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The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug.

Abstract Background The aim of this study was to assess the contribution of the reflective multidisciplinary discussion in determining the value contribution of innovative drugs through the multi-criteria decision analysis (MCDA). This methodology considers all relevant criteria for healthcare decision-making in a global, transparent, and systematic manner and from the perspective of relevant stakeholders. The determination of value contribution of tabelecleucel for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD) compared to salvage therapy was used as an example. Results Tabelecleucel obtained a value contribution score of 0.63 and increased to 0.75 after the reflective discussion. EBV+ PTLD was considered a life-threatening disease (5.0 ± 0.0), with a significant unmet need for an approved treatment (5.0 ± 0.0). Tabelecleucel was perceived as bringing improvements in terms of efficacy (4.2 ± 0.8) and safety (3.8 ± 0.8) compared to the salvage therapy. Most experts considered that the high efficacy and safety results could represent an improvement in the quality of life of patients (2.3 ± 1.2) along with savings in medical costs (2.3 ± 2.0) and non-medical costs (2.7 ± 1.6) compared to the salvage therapy. However, others emphasized the need of more evidence to confirm these improvements and savings over time. Tabelecleucel was regarded as potentially modifying the clinical course of the disease (4.3 ± 0.8) and supported by high-quality evidence (3.2 ± 0.4). All contextual criteria were valued highly positively for tabelecleucel. "Safety/Tolerability" and "Other medical costs" were the criteria that experienced the highest change in the re-test conducted after the reflective discussion. The reflective discussion allowed resolving doubts or misinterpretations of the experts, so the re-test obtained more accurate and consistent results of the value contribution of tabelecleucel. Conclusions The study shows that the MCDA methodology is a useful tool for decision-making on innovative treatments for the management of rare diseases. It also highlights the importance of reflective multidisciplinary discussion for its ability to resolve doubts or misinterpretations of experts, subsequently allowing to obtain more consistent and reliable results on the value contribution of the drug, being potentially more positive.

Background: Ustekinumab (UST) is an effective treatment option in Crohn’s disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. Objectives: The aim of our study was to analyze the relationship between UST through levels (UST TL ) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. Design: We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. Methods: The following variables were analyzed at the initiation of UST and at each UST TL measurement: clinical response and remission using the Harvey–Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of UST TL ) and P2 (time between UST TL1 and the second determination of UST TL ). Results: We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median UST TL1 was 3.1 μg/mL (1.6–5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with UST TL1 significantly higher than those who did not achieve remission (3.7 μg/mL (2.3–5.4) vs 2.3 μg/mL (1.1–5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); UST TL (7.2 μg/mL (4.7–11.7) vs 3.4 μg/mL (1.9–6.4); p

Abstract Background Prurigo nodularis (PN) is a chronic, debilitating dermatologic disease characterised by the presence of highly pruritic nodular lesions. PN highly impacts on patients' quality of life as there are no specific treatments available in Spain. Objectives Determine the main value drivers in the treatment of PN in Spain and its main unmet needs using Multi‐Criteria Decision Analysis (MCDA). Methods Literature review to synthesise relevant evidence in an evidence matrix based on the MCDA EVIDEM framework adapted to Spain. A multidisciplinary panel composed of dermatologists, hospital pharmacists and a patient weighted (5‐point scale; 0 minimum importance, 5 maximum importance) and scored each criterion included in the framework (from −5 to 5 or 0 to 5 depending on the criterion). Results were discussed in a reflective group session. Results PN was considered a severe (3.3 ± 0.7) and infrequent (2.0 ± 0.7) disease, with high unmet needs (4.2 ± 0.7) mainly due to the lack of available treatments with specific indication for PN. Current off‐label treatments were perceived to have limited efficacy/effectiveness (1.8 ± 1.1), an unfavourable long‐term safety profile (2.1 ± 0.9) and low therapeutic impact (1.7 ± 1.1). The measure of patient‐reported outcomes (2.7 ± 0.9) was perceived as important, but available tools are not specific. Although the cost of available treatments was not considered high (2.4 ± 1.5), experts agreed that PN is associated with moderately high other medical costs (3.6 ± 1.1) and indirect costs (3.1 ± 0.9). Experts considered that current guidelines and consensus (2.6 ± 0.7) are not clear on severity criteria and treatment algorithm. The quality of evidence (1.4 ± 0.5) of currently used off‐label treatments was perceived as low due to a lack of published clinical trials. Conclusions PN was considered a severe disease associated with relevant unmet needs, including the lack of specific and effective treatments for PN, the lack of consensus on the disease definition, defined severity criteria, prevalence estimations and awareness of PN in Spain.

BackgroundAlemtuzumab (ALZ) is a humanized monoclonal antibody approved for the treatment of patients with highly active relapsing-remitting multiple sclerosis (RRMS) administered in two annual courses. The objective of this study was to describe the effectiveness and safety data of ALZ and to report the health resource utilization in patients receiving this treatment.MethodsIn this retrospective, non-interventional study, information was retrieved from patients' medical charts at one center in Spain. Included patients were ≥18 years old, and ALZ treatment was initiated between 1 March 2015 and 31 March 2019, according to routine clinical practice and local labeling.ResultsOf 123 patients, 78% were women. The mean (standard deviation, SD) age of patients at diagnosis was 40.3 (9.1) years, and the mean time since diagnosis was 13.8 (7.3) years. Patients were previously treated with a median (interquartile range; IQR) number of two (2.0–3.0) disease-modifying treatments (DMTs). Patients were treated with ALZ for a mean (SD) of 29.7 (13.8) months. ALZ reduced the annualized relapse rate (ARR) (1.5 before vs. 0.05 after; p < 0.001) and improved the median EDSS (4.63 before vs. 4.00 after; p < 0.001). Most (90.2%) patients were relapse-free while receiving ALZ. The mean number of gadolinium-enhancing [Gd+] T1 lesions was reduced (1.7 before vs. 0.1 after; p < 0.001), and the mean number of T2 hyperintense lesions was maintained (35.7 before vs. 35.4 after; p = 0.392). A total of 27 (21.9%) patients reported 29 autoimmune diseases: hyperthyroidism (12), hypothyroidism (11), idiopathic thrombocytopenic purpura (ITP) (3), alopecia areata (1), chronic urticaria (1), and vitiligo (1). The mean number of health resources (outpatient visits, emergency room visits, hospital admissions, and tests performed in the hospital) used while patients were treated with ALZ progressively decreased from year 1 to year 4, except for a slight increase at year 2 of outpatient visits.ConclusionThe ReaLMS study provides real-world evidence that ALZ can promote clinical and magnetic resonance imaging disease remission, as well as disability improvement in patients with MS, despite several prior DMT failures. The ALZ safety profile was consistent with data available from clinical trials and other real-world studies. Healthcare resource use was reduced throughout the treatment period.

Objective: The main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive effect. One of the main secondary goals is to analyze allele frequencies and the association of polymorphisms rs895819 (miR27A) and rs1801160 (DPYD*6) with toxicity by conducting an observational study to determine their clinical relevance and standardize a dose adjustment recommendation.Method: The study has an single-center ambispective, quasi-experimental design and is based on a multidisciplinary protocol involving implementation and standardization of DPYD*2A; DPYD*13; c.2846A>T; and HapB3 measurements. Following these measurements, pharmacogenetic counseling will be carried out and its clinical impact will be evaluated. The primary endpoint of the study is severe toxicity and/or mortality. The toxicity observed in two groups with similar epidemiological characteristics will be compared: the intervention group (candidates for treatment with fluoropyrimidines who will be subjected to the protocol) and the control group (retrospective cohort). Additionally, rs895819 (MIR27A) and rs1801160 (DPYD*6) will be determined. Testing for these variants is not part of the hospital’s daily practice, nor are they included in clinical guidelines. However, according to recently published studies, the activity of dihydropyrimidine dehydrogenase might be affected by these variants, as they may be associated with toxicity. The results of the measurements of these two variants will not be incorporated to pharmacogenetics counseling until their association with toxicity is determined by means of the observational study to be conducted. The project, as well as the patient information sheet and the informed consent form, were approved by the Ethics Committee of the participating center (code 20/006).

Abstract Background Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a

Objective: To establish a series of recommendations based on available evidence for monitoring surface contamination in the areas devoted to compounding hazardous drugs in pharmacy departments.Method: Based on a literature search in the Medline and Embase databases (search period: January 2009 to July 2019), as well as on a review of standards and recommendations issued by different healthcare organizations, a committee of experts from the Spanish Society of Hospital Pharmacists defined a series of safe practices for handling hazardous drugs and monitoring compounding work surfaces. Recommendation decisions were adopted by consensus among the members of the expert group, considering the recommendations reviewed, the monitoring situation in Spanish hospital departments, and the associated costs.Results: Ten recommendations were formulated, structured into eight sections. They include aspects related to the drugs to be monitored; the areas to be monitored; when samples should be taken; risk determination and preparation of a sampling protocol; analytical techniques; contamination thresholds; and design of an action plan based on the sampling and decontamination results obtained.Conclusions: Surface monitoring allows hazardous drugs detection and evaluation of the effectiveness of current protocols for the safe handling of such drugs in hospital pharmacy departments. The evaluation should include an analysis of the efficacy of engineering controls, work practices and cleaning and decontamination processes.

Objective: To publicize the results regarding the general characteristics, human resources, materials and information systems of Spanish hospital pharmacy departments arising from SEFH’s 2019 Survey on the Situation of Spanish Hospital Pharmacy Departments. Method: An online questionnaire was sent to the heads of the 368 hospital pharmacy departments affiliated to SEFH. The questionnaire included 77 questions grouped into 8 dimensions. The information was collected between March and September 2019. Results: The overall response rate was 54.3%. Sixty-nine percent of hospitals were public and the most commonly reported hospital size was 101-250 beds. Nine percent of responding hospitals remained open round the clock and 57.5% did not offer a continued care service. A total of 41.9% of hospitals dispensed medications to outpatients in the afternoon and 52.7% of hospital pharmacy departments were accredited to some quality standard. The mean number of specialist pharmacists per pharmacy Department was 5.34 (SD: 6.22); 47% of pharmacists spent at least half their working day in a clinical unit. Hospital pharmacy departments had a mean of 0.3 (SD: 0.7) or 0:9 (SD: 1.4) automated storage and dispensing carousels, depending on whether they were horizontal or vertical, respectively. A total of 16.1% of beds were assisted by automated dispensing systems, a figure that reached 33.5% in hospitals with more than 1,000 beds. Three percent of hospital pharmacy departments had a robotized system for compounding chemotherapy medications and 24.8% had a raceability and safety system. Smart infusion pumps were used by 21.4% of hospitals. Electronic prescriptions were implemented in 98.8% of hospitals for inpatients and in 62% for outpatients. Conclusions: Spanish hospital pharmacy departments face a shortage of specialist pharmacists, although incorporation of such professionals to clinical units has doubled in the last few years. There has been an increase in the level of automation of the logistic processes involved in medication dispensing, but there is still significant room for improvement in the area of robotized dispensing and compounding traceability systems. This data could play an invaluable role in the design of future action plans.

Background: Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase-producing Gram-negative bacteria infections. Our objectives were to analyze the results of carbapenem de-escalation therapy in complicated urinary tract infections (UTIs) attended in a third-level Spanish hospital and to evaluate the impact of pharmacist recommendation in this practice, the outcomes obtained, and associated factors. Methods: This prospective observational study of carbapenem prescriptions and de-escalation performance was conducted in a third-level hospital between August 1 2013 and July 31, 2014. Data were gathered on carbapenem treatment duration, de-escalation, length of hospital stay, mortality rate, and associated re-admissions. Results: De-escalation, which was only ordered for patients with positive cultures, was conducted in 49.7% of the 163 patients with complicated UTI. More than half (69.1%) of pharmacist interventions were accepted. De-escalation reduced the median hospital stay by five days (p = 0.030). Crude hospital mortality was lower in the de-escalation group (7.4% vs. 29.3%, p

Abstract The main objective was to determine the prevalence of real drug–drug interactions (DDIs) of immunosuppressants in transplant patients. We conducted a prospective, observational 1‐year study at a tertiary hospital, including all transplanted patients. We evaluated data from monitoring blood concentrations of immunosuppressive drugs and adverse drug events (ADEs) caused by DDIs. The DDIs were classified as C, D, or X according to their Lexi‐Interact rating (C = monitor therapy, D = consider therapy modification, X = avoid combination). The clinical importance of real DDIs was expressed in terms of patient outcomes. The causality of DDIs was determined using Drug Interaction Probability Scale. The data were analyzed using Statistical Package for Social Sciences v. 25.0. A total of 309 transplant patients were included. Their mean age was 52.0 ± 14.7 years (18–79) and 69.9% were male. The prevalence of real DDIs was 21.7%. Immunosuppressive drugs administered with antifungal azoles and tacrolimus (TAC) with nifedipine have a great clinical impact. Real DDIs caused ADEs in 22 patients. The most common clinical outcome was nephrotoxicity (1.6%; n = 5), followed by hypertension (1.3%; n = 4). Suggestions for avoiding category D and X DDIs included: changing the immunosuppressant dosage, using paracetamol instead of non‐steroidal anti‐inflammatory drugs, and interrupting atorvastatin. The number of drugs prescribed and having been prescribed TAC was associated with an increased risk of real DDIs. There are many potential DDIs described in the literature but only a small percentage proved to be real DDIs, based on the patients´ outcomes.

Objective: The aim of this study was to evaluate the safety and efficacy of de-escalation in patients under treatment with carbapenems and its impact on clinical outcomes. Methods: A prospective observational study was conducted for 1 year. Patients administered active carbapenems for at least 24 h were included. Primary outcomes were in-hospital mortality, mortality at 30 days after carbapenem prescription, and infection-related readmission within 30 days. De-escalation was defined as the substitution of carbapenem with narrower spectrum antimicrobial agents or its discontinuation during the first 96 h of treatment. Results: The study included 1161 patients, and de-escalation was performed in 667 (57.5%) of these. In the de-escalation group, 54.9% of cultures were positive. After propensity score matching, 30-day mortality was lower (17.4% vs. 25.7%, p = 0.036), carbapenem treatment was 4 days shorter (4 vs. 8 days, p

Background The objective of this review was to investigate trends in clinical trial design, specifically, the primary outcomes used, interpretation of results, and the magnitude of the benefits described in phase III controlled clinical trials in the first‐line treatment of patients with advanced non‐small cell lung cancer (NSCLC). Methods Seventy‐six trials published between 2000 and 2012 were selected from a total of 122 identified in a structured search. Results Overall survival (OS) was evaluated as the primary study endpoint in 50 (65.8%) trials, followed by progression‐free survival (PFS) in 15 (19.7%), and other variables, such as toxicity, quality of life (QoL), and response rate in 11 (14.5%). Ten (66.7%) out of 15 clinical trials using PFS as the primary endpoint were published between 2010 and 2012. Median overall survival (mOS) was 9.90 months (interquartile range: 3.5) with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in mOS was obtained in only 13 (18.8%) trials. A total of 41 (53.9%) studies concluded that the result was positive. Of these, only 16 (39.1%) showed a statistically significant benefit in OS. QoL was assessed in 46 trials (60.5%) and of these, 10 (21.7%) reported significant improvements. Conclusions These findings raise important questions about how clinical benefits are measured in clinical trials in advanced NSCLC. Appropriate clinically relevant outcome variables should be established and validated, and post‐marketing studies should be requested by regulatory authorities to ensure meaningful clinical benefits in OS and QoL.

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP), and Hospital Pharmacy (SEFH) we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer.

Objectives: to develop an integrated computer software application for specialized nutritional support, integrated in the electronic clinical record, which detects automatically and early those undernourished patients or at risk of developing undernourishment, determining points of opportunity for improvement and evaluation of the results. Methods: the quality standards published by the Nutrition Work Group of the Spanish Society of Hospital Pharmacy (SEFH) and the recommendations by the Pharmacy Group of the Spanish Society of Parenteral and Enteral Nutrition (SENPE) have been taken into account. According to these quality standards, the nutritional support has to include the following healthcare stages or sub-processes: nutritional screening, nutritional assessment, plan for nutritional care, prescription, preparation and administration. Results: this software allows to conduct, in an automated way, a specific nutritional assessment for those patients with nutritional risk, implementing, if necessary, a nutritional treatment plan, conducting follow-up and traceability of outcomes derived from the implementation of improvement actions, and quantifying to what extent our practice is close to the established standard. Conclusions: this software allows to standardize the specialized nutritional support from a multidisciplinary point of view, introducing the concept of quality control per processes, and including patient as the main customer

Objetivos: Evaluar el impacto cardiovascular asociado al consumo de antiinflamatorios no esteroideos en un Área de Salud, estimando la asociación entre la prescripción previa de un antiinflamatorio no esteroideo al episodio de síndrome coronario agudo. Material y Métodos: Se realiza un estudio retrospectivo observacional de casos cruzados de 5 años de duración, del 1 de Enero de 2008 hasta el 31 de diciembre de 2012. Los pacientes en primer lugar fueron casos y controles (n=1.317) que tuvieron eventos cardiovasculares y fueron al servicio de Urgencias del Hospital por dicho motivo. Área de Salud de Alcázar de San Juan. Medida principal: Asociación del riesgo de sufrir un síndrome coronario agudo mediante el Odds Ratio con el consumo de antiinflamatorios no esteroideos. Resultados: La asociación entre el síndrome coronario agudo y el consumo de Antiinflamatorios fue positiva y significativa, (OR 1,42; IC95% 1,06-1,9). Esta asociación fue de mayor magnitud en pacientes con menor comorbilidad, Charlson ≤ 1 (OR 1,66; IC95% 1,15 - 2,40) frente a los de mayor comorbilidad, Charlson > 1 (OR 1,07; IC95% 0,65 - 1,76). Esta modificación de efecto se debió en parte al consumo concomitante de fármacos que previenen contra patologías cardiovasculares como los antiagregantes, anticoagulantes y estatinas. Conclusiones: El consumo de antiinflamatorios no esteroideos se ha asociado a un mayor riesgo de síndrome coronario agudo, por lo que es necesario realizar un seguimiento a los pacientes que consuman estos fármacos, no debiéndose tomar durante tiempos prolongados ni a dosis altas.