Evaluación de la productividad del área comercial y logística de la empresa EQUIPSA Nicaragua, al implementar una estrategia de administración de relación con los clientes CRM

La investigación presenta un diagnostico real del grado de implementación de una estrategia CRM en la empresa EQUIPSA, según la estructura de implementación del CRM con base en la ejecución de los siguientes procesos: desarrollo, administración y dirección, medición y evaluación. EQUIPSA, empresa con presencia regional que provee servicios de mantenimientos y venta de repuestos de ocho divisiones de negocios; a partir del año 2017, inicio el proceso de implementación de ZOHO CRM, que permite la administración eficiente de la relación con los clientes

Farmacología y toxicología en I+D+i: adquisición de competencias a través de un ejemplo de desarrollo de un fármaco

The implementation of the subject Pharmacology and Toxicology in R+D+i in the Pharmacy Degree, has led to the launch of a new methodological approach and teaching performance with the aim of developing the generic skills of the University of Barcelona (e.g., self-learning, team-working). An additional objective was students' integration of knowledge from different subjects in the degree which form the basis of the preclinical and clinical development of a drug. For this purpose, the teaching strategy used in the development of the subject was based on: 1) re-developing the content that students had been taught previously or were being taught in the same semester as a part of other subjects, and framing them in the environment of the pharmaceutical industry, 2) introducing new and previously unseen contents to do with drug development and toxicology, 3) developing a battery of activities to be undertaken by teams of students relating to the R+D+i of a particular drug. During the development of these activities, students have to acquire generic skills in addition to the subject-specific skills. The results obtained from the student survey give us grounds for satisfaction and allow us to consider that we have reached the goal of improving students' learning in Pharmacology and Toxicology applied to drug development in the pharmaceutical world today

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice

Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. The present work was addressed to determine whether MR309 might exert preventive effects on CNP development by repeated administration during the first week after SCI in mice. To this end, the MR309 (16 or 32 mg/kg i.p.) modulation on both thermal hyperalgesia and mechanical allodynia development were evaluated weekly up to 28 days post-injury. In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development

Liquid fructose downregulates SIRT1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells

Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25 mM for 24 h. The expression and activity of the enzymes and transcription factors relating to fatty acid β-oxidation were evaluated. Fructose inhibited the activity of fatty acid β-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation

Development of a novel 1 receptor biosensor based on its heterodimerization with binding immunoglobulin protein in living cells

The σ1 receptor (S1R) is a ligand-regulated non-opioid intracellular receptor involved in several pathological conditions. The development of S1R-based drugs as therapeutic agents is a challenge due to the lack of simple functional assays to identify and classify S1R ligands. We have developed a novel nanoluciferase binary technology (NanoBiT) assay based on the ability of S1R to heteromerize with the binding immunoglobulin protein (BiP) in living cells. The S1R-BiP heterodimerization biosensor allows for rapid and accurate identification of S1R ligands by monitoring the dynamics of association-dissociation of S1R and BiP. Acute treatment of cells with the S1R agonist PRE-084 produced rapid and transient dissociation of the S1R-BiP heterodimer, which was blocked by haloperidol. The effect of PRE-084 was enhanced by calcium depletion, leading to a higher reduction in heterodimerization even in the presence of haloperidol. Prolonged incubation of cells with S1R antagonists (haloperidol, NE-100, BD-1047, and PD-144418) increased the formation of S1R-BiP heteromers, while agonists (PRE-084, 4-IBP, and pentazocine) did not alter heterodimerization under the same experimental conditions. The newly developed S1R-BiP biosensor is a simple and effective tool for exploring S1R pharmacology in an easy cellular setting. This biosensor is suitable for high-throughput applications and a valuable resource in the researcher's toolkit

Urinary bladder sigma-1 receptors: A new target for cystitis treatment

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.phrs.2020.104724.No adequate treatment is available for painful urinary bladder disorders such as interstitial cystitis/bladder pain syndrome, and the identification of new urological therapeutic targets is an unmet need. The sigma-1 receptor (σ1-R) modulates somatic pain, but its role in painful urological disorders is unexplored. The urothelium expresses many receptors typical of primary sensory neurons (e.g. TRPV1, TRPA1 and P2X3) and high levels of σ1- R have been found in these neurons; we therefore hypothesized that σ1-R may also be expressed in the urothelium and may have functional relevance in this tissue. With western blotting and immunohistochemical methods, we detected σ1-R in the urinary bladder in wild-type (WT) but not in σ1-R-knockout (σ1-KO) mice. Interestingly, σ1-R was located in the bladder urothelium not only in mouse, but also in human bladder sections. The severity of histopathological (edema, hemorrhage and urothelial desquamation) and biochemical alterations (enhanced myeloperoxidase activity and phosphorylation of extracellular regulated kinases 1/2 [pERK1/2]) that characterize cyclophosphamide-induced cystitis was lower in σ1-KO than in WT mice. Moreover, cyclophosphamide-induced pain behaviors and referred mechanical hyperalgesia were dose-dependently reduced by σ1-R antagonists (BD-1063, NE-100 and S1RA) in WT but not in σ1-KO mice. In contrast, the analgesic effect of morphine was greater in σ1-KO than in WT mice. Together these findings suggest that σ1-R plays a functional role in the mechanisms underlying cyclophosphamide-induced cystitis, and modulates morphine analgesia against urological pain. Therefore, σ1-R may represent a new drug target for urinary bladder disorders.Spanish Ministry of Economy and Competitiveness (MINECO) SAF2016-80540-REuropean Regional Development Funds (ERDF), Junta de Andalucia grant CTS 109Esteve PharmaceuticalsInnovative Medicines Initiative 2 Joint Undertaking 777500European Union's Horizon 2020 research and innovation programmeEFPI

L'avaluació continuada i la millora en el rendiment acadèmic: el cas de de la Farmacologia i Toxicologia en R+D+i del Grau de Farmàcia

Podeu consultar la Vuitena trobada de professorat de Ciències de la Salut completa a: http://hdl.handle.net/2445/66524Des de la implantació de Espai Europeu d’Educació Superior i l’adopció per part de les universitats de l’avaluació continuada (AC) com a sistema d’acreditació del aprenentatges, existeix la preocupació tant per part dels estudiants com dels professors, que l’AC, entesa com la suma de proves i/o evidències parcials d’avaluació, ens porta a una disminució de notes en la franja alta de qualificació..

Inhibition of Cardiac Hypertrophy by Triflusal (4-Trifluoromethyl Derivative of Salicylate) and Its Active Metabolite

ABSTRACT The nuclear factor (NF)-B signaling pathway is an important intracellular mediator of cardiac hypertrophy. The aim of the present study was to determine whether triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a salicylate derivative used as antiplatelet agent, and its active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) inhibit cardiac hypertrophy in vitro and in vivo by blocking the NF-B signaling pathway. In cultured neonatal rat cardiomyocytes, HTB (300 M, a concentration reached in clinical use) inhibited phenylephrine (PE)-induced protein synthesis ([ 3 H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF), and sarcomeric disorganization. Assessment of the effects of triflusal in pressure overload-induced cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to body weight and in a reduction of the mRNA levels of the cardiac hypertrophy markers ANF and ␣-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the NF-B binding activity in cardiac nuclear extracts of banded rats that was prevented by triflusal treatment. It is noteworthy that banded rats treated with oral triflusal, compared with untreated rats, showed enhanced protein levels of IB␣, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally, HTB increased phospho-IB␣ levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this drug prevented proteosome-mediated degradation of IB␣. These results indicate that triflusal, a drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the NF-B signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of IB␣. Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden deat