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INTRODUCTION: Small cell lung cancer (SCLC) is an extremely aggressive tumour which metastasizes early. Even if chemotherapy can achieve an initial regression, relapses due to chemo-resistance are almost inevitable. Sethi et al (Nat Med. 1999;5:662-668) reported that matrix proteins are essentially involved in the development of drug resistance. SCLC cells in suspension culture secrete negligible amounts of matrix proteins AIM: For a more detailed study of the SCLC ability to produce matrix proteins we applied a recently introduced cell culture model of adherence selected SCLC (Salge et al. J Cancer Res Clin Oncol. 2001;127(2):139-411) and analysed pleural effusions form lung cancer patients. MATERIALS AND METHODS: Adherent cells were selected from the SCLC cell line NCI-H69 after exposure to cellular stress. Pleural effusion were obtained from lung cancer patients (SCLC and NSCLC) and from pleural effusions (PE) with congestive heart failure Protein expression was analysed by western blotting (WB) and flow cytometry using specific antibodies against the fibronectin extra domain A (FnEDA) and B (FnEDB) (Sirius, Italy), and for integrins alpha 1-5 and beta 1-3. Drug resistance was assessed with the metabolic stain MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromid). RESULTS: SCLC suspension cells expressed negligible amounts of fibronectin. In contrast, adherent H69 cells, which showed a significantly reduced chemo-sensitivity against carboplatin and doxorubicin, strongly expressed FnEDA and to a lesser extent FnEDB. Furthermore, in adherent cells expression of various integrins was up-regulated, in particular integrins alpha5/beta3, representing potential binding sites for FnEDA/FnEDB. Analysis of pleural effusions clearly showed the presence of FnEDA/ FnEDB in those of lung cancer patients, whereas in benign pleural effusion almost no FnEDA/ FnEDB was found. CONCLUSIONS: Our data reveal the presence of Fn, and its splice variants FnEDA/EDB in particular, in adherent SCLC cells as well as in malignant PE. We assume that the splice variants FnEDA/ FnEDB are linked to cancer progression and chemo-resistance in this tumour type.
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PURPOSE: Most common clinical studies with antiepileptic drugs do not reflect medical everyday practice due to their strict in- and exclusion criteria and specifications of treatment regimens. Here we present a large non-interventional registry with the intention to evaluate the spectrum of applications in daily use and the efficacy and tolerability of intravenously given levetiracetam (LEV-iv). METHODS: In a prospective approach of 17 neurological and neuropediatric centres in Germany LEV-iv treated patients of all ages were included over a period of 10 months. The observational period was 10 days with daily documentation of LEV-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events (AEs). In addition, treatment efficacy and tolerability were assessed by patients and physicians at study end as well as practicability of LEV-iv using a five-step scale. RESULTS: In 95 patients LEV-iv was administered, 93 were included into the analysis. The median LEV-iv dose was 1500 mg (range 110-6000 mg) per day. Median age was 66 years (range 0.7-90.3 years). The majority of patients (n=70, 75%) suffered from status epilepticus (SE, n=55, 59%) and acute seizure clusters (n=15, 16%). Of those with SE, 41 patients (75%) had SE for the first time. Acute seizure clusters and SE terminated in 83% after LEV-iv administration. A total of 29 adverse events were reported in 17 of the 95 patients from the safety set. Ten of these were at least possibly related to LEV-iv treatment. Slight decrease of blood pressure during the infusion (3 patients each) was captured most frequently. No serious side effect was observed. Physicians rated the efficacy and tolerability of LEV-iv treatment as good or very good in 78% and 82% of the cases, respectively. CONCLUSION: In this large observational study of everyday practise the use of LEV-iv exhibited a remarkable good response and tolerability in patients with acute onset seizures (mostly SE). Further randomized controlled studies, like the established status epilepticus trial (ESET) are needed to confirm these findings.
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Anticonvulsivantes/administración & dosificación , Piracetam/análogos & derivados , Estado Epiléptico/tratamiento farmacológico , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/efectos adversos , Niño , Preescolar , Femenino , Alemania , Humanos , Lactante , Levetiracetam , Masculino , Persona de Mediana Edad , Piracetam/administración & dosificación , Piracetam/efectos adversos , Estudios Prospectivos , Sistema de Registros , Adulto JovenRESUMEN
Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).
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Hipersensibilidad a las Drogas/prevención & control , Drogas en Investigación/normas , Guías como Asunto/normas , Terminología como Asunto , Alergia e Inmunología/normas , Hipersensibilidad a las Drogas/inmunología , Industria Farmacéutica/organización & administración , Industria Farmacéutica/normas , Drogas en Investigación/efectos adversos , Drogas en Investigación/uso terapéutico , Humanos , Innovación Organizacional , Política Organizacional , Estándares de ReferenciaRESUMEN
Treatment of haemophilia A by infusions of the clotting factor VIII (FVIII) results in the development of inhibitors/anti-drug antibodies in up to 25 % of patients. Mechanisms leading to immunogenicity of FVIII products are not yet fully understood. Amongst other factors, danger signals as elicited upon infection or surgery have been proposed to play a role. In the present study, we focused on effects of danger signals on maturation and activation of dendritic cells (DC) in the context of FVIII application. Human monocyte-derived DC were treated with FVIII alone, with a danger signal alone or a combination of both. By testing more than 60 different healthy donors, we show that FVIII and the bacterial danger signal lipopolysaccharide synergise in increasing DC activation, as characterised by increased expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. The degree and frequency of this synergistic activation correlate with CD86 expression levels on immature DC prior to stimulation. In our assay system, plasma-derived but not recombinant FVIII products activate human DC in a danger signal-dependent manner. Further tested danger signals, such as R848 also induced DC activation in combination with FVIII, albeit not in every tested donor. In our hands, human DC but not human B cells or macrophages could be activated by FVIII in a danger signal-dependent manner. Our results suggest that immunogenicity of FVIII is a result of multiple factors including the presence of danger, predisposition of the patient, and the choice of a FVIII product for treatment.
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Células Dendríticas/efectos de los fármacos , Factor VIII/farmacología , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Linfocitos B/efectos de los fármacos , Antígeno B7-2/análisis , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Sinergismo Farmacológico , Factor VIII/inmunología , Factor VIII/aislamiento & purificación , Factor VIII/uso terapéutico , Femenino , Hemofilia A/inmunología , Humanos , Imidazoles/farmacología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Plasma , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
Registries for rare diseases provide a tool for obtaining an overview of the clinical situation and can be used to discover points of improvement and to monitor long-term safety. Registries could also become a powerful tool to provide supporting information for marketing authorization. There is an urgent need for a pan-European or global strategy that supports consistent data. Therefore, transparency in data collection, harmonization of the database structures, and the convergence of scientific approaches are required.
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Bases de Datos Factuales , Medicina Basada en la Evidencia/métodos , Hemofilia A , Sistema de Registros , Acceso a la Información , Sistemas de Administración de Bases de Datos , Bases de Datos Factuales/normas , Medicina Basada en la Evidencia/normas , Guías como Asunto , Hemofilia A/diagnóstico , Hemofilia A/epidemiología , Hemofilia A/terapia , Humanos , Sistema de Registros/normasRESUMEN
Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real-life data sources may fill current evidence gaps concerning rare diseases.
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Hemofilia B , Humanos , Calidad de Vida , Enfermedades RarasAsunto(s)
Productos Biológicos/normas , Aprobación de Drogas/legislación & jurisprudencia , Evaluación Preclínica de Medicamentos/normas , Evaluación de Medicamentos/legislación & jurisprudencia , Industria Farmacéutica/legislación & jurisprudencia , Legislación de Medicamentos/organización & administración , Animales , Alemania , HumanosRESUMEN
The official experimental testing of biomedicinal products provides a very significant contribution to ensuring quality, safety and efficacy of these indispensable medicines. Already in the prelicensing phase or to elucidate clusters of increased adverse effects, official medicinal control laboratories are committed to perform experimental testing. The official batch release can be seen as external quality control of the manufacturer's release testing. For proficient performance in these tasks, scientific research is required, in particular on the development and refinement of test methods, and considering the continuous development of innovative biomedicinal products. This article is aimed at introducing the present thematic issue and in particular the regulatory basis of experimental product testing, and illustrates by means of several examples its great importance for the sake of the patients.
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Productos Biológicos/normas , Aprobación de Drogas/legislación & jurisprudencia , Evaluación Preclínica de Medicamentos/normas , Evaluación de Medicamentos/legislación & jurisprudencia , Legislación de Medicamentos/organización & administración , Vigilancia de Productos Comercializados/normas , Garantía de la Calidad de Atención de Salud/legislación & jurisprudencia , Contaminación de Medicamentos/legislación & jurisprudencia , Industria Farmacéutica/legislación & jurisprudencia , Alemania , Laboratorios/legislación & jurisprudencia , Administración de la Seguridad/legislación & jurisprudenciaRESUMEN
Inferring the cause of another person's emotional state is relevant for guiding behavior in social interactions. With respect to their potentially evoked behavioral reactions some emotional states like anger or happiness are considered to have high social impact while others such as fear and sadness have low social impact. We conducted a functional magnetic resonance imaging study to map the brain activation patterns related to reasoning about facial expressions of emotions with high or low social impact in twenty-six healthy volunteers with good emotional competence, self-reported empathy, and explicit facial affect recognition abilities. Our data show that empathic reasoning was faster and more accurate for high impact emotional states than for low impact emotional states. Activated brain areas involved brain circuits associated with basic and higher order empathy and decision-making in the dorsomedial and dorsolateral frontal cortex. However, activation in higher order areas was less during reasoning about emotional states of high social impact. Taken together, reasoning of high and low impact emotional states relied on similar empathy-related brain areas with reasoning about emotional states of low social impact being more erroneous and requiring more cognitive resources.
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Encéfalo/fisiología , Toma de Decisiones/fisiología , Emociones/fisiología , Expresión Facial , Percepción Social , Adulto , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The Biological Standardisation Programme (BSP) of the European Directorate for the Quality of Medicines & HealthCare (EDQM) was founded in 1992 with the objective to provide the necessary tools for the quality controls prescribed by the European Pharmacopoeia (Ph. Eur.). The BSP accomplishes this task by establishing reference standards and materials, as well as standardised control methods. A key aspect of BSP's work on development of methods is the validation of methods which can replace Ph. Eur. tests involving animals. The current area of work includes vaccines (for human and animal use), medicines produced from human plasma, hormones, cytokines, allergens, as well as reference materials and methods for determination of impurities and contaminations. BSP closely collaborates with the World Health Organization (WHO) and national authorities; many reference standards are established in joint projects with WHO. Participants of studies for establishing of reference materials and methods are mainly national control laboratories and manufacturers. BSP has to date run 131 projects, whereby 121 reference materials were established. Method development was the objective of 38 projects, with 21 thereof aiming at replacement of animal tests. BSP is funded by the EDQM (Council of Europe) and by the European Commission. With its activities BSP makes a significant contribution to quality, safety and efficacy of biological medicinal products in Europe and beyond, and serves thereby health and well-being of human beings and animals.
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Bioensayo/normas , Evaluación de Medicamentos/normas , Laboratorios/normas , Preparaciones Farmacéuticas/normas , Vigilancia de Productos Comercializados/normas , Europa (Continente) , Unión Europea/organización & administración , Internacionalidad , Estándares de Referencia , Valores de Referencia , Organización Mundial de la Salud/organización & administraciónRESUMEN
National Regulatory Authorities (NRAs) establish deferral criteria for donors with risk factors for transfusion transmissible infections (TTI). In most jurisdictions, epidemiological data show that men who have sex with men (MSM) have a significantly higher rate of TTI than the general population. Nevertheless, changes from an indefinite donor deferral for MSM have been considered in many countries in response to concerns over a perceived discrimination and questioning of the scientific need. Changes to MSM donor deferral criteria should be based on sound scientific evidence. Safety of transfusion recipients should be the first priority, and stakeholder input should be sought.
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Donantes de Sangre , Homosexualidad Masculina , Políticas de Control Social , Adulto , Seguridad de la Sangre , Selección de Donante , Humanos , Masculino , Factores de Riesgo , Reacción a la Transfusión , Viremia/etiologíaRESUMEN
This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement.
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Factores de Coagulación Sanguínea/uso terapéutico , Hemofilia A/tratamiento farmacológico , Niño , Consenso , Europa (Continente) , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
UNLABELLED: The German Haemophilia Registry records online data from patients with haemophilia A, haemophilia B, von Willebrand`s disease and other coagulation factor deficiency disorders since 2009. Patient's pseudonymised data will only be enrolled in the German Haemophilia Registry if the patient signs an informed consent. Without the informed consent, only aggregated data according to §21 German Transfusion Law are reported. These data include the number of persons with congenital haemostasis disorders classified to type of disease and severity as well as patients' age, and the consumption of clotting factor according to each group. RESULTS: The highest number of patients with haemophilia was reported in 2010: 3375 patients with haemophilia A and 614 with haemophilia B respectively; the highest number of patients with von Willebrand's disease was 1473, reported in 2011. CONCLUSION: In comparison to data from registries in Austria and Switzerland it can be assumed that most of the patients with severe haemophilia are registered in the German Haemophilia Registry whereas patients with moderate and mild forms are still missing.
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Factores de Coagulación Sanguínea/uso terapéutico , Encuestas de Atención de la Salud , Hemofilia A/mortalidad , Hemofilia A/terapia , Sistema de Registros/estadística & datos numéricos , Enfermedades de von Willebrand/mortalidad , Enfermedades de von Willebrand/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Austria/epidemiología , Niño , Preescolar , Femenino , Alemania/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de Supervivencia , Suiza/epidemiología , Adulto JovenAsunto(s)
Eliminación de Componentes Sanguíneos/normas , Transfusión de Componentes Sanguíneos/normas , Contaminación de Medicamentos/prevención & control , Etiquetado de Medicamentos/normas , Notificación Obligatoria , Guías de Práctica Clínica como Asunto , Transfusión de Componentes Sanguíneos/legislación & jurisprudencia , Donantes de Sangre/legislación & jurisprudencia , Contaminación de Medicamentos/legislación & jurisprudencia , AlemaniaRESUMEN
This report covers the blood supply situation in Germany over the past 12 years and provides detailed data on the years 2010 and 2011. Nearly 7.6 million donations, thereof 4.9 million whole blood donations, were reported in 2011 - the highest number since 1998. At the same time, 4.8 million red blood cell concentrates (RBC) were produced, the highest amount per year to date. While the RBC loss rate increased for both the manufacturers and the users, the RBC transfusion rate decreased for the first time since 2003. The number of platelet concentrates increased again to 0.57 million. About 60 % of this originated from apheresis donations. An amount of 3.4 million liters of plasma for fractionation was provided. Around 60 % was processed in Germany. The number of hematopoietic stem cell transplantations increased from 5,922 in 2009 to 7,093 in 2011. More than 99 % of the 16,364 transplants derived from peripheral blood and marrow; 43 % of the preparations were transplanted in Germany and 27 % were exported. Overall, the supply of blood products is considered to be good. However, because data are collected on an annual basis, seasonal shortages cannot be detected.
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Eliminación de Componentes Sanguíneos/estadística & datos numéricos , Donantes de Sangre/provisión & distribución , Transfusión Sanguínea/estadística & datos numéricos , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Sistema de Registros , AlemaniaRESUMEN
The recognition of emotional facial expressions is an important means to adjust behavior in social interactions. As facial expressions widely differ in their duration and degree of expressiveness, they often manifest with short and transient expressions below the level of awareness. In this combined behavioral and fMRI study, we aimed at examining whether or not consciously accessible (subliminal) emotional facial expressions influence empathic judgments and which brain activations are related to it. We hypothesized that subliminal facial expressions of emotions masked with neutral expressions of the same faces induce an empathic processing similar to consciously accessible (supraliminal) facial expressions. Our behavioral data in 23 healthy subjects showed that subliminal emotional facial expressions of 40 ms duration affect the judgments of the subsequent neutral facial expressions. In the fMRI study in 12 healthy subjects it was found that both, supra- and subliminal emotional facial expressions shared a widespread network of brain areas including the fusiform gyrus, the temporo-parietal junction, and the inferior, dorsolateral, and medial frontal cortex. Compared with subliminal facial expressions, supraliminal facial expressions led to a greater activation of left occipital and fusiform face areas. We conclude that masked subliminal emotional information is suited to trigger processing in brain areas which have been implicated in empathy and, thereby in social encounters.
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Encéfalo/irrigación sanguínea , Emociones/fisiología , Expresión Facial , Juicio/fisiología , Tiempo de Reacción/fisiología , Adulto , Encéfalo/fisiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangre , Reconocimiento Visual de Modelos , Estimulación Luminosa , Adulto JovenRESUMEN
The Rehabilitation Gaming System (RGS) has been designed as a flexible, virtual-reality (VR)-based device for rehabilitation of neurological patients. Recently, training of visuomotor processing with the RGS was shown to effectively improve arm function in acute and chronic stroke patients. It is assumed that the VR-based training protocol related to RGS creates conditions that aid recovery by virtue of the human mirror neuron system. Here, we provide evidence for this assumption by identifying the brain areas involved in controlling the catching of approaching colored balls in the virtual environment of the RGS. We used functional magnetic resonance imaging of 18 right-handed healthy subjects (24 ± 3 years) in both active and imagination conditions. We observed that the imagery of target catching was related to activation of frontal, parietal, temporal, cingulate and cerebellar regions. We interpret these activations in relation to object processing, attention, mirror mechanisms, and motor intention. Active catching followed an anticipatory mode, and resulted in significantly less activity in the motor control areas. Our results provide preliminary support for the hypothesis underlying RGS that this novel neurorehabilitation approach engages human mirror mechanisms that can be employed for visuomotor training.
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Encéfalo/fisiología , Imaginación , Desempeño Psicomotor , Interfaz Usuario-Computador , Adulto , Anticipación Psicológica , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neuronas Espejo/fisiologíaRESUMEN
Matrix metalloproteinases (MMPs) have been implicated to play an important role in the destruction of the extracellular matrix in diseases of the central nervous system. This study investigated whether the expression of one of these proteases, MMP-9 in blood, is related to the size of human brain infarcts assessed with magnetic resonance imaging. Consecutively, twenty-one acute stroke patients were included prospectively into our study. In blood samples drawn within 24 h after onset, MMP-9 RNA-expression and proteolytic-activity were analyzed by quantitative polymerase chain reaction and gelatin zymography, respectively. The ischemic lesion volumes in time to peak perfusion maps and diffusion weighted imaging were measured morphometrically. RNA-expression levels of MMP-9 in peripheral blood mononuclear cells (PBMCs) correlated with the brain infarct lesion (TTP-delay 4 s, r = -0.61, p = 0.007; TTP-delay 6 s: r = -0.58, p = 0.012; DWI r = -0.47; p = 0.047). Our preliminary results demonstrate that MMP-9 RNA is upregulated in PBMCs in proportion to ischemia. These findings suggest that MMP-9 might contribute to the manifestation of ischemic brain damage. Since MMP-9 is upregulated in acute ischemia inhibition of MMP-9 may represent a complementary treatment target in acute stroke therapy.