Nucleoside analog reverse transcriptase

Pharmacology Lamivudine/zidovudine combination tablets contain 2 synthetic nucleoside analog reverse transcriptase inhibitors with activity against HIV. Lamivudine in combination with zidovudine has exhibited synergistic antiretroviral activity. Refer to lamivudine and zidovudine individual monographs. Pharmacokinetics One combination lamivudine/zidovudine (150/300 mg) tablet is bioequivalent to a 150 mg lamivudine tablet plus a 300 mg zidovudine tablet. 

Adults The recommended dosage is 600 mg once daily in combination with a protease inhibitor or nucleoside analog reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentration following administration of efavirenz with food may lead to an increase in adverse events. 

Category Nucleoside analog reverse transcriptase inhibitor Half-life 1.5 hours... 

Trade name Zerit (Bristol-Myers Squibb) Indications Human immunodeficiency virus (HIV) Category Antiretroviral Nucleoside analog reverse transcriptase inhibitor Half-life 1.44 hours... 

Lamivudine/zidovudine is a nucleoside analog reverse-transcriptase inhibitor combination that inhibits replication of HIV by incorporation into HIV DNA and producing an incomplete, nonfunctional DNA. They are indicated in the treatment of HIV infection. 

FIGURE 50-3 Intracellular activation of nucleoside analog reverse transcriptase inhibitors. Drugs and phosphory-lated anabolites are abbreviated the enzymes responsible for each conversion are spelled out. The active antiretroviral anabolite for each drug is shown in the blue box. Key ZDV, zidovudine d4T, stavudine ddC, dideoxycytidine FTC, emtricitabine 3TC, lamivudine ABC, abacavir ddl, didanosine DF, disoproxil fumarate MP, monophosphate DP, diphosphate TP, triphosphate AMP, adenosine monophosphate CMP, cytosine monophosphate dCMP, deoxycytosine monophosphate IMP, inosine 5 -monophosphate PRPP, phosphoribosyl pyrophosphate NDR, nucleoside diphosphate. 

The nucleoside analog reverse transcriptase inhibitor zidovudine (AZT). 

Compounds featuring this typical functionalized cyclopentane unit are the platelet aggregation inhibitor compound (1) of AstraZeneca, the HCV NS3 NS4A protease inhibitor (2) claimed by Tibotec for the treatment of Hepatitis C, and a Neuraminidase (Sialidase) inhibitor (3) discovered by Biocryst for the treatment of influenza (Figure 4.6). Likewise, the widely used nucleoside analog reverse transcriptase inhibitor Abacavir (4), administered against HIV, produced by GlaxoSmithKline, as well as Medivir s beta-secretase 1 (BACE 1) inhibitor (5) for the treatment of Alzheimer s dementia can be probably derived from this hydroformylation protocol. 

The enantiopure A-Ts cyclopentene carboxamide 35, obtained by a [2+2] cycloaddition and an enzymatic resolution, could also be a platform to synthesize the antiviral agent ( )-abacavir 38 (Scheme 41.8), which is a nucleoside analog reverse transcriptase inhibitor used in combination... 

Zalcitabine (2, 3 dideoxycytidine ddC) is a synthetic cytosine analog reverse-transcriptase inhibitor. It is active against HIV-I, HIV-2, and hepatitis B virus (HBV). The in vitro ICjo of zalcitabine against HIV-1 ranges from 2 nM in monocytes-macrophage cell lines to 0.5 pM in human peripheral blood mononuclear cells. Zalcitabine has considerably more antiretroviral activity in monocytes-macrophage cell lines than other nucleoside analogs, but the potential clinical utility of this observation is uncertain. 

In analogy with the designation of NRTIs and NNRTls for the nucleoside and nonnucleoside type of reverse transcriptase (RT) inhibitors to target HIV, the corresponding inhibitors to target HCV may be termed NRRIs (for nucleoside RNA replicase inhibitors) and NNRRIs (for nonnucleoside RNA replicase inhibitors). 

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... 

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. 

Zidovudine is an antiretroviral drug that is clinically active against HIV-1 and is intended to treat HIV-infected patients. Zidovudine is an analog of thymidine that inhibits replication of the AIDS virus. It also turned into mono-, di-, and triphosphates by the same cellular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides. Zidovudine-triphosphate is then included in the terminal fragment of the growing chain of viral DNA by viral reverse transcriptase, thus causing the viral DNA chain to break apart in cells infected with the virus. 

Pharmacology Tenofovir disoproxil, an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, inhibits the activity of HIV reverse transcriptase. 

Pharmacology Lamivudine is a synthetic nucleoside analog with activity against HIV and hepatitis B virus (HBV). Lamivudine is phosphorylated intracellularly to lamivudine 5 -triphosphate (L-TP). Incorporation of the monophosphate form into viral DMA by HBV polymerase results in DMA chain termination. L-TP also inhibits the RNA- and DNA-dependent DMA polymerase activities of HIV-1 reverse transcriptase. 

Pharmacology Zalcitabine, active against HIV, is a synthetic pyrimidine nucleoside analog of the naturally occurring nucleoside deoxycytidine in which the 3 -hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5 -triphosphate (ddCTP), by cellular enzymes. ddCTP inhibits the activity of the HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine 5 -triphosphate (dCTP), and by its incorporation into viral DMA. 

Pharmacology Emtricitabine is a synthetic nucleoside analog of cytosine. Emtricitabine inhibits the activity of the HIV-1 reverse transcriptase, which results in chain termination. 

Mechanism of Action Apurine nucleoside analog that is intracellularly converted into a triphosphate, which interferes with RNA-directed DNA polymerase (reverse transcriptase). Therapeutic Effect Inhibits replication of retroviruses, including HIV. Pharmacokinetics Variably absorbed from the GI tract. Protein binding less than 5%. Rapidly metabolized intracellularly to active form. Primarily excreted in urine. Partially (20%) removed by hemodialysis. Half-life 1.5 hr metabolite 8-24 hr. 

Mechanism of Action A guanosine nucleoside analog that inhibits hepatitis B viral polymerase, which blocks reverse transcriptase activity. Therapeutic Effect Interferes with viral DNA synthesis. 

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49-2). Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. 

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