Nucleotide 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... 

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. 

Dual nucleoside (nucleotide) reverse transcriptase inhibitor (NtRTI) backbones... 

Nucleoside (Nucleotide) reverse transcriptase inhibitors (NtRTIs) ... 

A study of the potency of the antibiotic daptomycin cited plasma protein binding of 92%, but it claimed only a 2-fold shift in potency in serum (expected 12-fold) [68]. This type of discrepancy is relatively common and can often reflect substantial binding to components in the "serum-free" media. In the cases of HIV-directed non-nucleotide reverse transcriptase inhibitors, this has been dealt with by measuring the unbound drug concentration in the "serum-free" medium and using that data to calculate the intrinsic, serum-free potency [69]. 

The current standard of care recommends the use of potent three-drug combinations, which typically involves two nucleoside/nucleotide reverse transcriptase inhibitors with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). By attacking HIV infection with three drugs at one time, practitioners seek to avoid the emergence of resistance strains within the patient. 

The purpose of this study is to determine whether once-daily dosing of the lopinavir/ritonavir (Kaletra) tablet in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors will reduce HIV viral load to very low levels in patients who have detectable viral loads with their current antiretroviral therapy. 

Study Design Treatment, randomized, open label, active control, parallel assignment, safety/efficacy study Official Title A Phase III, Randomized, Open-Label Study of Lopina-vir/Ritonavir Tablets 800/200mg Once-Daily Versus 400/100mg Twice-Daily When Co-administered With Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects Primary Outcome Measures ... 

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. 

Nucleotide reverse transcriptase inhibitor Tenofovir (TDF) 300 mg once daily >30 days-13 yrs 120 mg/m daily for 2 weeks, then 200 mg/m twice daily Safety and efficacy not well... 

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). 

It is non-nucleotide reverse transcriptase inhibitor extensively metabolized by the CYP3A P450 isoform to hydroxylated metabolites and excreted in urine. It is indicated in combination with other anti-retroviral agents in a dose of 200 mg OD-BD for first 14 days. It is also been shown to be effective in the prevention of transmission of HIV from mother to new bom. 

It is also an non-nucleotide reverse transcriptase inhibitor having long half-... 

The pharmacokinetics of lamivudine are described earlier in this chapter (see section, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV cell lines (17-19 hours) than in HIV-infected cell lines (10.5-15.5 hours) allows for lower doses and less ffeguent administration. Lamivudine can be safely administered to patients with decompensated liver disease. 

Raltegravir, or Isentress (1), is the first FDA-approved inhibitor of HIV integrase. HIV/AIDS drugs are categorized according to their mode of action as nucleoside and nucleotide reverse transcriptase inhibitors [NRTIs, e.g., tenofovir (2)], nonnucleotide reverse transcriptase inhibitors [NNRTIs, e.g., efavirenz (3)] protease inhibitors [Pis, e.g., ritonavir (4)], fusion inhibitors [e.g., enfuvirtide (5)], entry inhibitors... 

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

NtRTI nucleotide reverse transcriptase inhibitor RSV respiratory syncytial virus... 

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors, including... 

NRTI nucleoside/nucleotide reverse transcriptase inhibitor... 

Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Qin Ther 2000 22 ... 

Nonnucleoside RTIs that do not require metabolic activation (e.g., delavirdine and nevirapine, efavirenz, which are not myelosuppressants) and a nucleotide reverse-transcriptase inhibitor (adefovir) have been introduced. Resistance emerges rapidly if these drugs are used as individual agents for management of HIV infection. However, they may provide additive or synergistic activity against HIV if used in combination regimens with NRTIs and/or Pis. 

There are also now a number of non-nucleotide reverse transcriptase inhibitors and the most useful of these are nevirapine (Viramune, 1996) and delaviridine (Rescriptor, 1997), which appear to act at an allosteric site close to the active site of RT. This means that they block the subtle (and apparently essential) changes in the three-dimensional structure that occur when nucleotide substrates bind to the active site of RT. 

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