Potential molecular patterns for tuberculosis susceptibility in diabetic patients with poor glycaemic control: a pilot study.

Type 2 diabetes (DM2) is an increasingly prevalent disease that challenges tuberculosis (TB) control strategies worldwide. It is significant that DM2 patients with poor glycemic control (PDM2) are prone to developing tuberculosis. Furthermore, elucidating the molecular mechanisms that govern this susceptibility is imperative to address this problem. Therefore, a pilot transcriptomic study was performed. Human blood samples from healthy controls (CTRL, HbA1c < 6.5%), tuberculosis (TB), comorbidity TB-DM2, DM2 (HbA1c 6.5-8.9%), and PDM2 (HbA1c > 10%) groups (n = 4 each) were analyzed by differential expression using microarrays. We use a network strategy to identify potential molecular patterns linking the differentially expressed genes (DEGs) specific for TB-DM2 and PDM2 (p-value < 0.05, fold change > 2). We define OSM, PRKCD, and SOCS3 as key regulatory genes (KRGs) that modulate the immune system and related pathways. RT-qPCR assays confirmed upregulation of OSM, PRKCD, and SOCS3 genes (p < 0.05) in TB-DM2 patients (n = 18) compared to CTRL, DM2, PDM2, or TB groups (n = 17, 19, 15, and 9, respectively). Furthermore, OSM, PRKCD, and SOCS3 were associated with PDM2 susceptibility pathways toward TB-DM2 and formed a putative protein-protein interaction confirmed in STRING. Our results reveal potential molecular patterns where OSM, PRKCD, and SOCS3 are KRGs underlying the compromised immune response and susceptibility of patients with PDM2 to develop tuberculosis. Therefore, this work paved the way for fundamental research of new molecular targets in TB-DM2. Addressing their cellular implications, and the impact on the diagnosis, treatment, and clinical management of TB-DM2 could help improve the strategy to end tuberculosis for this vulnerable population.

Current Strategy for Targeting Metallo-ß-Lactamase with Metal-Ion-Binding Inhibitors.

Currently, antimicrobial resistance (AMR) is a serious health problem in the world, mainly because of the rapid spread of multidrug-resistant (MDR) bacteria. These include bacteria that produce ß-lactamases, which confer resistance to ß-lactams, the antibiotics with the most prescriptions in the world. Carbapenems are particularly noteworthy because they are considered the ultimate therapeutic option for MDR bacteria. However, this group of antibiotics can also be hydrolyzed by ß-lactamases, including metallo-ß-lactamases (MBLs), which have one or two zinc ions (Zn2+) on the active site and are resistant to common inhibitors of serine ß-lactamases, such as clavulanic acid, sulbactam, tazobactam, and avibactam. Therefore, the design of inhibitors against MBLs has been directed toward various compounds, with groups such as nitrogen, thiols, and metal-binding carboxylates, or compounds such as bicyclic boronates that mimic hydrolysis intermediates. Other compounds, such as dipicolinic acid and aspergillomarasmin A, have also been shown to inhibit MBLs by chelating Zn2+. In fact, recent inhibitors are based on Zn2+ chelation, which is an important factor in the mechanism of action of most MBL inhibitors. Therefore, in this review, we analyzed the current strategies for the design and mechanism of action of metal-ion-binding inhibitors that combat MDR bacteria.

Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain.

BACKGROUND: Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES: The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS: Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). FINDINGS: Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of ß-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS: Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.

Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New ß-Estrogen Receptor Activators with Potential for Pharmacological Obesity Treatment.

Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERß) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERß activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (-24.27 ± 0.34 kcal/mol), 2 (-23.33 ± 0.3 kcal/mol), and 6 (-29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERß with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERß nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERß ligands could be promising molecules for obesity control.

Fluoroquinolone Analogs, SAR Analysis, and the Antimicrobial Evaluation of 7-Benzimidazol-1-yl-fluoroquinolone in In Vitro, In Silico, and In Vivo Models.

Structure-activity relationship (SAR) studies allow the evaluation of the relationship between structural chemical changes and biological activity. Fluoroquinolones have chemical characteristics that allow their structure to be modified and new analogs with different therapeutic properties to be generated. The objective of this research is to identify and select the C-7 heterocycle fluoroquinolone analog (FQH 1-5) with antibacterial activity similar to the reference fluoroquinolone through in vitro, in silico, and in vivo evaluations. First, SAR analysis was conducted on the FQH 1-5, using an in vitro antimicrobial sensibility model in order to select the best compound. Then, an in silico model mechanism of action analysis was carried out by molecular docking. The non-bacterial cell cytotoxicity was evaluated, and finally, the antimicrobial potential was determined by an in vivo model of topical infection in mice. The results showed antimicrobial differences between the FQH 1-5 and Gram-positive and Gram-negative bacteria, identifying the 7-benzimidazol-1-yl-fluoroquinolone (FQH-2) as the most active against S. aureus. Suggesting the same mechanism of action as the other fluoroquinolones; no cytotoxic effects on non-bacterial cells were found. FQH-2 was demonstrated to decrease the amount of bacteria in infected wound tissue.

In vitro evaluation of the antagonistic activity of native strains of Trichoderma spp. against Fusarium spp.

Five samples of agricultural soil and five samples of Aloe barbadensis (P. Mill., 1768) plants with symptoms of wilt and root necrosis were collected in five localities of the state of Tamaulipas, México. The aims of this study were the morphological identification, molecular identification and in vitro evaluation of the antagonistic activity of Trichoderma spp. on Fusarium spp. Four strains of Trichoderma asperellum, one strain of Trichoderma harzianum and five strains of Fusarium oxysporum were identified by morphological and molecular methods. The evaluation of the antagonistic activity of T. harzianum isolate (TP) showed the highest inhibition in Fusarium spp. (78.80%). The evaluation of the antagonistic activity of Trichoderma spp. extracts in Fusarium spp. did not show significant differences between treatments (P ≤ 0.05), with Trichoderma growth percentages that oscillated between 81.08 and 94.38%. The native isolate of T. harzianum (TP) showed significant competitive capability against the mycelial growth of F. oxysporum. Trichoderma species are promising agents of biological control in the central area of the State Tamaulipas, Mexico.

Virtual reality is beneficial in decreasing pain in labouring women: A preliminary study.

BACKGROUND: Women use a range of non-pharmacological pain relief methods to reduce labour pain intensity and to help manage labour pain. AIMS: The purpose of this intervention study was to determine whether virtual reality would have an effect on labour pain intensity. Virtual reality has been shown to be effective in reducing pain in other acute pain settings. MATERIALS AND METHODS: This study was an intervention study in labour in a cross-over within-subjects design (Clinical Trials Registry Number: ACTRN12618001776291P). Fourteen participants reported their pain and had their heart rate and blood pressure measured during active labour while using and not using virtual reality. RESULTS: There were significantly lower reported pain scores (6.14 compared to 7.61, P < 0.001) and maternal heart rate (79.86 beats per minute compared to 85.57, P = 0.033) and mean arterial pressure (88.78 mmHg compared to 92.61 mmHg, P = 0.022) were lower when using virtual reality compared to when not using virtual reality during active labour. CONCLUSION: This study makes an important contribution to the field of virtual reality in labour and birth. It is consistent with other recent findings of reduced pain in labour and links decreased pain scales to heart rate and blood pressure, the physiological markers of pain.

Polyamines Influence Mouse Sperm Channels Activity.

Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl-]i, calcium [Ca2+]i, sodium [Na+]i, potassium [K+]i, the membrane Vm, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane Vm during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na+/H+ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.

Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase.

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05-4.935 µg/mL), while folic acid showed activity against E. histolytica (0.186 µg/mL) and G. lamblia (5.342 µg/mL).

Tailoring Cognitive Behavioral Therapy for Depression and Anxiety Symptoms in Mexican Terminal Cancer Patients: A Multiple Baseline Study.

The purpose of this study was to assess the effect of tailored cognitive behavioral therapy (CBT) on depression and anxiety symptoms present in Mexican terminal cancer patients. A non-concurrent multiple baseline design was used across individuals. Nine patients participated in the study, each receiving four to six therapy sessions. The effect size of the intervention range (NAP and Tau indexes) in the nine patients indicates that CBT intervention resulted in weak to moderate impact for anxiety and depression symptoms in this population. The overall standardized mean difference is also moderate, with a reduction of 0.54 and 0.76 standard deviations in depression and anxiety symptoms, respectively. This study provides initial evidence to support a positive effect from CBT on patients with terminal cancer and with mood disorders when facing their impending death.

Circulating miR-146a, miR-34a and miR-375 in type 2 diabetes patients, pre-diabetic and normal-glycaemic individuals in relation to ß-cell function, insulin resistance and metabolic parameters.

The pathogenesis of type 2 diabetes (T2D) is associated with a progressive loss of pancreatic ß-cell mass. It is known that miR-146a, miR-34a, and miR-375 are involved in ß-cell functionality. In this work, we evaluated the levels of these miRNAs in normal-glycaemic individuals, pre-diabetic, and T2D patients in relation to ß-cell functionality, insulin resistance, and metabolic parameters. The relative expression of the miRNAs was evaluated in serum samples by real-time polymerase chain reaction. In a principal component analysis, we observed that T2D patients and pre-diabetic individuals were not associated with ß-cell functionality. However, in a correlation matrix analysis, we detected that miR-34a was related to miR-146a and insulin resistance. The relative expression of miR-375 was correlated with cholesterol and low-density lipoprotein levels. A decrease of ß-cell function in pre-diabetic individuals and T2D patients was observed. The insulin resistance was higher in pre-diabetic individuals and T2D patients. The relative expression of miR-146a in pre-diabetic individuals, T2D patients with insulin treatment, and T2D patients with nephropathy and diabetic foot was decreased. In addition, miR-34a was increased in T2D patients who were overweight and obese. The relative expression of miR-375 was increased in T2D patients with poor glycaemic control, while a decrease was seen in T2D patients with nephropathy and diabetic foot. Circulating miR-375, miR-34a, and miR-146a were not associated with ß-cell functionality, but their expression was differentially affected by glycaemia, obesity, insulin treatment, and the presence of nephropathy and diabetic foot.

Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors.

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 µM) and trypomastigote (IC50 = 166.21 ± 14.5 µM and 185.1 ± 8.5 µM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

Proteome-wide analysis of human motif-domain interactions mapped on influenza a virus.

BACKGROUND: The influenza A virus (IAV) is a constant threat for humans worldwide. The understanding of motif-domain protein participation is essential to combat the pathogen. RESULTS: In this study, a data mining approach was employed to extract influenza-human Protein-Protein interactions (PPI) from VirusMentha,Virus MINT, IntAct, and Pfam databases, to mine motif-domain interactions (MDIs) stored as Regular Expressions (RegExp) in 3DID database. A total of 107 RegExp related to human MDIs were searched on 51,242 protein fragments from H1N1, H1N2, H2N2, H3N2 and H5N1 strains obtained from Virus Variation database. A total 46 MDIs were frequently mapped on the IAV proteins and shared between the different strains. IAV kept host-like MDIs that were associated with the virus survival, which could be related to essential biological process such as microtubule-based processes, regulation of cell cycle check point, regulation of replication and transcription of DNA, etc. in human cells. The amino acid motifs were searched for matches in the immune epitope database and it was found that some motifs are part of experimentally determined epitopes on IAV, implying that such interactions exist. CONCLUSION: The directed data-mining method employed could be used to identify functional motifs in other viruses for envisioning new therapies.

Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana.

Leishmaniasis is a neglected tropical disease caused by the parasite of the genus Leishmania. About 13 million people are infected worldwide, and it is estimated that 350 million are at risk of infection. Clinical manifestations depend on the parasite species and factors related to the host such as the immune system, nutrition, housing, and financial resources. Available treatments have severe side effects; therefore, research currently focuses on finding more active and less toxic compounds. Quinoxalines have been described as promising alternatives. In this context, 17 isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated as potential leishmanicidal agents. Their effect on the cell metabolism of Leishmania mexicana promastigotes and their cytotoxic effects on the J774.A1 cell line and on erythrocytes were evaluated, and their selectivity index was calculated. Compounds T-069 (IC50 = 1.49 µg/mL), T-070 (IC50 = 1.71 µg/mL), T-072 (IC50 = 6.62 µg/mL), T-073 (IC50 = 1.25 µg/mL), T-085 (IC50 = 0.74 µg/mL), and T-116 (IC50 = 0.88 µg/mL) were the most active against L. mexicana promastigotes and their mechanism of action was characterized by flow cytometry and microscopy. Compound T-073, the most selective quinoxaline derivative, induced cell membrane damage, phosphatidylserine exposition, reactive oxygen species production, disruption of the mitochondrion membrane potential, and DNA fragmentation, all in a dose-dependent manner, indicating the induction of regulated necrosis. Light and transmission electron microscopy showed the drastic morphological changes induced and the mitochondrion as the most sensitive organelle in response to T-073. This study describes the mechanism by which active isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide quinoxalines affect the parasite.

Anti-Mycobacterium tuberculosis Activity of Esters of Quinoxaline 1,4-Di-N-Oxide.

Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 °C.

[Estrategias de afrontamiento para el manejo del estrés y su relación con el nivel de obesidad y calidad de vida en pacientes candidatos a cirugía bariátrica].

INTRODUCTION: Stress is a variable that may play an important role in the development of obesity and in the quality of life of patients who are candidates for bariatric surgery, since stress is linked to the consumption of hypercaloric foods, sedentariness and higher incidence of psychological disorders. OBJECTIVE: To describe the most common types of stress coping strategies in patients who are candidates for bariatric surgery and establish their relationship with body mass index and quality of life perception. METHOD: One-hundred and one patients with severe obesity who were candidates for bariatric surgery were evaluated by means of the Stress Coping Questionnaire and the Quality of Life and Health Inventory. RESULTS: The most commonly used coping type is action and the most common strategy is focus on problem solving. Five coping strategies were significantly associated with quality of life; there was no significant association with body mass index. CONCLUSION: There is an association between some coping styles and quality of life in individuals who are candidates for bariatric surgery.

INTRODUCCIÓN: El estrés es una variable que puede desempeñar un papel importante en el desarrollo de la obesidad y en la calidad de vida de los pacientes candidatos a cirugía bariátrica, ya que se vincula a la ingesta de alimentos hipercalóricos, sedentarismo y mayor incidencia de trastornos psicológicos. OBJETIVO: Describir el tipo y estrategias de afrontamiento al estrés más frecuentes en los pacientes candidatos a cirugía bariátrica y establecer su relación con el índice de masa corporal y su percepción de calidad de vida. MÉTODO: Se evaluaron 101 pacientes con obesidad severa candidatos a cirugía bariátrica por medio del Cuestionario de Afrontamiento al Estrés y el Inventario de Calidad de Vida y Salud. RESULTADOS: El tipo de afrontamiento más utilizado es la acción y la estrategia más frecuente es la focalización en solución de problemas. Cinco estrategias de afrontamiento se asociaron significativamente con la calidad de vida; no hubo asociación significativa con el índice de masa corporal. CONCLUSIÓN: Existe asociación entre algunos estilos de afrontamiento y la calidad de vida de los individuos candidatos a cirugía bariátrica.

Characteristic plethysmographic findings in a guinea pig model of COPD.

AIM OF THE STUDY: Long-term exposure to cigarette smoke generates chronic obstructive pulmonary disease (COPD) in guinea pigs, but a comprehensive evaluation of changes in lung function, as assessed by barometric whole body plethysmography (WBP), is lacking. MATERIALS AND METHODS: Female guinea pigs were exposed to the smoke of 20 cigarettes/day, 5 days/week, during 10 weeks (COPD group, n = 8), and were compared with unexposed female guinea pigs of the same age (control group, n = 8). WBP was performed in both groups, followed by lung histology. RESULTS: At the end of the exposure period, guinea pigs in the COPD group had higher respiratory frequency, while duty cycle (Ti/Ttot) was unaffected. There was a trend toward minute ventilation (MV) and expiratory flow at the mid-tidal volume (EF50) to be higher in the COPD group. Enhanced pause (Penh) was lower, while time of braking (TB) and time to PEF relative to Te (Rpef) were higher in the COPD group. All guinea pigs exposed to tobacco smoke developed emphysematous lesions in their lungs and gained less body weight than controls. CONCLUSIONS: In this COPD model, exposure to cigarette smoke produced changes in WBP characterized by a shallow breathing pattern with decreased Penh and a trend toward increasing EF50 (probably due to decreased elastic recoil), increased TB (suggesting dynamic laryngeal narrowing), and a trend of increasing MV (probably due to a higher metabolic rate). Many of these functional changes resemble those observed in patients with COPD and corroborate the suitability of this guinea pig model for the study of COPD.

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies.

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three ß-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8-26.1 µg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1-46.7 µg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90-60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors.

Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.

Costs of Extending the Noncontributory Pension Program for Elderly: The Mexican Case.

Population aging coupled with high poverty rates among older persons and a lack of access to social-security benefits or traditional support systems have led governments in low and middle-income countries to introduce non-contributory pension programs for the elderly. This article reviews a non-contributory pension program introduced in Mexico in 2007 that has since expanded greatly. We use a variety of sources to estimate current and future costs of this program.