Dapivirine

"目錄號: HY-14266

Anti-infection-

Dapivirine(TMC 120, TMC 120 R147681)是HIV非核苷逆轉錄酶抑制劑(NNRTI)溃论,IC50為24 nM,能抑制包括NNRTI抗性的各種HIV-1毒株。

HIVReverse Transcriptase

相關產(chǎn)品

Dolutegravir-Maraviroc-Elvitegravir-Atazanavir sulfate-Tenofovir Disoproxil Fumarate-Tipranavir-Triciribine-Emtricitabine-Efavirenz-Miltefosine-Ritonavir-Delavirdine mesylate-Lamivudine-Abacavir-BI 224436-

生物活性

Description

Dapivirine(TMC 120, TMC 120 R147681) is a NNRTI for HIV reverse transcriptase with IC50 of 24 nM, inhibits a broad panel of HIV-1 isolates from different classes, inclucing a wide range of NNRTI-resistant isolates.IC50 value: 24 nM [1]Target: HIV reverse transcriptase; NNRTIsin vitro: TMC120-R147681 is a diarylpyrimidine with high activity against wild-type and mutant HIV. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV, TMC120-R147681 apparently blocked infection in the primary cultures at a 10 nM concentration, but secondary cultures revealed that a 100 nM concentration was needed to completely prevent proviral integration [1]. Dapivirine is well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants with CC50 (50% cytotoxic concentration) of 10 μM to 20 μM. Dapivirine potently inhibits infection by both X4- and R5-utilizing HIV-1 strains with IC50 of 1.46 nM in cell-based assays. Dapivirine potently inhibits HIV-1BaL infection of human ectocervical explant tissue in a dose-dependent manner, as evaluated by the reduction in both p24 release and provirus content in cultured explants. Dapivirine inhibits the transmission of virus to permissive T cells in a dose-dependent manner, with an IC50 of 0.1 nM. Dapivirine results in significant inhibition of HIV infection when explants are challenged with virus immediately with IC90 of 100 nM. Dapivirine is also able to inhibit viral dissemination by migratory cells [2].in vivo: Dapivirine-containing gel at vaginal level inhibits cell-associated HIV infection in mice [3]. More placebo (7 of 12) than Dapivirine (3 of 24) gel users has positive vaginal swab results, with white blood cells being the most common finding. Dapivirine (0.05%) results in Cmax of 715 pg/mL, AUC of 15 ng×h/mL and T1/2 of 89.87 hours in plasma after 14 days post-dose. Mean Dapivirine (0.05%) concentrations in vaginal fluids collected at the introitus, mid vagina, and cervix are in the range of 62-265 μg/g on day 1 [4].

Clinical Trial

NCT02808949

International Partnership for Microbicides, Inc.

Human Immunodeficiency Virus

February 2015

Phase 1

NCT02010593

International Partnership for Microbicides, Inc.-National Institute of Allergy and Infectious Diseases (NIAID)

Human Immunodeficiency Virus

December 2013

Phase 2

NCT01731574

International Partnership for Microbicides, Inc.

HIV

December 2012

Phase 1

NCT02862171

International Partnership for Microbicides, Inc.

HIV Prevention

August 2016

Phase 3

NCT00799058

International Partnership for Microbicides, Inc.

HIV-1 Infections

June 2009

Phase 1-Phase 2

NCT03044379

International Partnership for Microbicides, Inc.

HIV 1 Infection

September 29, 2015

Phase 1

NCT02920827

International Partnership for Microbicides, Inc.

HIV Infections

August 2009

Phase 1

NCT02847286

International Partnership for Microbicides, Inc.

HIV- Prevention

September 1, 2015

Phase 1

NCT01924091

International Partnership for Microbicides, Inc.

Pharmaokinetics

September 2013

Phase 1

NCT01277640

International Partnership for Microbicides, Inc.

Topical Penile Exposures

March 2011

Phase 1

NCT00700284

International Partnership for Microbicides, Inc.-Tibotec Pharmaceutical Limited

HIV Infections

October 2004

Phase 1

NCT01071174

International Partnership for Microbicides, Inc.

HIV Infections

April 2010

Phase 1-Phase 2

NCT01337583

International Partnership for Microbicides, Inc.

HIV Infections

July 2011

Phase 3

NCT01337570

International Partnership for Microbicides, Inc.

HIV Infections

July 2011

Phase 3

NCT01952561

International Partnership for Microbicides, Inc.

Pharmacokinetics

November 2013

Phase 1

NCT01242579

International Partnership for Microbicides, Inc.

HIV Infections

January 2011

Phase 1

NCT00304642

International Partnership for Microbicides, Inc.

HIV Infections

November 2005

Phase 1

NCT02028338

International Partnership for Microbicides, Inc.-Microbicide Trials Network-National Institutes of Health (NIH)

Human Immunodeficiency Virus

March 2014

Phase 2

NCT00917904

International Partnership for Microbicides, Inc.

HIV Infections-Acquired Immunodeficiency Syndrome-Healthy

July 2009

Phase 1-Phase 2

NCT00332995

International Partnership for Microbicides, Inc.-Tibotec Pharmaceutical Limited

HIV Infections

July 2005

Phase 1

NCT00917891

International Partnership for Microbicides, Inc.

HIV Infections-Acquired Immunodeficiency Syndrome

November 2009

Phase 1-Phase 2

NCT01144676

International Partnership for Microbicides, Inc.

HIV Infections

April 2010

Phase 1

NCT01363037

International Partnership for Microbicides, Inc.

HIV Infections

November 2011

Phase 1

NCT02858037

International Partnership for Microbicides, Inc.

Human Immunodeficiency Virus

August 2016

Phase 3

NCT02858024

International Partnership for Microbicides, Inc.

HIV

January 2015

Phase 1

NCT00613249

International Partnership for Microbicides, Inc.

HIV Infections

November 2007

Phase 1

NCT01617096

International Partnership for Microbicides, Inc.-National Institute of Allergy and Infectious Diseases (NIAID)

HIV Infections

June 2012

Phase 3

NCT00469768

International Partnership for Microbicides, Inc.

HIV Infections

May 2007

Phase 1

NCT01548560

International Partnership for Microbicides, Inc.

HIV Infections

August 2012

Phase 1

NCT00309205

International Partnership for Microbicides, Inc.

HIV Infections-HIV-1

December 2005

Phase 1-Phase 2

NCT00304668

International Partnership for Microbicides, Inc.

HIV Infections

Phase 1-Phase 2

NCT00303576

International Partnership for Microbicides, Inc.

HIV Infections

October 2005

Phase 1-Phase 2

NCT03074786

International Partnership for Microbicides, Inc.-Gilead Sciences

HIV-1-infection

November 2017

Phase 2

NCT01755741

International Partnership for Microbicides, Inc.

Human Immunodeficiency Virus

February 2013

Phase 2

NCT01755754

International Partnership for Microbicides, Inc.

Human Immunodeficiency Virus

August 2013

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References

[1].Van Herrewege Y, et al. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004 Jan;48(1):337-9.

[2].Fletcher P, et al. Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2009 Feb;53(2):487-95.

[3].Di Fabio S, et al. Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS. 2003 Jul 25;17(11):1597-604.

[4].Nel AM, et al. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel. J Acquir Immune Defic Syndr. 2010 Oct;55(2):161-9.

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