同: stavudine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/03 21:03:44」(JST)

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

History

Stavudine was first synthesized 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.

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 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."^[4]

Sources

^ J.P. Horwitz et al.. J. Org. Chem. 31. 205 (1966).
^ 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.
^ http://www.ncbi.nlm.nih.gov/pubmed/20073992
^ 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.

UpToDate Contents

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1. ヌクレオシド系逆転写酵素阻害剤の薬理学 pharmacology of nucleoside reverse transcriptase inhibitors
2. HIVヌクレオシド系逆転写酵素阻害剤のミトコンドリア毒性 mitochondrial toxicity of hiv nucleoside reverse transcriptase inhibitors
3. 抗レトロウイルス療法の潜在的副作用に関するHIV感染患者を対象としたカウンセリング counseling hiv infected patients regarding potential side effects of antiretroviral therapy
4. 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
5. HIV関連リポジストロフィーの治療 treatment of hiv associated lipodystrophy

English Journal

The DiPPro Approach: Synthesis, Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs.

Schulz T1, Balzarini J, Meier C.Author information 1Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg (Germany).AbstractBioreversible protection of the β-phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure-activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids of various lengths and d4T as a model nucleoside. For synthesis of the lipophilically modified diphosphate group, preformed phosphoramidites were allowed to react with nucleotides, and the β-P(III) moiety was subsequently oxidized. The chemical and enzymatic stability of these prodrugs was studied in different media such as phosphate buffer (pH 7.3) or CEM cell extracts. In all media, the hydrolysis rate was clearly dependent on the acyl moiety and decreased with increasing alkyl chain length. The compounds showed a markedly lower half-life in cell extracts than in pH 7.3 phosphate buffer due to the presence of enzyme-catalyzed cleavage. In all media, the DiPPro compounds released d4T diphosphate (d4TDP) as the main product beside d4TMP. In antiviral assays, the compounds proved to be at least as potent as d4T against HIV-1 and 2 in wild-type CEM/0 cells. As a proof of concept, compounds with longer acyl residues showed very good anti-HIV activities in thymidine-kinase-deficient cells (CEM/TK(-) ), indicating their ability to penetrate cell membranes and the delivery of phosphorylated metabolites.
ChemMedChem.ChemMedChem.2014 Apr;9(4):762-75. doi: 10.1002/cmdc.201300500. Epub 2014 Mar 11.
Bioreversible protection of the β-phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure-activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids
PMID 24616176

Characteristics and Factors Associated with the Clinical Forms of Lipoatrophy during Highly Active Antiretroviral Therapy in Ouagadougou, Burkina Faso.

Guira O1, Tiéno H, Yaméogo B, Diendéré AE, Korsaga N, Sagna Y, Zoungrana L, Diallo I, Traoré R, Drabo JY.Author information 1Unité de formation et de recherche en sciences de la santé, Université de Ouagadougou, Ouagadougou, Burkina Faso.AbstractBackground: We aimed to study the factors associated with clinical forms of lipoatrophy in patients receiving highly active antiretroviral therapy (HAART) in Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso. Methods: This cross-sectional review from March 10 to November 10, 2011, included a nonprobability sample of HIV-infected adults receiving antiretroviral (ARV) medications for at least 6 months and monitored in the internal medicine department. The diagnosis of lipoatrophy was clinical. Results: Three hundred patients were included. The sex ratio was 0.4 and the mean age was 42.1 ± 8.5 years. The mean duration of HAART was 73.2 ± 30.9 months. In all, 97 (32.3%) patients had lipoatrophy: 75 (25%) isolated and 22 (7.3%) mixed syndrome. Facial lipoatrophy was frequent (61.8%). Isolated lipoatrophy was associated with male sex (P = .002) and body mass index ≤25 (P < .05). Mixed syndrome was associated with female sex (P = .002), age >42 years (P < .05), physical activity (P = .003), smoking (P = .001), stavudine (d4T; P = .0001), or protease inhibitors (P = .01). Conclusion: Prevention of lipoatrophy associated with HAART requires the exclusion of modifiable risk factors that we identified.
Journal of the International Association of Providers of AIDS Care.J Int Assoc Provid AIDS Care.2014 Mar-Apr;13(2):184-7. doi: 10.1177/2325957413503369. Epub 2013 Oct 10.
Background: We aimed to study the factors associated with clinical forms of lipoatrophy in patients receiving highly active antiretroviral therapy (HAART) in Yalgado Ouédraogo Teaching Hospital, Ouagadougou, Burkina Faso. Methods: This cross-sectional review from March 10 to November 10, 2011, incl
PMID 24114724

cART prescription trends in a prospective HIV cohort in rural Tanzania from 2007 to 2011.

Franzeck FC1, Letang E, Mwaigomole G, Jullu B, Glass TR, Nyogea D, Hatz C, Tanner M, Battegay M.Author information 1Swiss Tropical and Public Health Institute (SwissTPH), Socinstrasse 57, CH-4051 Basel, Switzerland. fcfranzeck@gmail.com.AbstractBACKGROUND: Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first-line regimens due to frequent and severe side effects. This study describes the implementation of this recommendation and trends in usage of antiretroviral therapy combinations in a cohort of HIV-positive patients in rural Tanzania.
BMC infectious diseases.BMC Infect Dis.2014 Feb 20;14:90. doi: 10.1186/1471-2334-14-90.
BACKGROUND: Since 2010, World Health Organization (WHO) guidelines discourage using stavudine in first-line regimens due to frequent and severe side effects. This study describes the implementation of this recommendation and trends in usage of antiretroviral therapy combinations in a cohort of HIV-p
PMID 24552395

Japanese Journal

抗ウイルス剤の創製を目指した新規炭素環ヌクレオシド類の合成

熊本浩樹
昭和大学薬学雑誌 1(1), 1-15, 2010-03
NAID 40018726213

High throughput LC-MS/MS method for simultaneous quantification of lamivudine, stavudine and nevirapine in human plasma

MISTRI Hiren N.,JANGID Arvind G.,PUDAGE Ashutosh,GOMES Noel,SANYAL Mallika,SHRIVASTAV Pranav
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 853(1), 320-332, 2007-06-15
NAID 10025804437

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リンク元	「サニルブジン」「核酸系逆転写酵素阻害薬」「stavudine」

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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	DB00649
ChemSpider	17270
UNII	BO9LE4QFZF
KEGG	D00445
ChEMBL	CHEMBL991
NIAID ChemDB	000005
Chemical data
Formula	C10H12N2O4
Mol. 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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