Didanosine 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... 

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir ZDV, zidovudine. 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

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... 

PENTAMIDINE ISETIONATE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS t adverse effects with didanosine, tenofbvir and zidovudine Additive toxicity Monitor FBC and renal function closely. Consider stopping didanosine while pentamidine is required for Pneumocystis jiroveci pneumonia... 

EFAVIRENZ NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS-DIDANOSINE (ENTERIC-COATED), TENOFOVIR A high treatment failure rate is reported when tenofovir, enteric-coated didanosine and efavirenz are co administered Unknown Use this combination with caution... 

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 GANCICLOVIRAfALGANCIC LOVIR 1. T adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly 1 efficacy of ganciclovir 1. Uncertain possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain L bioavailability 1. Avoid if possible otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance if in doubt, consider alternative cytomegalovirus prophylaxis... 

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. 

Didanosine is a nucleoside reverse transcriptase inhibitor structurally related to inosine. It is converted intracellularly to dideoxyadenosine triphosphate. It acts against retroviruses, including HIV. 

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. 

Didanosine is a nucleoside reverse transcriptase inhibitor that inhibits replication of HIV by interfering with DNA synthesis. Didanosine (Videx) is used for treatment of HIV-1 infection in combination with other antiretrovirals. Didanosine EC (Videx EC) is used in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults who require once-daily administration of didanosine or an alternative didanosine formulation. 

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... 

In the initial management of this patient, two nucleoside reverse transcriptase inhibitors (NRTIs) were administered. Hematologic suppression is a major adverse effect of zidovudine, while peripheral neuropathy and pancreatitis are important toxicities of didanosine. The gastrointestinal symptoms, together with the elevated amylase levels, were the reasons for discontinuance of didanosine and the substitution of another nucleoside reverse transcriptase inhibitor (lamivudine) in the drug regimen. See answer to question 3, above. 

Cytotoxicity Acetaminophen, didanosine, isoniazid, L-asparaginase, mesalamine, metronidazole, nucleoside reverse transcriptase inhibitors (NRTIs), pentamidine, protease inhibitors, sitagliptin, statins, valproic acid... 

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)... 

In a nested case-control study conducted by the Swiss HIV Cohort there was a strong association between prolonged exposure to didanosine and non-cirrhotic portal hypertension [107 ]. In 15 patients with non-cirrhotic portal hypertension and 75 controls matched for duration of HIV infection, absence of viral hepatitis, and duration of follow-up, cumulative exposure to antiretroviral drug therapy (OR per year = 1.3 95% Cl = 1.0,1.6), nucleoside reverse transcriptase inhibitors (OR = 1.3 95% Cl = 1.1, 1.7), didanosine (OR = 3.4 95% Cl = 1.5, 8.1), ritonavir (OR = 1.4 95% Cl = 1.0, 1.9), and nelfinavir (OR = 1.4 95% Cl = 1.0,1.9) were longer in the patients with portal hypertension. Exposure to non-nucleoside reverse transcriptase inhibitors and other protease inhibitors were not different. 

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

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

The nucleoside analogue reverse transcriptase inhibitors (NRTIs) include abacavir, didanosine, lamivudine, stavu-dine, tenofovir, zalcitabine, and zidovudine (all rINNs). The following abbreviations have been used and may still be encountered in published papers ... 

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