PROGRESSIVE MULTIPHOCAL LEUCOENCEPHALOPATHY (PML ...

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ABSTRACTS P01 TOTAL KNEE REPLACEMENT AS AN OSTEOARTHRITIS STUDY OUTCOME: PREDICTORS DERIVED FROM LONG-TERM OBSERVATION FOLLOWING A RANDOMIZED CLINICAL TRIAL Raynauld J.-P.1, Martel-Pelletier J.1, Dorais M.2, Abram F3, Haraoui B.1, Choquette D.1, Pelletier J.-P.1 1 Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, QC, Canada; 2 StatSciences Inc., Notre-Dame de l’Iˆle-Perrot, QC, Canada; 3Research & Development, ArthroVision Inc., Montreal, QC, Canada

Using data from 4-year knee OA clinical trial, we wanted to find predictors of incidence of total knee replacement (TKR). Patients of a controlled trial evaluating CS impact (Condrosan, Bioibe´rica S.A.) (400 mg BID) vs. placebo who had MRI acquisitions and clinical evaluations were contacted to evaluate retrospectively the incidence of TKR. Pati ents (n = 57) who received study medication and had all MRI evaluations were selected. A total of 13 TKRs (22.8%) were performed. There were more TKRs performed within the placebo (n = 9) than the CS group (n = 4) (69% vs. 31%, P = 0.15, logistic regression). We investigated predictors of TKRs by comparing patients who had TKR (n = 13) to those who did not (n = 44). Baseline values WOMAC pain (P = 0.01, logistic regression), function (P = 0.04), bone marrow lesions (BMLs) in the medial tibial plateau (P = 0.0008), global knee (0.02), C-reactive protein level (P = 0.05) were strong predictors of TKR. Changes at 1 year in medial cartilage volume >7% (P = 0.03), the change in WOMAC pain (P = 0.02) and function (P = 0.02) also predicted the occurrence of TKR. Time to occurrence of TKR also favored CS group vs. placebo (Log-Rank, P = 0.14). Cox regressions that included age, sex, and BMI in the model indicated that WOMAC pain (P = 0.0006), BML in the medial compartment (P = 0.0007) and CRP (P = 0.02) were the strongest predictors of TKR over time. Treatment with CS appeared to reduce the need for TKR. Predictors of long-term occurrence of a TKR were greater levels of knee pain, lower level of function and presence of BML at baseline, and greater loss of cartilage over time.

P02 PROGRESSIVE MULTIPHOCAL LEUCOENCEPHALOPATHY (PML) ASSOCIATED WITH THE INITIATION OF ANTIRETROVIRAL THERAPY Penãtaro J.S.1, Ezzeldin M.1, Arnaiz J.A.1, Manzardo C.2 1

Hospital Clinic of Barcelona, Department of Clinical Pharmacology, University of Barcelona, Spain; 2Hospital Clinic of Barcelona, Department of Infectious Diseases, University of Barcelona, Barcelona, Spain Introduction: We describe a case of PML associated with the introduction of High Activity Antiretroviral Therapy (HAART). Patients and methods: We reviewed the clinical history of the patient and the scientific literature regarding this pathology. Results: The patient we describe was infected with the HIV, and developed PML 2 months after the initiation of HAART with abacavir, lamivudine and lopinavir-ritonavir. The brain MRI showed inflammatory plaques in cerebellum. High-dose corticosteroid treatment was administered, together with antiretroviral treatment. The patient finally presented a slow progressive recovery. PML is an infectious disease caused by the JC virus. This pathogen infects oligodendrocytes taking advantage of the immunosupression caused by the HIV.

Furthermore, PML has also been associated with hematologic malignancies and monoclonal antibodies like natalizumab, efalizumab and rituximab. Before HAART era, PML mortality was almost 100%. Since the introduction of new antiretrovirals 10 years ago, overall survival reached 60%. However, there are reports in the literature of HIV patients without PML that developed the disease (unmasking PML) or worsened it (paradoxycal PML) after the initiation of the antiretroviral treatment, sometimes with an associated inflammatory reaction (IRIS-PML). Corticosteroids proved to be useful to treat this subtypes. Other new drugs have been tested, like 5-HT2a antagonists and IL-2, although no solid evidence has been found for their use. Conclusions: PML is a serious opportunistic disease that sometimes is linked with the starting of HAART. Some beneficial results have been obtained with 5-HT2a antagonists and IL-2, however there is no solid evidence yet for their regular clinical use. Corticosteroids can be considered useful to treat PML-IRIS subtypes.

P03 ALBATROSS-II – A LOCALLY INJECTED BRADYKININ ANTAGONIST FOR TREATMENT OF OSTEOARTHRITIS. AN ONGOING, SEQUENTIAL ASCENDING-DOSE STUDY, TO EVALUATE THE SAFETY, TOLERABILITY, PK AND PD OF INTRA-ARTICULAR DOSES OF FASITIBANT INPATIENTS WITH SYMPTOMATIC OSTEOARTHRITIS OF THE KNEE Paredes I.1, Adler M.2, Borra`s L.1, Colombo M.3, Creus L.1, Cuadripani S.1, Guerrero C.1, Koch I.2, Mazzei P.3, Palau S.1, Piza` B.1, Poggiali G.3, Sayed Y.1, Capriati A.3, Corporate Clinical ResearchMENARINI GROUP 1

Badalona (Laboratorios Menarini S.A.); 2Berlıń; 3Florence

Osteoarthritis causes disability in ageing population. Established treatments provide insufficient symptom relief and significant adverse effects. Fasitibant is a potent-non-peptide B2-receptor-antagonist under clinical development for osteoarthritis. A previous, dose-finding study provided encouraging results following two intra-articular injections, with an inverse correlation between dose-adjusted plasma concentrations and BMI/body surface area. The excellent safety profile of fasitibant warrants exploring higher doses. ALBATROSS study aims to evaluate safety/ tolerability of fasitibant in three ascending doses, by single intraarticular administration, to assess the pharmacokinetics of the product in monotherapy or combined with sodium hyaluronate as well as to evaluate effect on serum osteoarthritis biomarkers. This is a placebo-controlled, parallel-group study in 60 knee-osteoarthritis patients administered ascending doses of fasitibant or placebo by an intraarticular single injection in the knee. Safety and tolerability of treatments will be assessed in each cohort of patients prior to progress to the next higher-dose cohort. An additional cohort will be assigned to fasitibant at the highest dosage level + sodium hyaluronate acid or sodium hyaluronate + placebo to obtain preliminary data on the synergic effect of this extemporaneous combination. Pharmacokinetics, osteoarthritis biomarkers including bradikynin, as well as patient-reported outcomes will be assessed for 2-weeks. This phase Ib/IIa study is designed to collect relevant information on safety, PK-PD and clinical benefit of fasitibant directly into the target population. Risk/benefit profile and anticipation of relevant data have been taken into account when selecting patients versus healthy volunteers for the study.

2012 The Authors Basic & Clinical Pharmacology & Toxicology 2012 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 111 (Suppl. 1), 12–40

13 P04 IVRS/IWRS OFFERED OPPORTUNITIES IN CLINICAL TRIALS: REMOVAL OF USE-BY-DATES FROM IMP LABELS AND PROGRAM POOLING 1

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Guerrero C. , Borra`s L. , Creus L. , Cuadripani S. , Otranto I , Palau S.1, Paredes I.1, Piza` B.1, Sayed Y.1, Scartoni S.2, Capriati A.2, Corporate Clinical Research- MENARINI GROUP: 1

Badalona (Laboratorios Menarini S.A.); 2Florence

Interactive voice/web-response systems (IVRS/IWRS), initially developed for treatment allocation as per randomisation list, are now used for implementing complex randomisation schemes and have expanded into areas unrelated to IMP such as unblinding and tracking patient status on study. Two examples of innovative use of IVRS/IWRS in drug management are their use to allow removing use-by-dates from IMP labels and the so-called ‘program pooling’ (use of the same IMP batch for multiple ongoing studies). The feasibility of applying these innovative strategies was evaluated in three multicentre-international registrative trials, belonging to the clinical development plan for one investigational product, retrospectively in one study (phase-II dose –finding study) or prospectively in two other studies (confirmatory phase-III trials), simulating the implementation of these strategies to identify their advantages and drawbacks assessing their pros and cons. The results and conclusions are that these 2 innovative approaches, aiming to optimize drug management in multicentre, international clinical trials, are theoretically efficacious and efficient by simplifying the processes of IMP distribution and storage, decreasing the risks associated to the current standard approaches and optimising the cost, since the removal of use-by-dates reduces the risks of mistake associated to re-labelling or replacement of the study medication when the use-by-date from IMPs is modified and program pooling allows study-medication supplies to be prepared more quickly and at lower cost. Main current disadvantages are the absence of harmonized regulations across ICH regions and the lack of experience/insufficient standardization of these processes, making their implementation still very challenging.

P05 PAEDIATRICS CLINICAL TRIALS AT THE UNIVERSITY HOSPITAL VALL D’HEBRON (PERIOD 2004–2011) Cucurull E., Rodrı´guez A., Ramio´ X., Fuentes I., Navarro M. University Vall d’Hebron Hospital, Barcelona, Spain The objective of this study was to describe the characteristics of paediatrics clinical trials evaluated in the period 2004–2011. There was a descriptive study of the clinical trial protocols evaluated by Institutional Review Board (IRB) of the Hospital in this period. The data have been extracted from IRB’s database and evaluation reports conducted by the Clinical Pharmacology department. Hundred and seven protocols have been evaluated (7% of all), 5% of the trials were not approved and 10% were cancelled. In the 78% of the trials, the sponsor was a pharmaceutical company. Forty-seven percent of the trials were Phase III, 66% were controlled (75% with an active control), 64% were randomized and 56% had an open design. Efficacy was the primary endpoint in the 71% of the trials and safety was in the 27%. More frequent subgroup age was 2–11 years (in the 78% of the trials). The most evaluated disease were tumours according to the ICD-10 classification (17%) and the most evaluated drugs, according to the ATC classification, were the antineoplastic chemotherapy (group L). Four in five protocols evaluated by IRB have been sponsored by pharmaceuticals companies. Nearly half were in Phase III and more than a third were not controlled. A third of the controlled clinical trials were not randomized. The most frequent population were oncologic patients from 2 to 11 years.

P06 CONDROITIN SULFATE DECREASES CHEMOKINE LEVELS AND SYNOVITIS IN KNEE OA PATIENTS Monfort J.1, Escudero P.2,3, Orellana C.4, Piqueras L.3, Tio L.5, Montan˜e´s F.1, Garcia N.5, Company C.2,3, Benito P.1, Sanz M.J.2,3 1 Hospital del Mar of Barcelona, Barcelona, Spain; 2Department of Pharmacology and 3Universitary Clinic Hospital Research FoundationINCLIVA, University of Valencia, Valencia, Spain; 4Corporacio´ Sanita`ria Parc Taulı´, Sabadell, Spain; 5GRICIC.FIMIM, Barcelona, Spain

The aim of this study was to compare the effect of CS vs. acetaminophen on synovitis and chemokine concentrations in OA patients. Synovitis assessed by sonography and synovial effusion quantified by artrhocentesis were evaluated in 45 patients treated with CS (800 mg/ day) or acetaminophen (4 g/day) for 6 months. Patients were followedup until month 9 to evaluate carry-over effect. Levels of CXCL16, fractalkine/CX3CL1, MCP-1/CCL-2, RANTES/CCL5 and GRO-a/CXCL1 were determined by ELISA. Depending on the variable studied differents analysis where performed: ANCOVA (for continuous variables); Wilcoxon test (chemokine variations). t-test or a chi-squared test (comparison between the two groups). Eligible patients had clinical and radiographic evidence of OA (K&L grade 2 and 3) with synovitis. At the end of the study, CS significantly reduced synovitis compared to acetaminophen. This significant reduction was also detected in MCP-1 and fracktalkine synovial levels. Compared to baseline, CS patients showed significant reductions in synovitis (25.5%) and impairment of synovial hypertrophy (61.9% reduction). These effects were accompanied by significant decreases in synovial and serum MCP-1 content. In the acetaminophen-treated group no effect on synovitis was observed and increased synovial RANTES levels were even detected. Additionally, CS but not acetaminophen effectively reduced functional incapacity after 6 months of treatment. CS functional improvement remained after 3 months treatment cessation (month 9) thus confirming CS carry-over effect. These results indicate that CS but not acetaminophen effectively reduces clinical symptoms and synovitis in OA patients. Evidence of its antiinflammatory effect has been also provided since it can decrease levels of relevant chemokines.

P07 MULTICENTRIC OBSERVATIONAL STUDY OF ACUTE RENAL FAILURE ASSOCIATED TO RENIN-ANGIOTENSIN SYSTEM INHIBITORS Pedro´s C.1, Rebolledo M.2, Agustı´ A.2, Montane´ E.3, Calvo G.4, for the Study FRAxISRA Investigators 1

Clinical Pharmacology Service, Belvitge University Hospital, IDIBELL Foundation, L’Hospitalet de Llobregat, Spain; 2Clinical Pharmacology Service, Vall d’Hebron Hospital, Barcelona, Spain; 3Clinical Pharmacology Service, Germans Trias I Pujol Hospital, Badalona, Spain; 4Clinical Pharmacology Service, Hospital Clinic, Barcelona, Spain Objectives: To estimate the prevalence of hospital admission (HA) due to acute renal failure (ARF) associated to renin-angiotensin system inhibitors (RASIs) and characterize such cases. Methods: A multicentric single-cohort study of patients admitted with ARF was conducted from September 2009 to February 2011. Dialyzed patients and obstructive ARFs were excluded. Information on demographic and clinical characteristics, laboratory parameters and pharmacological exposures was obtained. The Acute Dialysis Quality Initiative Group definition and severity classification of ARF, the WHO definition of adverse drug reaction, and the methods of causality assessment of the Spanish Pharmacovigilance System were used. Results: A total of 1040 patients admitted with ARF were included (prevalence: 1.3% [CI 95% 1.2–1.4]). Pharmacological toxicity was suspected in 607 cases (prevalence: 0.75% [CI 95% 0.69–0.81]). There were 422 cases with suspect RASIs (prevalence: 0.52% [CI 95% 0.47–0.58]); 51% of patients were male, 79% were ‡65 years, 37% had chronic renal failure and 16% had other renal disease. The severity was risk in 25%,


14 injury in 41% and failure in 34%. Renal replacement therapy was required by 4% of patients, 19% had complications and 1.7% died of causes related to ARF. All patients had had any cause of renal hypoperfusion. The RASI involved in more cases was enalapril (57%); 13% of patients had received high doses of RASIs; 74% concomitantly took non-steroidal anti-inflammatory drugs (NSAIDs) or diuretics. Conclusion: ARF associated to RASIs accounts for 40% of HA; the estimated prevalence is 5/1000 urgent HA. Preventive strategies should be implemented (mainly in elderly patients and those with renal diseases), the recommended doses of RASIs should be used, concomitant use of diuretics should be optimised, NSAIDs should be avoided, the renal function should be monitored, and any clinical situation likely to induce renal hypoperfusion should be properly managed.

P08 HOSPITAL ADMISSIONS DUE TO VENOUS THROMBOEMBOLIC EVENTS ASSOCIATED TO HORMONAL CONTRACEPTION USE Quijada Manuitt M., Pedro´s C., Quintana B., Arnau J.M. Clinical Pharmacology Service, Belllvitge University Hospital, IDIBELL Foundation, L’Hospitalet de Llobregat, Spain Objectives: To analyze the venous thromboembolic events (VTEs) associated to hormonal contraception (HC) use leading to hospital admission and to assess risk factors (RFs). Methods: A retrospective study of the VTEs associated to HC requiring hospitalization identified by the Pharmacovigilance Programme of the Bellvitge Universitiy Hospital was performed. Patients, in-hospital stay, VTEs, and contraceptive drugs characteristics, as well as RFs and recommendations at discharge were analyzed. Results: Twenty-five cases were identified (mean age [standard deviation, SD]: 30.8 [7.6] years). Most patients were admitted in Pneumology and Internal Medicine services (44% and 36%, respectively). The most frequent VTEs were deep vein thrombosis with pulmonary embolism (PE) (48%), isolated PE (32%) and cerebral thrombosis (12%). The contraceptive product was a combination of oestrogen (ethinylestradiol) and progestagen in 24 cases and a progestogen alone in one. The most frequent progestagen were drospirenone (11 cases) and cyproterone (5). The duration of use was longer than 1 year in 64% of cases. Any RF was found in 84% of women (n = 21); five of them had more than two RFs. The most frequent RFs were immobilization (52%), obesity (43%) and smoking (38%). The in-hospital length of stay (mean [SD]) was 12.5 (7.6) days. At discharge, 36% of women had recovered. The discontinuation of HC was recommended in 44% of discharge reports. Conclusions: RFs are common in women admitted due to VTEs associated to HC use, which highlights the need for careful assessment of RFs when selecting a contraceptive method. At discharge, the lack of recommendations regarding the most appropriate contraceptive method is common and entails a clear chance for improvement.

P09 IMPORTANCE OF THE HISTORY OF INFIRMARY IN A PHASE UNIT I Bedoya Soto D., Redin Vidarte M., Reis Carvalho J., Azanza Perea M.E. Unit of Clinical Investigation (UIC), Clinical Pharmacology Service, University Hospital of Navarra The process of healthy volunteer recruitment for clinical trials in the Phase I Unit is a long and costly process both in time spent by technical staff as by volunteers. The aim of this work is to assess if a history made by nurses before the volunteer selection phase can ease this process. A retrospective study was made with the clinical records of the volunteers who have taken part in several selection processes throughout the year 2011 in the Unit of Clinical Investigation (UIC) of the University Hospital of Navarra. After checking the selection criteria in the form that the volunteers complete when come to the Unit for registration, we pro-

ceeded to develop a specific nursing history. Of the 537 pre-selected volunteers in 2011, 276 (51.3%) were included in a trial, 261 were excluded for different reasons. Using the history of nursing would have rejected 130 volunteers for the pre-selection, 49.8% of all volunteers excluded. In addition, through a table of estimated time of dedication, we have calculated that the time saved would be 34.6%. The use of a nursing history designed for the healthy volunteer registration process at UIC, improves the selection process and can minimize the time and the economic resources. With these results, we try to conduct a prospective study, applying the history of nursing to assess its real impact on the selection process of volunteer in our Unit of Clinical Investigation.

P10 DRUG-RELATED ACUTE RENAL FAILURE IN HOSPITALIZED PATIENTS Iavecchia M.1, Agustı´ A.1,2,3, Sabate M.1,2,3, Cereza G.1,3, Vidal X.1,2,3, Ramos N.4, De La Torre J.4, Segarra A.4 1 Fundacio´ Institut Catala` de Farmacologia; 2Servicios de Farmacologıá Clıńica; 3Universitat Auto`noma de Barcelona; 4y Nefrologıá, Hospital Universitario Vall d’Hebron

Objectives: To determine the incidence of drug-related acute renal failure (ARF) in hospitalized patients. To describe their demographic and clinical characteristics, the involved drugs, contributing factors, mortality and length of stay (LOS). Methods: Analysis of a prospective cohort of adult patients admitted to non-critical services with ARF (increased serum creatinine ‡0.5 mg/dl if baseline £2.5 mg/dl or >20% if baseline >2.5 mg/dl, in two consecutive determinations) was carried out. The Spanish Pharmacovigilance System criteria were used to assess drug causality. Results: Between July 2010 and July 2011, one hundred twenty patients fulfilled the inclusion criteria. The incidence of ARF was 1.5 cases/1000 bed-days. Median age was 69 (30–94) years and 59.2% were males. The median maximum creatinine was 2.8 (1.1–7.38)mg/dl. Seventy nine percent presented injury or renal failure (RIFLE classification) and 12.5% did not recover. Sixteen patients (13%) died, three related to ARF. Their mean LOS was 24 (4–78) days (the hospital average is 8.8 days). In 65 cases (54%) ARF was drug-related but in 83% (54 patients) of these at least one contributing factor was present (chronic renal failure 32%, volume depletion 38%, hemodynamic disorder 32%, and surgery 40%). No difference was found between cases with drug-related ARF and those not drug-related. The therapeutic subgroups most frequently involved were: diuretics (32.2%), renin-angiotensin system inhibitors (17.5%), immunosuppressants (18%), beta-blockers (7.7%), NSAIDS (6%) and contrast media (6%). Conclusions: During hospitalization, more than a half of ARF cases are drug-related but often other contributing factors are present. Their length of hospital stay is longer than the hospital average length of stay. A significant percentage does not recover renal function.

P11 BILIRUBIN AS SURROGATE MARKER FOR TOXICITY AND EXPOSURE TO ATAZANAVIR Lozano R.1, Apesteguia A.F.2, Domeque N.3, Gonzalez J.3, Velilla A.4 1 Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Pharmacy Departament, Hospital clinico Lozano Blesa; 3Addictive Behavior Unit, Departament Psychiatry, Hospital Real Ntra Sra de Gracia; 4Community Clinical Pharmacist

Introduction: Based on Bilirubin and Atazanavir binding competition to OATP1B1 for uptake by the liver, we have studied Bilirubin as a surrogate marker of exposure to Atazanavir Patients and methods: Forty-seven patients on Atazanavir/r, 300/ 100 mg/day, for over 6 months. We analyzed blood for total Bilirubin,


15 (BT) and HIV viral load (VL) and calculated the probability of treatment failure (VL >104copies/ml). BT values to determine the risk of underexposure and/or antiviral toxicity was calculated according to: dCbil = [1/(E0)2 Kbil*Katz]*dCatz and Dbil1/Dbil2 = Datz1/Datz2 where (atz = Atazanavir Concentration; bil = bilirubin concentration) Results: Ninety-two percent of patients had VL 104copies/ ml. Regarding Bilirubin: 13% of the patients on Atazanavir, had BT 5.5 mEq/l, vs. 6% and 12%, respectivily, in B. In accordance with the data, is important to encourage an adjustment of dose and/or reevaluation of initial, when K>5.5 mEq/l and/or the ratio Na/K 5.5 and/or Na/K 1.5 mg/dl; B group, the 1st (15%) Cr = 0.95 ± 0.61 mg/dl, the 2nd (42%) Cr = 1.2 ± 0.8 mg/dl and remaining 43% composed of patients Cr >1.5 mg/dl and C group: the 1st (33%) Cr = 0.60 ± 0.25 mg/dl, the 2nd (41%) Cr = 0.91 ± 3.6 mg/dl and 3rd (26%) Cr = 1.3± 0.7 mg/dl. There was an initial decrease of 29% of the Cr values, 0.91 mg/dl (1st subpopulation of C group) vs. 0.67 mg/dl (1st of A group), whereas when the treatment is extended over 1 year, the percentage of patients, with Cr values above of 1.5 m/dl, increases from 13% of in A group to 43% in B. Increased parasympathetic tone and decreased heart rate, causes an initial reduction in plasma aldosterone and/or renin, which is compensated by duration of treatment for more than 1 year. Conclusion: Digoxin causes a decreased initial serum creatinine value of approximately 29%, increasing this to values >1.5 mg/dl, in 43% of patients, when treatments are longer than 1 year.

P13 ASSESSMENT OF THE BLOOD POTASSIUM AND RATIO K/NA IN PATIENTS ON DIGOXIN Lozano R.1, Canovas C.2, Gamboa B.2, Mesa P.2, Velilla A.3, Garcia-Arilla E.2 1

Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Geriatrics Departament, Hospital Real Ntra Sra de Gracia; 3Community Clinical Pharmacist

Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Psychiatry Departaments, Hospital Real Ntra Sra de Gracia Introduction: We estimated the risk of thrombovascular events, based on the values of C-reactive protein in patients on clozapine. Patients and methods: Sample of 26 patients on clozapine over 2 years. We analized: C-reactive protein (CRP), prolactin (PRL), cortisol, TSH, thyroxine, glucose (Glu), cholesterol (Chol), LDL, HDL and body mass index (BMI). To calculate the relative risk (RR), we used data from ‘hearth Framingham study’ for Coronary Heart Disease, CHD, ‘Emerging Risk Factors Collaboration’ for stroke and ‘Copenhagen General Population Study’1,2 for DVT. Results: PCR = 4.71 ± 4.7 mg/l, PRL = 523 ± 537 lUI/ml, cortisol = 19.7 ± 7.1 lg/dl, TSH = 2.7 ± 1.5 lUI/ml, thyroxine = 1.1 ± 0.2 ng/dl, Glu = 108 ± 25 mg/dl, Col = 197 ± 46 mg/dl, TG = 146 ± 75 mg/dl, LDL = 123 ± 43 mg/dl, HDL = 50 ± 16 mg/dl and BMI = 28.7 ± 5.6 kg/m2 According to PCR results obtained from the patients were grouped according to their overall risk, in: Low risk, CRP 200 ng/ml (two subpoblations with mean values of 275 ng/ml and 302 ng/ml respectively) and 10% patients with TSH >4.6 ± 2 lUI/ml (two subpoblations with mean values of 5.8 lUI/ml and 1.25 lUI/ml) and bimodal poblational curves in both cases (P < 0.001). The defieciencia of VitB12 found in our sample was 8%, nearly coincident with the 10% bibliography previously described by several authors. Due to the existence of inverse correlation between homocysteine levels and VitB12 in the subpopulation with values VitB12 < 200 pg/l, vitamin supplementation can help patient recovery, being recommended measurement of serum VitB12 level in all patients with treatment-resistant depressive symptoms or risk factors for vitamin deficiency. Conclusion: Up to 8% of patients with depressive symptoms had VitB12 < 200 ng/ml and homocysteine >1010 lM/l.

P16 SSCHIZOPHRENIA: INFLUENCE OF SINGLE NUCLEOTIDE POLYMORPHISMS ON PEPTIDIC SEQUENCES Lozano R.1, Marin R.2, Freire I.2, Sebastian F.2, Santacruz M.J.2, Velilla A.3 1 Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Psychiatry Departament, Hospital Real Ntra Sra de Gracia; 3Community Clinical Pharmacist

Introduction: Analyze the base exchange influence of the 100 most active SNP‘s in schizophrenic patients on peptidic sequences. Methods: Analysis of the 100 most important SNPs found in schizophrenic patients from five studies on schizophrenia GWAS collected by Need (2009) ‘A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia.’ PLoS Genet 5 (2), calculation of the base exchange rate of A, C, G and T and final assessment of their influence on different ‘Motifs’ present in the isomorphic proteins. Results: The base exchange percentage was: A/G = 12%, C/T = 29%, G/A = 16%, A/C = 7%, C/A = 5%, G/T = 10%; T/C = 15% T/G = 6% being the sustitute base: T = 39%, C = 22%, G = 18% and A = 21% and replaced basis: C = 34%, G = 26%, T = 21% and A = 19%.

The base percentage of corresponding to the different RNA codons, encoding each amino acid is: Ala(A)=G42,C42,U8,A8;Lys(K)=A83,G17;Arg(R)=C28,G44,U6,A22;Met(M)=A33,U33,G33;Asn(N)=A67,U16, C16;Phe(F)=U83,C17;Asp(D)=G33,A33,U16,C16;Pro(P)=C75,U8,A8,G8; Cys(C)=U50,G33,C27;Gln(Q)=A50,C33,A27;Ser(S)=U33,C33,A16,G17; Glu(E)=G50,A50;Thr(T)=A42,C42,U8,G8;Gly(G)=G75,U9,C8,A8;Trp (W)=U33,G67;His(H)=C50,A30,U20;Tyr(Y)=U50,A30,C20;Ile(I)=A44, U44,C22;Val(V)=G31,U31,C22,A22;Leu(L)=U50,A11,G11,C28. The double percentage (39%) of T (U) as a sustitute base against rest of them, in addition with location of the SNP‘s in intergenic regions of chromosomes, allows us to hypothesize that these chromosomic regions encode ncRNA; whereas quantitative analysis of codons that encoding different aminoacids, allows us to state that different protein isoforms containing Motifs with Phenylalanine (higher proportion of T in their codons) and Proline (higher proportion of C), where T and C are the bases mostly sustitute and replaced respectively, would be that would result exchanged. Conclusion: Thymine (39%) was the most frequent sustitute base and cytosine (34%) the replaced. The proteinic Isoforms involved would be those containing in their peptidic sequence Motif‘s with Phenylalanine and/or Proline.

P17 INFLUENCE OF ANTIPSYCHOTIC TREATMENT ON C3, C4 COMPONENTS OF COMPLEMENT SYSTEM Lozano R.1, Marin R.2, Pascual A.2, Freire I.2, Sebastian F.2, Santacruz M.J.2 1 Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Psychiatry Departament, Hospital Real Ntra Sra de Gracia

Introduction: To evaluate the influence of risperidone plus clozapine on innate immunity represented by components C3 and C4 of the complement system. Patients and methods: Forty-five patients on risperidone and clozapine, 3.5 ± 1.6 mg and 206 ± 120 mg, for over 5.1 years: 61% schizophrenia (F.20), 34% Schizoaffective Disorder (F.25) and 5% other diagnoses. We analyzed blood for C3, C4, prolactin (PRL), cortisol, thyroxine and calculated iC3 (C3 exposed to antipsychotics/C3 not exposed) and iC4 (C4 exposed to antipsychotics/C4 not exposed) ratio. Results: PRL = 607.2 ± 633 lUI/ml, cortisol = 18.7 ± 6.7 lg/dl, TSH = 3.1 ± 2.3 lUI/ml, thyroxine = 1.1 ± 0.2 ng/dl, C3 = 133.7 ± 24.3 mg/dl and C4 = 28.5 ± 9.7 mg/dl. The average values of C3 and C4 were 15–25% lower in patients on antipsychotic treatment compared with values for patients not exposed to antipsichotics; After Kernel‘s test, we identified three subpopulations for iC3: with values of 0.8 ± 0.2, 0.9 ± 0.3 and 1.2 ± 0.4 and two for iC4, with values of 0.9 ± 0.3 and 1.2 ± 0.5. The blockade of HT2A and D2 receptors, among others, located at the CNS and immune system cells, produced by risperidone and clozapine, causes an alteration in the production of C3 and C4, in agreement with several authors who propose a regulation of the immune response by neurotransmitters released from CNS cells, being the immune system cells able to express receptors for neurotransmitters such as dopamine and serotonin, constituting this their immunomodulatory role. Conclusion: Risperidone plus Clozapine alters plasma levels of C3 and C4, showing that serotonergic and dopamine´rgic receptors would be involved in the modulation of their release.

P18 INFLUENCE OF LONG-TERM ANTIPSYCHOTIC TREATMENT ON INMUNOGLOBULIN PLASMA CONCENTRATION Lozano R.1, Freire I.2, Marin R.2, Pascual A.2, Santacruz M.J.2, Sebastian F.2 1 Pharmacy Departament, Hospital Real Ntra Sra de Gracia; 2Psychiatry Departament, Hospital Real Ntra Sra de Gracia

Introduction: To evaluate the influence of antipsychotics on acquired immunity parameters.


17 Patients and methods: One hundred and forty-five patients on Risperidone plus Clozapine, 3.5 ± 1.6 mg and 206 ± 120 mg, over 5 years: 61% schizophrenia (F.20), 34% Schizoaffective Disorder (F.25) and 5% other diagnoses . We analyzed: IgG, IgA, IgM, prolactin (PRL), cortisol, thyroxine, cholesterol, LDL, HDL, triglycerides and body mass index (BMI), and calculated iG (IgG on antipsychotic/IgG without antipsychotic), iA (IgA on antipsychotic/IgA without antipsychotic) and IM (IgM on antipsychotic/ IgM without antipsychotic) ratio. Results: IgG = 950 ± 235 mg/dl IgA = 202 ± 89 mg/dl, IgM = 94 ± 67 mg/dl BMI = 30 ± 5 kg/m2, cortisol = 18.3 ± 5.3 mg/dl, cholesterol = 202± 40 mg/dl, triglycerides 150 ± 85 mg/dl, LDL = 128 ± 34 mg/dl, PRL = 607.2 ± 633 lUI/ml, TSH = 3.1 ± 2.3 lUI/ml and thyroxine = 1.1 ± 0.2 ng/dl. After Kernel test, we obtained, for iG a single main population, 0.8 ± 0.19, for iA two main subpopulations with values of 0.57 ± 0.14 and 0.76 ± 0.17, respectively, and finally for iM a single main population, 0.5 ± 0.16. The blockade by clozapine and risperidone, of D2 and HT2A receptors, mainly located on immune cells, leads to a decrease in plasma levels of IgG, IgA and IgM in the order of 25–50%, consistent with the recent years findings suggest that the CNS also has the ability to interact with the peripheral immune system through the synthesis and release of neurotransmitters, can regulate the differentiation and function of innate immunity and acquired immunity cells (Engelhardt and Ransohoff, 2005, Levite, 2008, Tian et al., 2009). Conclusion: Risperidone and Clozapine causes a decrease in IgG, IgA, and IgM plasma levels of 25–50%. being dopamine and/or serotonin receptors primarily involved in the modulation of their release.

P19 IMPROVED DEFINITION OF HY’S LAW FOR PREDICTING DILI-INDUCED ACUTE LIVER FAILURE (ALF) Lucena M.I.1, Robles-Dıáz M.2, Medina-Ca´liz I.1, Cabello M.R.1, Kaplowitz N.3, Andrade R.J.2 1 Servicio de Farmacologıá Clıńica, Hospital Virgen de la Victoria, Facultad de Medicina, Universidad de Ma´laga, Instituto de Investigacioń Biome´dica de Ma´laga (IBIMA); 2Unidad de Hepatologıá, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Ma´laga, Instituto de Investigacioń Biome´dica de Ma´laga (IBIMA), Centro de Investigacioń Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas; 3USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, USA

Hy’s Law dictates that an increased risk for serious DILI outcomes presents when ALT >3 · ULN and TB‡2 · ULN, other liver causes being discarded. We aimed to examine the best way to define Hy’s law by analyzing whether the R value provides a better way of identifying hepatocellular (HC) vs. chol contribution to injury, and whether an AP value ‡2 · ULN indicates Chol predominance and low risk of ALF/OLT. Methods: The study population included DILI patients retrieved from the SpanishDILI Registry. Pattern of liver injury and ALF/OLT were ascertained. R‡5 + TB‡2 and AP at onset, peak ALT and peak TB were analyzed. Results: Thirty-three out of 819 DILI patients included in the study had ALF/OLT. Seven hundred and eighty-five patients had information about AP values. Fifity-seven percent of the cases had HC injury (R ‡5). Out of these, 28 patients (6.2%) had ALF/OLT, while only 5 (1.5%) in the Chol/Mix group. To ascertain the best time for predicting ALT/OLT cases, we analyzed all cases that fulfilled ‘Hy’s Law’ definition at various time points. Twenty-five out of 302 with Hy’s Law, defined as HC (R‡5) + TB‡2 · ULN, at onset developed ALF/OTL which represents 8.3%. The corresponding figures at peak ALT were 21 out of 308 (6.8%) and only 11 ‘Hy’s Law’ cases out of 234 (4.7%) were identified at peak TB. Incidences of AP ‡2 · ULN in HC (R‡5) cases which did or did not go on to develop ALF/OLT were similar (6/28, 21.4% vs. 70/ 422, 16.6%, respectively). Conclusions: DILI patients with HC injury (R‡5) show a higher risk of ALF/OLT than Chol/Mix damage, with highest predictive

value at DILI onset. Hence, the best way to define Hy’s law is using R‡5 with TB ‡2 · ULN at the first blood test available after presentation. AP ‡2 · ULN in HC cases(R‡5) does not predict a lower risk of ALF/OLT. Funding:Spanish Medicine Agency. CIBERehd by ISCiii

P20 DRUG-INDUCED DILATED CARDIOMYOPATHY Mantilla A.M., Garcia N., Cereza G. Fundacio´ Institut Catala` de Farmacologia, Clinical Pharmacology Service, Vall d’Hebron Hospital, Barcelona, Spain Objective: To describe the characteristics of spontaneous reports (SR) of suspected drug-induced dilated cardiomyopathy (DCM). Methods: We reviewed the SR of cardiomyopathy collected by the Spanish Pharmacovigilance System from 1983 to May 2012. Hypertrophic, restrictive, ischemic, and those associated with valvular disease, hypertension, metabolic and inflammatory diseases were excluded. We analyzed age and gender of patients, seriousness and outcome of the reaction, suspected drugs, previous knowledge of the drug-reaction association and the existence of alternative causes. Results: We identified 65 SR of cardiomyopathy, of which 51 corresponded to DCM and were included in the study. The median age of patients was 49.5 years (8 months–76 years) 30 were women. All were serious cases and four resulted in death. In 12 cases DCM was associated with heart failure. The 51 reports included 79 suspected drugs. The most frequent were antineoplastic agents, immunosuppressants and immunomodulators (48), followed by anti-infectives (13). Individual drugs most frequently reported were: doxorubicin, trastuzumab and cyclophosphamide. Alternative causes were ruled-out in 26 exposures. In 32 drug exposures (40.5%), drug-reaction association was poorly known or unknown; in 3 of them (adalimumab, anagrelide and hydroxychloroquine) non pharmacological explanations were dismissed. Conclusions: The DMC is a serious adverse reaction (AR) from some drugs. The most frequently drugs involved are the antineoplastics, but there are others whose relationship with cardiomyopathy is less well established. Despite the difficulty in the causality assessment, druginduced DCM should be included in the differential diagnosis.

P21 EPIDEMIOLOGY OF IN-HOSPITAL AGRANULOCYTOSIS IN BARCELONA (1981–2011) Puig Treserra R.1, Vendrell Bosch L.2, Ibań˜ez Mora L.2, Sancho Ponce E.3, Laporte Rosello´ J.R.4, Grup per l’Estudi de la Agranulocitosis i i l’apla`sia medullar de Barcelona 1

Fundacio´ Institut Catala` de Farmacologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 2Servei de Farmacologia Clıńica, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 3Servei d’Hematologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 4Servei de Farmacologia Clıńica, Fundacio´ Institut Catala` de Farmacologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain; The objective of this study is to describe the main epidemiological characteristics and exposure to drugs of a series of consecutive in-hospital agranulocytosis cases gathered in the Metropolitan area of Barcelona (MBA) (1981–2011). Little is known about the epidemiology of in-hospital agranulocytosis cases. Design: descriptive study. Potential cases were patients with a neutrophil count 45 years and smokers, 87% were excluded due to: start of inhaled treatment over 6 months, spirometry more than 1 year before the diagnosis of COPD, treated with oral corticosteroids, previous diagnosis of asthma, dementia, immunosuppression or institutionalized. Baseline data: A total of 2224 exposed to IC and 1613 unexposed. The mean (SD) age was 65.5 (9.9) years and 87% were male, the IC group were older and had more diabetes mellitus. Half of the patients were active smokers at inclusion, less frequently in the IC cohort (51.5% vs. 55.6%). No differences in the history of influenza vaccination and pneumococcal vaccines, but the IC cohort had a greater prior use of antibiotics and oral corticosteroids. Conclusions: The IC cohort has more evolution of the COPD than the not exposed cohort.

P26 ADVERSE REACTIONS ASSOCIATED TO DABIGATRAN IDENTIFIED THROUGH SPONTANEOUS REPORTING SYSTEM Tarapue´s Romań M.1, Cereza Garcıá G.1,2, Garcia Dolade´ N.1,2 1 Department of Pharmacology, Therapeutics and Toxicology, Universitat Auto`noma de Barcelona, E-08193 Bellaterra (Cerdanyola del Valle`s), Spain; 2Fundacio´ Institut Catala` de Farmacologia. Barcelona, Spain

Objective: To describe the main characteristics of spontaneous reports of adverse drug reactions (ADRs) attributed to dabigatran. Patients and methods: Spontaneously reported cases to dabigatran received in the Spanish Phamacovigilance System (SPS) until May 2012 were selected. The variables studied were demographic and ADRs characteristics, contributing factors and the therapeutic indication. Results: During the period of study the SPS received 135 spontaneous reports describing 217 ADRs induced by dabigatran. Patients’ median age was of 77 years; and 53.3% was >75 years. The 54.7% (73) were women. The outcome was recovered in 51.1% (69). Most cases (85.5%)

were serious; and 9.6% were mortal. The therapeutic indication was non-valvular atrial fibrilation in 64.4% and prevention of venous thromboembolism in 23.0%. The most frequent ADRs were digestive (34.1%), followed by neurological (10.6%), general (9.7%), vascular (7.8%) and respiratory (6.9%). Seventy-two reports (53.3%) described 85 hemorrhagic ADR, and 52.9% (45) were gastrointestinal bleeding (GIB): 17 upper, 19 lower and 9 without specific location. These bleedings were frequently in elderly (55; 76.4%), especially in elderly >75 years (44; 61.1%). Chronic renal failure was present in 17 (23.7%) of these patients. In 90.3% (65) bleeding was serious; and 10 cases were mortal. Conclusion: Over half reports describes hemorrhagic ADRs, more frequently gastrointestinal. Hemorrhagic ADRs were serious, concentrate the most of mortal cases, and affect above all elderly patients older than 75 years. Cautious use and close monitoring of contributing factors are necessary for avoid hemorrhagic events. Further investigations are required in order to deepen the potential contributing factors.

P27 OFF-LABEL DRUGS AND SCIENTIFIC EVIDENCE Simon C., Rebolledo Aguëra M., Ma´rquez Rodrı´guez P., Ferrer Artola A., Vallano Ferraz A., Arnau de Bolo´s J.M. Farmacologıá Clıńica, IDIBELL, Hospital Universitari de Bellvitge-ICS, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain Introduction: In the hospitals of Health Catalan Institute, regulation requires the approval of off-label drugs use by the medical director of each hospital. We assessed the requested off-label drugs and the scientific evidence in each indication. Materials and methods: A retrospective observational study was carried out. Requests for off-label drug applied to the medical director of our centre were selected (January 2009–June 2012). Information about drugs (ATC classification and year of marketing), indications and evidence based on published and ongoing clinical trials (CT) assessing drug efficacy in the indication applied for were collected. Results: We analyzed 316 requests (38 drugs and 91 indications), and 224 (71%) were for drugs marketed from 2000. The drugs of group L (144: 46%) and M (83, 26%) were the most requested. The main indications were gastrointestinal (78, 25%) and neurological (58, 18%). Published CT were identified in 205 (65%) of the applications, ongoing CT in 52 (16%) and no evidence of published CT or in progress in 59 (19%). More published and ongoing CT for drugs marketed from 2000 (74% and 75%) were identified than for those marked before 2000 (42% and 36%). There were more published CT for drugs in group M (96%) and less for those in group R (15%). There were more ongoing CT for drugs in group M (83%) and less for those in group N (9%). Conclusions: Most of requested off-label drugs were marketed in the last decade. Some evidence based on published and ongoing CT was found. However, there was a wide variability among the different drugs and the scientific evidence for each indication.

P28 ANALYSIS OF THE QUALITY OF APPLICATIONS FOR AUTHORISATION OF CLINICAL TRIALS ON MEDICINAL ˜ OLA PRODUCT (CTA) RECEIVED IN THE AGENCIA ESPAN DE MEDICAMENTOS Y PRODUCTOS SANITARIOS (AEMPS) BETWEEN 2009 AND 2011 Moledo Freire P.E., Pe´rez Bravo L.A., Gode´ Moreu M., Becerril Chamorro E., Serrano Castro M.A. Agencia Espanõla de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain The AEMPS has reviewed the causes for considering a CTA received between 2009 and 2011 non valid, and the time elapsed between the date of entry and the date of considering the application valid (starting the assessment), on the basis of the information available on the AEMPS CT database as of January 4th, 2012.


20 Between 2009 and 2011 the AEMPS received 2241 CTA and 54.3% of them required an amendment of the application. With respect to CTAs considered non valid, the main causes for requesting the CTA amendment were related to: the application form (39.5%), the payment of fee (20.5%), the cover letter (18%), the protocol (15.3%), the Investigator’s Brochure or SmPC (15%), the manufacture of investigational medicinal product (IMP) (14%), the qualification of IMP as ‘producto en fase de investigacioń clıńica’ (PEI) (9.4%), incomplete documentation (7.7%), inconsistencies in the CTA (7.3%), the lack of nomination by the sponsor of the applicant or legal representative (6.7%), the IMPD (5.3%), submision with incorrect format (4%), elaboration or modification of the IMP by a Hospital Pharmacy Service (4%), illegible documents (3%) and bad IMP identification (3.5%). The mean time needed to validate a CTA requiring correction, discounting the sponsor’s response time, was 11 days compared to 5 days when no amendment was needed. CTA validation time could be reduced by improving the CTA form and cover letter data, reducing mistakes in the fee payment, signature of protocol by the principal or coordinator investigator and presentation of the necessary documentation related to IMP.

P29 OVERVIEW OF THE CLINICAL TRIALS (CT) TEMPORARILY HALTED DURING THE YEAR 2011 Serrano Castro M.A., de Mingo Ballesteros M.Y., Martıńez Martıńez B., Moledo Freire P.E., Gonza´lez Go´mez-Platero C. Agencia Espanõla de Medicamentos y Productos Sanitarios (AEMPS), Spain Ongoing CT in Spain halted during 2011 were analysed on the basis of the information available on the AEMPS CT database as of 3th July 2012. In 2011, 36 CT were halted by sponsor, being 83% international multi-centre. Most of them were Phase II (44%) and Phase III (39%). Sponsor was located outside Spain in 64%. Ninety-four per cent were sponsored by a pharmaceutical company. In 78% the target population was adults and elderly people and only children in 10%. In 84% men and women participated, only women in 9% and only men in 7%. The predominant therapeutic areas were: antineoplastic and immunomodulating agents (36%), antiinfectives (22%), and digestive tract and metabolism (11%). From these CT, 27% refer to investigational medicinal products classified as ‘product under clinical investigation’ (PEI ). The main causes for the temporary halt included: safety reasons (46%), lack of efficacy (39%) and quality/supply shortage of medicinal product (14%). Thirty-six % were restarted and 17% early terminated. Less than 1 year elapsed between the approval and the early termination in 56%, between 1 and 2 years in 28% and between 2 and 4 years in 17%. The time for notification of early termination to the competent authority was £15 days in 67%. Most of the CT halted in 2011 were with antineoplastic drugs or immunomodulating agents, of early phase, promoted by pharmaceutical companies, multi-centre and international and include adults and elderly people. The most frequent causes for halt were safety problems and lack of efficacy.

population included adults and elderly people and only children in 5%. In 87% men and women participated, only women in 7% and only men in 5%. The predominant therapeutic areas were: antineoplastic and immunomodulating agents (42%), nervous system (14%), musculoskeletal system (8%) and digestive tract and metabolism (8%). From these CT, 65% refer to investigational medicinal products classified as ‘product under clinical investigation’ (PEI ). The main causes for the early termination included: lack of efficacy (31%), difficulty of recruitment (30%) and safety reasons (17%). Less than 1 year elapsed between the approval and the early termination in 32%, between 1 and 3 years in 49% and more than 3 years in 19%. The time for notification of early termination to the competent authority was £ 15 days in 55%. Most of the CT early terminated in 2011 were with antineoplastic drugs and immunomodulating agents, phase III, promoted by pharmaceutical companies, multisite and international and include adults and elderly people. The predominant causes for termination were lack of efficacy and difficulty of recruitment.

P31 IMPROVING QUALITY OF PRESCRIPTION IN PRIMARY CARE HEALTH CENTER THROUGH A THERAPEUTIC INTERVENTION WITH EQUIVALENT DRUGS: PRELIMINARY RESULTS Vedia C., Garcia-Vicente J.A., Massot M., Morales C., Pastor E., Valle`s R. DAP Metropolitana Nord. Institut Catala` de la Salut To increase the prescription of recommended drugs in primary care healrh center (PCHC) as well as improve efficiency in the prescription, by changing to therapeutic equivalents (TE) drugs. Methods: Before-after intervention study in 64 primary health care centers (CCP) of Institut Catala` de la Salut (ICS). Study period: year 2012. Intervention: a) analysis of 2011 prescription of the CCP. b) Drugs detection with less adherence to recommendations prescription and identification more efficient drugs with TE. c) Formative sessions in each CCP and sending of relation of patients likely to change (February–March 2012). Variables: variation in quality o quantity indicators of recommended drugs, change in the number of patients susceptible to change, change in cost/DDD subgroup drug. Results: Were selected the following pharmacological groups: proton pump inhibitors (PPIs), statins, bisphosphonates and urologic drugs (alpha-reductase inhibitors and alpha-adrenergic blockers). The preliminary analysis (January–May 2012) showed an improvement of recommended drugs for IBP (2011: 88.83% and 2012: 89.74%) and statins (2011: 69 73% and 2012: 70.22%). The percentage of improvement in DHD was 4.39% for bisphosphonates and 6.31% for urological. A reduction in the number of susceptible patients was: -8.66% for IBP, -6.05% for statins, -16.28% for bisphosphonates and at -1.6% in urology. The variation in cost/DDD was -4.03% for IBP, -2.35% for statins, -1.10% to bisphosphonates and -6.48% for urological. Conclusions: Preliminary results show that the change of TE contributes to increased quality and efficiency in the prescription.

P30 OVERVIEW OF CLINICAL TRIALS (CT) EARLY TERMINATED DURING THE YEAR 2011

P32 DRUGS FOR ALZHEIMER’S DISEASE: DESCRIPTION OF THE POPULATION TREATED IN CATALONIA AND IMPACT OF NEW PHARMACEUTICAL FORMS IN ITS PRESCRIPTION PROFILE

Serrano Castro M.A., de Mingo Ballesteros M.Y., Moledo Freire P.E., Martıńez Martıńez B., Gonza´lez Go´mez-Platero C.

Guerrero A.1, Capella` D.2, Castells X.2, Baena J.M.1, Diego del Rıó L.3, Elorza J.M.4

Agencia Espanõla de Medicamentos y Productos Sanitarios (AEMPS)

1 Catalan Health Institute; 2University of Girona; 3Drug Information Center of Catalonia; 4Primary Care Investigation Institute Jordi Gol i Gurina

CT early terminated during 2011 were analysed on the basis of the information available on the AEMPS CT database as of 3th July 2012. In 2011, 102 CT were early terminated by the sponsor, being 80% international multi-centre. Most of them were phase III (53%) followed by phase II (29%). Sponsor was located outside Spain in 57%. Ninety-five percent were sponsored by a pharmaceutical company. In 78% the target

Objective: To describe the treatment of Alzheimer’s disease (AD) initiated in Catalonia between 2006 and 2009 and to analyze possible changes in its prescription profile. Material and methods: We studied a cohort of patients starting treatment in 280 primary care centers managed by the Catalan Health


21 Institute (85% of Catalonia population). We used the SIDIAP database containing patients’s anonymized information from the medical records (patient characteristics, diseases, procedures and billing). Results: Seventeen thousand six hundred and ninety-six patients (66% women) began treatment for AD. The diagnoses recorded were 54% AD, 13% nonspecific dementia, 10% and 6% vascular dementia and Parkinson and the most frequent comorbilities were hypertension (56%), dyslipidemia (37%), diabetes (23%) and stroke (11%). The drugs used were acetylcholinesterase inhibitors – AI – (29% donepezil, 19% rivastigmine and 22% galantamine) and memantine was 30% of new prescriptions. The marketing in 2008 of both rivastigmine patches and the single daily oral dose made this drug the most widely initially used treatment while initial donepezil treatments decreased. Initial treatment with AI was similar in patients in the age groups of 71–80 and 81–90 years, while memantine was more frequently started in patients between 81 and 90 years. All drugs were more often prescribed in women. Conclusions: The use of drugs for AD is more common in women. Monotherapy with AI is the initial treatment and memantine is more frequently started in older patients. The marketing of rivastigmine patches and the single daily oral dose of rivastigmine have promoted its use, making it the most common initial treatment.

P33 POTENTIALLY PREVENTABLE ADVERSE DRUG REACTIONS: LONG WAY TO GO

To compare the results of applying three methods for the causality assessment of adverse drug reactions (ADRs). All the ADRs identified through the Hospital Pharmacovigilance Program during 2011 were selected. Two reviewers applied three methods for the causality assessment: the Naranjo algorithm, the algorithm used by the Spanish Pharmacovigilance System (SEFV), and the method proposed by the WHO (WHO-UMC system). A descriptive statistical analysis and the intraclass correlation coefficient were performed. A total of 79 suspected ADRs were analyzed. The mean (SD) scores with the Naranjo algorithm was 2.9 (0.5) and with SEFV algorithm 3.7 (0.7). With the WHO-UMC system, the ADRs were classified as Definite, Probable or Possible 68%, 29%, and 2.5%, respectively; with the Naranjo algorithm 7.5%, 78.5%, and 14% of the ADRs; and with the SEFV algorithm 5%, 69.5%, and 17.5%. There was correlation between the scores of the Naranjo and SEFV algorithms (ICC 0.79, 95% CI 0.67–0.87). The highlighted limitations of each method are: the distribution of the criteria in different categories of attribution (WHO-UMC system), the lack of detailed assessment for the latency period (Naranjo), and low scores with ADRs resulting in death (SEFV algorithm). The causality classification of the ADRs was similar with the Naranjo and SEFV algorithms. Most of the ADRs were classified as Probable and only a minority as Definitive, these results are similar to those obtained in other studies. New methods focused on the ADRs outcomes or specifically on the affected organ could be designed.

Bernal Y.1, Montane´ E.1,2, Barriocanal A.3, Arellano A.L.1, Garcıá F.1, Costa J.1,2 1

Service of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol; 2Department of Pharmacology, Therapeutics and Toxicology, Universitat Auto`noma de Barcelona, Spain; 3Fundacio´ Institut d’Investigacio´ en Cie`ncies de la Salut Germans Trias i Pujol To evaluate the characteristics of the adverse drug reactions (ADRs) that could be potentially preventable (PP). All the ADRs identified through the Hospital Pharmacovigilance Program in 2011 were selected. Two reviewers evaluated their preventability with the Schumock criteria, and their causality was assessed with the Naranjo algorithm. A descriptive statistical analysis was performed. A total of 79 suspected ADRs were analyzed; 79% (22) were severe and 54% (15) happened in hospital. A third (35%, 28) were considered PP (6 of them (21%) met almost two Schumock criteria). According to the Naranjo algorithm, 75% (21) were Probable and 18% (5) Definite. Most of the ADRs were hematologic, hepatic or renal (4, 14%). The most frequently involved drugs were antimicrobials (9, 32%) and drugs acting in the nervous system (8, 29%). The etiologies of PP ADRs were: drugdrug interactions (17, 61%) (mostly pharmacodynamic interactions, enhancing therapeutic effects), incorrect administration schedule on the dose, interval or route (9, 32%), positive rechallenge with the suspected drug (5, 18%), wrong prescription by indication (4, 14%), and toxic plasma drug concentrations (1, 4%). One third of the identified ADRs were considered PP. Drug interactions and errors in the drug administration schedule were the most frequently causes of PP ADRs. Methods to avoid ADRs should focused on improving clinical history of patients, monitoring plasma levels of drugs with narrow therapeutic index, and being cautious when administering potent enzyme inhibitor drugs or drugs with similar therapeutic effect.

P34 CAUSALITY ASSESSMENT OF ADVERSE DRUG REACTIONS: COMPARISON OF THREE METHODS

P35 ASEPTIC MENINGITIS NOTIFIED TO THE SPANISH PHARMACOVIGILANCE SYSTEM Berdaguer M.S.1, Torello´ Iserte J.1,2, Castillo Ferrando J.R.1,2, Merino Kolly M.N.2, Jimeńez Martıń C.M.2 1

Clinical Pharmacology Service . Hospital U. Virgen del Rocıó (Sevilla); Andalusian Pharmacovigilance Centre

2

We analyzed all cases of aseptic meningitis notified to the Spanish Pharmacovigilance System. We performed a search of spontaneous case reports loaded on the FEDRA database (4/23/2012). Selection criteria: non-infectious meningitis SMQ terms of specific search at MedRA. All cases with potential infectious cause of meningitis were excluded. We found 106 validated cases. Seriousness criteria: 93 (88%) serious; 69 (65%) hospitalization caused; 29 (27%) life threatening. Age: median 33 years old (range: 4 month–88 year) and gender: 52% women. From all 239 side signs/symptoms reported, the most notified were headaches (22%), pyrexia (18%), nausea/vomiting (15%), paresthesia (5%). From all 175 suspected drugs, the more implicated were: vaccines (n = 32/ 106; 30%); human immunoglobulin (n = 19/106; 18%), and Non Steroid Anti-inflamatory Drugs (NSAIDs) (n = 18/106; 17%). Latency period was: median of 4 days (RIQ: 2–21). From 106 cases notified, 14 (13%) were considered of unknown cause and 16 (15%) were considered as a hardly known cause. In 19/106 (18%) there was a positive re-challenge, in most of them 9/19 (47%) ibuprofen was involved. 13/19 (68%) of the cases with a positive re-challenge were previously known SAR: ibuprofen (n = 9); indomethacin (n = 1), 2 amoxicillin/clavulanate (n = 2), 1 human immunoglobulin IgG (n = 1). In 5/14 (36%) of the cases associated to ibuprofen a medical history of concomitant immune system disorders was present as a contribution factor. Aseptic meningitis can be associated to commonly used drugs, such as NSAIDs. There is documentation supporting that aseptic meningitis is a recurrent SAR despite the fact that is described in the SPC. Maria Soledad Berdaguer – [email protected]

Bernal Y.1, Montane´ E.1,2, Barriocanal A.3, Arellano A.L.1, Garcıá F.1, Costa J.1,2 1

Service of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol; 2Department of Pharmacology, Therapeutics and Toxicology, Universitat Auto`noma de Barcelona, Spain; 3Fundacio´ Institut d’Investigacio´ en Cie`ncies de la Salut Germans Trias i Pujol 2012 The Authors Basic & Clinical Pharmacology & Toxicology 2012 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 111 (Suppl. 1), 12–40

22 P36 TREATMENT DISCONTINUATION IN CLINICAL TRIALS OF METHYLPHENIDATE AND ATOMOXETINE FOR ADULTS WITH ATTENTION DEFICIT/HYPERACTIVITY DISORDER: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CLINICAL TRIALS. Castells X.1, Cunill R.2, Riera M.3, Capella` D.1 1

TransLab rearch group, Departament de cie`ncies me`diques, Universitat de Girona, Spain; 2Unitat d’hospitalitzacio´ psiquia`trica penitencia`ria, Parc sanitari Sant Joan de Deú, Spain; 3Comite` d’E`tica d’Investigacio´ Clıńica de l’Hospital Universitari de Girona Doctor Josep Trueta, Spain The European Medicine Agency requires efficacy data on attention deficit/hyperactivity disorder (ADHD) symptoms severity to approve a medication for the treatment of adults with ADHD. These data do not enable a suitable assessment of the risk:benefit relationship. All cause treatment discontinuation could help at appraising this relationship. Objective: To compare all-cause treatment discontinuation, efficacy and safety between methylphenidate or atomoxetine and placebo in adults with ADHD. Methods: A systematic review of randomized clinical trials (RCT) investigating methylphenidate or atomoxetine was performed. Study endpoints were: (i) all-cause treatment discontinuation, (ii) adverse events (AE)induced discontinuation and (iii) ADHD symptom severity improvement. Results: Nineteen RCT enrolling 4.425 patients were included. Both drugs were more efficacious than placebo to reduce ADHD symptom severity. Nevertheless, the proportion of patients that dropped out the study was higher amongst patients receiving the active treatment, though this difference was only statistically significant for atomoxetine (RR = 1.18 [0.86, 1.60] y RR = 1.13 [1.01, 1.29]). AE-induced discontinuation was higher with methylphenidate and atomoxetine than with placebo. Conclusion: All-cause treatment discontinuation appears higher with methylphenidate and atomoxetine than with placebo, though this difference was statistically significant only for atomoxetine. This finding could indicate that ADHD symptom improvement with these drugs does not compensate for their side effects, suggesting an unsuitable risk:benefit relationship.

P37 BISPHOSPHONATES OVER 5 YEARS: INTERVENTION TO IMPROVE ADEQUACY Guerrero A.1, Noguer M.2, Pellicer M.A.1, Nadal M.1, Palacios M.3, Modamio P.2 1 Catalan Health Institute, Primary Care, Girona, Spain; 2Pharmacy Faculty, University of Barcelone, Barcelone, Spain; 3Catalan Health Service, Girona, Spain

Objective: To evaluate the impact of an intervention on patients who have been treated with bisphosphonates for 5 years or more (PB5y). To analyze the characteristics of PB5y. Material and methods: Quasi-experimental pre-post controlled study, conducted in 21 primary care centers (421,424 inhabitants): 10 intervention and 11 control. Characteristics of a sample of 300 PB5y from the intervention group were analyzed. Demographic characteristics, diagnoses, treatments, risk factors for osteoporosis and fracture risk calculated by FRAX were collected from computerized medical record (CMR). INTERVENTION (second semester’11): clinical session with exposure of results of the sample analysis, review of the evidences of risk related to the use of bisphosphonates and distribution to each professional of a list of patients to review. CONTROL EQUIPMENT: clinical session reviewing literature. Results: Sample characteristics: median age 75 years (SD 9.1), 95.3% female. Diagnostics (Unregistered 20.7%): 3% osteopenia, osteoporosis with fracture 21%, 55% osteoporosis without fracture. Risk factors: mean BMI 27.4 (SD 7.1) (available in 43.3%), previous fracture 21% (0.3% atypical), tobacco 3.3%, alcohol 0.7%; risk comorbidities 14.3%, corticosteroids 10%.

FRAX (calculable at 40.3%): average risk of major osteoporotic fracture 12.3 (SD 8) and hip fracture risk of 5.7 (SD 4.9). Treatment: Alendronate 58%, risedronate 33%, ibandronate 8%, mean duration 6.6 years (SD: 1.04), maximum 9.2 years. In March’11 there were 1490 PB5y in the study group and 583 in May’12 (61% reduction). The control group had 1348 PB5y and 1140 (15.4% reduction). The improvement of the adequacy of treatment in the intervention centers was statistically significant (v2 = 612.69 P < 0.005). Conclusions: The intervention improved the adequacy of treatment with bisphosphonates since a high percentage of patients had low risk of fracture. Data logging in CMR could improve and this is important to evaluate treatment adequacy.

P38 ARE RE-LY PATIENTS SIMILAR TO THE REAL ONES? Guerrero A.1, Lo´pez E.2, Pellicer M.A.1, Nadal M.1, Aguilar R.2, Sunyer N.2 1 Catalan Health Institute, Primary Care, Girona; 2Catalan Health Institute, Josep Trueta Hospital, Girona

Objective: To compare the characteristics of patients included in the RE-LY trial with patients treated with dabigatran in April’12 in Girona. Material and methods: Retrospective observational study. We analyzed demographic data, use of other drugs, glomerular filtration and parameters necessary for calculating CHADS2 and HAS-BLED scales of the 65 patients with authorized electronic prescription of dabigatran in April’12 in one Primary Care Area (564,891 inhabitants). Results: Forty-seven percent men (RE-LY 63.5%) 74.9 ± 10 years old with a range of 53–98 (RE-LY 71). The weight (reported in 44 patients) was 74.6 ± 13 kg with a range of 45–110 (RE-LY 83). Seventy percent of patients were taking 220 mg/day (RE-LY 49.7%) and 22% 300 mg/day (50.3% RE-LY). Glomerular filtration rate was only recorded in 71% of patients and in 19.5% of these was 8 h) and 716 visits (0.50. Forty-four patients were included, corresponding to 66 registries (1 registry = 1 patient + 1 drug). The early use of a bayesian-based tool for causality assessment in DILI identified 67% of the cases classified as probable by the CIOMS algorithm applied a posteriori. Mean PrP and PsP1 values were significantly higher for registries classified as probable than for possible and unlikely ones. Bayesian-based probabilistic methods are an alternative tool to CIOMS algorithm in the early diagnosis of DILI.


25 P47 EVALUATION OF THE PROPER USE OF TRANSFUSION OF BLOOD COMPONENTS IN EMERGENCY DEPARTMENTS: RESULTS OF THE FIRST PHASE

Renal function and serum troughs should be closely monitored since the second week of treatment in adults, intensive care patients and those who receive nephrotoxic agents concurrently.

Tong H.Y.1, Medrano N.1, Caparro´s A.P.1, Quintana M.2, Borobia A.M.1,2, Frıás J.1 1

Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autońoma de Madrid, IdiPAZ, Spain; 2 Emergencies Department, Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autońoma de Madrid, IdiPAZ, Spain Knowledge of blood usage patterns helps to address major issues such as the management of massive transfusion events and minimization of transfusion risk. We designed a study to assess and describe the use of transfusion of blood products (TBP) before and after an educational intervention. The study population included all patients who received at least one TBP in Emergency Department of five hospitals of different regions in Spain (Madrid, Toledo, Bilbao, Talavera de la Reina and Cuenca), for two periods of 3 months before and after an educational intervention. Results are presented before the educational intervention. There were 1230 transfusions within 3 months (red blood cells (RBC):1018, platelet: 147 and fresh frozen plasma (FFP):65). Patients had 71.6 ± 16.5 years. The main reason for transfusion was: presence of acute symptoms (26.5%) followed by laboratory criteria (19.5%). RBC were the most commonly utilized component (2032), followed by platelet (267) and FFP(127). The mean hemoglobin pre and post-transfusional was 7.9 and 9.6 mg/dl. Mean count of platelet pre and post-transfusional was 162.000 and 154.000. INR pre and post-transfusional was 3.59 and 1.50. In preliminary results, the adequacy analysis was appropriate in 73.13% of cases. Of the three series, RBC was adequate in 77.9% of cases and platelet in 57.86% in contrast 58.73% of patients who received FFP were inadequate. In evaluated hospitals, over 70% of TBP is done properly according to national recommendation especially RBC transfusion; however it is worrying that more than half of the indications for administration of plasma may be incorrect.

P48 VANCOMYCIN-INDUCED ACUTE KIDNEY INJURY DETECTED BY A PROSPECTIVE PHARMACOVIGILANCE PROGRAM FROM LABORATORY SIGNALS

P49 IMPROVING THE SUITABILITY OF LINEZOLID USE DECREASES THE INCIDENCE OF LINEZOLID RESISTANCE AMONG GRAM-POSITIVES Ramı´rez E.1, Go´mez-Gil R.2, Borobia A.M.1, Zegarra C.1, Munõz-Romo R.1, Frıás J.1 1 Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autońoma de Madrid, IdiPAZ, Spain; 2 Department of Microbiology, La Paz University Hospital, Spain

Surveillance studies have shown the emergence of patient infections with linezolid-resistant strains. We evaluated the relationship between the suitability of linezolid use and the spread of linezolid resistance among gram-positives in a single tertiary referral centre. In a first drug-use study we conducted a prospective prescription-indication study in intensive care areas, and in the haematology, neurosurgery, vascular surgery and nephrology wards during 2009. This was followed by, an intervention, feeding back audit results, made in May-June 2010. Later a second druguse study of linezolid, was conducted with the same objectives and methodology of the first study through December 2010. To assess the antimicrobial pressure of Linezolid an ecological study was conducted from 2006 to 2010 in the same hospitalization wards. Linezolid indications were considered suitable in 38.46% of cases in the first drug-use study and in 51.22% of cases in the second; there was an increase of 25% over the first study. Linezolid consumption fell by 57% in the second half of 2010. A significant correlation was found between the suitability of its use (DDD/1000 patient days) and linezolid resistant strains incidence per 1000 patient days (r = 0.93, P = 6.9e-024). Eighty-five percent of the variability in linezolid resistance incidence was predicted by the suitability of its use. The 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 for Staphylococcus aureus (r = 0.051, P = 0.704). A relationship was found between the suitability of use and the incidence of Enterococcus faecium, Staphylococcus epidermidis and Staphylococcus haemolyticus linezolid-resistant strains.

Ramı´rez E., Borobia A.M., Tong H.Y., Medrano N., Carcas A.J., Frıás J. Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autońoma de Madrid, IdiPAZ, Spain The aim of this article was to report the incidence of acute kidney injury (AKI) and associated risk factors in patients with vancomycin trough level >20 mg/l, in a tertiary hospital under a Pharmacovigilance Program using Laboratory Signals in Hospital This was a prospective follow up of all serum vancomycin trough levels >20 mg/l cases between June-2010 and May-2011. Acute kidney injury (AKI) was defined using RIFLE criteria. Patients with vancomycin-induced AKI (VIAKI) were compared with vancomycin-tolerant ones. During 12 months of study, 300 samples corresponding to 208 cases were monitored. Excluding extraction errors in blood samples, vancomycin did not alter renal function in 67.6% of cases, and 13.7% of AKI cases were induced by other causes. Nephrotoxicity without AKI criteria was found in 10.8% of cases. VIAKI occurred in 7.8% of cases (95%CI:4.6–12.4), 9.2% (95%CI:5.2–14.64) of 164 adults and 4.2% (95%CI:1.1–21.1) of 24 children (