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Dolutegravir (GSK1349572)

Description of : Dolutegravir (GSK1349572): Dolutegravir (formerly know as GSK1349572) is an experimental new drug under investigation for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Also known as S/GSK1349572 or just "572", the drug is under development by GlaxoSmithKline (GSK). Studies have shown dolutegravir to be effective in patients with resistance to the only currently available integrase inhibitor, raltegravir. Clinical trials are underway to support dolutegravir in combination with abacavir and lamivudine, in a new new fixed dose combination called 572-Trii. Results from the 96-week comparison with efavirenz, SPRING-1, showed dolutegravir 50mg orally to be effective at reducing HIV viral load and raising CD4 counts in integrase-naive patients. (source: http://en.wikipedia.org/wiki/Dolutegravir).

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2: Rhodes MC, Laffan S, Genell C, Gower J, Maier C, Fukushima T, Nichols G, Eaton Bassiri A. Assessing a Theoretical Risk of Dolutegravir-Induced Developmental Immunotoxicity in Juvenile Rats. Toxicol Sci. 2012 Jul 12. [Epub ahead of print] PubMed PMID: 22790968.

3: Adams JL, Greener BN, Kashuba AD. Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS. 2012 Jul 19. [Epub ahead of print] PubMed PMID: 22789987.

4: Lennox JL. The use of HIV-1 integrase inhibitors in antiretroviral naive patients. Curr Opin HIV AIDS. 2012 Jul 19. [Epub ahead of print] PubMed PMID: 22789985.

5: Shamroe CL, Bookstaver PB, Rokas KE, Weissman SB. Update on raltegravir and the development of new integrase strand transfer inhibitors. South Med J. 2012 Jul;105(7):370-8. PubMed PMID: 22766666.

6: Saladini F, Meini G, Bianco C, Monno L, Punzi G, Pecorari M, Borghi V, Di Pietro M, Filice G, Gismondo MR, Micheli V, Penco G, Carli T, De Luca A, Zazzi M; for the ARCA Collaborative Group. Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naïve and pretreated patients. Clin Microbiol Infect. 2012 May 28. doi: 10.1111/j.1469-0691.2012.03917.x. [Epub ahead of print] PubMed PMID: 22716970.

7: Quashie PK, Sloan RD, Wainberg MA. Novel therapeutic strategies targeting HIV integrase. BMC Med. 2012 Apr 12;10:34. Review. PubMed PMID: 22498430; PubMed Central PMCID: PMC3348091.

8: Nguyen HL, Ruxrungtham K, Delaugerre C. Genetic barrier to the development of resistance to integrase inhibitors in HIV-1 subtypes CRF01_AE and B. Intervirology. 2012;55(4):287-95. Epub 2012 Mar 23. PubMed PMID: 22456540.

9: Chen S, Min SS, Peppercorn A, Borland J, Lou Y, Song I, Fujiwara T, Piscitelli SC. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacotherapy. 2012 Apr;32(4):333-9. doi: 10.1002/j.1875-9114.2012.01033.x. Epub 2012 Mar 15. PubMed PMID: 22422361.

10: Katlama C, Murphy R. Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs. 2012 Apr;21(4):523-30. Epub 2012 Mar 2. Review. PubMed PMID: 22380682.

11: Demeulemeester J, Tintori C, Botta M, Debyser Z, Christ F. Development of an AlphaScreen-based HIV-1 integrase dimerization assay for discovery of novel allosteric inhibitors. J Biomol Screen. 2012 Jun;17(5):618-28. Epub 2012 Feb 14. PubMed PMID: 22337657.

12: Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs. 2012 Mar;21(3):395-401. Epub 2012 Feb 10. Review. PubMed PMID: 22321026.

13: Quashie PK, Mesplède T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR, Wainberg MA. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol. 2012 Mar;86(5):2696-705. Epub 2011 Dec 28. PubMed PMID: 22205735; PubMed Central PMCID: PMC3302270.

14: Song I, Borland J, Chen S, Patel P, Wajima T, Peppercorn A, Piscitelli SC. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012 Mar;56(3):1627-9. Epub 2011 Dec 19. PubMed PMID: 22183173; PubMed Central PMCID: PMC3294934.

15: Waki K, Sugawara Y. Implications of integrase inhibitors for HIV-infected transplantation recipients: raltegravir and dolutegravir (S/GSK 1349572). Biosci Trends. 2011;5(5):189-91. PubMed PMID: 22101373.

16: Johnson BC, Métifiot M, Pommier Y, Hughes SH. Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity. Antimicrob Agents Chemother. 2012 Jan;56(1):411-9. Epub 2011 Oct 28. PubMed PMID: 22037850; PubMed Central PMCID: PMC3256025.

17: van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, Rockstroh JK, Almond S, Song I, Brothers C, Min S. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012 Feb;12(2):111-8. Epub 2011 Oct 20. PubMed PMID: 22018760.

18: Boyd M. Dolutegravir--a promising antiretroviral in development. Lancet Infect Dis. 2012 Feb;12(2):90-1. Epub 2011 Oct 20. PubMed PMID: 22018759.

19: Canducci F, Ceresola ER, Boeri E, Spagnuolo V, Cossarini F, Castagna A, Lazzarin A, Clementi M. Cross-resistance profile of the novel integrase inhibitor Dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis. 2011 Dec 1;204(11):1811-5. Epub 2011 Oct 7. PubMed PMID: 21984737.

20: Cotelle P. 3-Hydroxy-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-ones as new HIV-1 integrase inhibitors WO2011046873 A1. Expert Opin Ther Pat. 2011 Nov;21(11):1799-804. doi: 10.1517/13543776.2011.624272. Epub 2011 Oct 6. PubMed PMID: 21974685.

21: Malet I, Fourati S, Charpentier C, Morand-Joubert L, Armenia D, Wirden M, Sayon S, Van Houtte M, Ceccherini-Silberstein F, Brun-Vézinet F, Perno CF, Descamps D, Capt A, Calvez V, Marcelin AG. The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype. J Antimicrob Chemother. 2011 Dec;66(12):2827-30. Epub 2011 Sep 19. PubMed PMID: 21933786.

22: Hightower KE, Wang R, Deanda F, Johns BA, Weaver K, Shen Y, Tomberlin GH, Carter HL 3rd, Broderick T, Sigethy S, Seki T, Kobayashi M, Underwood MR. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother. 2011 Oct;55(10):4552-9. Epub 2011 Aug 1. PubMed PMID: 21807982; PubMed Central PMCID: PMC3187001.

23: Hare S, Smith SJ, Métifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. Epub 2011 Jun 30. PubMed PMID: 21719464; PubMed Central PMCID: PMC3187526.

24: Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli S, Lalezari J. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45. PubMed PMID: 21716073.

25: Song I, Borland J, Min S, Lou Y, Chen S, Patel P, Wajima T, Piscitelli SC. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011 Jul;55(7):3517-21. Epub 2011 May 9. PubMed PMID: 21555764; PubMed Central PMCID: PMC3122457.

26: Garrido C, Soriano V, Geretti AM, Zahonero N, Garcia S, Booth C, Gutierrez F, Viciana I, de Mendoza C. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients--impact of HIV subtypes and prior raltegravir experience. Antiviral Res. 2011 Jun;90(3):164-7. Epub 2011 Mar 23. PubMed PMID: 21439330.

27: Song I, Borland J, Chen S, Lou Y, Peppercorn A, Wajima T, Min S, Piscitelli SC. Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011 Jul;72(1):103-8. doi: 10.1111/j.1365-2125.2011.03947.x. PubMed PMID: 21342217; PubMed Central PMCID: PMC3141191.

28: Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. Epub 2009 Nov 2. PubMed PMID: 19884365; PubMed Central PMCID: PMC2798521.