported in treatment naive patients. It was only reported in those patients with sustained virologic suppression. These findings are not generalized to Stavudine used in ART naive patients who have high viral loads.

On Monday 30 November 2009, the World Health Organization 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."[5]

Mechanism of action[edit]

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 replication by incorporating into the DNA strand.

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[edit]

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.

History[edit]

Stavudine was first made in the 1960s by Jerome Horwitz.[6][7] It was subsequently reconsidered as an anti-HIV agent by the Rega Institute for Medical Research in Belgium. Stavudine was developed by Dr. William Prusoff and Dr. Tai-Shun Lin and subsequently 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 June 25, 2008.

Sources[edit]

  1. ^ "Stavudine". The American Society of Health-System Pharmacists. Retrieved Jul 31,15.  Check date values in: |access-date= (help)
  2. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ Magula, N; Dedicoat, M (28 January 2015). "Low dose versus high dose stavudine for treating people with HIV infection.". The Cochrane database of systematic reviews. 1: CD007497. doi:10.1002/14651858.CD007497.pub2. PMID 25627012. 
  4. ^ Wangsomboonsiri W, Mahasirimongkol S, Chantarangsu S, et al. (February 15, 2010). "Association between HLA-B*4001 and lipodystrophy among HIV-infected patients from Thailand who received a stavudine-containing antiretroviral regimen". Clinical Infectious Diseases. 50 (4): 597–604. doi:10.1086/650003. PMID 20073992. 
  5. ^ "New HIV recommendations to improve health, reduce infections and save lives". World Health Organization. November 30, 2009. 
  6. ^ J. P. Horwitz, J Chua, M DaRooge et al. (1966). "Nucleosides. IX. The formation of 2′,3′-unsaturated pyrimidine nucleosides via a novel β-elimination reaction". Journal of Organic Chemistry. 31: 205. doi:10.1021/jo01339a045. PMID 5900814. 
  7. ^ 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.

References[edit]

  • De Clercq E. (December 1988). "Perspectives for the chemotherapy of AIDS". Chemioterapia. 7 (6): 357–64.