Facultad de Ciencias de la Salud

Atherosclerosis is one of the most relevant and prevalent cardiovascular diseases of our time. It is one of the pathological entities that increases the morbidity and mortality index in the adult population. Pathophysiological connections have been observed between atherosclerosis and the gut microbiome (GM), represented by a group of microorganisms that are present in the gut. These microorganisms are vital for metabolic homeostasis in humans. Recently, direct and indirect mechanisms through which GM can affect the development of atherosclerosis have been studied. This has led to research into the possible modulation of GM and metabolites as a new target in the prevention and treatment of atherosclerosis. The goal of this review is to analyze the physiopathological mechanisms linking GM and atherosclerosis that have been described so far. We also aim to summarize the recent studies that propose GM as a potential target in atherosclerosis management.

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with CKD. We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and MRA eplerenone alone and in combination in patients with CKD. Methods: We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hr, eGFR 30-90 ml/min per 1.73 m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results: Of 57 patients screened, 46 were randomly assigned (mean eGFR, 58.1 ml/min per 1.73 m2; median UACR, 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% confidence interval [CI], -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; P<0.001 versus dapagliflozin; P=0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (r=-0.13; P=0.47; r=-0.08; P=0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n=8; 17.4%) compared with dapagliflozin (n=0; 0%) or dapagliflozin-eplerenone (n=2; 4.3%; P between-groups=0.003). Conclusions: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.

Actualmente, la mitad de la población muere en los hospitales, lejos del hogar, en ocasiones, también lejos de familiares y amigos; rodeado de personas con culturas, religiones y valores diferentes. Por otro lado, vivimos en una sociedad que niega y oculta la muerte; no se detiene a reflexionar sobre ella; y cuando llega ese momento, se convierte en un proceso doloroso e insoportable, atenazado por el miedo; lleno de interrogantes sin respuestas. Esta situación conlleva que, frecuentemente en el final de la vida, se generen conflictos éticos cuyas soluciones son difíciles de determinar y provocan dolor en aquellos que intervienen en la toma de decisiones. Garantizar el derecho de autonomía cuando aparece la incapacidad y la muerte es uno de los desafíos de las sociedades modernas. Partiendo del Documento de Voluntades Anticipadas y queriendo avanzar un paso más, surge en los Estados Unidos el proceso de Planificación Anticipada de la Asistencia Sanitaria como medio para preservar el derecho de autodeterminación de toda persona en cualquier circunstancia. El éxito de este proceso se encuentra en que proporciona al paciente, la familia y allegados un tiempo único para aceptar la finitud de la vida y afrontar la muerte en paz.

In this paper, molecular topology was used to develop a mathematical model capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones, widely used nowadays because of their broad spectrum of activity, well tolerance profile and advantageous pharmacokinetic properties. The topological model of activity obtained included two discriminant functions, selected by a combination of various statistical paremeters such as Fisher-Snedecor F and Wilk's lambda, and allows the reliable prediction of antibacterial activity in any organic compound. After a virtual pharmacological screening on a library of 6375 compounds, the model has selected 263 as active compounds, from which 40% have proven antibacterial activity. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of pharmacological activities. These models are very helpful in the discovery of new applications of natural and synthetic molecules with different chemical or biological properties. Therefore, we finally present 158 strong candidates to be developed as novel antibacterials.

Objective: To assess the effect of different dosages of pain neuroscience education (PNE) programs on central nociceptive processing in patients with fibromyalgia. Second, to compare the effects of different dosages of PNE programs on numerical pain rating scale (NPRS), disability, and psychological variables. Design: Single-blind randomized controlled trial. Setting: Three fibromyalgia centers in Spain (Valencia, Alcorcón, Alcalá de Henares). Subjects: Seventy-seven patients with fibromyalgia. Methods: Participants were randomized to four groups of PNE: 1) high-dose PNE (N = 20), 2) low-concentrated dose PNE (N = 20), 3) diluted low-dose PNE (N = 20), and (4) control treatment (N = 17), conducted in two 30-50-minute sessions in groups of four to six participants. Conditioned pain modulation (CPM), temporal summation (TS), and pressure pain thresholds (PPTs) were assessed at baseline and at three-month follow-up. Secondary outcome measures were the Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, and Pain Anxiety Symptoms Scale. Results: There were significant between-group differences for NPRS in favor of the groups receiving high-dose PNE, with a large effect size at three-month follow-up (P < 0.01, η2p = 0.170), but there were no significant differences between groups for the remaining variables (P > 0.05). All groups improved for central nociceptive processing, psychological variables, disability, and pain intensity (NPRS). Conclusions: In patients with fibromyalgia, higher dosages of PNE produced a larger improvement in pain severity at three-month follow-up than other dosages of PNE and biomedical education. However, PNE was not superior to biomedical education in the central nociceptive processing, disability, or psychological variables in patients with fibromyalgia.

The objective of this research was to develop and evaluate an ocular insert for the controlled drug delivery of moxifloxacin which could perhaps be used in the treatment of corneal keratitis or even bacterial endophthalmitis. We have evaluated the ex vivo ocular diffusion of moxifloxacin through rabbit cornea, both fresh and preserved under different conditions. Histological studies were also carried out. Subsequently, drug matrix inserts were prepared using bioadhesive polymers. The inserts were evaluated for their physicochemical parameters. Ophthalmic ex vivo permeation of moxifloxacin was carried out with the most promising insert. The formulate insert was thin and provided higher ocular diffusion than commercial formulations. Ocular diffusion studies revealed significant differences between fresh and frozen corneas. Histological examinations also showed differences in the thickness of stroma between fresh and frozen corneas. The ophthalmic insert we have developed allows a larger quantity of moxifloxacin to permeate through the cornea than existing commercial formulations of the drug. Ocular delivery of moxifloxacin with this insert could be a new approach for the treatment of eye diseases.

Leishmaniasis, African sleeping sickness and Chagas disease, caused by the kinetoplastid parasites Leishmania spp, Trypanosoma brucei and Trypanosoma cruzi, respectively, are among the most important parasitic diseases, affecting millions of people and considered to be within the most relevant group of neglected tropical diseases. The main alternative to control such parasitosis is chemotherapy. Nevertheless, the current chemotherapeutic treatments are far from being satisfactory. This review outlines the current understanding of different drugs against leishmaniasis, African sleeping sickness and Chagas disease, their mechanism of action and resistance. Recent approaches in the area of anti-leishmanial and trypanocidal therapies are also enumerated, new modulators from the mode of action, development of new formulations of old drugs, therapeutic switching and “in silico” drug design.

A series of compounds containing the nitrobenzene and sulfonamido moieties were synthesized and their leishmanicidal effect was assessed in vitro against Leishmania infantum promastigotes. Among the compounds evaluated, the p-nitrobenzenesulfonamides 4Aa and 4Ba, and the p-nitroaniline 5 showed significant activity with a good selectivity index. In a Balb/c mice model of L. Infantum, administration of compounds 4Aa, 4Ba or 5 (5 mg/kg/day for 10 days, injected ip route) led to a clear-cut parasite burden reduction (ca. 99%). In an attempt to elucidate their mechanism of action, the DNA interaction of 4Aa and 5 was investigated by means of viscosity studies, thermal denaturation and nuclease activity assay. Both compounds showed nuclease activity in the presence of copper salt. The results suggest that compounds 4Aa, 4Ba and 5 represent possible candidates for drug development in the therapeutic control of leishmaniasis.

Percutaneous transdermal absorption of esculetin (6,7-dihydroxycoumarin), an oxidative damage inhibitor, was evaluated by means of in vitro permeation studies in which vertical Franz-type diffusion cells and pig ear skin were employed. To determine the absorption of esculetin, we validated a simple, accurate, precise, and rapid HPLC-UV method. Additionally, the effects of several percutaneous enhancers were studied. Pretreatment of porcine skin was performed with ethanol (control vehicle), decenoic acid, oleic acid, R-(+)-limonene, and laurocapram (Azone®) (5% in ethanol, w/w, respectively). Pretreatment of skin with oleic acid or laurocapram led to statistically significant differences in the transdermal flux of esculetin with respect to controls. Of the two enhancers, laurocapram showed the greatest capacity to enhance the flux of esculetin across pig skin.

Background: Pazopanib, a new oral angiogenesis inhibitor, has demonstrated clinical activity against multiple solid tumors and was approved for the treatment of patients with advanced renal cell carcinoma. As an exposure-response relationship has been observed for pazopanib, its therapeutic drug monitoring could be a valuable tool in clinical practice. Therefore, the aim of this study was to develop and validate a selective and precise high performance liquid chromatography-ultraviolet method for the measurement of pazopanib in plasma from patients with cancer. Methods: After liquid-liquid extraction with diethyl ether, pazopanib and gefitinib (internal standard) were separated using isocratic elution on an Ultrabase C18 column using a mobile phase consisting of a mixture in vol/vol proportion of 47:53 of ammonium acetate (pH, 7; 0.02 mol/L) and acetonitrile/methanol (70:30, vol/vol) pumped at a constant flow rate of 1 mL/min. Quantification was performed at 260 nm. Method validation was undertaken as per the guidelines for Bioanalytical Method Validation published by the Food and Drug Administration and European Medicines Agency. Results: Calibration curves were linear over the range 0.5-100 mcg/mL. Interday and intraday coefficients of variations were less than 4.5%. The limit of detection and the lower limit of quantification were 0.2 and 0.5 mcg/mL, respectively. Recovery of pazopanib from plasma was >80%. Conclusions: This is the first high performance liquid chromatography-ultraviolet method for pazopanib quantification that has been validated within a wide range of plasma concentrations and is a suitable method for therapeutic drug monitoring of pazopanib.