The new preservative-free ophthalmic formulation of bilastine 0.6% preserves the ocular surface epithelial integrity in a comparative in vitro study.

Allergic conjunctivitis (AC) is the most common form of allergic eye disease and an increasingly prevalent condition. Topical eye drop treatments are the usual approach for managing AC, although their impact on the ocular surface is not frequently investigated. The aim of this study was to perform a comparative physicochemical characterization, and in vitro biological evaluations in primary conjunctival and corneal epithelial cells of the new multidose preservative-free bilastine 0.6% and main commercially available eye drops. MTT assay was used to measure cell viability; oxidative stress was analyzed with a ROS-sensitive probe; and apoptosis was evaluated monitoring caspase 3/7 activation. Differences in pH value, osmolarity, viscosity and phosphate levels were identified. Among all formulations, bilastine exhibited pH, osmolarity and viscosity values closer to tear film (7.4, 300 mOsm/l and ~ 1.5-10 mPa·s, respectively), and was the only phosphates-free solution. Single-dose ketotifen did not induce ROS production, and single-dose azelastine and bilastine only induced a mild increase. Bilastine and single-dose ketotifen and azelastine showed high survival rates attributable to the absence of preservative in its formulation, not inducing caspase-3/7-mediated apoptosis after 24 h. Our findings support the use of the new bilastine 0.6% for treating patients with AC to preserve and maintain the integrity of the ocular surface.

Radiofrequency-assisted transection of the pancreas versus stapler in distal pancreatectomy: study protocol for a multicentric randomised clinical trial (TRANSPAIRE).

INTRODUCTION: To date, no pancreatic stump closure technique has been shown to be superior to any other in distal pancreatectomy. Although several studies have shown a trend towards better results in transection using a radiofrequency device (radiofrequency-assisted transection (RFT)), no randomised trial for this purpose has been performed to date. Therefore, we designed a randomised clinical trial, with the hypothesis that this technique used in distal pancreatectomies is superior in reducing clinically relevant postoperative pancreatic fistula (CR-POPF) than mechanical closures. METHODS AND ANALYSIS: TRANSPAIRE is a multicentre randomised controlled trial conducted in seven Spanish pancreatic centres that includes 112 patients undergoing elective distal pancreatectomy for any indication who will be randomly assigned to RFT or classic stapler transections (control group) in a ratio of 1:1. The primary outcome is the CR-POPF percentage. Sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-ß), expected POPF in control group of 32%, expected POPF in RFT group of 10% and a clinically relevant difference of 22%. Secondary outcomes include postoperative results, complications, radiological evaluation of the pancreatic stump, metabolomic profile of postoperative peritoneal fluid, survival and quality of life. Follow-ups will be carried out in the external consultation at 1, 6 and 12 months postoperatively. ETHICS AND DISSEMINATION: TRANSPAIRE has been approved by the CEIM-PSMAR Ethics Committee. This project is being carried out in accordance with national and international guidelines, the basic principles of protection of human rights and dignity established in the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, October 2013), and in accordance with regulations in studies with biological samples, Law 14/2007 on Biomedical Research will be followed. We have defined a dissemination strategy, whose main objective is the participation of stakeholders and the transfer of knowledge to support the exploitation of activities. REGISTRATION DETAILS: ClinicalTrials.gov Registry (NCT04402346).

Ocular Biodistribution of Once-Daily 0.6% Bilastine Eye Drops Reveals Highest Levels in Conjunctiva Up to 24 h Postadministration.

Purpose: Bilastine is a second-generation antihistamine that has been shown to be effective for treatment of allergic conjunctivitis. The objective of this study was to evaluate the pharmacokinetics (PKs) and biodistribution of 0.6% bilastine preservative-free eye drops. Methods: Bilastine was quantified in the conjunctiva, cornea, aqueous humor, vitreous humor, iris/ciliary body, retina/choroid, crystalline lens, and plasma, following a single topical administration to male Dutch-belted rabbits. Results: Concentrations of bilastine were highest in the conjunctiva [Cmax: 2,545.04 ng/g, at 6 h postadministration; area under the concentration-time curve (AUCt): 11,382.40 ng·h/g] and cornea (Cmax: 609.11 ng/g, at 1 h postadministration; AUCt: 1,993.88 ng·h/g), followed by the iris/ciliary body, retina/choroid, aqueous humor, plasma, vitreous humor, and crystalline lens. Quantifiable bilastine concentrations were observed up to 24 h after instillation in the conjunctiva (388.45 ng/g), cornea (28.68 ng/g), iris/ciliary body (12.42 ng/g), retina/choroid (1.91 ng/g), and crystalline lens (0.12 ng/g). In plasma, aqueous humor, and vitreous humor, bilastine was detected up to 12 h postadministration (0.18 ng/mL, 0.40 ng/mL, and 0.32 ng/g, respectively). Conclusions: PKs and biodistribution of 0.6% bilastine eye drops in rabbits revealed a marked preferential distribution in the conjunctiva (target tissue), with sustained levels up to 24 h. These findings are consistent with clinical efficacy trials supporting once-daily administration of topical bilastine for treatment of allergic conjunctivitis.

Prolapso rectal incarcerado: rectosigmoidectomía perineal urgente / Strangle rectal prolapse: Emergency perineal rectosigmoidectomy

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Adaptación de la escala ESCID para medir el dolor en pacientes críticos con daño cerebral / Adaptation of the ESCID scale to measure pain in critical patients with brain damage

OBJETIVO: evaluar la validez de constructo y la fiabilidadde la adaptación de la escala de conductas indicadoras de dolor (ESCID), para valorar el dolor en pacientes críticos con daño cerebral, no comunicativos y sometidos a ventilación mecánica. MÉTODO: sujetos: estudio multicéntrico, observacional. Se llevará a cabo en pacientes críticos con lesión cerebral adquirida, mayores de edad, sometidos a ventilación mecánica invasiva y sin capacidad de comunicación, ingresados en unidades de cuidados intensivos de cuatro hospitales universitarios de tercer nivel de la Comunidad de Madrid. En todos los sujetos se evaluará el dolor con dos instrumentos simultáneamente (ESCID-DC y videograbación). La evaluación del dolor con ESCID-DC se realizará por dos observadores independientes con resultado ciego entre ellos, ante la aplicación de dos procedimientos dolorosos (aspiración de secreciones traqueales y presión en lecho ungueal), y un procedimiento no doloroso. La medición se efectuará únicamente una vez por cada paciente y procedimiento. La medición del dolor se hará en tres momentos: cinco minutos antes, durante y 15 minutos después de cada procedimiento. Cinco minutos antes de iniciar los procedimientos y hasta diez minutos después, dos videocámaras (una enfoca el cuerpo completo, otra solo la cara) captarán imágenes y audio, para posteriormente analizar los cambios gestuales y corporales del sujeto en cada momento, y poder correlacionarlos con los ocho indicadores conductuales de la escala ESCID-DC. CONCLUSIONES: contar con una escala de este tipo con buenas propiedades psicométricas mejorará el manejo del dolor de los pacientes con daño cerebral y, por tanto, la eficacia del tratamiento

OBJECTIVE: to evaluate the validity of the concept and the reliability of the adaptation of the Scale of Behavior Indicators of Pain (ESCID) in order to assess pain in critical patients with brain damage, who are non-communicative and undergoing mechanical ventilation. METHOD: subjects: a multicenter observational study. It will be conducted on critical patients with acquired brain damage, of age, undergoing invasive mechanical ventilation, and unable to communicate, who have been admitted to intensive care units from four 3rd level University Hospitals from the Community of Madrid. Pain will be evaluated in all subjects with two instruments simultaneously (ESCID-DC and video recording). Pain evaluation through ESCID-DC will be conducted by two independent observers with blind results between them, with the application of two painful procedures (aspiration of tracheal secretions and pressure on the nail bed) and a non-painful procedure. Measurement will only be conducted once per patient and procedure. Pain measurement will be conducted at three time points: fiveminutes before, during, and fifteenminutes after each procedure. Five minutes before initiating the procedure and up to ten minutes afterwards, two video cameras will capture images and audio (one will focus on the entire body, the other one only on the face), in order to capture and subsequently analyze the gestural and body changes of the subject at each moment, and to be able to correlate them with the eight behavior indicators of the ESCID-DC scale. CONCLUSIONS: the availability of this type of scale, with good psychometric properties, will improve pain management for patients with brain damage and, therefore, treatment efficacy

Abdomen agudo en paciente anciano / Acute abdomen in an elderly patient

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Marcha nórdica para prevención cardiovascular en pacientes con cardiopatía isquémica crónica o síndrome metabólico / Nordic walking for cardiovascular prevention in patients with ischaemic heart disease or metabolic syndrome

Antecedentes y objetivo: La enfermedad aterosclerótica ha aumentado en Europa debido, en parte, al estilo de vida sedentario de la población. El ejercicio físico es efectivo en prevención cardiovascular. La marcha nórdica (MN) moviliza numerosos grupos musculares y es muy popular en el norte de Europa. No se tienen datos en el entorno sanitario del área mediterránea. Proponemos un programa de MN para promover la actividad física y el control de factores de riesgo cardiovascular (FRCV), mejorar la calidad de vida y el cumplimiento terapéutico en pacientes con cardiopatía isquémica crónica o síndrome metabólico. Métodos: Se seleccionaron pacientes con FRCV no controlados. Realizaron 2 sesiones semanales durante un año. Los datos basales de la historia clínica, cuestionarios de calidad de vida y cumplimiento terapéutico se compararon con los obtenidos tras el programa. Resultados: Los FRCV no controlados se redujeron de 4,78 a 3, con una tendencia a la mejoría de la calidad de vida y el cumplimiento terapéutico. Conclusiones: Un programa de MN es factible en el sistema sanitario público y puede ser útil para mejorar el control de los FRCV (AU)

Background and objective: The incidence of atherosclerotic diseases has increased in Europe due in part to the population’s sedentary lifestyle. Physical activity is useful for cardiovascular prevention. Nordic walking (NW) mobilizes a great number of muscular groups and is very popular in northern Europe. There is no data available on its impact in the healthcare system of the Mediterranean area. We propose the implementation of a NW program to promote physical activity and control cardiovascular risk factors (CVRF), as well as to improve quality of life and the adherence to medical treatment in patients with a chronic ischemic heart disease or metabolic syndrome. Methods: We selected patients with uncontrolled CVRFs. These patients performed 2 weekly sessions of NW over the course of one year. Baseline data extracted from the patients’ medical history, quality of life questionnaires and on adherence to treatment was compared with the results obtained at the end of the program. Results: A reduction in the rate of CVRFs from 4.78 to 3 was observed, with an evident trend towards the improvement of the patients’ quality of life and a better adherence to the treatment. Conclusions: The implementation of a NW program is feasible in the public healthcare system and can aid in the management of CVRFs (AU)

Nordic walking for cardiovascular prevention in patients with ischaemic heart disease or metabolic syndrome. / Marcha nórdica para prevención cardiovascular en pacientes con cardiopatía isquémica crónica o síndrome metabólico.

BACKGROUND AND OBJECTIVE: The incidence of atherosclerotic diseases has increased in Europe due in part to the population's sedentary lifestyle. Physical activity is useful for cardiovascular prevention. Nordic walking (NW) mobilizes a great number of muscular groups and is very popular in northern Europe. There is no data available on its impact in the healthcare system of the Mediterranean area. We propose the implementation of a NW program to promote physical activity and control cardiovascular risk factors (CVRF), as well as to improve quality of life and the adherence to medical treatment in patients with a chronic ischemic heart disease or metabolic syndrome. METHODS: We selected patients with uncontrolled CVRFs. These patients performed 2 weekly sessions of NW over the course of one year. Baseline data extracted from the patients' medical history, quality of life questionnaires and on adherence to treatment was compared with the results obtained at the end of the program. RESULTS: A reduction in the rate of CVRFs from 4.78 to 3 was observed, with an evident trend towards the improvement of the patients' quality of life and a better adherence to the treatment. CONCLUSIONS: The implementation of a NW program is feasible in the public healthcare system and can aid in the management of CVRFs.

Complicaciones asociadas al catéter venoso central en pacientes hematológicos / Complications associated to central venous catheters in hematology patients

OBJETIVO: Conocer la incidencia de complicaciones asociadas a los catéteres venosos centrales (tunelizados, reservorios y PICC), en pacientes con patología oncohematológica, ingresados en Unidades de Hematología o Trasplantes de Progenitores Hematopoyéticos, en dos hospitales terciarios. METODOLOGÍA: Se desarrolló un estudio descriptivo transversal donde se recogieron datos sociodemográficos, clínicos, complicaciones y seguimiento del protocolo de cuidados. A cada catéter se le asignó un número de identificación correlativo. Se recogió información de 366 catéteres: 185 en el Hospital Universitario Ramón y Cajal (HURYC): 80 tunelizados, 40 reservorios y 65 PICC; 181 en el Hospital Universitario Gregorio Marañón (HUGM): 101 tunelizados y 80 reservorios. RESULTADOS: Las principales complicaciones en los tunelizados fueron las infecciones (13,7% en el HURYC vs.6,8% en el HUGM; p < 0,001) y las oclusiones (al menos una vez 3,8% vs.21,8%). En los reservorios se confirmaron un 5% de infecciones en el HURYC frente a 1,2% en el HUGM; se ocluyeron al menos una vez un 10% en el HUGM. No se detectaron otras complicaciones significativas. Respecto a los PICC solo se recogió información en el HURYC, donde las complicaciones fueron: flebitis 10,8%; trombosis 7,7%; infección o sospecha 4,6%; oclusión al menos una vez 7,7%. CONCLUSIONES: La diferencia entre hospitales respecto a la infección y oclusión, puede asociarse a las distintas pautas de cuidados. Destaca la alta incidencia de flebitis y trombosis en PICC

OBJECTIVE: To discover the incidence of central venous catheters (tunnelled, subcutaneous and PICC) in patients with onco-hematological conditions, hospitalized in the Hematology or Transplantations of Hematopoietic Stem Cells Units, in two tertiary care hospitals. METHODOLOGY: A cross-sectional, descriptive study form was developed in order to gather sociodemographic, clinical data as well as complications and follow-up of the care protocol. Each catheter was assigned a correlative identification number. Information was collected on 366 catheters: 185 in the University Hospital Ramón y Cajal (HURYC), 80 tunnelled, 40 subcutaneous venous access and 65 PICC, and 181 in the University Hospital Gregorio Marañón (HUGM), 101 tunnelled and 80 subcutaneous venous access. Findings: Major complications in the tunnellized were infections (13.7% in HURYC vs.6.8% in HUGM - p < 0 .001) and occlusions (at least once in 3.8% vs.21.8%). In subcutaneous venous access, infections were confirmed in 5% in HURYC vs.1.2% in HUGM. There were occlusions at least once in 10% in HUGM and no other significant complications were detected. Regarding PICC, information was only collected in HURYC, where complications were phlebitis 10.8%, thrombosis 7.7%, confirmed or suspected infection 4.6%, occlusion at least once 7.7%. CONCLUSIONS: Differences between hospitals with regard to major complications, infection and occlusion may be related to different care protocol. We need to stress the high incidence of phlebitis and thrombosis in PICC catheters, compared with data of lower incidence of other papers

[Complications associated to central venous catheters in hematology patients]. / Complicaciones asociadas al catéter venoso central en pacientes hematológicos.

OBJECTIVE: To discover the incidence of central venous catheters (tunnelled, subcutaneous and PICC) in patients with onco-hematological conditions, hospitalized in the Hematology or Transplantations of Hematopoietic Stem Cells Units, in two tertiary care hospitals. METHODOLOGY: A cross-sectional, descriptive study form was developed in order to gather sociodemographic, clinical data as well as complications and follow-up of the care protocol. Each catheter was assigned a correlative identification number. Information was collected on 366 catheters: 185 in the University Hospital Ramón y Cajal (HURYC), 80 tunnelled, 40 subcutaneous venous access and 65 PICC, and 181 in the University Hospital Gregorio Marañón (HUGM), 101 tunnelled and 80 subcutaneous venous access. FINDINGS: Major complications in the tunnellized were infections (13.7% in HURYC vs. 6.8% in HUGM - p<0.001) and occlusions (at least once in 3.8% vs. 21.8%). In subcutaneous venous access, infections were confirmed in 5% in HURYC vs. 1.2% in HUGM. There were occlusions at least once in 10% in HUGM and no other significant complications were detected. Regarding PICC, information was only collected in HURYC, where complications were phlebitis 10.8%, thrombosis 7.7%, confirmed or suspected infection 4.6%, occlusion at least once 7.7%. CONCLUSIONS: Differences between hospitals with regard to major complications, infection and occlusion may be related to different care protocol. We need to stress the high incidence of phlebitis and thrombosis in PICC catheters, compared with data of lower incidence of other papers.

Efficiency of an intensive educational program for informal caregivers of hospitalized, dependent patients: cluster randomized trial.

BACKGROUND: Educational initiatives for informal caregivers have proved efficient at reducing some of their symptoms, consequence of their involvement in care giving. However, more progress must be made in terms of the design of more successful interventions. AIMS: Randomized clinical trial to test the efficiency of an Education Program for Primary Informal Caregivers of Hospitalized Dependent Patients in relation to their burden, mental and physical health, and care related knowledge. DESIGN: Cluster Randomized Trial. SAMPLE: 151 participants, primary caregivers of hospitalized, dependent patients, carried out from February 2009 to March 2010. They were assigned at random to two groups: one received an intensive educational program (n = 78), and the other just a generic speech (n = 73). The degree of burden of caregivers was recorded (Zarit Test), as well as their physical and mental health (SF12) and their knowledge of caregiving, before, immediately, after and one and a half months after the intervention. These analyses were carried out according to the Generalized Estimated Equations Method, in order to assess any possible improvements. RESULTS: Participants´ burden did not improve, as measured by Zarit Test (p = 0,338), nor did their physical (p = 0,917) or mental health (p = 0,345). However there was an improvement in their hygiene caregiving (p = 0,001) and mobility care giving (p = 0,001). CONCLUSIONS: Caregivers found useful the education program, providing them with an informal support group. Interventions need to be longer and more customized as well as adapted to specific demands. There is a lack of validated questionnaires to assess improvements in care knowledge. There is a need to develop programs that contemplate continuity of care from primary to specialized caregiving. TRIAL REGISTRATION: Cluster randomized trial: ESCPD2010.

Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

An overview of bilastine metabolism during preclinical investigations.

Knowledge of the biotransformation of oral H1 antihistamines is clinically important because it can define their pharmacokinetic profile through possible effects on absorption (i.e., first-pass metabolism) and elimination. Further, clinically significant interactions with inhibitors of cytochrome P450 (CYP) have previously been reported for drugs of this therapeutic group, such as terfenadine and astemizole, indicating the possibility of drug-drug interactions involving agents that share the same metabolic pathway. The aim of this article was to review the preclinical testing of a new antihistamine (i.e., bilastine) in terms of its biotransformation in various animal species, including humans, and to evaluate its potential for possible drug-drug interactions involving the CYP system. A wide array of preclinical experiments were reviewed, all of which demonstrated that bilastine undergoes minimal metabolism in all species tested to date, including humans. Further, bilastine did not interact significantly, either as an inhibitor or inducer, with the CYP enzyme system, suggesting a low propensity for involvement in drug-drug interactions. These characteristics demonstrate the potential for bilastine to be a good choice for allergic patients receiving treatment for other concomitant diseases, including those with renal or hepatic dysfunction.

Interactions of bilastine, a new oral H1 antihistamine, with human transporter systems.

Membrane transporters play a significant role in facilitating transmembrane drug movement. For new pharmacological agents, it is important to evaluate potential interactions (e.g., substrate specificity and/or inhibition) with human transporters that may affect their pharmacokinetics, efficacy, or toxicity. Bilastine is a new nonsedating H1 antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The in vitro inhibitory effects of bilastine were assessed on 12 human transporters: four efflux [multidrug resistance protein 1 (MDR1) or P-glycoprotein, breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), and bile salt export pump) and eight uptake transporters (sodium taurocholate cotransporting polypeptide, organic cation transporter (OCT)1, organic anion transporter (OAT)1, OAT3, OCT2, OATP2B1, OATP1B1, and OATP1B3). Only mild inhibition was found for MDR1-, OCT1-, and OATP2B1-mediated transport of probe substrates at the highest bilastine concentration assayed (300 µM; half-maximal inhibitory concentration: ≥300 µM). Bilastine transport by MDR1, BCRP, OAT1, OAT3, and OCT2 was also investigated in vitro. Only MDR1 active transport of bilastine was relevant, whereas it did not appear to be a substrate of OCT2, OAT1, or OAT3, nor was it transported substantially by BCRP. Drug-drug interactions resulting from bilastine inhibition of drug transporters that would be generally regarded as clinically relevant are unlikely. Additionally, bilastine did not appear to be a substrate of human BCRP, OAT1, OAT3, or OCT2 and thus is not a potential victim of inhibitors of these transporters. On the other hand, based on in vitro evaluation, clinically relevant interactions with MDR1 inhibitors are anticipated.

Humanización del cuidado / Humanising health care

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