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Harilall, Sheri-Lee, Yahya E. Choonara, Girish Modi, et al. "Design and Pharmaceutical Evaluation of a Nano-Enabled Crosslinked Multipolymeric Scaffold for Prolonged Intracranial Release of Zidovudine." Journal of Pharmacy & Pharmaceutical Sciences 16, no. 3 (2013): 470. http://dx.doi.org/10.18433/j3r88k.
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Purpose. Nanomedicine explores and allows for the development of drug delivery devices with superior drug uptake, controlled release and fewer drug side-effects. This study explored the use of nanosystems to formulate an implantable drug delivery device capable of sustained zidovudine release over a prolonged period. Methods. Pectin and alginate nanoparticles were prepared by applying a salting out and controlled gelification approach, respectively. The nanoparticles were characterized by attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS) and were further evaluated for zidovudine (AZT) entrapment efficiency. Multipolymeric scaffolds were prepared by crosslinking carboxymethyl cellulose, polyethylene oxide and epsilon caprolactone for entrapment of zidovudine-loaded alginate nanoparticles to impart enhanced controlled release of zidovudine over the time period. Swelling and textural analysis were conducted on the scaffolds. Prepared scaffolds were treated with hydrochloric acid (HCl) to reduce the swelling of matrix in the hydrated environment thereby further controlling the drug release. Drug release studies in phosphate buffered saline (pH 7.4, 37°C) were undertaken on both zidovudine-loaded nanoparticles and native scaffolds containing alginate nanoparticles. Results. A higher AZT entrapment efficiency was observed in alginate nanoparticles. Biphasic release was observed with both nanoparticle formulations, exhibiting an initial burst release of drug within hours of exposure to PBS, followed by a constant release rate of AZT over the remaining 30 days of nanoparticle analysis. Exposure of the scaffolds to HCl served to reduce the drug release rate from the entrapped alginate nanoparticles and extended the AZT release up to 30 days. Conclusions. The crosslinked multipolymeric scaffold loaded with alginate nanoparticles and treated with 1% HCl showed the potential for prolonged delivery of zidovudine over a period of 30 days and therefore may be a potential candidate for use as an implantable device in treating Aids Dementia Complex.
 
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Khandazhinskaya, А. L., and E. A. Shirokova. "AZT 5’-Phosphonates: Achievements and Trends in the Treatment and Prevention of HIV Infection." Acta Naturae 5, no. 3 (2013): 54–61. http://dx.doi.org/10.32607/20758251-2013-5-3-54-61.
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Despite the numerous drawbacks, 3-azido-3-deoxythymidine (AZT, Zidovudine, Retrovir) remains one of the key drugs used in the treatment and prevention of HIV infection in both monotherapy and HAART. A strategy in searching for new effective and safe AZT agents among latent (depot) forms of AZT has yielded its first positive results. In particular, the sodium salt of AZT 5-H-phosphonate (Nikavir, phosphazide) has demonstrated clinical advantages over parent AZT: first and foremost, lower toxicity and better tolerability. It can be effectively used for the prevention of vertical transmission from mothers to babies and as an alternative drug for HIV-infected patients with low tolerance to Zidovudine. Preclinical studies of another phosphonate, AZT 5-aminocarbonylphosphonate, have demonstrated that it releases AZT when taken orally. Pharmacokinetic studies have shown a prolonged action potential. Based on the analysis of both toxicological and pharmacological data, AZT 5-aminocarbonylphosphonate has been recommended for clinical trials.
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Brown, Stacy D., Michael G. Bartlett, and Catherine A. White. "Pharmacokinetics of Intravenous Acyclovir, Zidovudine, and Acyclovir-Zidovudine in Pregnant Rats." Antimicrobial Agents and Chemotherapy 47, no. 3 (2003): 991–96. http://dx.doi.org/10.1128/aac.47.3.991-996.2003.
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ABSTRACT The pharmacokinetics and placental transfer of acyclovir and zidovudine monotherapies and acyclovir-zidovudine combination therapy were compared in the pregnant rat. Timed-pregnancy Sprague-Dawley rats were used for the study. Doses of 60 mg of each drug/kg of body weight in monotherapy and in combination therapy were given by intravenous bolus, and samples of maternal plasma, amniotic fluid, fetal tissue, and placental tissue were collected over a period of 8 h postdose. Concentrations of each drug in the various matrices were measured by high-performance liquid chromatography. All data were analyzed by using WinNonlin. A one-compartment model with first-order elimination was used to fit the AZT plasma data from the combination therapy rats, but the plasma data from the other groups were fit to a two-compartment model. Tissue data were analyzed by noncompartmental analysis to generate area-under-the-concentration-time-curve values. Implementation of the combination therapy altered the pharmacokinetics of each drug compared to its monotherapy pharmacokinetics. The combination of these two drugs may potentiate fetal and amniotic fluid exposures to each drug.
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Stankov, Metodi V., Reinhold E. Schmidt, and Georg M. N. Behrens. "Zidovudine Impairs Adipogenic Differentiation through Inhibition of Clonal Expansion." Antimicrobial Agents and Chemotherapy 52, no. 8 (2008): 2882–89. http://dx.doi.org/10.1128/aac.01505-07.
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ABSTRACT Lipoatrophy is a prevalent side effect of treatment with thymidine analogues. We wished to confine the time point of the antiadipogenic effect of zidovudine (AZT) during adipogenesis and to evaluate the antiproliferative effect of AZT on adipocyte homeostasis. We investigated the effects of AZT on adipogenesis in 3T3-F442A cells and studied their proliferation, differentiation, viability, and adiponectin expression. Cells were exposed to AZT (1 μM, 3 μM, 6 μM, and 180 μM), stavudine (d4T; 3 μM), or dideoxycytosine (ddC; 0.1 μM) for up to 15 days. Differentiation was assessed by real-time PCR and quantification of triglyceride accumulation. Proliferation and clonal expansion were determined by a [3H]thymidine incorporation assay. When they were induced to differentiate in the presence of AZT at the maximum concentration in plasma (C max) and lower concentrations, 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol and failed to express normal levels of the later adipogenic transcription factors, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ. AZT exerted an inhibitory effect on the completion of the mitotic clonal expansion, which resulted in incomplete 3T3-F442A differentiation and, finally, a reduction in the level of adiponectin expression. In addition, AZT impaired the constitutive proliferation in murine and primary human subcutaneous preadipocytes. In contrast, incubation with d4T and ddC at the C max did not affect either preadipocyte proliferation or clonal expansion and differentiation. We conclude that the antiproliferative and antiadipogenetic effects of AZT on murine and primary human preadipocytes reveal the impact of the drug on fat tissue regeneration. These effects of the drug are expected to contribute to disturbed adipose tissue homeostasis and to be influenced by differential drug concentration and penetration in individual patients.
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Mariano, DOC, D. de Souza, DF Meinerz, et al. "The potential toxicological insights about the anti-HIV drug azidothymidine-derived monoselenides in human leukocytes: Toxicological insights of new selenium-azidothymidine analogs." Human & Experimental Toxicology 36, no. 9 (2016): 910–18. http://dx.doi.org/10.1177/0960327116674529.
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Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5′-Se-(phenyl)zidovudine; 5′-Se-(1,3,5-trimethylphenyl)zidovudine; 5′-Se-(1-naphtyl)zidovudine; 5′-Se-(4-chlorophenyl)zidovudine) (C4); 5′-Se-(4-methylphenyl)zidovudine (C5); and 5′-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.
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Jones, Jan L. "Drugs for AIDS/HIV:Assessing the Evidence." International Journal of Technology Assessment in Health Care 14, no. 3 (1998): 567–72. http://dx.doi.org/10.1017/s0266462300011533.
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AbstractThis article highlights factors that may cause bias in individual controlled trials or meta-analysis of zidovudine (AZT) in HIV disease. The overall benefit of AZT and antiretroviral drug combinations in the progression of HIV disease is probably greater than has been or can ever be shown in an ethical controlled trial.
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Driscoll, JS, DL Mayers, JP Bader, OS Weislow, DG Johns, and RW Buckheit. "2′-Fluoro-2′,3′-Dideoxyarabinosyladenine (F-ddA): Activity against Drug-Resistant Human Immunodeficiency Virus Strains and Clades A-E." Antiviral Chemistry and Chemotherapy 8, no. 2 (1997): 107–11. http://dx.doi.org/10.1177/095632029700800204.
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2′-Fluoro-2′,3′-dideoxyarabinosyladenine (F-ddA), an anti-human immunodeficiency virus (HIV) drug currently in clinical trial, was compared with zidovudine (AZT), ddl and ddC for anti-HIV activity and potency in HIV-1 strains both sensitive and resistant to zidovudine, ddl and non-nucleoside reverse transcriptase inhibitors. A variety of host cell systems [MT-2, MT-4, phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC)] was used. F-ddA was effective against each of the drug-resistant isolates, including the strain resistant to ddl, the other purine dideoxynucleoside evaluated in this study. The anti-HIV-1 activities of F-ddA and zidovudine were also determined against clades A-E in PHA-PBMCs. Although activities were similar, zidovudine was significantly more potent than F-ddA in the PHA-PBMC system.
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Wainberg, Mark A., Andre Dascal, and Jack Mendelson. "Anti-Retroviral Strategies for AIDS and Related Diseases." Canadian Journal of Infectious Diseases 2, no. 3 (1991): 121–28. http://dx.doi.org/10.1155/1991/487657.
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The replication cycle of human immunodeficiency virus type 1 (HIV-1) and other retroviruses consists of four stages: attachment of the virus to specific receptors on the cell surface; uncoating of the viral nucleic acid and conversion to DNA; production of viral RNA and proteins; and assembly and liberation of progeny virus from the cell. Each of these steps represents a potential target for antiviral chemotherapy. Combinations of drugs which act against different steps in the viral replication cycle might be expected to have synergistic potential. Zidovudine (AZT) is the most widely used drug to date for impeding the replication of HIV-1. Although AZT therapy has been reasonably successful, it has not been free from toxicity. In addition, there have been several reports of isolation of AZT-resistant variants of HIV-1.
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Christmas, James T., Bertis B. Little, Kraig A. Knoll, Roger E. Bawdon, and Larry C. Gilstrap III. "Teratogenic and Embryocidal Effects of Zidovudine (AZT) in Sprague-Dawley Rats." Infectious Diseases in Obstetrics and Gynecology 2, no. 5 (1995): 223–27. http://dx.doi.org/10.1155/s1064744995000068.
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Objective: The purpose of the present investigation was to analyze the effets of zidovudine on the postimplantation embryo and fetus.Methods: Pregnant Sprague-Dawley rats were given various doses (10 mg/kg, 30 mg/kg, 150 mg/kg) of zidovudine or saline by an endotracheal tube during the period of embryogenesis (days 6–8, 9–11, 6–11 postconception). The animals were sacrificed on days 18–19 of pregnancy, and their fetuses were removed by hysterotomy. Autopsies under low (15×) and high (40×) power light microscopy were performed on all fetuses.Results: There was no statistically significant difference among the groups with respect to maternal weight gain. There were more pregnancy resorptions in the group receiving high-dose zidovudine (150 mg/kg/day) throughout embryogenesis than in the control group (P = 0.001, respectively). Four major structural anomalies were noted among the 689 fetuses examined, but zidovudine was not associated with an increased frequency of congenital anomalies in rats when it was administered in doses similar to, 3-, and 15-fold higher than the regimen recommended for adult humans. The drug, however, was embryocidal in the high-dose group (P = 0.002).Conclusions: These findings are consistent with previous studies of preimplantation mouse embryos that demonstrated an embryocidal effect on preimplantation conceptuses. In summary, post-implantation embryonic zidovudine exposure was associated with significantly increased pregnancy losses (resorptions and intrauterine deaths).
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Bazzoli, C., H. Bénech, E. Rey, et al. "Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients." Antimicrobial Agents and Chemotherapy 55, no. 7 (2011): 3423–31. http://dx.doi.org/10.1128/aac.01487-10.
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ABSTRACTThe population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.
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Ramanathan, Raghu, and Karthikeyan Sivanesan. "Investigations on the Influence of Zidovudine in the Pharmacokinetics of Isoniazid and Its Hepatotoxic Metabolites in Rats." Journal of Pharmacy Practice 32, no. 1 (2017): 9–18. http://dx.doi.org/10.1177/0897190017735424.
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The HIV-infected patients are co-infected with many bacterial infections in which tuberculosis is most common found worldwide. These patients are often administered with combined therapy of anti-retroviral and anti-tubercular drugs which leads to several complications including hepatotoxicity or adverse drug interactions. The drug-drug interactions between the anti-retroviral and anti-tubercular drugs are not clearly defined and hence, this study was conducted to evaluate the pharmacokinetic drug-drug interactions of Zidovudine (AZT) with Isoniazid (INH) and its hepatotoxic metabolites. Seventy two rats were randomly divided into two major groups with their sub-groups each comprising 6 animals. The Group I received INH alone at a dose of 25 mg/kg; b.w and Group II received AZT (50 mg/kg; b.w) along with INH orally. Pharmacokinetic studies of INH and its metabolites i.e., acetyl hydrazine (ACHY) and hydrazine (HYD) shows that INH and ACHY attains maximum plasma concentration ( Cmax) within 30 minutes and HYD attains Cmax at 1 hour after INH administration and all these analytes disappear from plasma within 4 hours. Pharmacokinetic studies also revealed that AZT treatment did not showed any drug-drug interactions and have no effect on the T1/2, plasma clearance, AUC, Cmax and Tmax of INH and its hepatotoxic metabolites.
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Desai, Varsha G., Taewon Lee, Carrie L. Moland, et al. "Evaluation of Hepatic Mitochondria and Hematological Parameters in Zidovudine-TreatedB6C3F1Mice." AIDS Research and Treatment 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/317695.
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The effects of 12-week exposure to zidovudine (AZT) at 400, 500, and 600 mg/kg/d were examined on expression of 542 mitochondria-related genes and mitochondrial DNA (mtDNA) copy number in the liver of male and female B6C3F1mice to understand mitochondrial role in sex-related differences in development of lactic acidosis. Plasma lactate levels and hematologic parameters were also examined. Results indicated increased red blood cell (RBC) count in vehicle-treated controls, whereas a dose-related decline in the RBC count was noted in AZT-treated mice compared to the basal levels before treatments began. These decreases were associated with significant dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin levels. This effect was greater in AZT-treated females compared to males. In both sexes, 12-week AZT or vehicle exposure significantly reduced plasma lactate levels compared to the basal levels. Results also showed modest, but significant, changes in the expression of genes associated with apoptosis and lipid metabolism at 600 mg/kg/d AZT. Neither drug nor sex influenced hepatic mtDNA copy number. Altogether, 12-week AZT exposure as high as 600 mg/kg/d did not impair hepatic mitochondria or induce lactic acidosis in B6C3F1mice. However, AZT-mediated hematologic toxicity appeared to be greater in females compared to males.
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García-Lerma, J. Gerardo, Hamish MacInnes, Diane Bennett, Hillard Weinstock, and Walid Heneine. "Transmitted Human Immunodeficiency Virus Type 1 Carrying the D67N or K219Q/E Mutation Evolves Rapidly to Zidovudine Resistance In Vitro and Shows a High Replicative Fitness in the Presence of Zidovudine." Journal of Virology 78, no. 14 (2004): 7545–52. http://dx.doi.org/10.1128/jvi.78.14.7545-7552.2004.
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ABSTRACT Drug-naive patients infected with drug-resistant human immunodeficiency virus type 1 (HIV-1) who initiate antiretroviral therapy show a shorter time to virologic failure than patients infected with wild-type (WT) viruses. Resistance-related HIV genotypes not commonly seen in treated patients, which likely result from reversion or loss of primary resistance mutations, have also been recognized in drug-naive persons. Little work has been done to characterize the patterns of mutations in these viruses and the frequency of occurrence, their association with phenotypic resistance, and their effect on fitness and evolution of resistance. Through the analysis of resistance mutations in 1082 newly diagnosed antiretroviral-naive persons from the United States, we found that 35 of 48 (72.9%) persons infected with HIV-1 containing thymidine analog mutations (TAMs) had viruses that lacked a primary mutation (T215Y/F, K70R, or Q151M). Of these viruses, 9 (25.7%) had only secondary TAMs (D67N, K219Q, M41L, or F77L), and all were found to be sensitive to zidovudine (AZT) and other drugs. To assess the impact of secondary TAMs on the evolution of AZT resistance, we generated recombinant viruses from cloned plasma-derived reverse transcriptase sequences. Two viruses had D67N, three had D67N and K219Q/E, and three were WT. Four site-directed mutants with D67N, K219Q, K219E, and D67N/K219Q were also made in HIV-1HXB2. In vitro selection of AZT resistance showed that viruses with D67N and/or K219Q/E acquired AZT resistance mutations more rapidly than WT viruses (36 days compared to 54 days; P = 0.003). To investigate the factors associated with the rapid selection of AZT mutations in these viruses, we evaluated fitness differences among HXB2WT and HXB2D67N or HXB2D67N/K219Q in the presence of AZT. Both HXB2D67N/K219Q and HXB2D67N were more fit than HXB2WT in the presence of either low or high AZT concentrations, likely reflecting low-level resistance to AZT that is not detectable by phenotypic testing. In the absence of AZT, the fitness cost conferred by D67N or K219Q was modest. Our results demonstrate that viruses with unique patterns of TAMs, including D67N and/or K219Q/E, are commonly found among newly diagnosed persons and illustrate the expanding diversity of revertant viruses in this population. The modest fitness cost conferred by D67N and K219Q supports persistence of these mutants in the untreated population and highlights the potential for secondary transmission. The faster evolution of these mutants toward AZT resistance is consistent with the higher viral fitness in the presence of AZT and shows that these viruses are phenotypically different from WT HIV-1. Our study emphasizes the need for clinical studies to better define the impact of these mutants on treatment responses and evolution of resistance.
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Fayz, Shirin, and T. Inaba. "Zidovudine Azido-Reductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole, and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors." Antimicrobial Agents and Chemotherapy 42, no. 7 (1998): 1654–58. http://dx.doi.org/10.1128/aac.42.7.1654.
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ABSTRACT AZT (zidovudine, 3′-azido-3′-deoxythymidine), although metabolized primarily to AZT-glucuronide, is also metabolized to 3′-amino-3′-deoxythmidine (AMT) by reduction of the azide to an amine. The formation of the myelotoxic metabolite AMT has not been well characterized, but inhibition of AMT formation would be of therapeutic benefit. The aim of this study was to identify compounds that inhibit AMT formation. Using human liver microsomes under anaerobic conditions and [2-14C]AZT, Km values of AZT azido-reductase, estimated by radio-thin-layer chromatography, were 2.2 to 3.5 mM (n = 3). Oxygen completely inhibited this NADPH-dependent reduction. Thirteen of the 28 compounds tested inhibited the formation of AMT. In addition to the CYP3A4 inhibitors ketoconazole, fluconazole, indinavir, ritonavir, and saquinavir, metyrapone strongly inhibited AMT formation. An unexpected finding was the more-than-twofold increase in AMT formation in the presence of ethacrynic acid, dipyridamole, or indomethacin. Such activation of toxic metabolite formation would impair drug therapy.
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Wainberg, Mark A., Ronald Rooke, Michel Tremblay, et al. "Clinical Significance and Characterization of AZT-Resistant Strains of HIV-1." Canadian Journal of Infectious Diseases 2, no. 1 (1991): 5–11. http://dx.doi.org/10.1155/1991/124860.
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A number of laboratories have now independently confirmed that zidovudine (AZT)-resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (AIDS), while in others, isolation of drug-resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease.
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Mezzaroma, Ivano, Gianpiero D'Offizi, Elena Pinter, et al. "Immunological, Clinical and Epidemiological Aspects of an HIV-1 Positive Drug Abuser Cohort." Journal of Drug Issues 24, no. 4 (1994): 657–72. http://dx.doi.org/10.1177/002204269402400407.
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We analyzed a cohort of intravenous drug abusers with HIV-1 disease attending our institute in the years 1985–1993. We focused particular attention on the epidemiological analysis of patients, and their clinical, immunological and infectious conditions. The significance of biological markers, particulary CD4+ lymphocyte count and the occurence of other viral infections such as Cytomegalovirus, Epstein-Barr virus, Herpes Simplex virus and Hepatitis B and C viruses in the progress of HIV-1 disease were evaluated. At least two-thirds of the patients at different stages of HIV-1 were treated with antiretroviral drugs: zidovudine (AZT) from 1987 up to the present and more recently didanosine (DDI) alone or in combination with AZT. Psychological and behavioral aspects of our HIV-1 infected drug abusers, in particular needle exchange and condom use, were analyzed.
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Mathes, L. E., K. A. Hayes, and G. Kociba. "Evidence that high-dosage zidovudine at time of retrovirus exposure reduces antiviral efficacy." Antimicrobial Agents and Chemotherapy 40, no. 9 (1996): 2183–86. http://dx.doi.org/10.1128/aac.40.9.2183.
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The antiviral efficacy of prophylactic 3'-azido-3'-deoxythymidine (AZT) therapy administered by continuous infusion or intermittent injection was compared in pediatric cats infected with feline leukemia virus. A 4-week treatment regimen of AZT was initiated at -48, 8, or 96 h postinfection (p.i.). For AZT therapy begun at -48 h p.i., significant efficacy was attained when therapy was given by continuous infusion but not by intermittent injection. However, when AZT therapy was delayed until 96 h p.i., both continuous infusion and intermittent injection gave complete protection. The results suggest that intermittent AZT administration is less efficacious than continuous infusion. Higher peak AZT concentrations in plasma associated with intermittent injection compared with those associated with continuous infusion may be immunotoxic, thus reducing the drug-induced vaccine effect. Furthermore, AZT toxicity seemed to be restricted to a window of sensitivity close to the time of virus challenge because delaying the start of AZT therapy until 96 h p.i. was highly efficacious, regardless of the method of administration.
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Qian, M., A. R. Swagler, M. Mehta, C. T. Vishwanathan, and J. M. Gallo. "Pharmacokinetic Evaluation of anti-HIV Drug Interactions: Effect of Zidovudine on 2′-3′-Dideoxyinosine Kinetics in Monkeys." Antiviral Chemistry and Chemotherapy 4, no. 3 (1993): 155–59. http://dx.doi.org/10.1177/095632029300400304.
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The current investigation was conducted to determine if zidovudine (AZT) altered the pharmacokinetics of dideoxyinosine (ddl) in non-hurnan primates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg−1 of ddl intravenously in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT plasma concentrations of about 4 μg ml−1 in six animals (low dose group) and 11 μg ml−1 in three others (high dose group). Serial blood samples were collected, and pharmacokinetic parameters for ddl were calculated based on plasma ddl concentrations measured by HPLC techniques. The pharmacokinetics of ddl given alone in the first phase of the low ( n = 6) and high ( n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h−1 kg−1, and a mean steady state volume of distribution of 1.02 and 0.891 kg−1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time profiles of ddl were similar for each monkey, and no statistical differences were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter the pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.
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Snyder, Stuart, D. Z. D'Argenio, Owen Weislow, John A. Bilello, and G. L. Drusano. "The Triple Combination Indinavir-Zidovudine-Lamivudine Is Highly Synergistic." Antimicrobial Agents and Chemotherapy 44, no. 4 (2000): 1051–58. http://dx.doi.org/10.1128/aac.44.4.1051-1058.2000.
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ABSTRACT Administration of the combination of indinavir-zidovudine-lamivudine has been demonstrated to cause a large fraction of treated patients to have a decline in human immunodeficiency virus type 1 (HIV-1) copy number to below the detectability of sensitive assays. A recent investigation (G. L. Drusano, J. A. Bilello, D. S. Stein, M. Nessly, A. Meibohm, E. A. Emini, P. Deutsch, J. Condra, J. Chodakewitz, and D. J. Holder, J. Infect. Dis. 178:360–367, 1998) demonstrated that the durability of the antiviral effect was affected by combination chemotherapy. Zidovudine-lamivudine-indinavir differed significantly from the combination of zidovudine plus indinavir. We hypothesized that the addition of lamivudine might alter the regimen, producing a synergistic anti-HIV effect. In vitro analysis of drug interaction demonstrated that zidovudine-indinavir interacted additively. The addition of lamivudine in concentrations which suppressed viral replication by 20% or less by itself demonstrated marked increases in the synergy volume, increasing the synergy volume 20-fold with the addition of 320 nM lamivudine (which does not suppress HIV by itself) and 40-fold with the addition of 1,000 nM lamivudine (20% viral inhibition as a single agent). A fully parametric analysis with a newly developed model for three-drug interaction confirmed and extended these observations. The interaction term (αIND,AZT,3TC) for all three drugs showed the greatest degree of synergy. This marked synergistic interaction among the three agents may explain some of the clinical results which differentiate this regimen from the double-drug regimen of zidovudine plus indinavir.
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Boyer, Paul L., Kalyan Das, Eddy Arnold, and Stephen H. Hughes. "Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase." Antimicrobial Agents and Chemotherapy 59, no. 12 (2015): 7184–96. http://dx.doi.org/10.1128/aac.05069-14.
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ABSTRACTAlthough anti-human immunodeficiency virus type 1 (HIV-1) therapies have become more sophisticated and more effective, drug resistance continues to be a major problem. Zidovudine (azidothymidine; AZT) was the first nucleoside reverse transcriptase (RT) inhibitor (NRTI) approved for the treatment of HIV-1 infections and is still being used, particularly in the developing world. This drug targets the conversion of single-stranded RNA to double-stranded DNA by HIV-1 RT. However, resistance to the drug quickly appeared both in viruses replicating in cells in culture and in patients undergoing AZT monotherapy. The primary resistance pathway selects for mutations of T215 that change the threonine to either a tyrosine or a phenylalanine (T215Y/F); this resistance pathway involves an ATP-dependent excision mechanism. The pseudo-sugar ring of AZT lacks a 3′ OH; RT incorporates AZT monophosphate (AZTMP), which blocks the end of the viral DNA primer. AZT-resistant forms of HIV-1 RT use ATP in an excision reaction to unblock the 3′ end of the primer strand, allowing its extension by RT. The T215Y AZT resistance mutation is often accompanied by two other mutations, M41L and L210W. In this study, the roles of these mutations, in combination with T215Y, were examined to determine whether they affect polymerization and excision by HIV-1 RT. The M41L mutation appears to help restore the DNA polymerization activity of RT containing the T215Y mutation and also enhances AZTMP excision. The L210W mutation plays a similar role, but it enhances excision by RTs that carry the T215Y mutation when ATP is present at a low concentration.
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Nguyen, Thi Thinh, and Cuu Khoa Nguyen. "Process evaluation for simultaneous determinationof Zidovudine and Lamivudineon the nanocarrier dendrimerby HPLC-PDA method." Ministry of Science and Technology, Vietnam 63, no. 5 (2021): 29–34. http://dx.doi.org/10.31276/vjst.63(5).29-34.
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To determine Zidovudine (AZT) and Lamivudine (3TC) at the same time based on PAMAM dendrimer modified with Pluronic F127, application as anti-HIV drug control. A fast, accurate HPLC-PDA determination of AZT and 3TC with high reliability and selectivity has been developed and validated according to ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines. The chromatography was carried out by C18 inversion column using the mobile phase of phosphate buffer solution of pH 2.5 - methanol (65:35), flow rate 1.0 ml/min, and detective wavelength 266 nm. The retention times of AZT and 3TC are 3.5 and 4.3 minutes, respectively with 3.15 resolution. Linearity ranges from 2.16 to 324.53 μg/ml for AZT, and from 2.54 to 152.10 μg/ml for 3TC (r=1.000); mean recovery 100.3% (RSD=0.36%) for AZT and 99.73% (RSD=0.50%) for 3TC. The evaluation results showed that the accuracy and suitability of the method in the analysis of active ingredients AZT and 3TC on the PAMAM G3.0-F127@AZT/3TC dendrimer nano carrier system are adequate.
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Francke, Sabine, Charles G. Orosz, Kathleen A. Hayes, and Lawrence E. Mathes. "Effect of Zidovudine on the Primary Cytolytic T-Lymphocyte Response and T-Cell Effector Function." Antimicrobial Agents and Chemotherapy 44, no. 7 (2000): 1900–1905. http://dx.doi.org/10.1128/aac.44.7.1900-1905.2000.
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ABSTRACT Azidothymidine (AZT) and other nucleoside analogues, used to treat AIDS, can cause severe clinical side effects and are suspected of suppressing immune cell proliferation and effector immune cell function. The purpose of the present study was to quantitatively measure the effects of AZT on cytotoxic T-lymphocyte (CTL) priming and to determine if the major histocompatibility complex-restricted CTL killing was affected by AZT exposure. For this purpose, we employed a murine alloantigen model and limiting-dilution analysis (LDA) to estimate cytotoxic effector cell frequencies of alloreactive splenocytes treated with drug during antigen sensitization. This noninfectious model was chosen to avoid analysis of a virus-compromised immune system. Exposure of splenocytes to therapeutic concentrations of AZT (2 to 10 μM) caused a two- to threefold dose-dependent reduction in CLT precursor frequency. This reduction was caused by decreased proliferation of alloantigen-specific CTLs rather than loss of function, because full cytolytic function could be restored by adjusting the AZT-treated effector/target cell ratios to that of untreated cells. In addition, when AZT was added to the assay system at various times during antigen sensitization there was a time-related loss of the suppressive effect on the generation of cytolytic effector function, suggesting that functional CTLs are not affected by even high doses of AZT. Taken together, the data indicate that the reduction of CTL function associated with AZT treatment is due to a quantitative decrease of effector cell precursor frequency rather than to direct drug cytotoxicity or interference with mediation of cytolysis. Furthermore, antigen-naive immune cells were most sensitive to this effect during the first few days following antigen encounter.
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Hammer, SM, JM Gillis, P. Pinkston, and RM Rose. "Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages." Blood 75, no. 6 (1990): 1215–19. http://dx.doi.org/10.1182/blood.v75.6.1215.1215.
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Abstract The alveolar macrophage (AM), as a representative human tissue macrophage, was used in an in vitro system to examine the anti-human immunodeficiency virus type-1 (HIV-1) activity of zidovudine (AZT) and granulocyte-macrophage colony-stimulating factor (GM-CSF). AMs were infected with the IIIB strain of HIV-1 and exposed to AZT (1 mumol/L), GM-CSF (30 U/mL), a combination of AZT (1 mumol/L)/GM-CSF (30 U/mL), or medium control. At 10 or 20 days post-infection, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear leukocytes (PBMLs) were added to the AM cultures as stimulated target cells. AZT effectively suppressed HIV replication and prevented transfer/amplification in target PBMLs as long as the drug was maintained in the medium. GM-CSF neither suppressed nor augmented HIV replication. The combination of AZT/GM-CSF was comparable with AZT alone in suppressing both the initial infection of AMs and the transfer to target PBMLs as long as the agents were maintained in the cultures. However, when the drugs were removed at the same time that PHA-stimulated PBMLs were added to the culture, the combination of AZT/GM-CSF was found to be more effective than AZT alone in preventing the transfer/amplification of HIV in the target lymphocytes. These results suggest that (1) AZT is effective in inhibiting HIV-1 infection in mononuclear phagocytes; (2) GM-CSF neither inhibits nor augments the replication of the IIIB strain of HIV in human AMs; and (3) the combination of AZT and GM-CSF may have an enhanced anti-HIV-1 activity compared with AZT alone. Clinical trials with the two agents in combination appear warranted.
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Hammer, SM, JM Gillis, P. Pinkston, and RM Rose. "Effect of zidovudine and granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus replication in alveolar macrophages." Blood 75, no. 6 (1990): 1215–19. http://dx.doi.org/10.1182/blood.v75.6.1215.bloodjournal7561215.
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The alveolar macrophage (AM), as a representative human tissue macrophage, was used in an in vitro system to examine the anti-human immunodeficiency virus type-1 (HIV-1) activity of zidovudine (AZT) and granulocyte-macrophage colony-stimulating factor (GM-CSF). AMs were infected with the IIIB strain of HIV-1 and exposed to AZT (1 mumol/L), GM-CSF (30 U/mL), a combination of AZT (1 mumol/L)/GM-CSF (30 U/mL), or medium control. At 10 or 20 days post-infection, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear leukocytes (PBMLs) were added to the AM cultures as stimulated target cells. AZT effectively suppressed HIV replication and prevented transfer/amplification in target PBMLs as long as the drug was maintained in the medium. GM-CSF neither suppressed nor augmented HIV replication. The combination of AZT/GM-CSF was comparable with AZT alone in suppressing both the initial infection of AMs and the transfer to target PBMLs as long as the agents were maintained in the cultures. However, when the drugs were removed at the same time that PHA-stimulated PBMLs were added to the culture, the combination of AZT/GM-CSF was found to be more effective than AZT alone in preventing the transfer/amplification of HIV in the target lymphocytes. These results suggest that (1) AZT is effective in inhibiting HIV-1 infection in mononuclear phagocytes; (2) GM-CSF neither inhibits nor augments the replication of the IIIB strain of HIV in human AMs; and (3) the combination of AZT and GM-CSF may have an enhanced anti-HIV-1 activity compared with AZT alone. Clinical trials with the two agents in combination appear warranted.
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Boyer, Paul L., Stefan G. Sarafianos, Edward Arnold, and Stephen H. Hughes. "Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase." Journal of Virology 75, no. 10 (2001): 4832–42. http://dx.doi.org/10.1128/jvi.75.10.4832-4842.2001.
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ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.
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Taylor, D. L., T. M. Brennan, C. G. Bridges, M. S. Kang, and A. S. Tyms. "Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase." Antiviral Chemistry and Chemotherapy 6, no. 3 (1995): 143–52. http://dx.doi.org/10.1177/095632029500600303.
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The anti-human immunodeficiency virus type 1 (HIV-1) activity of the α-glucosidase 1 inhibitor 6-0-butanoylcastanospermine (MDL 28574) was assessed in combination with the 2′,3′-dideoxynucleoside analogues zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MDL 28574 was also evaluated in combination with the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine and the HIV proteinase inhibitor saquinavir (Ro-31-8959). Drug interactions were examined by the isobologram technique and by calculating combination indices (C.l.s). In all cases synergistic inhibition of HIV-1 replication was observed. In three-drug combinations, a marked synergistic antiviral effect was also observed, with C.I. values in the range 0.35-0.44 for MDL 28574 in combination with AZT and nevirapine, and in the range 0.34-0.67 for MDL 28574 in combination with AZT and saquinavir. Moreover, the combination of MDL 28574 with other drugs did not produce detrimental effects on cell division. MDL 28574 is currently in clinical trials and may have an important role in combination chemotherapy for HIV infections.
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Abongwa, Lem Edith, Anthony N. Kibera, Charles Fokunang, et al. "PO 8190 RISK FACTORS OF SEVERE HEPATOTOXICITY AMONG HIV-1 PATIENTS INITIATED ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY IN THE NORTHWEST REGION OF CAMEROON." BMJ Global Health 4, Suppl 3 (2019): A21.3—A22. http://dx.doi.org/10.1136/bmjgh-2019-edc.54.
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BackgroundHepatotoxicity due to highly active antiretroviral therapy (HAART) has gained prominent attention since it can be affected by many factors. The aim of this study was to determine the prevalence of hepatotoxicity and related risk factors of severe hepatotoxicity following HAART initiation.MethodsA total of 100 newly diagnosed HIV drug-naive patients within the age range of 18–61 years were recruited and followed up for 24 weeks and were placed on either Tenofovir (TDF)+Lamivudine (3TC)+Efavirenz (EFV) or Zidovudine (AZT) +Lamivudine + Nevirapine (NVP) or Zidovudine +Lamivudine + Efavirenz regimen. Sociodemographic data was obtained using pretested questionnaires. Venous blood samples were collected to measure aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), using colometric enzymatic reaction. Hepatotoxicity was classified based on age and sex. Data was analysed using SPSS.ResultsThe level of significance was set at 5%. A total of 37 (38%) and 49 (49%) patients presented with hepatotoxicity; 15% and 28% of these patients had severe hepatotoxicity at 4 and 24 weeks, respectively. Serum levels of all enzymes increased significantly (p<0.05) with increased treatment duration. Univariate analysis revealed that the risk factor of developing severe hepatotoxicity was significantly (p<0.05) greater in patients<30 years, males, low BMI, low monthly income earners and patient on AZT+3TC +NVP regimen. While multivariate analysis at p<0.09 showed that age <30 years, Low BMI, low monthly income, or the use of AZT+3TC +NVP regimen were independent risk factors.ConclusionLow BMI,<30 years, low monthly income and the use of AZT+3TC+NVP regimen were identifiable risk factors for the development of severe hepatotoxicity. As such, these factors should be considered as important for strategy by clinicians to prevent hepatotoxicity.
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Kovalev, I. E., and N. V. Shipulina. "Interaction of the anti-HIV drug azidothymidine (zidovudine, AZT) with cytochrome P-450." Pharmaceutical Chemistry Journal 28, no. 5 (1994): 303–6. http://dx.doi.org/10.1007/bf02218423.
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Feng, J. S., J. Y. Crouch, P. Y. Tian, H. L. Lucia, and G. D. Hsiung. "Zidovudine Antagonizes the Antiviral Effects of Ganciclovir against Cytomegalovirus Infection in Cultured Cells and in Guinea Pigs." Antiviral Chemistry and Chemotherapy 4, no. 1 (1993): 19–25. http://dx.doi.org/10.1177/095632029300400103.
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The antiviral effects of ganciclovir (DHPG) combined with zidovudine (AZT) at several dosages against cytomegalovirus infection were evaluated in cultured cells and in Hartley guinea pigs. Combinations of DHPG and AZT at fixed ratios ranging from 1:0.1 to 1:1 showed reduced antiviral effects of DHPG in cultured human lung fibroblast (HEL) cells and guinea pig embryo (GPE) cells infected with human cytomegalovirus and guinea pig cytomegalovirus, respectively. Synergistic cytotoxicity (CI values < 1) was noted in HEL and GPE cell cultures at all DHPG/AZT combinations tested. In vivo experiments using a fixed ratio at three dosage levels for treatment of GPCMV infected guinea pigs for 5 days did not show significant antagonistic antiviral nor synergistic toxic effects at lower dosages. When GPCMV infected guinea pigs were treated with DHPG and AZT in combinations at 40/20, 40/40 and 40/80 mg kg−1 day 1 for 7 days, a significant increase of GPCMV infectivity titres in the salivary gland, lung and spleen were noted when compared with those animals treated with DHPG 40mg kg−1 day−1 alone. In addition, histopathological findings showed more cytotoxicity in the bone marrow of infected and non-infected animals treated wth DHPG/AZT combinations than animals treated with each drug alone. These results suggest that AZT antagonizes the antiviral effects of DHPG against HCMV and GPCMV replication in cultured cells and GPCMV infection in guinea pigs with increased cytotoxicity in cultured cells and in bone marrow of animals receiving the drug combinations.
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Trapnell, Carol Braun, Raymond W. Klecker, Carlos Jamis-Dow, and Jerry M. Collins. "Glucuronidation of 3′-Azido-3′-Deoxythymidine (Zidovudine) by Human Liver Microsomes: Relevance to Clinical Pharmacokinetic Interactions with Atovaquone, Fluconazole, Methadone, and Valproic Acid." Antimicrobial Agents and Chemotherapy 42, no. 7 (1998): 1592–96. http://dx.doi.org/10.1128/aac.42.7.1592.
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ABSTRACT Zidovudine (3′-azido-3′-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5′-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were >100 and 8 μg/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 μg/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 μg/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.
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Ackiron, Evan. "Patents for Critical Pharmaceuticals: The AZT Case." American Journal of Law & Medicine 17, no. 1-2 (1991): 145–80. http://dx.doi.org/10.1017/s0098858800007954.
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Patents and other statutory types of market protections are used in the United States to promote scientific research and innovation. This incentive is especially important in research intensive fields such as the pharmaceutical industry. Unfortunately, these same protections often result in higher monopoly pricing once a successful product is brought to market. Usually this consequence is viewed as the necessary evil of an incentive system that encourages costly research and development by promising large rewards to the successful inventor. However, in the case of the AIDS drug Zidovudine (AZT), the high prices charged by the pharmaceutical company owning the drug have led to public outcry and a re-examination of government incentive systems.This Note traces the evolution of these incentive programs — the patent system, and, to a lesser extent, the orphan drug program — and details the conflicting interests involved in their development. It then demonstrates how the AZT problem brings the interest of providing inventors with incentives for risky innovative efforts into a sharp collision with the ultimate goal of such systems: ensuring that the public has access to the resulting products at a reasonable price. Finally, the Note describes how Congress and the courts have attempted to resolve these problems in the past, and how they might best try to solve the AZT problem in the near future.
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Ferrando, Stephen J., Tamara L. Wall, Steven L. Batki, and James L. Sorensen. "Psychiatric Morbidity, Illicit Drug Use and Adherence to Zidovudine (AZT) Among Injection Drug Users with HIV Disease." American Journal of Drug and Alcohol Abuse 22, no. 4 (1996): 475–87. http://dx.doi.org/10.3109/00952999609001674.
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Casabianca, Anna, Giuliana Vallanti, and Mauro Magnani. "Competitive PCR for Quantification of BM5d Proviral DNA in Mice with AIDS." Journal of Clinical Microbiology 36, no. 8 (1998): 2371–74. http://dx.doi.org/10.1128/jcm.36.8.2371-2374.1998.
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Murine AIDS in C57BL/6 mice is caused by a unique mixture of murine leukemia viruses. We report the use of a competitive PCR to detect and quantitate BM5d proviral DNA. This assay allowed discrimination among endogenous wild-type murine retroviruses and BM5d sequences. Furthermore, the method was subsequently used to evaluate the amount of BM5d in infected mice and in infected AZT (zidovudine)-treated mice, providing an effective way to quantitatively evaluate drug efficacy in the murine AIDS model.
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Theys, K., K. Deforche, P. Libin, R. J. Camacho, K. Van Laethem, and A. M. Vandamme. "Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine." Journal of General Virology 91, no. 8 (2010): 1898–908. http://dx.doi.org/10.1099/vir.0.022657-0.
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A better understanding of human immunodeficiency virus type 1 drug-resistance evolution under the selective pressure of combination treatment is important for the design of long-term effective treatment strategies. We applied Bayesian network learning to sequences from patients treated with the reverse transcriptase inhibitor combination of zidovudine (AZT) and lamivudine (3TC) to identify the role of many treatment-selected mutations in the development of resistance. Based on the Bayesian network structure, an in vivo fitness landscape was built, reflecting the necessary selective pressure under treatment, to evolve naive sequences to sequences obtained from patients treated with the combination. This landscape, combined with an evolutionary model, was used to predict resistance evolution in longitudinal sequence pairs. In our analysis, mutations 41L, 70R, 184V and 215F/Y were identified as major resistance mutations to the combination of AZT and 3TC, as they were associated directly with treatment experience. The network also suggested a possible role in resistance development for a number of novel mutations. Estimated fitness, using the landscape, correlated significantly with in vitro resistance phenotype in genotype–phenotype pairs (R 2=0.70). Variation in predicted evolution under selective pressure correlated significantly with observed in vivo evolution during AZT plus 3CT treatment. In conclusion, we confirmed current knowledge on resistance development to the combination of AZT and 3CT, but additional novel mutations were identified. Moreover, a model to predict resistance evolution during AZT and 3CT treatment has been built and validated.
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Quevedo, Mario A., Sergio R. Ribone, Guillermo N. Moroni, and Margarita C. Briñón. "Binding to human serum albumin of zidovudine (AZT) and novel AZT derivatives. Experimental and theoretical analyses☆." Bioorganic & Medicinal Chemistry 16, no. 6 (2008): 2779–90. http://dx.doi.org/10.1016/j.bmc.2008.01.007.
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Pandharpurkar, Deepak, Gudikandula Krishna, and P. Mallikarjun. "Clinical and immunological responses of zidovudine lamivudine-nevirapine versus tenofovir lamivudine-efavirenz antiretroviral treatment among HIV-1 infected adults: Gandhi Hospital, Telangana, India." International Journal of Research in Medical Sciences 7, no. 6 (2019): 2177. http://dx.doi.org/10.18203/2320-6012.ijrms20192494.
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Background: HAART (Highly active antiretroviral therapy) is the cornerstone of management of patients with HIV infection. Antiretroviral therapy was started in the year 1986 with the first drug Zidovudine (ZDV). Later on, other antiretroviral drugs (NRTIs, NNRTIs and Pls) were introduced. Dual and mono therapies were used initially but the problem of resistance emerged. Currently, 3 or more ARV drugs are recommended globally for the treatment of people with HIV infection.Methods: A cross-sectional descriptive study conducted at a tertiary care Hospital over 200 patients, two commonly used medications are ZLN (Zidovudine+Lamivudine+Nevirapine) and TLE (Tenofovir+Lamivudine+Efavirenz ). The factors considered to affect the clinical and immunologic outcomes in both groups were assessed using baseline CD4 count, WHO clinical staging, presence of chronic diarrhea, anemia, and baseline weight, occurrence of TB, and switching of ART regimen.Results: A total of 200 patients were included in the study. ART documents of 100 patients are on Zidovudine+Lamivudine+Nevirapine) and 100 patients are on TLE (Tenofovir+Lamivudine+Efavirenz) regimen. Out of 200 patients, 97 were males and 103 were females. Maximum number of subjects were in the age of 15-45 years (82.5%) followed by 45 and above (17.5%). Mean age was 34.5±2.5 (years) with range 15 to 65 years. The baseline CD4 count of the patients, 94 were <350 and 6 were ≥350 on ZLN, in case of TLE 82 were <350 and 18 were ≥350. CD4 count after 6 months in 200 patients as follows, 60 were <350 and 40 were ≥350 in case of TLE 53 were <350 and 47 were ≥350.Conclusions: This research finding concluded that there is no critical difference between the two medications in regards to serious adverse events but did find that TDF is superior to AZT in terms of immunologic response and adherence and more frequent emergence of resistance.
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Ramos, Juan Carlos, Luis M. Diaz, Michele Manrique та ін. "Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia". Blood 112, № 11 (2008): 2524. http://dx.doi.org/10.1182/blood.v112.11.2524.2524.
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Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported.
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Butanda-Ochoa, Armando, Diego Rolando Hernández-Espinosa, Marisela Olguín-Martínez, et al. "A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/8356175.
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The 3′-azido-3′-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration.
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Wang, Xin, Hiromichi Tanaka, Masanori Baba, and Yung-chi Cheng. "Retention of Metabolites of 2′,3′-Didehydro-3′-Deoxy-4′-Ethynylthymidine, a Novel Anti-Human Immunodeficiency Virus Type 1 Thymidine Analog, in Cells." Antimicrobial Agents and Chemotherapy 53, no. 8 (2009): 3317–24. http://dx.doi.org/10.1128/aac.00302-09.
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ABSTRACT 2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine (4′-Ed4T), a novel thymidine analog, has more potent anti-human immunodeficiency virus type 1 (HIV-1) activity than its progenitor, stavudine (d4T). The profile of the intracellular metabolites of 4′-Ed4T was qualitatively similar to that of zidovudine (AZT) but not to that of d4T, while after drug removal it showed more persistent anti-HIV activity than AZT or d4T in cell culture. When CEM cells were exposed to various concentrations of 4′-Ed4T, 4′-Ed4T was efficiently taken up by the cells and was readily phosphorylated to 4′-Ed4T monophosphate (4′-Ed4TMP), 4′-Ed4T diphosphate (4′-Ed4TDP), and 4′-Ed4T triphosphate (4′-Ed4TTP). Most importantly, 4′-Ed4TTP, the active metabolite of 4′-Ed4T, persisted significantly longer than 4′-Ed4TDP and 4′-Ed4TMP after drug removal. We further investigated the efflux profiles of 4′-Ed4T in the comparison with those of AZT in CEM cells. After drug removal, both 4′-Ed4T and AZT were effluxed from the cells in a time- and temperature-dependent manner. However, the efflux of 4′-Ed4T from cells was much less efficient than that of AZT. 4′-Ed4T was effluxed from cells only in its nucleoside form, while AZT was effluxed from cells in both its nucleoside and monophosphate forms. The mechanism-of-action study showed that the efflux of 4′-Ed4T or AZT nucleoside might be due to unknown nucleoside transporters which were not related to the equilibrative nucleoside transporters, while the efflux of AZT monophosphate might be due to multidrug resistance protein 4 (MRP4/ABCC4). The results demonstrated that no detectable 4′-Ed4TMP efflux and the less efficient efflux of 4′-Ed4T nucleoside from cells might be one of the biochemical determinants of its persistent antiviral activity in cell culture.
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Wurtzer, Sebastien, Séverine Compain, Henri Benech, Allan J. Hance, and François Clavel. "Effect of Cell Cycle Arrest on the Activity of Nucleoside Analogues against Human Immunodeficiency Virus Type 1." Journal of Virology 79, no. 23 (2005): 14815–21. http://dx.doi.org/10.1128/jvi.79.23.14815-14821.2005.
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ABSTRACT Human immunodeficiency virus (HIV) reverse transcription can be notably affected by cellular activation, differentiation, and division. We hypothesized that changes in the cell cycle could also affect HIV susceptibility to nucleoside analogues, which compete with natural nucleotides for incorporation into viral DNA and inhibit viral replication through premature termination of reverse transcription. Proliferating HeLa-derived indicator cells were arrested in the S/G2 phase with etoposide, a topoisomerase II inhibitor, or in the G1/S phase with aphidicolin, a polymerase α inhibitor. Cell cycle arrest by both agents induced a remarkable decrease in HIV susceptibility to zidovudine (AZT). This decrease was seen both with a single-cycle infectivity assay and with a viral DNA quantitation assay, indicating that the effect of cell cycle arrest was exerted at the reverse transcription stage. The increase in the 50% inhibitory concentration (IC50) seen with arrested cells was strongest for AZT (23-fold) and stavudine (21-fold) but more modest for other drugs (lamivudine, 11-fold; dideoxyinosine, 7-fold; and nevirapine, 3-fold). In drug-resistant reverse transcriptase mutants, the increase in AZT IC50 (relative to that in dividing cells) was most prominent with a Q151M mutant and was comparable to the wild type in other drug-resistant mutants. Quantitation of intracellular pools of dTTP and AZT 5′-triphosphate (AZTTP) showed that etoposide treatment induced a significant increase in intracellular dTTP and consequently a decrease in AZTTP/dTTP ratios, suggesting that the decrease in viral susceptibility to AZT was caused by reduced incorporation of the analogue into nascent viral DNA. These results emphasize the importance of cellular proliferation and deoxynucleoside triphosphate metabolism in HIV susceptibility to nucleoside analogues and underscore the need to study the activities of drugs of this class with natural target cells under physiological conditions of activation and proliferation.
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Kohli, Seema, Abhisek Pal, and Suchit Jain. "PREPARATION, CHARACTERIZATION AND EVALUATION OF POLY (LACTIDE –CO –GLYCOLIDE) MICROSPHERES FOR THE CONTROLLED RELEASE OF ZIDOVUDINE." International Journal of Pharmacy and Pharmaceutical Sciences 9, no. 12 (2017): 70. http://dx.doi.org/10.22159/ijpps.2017v9i12.18377.
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Objective: The purpose of this research work was to develop and evaluate microspheres appropriate for controlled release of zidovudine (AZT).Methods: The AZT loaded polylactide-co-glycolide (PLGA) microspheres were prepared by W/O/O double emulsion solvent diffusion method. Compatibility of drug and polymer was studied by Fourier-transform infrared spectroscopy (FTIR). The influence of formulation factors (drug: polymer ratio, stirring speed, the concentration of surfactant) on particle size encapsulation efficiency and in vitro release characteristics of the microspheres was investigated. Release kinetics was studied and stability study was performed as per ICH guidelines.Results: Scanning electron microscopy (SEM) images show good reproducibility of microspheres from different batches. The average particle size was in the range of 216-306 μm. The drug-loaded microspheres showed 74.42±5.08% entrapment efficiency. The cumulative percentage released in phosphate Buffer solution (PBS) buffer was found to be 55.32±5.89 to 74.42±5.08 %. The highest regressions (0.981) were obtained for zero order kinetics followed by Higuchi (0.968) and first order (0.803).Conclusion: Microsphere prepared by double emulsion solvent diffusion method was investigated and the results revealed that 216-306 μm microsphere was successfully encapsulated in a polymer. FT-IR analysis, entrapment efficiency and SEM Studies revealed the good reproducibility from batch to batch. The microspheres were of an appropriate size and suitable for oral administration. Thus the current investigation show promising results of PLGA microspheres as a matrix for drug delivery and merit for In vivo studies for scale up the technology.
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Chien, S. C., A. T. Chow, M. C. Rogge, R. R. Williams, and C. W. Hendrix. "Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine." Antimicrobial Agents and Chemotherapy 41, no. 8 (1997): 1765–69. http://dx.doi.org/10.1128/aac.41.8.1765.
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This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.
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Pan-Zhou, Xin-Ru, Lixin Cui, Xiao-Jian Zhou, Jean-Pierre Sommadossi, and Victor M. Darley-Usmar. "Differential Effects of Antiretroviral Nucleoside Analogs on Mitochondrial Function in HepG2 Cells." Antimicrobial Agents and Chemotherapy 44, no. 3 (2000): 496–503. http://dx.doi.org/10.1128/aac.44.3.496-503.2000.
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ABSTRACT Numerous studies have reported effects of antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus nucleoside analogs, zidovudine (3′-azido-3′-deoxythymidine) (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehydro-2′,3′-deoxythymidine (d4T), and β-L-2′,3′-dideoxy-3′-thiacytidine (3TC), as well as the metabolite of AZT, 3′-amino-3′-deoxythymidine (AMT), on mitochondrial function in a human hepatoma cell line, this issue has been reexamined. Evidence for a number of mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in lactic acid levels. Only in mitochondria isolated from AZT (50 μM)-treated cells was significant inhibition of cytochrome c oxidase and citrate synthase found. Our investigations also demonstrated that AZT, d4T, and 3TC did not affect the synthesis of the 11 polypeptides encoded by mitochondrial DNA, while ddC caused 70% reduction of total polypeptide content and ddI reduced by 43% the total content of 8 polypeptides (including NADH dehydrogenase subunits 1, 2, 4, and 5, cytochromec oxidase subunits I to III, and cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent mitochondrial dysfunction is more prevalent with AZT treatment.
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Santoro, Maria InÊs Rocha Miritello, Tatiana Tatit Fazio, Anil Kumar Singh, and Erica Rosa Maria Kedor-Hackmann. "Quantitative Determination and Sampling of Lamivudine and Zidovudine Residues for Cleaning Validation in a Production Area." Journal of AOAC INTERNATIONAL 90, no. 3 (2007): 715–19. http://dx.doi.org/10.1093/jaoac/90.3.715.
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Abstract Lamivudine (3TC) and zidovudine (AZT) are systemic antiviral substances extensively used in human immunodeficiency virus (HIV) infected patients. Nowadays, 3TC, AZT, and several other pharmacologically potent pharmaceuticals are manufactured in the same production area. To assure quality of drug products and patient safety, properly validated cleaning methodology is necessary. A carefully designed cleaning validation and its evaluation can ensure that residues of 3TC and AZT will not carry over and cross contaminate the subsequent product. The aim of this study was to validate a simple analytical method for verification of residual 3TC and AZT in equipment used in the production area and to confirm the efficiency of the cleaning procedure. The liquid chromatography method was validated using a Nova-Pak&lt;sup/&gt; C18 column (3.9 150 mm, 4 m particle size) and methanolwater (20 + 80, v/v) as the mobile phase at a flow rate of 1.0 mL/min. Ultraviolet detection was made at 266 nm. The calibration curve was linear over a concentration range of 2.022.0 g/mL with a correlation coefficient of 0.9998. The detection and quantitation limits were 0.36 and 1.21 g/mL, respectively. The intra-day and interday precision expressed as relative standard deviation were below 2.0%. The mean recovery of the method was 99.19%. The mean extraction recovery from manufacturing equipment was 83.5%.
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de la Carrière, Laurence Carron, Sylvie Paulous, François Clavel, and Fabrizio Mammano. "Effects of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Reverse Transcriptase Processing, Activity, and Drug Sensitivity." Journal of Virology 73, no. 4 (1999): 3455–59. http://dx.doi.org/10.1128/jvi.73.4.3455-3459.1999.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an impairment of protease function. Such fitness-impaired viruses display Gag precursor maturation defects. Here, we report that some protease inhibitor-resistant viruses also display abnormalities in the processing of reverse transcriptase (RT) by the protease. In three recombinant viruses carrying resistant protease sequences from patient plasma, we observed a marked decrease in the amount of mature RT subunits and of particle-associated RT activity compared to their parental pretherapy counterparts. We investigated the possibility that a decrease in the amount of particle-associated mature RT could affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (AZT) when a virus which carried AZT mutations was processed by a resistant protease. Interestingly, the presence of AZT-resistance mutations partially rescued the replication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.
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Chong, Youhoon, Katyna Borroto-Esoda, Phillip A. Furman, Raymond F. Schinazi, and Chung K. Chu. "Molecular Mechanism of DAPD/DXG against Zidovudine- and Lamivudine- Drug Resistant Mutants: A Molecular Modelling Approach." Antiviral Chemistry and Chemotherapy 13, no. 2 (2002): 115–28. http://dx.doi.org/10.1177/095632020201300205.
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In order to understand molecular mechanism of antiviral drug resistance of HIV-1 reverse transcriptase (RT) as well as potent antiviral activity of 2,6-diaminopurine dioxolane (DAPD) [prodrug of (–)-β-D-dioxolane guanine (DXG)] against drug-resistant RTs, molecular modelling studies of three structurally distinct nucleoside RT inhibitor (NRTI)-triphosphates (TP) [zidovudine (AZT)-TP, lamivudine (3TC)-TP and DXG-TP] complexed with the wild-type (WT) and mutated RT were conducted. The computational analyses indicated that the antiviral activity and the calculated relative binding energy of the RT inhibitor triphosphates can be correlated, and the minimized structures gave information on the molecular mechanism of drug resistance conferred by mutations. The interactions between the NRTI-TP and adjacent amino acid residues (Lys65, Lys70, Arg72, Tyr115 and/or Gln151) played important roles in stabilizing the enzyme—inhibitor complex. Particularly, Arg72 was found to stabilize the dioxolane and oxathiolane sugar moiety through hydrogen bonding, which was responsible for favourable binding affinity of DXG-TP to AZT- as well as 3TC-resistant mutants. The conformational changes in these amino acid residues caused by mutation always affected the changes in the tertiary structures of enzyme-inhibitor complexes through either closing or opening the gap between the fingers and palm domains. The enzyme-inhibitor complexes with good binding affinity showed tight binding modes by closing the gap between the two domains, whereas weak inhibitors gave open and loose complexes.
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Durand-Gasselin, Lucie, David Da Silva, Henri Benech, Alain Pruvost, and Jacques Grassi. "Evidence and Possible Consequences of the Phosphorylation of Nucleoside Reverse Transcriptase Inhibitors in Human Red Blood Cells." Antimicrobial Agents and Chemotherapy 51, no. 6 (2007): 2105–11. http://dx.doi.org/10.1128/aac.00831-06.
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ABSTRACT The intracellular metabolism of nucleoside reverse transcriptase inhibitors (NRTI) in mononuclear cells has been thoroughly studied, but that in red blood cells (RBC) has been disregarded. However, the phosphorylation of other analogous nucleosides (in particular, ribavirin) has been described previously. In this study, we investigated for the first time the phosphorylation of NRTI in human RBC. The presence of intracellular zidovudine (AZT) monophosphate, AZT triphosphate, lamivudine (3TC) triphosphate, and tenofovir (TFV) diphosphate, as well as endogenous dATP, dGTP, and dTTP, in RBC collected from human immunodeficiency virus-infected patients was examined. We observed evidence of a selective phosphorylation of 3TC, TFV, and endogenous purine deoxynucleosides to generate their triphosphate moieties. Conversely, no trace of AZT phosphate metabolites was found, and only faint dTTP signals were visible. A comparison of intracellular TFV diphosphate and 3TC triphosphate levels in RBC and peripheral blood mononuclear cells (PBMC) further highlighted the specificity of NRTI metabolism in each cell type. These findings raise the issue of RBC involvement in drug-drug interaction, drug pharmacokinetics, and drug-induced toxicity. Moreover, the typical preparation of PBMC samples by gradient density centrifugation does not prevent their contamination with RBC. We demonstrated that the presence of RBC within PBMC hampers an accurate determination of intracellular TFV diphosphate and dATP levels in clinical PBMC samples. Thus, we recommend removing RBC during PBMC preparation by using an ammonium chloride solution to enhance both the accuracy and the precision of intracellular drug monitoring.
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Walsh, Kimberley, Kathy Kaye, Bart Demaerschalk, Sarah Stewart, Jeff Crukley, and Robert Hammond. "AZT Myopathy and HIV-1 Polymyositis: One Disease or Two?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 29, no. 4 (2002): 390–93. http://dx.doi.org/10.1017/s0317167100002286.
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Purpose:This paper discusses the association between inflammatory and mitochondrial pathologies in patients with HIV-1/AIDS treated with zidovudine (AZT).Methods:We present the clinical and pathological details of a 52-year-old HIV-1 positive male who presented with progressive muscle weakness. We also review the current literature and address the debated pathogenesis of the inflammatory pathology.Results:Muscle biopsy revealed evidence of both HIV-1 polymyositis and AZT myopathy. Six months after initiation of corticosteroid therapy and discontinuation of AZT, the patient’s symptoms had greatly improved. The biopsy was repeated to show that both pathologies had resolved.Conclusion:The perceived overlap in the pathological spectra of HIV-1 polymyositis and AZT myopathy has produced some debate on causation and treatment. Unfortunately, there have been very few reports where a repeat biopsy following a drug washout period confirmed resolution of the pathology. Furthermore, affected patients have not been treated in a uniform fashion. Whether this represents one disease or two remains uncertain. The clinical relevance of this issue lies in the potential for harm from the unnecessary use of corticosteroids. This question may be best addressed by a randomized clinical trial.
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Fujiwara, Tamio, Akihiko Sato, Mohamed El-Farrash, et al. "S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1." Antimicrobial Agents and Chemotherapy 42, no. 6 (1998): 1340–45. http://dx.doi.org/10.1128/aac.42.6.1340.
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ABSTRACT S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.
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Trivedi, Jay, Mahesh Mohan, and Siddappa N. Byrareddy. "Drug Repurposing Approaches to Combating Viral Infections." Journal of Clinical Medicine 9, no. 11 (2020): 3777. http://dx.doi.org/10.3390/jcm9113777.
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Development of novel antiviral molecules from the beginning costs an average of $350 million to $2 billion per drug, and the journey from the laboratory to the clinic takes about 10–15 years. Utilization of drug repurposing approaches has generated substantial interest in order to overcome these drawbacks. A drastic reduction in the failure rate, which otherwise is ~92%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated the fact that it is more beneficial to reinvestigate the in-practice drugs for a new application instead of designing novel drugs. The first successful example of drug repurposing is zidovudine (AZT), which was developed as an anti-cancer agent in the 1960s and was later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast track clinical trials. Since that time, the drug repurposing approach has been successfully utilized to develop effective therapeutic strategies against a plethora of diseases. Hence, an extensive application of the drug repurposing approach will not only help to fight the current pandemics more efficiently but also predict and prepare for newly emerging viral infections. In this review, we discuss in detail the drug repurposing approach and its advancements related to viral infections such as Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).