Search

Metabolic reprogramming is a hallmark of cancer. We and other authors have previously shown that breast cancer subtypes present metabolism differences. In this study, breast cancer cell lines were treated with metformin and rapamycin. The response was heterogeneous across various breast cancer cells, leading to cell cycle disruption in specific conditions. The molecular effects of these treatments were characterized using sublethal doses, SNP genotyping and mass spectrometry-based proteomics. Protein expression was analyzed using probabilistic graphical models, showing that treatments elicit various responses in some biological processes, providing insights into cell responses to metabolism drugs. Moreover, a flux balance analysis approach using protein expression values was applied, showing that predicted growth rates were comparable with cell viability measurements and suggesting an increase in reactive oxygen species response enzymes due to metformin treatment. In addition, a method to assess flux differences in whole pathways was proposed. Our results show that these various approaches provide complementary information, which can be used to suggest hypotheses about the drugs’ mechanisms of action and the response to drugs that target metabolism.

In 2014, we established a pharmacogenetics unit with the intention of facilitating the integration of pharmacogenetic testing into clinical practice. This unit was centered around two main ideas: i) individualization of clinical recommendations, and ii) preemptive genotyping in risk populations. Our unit is based on the design and validation of a single nucleotide polymorphism (SNP) microarray, which has allowed testing of 180 SNPs associated with drug response (PharmArray), and clinical consultation regarding the results. Herein, we report our experience in integrating pharmacogenetic testing into our hospital and we present the results of the 2,539 pharmacogenetic consultation requests received over the past 3 years in our unit. The results demonstrate the feasibility of implementing pharmacogenetic testing in clinical practice within a national health system.

 Objective: To evaluate efficacy, safety, patient and investigators satisfaction, and cost of pain relief by time unit between methoxyflurane (a volatile anesthetic agent with known analgesic properties, non-opioid, self-administered using a hand-held inhalation device under trained supervision) and emergency analgesic standard of care treatment (SoC), over a period of 30 min from start of administration and time to first pain relief. Methods: InMEDIATE is a phase IIIb, randomized, open label, multicenter, parallel group trial. It will be conducted in 15 emergency hospital departments. A total of 310 patients, with moderate to severe pain secondary to trauma, will be randomized to receive either methoxyflurane or SoC. The primary end point of the study is the change in mean pain intensity as measured by a numeric rating scale from randomization to 3, 5, 10, 15 and 20 minutes after treatment administration (using mixed-effect model repeated measure) and time to first pain relief (survival analysis).Discussion: To the best of our knowledge, this is the first randomized trial of methoxyflurane vs active analgesic treatment to be carried out in Europe. The aim of the study is to evaluate the results in terms of efficacy and safety of methoxyflurane for the treatment of traumatic pain in Spanish emergency units (ambulances, emergency primary care, and emergency departments settings), in order to assess the incorporation of this drug into the emergency traumatic pain SoC.Trial Registration: EudraCT, 2017‐000338‐70Keywords: Methoxyflurane, Inhaled anesthetic, Sedation, Traumatic pain, Emergency units.

Acute and chronic paracetamol overdose in paediatric population: Protocol of a prospective study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity.

Aim: To evaluate the influence of two variants of P450 oxidoreductase (POR), rs2868177 and POR*28, on the stable dosage of acenocoumarol. Patients & methods: For this observational, cross-sectional study, patients were undergone stable anticoagulant treatment with acenocoumarol. Univariate and multiple regression analyses were performed to assess the influence of POR polymorphisms. Results: About 340 patients were enrolled. Multiple regression had a coefficient of determination (R2) of 51.5% and an Akaike information criterion of 234.22. The inclusion of POR*28 polymorphisms increased the R2 to 52.0% and reduced the Akaike information criteria to 230.58. The POR*28 heterozygote showed statistical significance in the algorithm. Conclusion: The POR*28 heterozygote appears to be associated with the stable dose of acenocoumarol, but its clinical contribution to the prediction of the dosing of this drug is minimal.

Sindrome nefrotico secundario a glomerulonefritis membranosa asociada al tratamiento con litio.

BACKGROUND: Therapeutic response to pharmacological therapy in humans shows large intrapatient and interpatient variability both in treatment efficacy and adverse drug reactions (ADR). Part of this variability can be explained by genetic polymorphisms in genes encoding TAC metabolism related proteins. The aim of this study is to evaluate the contribution of genetic variation in the CYP3A4, CYP3A5, CYP3A7, POR, NR1I2 and ABCB1 genes to this variability in order to achieve a better understanding of TAC pharmacokinetics and a more personalized approach for TAC dosing in a cohort of pediatric patients with stable serum concentrations after renal transplantation. METHODS AND DESIGN: This is a unicenter retrospective cross-sectional study. The protocol was approved by the Clinical Research Ethics Committee of the La Paz University Hospital (Madrid, Spain) and will be carried in this same hospital. 50 pediatric patients with stable serum concentrations after renal transplantation are expected to be included. Peripheral blood samples will be collected for molecular analysis (pharmacogenetics studies) and AUC estimation (C0, C1 and C3 hours after TAC administration). DISCUSSION: To date there are not dosing algorithms that can explain accurately TAC metabolism. The incorporation of a complete pharmacogenetic (PhGx) profile into these algorithms may help in the individualization and optimization of TAC treatment in pediatric renal transplant patients. STUDY REGISTRATION: FC/HULP_002/2014

Retrospective studies have identified elevated vancomycin trough levels20 mg/L as a predictor of nephrotoxicity with a high variable incidence of 12.6%-65%. However, the elevated levels may represent the effect of renal compromise rather than the cause of nephrotoxicity. The aim of this study was to report the incidence of acute kidney injury (AKI) and associated risk factors in adult patients with vancomycin trough levels20 mg/L in a prospective Pharmacovigilance Program from Laboratory Signals at a Hospital.This was a prospective follow-up of all cases with serum vancomycin trough levels20 mg/L between June 2010 and May 2011. AKI was defined using the Risk, Injury, Failure, Loss, End-stage criteria. Patients with vancomycin-induced AKI (VIAKI) were compared with vancomycin-tolerant patients.During 12 months of study, 271 samples corresponding to 179 cases were monitored. Vancomycin did not alter the renal function in 68.2% [95% confidence interval (CI): 60.8-74.9] of cases, and 13.4% (95% CI: 8.8-19.3) of AKI cases were induced by other causes. Nephrotoxicity without AKI criteria was found in 10.1% (95% CI: 6.1-15.4) of cases, and VIAKI occurred in 8.4% (95% CI: 4.8-13.4) of cases. The VIAKI group had a significantly lower basal glomerular filtration rate at baseline and higher vancomycin trough levels at the time of the signal. The majority of the group was in the intensive care unit and received nephrotoxic agents during vancomycin therapy. The most frequent stage of VIAKI was injury (53.3%). VIAKI occurred after 7 days (range: 3-14) of treatment, and in 53.3% of cases, the daily dose was30 mg/kg. Renal function was recovered at discharge in 73.3% of cases and 66.7% of cases had other suspected drugs.The Pharmacovigilance Program from Laboratory Signals at a Hospital provides early identification and early evaluation of cases. Renal function and vancomycin trough levels should be closely monitored from the second week of treatment in adults, intensive care patients, and those who receive concurrent nephrotoxic agents.

A fast-track anaemia clinic (FTAC) for the management of moderate-to-severe iron-deficiency anaemia (IDA) was established in our Emergency Department in 2010. In this FTAC, the replacement of packed red cell transfusion by ferric carboxymaltose administration was proven to be safe and effective. The aim of this study was a cost-analysis of IDA management in the FTAC, comparing this management with the previous standard care pathway consisting of packed red cell transfusion, if needed, and referral to outpatient specialised care.A cost study was performed for patients with IDA who were at risk of requiring transfusion (haemoglobin9 g/dL) but did not require hospitalisation. Total IDA treatment costs in the FTAC were compared to those theoretically incurred if these patients had been managed using the standard care pathway. In addition, a sensitivity analysis considering variations of up to ±30% in ferric carboxymaltose and packed red cell acquisition costs was performed (49 possible scenarios).Between 2012 and 2015, 238 IDA patients were treated in the FTAC. The average treatment cost was € 594±337/patient in the FTAC group and € 672±301/patient in the standard care pathway group, with a saving of € 78±28/patient (95% CI, 22-133; p0.001). The sensitivity analysis showed that IDA treatment costs in the FTAC (€ 480-722/patient), compared with those of the standard care pathway (€ 550-794/patient), resulted in significant cost-savings for all studied scenarios (€ 51-104/patient; p0.005).The administration of ferric carboxymaltose for IDA management in a FTAC may be cost-saving compared with the standard care pathway.

Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC0-24h, Cmax and Cmin after Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC0-24h and Cmin total variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure.

Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, p

Implementacion de la farmacogenetica en la practica clinica: hacia las estrategias de genotipado anticipado

Discriminative value of cardiopulmonary progressive exercise test in mitochondrial myopathy and chronic fatigue syndrome

Ciencia Iberoamericana para el mundo. La comunidad iberoamericana, aunque con problemas de definición, de identidad y de estructura política, es sin ninguna duda una entidad cultural estable en la conciencia de las naciones y de los pueblos. A nivel político la Declaración final de la I Cumbre de Jefes de Estado y de Gobierno Iberoamericanos, celebrada en 1991, consagra el reconocimiento de una comunidad iberoamericana que se plasma en la cooperación en áreas temáticas concretas a nivel institucional, cultural, económico y social. Dentro de los programas económicos, se incluyen como objetivos potenciar la investigación y la innovación con el fin de conseguir un desarrollo sostenible de la Región Iberoamericana. Además son indudables los lazos existentes en los ámbitos científicos y universitarios entre los diferentes países ibero-americanos; así, numerosas Universidades y organismos de investigación tienen convenios con otros países iberoamericanos. Solo la Universidad Autónoma de Madrid tiene casi 200 acuerdos y convenios de colaboración con países iberoamericanos (más de 120 con universidades de Centro y Sudamérica y casi 80 con universidades portuguesas).

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Toxicovigilance is the active process of identifying and evaluating the toxic risks existing in a community, and evaluating the measures taken to reduce or eliminate them. Objective: Through a validated toxicovigilance program (SAT-HULP) we examined the characteristics of acute poisoning cases (APC) attended in the Emergency Department (ED) of La Paz Hospital (Madrid, Spain) and assessed their economic impact on the health system. Material and Methods: The active poisoning surveillance system performs a daily search for cases in the hospital's computerized case records. Found cases are entered into a database for recording of type of poisoning episode, reasons for exposure, causative agent, signs and symptoms and treatment. We carried out a cross-sectional epidemiological study with analytical projection, based on an impact study on cost per survivor. The data for the costs attributable to cases of APC observed at HULP (outpatients and inpatients) was obtained from the based on the information provided by the diagnosis-related groups (DRG) through the corresponding hospital discharge reports (available through SAT-HULP). Results: During the first 30 month of SAT-HULP operation we found a total of 3,195 APC, a cumulative incidence rate of 1.75% of patients attended in the ED. The mean (SD) patient age was 40.9 (17.8) years and 51.2% were men. Drug abuse accounted for 47.5% of the cases. Suicide attempt was the second most frequent category (38.1%) and other causes accounted for 14.5% of APC. The total cost of hospital care for our hospital rose to € 1,825,263.24 (approximately € 730,105.30/year) resulting in a permanent occupation of 4 beds/year. Conclusions: SAT-HULP constitutes a validated toxicovigilance tool, which continuously integrates available data in real-time and helps health services manage APC data flexibly, including the consumption of resources from the health system.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9∗2 (rs1799853), CYP2C9∗3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases., This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013)

Detection and reporting of drug-induced life-threatening potassium disturbances and the study of associated factors under a Pharmacovigilance Program using Laboratory Signals at a Hospital (PPLSH) during a 2-year period.All serum potassium levels2 mmol/l or7 mmol/l detected at admission to the hospital, including those of patients who died in the emergency ward or during hospitalization, were monitored prospectively from January 2009 through to December 2010. The incidence rate of each etiology of potassium disturbances was calculated. Factors associated with drug-induced potassium disturbances were detected using a multiple logistic regression model.The incidence of true life-threatening drug-induced hyper- and hypokalemia events was 3 and 4.32 (Poisson 95 % confidence interval 1.62-10.24), respectively, per 10,000 admissions. Of the severe potassium disturbances, 32.3 % were drug-induced, and 23 % were lethal. We identified previously undescribed pharmacological causes of hyperkalemia (risedronate, doxazosin) and hypokalemia (acyclovir, teicoplanin, cefepime, meropenem, dexketoprofen colistimethate). Significant predictor factors associated with drug-induced hyperkalemia were the use of polypharmacy (5 drugs), age (74 years), sex (female) and kidney disease (glomerular filtration rate60 ml/min) with the presence of ≥4 comorbid conditions. The only predictor of drug-induced hypokalemia was the use of5 drugs. The triggering factor associated with drug-induced hyperkalemia and hypokalemia was azotemia and hypoalbuminemia, respectively.Drug-induced life-threatening potassium disturbances remain a relevant problem. Potential strategies for prevention are to avoid polypharmacy, early discontinuation of treatment of drugs causing hyperkalemia or nephrotoxicity in cases of various clinical situations (cardiac descompensation, infection, hypovolemia) or obstructive causes, and insistence on albumin control during hospitalization.

Background: The first generic PPI was introduced in Spain in 2001, and since then their prescriptions have increased steadily by about 200%. Aim: To evaluate the frequency of use and the appropriateness of indications of PPIs in hospitalised patients, and possible factors predicting their use. We also evaluated relevant PPI-drug interactions and serious adverse drug reactions (SADRs). Methods: This was a cross-sectional, prescription-indication drug-utilisation study in hospitalised patients with follow-up until discharge. Sampling was random and stratified by services, and was calculated to obtain an error in the precision of prescription of ±4% with a 95% confidence interval with maximum variability (50%). Results: 328 patients were included; 28.65% were prescribed a PPI at admission, 82.62% were prescribed a PPI during hospitalisation, and 54.75% at discharge, with inappropriate indications in 74.47%, 61.25% and 80.24% respectively. The OR of being discharged with PPIs was 3.01(95% CI:2.17 – 4.18, p=0.000). The inappropriate indication most frequently seen at admission and at discharge was antiplatelet therapy. During hospitalisation it was prophylaxis for stress ulcer in patients at low risk. PPI prescription at admission remained at discharge in 75.90% of cases, 73.02% without an acceptable indication. Being > 64 years old, taking > 4 drugs, co-medication (NSAIDs, antiaggregation and anticoagulation), certain hospital departments and length of stay > 15 days predicted 83.7% of prescriptions at discharge. Four relevant PPIdrug interactions were found, and 2 resulted in SADRs, thus the incidence per 1, 000 patients was 2.66 (Poisson 95% CI:0.62-7.23). Conclusions: There was a very high frequency of overuse of PPIs in inpatients and outpatients. Hospitalisation did not represent an opportunity for better prescription of PPIs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In USA and Europe the classical way to guarantee equivalence between different formulations is the bioequivalence (BE) study based on in vivo bioavailability. • The Biopharmaceutic Classification System (BCS) classifies active substances into four different groups according to their aqueous solubility and intestinal permeability. • Recently the European Medicines Agency (EMA) has released a new bioequivalence guideline for immediate release solid oral dosage forms that includes recommendations on BCS-based biowaivers. WHAT THIS STUDY ADDS • As far as we know this is the first time that the probability of proving BE of more than one hundred BE studies with 80 active substances categorized according to BCS was evaluated. • Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies. AIM The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra- and inter-subject coefficients of variation data from BE studies with generic products. RESULTS Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non-bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra-subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non-BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra-subject variability for Cmax or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies.

718 Background: mCRC is the 2º cause of death in the world. Development of targeted therapies has increased the survival. The efficacy of these drugs (such Bevacizumab and monoclonal antibodies against EGFR) depends on the use of genetic biomarkers such as KRAS and NRAS. The BRAF status acts as prognostic factor. The objective of this study was to perform a mutational analysis of KRAS/NRAS/BRAF in a cohort of 326 Spanish patients, and correlate the findings with clinical factors. Methods: We analyzed KRAS by chip-array analysis (Infiniti System, USA), NRAS using pyrosequencing on a Pyromark Q96MD instrument (Qiagen, USA) and BRAF mutations (in 80 of these samples) by means of Infiniti System (AutoGenomics, USA). Results: KRAS mutations 129/326 patients had KRAS mutation (31.2% in codon 12 and 6.7% in codon 13). The median age was 68.9, 55% male, 66.4% had left-sided tumor, 83% histologically grade 2 tumor. The pattern of spread was liver (51.1%), lung (33.3%) and peritoneum (11.6%). There were 6 types of mutation in codon 12 (p.Gly12Asp, p.Gly12Cys, p.Gly12Val, p.Gly12Arg, p.Gly12Ser, p.Gly12Ala) and 1 type in codon 13 (p.Gly13Asp). We apply a logistic model (age&sex corrected) to location, and we found association between KRAS wild type and left location, OR 1.73 [CI:1.03-2.9] p = 0.035 NRAS mutations: 13 patients had NRAS mutation (3.98%), 8 male, 92% had left-sided, 46% liver metastasis and 53.9% lung metastasis. Type of NRAS mutation: 1.6% in exon 2 (1.2% in codon 12 and 0.4% in codon 13) and 1.8% in exon 3 (0.2% in codon 59 and 1.6% in codon 61). In exon 2 we found 2 types of changes, 1 in codon 12 (p.Gly12Asp) and 1 in codon 13 (p.Gly13Arg). In exon 3 we found 5 types of changes, 1 in codon 59 (p.Ala59Thr) and 4 in codon 61 (p.Gln61Glu; p.Gln61Leu; p.Gln61Arg; p.Gln61His). BRAF mutation: 9/80 patients harboured mutations, all of them at the residue V600E. Conclusions: In our cohort 39.5% had mutations in KRAS, 3.98% in NRAS and 11% in BRAF. KRAS mutation is associated to right-sided location.

DRESS-syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a severe drug-induced hypersensitivity syndrome characterized by diffuse maculopapular rash, lymphadenopathy, multivisceral involvement, eosinophilia and atypical lymphocytes with a mortality rate of 10-40% (Seminars in Cutaneous Medicine and Surgery, 1, 250). It is described in adults treated with aromatic antiepileptics and less frequently with sulphonamides, and non-steroidal anti-inflammatory drugs (Clinics in Dermatology, 23, 171; Pediatrics, 108, 485). We report on an 11-year-old Caucasian boy hospitalized with a skin eruption, lymphadenopathy, acute hepatitis, renal tubular involvement, haematological abnormalities and human-herpevirus-6 reactivation, treated with sulfasalazine and naproxen for juvenile idiopathic arthritis (JIA). This is the first report in children with rheumatic disease and highlights the possibility of sulfasalazine and naproxen-induced-DRESS-syndrome in children with JIA.

We investigate the impact of sex and genotype on citalopram disposition in 35 healthy volunteers who received an oral dose of 20mg citalopram within a single-dose bioequivalence study. CYP2C19*2 and *3, and CYP2D6*4 mutations were determined by Real-Time PCR. The influence of sex and genotype was analyzed by a linear mixed model for repeated measures, including formulation, period, sequence, sex, CYP2C19 and CYP2D6 as fixed effects and subject nested sequence*sex*CYP2C19*CYP2D6 as the random one. Pharmacokinetic parameters were log-transformed and AUC(infinity) and C(max) adjusted to the administered dose/weight. The model yields a statistical significance in AUC(infinity) and CL/F for CYP2C19 and CYP2D6. Gender, formulation, sequence or period effects were not statistically significant. AUC(infinity) of CYP2C19*1/*2 and CYP2C19*2/*2 carriers is 44% and 118% higher than wild type, respectively; CYP2D6 volunteers carrying 1/4 have an AUC 23% higher than wild type. Our data also suggest that the influence of CYP2D6 on AUC(infinity) is very low when it is in association with CYP2C19*1/*1 while its influence is more apparent in association with CYP2C19*1/*2. In conclusion, we demonstrate the influence of CYP2C19 and CYP2D6 in the disposition of citalopram, and we suggest that the influence of CYP2D6 is more probable in volunteers with at least one defective allele of CYP2C19.

The detection and reporting of serious adverse drug reactions (SADRs) have become important components of monitoring and evaluation activities performed in hospitals. We present the implementation of a prospective pharmacovigilance program based on automatic laboratory signals (ALSs) at a hospital. We also report the general findings after the first year of operation of the program, which involved ALSs that indicate various SADRs: agranulocytosis, aplastic anemia, liver injury, thrombocytopenia, hyponatremia, and rhabdomyolysis. The number of hospitalizations during the year was 54,525, and 1,732 patients experienced at least one ALS. The review of electronic medical records (EMRs) showed that no alternative cause (i.e., no non-SADR explanation) for the ALS was identified in 520 (30%) of the patients. After the individual ALS-patient evaluation, a total of 110 SADRs (6.35% of those identified after reviewing EMRs and 21.15% of those requiring individual patient evaluations) were identified. In other words, in order to identify a single SADR, we had to review the electronic records of approximately 16 patients and personally visit 5 patients.

Resumen Introduccion El objetivo de este estudio es conocer el riesgo de enfermedad tromboembolica venosa (ETV) en pacientes medicos durante su ingreso y al alta hospitalaria, y estudiar los habitos de prescripcion de tromboprofilaxis y su adecuacion a los protocolos utilizados en nuestro medio. Material y metodo Para ello se realizo un estudio transversal con seguimiento prospectivo hasta el alta hospitalaria. Se incluyeron pacientes medicos de los Servicios de Medicina Interna, Neumologia y Oncologia, en los que se determino el grado de riesgo de ETV y el tipo de indicacion de tromboprofilaxis durante el ingreso y al alta hospitalaria. Resultados Se incluyeron 116 pacientes (52 en medicina interna, 35 en neumologia y 29 en oncologia), con una media de edad de 67 ± 17 anos (35 mujeres; 81 hombres). En el ingreso el 62,9% tenian alto riesgo de ETV, el 3,4% moderado, el 23,3% bajo y el 10,3% no tenian riesgo. Al alta hospitalaria estos porcentajes fueron de 35,6; 3,8; 24 y 34,6%, respectivamente. La proporcion de pacientes con prescripcion adecuada a la indicacion fue del 49,1%, tanto durante el ingreso como al alta hospitalaria.

Transfusion of blood components continues to be an important therapeutic resource into the 21The study cohort is made up of consecutive consenting adult patients (≥18 years old) who received RBCT in ED over a 3-month period and for whom relevant clinical data were collected and analysed.Data from 908 RBCT episodes (2±1 units per transfused patient) were analysed. RBCT was considered appropriate in 21.4% (n=195), with significant differences according to RBCT indication (p0.001), hospital level (p0.001) and prescribing physician (p=0.002). Pre-transfusion haemoglobin level (Hb) negatively correlated with RBCT appropriateness (r=-0.616; p0.01). Only 72.4% of appropriate RBCT had a post-transfusion Hb assessment (n=516). Of these, 45% were considered to be over-transfused (n=232), with significant differences according to RBCT indication (p=0.012) and prescribing physician (p=0.047). Overall, 584/1,433 (41%) of evaluable RBC units were unnecessarily transfused.The appropriateness of RBCT in ED is similar to other hospital departments, but the rate of over-transfusion was high. These data support the need for a reassessment after transfusion of each RBC unit before further units are prescribed. In view of these results, we recommend that physicians should be made more aware of the need to prescribe RBCT appropriately in order to reduce over-transfusion.

We conducted a prospective evaluation of non-chemotherapy-induced agranulocytosis (NIA) in a tertiary hospital in Spain. Through our Prospective Pharmacovigilance Program from Laboratory Signals at Hospital, we detected agranulocytosis cases over a period of 42 consecutive months. This report estimates incidence, drug causality, clinical features and outcomes of NIA cases and assesses laboratory differences with respect to non-NIA. We detected 1349 cases of agranulocytosis in 538 adult patients; of these, 43 cases in 40 patients were caused by non-chemotherapy drugs. The incidence rate for 10,000 patients during the study period was 2.75 [Poisson confidence interval (CI)-95%: 0.62-7.22]. The mean (S.D.) age was 48 (21) years. All cases were categorized as serious, because they required hospitalization (28 cases) or prolongation of hospitalization (15 cases). The outcome was recovery without sequela (39 cases), recovery with sequela (one case of toe amputation) or death (three cases, 7%). The most frequent cause of NIA was antimicrobial drugs (19 cases). The highest incidence rate per 10,000 defined daily doses was for cefepime (83.85; Poisson-CI 95%: 67-102.89). Automatic linear modelling (n = 75, R(2) = 77.9%) showed a significant inverse association with platelets, alkaline phosphatase, C-reactive protein, fibrinogen, lactate dehydrogenase; and direct association with mean corpuscular haemoglobin, and haematocrit. A generalized linear model retained platelets, total serum proteins, creatinine and haemoglobin. The findings suggest an immune-mediated destruction or myeloid toxicity, possibly facilitated by an increase in drug exposure. There might be additional contributing factors, such as nutritional deficiencies or chronic diseases, to develop NIA after exposure to a potentially causative drug.

Paracetamol (Acetaminophen) poisoning data can reveal the potential deficiencies of paracetamol poisoning management guidelines. We conducted a retrospective cohort study of patients >18years who were attended in the emergency department (ED) of a Spanish tertiary hospital, from 2005 to 2010 for suspected paracetamol overdose and who had measurable paracetamol concentrations. 208 patients suspected of paracetamol poisoning were identified. The annual incidence in the ED increased from 2.0 (95%-CI: 0.2-7.2) cases per 10,000 patients in 2005 to 3.4 (95%-CI: 1.1-8.8) in 2010. Only 7 of 98 patients (7.14%) with acute poisoning at toxic doses showed hepatotoxicity signs, 4 (57.1%) of whom presented acute liver failure (ALF) criteria, while 8 of 10 patients (80%) with chronic paracetamol poisoning at toxic doses presented hepatotoxicity and 3 (37.5%) with ALF criteria. The time required to find medical care was 9.0h for acute poisoning and 49.6h for chronic poisoning (p

Background. Methylphenidate (MPH) is widely used in treating children with attention-deficit-hyperactivity disorder. Hepatotoxicity is a rare phenomenon; only few cases are described with no liver failure.Case. We report on the case of a 12-year-old boy who received MPH for attention-deficit-hyperactivity disorder. Two months later the patient presented with signs and symptoms of hepatitis and MPH was discontinued, showing progressive worsening and developing liver failure and a liver transplantation was required. Other causes of liver failure were ruled out and the liver biopsy was suggestive of drug toxicity.Discussion. One rare adverse reaction of MPH is hepatotoxicity. The review of the literature shows few cases of liver injury attributed to MPH; all of them recovered after withdrawing the treatment. The probable mechanism of liver injury was MPH direct toxicity to hepatocytes. In order to establish the diagnosis of MPH-induced liver injury, we used CIOMS/RUCAM scale that led to an assessment of “possible” relationship. This report provides the first published case of acute MPH-induced liver failure with successful hepatic transplantation.Conclusions. It is important to know that hepatotoxicity can occur in patients with MPH treatment and monitoring the liver’s function is highly recommended.

There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. We retrospectively studied the patients of less than 18 years old with measurable paracetamol levels, who were brought to the emergency department (ED) of La Paz University Hospital, Madrid, Spain, for suspected paracetamol overdoses between 2005 and 2010. Ninety-two patients with suspected paracetamol poisoning were identified. In 2007, the incidence of paracetamol poisoning in the pediatric population was 0.8 [Poisson-95% confidence interval (CI): 0.03-3.69] per 10 000 inhabitants aged less than 18 years. The incidence in the same year was 1.53 (Poisson-95% CI: 0.24-5.57) per 10 000 patients in the pediatric ED. The most common cause of poisoning was attempted suicide (47.8%) in teenagers with a median age of 15 years, followed by accidental poisoning (42.2%) in babies with a median age of 2.65 years. Difference was seen in the frequency of hepatotoxicity between acute and chronic poisoning cases. Only 1 of 49 patients with acute poisoning showed hepatotoxicity [acute liver failure (ALF)], whereas 7 of 8 patients with chronic poisoning showed hepatotoxicity (3 cases of ALF). The average time to medical care was 6.83 hours for acute poisoning and 52.3 hours for chronic poisoning (P

To estimate the incidence and predictors of symptomatic arterial and venous thromboembolic events (TEE) from intravenous immunoglobulin (IVIg) therapy according to its indications.We performed a retrospective cohort study of patients seen at our institution and treated with IVIg over a 36-month period. Indications, comorbility and comedication associated with TEE were identified by a stepwise logistic regression analysis.Of 303 patients included with at least one infusion of IVIg over three years, TEE were identified in a total of 50 patients treated with IVIg, for an incidence of 16.9% (CI 95%: 13.0-21.6); 27 (54%) arterial (9.1%;CI 95%: 6.3-13.0%) and 23 (46%) venous TEE (7.8%; CI95%: 5.2-11.4%), overall mortality was 32%. Per indication there were more patients with autoimmune conditions, secondary immunodeficiency, dysimmune neuropathies, acute rejection of solid organ transplantation and sepsis. Patients with TEE were significantly older, were more likely to be men, they had more comorbid conditions; the doses of IVIg were high (589.4mg/kg/day vs 387.0mg/kg/day, p0.001) and differences in comedication were found. The stepwise logistic regression analysis retained high doses of IVIg (OR 3.03; CI 95%: 1.49-5.67) and diuretics therapy (OR 1.69; CI 95%: 1.06-3.97) when combined with the usual comorbid confounders.The incidence of TEE from IVIg therapy remains high at one in six patients treated. The most remediable factor is a high daily IVIg load. Decreasing the daily IVIg dose together with carefully weighing diuretics therapy and comorbid risk factors may be the keys to saving lives.

Vibrio cholerae 638 (El Tor, Ogawa), a new CTXΦ-negative hemagglutinin/protease-defective strain that is a cholera vaccine candidate, was examined for safety and immunogenicity in healthy adult volunteers. In a double-blind placebo-controlled study, no significant adverse reactions were observed in volunteers ingesting strain 638. Four volunteers of 42 who ingested strain 638 and 1 of 14 who received placebo experienced loose stools. The strain strongly colonized the human small bowel, as evidenced by its isolation from the stools of 37 of 42 volunteers. V. cholerae 638, at doses ranging from 4 × 10 7 to 2 × 10 9 vibrios, elicited significant serum vibriocidal antibody and anti-Ogawa immunoglobulin A antibody secreting cell responses.

Tacrolimus is used in renal and other organ transplantations for immunossupression therapy. Bioavailability of enterally administered tacrolimus is poor, and further reduced by gastrointestinal failure or enteral nutrition. In these situations, intravenous administration is necessary to prevent treatment failure. However, intravenous administration should be done in a continuous manner and it has been implicated in anaphylaxis, torsades de pointes, cardiac arrhythmia and other serious adverse events. Also it is more expensive than other routes of administration. Sublingual administration of tacrolimus has been used in some cases, and literature reports show that it provides therapeutic tacrolimus levels in lung and liver transplant recipients. Here, we report a first case of sublingual administration of tacrolimus in kidney transplantation.

Methotrexate (MTX) is considered the main agent for the treatment of rheumatoid arthritis (RA). Neurotoxicity is often mild, but severe encephalopathy can develop, especially with intrathecal or intravenous administration. In rare cases, this syndrome has been observed in patients on long-term low-dose oral administration. A 68-year-old male was diagnosed with RA and on treatment with oral MTX 25 mg weekly for 4 years. The patient started with progressive dysarthria, ataxia and cognitive dysfunction. Complementary tests were normal. Magnetic resonance imaging (MRI) showed hyperintense lesions in both cerebellar hemispheres on T2-weighted and FLAIR images with a diffusion restriction on diffusion-weighted imaging (DWI) and on the apparent diffusion coefficient map (ADC). On postgadolinium T1-weighted images, there were mild enhancements. Spectroscopy showed a demyelinating pattern. A pharmacogenetics determination was made, showing a heterozygous genotype in the MTHFR and ABCB1 genes. Medication with antirheumatic drug was stopped immediately on admission, and the patient gradually improved. MTX-induced leukoencephalopathy can occur even with low-dose administration. The exact pathogenic mechanism is still unknown, but it is hypothesised that it could be the result of a cumulative toxic effect on the blood–brain barrier. The nature of the relationship between the polymorphism and CNS toxicity is still unclear, and thus, further studies are warranted. Often located in the occipital lobes, the involvement of the cerebellum is quite rare. Early recognition of the condition and withdrawal of the drug lead to a better prognosis.

e26 Volume 35 Number 8S Results: The pharmacovigilance program involved 1 general hospital (Ass.2 ‘Isontina’, Gorizia-Italy), 12 pharmacies, and 24 GPs. From March 2012 to March 2013, Medigenia enrolled 2074 patients (52.4% women; mean age, 69 [8]).The system totally administered 62,499 drugs (68.2% prescriptions, 28.4% OTC, and 3.4% herbs), and 3028 were the DDIs identified among them. GPs received 2738 alerts for ADR risk (48% moderate risk, 23.2% high risk): treatment was changed 871 times (31.8%).The most frequent alert among high risk connected with hemorrhage (87.6%), involving primarily acetyl-salicylic acid and warfarin. Moderate risk concerned mainly neurologic sequels (38.2%) and involved in particular antineoplastic agents and phenytoin. Conclusion: People taking drugs are not always aware of the health risk they are going toward after a multidrug therapy or simply taking a medicine without asking GP, a trend that is increasing in the last years. Medigenia prevents ADR and their health sequels using a cloud-based approach for pharmacovigilance. Disclosure of Interest: None declared.

Aim: Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters. Materials & methods: A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg). Results: Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4). Conclusion: Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing, The work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union

Surveillance studies have shown the emergence of infections with linezolid-resistant bacteria. The relationship between appropriate linezolid use and the spread of linezolid resistance among Gram-positive microorganisms in a single tertiary referral centre was evaluated. In an initial observational study, a prospective prescription-indication study was conducted on intensive care areas and haematology, neurosurgery, vascular surgery and nephrology wards during 2009. An intervention through follow-up feedback on audit results from May-June 2010 was then conducted. From July-December 2010, a second drug-use study of linezolid was conducted, with the same objectives and methodology. To assess the antimicrobial pressure of linezolid, an ecological study was conducted from 2006-2010 in the same hospital wards. Indications for linezolid in the initial study were considered suitable in 38.5% of cases, whilst in the second study the rate was 51.2% (33% increase). Linezolid consumption fell by 57% in the second half of 2010. A significant correlation was found between its inadequate use (DDD/1000 patient-days) and the incidence of linezolid-resistant strains/1000 patient-days (r=0.93; P=6.9e-024); 85% of the variability in the incidence of linezolid resistance was predicted by its inadequate use. Its partial correlations were significant for Enterococcus faecium (r=0.407; P=0.049), Staphylococcus epidermidis (r=0.874; P=2.3e-008) and Staphylococcus haemolyticus (r=0.406; P=0.049) but not Staphylococcus aureus (r=0.051; P=0.704). A relationship was found between appropriate linezolid use and the incidence of linezolid-resistant strains of E. faecium, S. epidermidis and S. haemolyticus.

Objectives We have developed a genotyping system to determine the alleles of genes related to interindividual variability in acenocoumarol dosage requirements. This genotyping system is intended for routine clinical use and therefore it is essential that it be simple, fast and inexpensive. Design and methods We developed a PCR multiplex SNaPshot reaction that targets 6 SNPs (single nucleotide polymorphisms) in CYP2C9 , CYP4F2 , VKORC1 and APOE genes, which are associated with acenocoumarol dose requirements. Results We tested the multiplex in 152 samples and found it to be 100% concordant with the results of other methods. Conclusions We successfully produced a reliable multiplex system for simultaneously typing 6 SNPs. This system may be used as a model for accurate, simple and inexpensive genotyping of SNPs related to dose requirements. This information allows the prediction of drug efficiency in patients prior to treatment with acenocoumarol and the prevention of adverse drug reactions.

The purpose of this investigation was to describe the characteristics of the use of systemic antifungal agents (AFAs) and to evaluate their appropriateness of use. A prospective drug-utilisation study was conducted in intensive-care areas: haematology-oncology services and transplant units. Data were collected in three periods over 9 months. The required sample size was determined to be 113 patients (margin of error ±7%, 95% confidence interval [CI]), assuming a variability of 50%. Two different investigator groups evaluated the appropriateness of use separately; Cohen’s Kappa index was used to calculate the degree of agreement between groups. A total of 114 patients we included, of which 62 (54.4%) were children. A total of 150 prescriptions were administered; fluconazole was the most frequently prescribed (38%), followed by liposomal amphotericin B (22.7%) and caspofungin (18.7%). The indications were: (1) pre-emptive treatment of Candida in non-neutropaenic critically ill patients (35.1%), (2) treatment of systemic fungal infection (24.6%), (3) prophylaxis for systemic fungal infection (SFI) in immunocompromised patients (16.7%), (4) prophylaxis of SFI in transplant recipients (12.3%), (5) prophylaxis of SFI in preterm infants (5.3%), (6) treatment of SFI in neonates (6.1%). The Kappa index showed a substantial agreement (Kappa = 0.73). The indications were considered to be inappropriate in 71 (47.3%) episodes. The indications or dosages were inappropriate in 79 cases (52.7%). The indications, dosages or duration of treatment were inappropriate in 83 cases (55.3%). We conclude that AFAs are prescribed for a significant number of inappropriate indications.

The first generic PPI was introduced in Spain in 2001, and since then their prescriptions have increased steadily by about 200%.To evaluate the frequency of use and the appropriateness of indications of PPIs in hospitalised patients, and possible factors predicting their use. We also evaluated relevant PPI-drug interactions and serious adverse drug reactions (SADRs).This was a cross-sectional, prescription-indication drug-utilisation study in hospitalised patients with follow-up until discharge. Sampling was random and stratified by services, and was calculated to obtain an error in the precision of prescription of ±4% with a 95% confidence interval with maximum variability (50%).328 patients were included; 28.65% were prescribed a PPI at admission, 82.62% were prescribed a PPI during hospitalisation, and 54.75% at discharge, with inappropriate indications in 74.47%, 61.25% and 80.24% respectively. The OR of being discharged with PPIs was 3.01(95% CI:2.17-4.18, p=0.000). The inappropriate indication most frequently seen at admission and at discharge was antiplatelet therapy. During hospitalisation it was prophylaxis for stress ulcer in patients at low risk. PPI prescription at admission remained at discharge in 75.90% of cases, 73.02% without an acceptable indication. Being64 years old, taking4 drugs, co-medication (NSAIDs, antiaggregation and anticoagulation), certain hospital departments and length of stay15 days predicted 83.7% of prescriptions at discharge. Four relevant PPI-drug interactions were found, and 2 resulted in SADRs, thus the incidence per 1, 000 patients was 2.66 (Poisson 95% CI:0.62-7.23).There was a very high frequency of overuse of PPIs in inpatients and outpatients. Hospitalisation did not represent an opportunity for better prescription of PPIs.

There is evidence showing the importance of reaching immunosuppressant target concentrations as soon as possible. The aim of this study was to evaluate the relationship between tacrolimus trough concentrations within the first week after transplantation and the rate of acute rejection. In this descriptive-analytic study, we included 57 renal transplant patients receiving tacrolimus as the primary immunosuppressive drug. After univariate analysis, donor age, duration of hospital stay, and creatinine clearance (third month) showed significant differences between rejecters and nonrejecters. In addition, mean tacrolimus trough concentrations on day 5, day 7, mean of days 1-7, and mean of days 5-7 were found to be significantly lower in rejecters (P = 0.009, P = 0.012, P = 0.006, and P = 0.035, respectively). Receiver operating characteristic curve analysis with tacrolimus trough concentrations measured on days 5 and 7 was able to discriminate between patients with and without acute rejection (P = 0.028 and P = 0.048 after Bonferroni correction). The tacrolimus trough concentration with the best sensitivity-specificity balance was 9.3 ng/mL on day 5 and 8.7 ng/mL on day 7. In the Kaplan-Meier analysis, patients with tacrolimus trough concentrations below 9.3 mg/mL on day 5 showed a lower survival time without acute rejection (P = 0.048 after correction) in comparison with patients with tacrolimus trough concentrations above this concentration. After logistic regression, we obtained a model relating rejection with sex, donor age, and tacrolimus trough concentrations on day 5 (P = 0.004). No significant relationship between tacrolimus trough concentrations and delta creatinine clearance from week 1 to month 3 was obtained. These results confirm that tacrolimus trough concentrations during the first week are an important predictor of acute rejection. Therefore, it is critical to reach target blood concentrations of tacrolimus as soon as possible to improve allograft survival.

Aims To evaluate the influence of sex and CYP2D6 genotype on mirtazapine disposition within two bioequivalence studies in healthy volunteers. Methods Seventy-two healthy volunteers were included in two standard 2 × 2 crossover bioequivalence trials. Subjects received a single 30-mg oral dose of each mirtazapine formulation in each study period. Plasma concentrations were measured from 0 to 96 or 120 h by a HPLC with coupled mass spectrometry validated method. CYP2D6 genotyping was available for 68 subjects that were classified into three phenotypic groups depending on the number of active gene copies: extensive/ultrarapid metabolizers (UM-EM), intermediate (IM) and poor metabolizers (PM). To evaluate the influence of sex and genotype on mirtazapine disposition we performed a linear mixed model for repeated measures. Pharmacokinetic data were log-transformed and AUC and Cmax adjusted to the administered dose/weight. Factors included in the model were centre, formulation, period, sequence, sex and genotype as fixed effects, and subject nested sequence × sex × genotype as random one. A second model was also performed adding the interaction sex × genotype to the previous model. Results Mirtazapine disposition evaluated as AUC0–∞ is influenced by sex (p = 0.007) and CYP2D6 phenotype group (p = 0.01). Attending to the theoretical figures provided by the model, mean (95% CI) dose/weight adjusted AUC0–∞ (ng h/ml)/(mg/kg) is 1516.62 (1411.27–1628.22) in EM/UM, 1613.63 (1482.14–1758.55) in IM and 2049.28 (1779.78–2357.24) in PM. In the case of Cmax these figures also show a trend to higher values in PM, but it did not reach statistical significance. Females show a lower dose/weight adjusted AUC0–∞: 1594.39 (1477.70–1720.28) vs. 1837.65 (1694.67–1992.70). On the contrary dose/weight adjusted Cmax is higher in females than in males: 38.33 (34.79–42.28) vs. 32.66 (29.44–36.21). Conclusions Both CYP2D6 genotype group and sex influence the disposition of mirtazapine in healthy volunteers and confirm reported data in the literature obtained by different methods. No sex-by-genotype interaction could be detected.

Objective To evaluate the frequency of CYP2C9 polymorphisms in a cohort of Caucasians (Spanish Pyrenees), previously classified in autochthonous populations. Methods Blood samples from 154 anonymous volunteer donors were collected. All the individuals were autochthonous to their respective populations (four grandparents born in the region): 23 from Valle de Aran (Lerida), 29 from Alto Urgel (Lerida), 32 from La Cerdana (Gerona), 30 from Jacetania (Huesca) and 40 from Cinco Villas (Navarra). The analyses for allelic mutation, CYP2C9*2 and CYP2C9*3 , were identified with Taqman® Allelic Discrimination kits. Results No statistical differences were found when allelic frequencies in the five autochthonous populations were compared. Frequency distribution of genotypic classes (wt/wt, wt/mut and mut/mut) in Alto Urgel was different from that in La Cerdana, Cinco Villas and Jacetania samples. Comparison of Pyrenean and other European populations through exact test revealed significant differences in the distribution of genotypic classes: Alto Urgel, Barcelona, and Croatia yielded the highest significant differences. According to the exact test these populations were pooled in four groups. This classification produced a statistically significant percentage of variation explained by differences among groups (1.94%, P = 0.036), but not by differences among populations within groups ( P = 0.914), although most of the percentage of variance is explained by differences within populations (97.46%, P Conclusion This study increases the evidence of intra-population genotypic variability and highlights the significant genotypic heterogeneity when different autochthonous populations are considered, despite no clear differences in allelic frequencies do exist.

August 2015 e137 Functional Unit Risk Management, Hospital La Paz-Carlos III, IdiPAZ, Madrid, Spain; and Computing Service, Hospital La PazCarlos III, IdiPAZ, Madrid, Spain Background: Incidents, errors or adverse events affect 10 to 17% of hospitalized patients; more than half are related to drugs. The Functional Unit of Risk Management (FURM) has developed a Computerized System for Reporting Incidents, errors or adverse events (SINOIRES for its acronym in Spanish) which is voluntary, anonymous and confidential, allowing the analysis through online collaboration with Responsible of Clinical Safety (RCS) of the units involved. We described the results of the first year of work. Methods: SINOIRES has been developed as a project of JAVA programming Struts frame work as a database using Microsoft SQL Server with functionalities:(i) reporting form, and subsequent consult by the notifier by an identification code,(ii) information of method, characteristics and conditions of the system,(iii) management of incidents with 3 profiles: administrator, manager and RCS,(iv) communication between users of the system. Procedure: managers (4 FURM s members) access to the notifications assign state (open, in process, implementing improvements, closed), priority (high, medium, low), and assigned 2 or 3 RCS that analyse the notification. Once the analysis (not visible to the notifier) has been completed, managers decided the actions (visible to the notifier) and together with RSC monitoring the recommendations. Results: SINOIRES received 203 notifications in 2014: medication/ vaccine (63 notifications), continuity of care (18), infrastructure (17), diagnostic test (17), patient monitoring and care (16), patient identification (13), therapeutic procedure (10), clinical/diagnosis assessment (10), rest of phases (39). Were decided 104 systemic actions, of them one generalizable action to improve “the prescription and administration of intravenous paracetamol”. Conclusions: SINOIRES facilitates the notification and the study of incidents, allowing standardization of the procedure in the hospital, keeping the main features of confidentiality and feedback from the notifier. The system allows knowing the circumstances that favour the occurrence of human errors and system failures, to improve the defences of the organization.

August 2015 e131 Sant Pau, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain; IDIAP Jordi Gol, Barcelona, Spain; and SAP Barcelones Nord i Maresme, Institut Catala de la Salut, Barcelona, Spain Background or Introduction: Generic Drugs Products (GDP) have been subject of discussion for many years, and still now there is some controversy about their quality, effectiveness and safety compared to Innovators drugs. This survey tried to find what is the general perception and opinion from physicians and medical students about generic drugs products. Material and Methods: A questionnaire of 12 items focused mainly in effectiveness, safety, quality and adverse event occurrence was sent to physicians of a third level health care hospital and to medicine students. Individual demographic information and clinical practice data (specialty, years of experience, pharmaceutical sale representative visits, etc.) was asked. Results: One hundred fifty-five subjects answered the survey (n = 157). Physicians from specialties that are less related with clinical practice (who do not prescribe daily) showed to be more agreed with the affirmation that Innovators and GDP products have the same quality, effectiveness and adverse event occurrence compare with physician’s that prescribe daily. Internal medicine specialist tends to be more agreed with equivalence in term of effectiveness and adverse events occurrence than surgical specialist. Years of experience, number of patients by day and number of pharmaceutical sales representative’s visits by month showed an inversely proportional relationship to be in agreement with equivalence in quality, effectiveness and safety. Difference between medicine students and physician were found in questions related to quality, effectiveness and safety, physicians tend to be more in disagreement with the equivalence in those aspects between GDP and Innovators ones. All commented results were statistically significant (P values < 0.05). Conclusions: We found that physicians have some concerns about equivalence between GDP and Innovators ones regarding the quality, efficacy and safety of generic drugs, this concerns increase with years’ experience, number of patients visited and number of sales representatives visits, the fact of prescribing daily and to be surgical specialist. Students tend to be more agreed with equivalence between GDP and Innovators drugs. Nevertheless the response rate is a limitation of this study.