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1
Tucci, Amanda Resende, Raquel Mello da Rosa, Alice Santos Rosa, et al. "Antiviral Effect of 5′-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection." Molecules 28, no. 18 (2023): 6696. http://dx.doi.org/10.3390/molecules28186696.
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The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for the discovery of novel potential anti-coronavirus compounds. Here, the antiviral activity of selenium and tellurium containing AZT derivatives in human type II pneumocytes cell model (Calu-3) and monkey kidney cells (Vero E6) infected with SARS-CoV-2, and their toxic effects on these cells, was evaluated. Cell viability analysis revealed that organoselenium (R3a–R3e) showed lower cytotoxicity than organotellurium (R3f, R3n–R3q), with CC50 ≥ 100 µM. The R3b and R3e were particularly noteworthy for inhibiting viral replication in both cell models and showed better selectivity index. In Vero E6, the EC50 values for R3b and R3e were 2.97 ± 0.62 µM and 1.99 ± 0.42 µM, respectively, while in Calu-3, concentrations of 3.82 ± 1.42 µM and 1.92 ± 0.43 µM (24 h treatment) and 1.33 ± 0.35 µM and 2.31 ± 0.54 µM (48 h) were observed, respectively. The molecular docking calculations were carried out to main protease (Mpro), papain-like protease (PLpro), and RdRp following non-competitive, competitive, and allosteric inhibitory approaches. The in silico results suggested that the organoselenium is a potential non-competitive inhibitor of RdRp, interacting in the allosteric cavity located in the palm region. Overall, the cell-based results indicated that the chalcogen-zidovudine derivatives were more potent than AZT in inhibiting SARS-CoV-2 replication and that the compounds R3b and R3e play an important inhibitory role, expanding the knowledge about the promising therapeutic capacity of organoselenium against COVID-19.
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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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Tadepalli, S. M., L. Puckett, S. Jeal, L. Kanics, and R. P. Quinn. "Differential assay of zidovudine and its glucuronide metabolite in serum and urine with a radioimmunoassay kit." Clinical Chemistry 36, no. 6 (1990): 897–900. http://dx.doi.org/10.1093/clinchem/36.6.897.
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Abstract We developed an ancillary procedure for the ZDV-Trac RIA (Incstar) to allow simultaneous determination of both zidovudine (3'-azido-3'-deoxythymidine, ZDV, AZT, Retrovir) and its metabolite, the glucuronide of ZDV (3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine, ZDVG, GAZT), in human serum and urine. Using the ZDV-Trac RIA, we measured ZDV concentrations before and after ZDVG in samples was hydrolyzed to ZDV by beta-glucuronidase (EC 3.2.1.31); ZDVG concentration was calculated as the difference between the two results. This method enables rapid evaluation of a large number of samples with a total turn-around time of 6 h. The lower detection limit of the RIA was 0.27 micrograms/L; the measurements varied linearly with ZDV concentrations from 0.27 to 217 micrograms/L, with the 50% inhibitory concentration being approximately 10 micrograms/L. Analytical recoveries of inhouse serum and urine controls for both ZDV and ZDVG exceeded 90%. Coefficients of variation (CVs) of serum controls were less than 6% for ZDV and less than 11% for ZDVG; for urine controls, CVs for both ZDV and ZDVG were less than 6%. Results for ZDVG concentrations obtained by HPLC and by the ZDV-Trac RIA system compared well: r = 0.978, slope 1.0, for serum samples, and r = 0.993, slope 1.09, for urine samples.
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Song, Heng, George W. Griesgraber, Carston R. Wagner, and Cheryl L. Zimmerman. "Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats." Antimicrobial Agents and Chemotherapy 46, no. 5 (2002): 1357–63. http://dx.doi.org/10.1128/aac.46.5.1357-1363.2002.
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ABSTRACT In vitro studies have demonstrated that water-soluble, nontoxic phosphoramidates of azidothymidine (zidovudine [AZT]) have significant and specific anti-human immunodeficiency virus and anticancer activity. Although polar, these compounds are internalized and processed to the corresponding nucleoside monophosphates. Eight methyl amide and methyl ester phosphoramidate monoesters composed of d- or l-phenylalanine or tryptophan and AZT were synthesized. The plasma stability and protein binding studies were carried out in vitro. Then in vivo pharmacokinetic evaluations of six of the compounds were conducted. Sprague-Dawley rats received each compound by intravenous bolus dose, and serial blood and urine samples were collected. AZT and phosphoramidate concentrations in plasma and urine were quantitated by high-performance liquid chromatography with UV or fluorescence detection. Pharmacokinetic parameters were calculated by standard noncompartmental means. The plasma half-lives of the phosphoramidates were 10- to 20-fold longer than the half-life of AZT. Although the renal clearances of the phosphoramidates were similar to AZT, their total body clearances were significantly greater than that of AZT. The 3- to 15-fold-larger volume of distribution (V ss) for the phosphoramidates relative to AZT appeared to be dependent on the stereochemistry of the amino acid, with the largest values being associated with the l-amino acids. The increased V ss indicates a much greater tissue distribution of the phosphoramidate prodrugs than of AZT. Amino acid phosphoramidate monoesters of AZT have improved pharmacokinetic properties over AZT and significant potential as in vivo pronucleotides.
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Cho, Hyejin, and Kwang-sun Kim. "Repurposing of Ciclopirox to Overcome the Limitations of Zidovudine (Azidothymidine) against Multidrug-Resistant Gram-Negative Bacteria." Pharmaceutics 14, no. 3 (2022): 552. http://dx.doi.org/10.3390/pharmaceutics14030552.
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Multidrug-resistant (MDR) Gram-negative bacteria are the top-priority pathogens to be eradicated. Drug repurposing (e.g., the use of non-antibiotics to treat bacterial infections) may be helpful to overcome the limitations of current antibiotics. Zidovudine (azidothymidine, AZT), a licensed oral antiviral agent, is a leading repurposed drug against MDR Gram-negative bacterial infections. However, the rapid emergence of bacterial resistance due to long-term exposure, overuse, or misuse limits its application, making it necessary to develop new alternatives. In this study, we investigated the efficacy of ciclopirox (CPX) as an alternative to AZT. The minimum inhibitory concentrations of AZT and CPX against MDR Gram-negative bacteria were determined; CPX appeared more active against β-lactamase-producing Escherichia coli, whereas AZT displayed no selectivity for any antibiotic-resistant strain. Motility assays revealed that β-lactamase-producing Escherichia coli strains were less motile in nature and more strongly affected by CPX than a parental strain. Resistance against CPX was not observed in E. coli even after 25 days of growth, whereas AZT resistance was observed in less than 2 days. Moreover, CPX effectively killed AZT-resistant strains with different resistance mechanisms. Our findings indicate that CPX may be utilized as an alternative or supplement to AZT-based medications to treat opportunistic Gram-negative bacterial infections.
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Bradshaw, Patrick C., Jiaxin Li, and David C. Samuels. "A computational model of mitochondrial AZT metabolism." Biochemical Journal 392, no. 2 (2005): 363–73. http://dx.doi.org/10.1042/bj20050749.
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The mechanisms of the mitochondrial toxicity of AZT (azidothymidine; zidovudine) are not clear. The two main contenders are the incorporation of phosphorylated AZT into the mtDNA (mitochondrial DNA) and the competitive inhibition of natural deoxynucleotide metabolism. We have built a computational model of AZT metabolism in mitochondria in order to better understand these toxicity mechanisms. The model includes the transport of non-phosphorylated and phosphorylated forms of AZT into mitochondria, phosphorylation, and incorporation into mtDNA. The model also includes the mitochondrial metabolism of the natural deoxynucleotides. We define three simulated cell types, i.e. rapidly dividing, slowly dividing and postmitotic cells. Our standard simulation indicates that incorporation of AZT into mtDNA is highest in rapidly dividing cells because of the higher mitochondrial AZTTP (3′-azidothymidine-5′-triphosphate)/dTTP ratio in this cell type. However, under these standard conditions the rate of incorporation into mtDNA is too low to be a major cause of toxicity. These simulations relied on the assumption that phosphorylated AZT is transported with the same kinetics as phosphorylated thymidine. In simulations with mitochondria set to have a limited ability to transport phosphorylated AZT, AZTTP accumulates to toxic levels in the mitochondria of postmitotic cells, while low levels are maintained in mitochondria from rapidly dividing cells. This result is more consistent with the tissue toxicities observed in patients. Our model also predicts that inhibition by AZT of mitochondrial deoxycytidine phosphorylation by thymidine kinase 2 may contribute to the mitochondrial toxicity, since in simulations using a typical peak plasma AZT level the mtDNA replication rate is decreased by 30% in postmitotic cell simulations.
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Di Bella, Stefano, Roberto Luzzati, and Cristina Lagatolla. "Zidovudine (azidothymidine, AZT) unexpressed clinical potential against multidrug-resistant Gram-negative isolates." International Journal of Antimicrobial Agents 59, no. 1 (2022): 106500. http://dx.doi.org/10.1016/j.ijantimicag.2021.106500.
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Bianco, Maria da Conceição Avelino Dias, Debora Inacio Leite, Frederico Silva Castelo Branco, et al. "The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy." Molecules 27, no. 23 (2022): 8502. http://dx.doi.org/10.3390/molecules27238502.
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The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3′-azido-2′,3′-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.
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Szafrański, Przemysław W., Patryk Kasza, Mariusz Kępczyński, and Marek T. Cegła. "Fluorescent 1,2,3-triazole derivative of 3′-deoxy-3-azidothymidine: synthesis and absorption/emission spectra." Heterocyclic Communications 21, no. 5 (2015): 263–67. http://dx.doi.org/10.1515/hc-2015-0195.
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Abstract3′-Deoxy-3-azidothymidine (AZT, zidovudine) is a nucleoside-analog reverse transcriptase inhibitor, successfully used against the human immunodeficiency virus (HIV). Its structure contains an azide function, which makes it a useful substrate for 1,2,3-triazole synthesis, using the copper-catalyzed azide-alkyne cycloaddition, the flagship reaction of ‘click chemistry’. Herein we present the synthesis and spectral characterization of its 1,2,3-triazole derivative containing a fluorenylmethyloxycarbonyl (fmoc) fluorescent fragment. The preparation and characteristics of a novel fluorescent probe, 9H-fluoren-9-ylmethyl prop-2-yn-1-yl carbonate (propargyl-fmoc) is also presented.
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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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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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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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Hodson, Andrew, Silvia Montoto, Naheed Mir, et al. "Addition of Anti-Viral Therapy to Chemotherapy Improves Overall Survival In Acute and Lymphomatous Adult T-Cell Leukaemia/Lymphoma (ATLL)." Blood 116, no. 21 (2010): 3961. http://dx.doi.org/10.1182/blood.v116.21.3961.3961.
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Abstract Abstract 3961 Introduction: Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive T-cell malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. Outcomes with chemotherapy alone are poor and drug resistance is common. Projected 2 and 4 year survival rates were 16.7% and 5% for acute ATLL and 21.3% and 5.7% for lymphomatous ATLL have been reported (Shimoyama et al, 1991). Therapy with Zidovudine (ZDV) and Interferon-α (IFN) has been associated with improved response rates and overall survival in small studies. A recent meta-analysis has demonstrated the efficacy of ZDV/IFN over chemotherapy in acute and chronic ATLL but not in lymphomatous ATLL (Bazarbachi et al, 2010). Aims: To report the clinico-pathologic characteristics, treatment and outcome of patients diagnosed with ATLL in England from 1999 to 2009. Methods: 84 patients with ATLL were identified and their records individually reviewed. Epidemiological, clinical and biological data were collected including ATLL subtype, treatment, response and overall survival. Diagnosis was made on the basis of tissue involvement with a characteristic immunophenotype and confirmation of HTLV1 infection. Cases were classified according to Shimoyama. Results: ATLL was more frequent in females (1.5F:1M). Ethnic origin was Afro-caribbean (77%) or African (18%) in the majority. Median age 54.6 years.29 cases were acute, 44 lymphomatous, 9 chronic and 2 smouldering (cutaneous) ATLL. Presenting characteristics are tabulated. Corrected calcium (p=0.036) and lactate dehydrogenase (p=0.028) were significantly higher in acute v lymphomatous ATLL. Overall median survival (MS) was 7.5 months for acute, 10.2 months for lymphomatous, 47.6 months for chronic and 32.4 months for cutaneous ATLL. First line treatment for aggressive (acute or lymphomatous) ATLL was chemotherapy +/− AZT/IFN in all patients except 2 with acute ATLL not fit for chemotherapy. MS was 12.2 months in 26 patients receiving first line chemotherapy with ZDV/IFN compared to 4.4 months for 31 patients treated with chemotherapy alone (p=0.002). MS rates were best in patients who, having initially responded to chemotherapy, were treated with ZDV/IFN at relapse (19.6 months). By subtype, in acute ATLL, MS was 10.1 months in 20 patients receiving ZDV/IFN at any time (1st line or relapse) and 4.1 months in 9 patients who never received ZDV/IFN (p=0.004). Patients who received ZDV/IFN at any time had 19% and 10% 2 and 4 year overall survival (OS) respectively as compared to 0% 2 and 4 year OS in the absence of any ZDV/IFN. In lymphomatous ATLL, MS was 13.2 months in 22 patients receiving ZDV/IFN at any time and 5.5 months in 22 patients who never received ZDV/IFN (p=0.001). Patients who received ZDV/IFN at any time had 38% and 23% 2 and 4 year OS respectively compared to 0% 2 and 4 year OS in the absence of any ZDV/IFN. In the chronic ATLL group, 2 year OS was 100% but fell to 40% at 4 years after the development of acute ATLL in 3/9 cases. Conclusions: Our results point to the benefit of treatment with ZDV/IFN at some stage, given the failure of any patient to survive 2 years in the absence of this therapy. In the recent meta-analysis insufficient patient numbers with lymphoma were treated with adjunctive ZDV/IFN therapy to demonstrate any benefit, whilst first line therapy with ZDV/IFN alone was ineffective. However, we have documented significant clinical benefit from the addition of ZDV/IFN to chemotherapy in lymphomatous ATLL. Together these two studies suggest the following treatment approach to improve outcome in aggressive ATLL: Acute type– 1st line treatment with AZT/IFN alone. Lymphomatous type - 1st line treatment with chemotherapy and early addition of ZDV/IFN. This is a major step forward in ATLL therapy, but it is important to recognise that some patients will fail therapy and overall survival remains poor. Disclosures: Ardeshna: Roche: Funding data manager, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Sim, SM, DJ Back, and AM Breckenridge. "The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes." British Journal of Clinical Pharmacology 32, no. 1 (1991): 17–21. http://dx.doi.org/10.1111/j.1365-2125.1991.tb05607.x.
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Foletto, Vitória S., Taciéli F. da Rosa, Marissa B. Serafin, Angelita Bottega, and Rosmari Hörner. "Response to Letter to the Editor: “Zidovudine/azidothymidine (AZT) unexpressed clinical potential against multidrug-resistant Gram negatives”." International Journal of Antimicrobial Agents 59, no. 1 (2022): 106501. http://dx.doi.org/10.1016/j.ijantimicag.2021.106501.
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Kline, M. W., R. B. Van Dyke, J. C. Lindsey, et al. "A Randomized Comparative Trial of Stavudine (d4T) Versus Zidovudine (ZDV, AZT) in Children With Human Immunodeficiency Virus Infection." PEDIATRICS 101, no. 2 (1998): 214–20. http://dx.doi.org/10.1542/peds.101.2.214.
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Perno, CF, DA Cooney, WY Gao, et al. "Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages." Blood 80, no. 4 (1992): 995–1003. http://dx.doi.org/10.1182/blood.v80.4.995.995.
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Abstract Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2′,3′-dideoxy-3′- azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2′,3′-dideoxycytidine (ddC) and 2′,3′-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5′-triphosphate moieties. GM-CSF increased the levels of AZT-5′-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5′-triphosphate/thymidine-5′- triphosphate. In contrast, M-CSF-induced increases in AZT-5′- triphosphate were roughly matched by increases in thymidine-5′- triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5′-triphosphate were associated with parallel increases in the levels of deoxycytidine-5′-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5′-triphosphate/deoxycytidine- 5′-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.
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Perno, CF, DA Cooney, WY Gao, et al. "Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages." Blood 80, no. 4 (1992): 995–1003. http://dx.doi.org/10.1182/blood.v80.4.995.bloodjournal804995.
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Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2′,3′-dideoxy-3′- azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2′,3′-dideoxycytidine (ddC) and 2′,3′-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5′-triphosphate moieties. GM-CSF increased the levels of AZT-5′-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5′-triphosphate/thymidine-5′- triphosphate. In contrast, M-CSF-induced increases in AZT-5′- triphosphate were roughly matched by increases in thymidine-5′- triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5′-triphosphate were associated with parallel increases in the levels of deoxycytidine-5′-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5′-triphosphate/deoxycytidine- 5′-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.
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Pluda, J. M., D. J. Venzon, G. Tosato, et al. "Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy." Journal of Clinical Oncology 11, no. 6 (1993): 1099–107. http://dx.doi.org/10.1200/jco.1993.11.6.1099.
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PURPOSE To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas. PATIENTS AND METHODS The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma. RESULTS Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048). CONCLUSION HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors.
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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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Klaric, Julie A., Eli L. Perr, and Susan T. Lovett. "Identifying Small Molecules That Promote Quasipalindrome-Associated Template-Switch Mutations in Escherichia coli." G3: Genes|Genomes|Genetics 10, no. 5 (2020): 1809–15. http://dx.doi.org/10.1534/g3.120.401106.
Full textAbstract:
DNA can assemble into non-B form structures that stall replication and cause genomic instability. One such secondary structure results from an inverted DNA repeat that can assemble into hairpin and cruciform structures during DNA replication. Quasipalindromes (QP), imperfect inverted repeats, are sites of mutational hotspots. Quasipalindrome-associated mutations (QPMs) occur through a template-switch mechanism in which the replicative polymerase stalls at a QP site and uses the nascent strand as a template instead of the correct template strand. This mutational event causes the QP to become a perfect or more perfect inverted repeat. Since it is not fully understood how template-switch events are stimulated or repressed, we designed a high-throughput screen to discover drugs that affect these events. QP reporters were engineered in the Escherichia coli lacZ gene to allow us to study template-switch events specifically. We tested 700 compounds from the NIH Clinical Collection through a disk diffusion assay and identified 11 positive hits. One of the hits was azidothymidine (zidovudine, AZT), a thymidine analog and DNA chain terminator. The other ten were found to be fluoroquinolone antibiotics, which induce DNA-protein crosslinks. This work shows that our screen is useful in identifying small molecules that affect quasipalindrome-associated template-switch mutations. We are currently assessing more small molecule libraries and applying this method to study other types of mutations.
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Varga, Zoltán V., Peter Ferdinandy, Lucas Liaudet, and Pál Pacher. "Drug-induced mitochondrial dysfunction and cardiotoxicity." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 9 (2015): H1453—H1467. http://dx.doi.org/10.1152/ajpheart.00554.2015.
Full textAbstract:
Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.
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Tesfaye, Sisay, Melaku Hirigo, Dawit Jember, Mekdes Shifeta, and Worku Ketema. "Burden of Anemia among Human Immunodeficiency Virus-Positive Adults on Highly Active Antiretroviral Therapy at Hawassa University Compressive Specialized Hospital, Hawassa, Ethiopia." Anemia 2023 (October 14, 2023): 1–8. http://dx.doi.org/10.1155/2023/2170447.
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Background. Anemia is the most common hematologic abnormality associated with human immunodeficiency virus (HIV)-infected patients and affects 60% to 80% of patients in late-stage disease. It has a considerable impact on the progression of HIV to advanced stages. This study aimed at assessing the burden of anemia in adult HIV-infected patients who are on highly active antiretroviral therapy (HAART) and have follow-up at Hawassa University Comprehensive Specialized Hospital (HUCSH) Antiretroviral therapy (ART) clinic. Methods. A hospital-based retrospective study was conducted among HIV-positive adults on HAART at Hawassa University Compressive Specialized Hospital. The systematic sampling method was used to choose a total of 244 study participants. Data on demographic characteristics, related factors of anemia, latest hemoglobin, CD4, and ART regimens were collected using a structured data abstraction format. The data were cleaned and analyzed using SPSS version 21.0 after being manually checked for completeness. Multivariable logistic regression was carried out to detect elements associated with anemia. A P value of <0.05 was used as a cutoff point to announce statistical significance. Results. The records of 244 patients were examined in total. Anemia was present in 29.9% (95% CI 23.8–35.2) among adult HIV patients. Female sex (AOR: 2.576, 95% (CI: 1.295–5.127)), having tuberculosis (TB) (AOR: 4.873, 95% (CI: 1.534–15.484)), taking a zidovudine (ZDV)-containing ART regimen (AOR: 5.216, 95% (CI: 1.239–21.962)), having clinical WHO stage IV and III diseases (AOR: 3.077, 95% CI (1.244–7.612)), having body mass index (BMI) <18.5 kg/m2 (AOR: 2.391, 95% (CI: 1.138–5.023)), and taking cotrimoxazole prophylaxis (AOR: 3.860 95% (CI: 1.097–13.576)) were substantially linked to the development of anemia among adult HIV patients. Conclusion and Recommendation. This study showed that anemia is still a problem among HIV patients on HAART. The burden of anemia was found to be high among patients with advanced WHO clinical stages, having a BMI less than 18.5 kg/m2, TB/HIV coinfection, being on AZT-based ART regimens, and taking cotrimoxazole preventive therapy (CPT). Consequently, it is suggested that early preventative interventions, such as serial hemoglobin follow-up, iron supplementation, and education about dietary consumption, be undertaken targeting the aforementioned groups. In addition, the preferred first-line ART regimen as per the latest national and WHO guidelines is recommended, especially for the above groups.
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Heidari, Alireza, та Ricardo Gobato. "ANovel Approach to Reduce Toxicities and to Improve Bioavailabilities of DNA/RNAof Human Cancer Cells–Containing Cocaine (Coke), Lysergide (Lysergic AcidDiethyl Amide or LSD), Δ9–Tetrahydrocannabinol (THC) [(–)–trans–Δ⁹–Tetrahydrocannabinol],Theobromine (Xantheose),Caffeine, Aspartame (APM) (NutraSweet) and Zidovudine (ZDV)[Azidothymidine (AZT)] as Anti–Cancer Nano Drugs by Coassembly of DualAnti–Cancer Nano Drugs to Inhibit DNA/RNA of Human Cancer Cells Drug Resistance." 9 серпня 2018. https://doi.org/10.5281/zenodo.3843554.
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The aim of the present study was to reduce toxicities and to improve bioavailabilities of DNA/RNA of human cancer cells–containing Cocaine (Coke), Lysergide (Lysergic Acid Diethyl Amide or LSD), Δ<sup>9</sup>–Tetrahydrocannabinol (THC) [(–)–<em>trans</em>–Δ⁹–Tetrahydrocannabinol], Theobromine (Xantheose), Caffeine, Aspartame (APM) (NutraSweet) and Zidovudine (ZDV) [Azidothymidine (AZT)] as anti–cancer Nano drugs by coassembly of dual anti–cancer Nano drugs to inhibit DNA/RNA of human cancer cells drug resistance.
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Gushchina, Yu Sh, А. Yu Abramov, and Y. J. Haitham. "Pharmacoeconomic analysis of antiretroviral therapy regimes in the Syrian Arab Republic." FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology, June 13, 2023. http://dx.doi.org/10.17749/2070-4909/farmakoekonomika.2023.163.
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Background. Due to the significant prevalence of human immunodeficiency virus (HIV) and limited funding in the Syrian Arab Republic (SAR), pharmacoeconomic study of antiretroviral therapy (ART) regimens is relevant, as it allows to choose a rational, pharmacoeconomically reasonable therapy for HIV-infected patients.Objective: to perform pharmacoeconomic analysis of ART regimens HIV-infected in patients in SAR.Material and methods. The following algorithm of actions was used: assessment of the cost of prescribed antiretroviral drugs; cost analysis of applied ART regimens. From the auction documentation, information was taken on the total number of purchased drugs and their cost at the end of the auction. To calculate prices in rubles, currency conversion was carried out as of January 1, 2021. To calculate the cost of an assigned regimen, the summation of the costs of its components was carried out. Based on the obtained data, the average cost of combinations of certain antiretroviral drugs classes was calculated. To predict the results of using various ART regimens for 5 years, discounting was used for each year of the time horizon, except for the first year.Results. It was revealed that the most expensive drugs are the reserve series: Fuzeon® (enfuvirtide; F. Hoffmann-La Roche Ltd., Switzerland) – 66,492.1 rubles and Isentress® (raltegravir; Merck Sharp & Dohme, Netherlands) – 31,634.6 rubles, and the lowest price per package was noted for Russian drugs Timazid® (zidovudine) – 471.0 rubles and Nikavir® (phosphazide) – 743.8 rubles (both – AZT Pharma K.B. LLC, Russia). The average cost of the first prescribed regimen was 8,970.0 rubles/month, while the most expensive first-line regimens included a protease inhibitors class drug as the third component. As a result of the analysis of the cost of second-line and third-line regimens, it was revealed that the average cost of second-line therapy per month exceeded the average cost of first-line therapy by 4 times (40,154.2 rubles/month). The initial “azidothymidine, zidovudine / lamivudine + efavirenz” group had fewer hospitalizations, lower mortality, and fewer years of life expectancy lost than on “azidothymidine, zidovudine / lamivudine + atazanavir, ritonavir” and “phosphazide + didanosine + efavirenz” regimens.Conclusion. A pharmacoepidemiological study showed that the cost of second-line therapy per month was 40,154.2 rubles, which exceeded the average cost of first-line therapy by 4 times (9,266.1 rubles). It was revealed that the average cost of the first prescribed ART regimen based on two nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor was 2 times higher than the average cost of regimens based on two NRTIs + non-nucleoside reverse transcriptase inhibitors, which, along with clinical aspects, raised the question of the expediency of their appointment as first-line regimens.