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Introduction. Chemotherapy of HIV infection remains the only means of treating the disease. The process of development new and improving previously developed drugs is therefore considered a priority. One of the preclinical stage of drug efficacy testing is research in the virus-cell model system in vitro. The aim. To evaluate the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) 6HP and 3TC during HIV-1 replication in the neoplastic MT-4 cell line. Materials and methods. Two variants of the CD4+ T-lymphocyte MT-4 cell line (MT-4/1 and MT-4/2) transformed by Human T-lymphotropic virus type 1 (Retroviridae: Orthoretrovirinae: Deltaretrovirus: HTLV-1), with different levels of HIV-1 replication were used. Drugs ammonium-3’-azido-3’-deoxythymidine-5’-carbomoylphosphonat (6HP) and 2’,3’-dideoxy-3’-thiacytidine (3TC) were used to suppress the virus. Results and discussion. The replication activity of HIV-1 was observed to be higher in the MT-4/2 line than in the MT-4/1 line for different strains of the virus. The use of each of the substances separately showed a more significant inhibition of viral activity in MT-4/1 than in MT-4/2 cells. When used together, the inhibition level was almost the same in all cases and ranged from 87‒96% for the MT-4/1 line and 83‒89% for the MT-4/2 line. High efficacy was observed when using lower concentrations of drugs compared to individual use. Conclusion. The combined use of NRTIs 6НР and 3TС is promising for the treatment of HIV-infected patients at different stages of infection and with different levels of viral load.

Reducing neuroinflammation, a key contributor to brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The FDA-approved nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and multiple mouse models of neurodegenerative disease, but its effects on the brain have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed some of these effects. We also found that 3TC mitigated tauopathy-associated activation of key transcription factors that contribute to neuroinflammation and immune activation, and these changes were related to improved recognition memory performance. Collectively, our findings suggest that 3TC exerts protective effects against tauopathy in the hippocampus by modulating inflammation and immune activation, and they may provide helpful insight for ongoing clinical efforts to determine if 3TC and/or related therapeutics hold promise for treating neurodegeneration.

Introduction: Chemotherapy of HIV infection remains the only means of treating the disease. The process of development new and improving previously developed drugs is therefore considered a priority. One of the preclinical stage of drug efficacy testing is research in the virus-cell model system in vitro ., The Aim: To evaluate the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) 6HP and 3TC during HIV-1 replication in the neoplastic MT-4 cell line., Materials and Methods: Two variants of the CD4 + T-lymphocyte MT-4 cell line (MT-4/1 and MT-4/2) transformed by Human T-lymphotropic virus type 1 (Retroviridae: Orthoretrovirinae : Deltaretrovirus : HTLV-1 ), with different levels of HIV-1 replication were used. Drugs ammonium-3'-azido-3'-deoxythymidine-5'-carbomoylphosphonat (6HP) and 2',3'-dideoxy-3'-thiacytidine (3TC) were used to suppress the virus., Results and Discussion: The replication activity of HIV-1 was observed to be higher in the MT-4/2 line than in the MT-4/1 line for different strains of the virus. The use of each of the substances separately showed a more significant inhibition of viral activity in MT-4/1 than in MT-4/2 cells. When used together, the inhibition level was almost the same in all cases and ranged from 87‒96% for the MT-4/1 line and 83‒89% for the MT-4/2 line. High efficacy was observed when using lower concentrations of drugs compared to individual use., Conclusion: The combined use of NRTIs 6НР and 3TС is promising for the treatment of HIV-infected patients at different stages of infection and with different levels of viral load.

Reducing neuroinflammation, a key contributor to brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The FDA-approved nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and multiple mouse models of neurodegenerative disease, but its effects on the brain have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed some of these effects. We also found that 3TC mitigated tauopathy-associated activation of key transcription factors that contribute to neuroinflammation and immune activation, and these changes were related to improved recognition memory performance. Collectively, our findings suggest that 3TC exerts protective effects against tauopathy in the hippocampus by modulating inflammation and immune activation, and they may provide helpful insight for ongoing clinical efforts to determine if 3TC and/or related therapeutics hold promise for treating neurodegeneration. • Neuroinflammation is a major driver of brain aging and dementia. • The reverse transcriptase inhibitor 3TC modulates hippocampal RNA signatures of inflammation in rTg4510 tauopathy mice. • 3TC reduces neuroinflammatory transcription factors, and these effects are related to improvements in cognitive function. • 3TC may be a safe and viable therapeutic for targeting neuroinflammation and improving cognitive function. [ABSTRACT FROM AUTHOR]

Background: adherence and forgiveness are key factors for virologic success. We evaluated them for 3TC/DTG. Methods: pharmacy refills were used to calculate the proportion of days covered (PDC). Forgiveness was calculated as the achieved rate of HIV-RNA threshold by a given level of imperfect adherence. Results: 240 PLWH were included. The median follow-up was 819 days (IQR 450-1459) for a total of 681 person/years of follow-up. Adherence was very high with a median of 99% (IQR 95%-100%). Consequently, the virologic response was sustained with 83.8% of PLWH never exceeding a HIV RNA of 50 copies/ml and 95.8% of subjects with a steadily HIV-RNA < 200 copies/ml. A PDC lower than 80% was associated with a negative outcome irrespective of the HIV-RNA threshold considered. Conclusions: The extensive virologic efficacy of 3TC/DTG demonstrated both in clinical trials and real-world experiences seems to rely more on its friendliness than on its forgiveness. [ABSTRACT FROM AUTHOR]

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols. [ABSTRACT FROM AUTHOR]

The use of a combination antiretroviral therapy (cART) has changed dramatically the prognosis and the life expectancy of people living with HIV. The current treatment guidelines continue the convention of preferred cART based on combining a dual nucleoside reverse-transcriptase inhibitor (NRTI) backbone with a third "anchor" agent, such as a ritonavir (r)- or cobicistat (c)-boosted protease inhibitor (PI), a non-NRTI (NNRTI), or an integrase inhibitor (INI) boosted or unboosted. However, due to toxicities of NRTIs, sparing NRTI regimen has been studied for a long time with moderate success due to low efficacy (especially in patients with high viral load and low CD4) compare to standard triple therapy. New strategy with lamivudine (3TC) plus a boosted PI or INI showed promise results and indicated that modern two-drug regimens might now, in fact, become a reliable treatment for HIV-infected naïve patients. This article discusses recent data from dual therapy studies in naïve HIV-infected patients and the challenges behind this strategy. [ABSTRACT FROM AUTHOR]

Background: Dual therapies have been tested in selected patients, but there is no evidence for its advantages in clinical practice. The aim of this study was to evaluate in the clinical setting the long-term outcomes and the impacts on comorbidities of a dual therapy based on lamivudine plus darunavir boosted with ritonavir (DRV/r). Methods: A prospective cohort study of 106 patients who were switched to this dual regimen from April 2014 to December 2017 because of renal and bone toxicity, intolerance, or physician's decision was conducted. The primary study endpoint was the proportion of patients who were free of treatment failure at 48 and 96 weeks. Results: The mean age was 50 years, and 64% were hepatitis C virus-coinfected. At 48 weeks, the efficacy was 95% (95% confidence interval, 91–99%; ITT-e analysis; two changes due to toxicity, three because of drug–drug interactions -DDIs-). At week 96, 26 patients (25%) had discontinued this therapy (two virologic failures, one additional adverse event, 18 therapy changes to avoid DDIs). An increase in lipid parameters was observed during the first 6–12 months in the group discontinuing tenofovir disoproxil fumarate (p <.01), which was partly corrected at 96 weeks. Improvements in CD4/CD8 ratio (p =.04), bone mineral density (+1.17%; p =.07), estimated glomerular filtration rate (+7.7 mL/min in CKD patients; p =.02), urinary parameters (proteinuria, −23%), and overall cost (−43%) were observed. Conclusions: Our results demonstrated the long-term efficacy and safety of an antiretroviral regimen based on dual therapy with lamivudine plus boosted darunavir in the clinical setting. [ABSTRACT FROM AUTHOR]

Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an Lenantiomeric analog of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV) alone; ZDV + Recombinant Human Interferon-α (rHuIFN-α); ZDV + Lamivudine (3TC) and ZDV + valproic acid (Valp) on naturally feline immunodeficiency virus (FIV)-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP) and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-α. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups) only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV.

Background: Hypersensitivity reaction to antiretroviral treatment (ART) poses potential threats in maintenance of treatment. Lamivudine (3TC), is rare to cause rash. We are reporting 23 cases of 3TC-induced rash.Methods: An observational study conducted in the antiretroviral treatment center of a tertiary care hospital of North India from Feb 2009-Dec 2013 to record 3TC-induced rash. These were then recommended to start ART without 3TC and were followed up at 1-, 2-, and at 4-week intervals to monitor the toxicity, if any, with alternate therapy.Results: We observed 3TC-induced skin rash in 23 HIV-infected individuals (0.7%), out of 3213 HIV-infected individuals initiated on first line ART (zidovudine [ZDV]/tenofovir [TDF] + 3TC +nevirapine [NVP]/efavirenz [EFV] during the study period of 5 years [Feb 2009-Dec 2013]). The mean age of these 23 individuals was 37.5 ± 12.8 (17-60) years. Lamivudine rash was more common in women than men (F = 19, M = 4), with an overall mean age of 37.5 ± 12.8 (17-60) years. It was generalized, erythematous, maculopapular eruptions associated with intense itching with no associated mucosal involvement. Lamivudine was substituted with TDF in 19, didanosine (ddl) in 3 and abacavir (ABC) in 1 individual. Mean duration of follow-up is 11.1 ± 12.8 (3-42) months. CD4 count was repeated at 3 months and showed significant improvement (P = 0.002).Conclusion: Lamivudine-induced rash was found at a frequency of 0.7%. The correct and early recognition that the rash is due to 3TC, would save unnecessary substitution to a different class of drugs. [ABSTRACT FROM AUTHOR]

Mycoplasmas may colonize tumor tissue in patients. The cytostatic activity of gemcitabine was dramatically decreased in Mycoplasma hyorhinis -infected tumor cell cultures compared with non-infected tumor cell cultures. This mycoplasma-driven drug deamination could be prevented by exogenous administration of the cytidine deaminase (CDA) inhibitor tetrahydrouridine, but also by the natural nucleosides or by a purine nucleoside phosphorylase inhibitor. The M. hyorhinis -encoded CDA Hyor gene was cloned, expressed as a recombinant protein and purified. CDA Hyor was found to be more catalytically active than its human equivalent and efficiently deaminates (inactivates) cytosine-based anticancer drugs. CDA Hyor expression at the tumor site may result in selective drug inactivation and suboptimal therapeutic efficiency. [ABSTRACT FROM AUTHOR]

Abstract: Nucleoside reverse-transcriptase inhibitor (NRTI) drugs are a major component of highly-active antiretroviral therapy (HAART). NRTI combinations have been demonstrated as producing a sustained reduction in plasma viremia with an increased CD4 count, thereby showing clear clinical benefits. Therefore, the secondary effects caused by the combination of two NRTIs, mainly those related to amplification of genotoxic effects, due to increased risk of DNA damage caused by these drugs, should be carefully examined. We employed the standard version of the wing SMART in Drosophila melanogaster to obtain more detailed knowledge about the genotoxic profile of NRTI combinations of AZT+ddI, AZT+3TC and AZT+d4T. Our results showed that all combinations increased the frequencies of induction of mutant spots. The combinations AZT+ddI and AZT+3TC were shown to induce recombination rates ranging from 86.38% to 98.36% while AZT+d4T showed a large discrepancy between recombination and mutation percentages. The combination index demonstrated that 3TC and d4T produced antagonism while ddI showed synergistic effects in combination with AZT. [Copyright &y& Elsevier]

The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV) alone; ZDV + Recombinant Human Interferon-α (rHuIFN-α); ZDV + Lamivudine (3TC) and ZDV + valproic acid (Valp) on naturally feline immunodeficiency virus (FIV)-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP) and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-α. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups) only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV. [ABSTRACT FROM AUTHOR]

Objectives To compare the frequency of the selection of the M184V/I resistance mutation in HIV-infected patients who experienced virological failure while receiving emtricitabine (FTC) or lamivudine (3TC), administered with tenofovir disoproxil fumarate (TDF) and either efavirenz (EFV) or a ritonavir-boosted protease inhibitor (PI; lopinavir or atazanavir). Methods Patient data held at two clinical centres in France were analysed retrospectively. Eligible patients had experienced virological suppression (plasma HIV RNA <200 copies/mL) for ≥6 months before experiencing their first virological failure (at least two measurements of plasma HIV RNA ≥200 copies/mL). Results Of the 880 patients eligible for the study, 278 patients had experienced virological failure while receiving FTC + TDF + ritonavir-boosted PI, 257 while receiving FTC + TDF + EFV, 178 while receiving 3TC + TDF + EFV and 167 while receiving 3TC + TDF + ritonavir-boosted PI. Proportions of patients harbouring the M184V/I mutation were 24% (n = 62) for those who received FTC + TDF + EFV versus 51% (n = 91) for 3TC + TDF + EFV (P < 0.0001; Fisher’s exact test); proportions were 11% (n = 30) for FTC + TDF + ritonavir-boosted PI versus 22% (n = 37) for 3TC + TDF + ritonavir-boosted PI (P = 0.002; Fisher’s exact test). The use of lamivudine versus emtricitabine (P = 0.001), non-nucleoside reverse transcriptase inhibitors versus ritonavir-boosted PIs (P = 0.01) and the level of viral load at the time of virological failure (P = 0.01) were associated with selection of the M184V/I mutation (logistic regression analysis). Conclusions Emtricitabine and lamivudine showed differing resistance profiles when administered in combination with tenofovir disproxil fumarate and either efavirenz or a ritonavir-boosted PI. The prevalence of the M184V/I resistance mutation was significantly lower in patients who received emtricitabine and tenofovir disoproxil fumarate than in those who received lamivudine and tenofovir disoproxil fumarate. [ABSTRACT FROM PUBLISHER]

Two new phosphonate 3TC prodrugs were synthesized and studied in MT-4 cells as inhibitors of HIV replication. Their pharmacokinetic parameters were evaluated following intragastric administration in rabbits and oral administration in dogs. Both compounds were much less toxic than parent 3TC in cell cultures and could generate the active nucleoside in laboratory animals. Two new phosphonate 3TC prodrugs were studied in cell cultures as inhibitors of HIV replication. Their pharmaco-kinetic parameters were evaluated following administration in rabbits and dogs. [ABSTRACT FROM AUTHOR]

Purpose: To compare the development of the M184V/I substitution among antiretroviral treatment-naïve patients taking the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC) or lamivudine (3TC) from three phase 3 clinical trials of dual NRTIs (including either FTC or 3TC) plus the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV). Methods: Study subjects from three phase 3 clinical trials (FTC 301A, GS-99-903, and GS-01-934) were classified as virologic failures (VF) if they had confirmed &nvge;400 copies/mL of HIV-1 RNA at week 48 or early study drug discontinuation. Subjects with VF were genotyped by population sequencing. The prevalence of the M184V/I substitution in the FTC or 3TC groups was analyzed using Fisher exact test and in multivariate logistic regression analyses. Results: Among the 3 trials, 522 subjects were treated with FTC dosed once daily and 841 subjects were treated with 3TC dosed twice daily. Among VF subjects at week 48, 5/26 (19.2%) FTC-treated subjects and 27/77 (35.5%) 3TC-treated subjects developed the M184V/I mutation (P = .145). Using the denominator of all subjects treated, 5/522 (1.0%) FTC-treated subjects versus 27/841 (3.2%) 3TC-treated subjects developed the M184V/I substitution (P = .009). Multivariate analyses adjusting for baseline viral load, baseline CD4 cell counts, and baseline NRTI resistance showed that treatment with FTC had a significantly lower rate of M184V/I development than treatment with 3TC (odds ratio 0.32; P = .02). Conclusions: The results of this pooled analysis of 3 clinical trials indicate a lower frequency of development of the M184V/I mutation in subjects treated with FTC versus 3TC when combined in regimens containing dual NRTIs and EFV. [ABSTRACT FROM AUTHOR]

Abstract: Chemical conjugates between sodium cellulose sulfate (CS), displaying contraceptive and HIV-entry inhibiting properties, and nucleoside reverse transcriptase inhibitors (NRTIs) (3′-azido-2′,3′-dideoxythymidine (AZT), 3′-fluoro-2′,3′-dideoxythymidine (FLT), or 2′,3′-dideoxy-3′-thiacytidine (3TC)) were designed to simultaneously provide contraceptive and anti-HIV activity. Two linkers, acetate and succinate, were used to conjugate the nucleoside analogs with CS. The conjugates containing cellulose sulfate-acetate (CSA) (e.g., AZT–CSA and FLT–CSA) were found to be more potent than CS and other conjugates (e.g., AZT–succinate–CS, and FLT–succinate–CS). The presence of both sulfate and the acetate groups on cellulose were critical for generating maximum anti-HIV activity. In addition to showing equal potency against wild-type and multidrug resistant HIV-1, the AZT–CSA conjugate displayed significant contraceptive activity in an animal model, providing the initial proof-of-concept for the design and synthesis of dual-activity compounds based on these combinations. [Copyright &y& Elsevier]

Abstract: The increasing number of antiretroviral drugs leads to mounting possibilities of combinations for the antiretroviral therapy (ART) of HIV-1 infected patients. Thus, it is of interest to determine the most potent combination of antiretroviral drugs for the first ART to delay the development of drug resistance. We have investigated the differences in the inhibitory potencies of the nucleoside reverse transcriptase inhibitors (NRTI) lamivudine (3TC) and emtricitabine (FTC) using an in vitro model based on simultaneous infection of T cells with drug-sensitive and drug-resistant viruses. Changes of frequencies in these virus populations have been measured by allele-specific real-time PCR allowing simultaneous quantification of different HIV-1 variants in the same sample. We show that the suppression of drug-sensitive viruses is significantly enhanced by FTC compared to 3TC. Mathematical modeling of the distinct rates of suppression of drug-sensitive viruses revealed an approximately 3-fold higher antiretroviral potency for FTC compared to 3TC. [Copyright &y& Elsevier]

To delineate temporal changes in the integrity and function of mitochondria/cardiomyocytes in hearts from mice exposed in utero to commonly used nucleoside analogs (NRTIs), CD-1 mice were exposed in utero to 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during days 12–18 of gestation and hearts from female mouse offspring were examined at 13 and 26 weeks postpartum. Alterations in cardiac mitochondrial DNA (mtDNA) content, oxidative phosphorylation (OXPHOS) enzyme activities, mtDNA mutations, and echocardiography of NRTI-exposed mice were assessed and compared with findings in vehicle-exposed control mice. A hybrid capture-chemiluminescence assay showed significant twofold increases in mtDNA levels in hearts from AZT- and AZT/3TC-exposed mice at 13 and 26 weeks postpartum, consistent with near doubling in mitochondrial numbers over time compared with vehicle-exposed mice. Echocardiographic measurements at 13 and 26 weeks postpartum indicated progressive thinning of the left ventricular posterior wall in NRTI-exposed mice, relative to controls, with differences becoming statistically significant by 26 weeks. Overall, progressive functional changes occurred in mouse mitochondria and cardiac tissue several months after in utero NRTI exposures; AZT and 3TC acted in concert to cause additive cardiotoxic effects of AZT/3TC compared with either drug alone. [ABSTRACT FROM AUTHOR]

The current study was designed to delineate temporal changes in cardiomyocytes and mitochondria at the light and electron microscopic levels in hearts of mice exposed transplacentally to commonly used nucleoside analogs (NRTIs). Pregnant CD-1 mice were given 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during the last 7 days of gestation, and hearts from female mouse pups were examined at 13 and 26 weeks postpartum for histopathological or ultrastructural changes in cross-sections of both the ventricles and the interventricular septum. Using light microscopy and special staining techniques, transplacental exposure to AZT, 3TC, or AZT/3TC was shown to induce significant histopathological changes in myofibrils; these changes were more widespread at 13 weeks than at 26 weeks postpartum. While most light microscopic lesions resolved, some became more severe between 13 and 26 weeks postpartum. Transplacental NRTI exposure also resulted in progressive drug-specific changes in the number and ultrastructural integrity of cardiac mitochondria. These light and electron microscopic findings show that a subset of changes in cardiac mitochondria and myofibrils persisted and progressed months after transplacental exposure of an animal model to NRTIs, with combined AZT/3TC exposure yielding additive effects compared with either drug alone. [ABSTRACT FROM AUTHOR]

Abstract: The xenotropic murine leukemia virus-related virus (XMRV) is a human retrovirus, recently isolated from tissues of prostate cancer patients with impaired RNase L activity. In this study, we evaluated 10 licensed anti-HIV-1 compounds for their activity against XMRV, including protease inhibitors (PI), nucleoside reverse transcriptase (RT) inhibitors (NRTI), non-nucleoside RT inhibitors (NNRTI) and an integrase inhibitor. No PI affected XMRV production; even high concentrations of Ritonavir failed to inhibit the maturation of XMRV Gag polyproteins. Among the NRTI, NNRTI and integrase inhibitors used in this study, only AZT blocked XMRV infection and replication through inhibition of viral reverse transcription. This sensitivity of XMRV to AZT may be explained by the modest homology in the motif D sequences of HIV-1 and XMRV reverse transcriptases. If XMRV becomes established as an etiological agent for prostate cancer or other diseases, AZT may be useful for preventing or treating XMRV infections in humans. [Copyright &y& Elsevier]

Background The principal causes of liver enzyme elevation among HIV–hepatitis B virus (HBV) co-infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART-induced immune reconstitution and the exacerbation of chronic HBV infection. Objectives To investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV–HBV co-infected patients. Methods Retrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6-month period following 3TC withdrawal. Results 3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow-up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded. Conclusions HBV reactivation leading to liver dysfunction may be an under-reported consequence of 3TC withdrawal in HIV–HBV co-infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued. [ABSTRACT FROM AUTHOR]

The article presents a study which analyzes the mitochondrial tRNA genes and flanking regions in umbilical cord tissue from uninfected infants who receive AZT-based therapies for prophylaxis of HIV-1. It utilized the sensitive vertical denaturing gradient gel electrophoresis (DGGE) method. It disinfected biological specimens and isolate the DNA. Furthermore, the human mtDNA was amplified by PCR then heteroduplex formation and photoinduced crosslinking followed. It also involved DNA sequencing and estimation of degree of heteroplasmy or mutant fraction. Lastly, human TK6 B-lymphoblastoid cells were cultured and DGGE-based screening for mtDNA sequence variants was done. It did not establish the link of increased detection of sequence changes at two polymorphic sites in AZT-exposed infants.

Abstract: Because of their similarity to humans, non-human primates constitute useful preclinical models in which to examine potential human drug toxicities. Antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) toxicity is currently under investigation in Erythrocebus patas monkeys, and whereas NRTI pharmacokinetics have been studied in other monkey species, pharmacokinetics for Zidovudine plus Lamivudine (AZT/3TC) dosing have not been reported in the patas. Here we present 24 h serum pharmacokinetic parameters after a single oral exposure to the combination of AZT (40 mg) and 3TC (24 mg), doses equivalent to a human daily dose of Combivir®. The patas (n =3) AZT/3TC pharmacokinetic profiles were similar to those seen in other primate species. Average maximum serum concentrations (C max) for AZT and 3TC were 2.35 and 2.65 μg/ml, respectively, and were observed at 0.83 h (T max). C max was 13.34 μg/ml for the AZT-glucuronide (AZT-G) and was 0.023 μg/ml for the potentially toxic minor metabolite 3′-amino-3′-deoxythymidine (AMT), both occurring at about 1 h after dosing. Similar elimination half-times, 0.70 and 0.68 h−1, were found for AZT and AZT-G, respectively, while 3TC was eliminated about half as fast (0.33 h−1) resulting in AUC(0–∞) values of 6.97 μg/ml h for 3TC, 2.99 μg/ml h for AZT, 20.5 μg/ml h for AZT-G and 0.002 for AMT 6.97 μg/ml h. This study shows similar metabolism and pharmacokinetics for oral administration of AZT/3TC in the adult patas monkey, other primate species and humans. The data validate the use of the patas monkey for studies of NRTI toxicity. [Copyright &y& Elsevier]

What is already known about this subject • Prior to the conduct of this study, information on the pharmacokinetics of lamivudine in subjects with renal impairment was limited to patients on haemodialysis. (Br J Clin Pharmacol 1998; 46: 21–7). • No pharmacokinetic data were available on subjects receiving lamivudine who were concurrently receiving peritoneal dialysis. • With increasing numbers of individuals opting for peritoneal dialysis, the need to establish if dose modification was necessary in this setting was important to ensure efficacious and safe drug exposures were being obtained. What this study adds • This study demonstrated that similar to patients receiving haemodialysis, dose modifications based on reductions in renal function (i.e. decreased CLCR), also applied to subjects on peritoneal dialysis. Aims To establish whether peritoneal dialysis (PD) requires dosing modification from the CLCR-corrected lamivudine dose in end-stage renal failure subjects . Methods This was an open-label cohort study. A total of 12 subjects undergoing PD, six continuous ambulatory peritoneal dialysis (CAPD) and six automated peritoneal dialysis (APD), for at least 3 months received lamivudine 10 mg (5 mg ml −1 × 2 ml) daily for 8 consecutive days, followed by an intensive pharmacokinetic assessment. Urine and dialysate were collected from 0 to 24 h postdose on day 8 where possible. Pharmacokinetic parameters were calculated using noncompartmental techniques . Results The plasma pharmacokinetic results demonstrated that peritoneal dialysis clearance (CLD) of lamivudine was similar between APD and CAPD patients with median (range) of 0.19 l h−1 (0.14–0.25) and 0.1 l h−1 (0.09–0.25), respectively. CLD was approximately 1/15th to 1/30th of plasma clearance, demonstrating that peritoneal dialysis does not contribute significantly to overall lamivudine clearance in this patient population. The AUC(0,24 h) of lamivudine given 10 mg daily to APD and CAPD patients was 3430 ng ml−1 h and 3469 ng ml−1 h, respectively, similar to historical data obtained in patients with normal renal function administered at the normal dose of 100 mg daily (3781 ng ml−1 h). There were no clinically significant changes in any safety assessments that were attributable to lamivudine . Conclusions ESRD patients who receive CAPD or APD require no supplemental dosing. These patients should follow the standard dosing reduction for patients infected with HIV or HBV with renal dysfunction. [ABSTRACT FROM AUTHOR]

The article presents an analysis of the distinctive impact of lamivudine (3TC) and emtricitabine (FTC) without M1841 or V using patient samples with nucleoside reverse transcriptase inhibitor (NRTI) experience. It shows a significant comparison between 3TC and FTC phenotypic profiles in viruses with mutations chosen by other NRTIs.

Emtricitabine (FTC) and lamivudine (3TC) are deoxycytidine analogues with potent and selective inhibition of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication. The K65R mutation in the HIV reverse transcriptase (RT) confers reduced susceptibility to 3TC, ddC, ddI, abacavir, and tenofovir in vitro. The Q151M mutation confers reduced susceptibility to many of the approved anti-HIV nucleoside analogues with the exception of 3TC and tenofovir. The double mutation K65R/Q151M has been shown to be more resistant to many NRTIs than either of the single mutations alone. In this study, we measured the antiviral activity of FTC and 3TC against HIV-1 containing K65R, Q151M, and K65R/Q151M mutations. We also studied the steady-state kinetic properties for the inhibition of dCTP incorporation by FTC 5′-triphosphate (TP) and 3TC-TP. In addition, we measured the incorporation of dCTP, FTC-TP, and 3TC-TP into a random sequence DNA/DNA primer/template by the HIV-1 RTs using pre-steady-state kinetic analysis. Finally, we studied the incorporation of these deoxycytidine analogues into a HIV-1 genomic DNA/DNA primer/template by K65R HIV-1 RT to address certain concerns associated with DNA sequence specificity. Overall, this study demonstrated that K65R and K65R/Q151M related drug resistance to FTC and 3TC was mainly due to a significant decrease in the rate of incorporation. There was little to no effect on the binding affinities of the mutant HIV-1 RTs for the deoxycytidine analogues. The Q151M mutation remained sensitive to both FTC and 3TC in both cell culture and enzymatic assays. At a molecular level, FTC-TP was incorporated at least as efficiently as 3TC-TP for all of the HIV-1 RT and primer/templates tested. [ABSTRACT FROM AUTHOR]

Conformational properties and the energy barriers between the anti and the syn configurations of 3TC, ddC, AZT and d4T have been examined using the density functional theory. For 3TC, ddC and AZT the global minimum structure is the syn configuration of pyrimidine unit. Only thymine ring of d4T is at the anti conformation. Changing from the syn to the anti configuration, the furanose ring conformation is not generally affected for all compounds under consideration. [Copyright &y& Elsevier]

Methionine at position 184 of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) was changed to valine, isoleucine, threonine, or alanine in an HIV-1-based vector. The vectors were analyzed for replication capacity and for resistance to the nucleoside analog 2′,3′-dideoxy-3′thiacytidine (3TC) using a single-cycle assay. Viruses containing the valine or isoleucine mutations were highly resistant to 3TC and replicated almost as well as the wild-type virus. The virus containing the threonine mutation was resistant to 3TC, but replicated about 30% as well as the wild-type. The alanine mutation conferred partial resistance to 3TC, but replicated poorly. The amounts of viral DNA synthesized decreased in 3TC-treated cells when the cells were infected with wild-type virus and the M184A mutant. The effect of these mutations on the generation of the ends of the linear viral DNA was determined using the sequence of the 2-LTR circle junctions. The M184T mutation increased the proportion of 2-LTR circle junctions containing a tRNA insertion, suggesting that the mutation affected the RNase H activity of RT. [Copyright &y& Elsevier]

Unlike hydroxyurea, the CTP synthetase inhibitor acivicin and, to a lesser extent, two other inhibitors of CTP synthesis, increased the phosphorylation and anti-HIV-1 activity of 3TC in PHA-P-activated PBMC. These data suggest that to improve the antiretroviral activity of 3TC, it may be worth focusing on inhibition of CTP synthesis. [Copyright &y& Elsevier]

UMP-CMP kinase catalyses an important step in the phosphorylation of UTP, CTP and dCTP. It is also involved in the necessary phosphorylation by cellular kinases of nucleoside analogs used in antiviral therapies. The reactivity of human UMP-CMP kinase towards natural substrates and nucleotide analogs was reexamined. The expression of the recombinant enzyme and conditions for stability of the enzyme were improved. Substrate inhibition was observed for UMP and CMP at concentrations higher than 0.2 mm, but not for dCMP. The antiviral analog l-3TCMP was found to be an efficient substrate phosphorylated into l-3TCDP by human UMP-CMP kinase. However, in the reverse reaction, the enzyme did not catalyse the addition of the third phosphate to l-3TCDP, which was rather an inhibitor. By molecular modelling, l-3TCMP was built in the active site of the enzyme from Dictyostelium . Human UMP-CMP kinase has a relaxed enantiospecificity for the nucleoside monophosphate acceptor site, but it is restricted to d-nucleotides at the donor site. [ABSTRACT FROM AUTHOR]

summary. Adefovir is a potent nucleotide analog inhibitor of hepatitis B virus (HBV) DNA polymerase. Its oral prodrug adefovir dipivoxil has been approved for the treatment of chronic HBV infection. In this study, adefovir was characterized for its in vitro effects on mitochondrial DNA (mtDNA) synthesis and compared with the nucleoside analogues lamivudine (3TC), fialuridine (FIAU), and zalcitabine (ddC). No substantial changes in mtDNA content were detected in human hepatoblastoma HepG2 cells and normal human skeletal muscle cells following a 9-day treatment with 0.3–30 μ m adefovir, concentrations up to 500-fold higher than the peak serum levels in patients treated with adefovir dipivoxil. Similarly, mtDNA was unchanged in both cell types following treatment with 3TC. In contrast, 30–55% and > 90% reductions in mtDNA were observed following incubation with 30 μ m FIAU and ddC, respectively. The effects of FIAU on mtDNA became more pronounced following prolonged 18-day treatment of skeletal muscle cells while the effects of other drugs remained unchanged. [ABSTRACT FROM AUTHOR]

Oral adefovir dipivoxil (ADV) reduced viral load in transgenic mice expressing hepatitis B virus (HBV). Liver HBV DNA was reduced to <0.1 pg of viral DNA per μg of total DNA (pg/μg) following oral ADV therapy at a dosage of 100 mg/kg/day twice daily for 10 days as compared to a mean of 3.0 pg/μg for the placebo control group. Oral ADV treatment also reduced serum HBV DNA to 3.5 log10 genomic equivalents (ge)/ml compared to 5.3 log10 ge/ml for the placebo control group. With once daily treatments, ADV antiviral activity reached near maximum viral reduction by day 10 in the liver and reached an endpoint of liver virus inhibition at 1.0 mg/kg/day. The minimum effective dose was less than 0.1 mg/kg/day using inhibition of serum virus. Lamivudine (3TC) given orally at 500 mg/kg/day using the same treatment schedule marginally reduced the serum HBV DNA by 4-fold, but did not significantly reduce HBV liver DNA. Serum titer reduction was also identified in untreated or placebo-treated animals, which may have been caused by the stress of pre-treatment bleeding and multiple oral gavage treatments. This trauma/placebo-effect may have masked the extent of viral reduction in the serum in ADV- and 3TC-treated animals. Liver HBV RNA was not reduced by oral ADV treatments. The lack of RNA reduction was expected, because the HBV transgene is stably integrated into the chromosome and ADV inhibits polymerase activity after transcription of pregenomic RNA. ADV was identified to have potent anti-HBV activity in this HBV transgenic mouse model and could serve as a suitable positive control for future drug discovery experiments. [Copyright &y& Elsevier]

In vitro and in vivo prophylactic and therapeutic efficacy of AZT/3TC treatment was evaluated against feline immunodeficiency virus (FIV) infection. In vitro studies utilized FIV-infected peripheral blood mononuclear cells (PBMCs) or FIV-infected T-cell lines treated with AZT (azidothymidine) alone, 3TC alone, or AZT/3TC combination and tested for anti-FIV activity and drug toxicity. AZT/3TC combination had additive to synergistic anti-FIV activities in primary PBMC but not in chronically infected cell lines. In vivo studies consisted of four treatment groups (n=15) of SPF cats receiving AZT/3TC combination (5–75 mg/kg/drug PO BID for 8 or 11 weeks) and one control group (n=9) receiving oral placebo. Group I (n=6, 150 mg/kg/drug/day) was treated starting 3 days pre-FIV inoculation, whereas Group II (n=3, 150 mg/kg/drug/day) and Group III (n=3, 100 mg/kg/drug/day) treatments were simultaneous with FIV inoculation. Group IV treatment (n=3, 100 mg/kg/drug/day) was initiated 2 weeks post-FIV inoculation. All cats were monitored for drug toxicity and FIV infection. Eighty-three percent of cats in Group I and 33% of cats in Groups II and III were completely protected from FIV infection. A significant delay in infection and antibody seroconversion was observed in all unprotected cats from Groups I, II and III. Group IV cats had only a slight delay in FIV antibody seroconversion. Adverse drug reactions (anemia and neutropenia) were observed at high doses (100–150 mg/kg/drug/day) were reversible upon lowering the dose (20 mg/kg/drug/day). In contrast, AZT/3TC treatment had no anti-FIV activity in chronically infected cats. Furthermore, severe clinical symptoms caused by adverse drug reactions were observed in some of these cats. Overall, AZT/3TC treatment is effective for prophylaxis but not for therapeutic use in chronically FIV-infected cats. [Copyright &y& Elsevier]

To decrease the costs of producing the anti-HIV drug, lamivudine, an enzymatic conversion process was developed instead of the traditional chemical method. Thermostable cytidine deaminase was over-produced by cloning the cdd gene into E. coli JF611/pCJH53 from Bacillus caldolyticus. The purified cytidine deaminase was recovered from the lysate of the recombinant E. coli JF611/pCJH53 by removing heat-denatured proteins and eluting sequential chromatography. When the enzyme was used to deaminate (-)-β-l-(2R,5S)- and (+)-β-d-(2S,5R)-1,3-oxathiolanyl-cytosine, about 68% of the (+)-β-d-(2S,5R)-1,3-oxathiolanyl-cytosine was deaminated into the corresponding (+)-thiauridine maximally. [ABSTRACT FROM AUTHOR]

The purpose of this study was to characterize the renal uptake properties of the cytidine analog and antiretroviral agent 3TC. The uptake of radiolabelled 3TC was measured at 37°C in a continuous porcine renal epithelial cell line (i.e., LLC-PK[sub 1] cells) grown as a monolayer on an impermeable support. 3TC (5 µM) uptake (37°C) by the monolayer cells was saturable (K[sub m] = 1.2 ± 0.2 mM) but not significantly altered by various dideoxynucleoside analog drugs, nucleosides, and nucleoside transport inhibitors, suggesting that a nucleoside transporter is not involved in 3TC uptake. A number of endogenous organic cation probes and inhibitors significantly reduced 3TC uptake by the monolayer cells. Quinine, trimethoprim (TMP), and tetraethylammonium (TEA) inhibited 3TC uptake in a dose dependent manner with IC[sub 50] values of 0.6mM, 0.63mM, and 1.9 mM, respectively. In turn, the uptake of the typical organic cation substrate TEA was inhibited by high concentrations of 3TC. An outwardly directed proton gradient significantly increased the uptake of 3TC by the monolayer cells, suggesting the involvement of a proton exchange process. Conversely, in the presence of monensin, a Na[sup +] /H[sup +] ionophore, the uptake of 3TC was significantly reduced. These results suggest that the uptake of 3TC by a cultured renal epithelium may be mediated by an organic cation-proton exchanger. The observed clinical interaction between 3TC and trimethoprim may be explained by competition for a common renal organic cation tubular transporter.Key words: 3TC, kidney, uptake, LLC-PK[sub 1] , tubular elimination.La présente étude a eu pour but de caractériser les propriétés de la capture rénale de l'agent antirétroviral et analogue de la cytidine, 3TC. La capture du 3TC radiomarqué a été mesurée à 37 [sup o] C dans une lignée continue de cellules épithéliales rénales de porc (cellules LLC-PK[sub 1] ) cultivées en monocouches sur un support imperméable. La capture de 3TC (5 µM, 37 [sup o] C) par les monocouches de cellules a été saturable (K[sub m] = 1,2 ± 0,2 mM), mais elle n'a pas été modifiée de manière significative par divers analogues des didéoxynucléosides, nucléosides et inhibiteurs de transport des nucléosides, ce qui permet de croire qu'aucun transporteur de nucléosides n'a joué un rôle dans la capture. Plusieurs sondes de cations organiques endogènes et plusieurs inhibiteurs ont diminué de manière significative la capture de 3TC par les monocouches de cellules. La quinine, le TMP et le TEA ont inhibé la capture de 3TC de manière dose dépendante avec des valeurs de CI[sub 50] de 0,6 mM, 0,63 mM et 1,9 mM respectivement. De même, la capture du substrat typique des cations organiques, TEA, a été inhibée par de fortes concentrations de 3TC. Un gradient de protons orienté vers l'extérieur a significativement augmenté la capture de 3TC par les monocouches de cellules, suggérant la contribution d'un processus d'échange de protons. À l'opposé, en présence de monensine, un ionophore de Na[sup +] /H[sup +] , la capture de 3TC a été significativement réduite, Ces résultats permettent de croire que la capture de 3TC par un épithélium rénal en culture pourrait être véhiculée par un échangeur de cations/protons organiques. L'interaction clinique observée entre le 3TC et le triméthoprime pourrait être expliquée par une compétition pour un transporteur tubulaire rénal commun de cations organiques.Mots clés : 3TC, rein, capture, LLC-PK[sub 1] , élimination tubulaire.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]

In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-α and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the main-stay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomew et al., 1997; Tipples et al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed. [ABSTRACT FROM AUTHOR]

Purpose. Dideoxynucleoside bases are used for the treatment of acquired immune deficiency syndrome (AIDS), acting by inhibiting reverse transcriptase and preventing human immunodeficiency virus (HIV) replication. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2′-deoxy-3′-thiacytidine, lamivudine), a new dideoxynucleoside base, is currently undergoing Phase II/III trials, and has exhibited anti-HIV replication activity, a favorable adverse event safety profile, and is eliminated via renal mechanisms. Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney. Methods. An isolated perfused rat kidney (IPK) technique was used to screen several clinically relevant drugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant concentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxazole, ranitidine, and cimetidine. Results. Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (5000 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentrations studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively. Conclusions. These results indicate that caution should be exercised when the combination of 3TC and trimethoprim are administered to AIDS patients. [ABSTRACT FROM AUTHOR]

Abstract: We report on the first solution synthesis of lamivudine 5′-diphosphate in both high yield and purity. Efficient synthesis of lamivudine 5′-monophosphate was obtained through lamivudine H-phosphonate oxidation by (−)-(8,8-dichlorocamphorylsulfonyl)oxaziridine. Diphosphorylation was performed by nucleophilic substitution of the phosphorimidazolate derivative of lamivudine. HPLC coupled with UV or MS detection was found to be an invaluable tool for the follow-up of phosphorylation reactions. [Copyright &y& Elsevier]

Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes. [ABSTRACT FROM AUTHOR]