WordNet

a nucleoside reverse transcriptase inhibitor that is very effective in combination with zidovudine in treating AIDS and HIV (同)3TC

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/26 01:59:48」(JST)

wiki en

"3TC" redirects here. For the three-coach British electric trains sometimes known as 3TC, see British Rail Class 438.

Lamivudine (2′,3′-dideoxy-3′-thiacytidine, commonly called 3TC) is a potent nucleoside analog reverse transcriptase inhibitor (nRTI). It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.

Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine unfortunately leads to emergence of a resistant hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[1]

Mechanism of action

Lamivudine is an analogue of cytidine. It can inhibit both types (1 and 2) of HIV reverse transcriptase and also the reverse transcriptase of hepatitis B. It is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

Lamivudine is administered orally, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggests that lamivudine can cross the blood–brain barrier. Lamivudine is often given in combination with zidovudine, with which it is highly synergistic. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. Lamivudine showed no evidence of carcinogenicity or mutagenicity in in vivo studies in mice and rats at doses from 10 to 58 times those used in humans.^[2]

Resistance

See also: resistance mutation

In HIV, high level resistance is associated with the M184V/I mutation in the reverse transcriptase gene as first reported by Raymond Schinazi's group at Emory University. GlaxoSmithKline claimed that the M184V mutation reduces "viral fitness", because of the finding that continued lamivudine treatment causes the HIV viral load to rebound but at a much lower level, and that withdrawal of lamivudine results in a higher viral load rebound with rapid loss of the M184V mutation; GSK therefore argued that there may be benefit in continuing lamivudine treatment even in the presence of high level resistance, because the resistant virus is "less fit". The COLATE study has suggested that there is no benefit to continuing lamivudine treatment in patients with lamivudine resistance.^[3] A better explanation of the data is that lamivudine continues to have a partial anti-viral effect even in the presence of the M184V mutation.

In hepatitis B, lamivudine resistance was first described in the YMDD locus of the HBV reverse transcriptase gene. The HBV reverse transcriptase gene is 344 amino acids long and occupies codons 349 to 692 on the viral genome. The most commonly encountered resistance mutations are M204V/I/S.^[4] The change in amino acid sequence from YMDD to YIDD results in a 3.2 fold reduction in the error rate of the reverse transcriptase, which correlates with a significant growth disadvantage of the virus. Other resistance mutations are L80V/I, V173L and L180M.^[5]

History

Racemic BCH-189 (the minus form is known as Lamivudine) was invented by Dr. Bernard Belleau while at work at McGill University and Dr Paul Nguyen-Ba at the Montreal-based IAF BioChem International, Inc. laboratories in 1988 and the minus enantiomer isolated in 1989. Dr. Yung-Chi Cheng of Yale University in collaboration with R.F. Schinazi and D.C. Liotta first reported the anti-hepatitis B virus (HBV) activity of Lamivudine in cell culture which eventually led to the first oral antiviral agent for the treatment of HBV. Subsequently the group at Emory University headed by Dr. Dennis C. Liotta Dr. Woo-Baeg Choi and Dr. Raymond F. Schinazi developed a synthesis for the BCH-189 that gave exclusively the beta-enantiomers. They then went on to resolve the two enantiomers and demonstrated that the antiviral activity at non-toxic concentrations resided in the (-)-enantiomer, now called Lamivudine. The Emory patents to lamivudine were later invalidated by the original inventors. The drug's effectiveness for treating HIV in combination with AZT was discovered accidentally when a patient took Zidovudine secretly while in a clinical trial of Lamivudine monotherapy. The drug was later licensed to the British pharmaceutical company Glaxo by Biochem Pharma (now Shire Pharmaceuticals) for a 14 percent royalty. GlaxoSmithKline subsequently ceded the product to its ViiV Healthcare joint venture in 2009.

Lamivudine was approved by the Food and Drug Administration (FDA) on November 17, 1995 for use with zidovudine (AZT) and again in 2002 as a once-a-day dosed medication. The fifth antiretroviral drug on the market, it was the last NRTI for three years while the approval process switched to protease inhibitors. According to the manufacturer's 2004 annual report, its patent will expire in the United States in 2010 and in Europe in 2011.

Presentation

Epivir 150 mg or 300 mg tablets (GlaxoSmithKline; US and UK) for the treatment of HIV;
Epivir-HBV 100 mg tablets (GlaxoSmithKline; US only) for the treatment of hepatitis B;
Zeffix 100 mg tablets (GlaxoSmithKline; UK only) for the treatment of hepatitis B.
3TC 150 mg tablets (GlaxoSmithKline; South Africa) for the treatment of HIV;

Lamivudine is also available in fixed combinations with other HIV drugs:

Combivir (with zidovudine);
Epzicom/Kivexa (with abacavir);
Trizivir (with zidovudine and abacavir)

References

^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
^ "Epivir package insert" (PDF). GlaxoSmithKline. Retrieved January 20, 2011.
^ Fox Z, Dragsted UB, Gerstoft J et al. (2006). "A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: The COLATE trial". Antiviral Therapy 11 (6): 761–70. PMID 17310820.
^ http://hivdb.stanford.edu/index.html Stanford University Drug Resistance Database.
^ Koziel MJ, Peters MG (2007). "Viral hepatitis in HIV infection". N Engl J Med 356 (14): 1445–54. doi:10.1056/NEJMra065142. PMID 17409326.

External links

Epivir (manufacturer's website)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 慢性B型肝炎ウイルス感染に対するラミブジン単剤療法 lamivudine monotherapy for chronic hepatitis b virus infection
2. Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient selecting antiretroviral regimens for the treatment naive hiv infected patient
3. 小児におけるB型肝炎ウイルス感染の概要 overview of hepatitis b virus infection in children
4. B型肝炎のマネージメントの概要および症例 overview of the management of hepatitis b and case examples
5. 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

English Journal

Isolation and identification of an anti-hepatitis B virus compound from Hydrocotyle sibthorpioides Lam.

Huang Q, Zhang S, Huang R, Wei L, Chen Y, Lv S, Liang C, Tan S, Liang S, Zhuo L, Lin X.SourceThe First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China.
Journal of ethnopharmacology.J Ethnopharmacol.2013 Nov 25;150(2):568-75. doi: 10.1016/j.jep.2013.09.009. Epub 2013 Sep 16.
ETHNOPHARMACOLOGICAL RELEVANCE: Hydrocotyle sibthorpioides (Apiaceae) have been used as a folk remedy for the treatment of fever, edema, detoxication, throat pain, psoriasis and hepatitis B virus infections in China. The aim of this study is to isolate and identify an anti-HBV compound from this her
PMID 24051027

Outcomes by Sex following Treatment Initiation with Atazanavir plus Ritonavir or Efavirenz with Abacavir/Lamivudine or Tenofovir/Emtricitabine.

Smith KY, Tierney C, Mollan K, Venuto CS, Budhathoki C, Ma Q, Morse GD, Sax P, Katzenstein D, Godfrey C, Fischl M, Daar ES, Collier AC; ACTG 5202 Study Team.SourceRush University Medical Center.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.Clin Infect Dis.2013 Nov 18. [Epub ahead of print]
Background. To evaluate treatment responses to atazanavir plus ritonavir or efavirenz in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. Methods. Randomized trial of open label atazanavir plus ritonavir or efavirenz combined with abacavir/l
PMID 24253247

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity.

Xu HT, Colby-Germinario SP, Oliveira M, Han Y, Quan Y, Zanichelli V, Wainberg MA.SourceMcGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Journal of virology.J Virol.2013 Nov 13. [Epub ahead of print]
Clinical resistance to rilpivirine (RPV), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), is associated a mutation at position E138K in RT together with an M184I/V mutation that confers resistance against emtricitabine (FTC), a nucleoside RT inhibitor (NRTI) that is given together wi
PMID 24227862

Japanese Journal

Pure Red Cell Aplasia Induced by Lamivudine without the Influence of Zidovudine in a Patient Infected with Human Immunodeficiency Virus

Nakamura Kiwamu,Tateyama Masao,Tasato Daisuke,Haranaga Shusaku,Tamayose Maki,Yara Satomi,Higa Futoshi,Fujita Jiro
Internal Medicine 53(15), 1705-1708, 2014
We herein report the case of a patient with human immunodeficiency virus infection and acquired immune deficiency syndrome who was diagnosed with drug-induced pure red cell aplasia consequent to lamiv …
NAID 130004678378

Molecular analysis of the genes causing recessive demyelinating Charcot-Marie-Tooth disease in Japan

HAYASHI Makiko,ABE Akiko,MURAKAMI Tatsufumi,YAMAO Satoshi,ARAI Hidee,HATTORI Hideji,IAI Mizue,WATANABE Kyoko,OKA Nobuyuki,CHIDA Keiji,KISHIKAWA Yumiko,HAYASAKA Kiyoshi
Journal of human genetics 58(5), 273-278, 2013-05-01
NAID 10031177222

Molecular analysis of the genes causing recessive demyelinating Charcot-Marie-Tooth disease in Japan

Hayashi Makiko,Abe Akiko,Murakami Tatsufumi [他]
Journal of human genetics 58(5), 273-278, 2013-05
NAID 40019651872

Related Pictures

★リンクテーブル★

リンク元	「ラミブジン」「LAM」「核酸系逆転写酵素阻害薬」「lamivudine」

「ラミブジン」

Lamivudine
Systematic (IUPAC) name
	4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a696011
Pregnancy cat.	B3 (AU) C (US)
Legal status	POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	86%
Protein binding	Less than 36%
Half-life	5 to 7 hours
Excretion	Renal (circa 70%)
Identifiers
CAS number	134678-17-4
ATC code	J05AF05
PubChem	CID 73339
DrugBank	DB00709
ChemSpider	66068
UNII	2T8Q726O95
KEGG	D00353
ChEMBL	CHEMBL141
NIAID ChemDB	000388
Synonyms	L-2′,3′-dideoxy-3′-thiacytidine
PDB ligand ID	3TC (PDBe, RCSB PDB)
Chemical data
Formula	C8H11N3O3S
Mol. mass	229.26 g/mol
	SMILES O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H](SC2)CO;
	InChI InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m1/s1 ; Key:JTEGQNOMFQHVDC-RQJHMYQMSA-N ;
(what is this?) (verify)