同: d4T

同: Zerit, d4T

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/25 19:41:46」(JST)

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Stavudine (2′,3′-didehydro-2′,3′-dideoxythymidine, d4T, brand name Zerit) 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 on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[2]

Adverse eventsEdit

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.

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 use in Thailand.^[3]

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 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."^[4]

Mechanism of actionEdit

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.

PharmacokineticsEdit

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.

HistoryEdit

Stavudine was first synthesized in the 1960s by Jerome Horwitz.^[5]^[6] 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.

SourcesEdit

^ "Stavudine". The American Society of Health-System Pharmacists. Retrieved Jul 31,15. Check date values in: |access-date= (help)
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ 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.
^ "New HIV recommendations to improve health, reduce infections and save lives". World Health Organization. November 30, 2009.
^ 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 590081.
^ 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.

ReferencesEdit

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

UpToDate Contents

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1. Overview of antiretroviral agents used to treat HIV
2. HIV関連リポジストロフィーの治療 treatment of hiv associated lipodystrophy
3. HIV薬剤耐性検査の解釈についての手引 primer on interpretation of hiv drug resistance testing
4. HIV関連末梢神経障害の疫学、臨床症状、診断、および治療 epidemiology clinical manifestations diagnosis and treatment of hiv associated peripheral neuropathy
5. HIV感染患者におけるミトコンドリア毒性の治療および予防 treatment and prevention of mitochondrial toxicity in hiv infected patients

English Journal

Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment.

Bhatt NB1, Barau C2, Amin A2, Baudin E3, Meggi B4, Silva C3, Furlan V2, Grinsztejn B5, Barrail-Tran A6, Bonnet M3, Taburet AM7; the ANRS 12146-CARINEMO Study Group.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2014 Jun;58(6):3182-3190. Epub 2014 Mar 24.
This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the
PMID 24663014

Molecular basis of the association of H208Y and thymidine analogue resistance mutations M41L, L210W and T215Y in the HIV-1 reverse transcriptase of treated patients.

Betancor G1, Nevot M2, Mendieta J3, Gómez-Puertas P1, Martínez MA2, Menéndez-Arias L4.
Antiviral research.Antiviral Res.2014 Jun;106:42-52. doi: 10.1016/j.antiviral.2014.03.004. Epub 2014 Mar 22.
Thymidine analogue resistance mutations (TAMs) in HIV-1 reverse transcriptase (RT) associate in two clusters: (i) TAM1 (M41L, L210W and T215Y) and TAM2 (D67N, K70R, K219E/Q, and sometimes T215F). The amino acid substitution H208Y shows increased prevalence in patients treated with nucleoside analogu
PMID 24667336

Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384.

Leger PD1, Johnson DH, Robbins GK, Shafer RW, Clifford DB, Li J, McLaren PJ, Haas DW.
Journal of neurovirology.J Neurovirol.2014 Jun;20(3):304-8. doi: 10.1007/s13365-014-0235-9. Epub 2014 Feb 20.
Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed periphe
PMID 24554482

Japanese Journal

Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD)

Endocrine Journal 58(6), 475-484, 2011
NAID 130004443710

Prevalence of and Clinical Factors Associated with Lipoatrophy in HIV-Infected Koreans Receiving Highly Active Antiretroviral Therapy

Tohoku journal of experimental medicine 219(2), 145-153, 2009-10-01
NAID 10025534570

Molecularly imprinted polymer for analysis of zidovudine and stavudine in human serum by liquid chromatography-mass spectrometry

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 877(11), 1101-1108, 2009-04-15
NAID 10028015743

Related Pictures

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★リンクテーブル★

リンク元	「サニルブジン」「d4T」

「サニルブジン」

Stavudine
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	C (USA); B3 (AU);
Legal status	℞ (Prescription only);
Routes of; administration	Oral
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
ATC code	J05AF04
PubChem	CID: 18283
DrugBank	DB00649
ChemSpider	17270
UNII	BO9LE4QFZF
KEGG	D00445
ChEMBL	CHEMBL991
NIAID ChemDB	000005
Chemical data
Formula	C10H12N2O4
Molecular mass	224.213 g/mol
	SMILES O=C1/C(=C\N(C(=O)N1)[C@@H]/2O[C@@H](\C=C\2)CO)C ;
	InChI InChI=1S/C10H12N2O4/c1-6-4-12(10(15)11-9(6)14)8-3-2-7(5-13)16-8/h2-4,7-8,13H,5H2,1H3,(H,11,14,15)/t7-,8+/m0/s1 ; Key:XNKLLVCARDGLGL-JGVFFNPUSA-N ;
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　　[★]

英: sanilvudine
同: スタブジン stavudine(←洋書ではこちらが一般的),didehydrodeoxythymidine d4T
商: ゼリット Zerit、チミジン
関: 核酸系逆転写酵素阻害薬

「d4T」

　　[★] サニルブジン

同: stavudine

[AHFS2015-1] "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] 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.

[4] "New HIV recommendations to improve health, reduce infections and save lives". World Health Organization. November 30, 2009.

[5] 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 590081.

[6] 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.

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stavudine