NRTIs Nucleoside reverse transcriptase inhibitors

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

Isoniazid Daily for 9 monthsc,d In human immunodeficiency virus (HlV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). A (II) A (II)... 

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. 

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

Cross-resistance In clinical trials, patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. Consider the potential for cross-resistance between abacavir and other NRTIs when choosing new therapeutic regimens in therapy-experienced patients. 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI), launched for the treatment of HIV infection (Figure 8.6). It is currently in Phase III trials for the treatment of hepatitis B virus (HBV) infection. A prodrug of the NRTI alovudine— fosalvudine tidoxil—is currently in Phase II (Figure 8.1). 

In the HIV infected population, further evidence suggested that visceral fat accumulation, dyslipidemia, and insulin resistance are closely linked and associated with antiretroviral treatment, most pronounced with the use of protease inhibitors. In contrast, subcutaneous fat wasting is primarily determined by the choice of nucleoside reverse transcriptase inhibitor (NRTI). Switching studies have supported this notion, since substitution of stavudine has been associated with improvement in fat wasting, while switching a protease inhibitor had no beneficial effect in more than 30 clinical trials (142). 

Sluis-Cremer, N., Arion, D., and Parniak, M. A. (2000). Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Cell Mol. Life Sci. 57, 1408-1422. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

HIV is an RNA virus, meaning the viral genome is encoded as RNA instead of DNA. One key step in the virus cycle is to synthesize double-stranded viral DNA using viral RNA as a template. A viral enzyme called reverse transcriptase (RT) accomplishes this task. The reverse transcription process may be blocked by nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs have already been discussed somewhat in Chapter 6. 

Synthetic non-nucleoside RT inhibitor (NNRTI) in clinical use Synthetic nucleoside reverse transcriptase inhibitors (NRTIs) in clinical use metabolic conversion to the nucleoside triphosphate (NTP) (via the nucleoside monophosphate (NMP) and diphosphate (NDP)) gives DNA chain termination because of absence of 3 -hydroxyl (Note PMEA yields the phosphonate diphosphate ... 

Nucleoside reverse transcriptase inhibitors NRTIs are substrates for reverse transcriptase, which converts viral RNA into proviral DNA for incorporation into the host cell DNA. NRSIs are phosphorylated by host ceU enzymes to resemble normal nucleotides. When reverse transcriptase uses NRTI triphosphate instead of a nucleoside to form proviral DNA, the necessary chemical bonds cannot form and the DNA chain formed is left incomplete. 

Contemporary treatment of HIV infection requires the use of two nucleoside reverse transcriptase inhibitors (NRTI) combined with either a non-nucleoside reverse transcriptase inhibitors or a protease inhibitor. Which of the following NRTI backbones will you prefer to use in a patient recently diagnosed with HIV-associated dementia ... 

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of medications approved for the management of HIV infection. They are structural analogues of nucleic acids. They undergo intracellular phosphorylation to a triphosphate metabolite and it is this metabolite that is pharmacologically active against reverse transcriptase. Drugs in this class include abacavir, adefovir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. 

Thumbnail Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Nucleotide Reverse Transcriptase Inhibitors (NtRTIs), NNRTI, Pis ... 

In recent years, varions dmgs have been developed for the treatment of the human immunodeficiency vims (HIV) infection. The two most important compound classes are the HIV selective protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTI), and the non-nucleoside reverse transcriptase inhibitors (tiNRTI). Methods developed for TDM of these compounds are discussed here. TDM is required because of a high inter- and intra-individual variability. 

Nucleosides can be analysed by conventional reversed-phase (RP) LC with a buffered mobile phase. The separation of nucleotides is somewhat complicated by the dissociation of the phosphate groups and HINa exchange at these sites. As indicated for the phosphorylated anabolites of nucleoside reverse transcriptase inhibitors (NRTI, Ch. 13.2.4), ion-pair RPLC using 7V,7V-dimethylhexylamine (DMHA) can be applied to both reduce adduct formation and obtain sufficient retention [6-7]. Alternatively, enzymatic dephosphorylation of the nucleotides prior to LC-MS analysis can be performed. 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NRTI) ANTIRETROVIRAL... 

Some ofthe classical antiviral drugs in HIV therapy are nucleoside derivatives, and they are called nucleoside reverse transcriptase inhibitors (NRTIs). Zidovudine... 

Nucleoside reverse-transcriptase inhibitors (NRTIs) are components of most combination drug regimens used in HIV infection. Commonly, two NRTIs are used together with a protease [ inhibitor (PI). During the past 5 or 6 years, such highly active antiretroviral therapy (HAART)... 

Nucleoside reverse transcriptase inhibitors (NRTIs) are used in most drug regimes to treat HIV J... 

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