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Aims: To estimate the incidence and predictors of symptomatic arterial and venous thromboembolic events (TEE) from intravenous immunoglobulin (IVIg) therapy according to its indications., Methods: 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., Results: 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, p<0.001) 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., Conclusions: 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

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.

Background: Retrospective studies have identified elevated vancomycin trough levels >20 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 levels >20 mg/L in a prospective Pharmacovigilance Program from Laboratory Signals at a Hospital., Methods: This was a prospective follow-up of all cases with serum vancomycin trough levels >20 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., Results: 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 was >30 mg/kg. Renal function was recovered at discharge in 73.3% of cases and 66.7% of cases had other suspected drugs., Conclusions: 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.

Often the only available data in literature for sample size estimations in bioequivalence studies is intersubject variability, which tends to result in overestimation of sample size. In this paper, we proposed a preliminary model of intrasubject variability based on intersubject variability for Cmax and AUC data from randomized, crossovers, bioequivalence (BE) studies. From 93 Cmax and 121 AUC data from test-reference comparisons that fulfilled BE criteria, we calculated intersubject variability for the reference formulation and intrasubject variability from ANOVA. Lineal and exponential models (y=a(1-e-bx)) were fitted weighted by the inverse of the variance, to predict the intrasubject variability based on intersubject variability. To validate the model we calculated the coefficient of cross-validation of data from 30 new BE studies. The models fit very well (R2=0.997 and 0.990 for Cmax and AUC respectively) and the cross-validation correlation were 0.847 for Cmax and 0.572 for AUC. A preliminary model analyses allow us to estimate the intrasubject variability based on intersubject variability for sample size calculation purposes in BE studies. This approximation provides an opportunity for sample size reduction avoiding unnecessary exposure of healthy volunteers. Further modelling studies are desirable to confirm these results especially suggestions of the higher intersubject variability range., (© Georg Thieme Verlag KG Stuttgart · New York.)

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., (Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Purpose: 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., Methods: All serum potassium levels <2 mmol/l or >7 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., Results: 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 rate <60 ml/min) with the presence of ≥4 comorbid conditions. The only predictor of drug-induced hypokalemia was the use of >5 drugs. The triggering factor associated with drug-induced hyperkalemia and hypokalemia was azotemia and hypoalbuminemia, respectively., Conclusions: 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.

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., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE)., Methods and Design: This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment., Discussion: To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety., Trial Registration: Eudra CT. Identifier: 2009-016643-18.

The development of clinical practice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance with regard to adverse drug reactions. The potential of pharmacogenomic biomarkers 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 major gene/drug pairs. Of 11 potential barriers, the highest importance was attributed to lack of institutional support for pharmacogenomics testing, 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/drug pairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutics study, and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing.

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.

Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.

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 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)., 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.

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 C(max) 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., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)

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.

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 x 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 C(max) 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 x sex x genotype as random one. A second model was also performed adding the interaction sex x genotype to the previous model., Results: Mirtazapine disposition evaluated as AUC(0-infinity) 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 AUC(0-infinity) (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 C(max) 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 AUC(0-infinity): 1594.39 (1477.70-1720.28) vs. 1837.65 (1694.67-1992.70). On the contrary dose/weight adjusted C(max) 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 Arán (Lérida), 29 from Alto Urgel (Lérida), 32 from La Cerdaña (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 Cerdaña, 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<0.001)., 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.

Introduction: The aim of this study is to establish the risk of thromboembolic events and evaluation of the use of venous thromboembolism prophylaxis in hospitalized medical patients and after discharge, and their concordance with protocols used in our hospital., Material and Methods: We performed a cross-sectional with prospective follow-up until hospital discharge. It included all medical patients in Internal Medicine, Pneumology and Oncology Departments. The patient's thromboembolic risk and type of thromboembolism prophylaxis indication during hospitalization and after discharge were determined., Results: A total of 116 patients (52 in Internal Medicine Department, 35 in Pneumology Department and 29 in Oncology Department), with a mean age of 67 +/- 17 years (35 females; 81 males) were included. During hospitalization, 62.9% of the patients had a high risk of thromboembolic events, 3.4% a moderate risk, 23.3% low risk, and 10.3% had no risk. After discharge, these proportions were 35.6%, 3.8%, 24% and 34.6%, respectively. A total of 49.1% of the patients had an adequate indication of venous thromboembolism prophylaxis during the hospitalization and after discharge.