Nonnucleoside reverse transcriptase

Heterocycles as nonnucleoside reverse transcriptase inhibitors for therapy of HIV-1 infection 99F26. 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

Highly active antiretroviral therapy (HAART) based on protease inhibitors or nonnucleoside reverse transcriptase inhibitors was introduced in the industrialized world during the second half of the 1990s. The majority of studies are based on data from the United States of America. 

Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C (2006) Proteolytic processing of SDF-lalpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Nad Acad Sci USA 103(50) 19182-19187 von Giesen HJ, Roller H, Theisen A, Arendt G (2002) Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HlV-1-infected patients. J Acquir Immune Defic Syndr 29(4) 363-367... 

Treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) is the mainstay of treatment for HIV infection. 

NRTI, nucleoside reverse transcriptase inhibitor NNRTI, nonnucleoside reverse transcriptase inhibitor PI, protease inhibitor. 

TDF/FTC) Truvada Nonnucleoside Reverse Transcriptase Inhibitors FTC 2 00 mg tab (mL/minute) Dose 30-49 1 tablet q48hours Less than 30 Not recommended None See adverse events fo TDF and FTC See TDF and FTC... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) A noncompetitive inhibitor of the viral reverse transcriptase enzyme that binds to the active site of the enzyme itself, rather than by terminating the enzymatic product. NNRTIs are only active against human immunodeficiency virus-1. 

The nonnucleoside reverse transcriptase inhibitors (NNRTIs), used in the treatment of AIDS, provide interesting examples of clinically relevant noncompetitive inhibitors. The causative agent of AIDS, HIV, belongs to a virus family that relies on an RNA-based genetic system. Replication of the vims requires reverse transcription of the viral genomic RNA into DNA, which is then incorporated into the genome of the infected host cell. Reverse transcription is catalyzed by a virally encoded nucleic acid polymerase, known as reverse transcriptase (RT). This enzyme is critical for viral replication inhibition of HIV RT is therefore an effective mechanism for abrogating infection in patients. 

A series of 4,4-disubstituted quinazolin-2-ones derived from HTV nonnucleoside reverse transcriptase inhibitor leads have shown good in vitro potency and in vivo efficacy [28]. Using FLIPR assays on cell lines with different resting membrane potentials, TTA-Q3 (10) and TTA-Q6 (11)... 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Nonnucleoside reverse transcriptase inhibitors Protease inhibitors Amantadine Interferons Ribavirin... 

The answer is f. (Kat urtg, p 837.) Havirenz is a specific inhibitor of HIV-1 viral growth. Its mechanism of action involves inhibition of nonnucleoside reverse transcriptase. 

Nonnucleoside reverse transcriptase inhibitors (del-avirdine, efavirenz, nevirapine)... 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) for combination with dual NRTIs (strength of recommendation in parentheses)... 

Inhibiting viral replication with combination of potent antiretroviral therapy has been the most clinically successful strategy in the treatment of HIV infection. There have been three primary groups of drugs used nucleoside and nonnucleoside reverse transcriptase inhibitors and protease inhibitors (Pis) (Table 40-5). 

Isoniazid Daily for 9 months0 In HIV-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors, protease inhibitors, or nonnucleoside reverse transcriptase inhibitors A (II) A (II)... 

Novel nonnucleoside reverse transcriptase (NNRT) inhibitor, 18 722 Novel reactor systems, design of, 20 742-744... 

Drugs that affect voriconazole include the following barbiturates (long acting), cimetidine, nonnucleoside reverse transcriptase inhibitors (NNRIs), phenytoin, protease inhibitors, proton pump inhibitors, rifampin, rifabutin. 

HIV - The initial phase of a 6-month tuberculosis regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol for patients receiving therapy with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. These drugs are administered a) daily for at least the first 2 weeks, followed by twice weekly dosing for 6 weeks or b) daily for 8 weeks to complete the 2-month induction phase. The second phase of treatment consists of rifabutin and isoniazid administered twice weekly or daily for 4 months. 

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