RESUMEN

Background: Anaemia is associated with reduced quality of life and increased mortality risk among people living with HIV (PLHIV). Although antiretroviral therapy (ART) reduces the prevalence of anaemia, some patients remain at risk after commencing ART. Objectives: We estimated the incidence of anaemia after ART commencement and identified associated risk factors. Method: We analysed outpatient records at Newlands Clinic, Harare, Zimbabwe. Patients (≥ 5 years old) who were commenced on ART between January 2016 and December 2020 were included and were followed up for up to 2 years. Patients with anaemia at ART commencement and women who were pregnant at any time during follow-up were excluded. Cox proportional hazards regression was used to assess independent risk factors for anaemia. Results: During the study, 1110 patients ≥ 5 years old were commenced on ART with a prevalence of anaemia of 40.0%. Five hundred and twenty-nine patients met the inclusion criteria and were followed up for 823.7 person-years. The median age was 36.1 years and 290 (58.4%) were female. The incidence rate of anaemia after ART commencement was 176.1 per 1000 person-years (95% confidence interval [CI]: 149.6-207.2). Females (aHR: 2.09; 95% CI: 1.46-3.00, P < 0.001), zidovudine use (aHR: 3.50 96% CI: 2.14-5.71, P < 0.001), age 5-12 years or > 50 years, and the presence of World Health Organization stage III/IV disease (aHR: 2.19; 95% CI: 1.14-5.71, P = 0.019) had higher odds of developing anaemia. Conclusion: The incidence of anaemia after ART commencement was high. Female sex, zidovudine use, age and the presence of stage III/IV disease were independent risk factors for anaemia. Clinicians should screen PLHIV on ART regularly for anaemia.

RESUMEN

Limited treatment options and multidrug-resistant (MDR) Klebsiella pneumoniae present a significant therapeutic challenge, underscoring the need for novel approaches. Drug repurposing is a promising tool for augmenting the activity of many antibiotics. This study aimed to identify novel synergistic drug combinations against K. pneumoniae based on drug repurposing. We used the clinically isolated GN 172867 MDR strain of K. pneumoniae to determine the reversal resistance activity of zidovudine (AZT). The combined effects of AZT and various antibiotics, including nitrofurantoin (NIT) and omadacycline (OMC), were examined using the checkerboard method, growth curves, and crystal violet assays to assess biofilms. An in vitro combination activity testing was carried out in 12 isolates of K. pneumoniae. In vivo murine urinary tract and lung infection models were used to evaluate the therapeutic effects of AZT + NIT and AZT + OMC, respectively. The fractional inhibitory concentration index and growth curve demonstrated that AZT synergized with NIT or OMC against K. pneumoniae strains. In addition, AZT + NIT inhibited biofilm formation and cleared mature biofilms. In vivo, compared with untreated GN 172867-infected mice, AZT + NIT and AZT + OMC treatment decreased colony counts in multiple tissues (P < 0.05) and pathological scores in the bladder and kidneys (P < 0.05) and increased the survival rate by 60% (P < 0.05). This study evaluated the combination of AZT and antibiotics to treat drug-resistant K. pneumoniae infections and found novel drug combinations for the treatment of acute urinary tract infections. These findings suggest that AZT may exert significant anti-resistance activity.

RESUMEN

HIV is one of the most threatening health conditions with a highly increasing rate, affecting millions of people globally, and from its time of discovery until now, its potential cure cannot be explicitly defined. This challenge of having no/low effective drugs for the subjected virus has called for serious attention in the scientific world of virus disease therapeutics. Most of these drugs yields low effectiveness due to poor delivery; hence, there is a need for novel engineering methods for efficient delivery. In this study, two nanomaterilas (graphene; GP, and fullerene; C60) were modelled and investigated with sulfur (S), selenium (Se), and oxygen (O) atoms, to facilitate the delivery of zidovudine (ZVD). This investigation was computationally investigated using the density functional theory (DFT), calculated at B3LYP functional and Gd3bj/Def2svp level of theory. Results from the frontier molecular orbital (FMO), revealed that the GP/C60_S_ZVD complex calculated the least energy gap of 0.668 eV, thus suggesting a favourable interactions. The study of adsorption energy revealed chemisorption among all the interacting complexes wherein GP/C60_S_ZVD complex (-1.59949 eV) was highlighted as the most interacting system, thereby proving its potential for the delivery of ZVD. The outcome of this research urges that a combination of GP and C60 modified with chalcogen particularly, O, S, and Se can aid in facilitating the delivery of zidovudine.

RESUMEN

Antiretrovirals have improved considerably since the introduction of 3'-azido-3'-deoxythymidine (zidovudine or AZT), a molecule with also anticancer effects. Subsequently, a variety of other nucleosides have been synthesized. However, these medications are often associated with serious adverse events and the onset or exacerbation of degenerative processes, diseases, and syndromes, affecting mainly the mitochondria. In this study, we used Caenorhabditis elegans to investigate the toxicity potential of AZT and three new organoselenium derivatives with modifications in the 5' position of the sugar ring in place of the 5'-OH group, with the insertion of a neutral, an electron-withdrawing and an electron-donating group attached to the aryl selenol moiety: 5'-seleno-(4-chloro-phenyl)-3-(amino)-thymidine (ASAT-4-Cl), 5'-seleno-(phenyl)-3-(amino)-thymidine (ASAT-Ph), and 5'-seleno-(4-methoxyphenyl)-3-(amino)- thymidine (ASAT-4-OMe). Analyzes included worm survival, behavior parameters, high-resolution respirometry, citrate synthase activity, and ATP levels. Although all compounds negatively affected C. elegans, ASAT-4-Cl and ASAT-Ph showed lower toxicity compared to AZT, especially in mitochondrial viability and ATP production. Therefore, more studies must be carried out on the use of these new compounds as pharmacological interventions.

Asunto(s)

Caenorhabditis elegans , Compuestos de Organoselenio , Zidovudina , Animales , Caenorhabditis elegans/efectos de los fármacos , Zidovudina/toxicidad , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/toxicidad , Mitocondrias/efectos de los fármacos , Fármacos Anti-VIH/toxicidad

RESUMEN

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

Asunto(s)

Microbioma Gastrointestinal , Infecciones por Klebsiella , Klebsiella pneumoniae , Rifampin , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/inmunología , Infecciones por Klebsiella/mortalidad , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Rifampin/uso terapéutico , Rifampin/farmacología , Masculino , Zidovudina/uso terapéutico , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Intestinos/microbiología , Intestinos/patología , Intestinos/efectos de los fármacos , Intestinos/inmunología , Ratones Endogámicos C57BL , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Sepsis/inmunología , Sepsis/mortalidad , Ratones , Inmunidad Innata/efectos de los fármacos

RESUMEN

BACKGROUND: Dolutegravir (DTG) is a novel yet preferential first- and -second-line treatment for persons living with HIV (PLH). Owing to its recent introduction, DTG-based regimens have not undergone a comprehensive, systematic evaluation regarding their real-world utilization and safety profile among a sizeable Indian population. OBJECTIVE: This study aimed to assess the 24 week immunovirological outcomes, anthropometric and metabolic changes, tolerability, and adverse events (AEs) of DTG-based antiretroviral (ART) regimens. METHODS: A single-centre phase-IV non-interventional observational study involving 322 ART naïve and treatment-experienced PLH initiating DTG-based-regimens until October 2022 were followed up for outcomes at 24 weeks. RESULTS: At 24 weeks, all PLH (n = 113) in the naïve group, all PLH (n = 67) in the first-line substitution group, 93.9% PLH (n = 46) in the first-line failure group, and 95.7% PLH (n = 89) in the second-line substitution group were virologically suppressed to plasma HIV-RNA <1000 copies/mL. Virological suppression rates to plasma HIV-RNA <200 copies/mL and <50 copies/mL were consistent among PLH who received DTG as first- or second-line ART. The mean-unadjusted weight gain observed was 3.5 kg (SE: 0.330), and it was significantly higher in PLH with poorer health at baseline (either HIV-RNA ≥ 1000 copies/ml or CD4 cell count <350 cells/µL). Overall, 27.3% PLH (n = 88) gained ≥10% of their baseline body weight, corresponding to 3.7% incidence (n = 12) of treatment-emergent clinical obesity. DTG had an overall lipid-neutral effect, with an advantageous effect being observed in PLH switching from non-nucleoside analogue reverse-transcriptase inhibitors (NNRTI) or ritonavir-boosted protease inhibitors (b/PI), especially in dyslipidemic pre-treated PLH (median change in total cholesterol: 28.5 mg/dL and triglycerides: 51 mg/dL), possibly emanating from the withdrawal of the offending ART. The incidence of DTG-specific AEs, including CNS AEs, was low. Two PLH developed proximal myopathy and one developed transaminitis, warranting DTG discontinuation. Asymptomatic serum-CPK elevation and drug-induced transaminitis were seen in 25.2% (n = 27) and 3.2% (n = 10) PLH, respectively. No apparent negative effects on renal function were detected. CONCLUSION: Our results from a large Indian cohort indicate a favourable virological and metabolic response, with good tolerance of DTG-based ART at 24 weeks.

Asunto(s)

Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Adulto , Femenino , India/epidemiología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Piridonas/uso terapéutico , VIH-1/efectos de los fármacos , Persona de Mediana Edad , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Recuento de Linfocito CD4

RESUMEN

Zidovudine/lamivudine tablets are nucleoside reverse transcriptase inhibitors that are used to treat human immunodeficiency virus. The objective of this study was to investigate the bioequivalence and pharmacokinetics (PKs) of test and reference preparations of zidovudine/lamivudine tablets in healthy Chinese subjects. We designed a randomized, open, single-center, single-dose, 2-crossover experiment with a 7-day washout period involving 20 healthy subjects. The subjects were given a single dose of the test or reference preparation after fasting overnight for 10 hours. Blood samples were subsequently collected at scheduled time points from 0 hour (preadministration) up to 24 hours postadministration. The plasma concentrations of zidovudine and lamivudine were determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Analysis of variance (ANOVA) was used to compare differences in the mean values of key PK parameters between the 2 preparations. Bioequivalence was evaluated by 2 one-sided t-tests and 90% confidence intervals (CIs) of the geometric mean ratio (GMR). In total, 19 of the 20 subjects completed the trial. Based on the analysis of PK parameters, the relative bioavailability of zidovudine and lamivudine was 101.1% ± 2.0% and 100.3% ± 1.5%, respectively. ANOVA found no significant difference in primary PK parameters when compared between the 2 formulations, and the 90% CIs of the GMR of the 2 formulations were within the bioequivalence margins of 80%-125%. No serious adverse events occurred. Thus, we confirmed that the 2 preparations were bioequivalent in healthy Chinese volunteers. Our analysis demonstrated that both products showed good tolerance in all subjects.

Asunto(s)

Lamivudine , Zidovudina , Humanos , China , Voluntarios Sanos , Lamivudine/farmacocinética , Comprimidos , Equivalencia Terapéutica , Zidovudina/farmacocinética

RESUMEN

Aim: Development of dual-acting antibacterial agents containing Erlotinib, a recognized EGFR inhibitor used as an anticancer agent, with differently spaced benzenesulfonamide moieties known to bind and inhibit Helicobacter pylori carbonic anhydrase (HpCA) or the antiviral Zidovudine. Methods & materials: Through rational design, ten derivatives were obtained via a straightforward synthesis including a click chemistry reaction. Inhibitory activity against a panel of pathogenic carbonic anhydrases and antibacterial susceptibility of H. pylori ATCC 43504 were assessed. Docking studies on α-carbonic anhydrase enzymes and EGFR were conducted to gain insight into the binding mode of these compounds. Results & conclusion: Some compounds proved to be strong inhibitors of HpCA and showed good anti-H. pylori activity. Computational studies on the targeted enzymes shed light on the interaction hotspots.

Asunto(s)

Anhidrasas Carbónicas , Helicobacter pylori , Anhidrasas Carbónicas/metabolismo , Helicobacter pylori/metabolismo , Clorhidrato de Erlotinib/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Receptores ErbB/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Anhidrasa Carbónica IX , Bencenosulfonamidas

RESUMEN

Molecularly Imprinted Polymers (MIP) have demonstrated considerable potential when combined with electrochemical sensors, exhibiting high sensitivity, selectivity and reproducibility levels. The aim of this work is to detect Zivudine (ZDV) in serum samples by means of an interface imprinting technique-based electrochemical sensor. Thus, ZDV was used as a template for the creation of an MIP-based electrochemical sensor, and differential pulse voltammetry (DPV) was used as the determination technique for the molecule. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques were also used to characterize the electrochemical sensor capabilities, which showed a good linearity between 1.0 × 10-10 M and 1.0 × 10-9 M. ZDV was detected with a detection limit of 1.63 × 10-11 M, while the recovery analysis of spiked serum samples demonstrated that the sensor was highly selective.

RESUMEN

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Asunto(s)

Fármacos Anti-VIH , Infecciones por VIH , Complicaciones Infecciosas del Embarazo , Nacimiento Prematuro , Lactante , Niño , Embarazo , Recién Nacido , Femenino , Humanos , Infecciones por VIH/tratamiento farmacológico , Zidovudina/uso terapéutico , Mujeres Embarazadas , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Proyectos Piloto , Metabolómica , Inhibidores de Proteasas/uso terapéutico

RESUMEN

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.

Asunto(s)

COVID-19 , Selenio , Humanos , Antivirales/farmacología , Zidovudina , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Papaína , Péptido Hidrolasas , ARN Polimerasa Dependiente del ARN , Selenio/farmacología

RESUMEN

Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this article, we investigate a new approach to negate bacterial resistance: exploit the ß-lactam bond cleavage by ß-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrug-resistant Gram-negative pathogens commonly produce several ß-lactamases that are able to inactivate ß-lactam antibiotics, our most reliable and widely used therapeutic option. The chemical structure of these prodrugs is based on a monobactam promoiety, covalently attached to the active antibacterial substance, zidovudine (AZT). We describe the synthesis of 10 prodrug analogues (5a-h) in four to nine steps and their biological activity. Selective enzymatic activation by a panel of ß-lactamases is demonstrated, and subsequent structure-activity relationships are discussed. The best compounds are further evaluated for their activity on both laboratory strains and clinical isolates, preliminary stability, and toxicity.

Asunto(s)

Profármacos , beta-Lactamas , beta-Lactamas/farmacología , beta-Lactamasas , Zidovudina/farmacología , Profármacos/química , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias Gramnegativas

RESUMEN

BACKGROUND: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens. METHODS: A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses. RESULTS: We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% CI: 0.50; 0.80], a CR of 33% [95% CI: 0.24; 0.44], and a PR of 31% [95% CI: 0.24; 0.39] among individuals who received this regimen at any point during their treatment. Our subgroup analyses' findings demonstrated that patients who received front-line and combined AZT/IFN therapy responded better than those who received AZT/IFN alone. It is significant to note that patients with indolent subtypes of disease had considerably higher response rates than individuals with aggressive disease. CONCLUSION: IFN/AZT combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate.

Asunto(s)

Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Zidovudina/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Linfoma/tratamiento farmacológico

RESUMEN

A 48-year-old patient with stable residual schizophrenia experienced a syndromic psychosis relapse following an episode of severe combined immunohemolytic and pure red cell aplastic anemia, with a hemoglobin level of 4.7 g/dl. The anemia was attributed to her anti-HIV medication zidovudine. Her HIV infection had been well-controlled; no other organic precipitant of the psychosis was found. Following transfusion of 2 units of leukocyte-poor packed red cells, schizophrenia symptoms promptly recovered to her baseline. This was maintained at 3- and 6-month follow-ups without any need for antipsychotic dose adjustment. Following zidovudine discontinuation and a short course of oral prednisolone, her anemia gradually recovered.

RESUMEN

Zidovudine (AZT) is the most commonly prescribed antiviral drug for the treatment of human immunodeficiency virus (HIV) infection. However, its chronic administration causes toxic side effects limiting its use. This study aimed to evaluate the toxicity of different concentrations of AZT and novel chalcogen derivatives (7A, 7D, 7G, 7K, 7M) on locomotion, mitochondrial dysfunction, acetylcholinesterase (AChE) activity, and production of reactive oxygen species (ROS) in adult Drosophila melanogaster. Our results show that AZT and its derivative 7K at a concentration of 10 µM impaired flies' locomotor behavior. Furthermore, AZT and the derivatives 7K, 7A, and 7M induced mitochondrial dysfunction observed by a decrease in oxygen flux through mitochondrial complexes I and II. Neither of the compounds tested affected AChE activity or ROS production in flies. According to these data, AZT derivatives presented the following decreasing order of toxicity: 7K > AZT > 7G > 7A > 7M > 7D. Based on the chemical structure, it is possible to infer that the presence of the seleno-phenyl group in 7A and 7G increases their toxicity compared to compounds 7D and 7M. In addition, compounds 7G, 7M, and 7K with three carbon atoms as spacer were more toxic than analogs containing one carbon atom (7A and 7D). Finally, the insertion of a p-methoxyl group enhances toxicity (7K). Based on these results, excepting 7K, all other chalcogen derivatives presented lower toxicity than AZT and are potential drug candidates.

Asunto(s)

Fármacos Anti-VIH , Calcógenos , Animales , Humanos , Zidovudina/toxicidad , Drosophila melanogaster , Especies Reactivas de Oxígeno , Acetilcolinesterasa , Fármacos Anti-VIH/toxicidad

RESUMEN

Multidrug-resistant (MDR) Enterobacteriales infections have become an urgent global threat to public health. The aim of this study was to evaluate the efficacy of zidovudine-amikacin combination therapy in vitro and in vivo. Molecular characteristics and antibiotic resistance profiles of 53 amikacin-resistant MDR, extensively drug-resistant (XDR), or pan-drug-resistant (PDR) clinical isolates were examined via PCR and susceptibility testing. Checkerboard assays were performed for these 53 isolates to assess in vitro synergistic effects of the zidovudine-amikacin combination, and static time-kill experiments were performed for four XDR or PDR Enterobacteriales isolates. A Galleria mellonella model and a rat tissue cage infection model were established to assess in vivo synergistic effects. The aac(6')-Ib gene was detected in 25 (47.2%) isolates, followed by armA in 5 (9.4%) isolates, rmtB in 27 (50.9%) isolates, and rmtC in 3 (5.8%) isolates. Checkerboard assays showed the synergy of this combination against 38 (71.7%) isolates. The time-kill assays further confirmed that zidovudine strongly synergized with amikacin against four XDR or PDR Enterobacteriales isolates. The Galleria mellonella model study showed that the survival benefit of zidovudine-amikacin combination therapy was significantly better than that of monotherapy for those four Enterobacteriales isolates. Furthermore, the rat tissue cage infection model study showed that zidovudine-amikacin combination therapy displayed more potent bactericidal activity than monotherapy after 3 and 7 days of treatment for the above four isolates. Our data support the idea that the zidovudine-amikacin combination could be a plausible alternative therapy against infections with amikacin-resistant MDR Enterobacteriales, especially with XDR and PDR Enterobacteriales. IMPORTANCE Our study revealed for the first time that the zidovudine-amikacin combination shows a significant bactericidal effect against amikacin-resistant MDR, XDR, and PDR Enterobacteriales. Second, using in vitro and in vivo approaches, our study showed that zidovudine strongly synergized with amikacin against amikacin-resistant MDR Enterobacteriales isolates. Most importantly, with regard to survival benefit, pharmacokinetics, and bactericidal effects, our in vivo experiment demonstrated the effectiveness of zidovudine-amikacin.

RESUMEN

Extracellular vesicles (EVs) and their cargo have been studied intensively as potential sources of biomarkers in HIV infection; however, their DNA content, particularly the mitochondrial portion (mtDNA), remains largely unexplored. It is well known that human immunodeficiency virus (HIV) infection and prolonged antiretroviral therapy (ART) lead to mitochondrial dysfunction and reduced mtDNA copy in cells and tissues. Moreover, mtDNA is a well-known damage-associated molecular pattern molecule that could potentially contribute to increased immune activation, oxidative stress, and inflammatory response. We investigated the mtDNA content of large and small plasma EVs in persons living with HIV (PLWH) and its implications for viral replication, ART use, and immune status. Venous blood was collected from 196 PLWH, ART-treated or ART-naïve (66 with ongoing viral replication, ≥20 copies/mL), and from 53 HIV-negative persons, all recruited at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mtDNA level was measured by RT-qPCR. Regardless of HIV status, mtDNA was more abundant in large than small EVs. It was more abundant in EVs of viremic than aviremic and control participants and tended to be more abundant in participants treated with Tenofovir compared with Zidovudine. When ART treatment was longer than six months and viremia was undetectable, no variation in EV mtDNA content versus CD4 and CD8 count or CD4/CD8 ratio was observed. However, mtDNA in large and small EVs decreased with years of HIV infection and ART. Our results highlight the impact of viral replication and ART on large and small EVs' mtDNA content. The mechanisms underlying the differential incorporation of mtDNA into EVs and their effects on the surrounding cells warrant further investigation.

Asunto(s)

Vesículas Extracelulares , Infecciones por VIH , VIH-1 , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , VIH-1/fisiología , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Replicación Viral

RESUMEN

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.

Asunto(s)

Infecciones por VIH , Zidovudina , Animales , Humanos , Zidovudina/farmacología , Zidovudina/uso terapéutico , Longevidad , Factor de Transcripción Activador 4 , Caenorhabditis elegans/fisiología , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Retroviridae , Infecciones por VIH/tratamiento farmacológico

RESUMEN

In this study, two chemometrics methods, including partial least squares regression (PLS) and least squares support vector machine (LS-SVM) were applied for the simultaneous determination of zidovudine (ZDV) and lamivudine (LMV) in synthetic mixtures and anti-HIV pharmaceutical formulation. These approaches along with the spectrophotometric method were used to solve spectral overlapping problems between mentioned components. The results of PLS showed that the number of components for ZDV and LMV were 10 and 10 with mean square prediction error (MSPE) of 0.4045 and 2.1189, respectively. This method revealed recoveries ranging from 99.48% to 100.40% and 99.55% to 101.25% for ZDV and LMV, respectively. By applying leave-one-out cross-validation (LOO-CV), γ (regularization parameter) and σ2 (width of the function) values were found to be 50, 1500 and 210, 20 with root mean square error (RMSE) of 0.6156 and 0.3163 for ZDV and LMV, respectively. The mean recoveries obtained by the LS-SVM were 100.82% and 98.93% for ZDV and LMV, respectively. A comparison between the suggested methods and high-performance liquid chromatography (HPLC) as a reference technique was implemented, which did not show a significant difference. The results obtained in this research revealed that the chemometrics approaches can be efficient, simple, inexpensive, and precise for routine analysis and quality control of the drug.

Asunto(s)

VIH , Máquina de Vectores de Soporte , Composición de Medicamentos , Análisis de los Mínimos Cuadrados , Calibración , Espectrofotometría , Zidovudina/química , Lamivudine/química