Zalcitabine Lamivudine

Subsequent reports described a syndrome of type B lactic acidosis in patients treated with zidovudine and other nucleoside reverse transcriptase inhibitors, including stavudine, lamivudine, zalcitabine, and didanosine which has also been attribute to mitochondrial DNA toxicity [82-93]. 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, zalcitabine, and stavudine inhibit DNA polymerase gamma in mitochondria, block the elongation of mitochondrial DNA, and deplete mitochondrial DNA [78-80, 87, 92-94, 94a]. The link between NRH 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. 

SLC28A1 CNTl Pyrimidine nucleosides. Zidovudine, lamivudine, zalcitabine, cytarabine Liver, kidney, small intestine Gray et al., 2004 Kong... 

All but one of the drugs in this class are nucleosides that must be triphosphorylated at the 5 -hydroxyl to exert activity. The sole exception, tenofovir, is a nucleotide monophosphate analog that requires two additional phosphates to acquire full activity. These compounds inhibit both HIV-1 and HIV-2, and several have broad-spectrum activity against other human and animal retroviruses emtricita-bine, lamivudine, zalcitabine, and tenofovir are active against hepatitis B virus (HBV) in vitro, and tenofovir also has activity against herpes viruses. 

SPE LOD 260 ng/mL for lamivudine zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir deiavirdine nelimavir saquinavir ritonavir efavirenz] Solas, C. Li, Y.-F. Xie, M.-Y. Sommadossi, J.-P. Zhou, X.-J. Intracellular nucleotides of (-)-2, 3 -deoxy-3 -thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus, Aratimicro6..4 erats Chemother., 1998, 42, 2989-2995. 

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

Didanosine, 1-asparaginase, lamivudine, metformin, pentamidine, statins, stavudine, sulindac, valproic acid, and zalcitabine... 

Drugs that should not be combined due to overlapping toxi-cities include amprenavir oral solution plus ritonavir oral solution, atazanavir plus indinavir (due to enhanced hyperbilirubinemia), and any combination of didanosine, stavudine, and zalcitabine. Emtricitabine and lamivudine should not be combined because of their similar chemical structures, and antagonism can result when lamivudine is combined with zalcitabine, or stavudine is combined with zidovudine. 

Drugs that may interact with lamivudine include zalcitabine and trimethoprim/sulfamethoxazole. 

Pharmacology Abacavir is a synthetic carbocyclic synthetic nucleoside analog with inhibitory activity against HIV. Abacavir has synergistic activity in combination with amprenavir, nevirapine, and zidovudine and additive activity in combination with didanosine, lamivudine, stavudine, and zalcitabine in vitro. 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

Additional nucleoside analogues like the purine dideoxynucleosides lamivudine (3TC) and dideoxy-cytidine (ddC, zalcitabine) act in the same way as AZT. Resistance against these agents may show different patterns. They are generally less toxic than AZT. Adverse effects include diarrhoea and other gastrointestinal disturbances, headache, anxiety, restlessness and insomnia. Also hepatotoxicity can occur, probably because some of these drugs might have also some affinity for human DNA polymerases in the liver. 

TC Lamivudine ABC Abacavir d4T Stavudine ddC Zalcitabine ddl Didanosine TDF Tenofovir ZDV Zidovudine, also abbreviated as AZT FTC Emtricitabine NVP Nevirapine DLV Delavirdine EFV Efavirenz RTV, r Ritonavir Pl/r Ritonavir boosted protease inhibitor SQV Saquinavir IDV Indinavir LPV Lopinavir NEV Nelfinavir APV Amprenavir ATV Atazanavir DRV Darunavir... 

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. 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

Lamivudine is associated with an increased risk of pancreatitis in children and should be used with great caution in children who have had pancreatitis or are at high risk for it. Dosage adjustment is necessary in patients with renal impairment. Lamivudine should not be used in combination with zalcitabine, because they inhibit each other s activation by phosphorylation. Trimethoprim inhibits the renal elimination of lamivudine. 

Peripheral neuropathy occurs in up to 50% of patients taking zalcitabine. Stomatitis, esophageal ulceration, hepatotoxicity, rash, and pancreatitis may occur. Zalcitabine should be used with caution in individuals with a history of pancreatitis, liver disease, or alcohol abuse. Dosage adjustment is necessary for individuals with renal impairment. Zalcitabine should not be used in combination with didanosine, lamivudine, or stavudine. 

NRTIs) abacavir sulfate didanosine (ddl) lamivudine (3TC) stavudine (d4T) zalcitabine (ddC) zidovudine (AZT)... 

Lamivudine NRTI1 150 mg bid or 300 mg daily3 4 Nausea, headache, dizziness, fatigue Do not administer with zalcitabine... 

Zalcitabine NRTI1 0.75 mg tid3 Administer 1 h before or 2 h after an antacid Peripheral neuropathy oral ulcerations, pancreatitis, headache, nausea, rash, arthralgias Avoid concurrent cimetidine avoid concurrent neuropathic drugs (eg, ddl, zalcitabine, isoniazid). Do not administer with lamivudine... 

Potential adverse effects are headache, dizziness, insomnia, fatigue, and gastrointestinal discomfort, although these are typically mild. Lamivudine s bioavailability increases when it is -administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another therefore, their concurrent use should be avoided if possible. Short-term safety of lamivudine has been demonstrated for both mother and infant. 

Zalcitabine does not interact with zidovudine, and lamivudine inhibits its phosphorylation. It should not be administered with other drugs that cause neuropathy or pancreatitis including didanosine and stavudine. 

Lamivudine and emtricitabine are not used in combination since they are similar in their pharmacological effects and in the development of resistance. Since lamivudine is predominantly excreted in urine, its concurrent administration with drugs that utilize the same pathway for clearances should be carefully monitored. Lamivudine is also an inhibitor of the phosphorylation of zalcitabine. 

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. 

Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date. 

Potential drug interactions include an increased AUC of zalcitabine when administered in combination with probenecid or cimetidine and decreased bioavailability when zalcitabine is coadministered with antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy. 

High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, Ml 84V, L74V), and for that reason it tends to develop slowly. Although cross-resistance to lamivudine, didanosine, and zalcitabine has been noted in vitro in recombinant strains with abacavir-associated mutations, the clinical significance is unknown. 

Nevirapine = Viramune] (dipyridodiazepinone) [NRTIs in clinical use Abacavir (ABC) Adefovir dipivoxil (9-[2-Phosphonomethoxy)ethyl] -adenine PMEA) AZT Didanosine (= 2, 3 -Dideoxyinosine) Lamivudine Stavudine Zalcitabine (2, 3 -Dideoxycytidine]... 

LAMIVUDINE, TENOFOVIR, ZALCITABINE FOSCARNET SODIUM t adverse effects with tenofovir and possibly lamivudine and zalcitabine Uncertain possibly additive toxicity via competition for renal excretion Avoid if possible otherwise monitor FBC and renal function weekly... 

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... 

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