Stavudine Nucleoside reverse transcriptase 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... 

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. 

Other applications include bioequivalent measurements of bromazepam, an anticonvulsant, in human plasma. The lower limit of quantitation (LLOQ) was 1 ng/mL (Gongalves et al. 2005). Kuhlenbeck et al. (2005) studied antitussive agents (dextromethorphan, dextrophan, and guaifenesin) in human plasma LLOQ values were 0.05, 0.05, and 5 ng/mL, respectively. Other compounds studied were nucleoside reverse transcriptase inhibitors, zidovudine (AZT) and lamivudine (3TC) (de Cassia et al. 2004) and stavudine (Raices et al. 2003) in human plasma, and paclitaxel, an anticancer agent, in human serum (Schellen et al. 2000). 

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. 

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). 

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. 

ISONIAZID ANTIVIRALS-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS t adverse effects with didanosine and possibly stavudine Additive side-effects Monitor closely for the development of peripheral neuropathy, but no dose adjustment is required... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS ANTI HYPERTENSIVES AND HEART FAILURE DRUGS-VASODILATOR ANTI HYPERTENSIVES Risk of peripheral neuropathy when hydralazine is co-administered with didanosine, stavudine or zalcitabine Additive effect both drugs can cause peripheral neuropathy Warn patients to report early features of peripheral neuropathy if this occurs, the nucleoside reverse transcriptase inhibitor should be stopped... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RIBAVIRIN 1. t side-effects, risk of lactic acidosis, peripheral neuropathy, pancreatitis, hepatic decompensation, mitochondrial toxicity and anaemia with didanosine and stavudine 2.1 efficacy of lamivudine 1. Additive side-effects t intracellular activation of didanosine and stavudine 2. J intracellular activation of lamivudine 1. Not recommended. Use with extreme caution monitor lactate, LFTs and amylase closely. Stop co-administration if peripheral neuropathy occurs. Stavudine and didanosine carry a higher risk 2. Monitor HIV RNA levels if they T, review treatment combination... 

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. 

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, and didanosine which has also been attributed to mitochondrial DNA toxicity [95-106]. There are five types of DNA polymerase in human cells that catalyze the synthesis of new complementary DNA from the original DNA template (HIV encodes a reverse transcriptase DNA polymerase which uses RNA as the template). The active triphosphate metabolites of zidovudine, didanosine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [91-93,101,105-108]. The link between NRTl effects on mitochondrial DNA and lactic acidosis is not entirely clear but is most likely related to disturbances of oxidative phosphorylation and impaired pyruvate metabolism leading to lactate accumulation. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

Stavudine is a nucleoside reverse transcriptase inhibitor, which inhibits replication of HIV. It is indicated in the treatment of HlV-1 infection in combination with other antiretroviral agents. 

Ribavirin inhibits the phosphorylation and antiviral activity of pyrimidine nucleoside HIV reverse-transcriptase inhibitors such as zidovudine and stavudine but increases the activity of purine nucleoside reverse-transcriptase inhibitors (e.g., didanosine) in vitro. It appears to increase the risk of mitochondrial toxicity from didanosine (see Chapter 50). 

Anti-HIV drugs Nucleoside reverse transcriptase inhibitors Zidovudine Didanosine, lamivudine, stavudine, zalcitabine... 

Stavudine (d4T) is a nucleoside reverse transcriptase inhibitor. While it has only minor hema-totoxic potential, the dmg is markedly neurotoxic, causing dose-limiting peripheral neuropathy. Resistance occurs via mutations in the pol gene, which encodes for several proteins including reverse transcriptase. The answer is (B). 

Nucleoside reverse transcriptase inhibitors such as stavudine need to be phosphorylated within cells to a triphosphate anabolite before they become effective. In vitro studies using mononucleated blood cells found that zidovudine significantly inhibited this phosphorylation. Antagonism between zidovudine and stavudine has also been seen in a clinical study. The manufacturers and US guidelines currently do not recommend the combination. 

Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zalcitabine (production discontinued), and Zidovudine. Non-nucleoside Reverse Transcriptase Inhibitors include Delavirdine, Efavirenz, and Nevirapine. 

Combination of 16 ARVs seven HIV protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfmavir, ritonavir, and saquinavir), seven nucleoside reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, and zidovudine), and two nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine)... 

The lipoatrophy that has been associated with nucleoside reverse transcriptase inhibitors is accompanied by mitochondrial dysfunction, and in 10 patients who had taken stavudine, lamivudine, and lopinavir + ritonavir for over 6 years, mitochondrial function and morphology improved after switching from stavudine to tenofovir [60 ]. 

The group of nucleoside reverse transcriptase inhibitors (NRTIs) is composed of various nucleoside analogs zidovudine, stavudine, lamivudine, didanosine. 

Gynecomastia has been reported in a series of men taking saquinavir (5). In these cases the association was clear (particularly since there was positive dechallenge), but this is a rare effect and has not previously been reported with either this or other protease inhibitors, although it has been associated with the nucleoside analogue reverse transcriptase inhibitor stavudine. 

Stavudine is a nucleoside analogue reverse transcriptase inhibitor. Its most important adverse effects are peripheral neuropathy and increases in hepatic transaminases, both of which usually resolve on withdrawal. 

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. 

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