3TC

Nelfinavir is a nonpeptidic, rationally designed HIV protease inhibitor. Nelfinavir has demonstrated efficacy in both monotherapy and in combination with the reverse transcriptase inhibitors stavudine (d4T) or zivudine + 3TC. The major side effect is mild to moderate diarrhea. 

Fig. 13. Calculated 2H solid echo spectra for log-Gaussian distributions of correlation times of different widths. Note the differences of the line shapes for fully relaxed and partially relaxed spectra. The centre of the distribution of correlation times is given as a normalized exchange rate a0 = 1/3tc. For deuterons in aliphatic C—H bonds the conversion factor is approximately 4.10s sec-1...

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). 

Depending on the nature of the compound, the ddN analogues have been associated with varying toxic side effects such as bone marrow suppression (AZT), pancreatitis (ddl), hypersensitivity reactions (ABC), and neurologic complications consequently to mitochondrial toxicity (ddC), while others, such as 3TC and (-)FTC, have few, if any, side effects. 

The potent activity of D-DOT against AZT- and 3TC-resistant HIV-1 strains together with its excellent pharmacokinetic profile in rhesus monkeys suggest that further development of D-DOT towards HIV-1 chemotherapy is warranted (Asif et al. 2007). 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

The 5 -triphosphate metabolite of entecavir has been shown to accumulate in-tracellularly at concentrations that are inhibitory to 3TC-resistant HBV DNA polymerase (Levine et al. 2002). This would imply that entecavir should be active against HBV infections that have become resistant to treatment with lamivudine. Yet, it should be taken into account that treatment with lamivudine leads to the same... 

Das K, Xiong X, Yang H, Westland CE, Gibbs CS, Sarafianos SG, Arnold E (2001) Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (ETC), J Virol 75 4771 779... 

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... 

Fig. 1 Time couise of lactic acid yield and its concentration in SSF with or without pretreatment using 0.1 mol/l FICI with heating at 121 1 for 30 min. Famentation conditions 3TC, pH=5.0, initial load of bean curd refiise(BCR) 10 g, cellulase amount=l gin ILsuspension.

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). 

Lamivudine (3TC) 150-mg and 150 mg bid or CrCI None Minimal Renal excretion... 

NRTI—ZDV, ddl, d4T may cause hepatotoxicity associated with lactic acidosis 3TC, FTC, or TDF may cause HBV flare when these drugs are withdrawn Onset... 

D/C all antiretrovirals symptomatic support with fluids some patients require IV bicarbonate, hemodialysis, parenteral nutrition, or mechanical ventilation once syndrome resolves, consider using NRTIs with 4- mitochondrial toxicity (ABC, TDF, 3TC, or FTC) monitor lactate after restarting NRTIs some clinicians use NRTI-sparing regimens. 

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. 

The antiviral activity spectrum of the ddN analogues should, in principle, extend to all retroviruses as well as hepadnaviruses [i.e., hepatitis B virus (HBV)], since HBV, like retroviruses, replicates through an RNA template-driven RT process. Indeed, various ddN analogues (particularly, the L-enantiomeric forms 3TC, FTC, and L-DDC) have been shown to inhibit HBV replication [36-38]. Consequently, 3TC is, at present, pursued as a potential drug candidate for the treatment of both HIV and HBV infections. 

The 181 Tyr — Cys mutation, which is responsible for resistance to most NNRTIs, has been found to suppress the 215 mutation (Thr — Phe/ Tyr), which is responsible for resistance to AZT [94], and, vice versa, the 181 Tyr — Cys mutation can be suppressed by AZT, which thus means that the mutations at positions 181 and 215 counteract each other. Yet other mutations have proved to counteract each other 236 Pro — Leu vs 138 Glu —> Lys, and, as mentioned, 215 Thr > Phe/Tyr vs 184 Met > Val, and 215 Thr — Phe/Tyr vs 74 Leu > Val [47]. Based on the resistance mutations that counteract each other, combinations of different drugs could be envisaged—namely, combinations of AZT with either TIBO, a-APA, HEPT, nevirapine, or pyridinone—and these two drug combinations could be extended to three- or four-drug combinations by the addition of another ddN analogue (such as 3TC) and/or another NNRTI (such as BHAP or TSAO). 

In addition to complexes of the type, trans-[Tc02(pyr)2]+ (pyr pyridine or imidazole), various species, such as Jrans-[TcO(RO)X2(pyr)2] (R CH3 or CH3CH2 X Cl or Br) were detected in alcohol. Further complicated mixed-valence species, [X2(pyr)3Tc-0-Tc(pyr)2X3] and [X(pyr)4TcO Tc(pyr)X4], appeared on long standing or heating in pyridine [44,45]. Rather peculiar features were found in the substitution reaction of trans-[Tc02(py)4] + with 4-aminopyridine (apy) in mixtures of methanol and toluene in the presence of excess pyridine ([py] — 0.14 M) [46]. Its rate was expressed as... 

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