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Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product's benefit-risk balance at the time of approval, the limitations of nonclinical development, and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval, and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges, and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development, and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field., Graphical abstract, Most authorized ATMPs are based on small, open-label, uncontrolled, and single-arm pivotal trials using single and intermediate variables to evaluate outcomes. Health authorities are demanding methodologically sound clinical development to guide higher-quality evidence generation and decision-making. New standards for ATMP development are required to ensure consistency in clinical development.

Resumen Antecedentes y objetivos El dolor postoperatorio es frecuente en los hospitales. Se han desarrollado guias de practica clinica para el control del dolor postoperatorio (GPCDP) y para mejorar su tratamiento. El objetivo fue evaluar la prevalencia e intensidad del dolor postoperatorio y las pautas analgesicas, antes y despues de la implementacion de una GPCDP. Material y metodo Estudio observacional que incluyo 2 estudios transversales realizados en 2 periodos (anterior y posterior a la implementacion de una GPCDP). Incluyo a pacientes adultos postoperados el primer dia de ingreso en plantas de cirugia. Las variables demograficas, clinicas y farmacologicas se recogieron de las historias clinicas; la intensidad del dolor, mediante entrevista con los pacientes. Resultados Se incluyo a 306 pacientes en el primer periodo y 317 en el segundo. No hubo diferencias respecto a las variables demograficas y clinicas de los pacientes en los 2 periodos. La prevalencia del dolor fue del 92% (IC 95%: 87-95%) en el primer periodo y del 77% (IC 95%: 72-82%) en el segundo (p Conclusiones Tras la implementacion de la GPCDP se observo un descenso de la prevalencia e intensidad del dolor de los pacientes, pero sin llegar a ser optimo. Son necesarias medidas continuadas de formacion y evaluacion del dolor para un tratamiento adecuado a lo largo del tiempo.

Background and objectives Postoperative pain is common in hospitals. Clinical practice guidelines for the control of postoperative pain (CPGPP) have been developed to improve its treatment. The objective of this study was to evaluate the prevalence and intensity of postoperative pain and analgesic norms, before and after the implementation of a CPGPP. Material and method An observational study was carried out that included 2 cross-sectional studies in 2 separate periods, before and after implementation of the CPGPP. Adult patients postoperated on the first day of admission in the surgery plants were included. Demographic, clinical and pharmacological variables were collected from clinical histories. The intensity of the pain was collected through individual interviews with patients. Results We included 306 patients in the first period and 317 in the second. There were no differences between patients’ demographic and clinical variables and the 2 periods. The prevalence of pain was 92% (IC 95%: 87%–95%) in the first period and 77% (IC 95%: 72%–82%) in the second (p Conclusions After the implementation of the CPGPP, a decrease in the prevalence and intensity of pain in patients was observed, but without reaching an optimal level. Continued pain training and assessment measures are therefore necessary for proper pain treatment over time.

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.

The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and a parts per thousand yen10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics.

Postoperative pain is common in hospitals. Clinical practice guidelines for the control of postoperative pain (CPGPP) have been developed to improve its treatment. The objective of this study was to evaluate the prevalence and intensity of postoperative pain and analgesic norms, before and after the implementation of a CPGPP.An observational study was carried out that included 2cross-sectional studies in 2separate periods, before and after implementation of the CPGPP. Adult patients postoperated on the first day of admission in the surgery plants were included. Demographic, clinical and pharmacological variables were collected from clinical histories. The intensity of the pain was collected through individual interviews with patients.We included 306 patients in the first period and 317 in the second. There were no differences between patients' demographic and clinical variables and the 2periods. The prevalence of pain was 92% (IC 95%: 87%-95%) in the first period and 77% (IC 95%: 72%-82%) in the second (P0.05). The most frequent pain in the last 24hours was moderate or intense in 53% (IC 95%: 48%-59%) of patients in the first period and in 33% (IC 95%: 28%-38%) of the patients in the second (P 0.05).After the implementation of the CPGPP, a decrease in the prevalence and intensity of pain in patients was observed, but without reaching an optimal level. Continued pain training and assessment measures are therefore necessary for proper pain treatment over time.

Background The Catalan Healthcare System (CatSalut) runs a specific program for drug evaluation (PHF) aimed to guarantee equity in the access to innovative medications. PHF recommendations determine the degree of priority and mechanism for drug invoicing: clinical criteria with direct invoicing; individualised criteria requiring approval by an ad-hoc committee, and exceptional use with no budget allocation. In 2017, the program incorporated an EVIDEM based matrix for Multiple Criteria Decision Analysis a standard procedure. In 2018, the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) was included in the matrix for oncological drugs. This study retrospectively checked the consistency of recommendations issued by the PHF for oncological drugs with the ESMO-MCBS score. Methods The recommendations of the PHF between 2011 and 2018 for oncological drugs were retrieved from reports and meeting minutes. Pivotal studies were scored using ESMO-MCBS version 1.1 for each drug. Matchings and discrepancies were summarised, and the debate reflected in the minutes of the committees was retrieved. Results Throughout the period 2011 to 2018 a total of 47 decisions were made on 57 oncology drugs evaluated. All PHF recommendations for drugs with ESMO-MCBS scores ≥ 4 were positive. Discrepancies were seen for 2 drugs in the curative setting (A score and exceptional use), 8 drugs in the non-curative (1-2 score and clinical criteria) and 1 in the curative setting (C and clinical criteria). The main criteria supporting the PHF decisions for these products are summarised in the table. Table: 1628O . Curative Trial quality Mifamurtide Safety concerns Ipilimumab Managed agreement Pembrolizumab Non curative Consolidated use Bevacizumab Aflibercept Subgroups Nintedanib Eribuline Managed agreement Everolimus Cabazitaxel None Trastuzumab Abiraterone Conclusions Factors explaining discrepancies between PHF recommendations and ESMO-MCBS were mostly related to the context of the appraisal. ESMO-MCBS standardises efficacy but does not consider quality of trials, added value to other drugs or other factors. It may not be a single formula to reach decisions, but may be useful to ensure that the size of effect is systematically approached in appraisals, and to complement a multiple criteria based system. Legal entity responsible for the study CatSalut. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Biotechnological agents (BA) are increasingly being used in clinical practice. We aimed to determine, whether enquiries about them to a therapeutic consultation service have also become more frequent, and to describe the information requested in these consultations. Methods We retrospectively reviewed 14 104 therapeutic consultations collected in a computerised database between 2000 and 2014. Enquiries about BA (monoclonal antibodies, fusion proteins or cytokine antagonists) were chosen. Information on the type of BA, underlying condition, type of enquiry and affiliation of the enquirer was retrieved and compared with data from consultations about other agents. Results During the study period, 365 enquiries about 30 different BA were received. Only 4% of them were received before 2004, while 48.8% were received after 2010. Rituximab, infliximab, adalimumab and etanercept were most frequently enquired about. Agent selection (n=184) and/or adverse effects (n=174) were the most frequent reasons for making an enquiry. Most enquiries about an agent selection were made about an off-label use (n=164), mainly for systemic autoimmune diseases (n=61). Over half of the enquiries about adverse effects were about their teratogenic potential (n=96). Enquiries about BA more often requested an opinion (87.7% vs 77.7%) were made by physicians (89.9% vs 76.9%), from a hospital (81.6% vs 44.5%) and regarded a specific patient (87.4% vs 74.5%). Conclusions Therapeutic consultations about BA are increasing. Most of them are related to uncertainties of health professionals regarding any new medicine: their off-label use, actual adverse effects or the teratogenic potential of the involved agents.

The pharmacotherapy of schizophrenia relies on restoring a dysregulated striatal dopamine and prefrontal cortex glutamate neurotransmission. However, these treatments are usually insufficient to fully cover all the disease symptomatology (i.e., negative and cognitive symptoms). Thus, the search for alternative and/or complementary neurotransmitter systems involved in the etiology of schizophrenia constitutes a big challenge in psychiatry these days. Adenosine, a well known neuromodulator in the central nervous system, has been highlighted because its relationship with both dopaminergic and glutamatergic neurotransmission. Indeed, the disruption of adenosine homeostasis in the adult brain has multiple consequences in the circuitry implicated in the pathophysiology of schizophrenia. Consequently, the “adenosine hypothesis of schizophrenia” foresees that the disruption of adenosine homeostasis within certain brain areas has behavioral consequences resembling schizophrenia symptoms. Thus, it has been postulated that restoring adenosine concentration within the schizophrenia-related brain areas might have beneficial antipsychotic properties. Overall, as adenosine dysfunction can trigger endophenotypes of schizophrenia, the development of drugs targeting the adenosinergic system will definitely constitute a new opportunity for therapeutic intervention in schizophrenia.

To assess the prevalence of hospital admission related to adverse drug reactions (ADRs) in a third-level hospital, to analyse the associated factors, and to describe the reactions and the drugs involved. A cross-sectional study was conducted for a 120-day period. Patients that were urgently hospitalized entered the study. The primary endpoint was the ADR-related urgent admission. A descriptive analysis of demographic, clinical, and drug-related variables was performed. The association between the likelihood of urgent admission due to ADRs and age, gender, and number of drugs used was analysed. A descriptive analysis of the suspected drugs and the reactions in ADR-related admissions was performed. Overall, 186 out of 4,403 hospital admissions were due to ADRs (prevalence: 4.2 % [95 % CI 3.7–4.8 %]). Age (≥65 years: OR 1.59 [95 % CI 1.10–2.29]) and number of drugs used at the time of admission (3–5 drugs: OR 5.07 [95 % CI 2.71–9.59]; 6–9 drugs: OR 5.90 [95 % CI 3.16–11.0]; ≥10 drugs: OR 8.94 [95 % CI 4.73–16.89]), but not gender, were identified as independent factors associated with ADR-related hospitalization. The overall in-hospital stay for patients admitted with ADRs amounted to 1,785 days. The ADRs were mainly type A reactions (92 %). Acute renal failure related to renin-angiotensin system inhibitors, haemorrhage due to anticoagulants, and upper gastrointestinal bleeding related to antiplatelet drugs and/or non-steroidal anti-inflammatory drugs were the most frequent. Over 4 % of urgent hospitalizations are caused by ADRs, which are dose-related and predictable in more than 90 % of cases. The main risk factors are advanced age and polypharmacy.

Although the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last decade, under some premises the existence of a supramolecular organization of these receptors begins now to be widely accepted by the scientific community. Indeed, GPCR oligomers may enhance the diversity and performance by which extracellular signals are transferred to the G proteins in the process of receptor transduction, although the mechanism that underlie this phenomenon remains still unexplained. Recently, a trans-conformational switching model has been proposed as a mechanism allowing direct inhibition of receptor activation. Thus, heterotropic receptor-receptor allosteric regulations are behind the GPCR oligomeric function. Accordingly, we revise here how GPCR oligomerization impinge in several important receptor functions like biosynthesis, plasma membrane diffusion or velocity, pharmacology and signaling. Overall, the rationale of receptor oligomerization might lie in the cellular need of sensing complex extracellular signals and to translate into a simple computational mode.

Spontaneous reporting of adverse drug reactions (ADRs) in hospitals is scarce and several obstacles to such reporting have been identified previously.To assess the effectiveness of a multifaceted intervention based on healthcare management agreements for improving spontaneous reporting of ADRs by physicians in a hospital setting.In 2003, the spontaneous reporting of ADRs was included as one of the objectives of hospital physicians at the Vall d'Hebron Hospital, Barcelona, Spain, within the context of management agreements between clinical services and hospital managers. A continuous intervention related to these management agreements, including periodic educational meetings and economic incentives, was then initiated. We carried out an ecological time series analysis and assessed the change in the total number of spontaneous reports of ADRs, and the number of serious ADRs, unexpected ADRs, and ADRs associated with new drugs between a period previous to the intervention (from 1998 to 2002) and the period during the intervention (from 2003 to 2005). A time series analysis with ARIMA (Auto-Regressive Integrated Moving Average) models was performed.The median number of reported ADRs per year increased from 40 (range 23-55) in the first period to 224 (range 98-248) in the second period. In the first period, the monthly number of reported ADRs was stable (3.47 per month; 95% CI 1.90, 5.03), but in the second period the number increased progressively (increase of 0.74 per month; 95% CI 0.62, 0.86). In the second period, the proportion of reported serious ADRs increased nearly 2-fold (63.1% vs 32.5% in the first period). The absolute number of previously unknown or poorly known ADRs increased 4-fold in the second period (54 vs 13 in the first period). There was also an increase in the absolute number of suspected pharmacological exposures to new drugs (97 vs 28) and in the number of different new drugs suspected of causing ADRs (50 vs 19).A continuous intervention based on healthcare management agreements with economic incentives and educational activities is associated with a quantitative and qualitative improvement of spontaneous reporting of ADRs by hospital physicians.

The pharmacological treatment of schizophrenia is currently based on restoring striatal dopamine and prefrontal cortex glutamate neurotransmission. However, these therapies are usually insufficient to completely manage all disease symptoms (i.e., negative and cognitive symptoms). Thus, the study of alternative and/or complementary neurotransmitter systems, which might impinge onto the etiology of schizophrenia, constitutes a big challenge for modern neuropsychiatry. Adenosine is a well known neuromodulator in the central nervous system (CNS) with beneficial properties for a number of brain disorders. The physiological effects of this nucleoside are mediated by G protein-coupled adenosine receptors, which have clearly evolved as drug targets for the pharmacotherapy of certain CNS diseases (e.g., Parkinson disease). Interestingly, it has been demonstrated that adenosine is able to modulate not only the dopaminergic but also glutamatergic system, thus representing a promising candidate to restore the schizophrenia-associated dopamine-glutamate imbalance that may underlie the origins of the disease. Accordingly, the development of drugs targeting adenosine receptors will constitute a worthwhile challenge for current neuropharmacology, because these compounds will definitively enrich the pharmacological arsenal and the pharmacotherapeutic opportunities surrounding schizophrenia.

To assess analgesic drugs in the treatment of postoperative pain after traumatic and orthopaedic surgery (TOS). A systematic review of randomised clinical trials (RCTs). Electronic PubMed, EMBASE, The Cochrane Library, and hand searches. RCTs of analgesics administered by oral, intramuscular, intravenous, subcutaneous or rectal route, were compared to other analgesics or placebo, in patients under TOS. Study design, characteristics of the study population, analgesic drugs tested, pain intensity and pain relief scores, and adverse effects were assessed. Ninety-two RCTs (9,596 patients) met our inclusion criteria. Forty-two (46%) were placebo-controlled, and 50 (54%) were direct comparisons between non-opioid, opioid, and/or combinations of both. Patients’ mean age (SD) was 49 years (18). In most trials, gastrointestinal ulcer, liver and renal diseases were exclusion criteria. Only 30 trials (33%) were double-blind and reported standardised outcomes of pain intensity and pain relief; 19 of these were single-dose, and follow up of analgesic effects lasted no more than 12 h in 23 (77%). Globally, only nine trials (10%) were double blind, described dropouts or withdrawals, performed analysis by intention to treat, and reported the effects magnitude. Evidence from RCTs on the treatment of postoperative pain after TOS is inadequate for clinical decision making. Assessment of analgesics in pain after TOS should be based on agreed clinically relevant outcomes, in representative patients, and for longer observation periods. In addition, it should include direct comparisons between candidate drugs or their combinations and between various drug administration schedules.

The aim of this study was to compare developments in the utilisation of antihyperglycaemic drugs (AHGDs) in ten European countries.Data on the yearly utilisation of insulin and oral AHGDs were collected from public registers in Denmark, Finland, Norway, Sweden, Belgium, England, Germany, Italy, Portugal and Spain, and were expressed as defined daily doses per 1,000 inhabitants per day.Total AGHD utilisation increased everywhere, but at different rates and levels. Insulin utilisation doubled in England and Germany, but hardly changed in Belgium, Portugal or Italy. Sulfonylurea utilisation doubled in Spain, England and Denmark but was reduced in Germany and Sweden. Metformin utilisation increased greatly everywhere. There were two- to three-fold differences in AHGD utilisation even between neighbouring countries. In Finland, there were more users of both insulin (+120%) and oral AHGDs (+80%) than in Denmark, and the daily oral AHGD doses were higher. In Denmark and Sweden, AHGD utilisation was equal in subjects aged45 years, but in thoseor=45 years of age, both insulin and oral AHGD utilisation were twice as high in Sweden.The ubiquitous increase in AHGD utilisation, particularly metformin, seems logical, considering the increasing prevalence of type 2 diabetes and the results of the UK Prospective Diabetes Study. However, the large differences even between neighbouring countries are more difficult to explain, and suggest different habits and attitudes in terms of screening and management of type 2 diabetes.

Lithium use for bipolar disorder has decreased in the United States. We aimed at studying lithium prescription in Spain from 1985 to 2003. Prescription data, expressed in daily defined dose per 1,000 inhabitants per day, were obtained. Lithium prescription increased uninterruptedly from 0.21 to 0.79 DID. The psychiatric reform in Spain and a broader definition of BD during the last decades are possible explanations for this rise.

Fundamento y objetivo: La prescripcion de medicamentos al alta hospitalaria implica a menudo la continuacion del tratamiento en atencion primaria. El objetivo del presente estudio fue evaluar la prescripcion de medicamentos genericos al alta en un servicio hospitalario de urgencias. Material y metodo: Estudio descriptivo, longitudinal y retrospectivo, sobre una muestra aleatoria de informes medicos de un servicio hospitalario de urgencias durante un ano (agosto de 2000 a julio de 2001). Se recogio informacion sobre la especialidad del medico, los medicamentos genericos prescritos y la oferta correspondiente de especialidades farmaceuticas genericas (EFG). Los factores asociados con la prescripcion de medicamentos genericos se analizaron mediante analisis de regresion logistica. Resultados: Se selecciono una muestra de 1.245 informes medicos en los que constaban 2.315 medicamentos prescritos. A pesar de que existia oferta de EFG para un 33,3% (intervalo de confianza [IC] del 95%, 31,4-35,2) de las prescripciones, estas especificaban una EFG en un 9,5% (IC del 95%, 8,3-10,7) de los casos. El precio medio de los medicamentos de marca comercial prescritos para los que habia oferta de EFG fue de 7,09 e (IC del 95%, 6,54-7,63 e) y el de las EFG correspondientes, de 5,08 e (IC del 95%, 4,68-5,48 e). Las variables asociadas con la prescripcion de medicamentos genericos fueron el periodo (odds ratio [OR] = 1,35; IC del 95%, 0,99-1,84), la especialidad del medico (OR = 1,40; IC del 95%, 1,05-1,86), la oferta de EFG (OR = 1,76; IC del 95%, 1,30-2,39) y el precio bajo del medicamento prescrito (OR = 2,67; IC del 95%, 1,80-3,98). Conclusion: La prescripcion de los medicamentos genericos en los informes de alta de este servicio de urgencias hospitalarias fue reducida, a pesar de que en muchos casos habia EFG disponibles. Es necesario fomentar la prescripcion y el uso de medicamentos genericos en los hospitales.

En la Conferencia de la OARS (Osteoarthritis Research Society, 1996) los medicamentos utilizados en el tratamiento de la artrosis se clasificaron según su mecanismo de acción en fármacos de acción sintomática y/o acción modificadora del curso de la enfermedad. Los medicamentos de acción sintomática comprenden los que actúan de forma rápida, como los analgésicos, antiinflamatorios no esteroideos (AINE) y corticoides, y los que actúan de forma más lenta como la glucosamina (vía oral), el condroitinsulfato (vía oral) y el ácido hialurónico (vía intraarticular), que también se denominan fármacos modificadores de los síntomas (symptomatic slow acting drug for osteoarthritis o SYSADOA) o del curso de la enfermedad.

G-protein-coupled receptors (GPCRs) represent the main family of cell surface receptors and are virtually expressed in all eukaryotic cells. Interestingly, a large number of clinically used drugs exert their pharmacological effect via a GPCR, thus it seems crucial to deeply understand the biology of these receptors. The study of GPCR activation and signaling has been classically performed by physiological, biochemical and pharmacological approaches using radioactivity-based tools. However, apart from the potential hazards of radioisotope handling and environmental burden, these approaches have some technical limitations. Therefore, the development of fluorescence-based techniques in general and fluorescence and bioluminescence resonance energy transfer (FRET and BRET) in particular have revolutionized the way to study GPCR functioning both in vitro and in vivo. Indeed, these techniques allow the characterization and visualization of all the individual GPCR signaling steps (i.e. ligand binding, receptor activation, G-protein coupling, G-protein activation, GPCR desensitization) with high temporal and spatial resolution. Here, we review the use and impact of fluorescent-based methodologies on the deciphering of GPCR biology.

En este articulo se revisan los estudios publicados durante los ultimos 2 anos sobre eficacia y seguridad de los principales grupos de farmacos utilizados en el tratamiento del asma y que se han considerado de mayor interes clinico. Los estudios fueron identificados a partir de la base de datos bibliografica informatizada Sistema de Informacion Esencial en Terapeutica y Salud (SIETES). SIETES es una base de datos sobre farmacoepidemiologia, farmacologia clinica y terapeutica en lengua castellana, que incluye mas de 50.000 referencias a partir de la revision manual de unas 150 revistas medicas, tanto nacionales como internacionales, y que recibe el apoyo del Programa de Medicamentos Esenciales de la OMS. La seleccion de las citas se realiza desde una perspectiva critica y basada en criterios de terapeutica razonada y seleccion adecuada de medicamentos (eficacia, toxicidad, conveniencia y coste) que recomienda la OMS. Dado que un componente importante de la atencion medica es la prescripcion de medicamentos, SIETES prioriza las informaciones que puedan contribuir a guiar al usuario en la seleccion de las estrategias terapeuticas ­sean o no farmacologicas­ mas adecuadas para cada patologia. La base de datos SIETES se encuentra actualmente en fase de desarrollo y puede ser consultada en Internet www.sietes.org Se realizo una busqueda con la palabra clave «asma», durante los dos ultimos anos (1999 y 2000). Se seleccionaron articulos originales sobre ensayos clinicos, metaanalisis, revisiones sistematicas, estudios observacionales analiticos o descriptivos con una priorizacion en el ambito de la atencion primaria. Se excluyeron los articulos de revision no sistematica. En el proceso de seleccion se consideraron la calidad metodologica del trabajo, su validez externa y su impacto, asi como su aportacion en el tratamiento de esta patologia. La revision se ha estructurado segun los diferentes grupos de farmacos empleados en el tratamiento del asma.

Objective: This study aims to ascertain the variability in the use of antibiotics for the treatment of acute respiratoryinfections in several hospital emergency services in Spain, as well as the appropriateness of antibiotics prescription through evaluation by a panel of experts using available scientific evidence. Method: A cross-sectional study was carried out in the emergency services of 10 hospitals in different Spanish regions. We chose patients diagnosed as having acute respiratory infection, aged over 14 years. Among the collected variables were: type of respiratory infection, antibiotic prescription, comorbidity, qualification of the prescribing doctor andhospital admission. The consensus conference held by a panel of experts established first choice treatment and the alternative and inappropriate use for each respiratory infection, based on the available scientific evidence. All the observed prescriptions in our study were classified according to this pattern. Results : A sample of 2899 acute respiratory infections was studied (5.5% of all emergencies). Antibacterial agenttreatment was prescribed in 82.6% of these, varying according to the infection between 98.5% of pneumonias and 49% of croup-influenza-common cold. The most commonly used antibiotics were amoxicillin-clavulanate and cefuroxime. The global percentage of inappropriate prescription was 40.5% (95% CI; 35.4–45.5). The prescriptions were inappropriate in 16.9% of cases of pharyngotonsillitis, 17.8% of chronic bronchitis, 26.9% of acute bronchitis, 29.3% of pneumonias, 30.8% of otitis and sinusitis and in 70.8% of croup, flu, common cold and non-specified infections. Significant variability among participating centres was observed, both in choice of antibiotics and in their degree of appropriateness. Conclusions: There is excessive use of antimicrobial drugs in acute respiratory infections, and the majority are used for viral infections. There is indiscriminate use of broad spectrum antibiotics, which are valid in some infections but clearlyinappropriate in others. Similarly, there are important differences in the choice of antibiotics and their degree ofappropriateness among hospitals.

Hospital Universitario San Juan, Alicante: Maria Jesu´s Olaso, Javier Agullo´, Clara Faura.Hospital Torreca´rdenas, Almeri´a: Carmen Ferna´ndez Sa´nchez, Miguel Lorenzo Campos, Juan Manuel Rodri´guez Alonso.Hospital Quiru´rgic Adriano, Barcelona: Carmen Alerany Pardo, Paquita Alvarez Gonza´lez, Teresa Marti´n Benito.Hospital Universitari del Mar-IMIM, Barcelona: Magi´ Farre´, Maite Tera´n.Corporacio´ Sanita`ria Parc Tauli´, Sabadell: Montserrat Can˜ellas, Sergio Zavala, Josep Planell.Hospital Universitari de la Santa Creu i Sant Pau: Gonzalo Calvo, Rosa Morros, Silvia Mateo.Hospital General Vall d’Hebron, Barcelona: Carmen Bosch, Mari´a Jose´ Marti´nez.Hospital Universitario Virgen de la Victoria, Ma´laga: Maribel Lucena, Jose´ Antonio Gonza´lez, Gabriel Carranque.Hospital Cli´nico Universitario San Carlos, Madrid: Emilio Vargas, Amparo Gil Lo´pez-Oliva, Mi´riam Garci´a Mateos.Hospital Universitario Marque´s de Valdecilla, Santander: Mario Gonza´lez, Antonio Cuadrado.Hospital Universitario Virgen de la Macarena, Sevilla: Juan Antonio Dura´n, Pilar Ma´yquez, Mari´a Isabel Serrano.Hospital Universitario Virgen del Roci´o, Sevilla: Jaume Torello´, Juan Ramo´n Castillo, Mari´a de las Nieves Merino.

The value of heparin in the prevention of venous thromboembolism has been shown effective and safe by controlled studies. However, how these studies have influenced physicians' decisions in thrombo-prophylaxis is not known. With the aim of evaluating the frequency and the appropriateness of prophylaxis for venous thromboembolism in our centre, we performed a cross-sectional study on a specific day. Among 667 patients who were admitted to hospital on this day, 134 (20 per cent) were receiving heparin. This had been prescribed for the prophylaxis of venous thromboembolism to 82 (12 per cent) patients. Immobilization was the risk factor most strongly associated with prophylaxis. Prophylaxis with heparin was only used in 79 out of 444 high-risk patients (21.6 per cent). One hundred and eighty-three patients had been subject to major surgery and heparin was being given only to 34 of them (18.6 per cent). A wide variability in the use of prophylaxis, depending on the hospital ward, was also recorded. We conclude that prophylaxis with heparin is underused in our milieu.

Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A(2A) receptors (A(2A)Rs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D(2) receptor (D(2)R). Furthermore, it is assumed that the formation of balanced A(2A)R/D(2)R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A(2A)R activation reduces the affinity of striatal D(2)R for dopamine and the blockade of A(2A)R with specific antagonists facilitates function of the D(2)R. Thus, it may be postulated that A(2A)R antagonists are pro-dopaminergic agents. Therefore, A(2A)R antagonists will potentially reduce the effects associated with dopamine depletion in Parkinson's disease (PD). Accordingly, this class of compounds have recently attracted considerable attention as potential therapeutic agents for PD pharmacotherapy as they have shown potential effectiveness in counteracting motor dysfunctions and also displayed neuroprotective and anti-inflammatory effects in animal models of PD. Overall, we provide here an update of the current state of the art of these A(2A)R-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Intravenous immunoglobulin (IVIG) use in non-approved indications, the increase in consumption and its high cost recommend rationalisation in its utilisation.To assess the use of IVIG in Spanish hospitals.An observational, prospective and multicentre drug utilisation study was conducted in 13 tertiary Spanish hospitals. Data were collected for 3 months in patients receiving any IVIG. Patient demographics, indication for IVIG use, dosage regimen and cost of treatment were collected.Five hundred and fifty-four patients (mean age of 52 years) were included in the study. A total of 1,287 prescriptions were administered, and the average number of prescriptions per patient was 2.3. The mean daily dose was 24 g (range 0.6-90 g). Overall, IVIG was prescribed for authorised indications in 335 patients (60%) with 953 prescriptions (74%), for non-authorised indications with scientific evidentiary support in 86 patients (16%) with 137 prescriptions (11%), and non-authorised and non-accepted indications in 133 patients (24%) with 197 prescriptions (15%). The most frequent authorised indications were primary and secondary immunodeficiencies, and the most frequent non-authorised and non-accepted indications were multiple sclerosis and bullous dermatosis. The mean cost of IVIG per patient for authorised indications was 2,636.2euro, non-authorised indications with scientific support 5,262.1euroand non-accepted indications 3,555.8euro.IVIG is prescribed for a significant number of non-authorised and non-accepted indications with a notable cost. There is an important variability in IVIG prescriptions between hospitals, indicating room for improvement in IVIG use and the need for a consensus of protocol use.

The aim of this study was to assess the analgesic treatment and the prevalence of pain in patients treated with analgesics in hospitals.Adult patients treated with analgesics were selected from a sample of 1,675 patients in a cross-sectional study carried out in 15 Catalonian hospitals (Spain). Patient characteristics, type of analgesics, treatment schedules, patients' pain intensity and clinical ward and hospital characteristics were assessed. Adherence to analgesic use guidelines was established according to the principles and recommendations of internationally recognised guidelines for pain management. Pain was determined by asking patients about pain intensity by means of a visual analogue scale (VAS).Analgesics were prescribed for 1,173 patients (70%; 95% CI: 67.4-72.6), in whom 57% (95% CI: 54.2-59.8) had pain and in whom 30.5% (95% CI: 27.9-33.1) pain intensity was greater than 30 mm. Adherence to analgesic treatment guidelines was judged appropriate in only 26.9% (95% CI: 24.4-29.4%) of all patients. The administered analgesic dose was in the recommended dose range in 42% (95% CI: 54-58) of all analgesics and in 28% (95% CI: 24-32) of opioid analgesics. A minority of patients was treated with a rescue schedule or patient-controlled analgesia (2%; 95% CI: 1.4-2.6). Pain prevalence was higher in those with analgesic treatment that did not adhere to guidelines (63.6%; 95% CI: 60.4-66.8) than in those considered as having appropriate adherence to guidelines (39.3%; 95% CI: 33.8-44.6) (p0.001). Adherence to analgesic treatment guidelines was higher in the large hospitals (21%; 95% CI: 18-24) than in medium and small hospitals (13%; 95% CI: 9-16) (p0.001).Although analgesic use is high in the hospital settings, adherence to the principles and recommendations of pain guidelines is low, and pain is usually common in patients treated with analgesics. These results once again emphasise the need to improve analgesic use and pain management in hospitals.

Main problem: Little is known about the methodological quality of guidelines for low back pain treatment. We evaluated the methods used by the developers according to established standards. Methods: PubMed, guideline databases, and the World Wide Web were used to identify guidelines. Seventeen guidelines met the inclusion criteria: interventions for low back pain stated, recommendations based on or explicitly linked to evidence, and English version available. Guidelines were evaluated independently by two appraisers using a practical tool for this purpose, Users’ Guides to the Medical Literature, and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Results: Thirteen guidelines (76%) specified the most important therapies applied, but only nine (53%) included a complete description of the target population. Explicit processes to identify, select, and combine evidence were described in only six guidelines (35%). Few guidelines (3; 18%) explicitly considered all main outcomes when formulating therapeutic recommendations, and none contained a process to determine the relative value of different outcomes. Methodological criteria for grading the strength of the recommendations varied, and were often insufficiently specified. None of the guidelines assessed the impact of uncertainty associated with the evidence and values used. According to AGREE the quality score was highest for the scope and purpose, and clarity and presentation domains, and lowest for editorial independence and applicability. With regard to the recommendations, there was consensus for some of the interventions for acute pain (analgesics and NSAIDs, maintaining physical activity, and avoiding excessive bed rest), but explicit recommendations were lacking or ambiguous for 41% of the interventions. Most of the guidelines did not contemplate specific recommendations for chronic pain. Conclusions: A small number of the available guidelines for low back pain treatment achieved acceptable results for specific quality criteria. In general, the methods to develop the guidelines’ therapeutic recommendations need to be more rigorous, more explicit and better explained. In addition, greater importance should be placed on the recommendations for chronic pain.

Objective To survey the prevalence of pain in patients admitted to different hospitals of Catalonia and to describe which factors are related to pain. Methods A cross-sectional study was performed in 1675 patients from fifteen hospitals in Catalonia (Spain). Clinical and demographic data, as well as the existence of pain intensity evaluations and analgesic therapy, were obtained from medical charts. Characteristics of pain were given by patients after being interviewed by trained interviewers. The main-outcome measure was the existence of pain (at the interview, in the previous 24 h, at the admission and at any time after admission) that was assessed by a visual analogue scale (VAS). The relationship of prevalence of pain to patients’ characteristics was carried out by means of a multiple-logistic-regression model with pain presence as the dependent variable of interest. Results A great variability in the prevalence and intensity of pain among different hospitals was observed. At the time of the interview, 48.5% (95% CI: 46.1–50.9%) of the patients had pain and the median VAS was 40 mm (range: 10–100 mm), and the prevalence of pain during the previous 24 h was similar (47.6%; 95% CI: 45.2–50%). At admission, 26.7% (95% CI: 24.6–28.8%) of patients were in pain, whereas 62% (95% CI: 59.7–64.3%) reported having pain at some time during their stay. Pain intensity annotations were absent in 51.3% (95% CI: 47.9–54.7%) of the medical records of the patients with pain. The factors associated with pain were younger age, female gender, presence of surgery, orthopaedic surgery wards, large hospital and prescribed analgesics. Conclusion A high prevalence of clinically relevant pain in in-patients was found as well as a great variability according to type of patients, clinical wards and hospitals. This study gives clear evidence of the lack of adequate management of pain in the majority of the hospitals and calls for the implementation of organisational and educational measurements that may settle this epidemic problem.

Objective: To assess the efficacy of oral drugs in the treatment of spasticity in patients with nonprogressive neurologic disease (NPND). Methods: Systematic review of double-blind randomized controlled trials of antispastic oral drugs in the treatment of spasticity in NPND. Data sources: Electronic MEDLINE, PubMed, Cochrane Library, and hand searches. Results: Twelve studies (469 patients) were included (6 on stroke, 3 on spinal cord diseases, and 3 on cerebral palsy). Tizanidine was assessed in four trials (276 patients, 142 exposed), dantrolene in four (103, 93), baclofen in three (70, 55), diazepam in two (127, 76), and gabapentin in one (28, all exposed). Most trials were of small size, of short duration, and their methodologic quality was inadequate. Ten trials were controlled with placebo and only two were direct comparisons between drugs. Efficacy outcome variables were heterogeneous. Only four reports described the magnitude of the antispastic effect. The incidence of adverse drug effects (drowsiness, sedation, and muscle weakness) was high. Conclusion: Evidence on the efficacy of oral antispastic drugs in NPND is weak and does not include evaluation of patients’ quality of life. If any, efficacy is marginal. Adverse drug reactions were common. Better methodologic instruments are needed for the evaluation of antispastic treatment.

Objective: To describe the prescribing patterns and their quality in relation to the prescriber’s medical speciality in a defined population. Methods: The study was done on a random sample of all primary care medical prescriptions made through the social security system during 1 year in Andorra, a small European country. Number and type of prescribed medicines, prescribers’ medical speciality and patients’ age and gender were recorded. Medical specialities considered were General Practice, Paediatrics, Cardiology, Pneumology, Gynaecology, Ophthalmology and Other. A set of various quality indicators [World Health Organisation (WHO)/International Network for Rational Use of Drugs (INRUD) indicators and others] was used. Results: The number of medicines prescribed per encounter varied depending on the prescriber’s medical speciality and patient’s age. Cardiologists and pneumologists tended to prescribe more medicines than other medical specialities. Patients older than 65 years received more prescriptions than younger adults, mostly at the expense of cardiovascular drugs. The contribution of the various groups and subgroups of medicines and the scores of various prescribing indicators showed wide variability across the medical specialities. Conclusion: Prescribing patterns and indicators of prescription quality show wide variability depending on the prescriber’s medical speciality. This has important implications for priority setting in information, continuous education and research.

Drug prescription at hospital discharge often implies continuation of the treatment in primary health care. The aim of this study was to assess prescription of generics at discharge from a hospital emergency service.Longitudinal and retrospective study, on a random sample of medical reports in a hospital emergency service during one year (August 2000 to July 2001). Information on the medical specialty, prescribed generic drugs and marked availability of the corresponding generic drugs pharmaceutical specialties was collected. Factors associated with generic prescription were analyzed by means of logistic regression analysis.A sample of 1,245 medical reports was selected in which 2,315 drugs were prescribed. Although generic drugs were available for 33.3% (CI 95%, 31.4-35.2) of prescriptions, 9.5% (95% CI, 8.3-10.7) of prescribed drugs were generics. The average price of trademark prescribed medicines, for which there was a generic equivalent, was 7.09 Euros (95% CI, 6.54-7.63 Euros), and that of the corresponding generic versions was 5.08 Euros (95% CI, 4.68-5.48 Euros). Variables associated with generic drug prescription included the particular study period (OR=1.35; 95% CI, 0.99-1.84), the medical specialty of the prescriber (OR=1.40; 95% CI, 1.05-1.86), availability of generic drugs (OR=1.76; 95% CI, 1.30-2.39) and low price of prescribed drugs (OR=2.67; 95% CI, 1.80-3.98).In spite of the availability of generic drugs, prescription of generic drugs at discharge of this hospital emergency service was low. Prescription and use of generic drugs should be promoted in hospitals.

Los antiinflamatorios no esteroideos (AINE) son ampliamente prescritos para el tratamiento de cuadros clinicos de dolor y procesos inflamatorios. No obstante, producen efectos adversos gastrointestinales que pueden ser graves y ser causa de ingreso hospitalario, sobre todo en los pacientes de edad avanzada. Estos efectos adversos son un problema de extraordinaria relevancia clinica, por su magnitud y gravedad, y, por tanto, es muy importante su prevencion. La prevencion de las ulceras gastrointestinales inducidas por AINE y sus complicaciones se basa en: a) el uso, siempre que sea posible, de los analgesicos sin efecto antiinflamatorio, y b) si es necesario el uso de un AINE, en la seleccion de los que tienen menor riesgo, en el empleo de dosis bajas, y en el uso de tratamientos profilacticos asociados en los pacientes de mayor riesgo (edad avanzada, antecedentes de ulcera peptica y complicaciones gastrointestinales y tratamiento concomitante con farmacos anticoagulantes y corticoides, entre otros). En este articulo de actualizacion se revisan y discuten los articulos originales mas relevantes que se han publicado durante los ultimos anos y en los que se ha evaluado el uso de nuevos AINE con un hipotetico menor riesgo gastrointestinal y en la eficacia de diferentes estrategias terapeuticas para prevenir el riesgo de las ulceras inducidas por AINE. Se han utilizado las palabras clave Anti-inflammatory agents, Non-steroidal, NSAID, Peptic ulcer, Prevention and control y Helicobacter pylori para la identificacion y seleccion de los articulos mas relevantes, a partir de las bases de datos bibliograficas PubMed, SIETES (www.sietes. org), Cochrane Database of Systematic Reviews y Cochrane Controlled Trials Register, publicados desde el ano 2000.

Objective: Postoperative pain is inadequately treated in many surgical settings. The present study evaluates the impact of analgesic drug-use guidelines in the management of postoperative pain. Patients and methods: A prospective drug utilization study was carried out in 3 stages in a traumatology, orthopedic and rehabilitation tertiary hospital. The first stage, aimed at describing the patterns of use of analgesic strategies in the management of postoperative pain, identified habits, practices and misconceptions regarding this therapeutic area. After this, an ad hoc representative institutional working group agreed on analgesic drug-use guidelines for the management of postoperative pain. These were then published, presented and discussed with surgeons and nurses. After the guidelines had been implemented, their impact was evaluated in terms of the analgesics used, their dosage and their administration schedule. Results: 101 patients were studied before the implementation of the guidelines and 108 patients after. Patients receiving opiate analgesics during the immediate postoperative period increased from 70 94% (p < 0.05). First-choice analgesics used according to the guidelines increased from 40- 89% of choices after the implementation of the guidelines (p < 0.05). Administration of analgesics at regular predetermined intervals increased from 45 - 58% of medical orders, but this increase was not statistically significant (p = 0.07). Prescription of analgesics at adequate doses increased from 67 - 87% (p < < 0.05). Conclusion: Education on the treatment of postoperative pain is made up of several messages including the drug of choice and dose regimen. Prescribers seemed more receptive to a change in drug rather than issues related to the correct dose regimen. More research is needed to assess how educational activities can improve the management of postoperative pain.

Objective. To describe the variability and appropriateness of antibiotic prescriptions in community-acquired acute respiratory infections (ARI) during childhood in Spain. Methods. A descriptive, multicenter study of variability in clinical practice was conducted by evaluating a prospective series of pediatric patients attending the emergency rooms of 11 Spanish hospitals and diagnosed with community-acquired ARI. The appropriateness of the antibiotic prescriptions was assessed by comparing our clinical practice with consensus guidelines developed for this study. Results. We collected data from 6,249 ARI emergencies studied on 30 separate days. Antibiotics were prescribed in 58.7% of the ARI (bronchiolitis, 11.5%; bronchitis, 40.2%; pharyngotonsillitis, 80.9%; nonspecified ARI, 34.8%; pneumonia, 92.4%; otitis, 93.4%; sinusitis, 92.6%). The most commonly used antibiotics were amoxicillin/ clavulanate (33.2%), amoxicillin (30.2%), cefuroxime axetil (8.5%) and azithromycin (6%). According to the consensus guidelines developed for this study, therapy was considered to be appropriate in 63.1% of the ARI (first choice, 52.1%; alternative choice, 11.0%) and inappropriate in 36.9%. The percentages of inappropriate prescription according to ARI groups were: bronchiolitis, 11.5%; bronchitis, 31.5%; pharyngotonsillitis, 54.8%; nonspecified ARI, 34.7%; pneumonia, 13.9%; otitis, 25.6%; and sinusitis, 22.2%. Conclusions. There is excessive use of antibiotics in acute respiratory infections that are presumably viral in origin. An important number of ARI of potentially bacterial origin are treated with antibiotics that are not sufficiently efficacious or that have a broader spectrum than necessary.

1. Thromboembolic disease (TED) is an important cause of in-hospital morbidity and mortality. Although different prophylactic approaches have been shown to be effective and cost-effective, surveys have suggested that they are underused. The aim of this study was to estimate the prevalence of use of TED prophylaxis in our hospitals. 2. All patients admitted on a specified day to the Internal Medicine and General Surgery wards of seven Spanish university hospitals were included in the study. They were identified cross-sectionally and followed up until discharge or for 15 days. Information about the following variables was collected: risk factors for venous thromboembolism, prophylactic measures used (if any), contraindications to the use of each specific drug or other prophylactic measure, and dosage schedule of the drug used, if any. 3. Nine hundred and thirty-nine patients (53% men) were studied. The most common risk factors for venous thromboembolism were: age > or = 40 years (802; 85%), major surgery (298; 32%), immobilization > or = 6 days (285; 30%), obesity (241; 26%), and cancer (202; 22%). 4. Prophylactic measures were used in 320 patients (34%). Of these, 297 (93%) received heparin, mainly as low molecular weight heparins (248, 78%); physical measures were rarely used. 5. Five hundred and eighty-three patients (62%) fulfilled criteria for moderate or high risk of venous thromboembolism; only 275 (47%) of them received any form of prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Several randomised clinical trials (RCTs) of analgesics in postoperative pain after traumatic or orthopaedic surgery (TOS) have been published, but no studies have assessed the quality of these reports. We aimed to examine the quality of reporting RCTs on analgesics for postoperative pain after TOS. Methods Reports of RCTs assessing analgesics in postoperative pain after TOS were systematically searched from electronic databases. The quality of reports was assessed using the CONSORT checklist (scoring range from 0 to 22). The quality was considered poor when scoring was 12 or lesser. The publication year and the impact factor of journals were recorded. Results A total of 92 reports of RCTs were identified and 69 (75%) scored 12 or lesser in CONSORT checklist (range 5-17). The mean (SD) CONSORT score of all reports was 10.6 (2.7). Missing CONSORT items included primary and secondary outcome measures (11%), the specific objectives and hypothesis definition (12%), the sample size calculation (12%), the dates defining the periods of recruitment (12%), the discussion of external validity of findings (14%), the allocation sequence generation (24%), and the interpretation of potential bias or imprecision of results (25%). There was a little improvement in CONSORT scores over time (r = 0.62; p < 0.001) and with impact factor of journals (r = 0.30; p < 0.001). Conclusion Quality of reporting RCTs on analgesics after TOS is poor. Reporting of those RCTs should be improved according to methodological standard checklists in the next years.

The aim of this study was to investigate the long-term effectiveness and safety of inhaled antibiotic treatment in non-cystic fibrosis patients with bronchiectasis and chronic infection by Pseudomonas aeruginosa, after standard endovenous and oral therapy for long-term control of the infection had failed. After completing a 2-week endovenous antibiotic treatment to stabilize respiratory status, 17 patients were randomly allocated to a 12-month treatment either with inhaled ceftazidime and tobramycin (group A) or a symptomatic treatment (group B). One patient from group A abandoned inhaled treatment because of bronchospasm and another from group B died before the end of the study. The remaining 15 patients, seven from group A and eight from group B, completed the study. Both groups had similar previous characteristics. The number of admissions and days of admission (mean ± sem) of group A [0·6 (1·5) and 13·1 (34·8)] were lower than those of group B [2·5 (2·1) and 57·9 (41·8)] (P