RESUMEN
We report the direct solution-phase characterization of individual gold-core silver-shell nanoparticles through an electrochemical means, with selectivity achieved between the core and shell components based on their different redox activities. The electrochemically determined core-shell sizes are in excellent agreement with electron microscopy-based results, successfully demonstrating the electrochemical characterization of individual core-shell nanoparticles.
RESUMEN
BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.
Asunto(s)
Cardiotónicos/farmacología , Péptido 1 Similar al Glucagón/farmacología , Inmunoconjugados/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Fragmentos de Péptidos/farmacología , Albúmina Sérica/inmunología , Anticuerpos de Dominio Único/farmacología , Animales , Cardiotónicos/administración & dosificación , Cardiotónicos/sangre , Cardiotónicos/farmacocinética , Modelos Animales de Enfermedad , Exenatida , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/farmacocinética , Receptor del Péptido 1 Similar al Glucagón , Inmunoconjugados/administración & dosificación , Inmunoconjugados/sangre , Inmunoconjugados/farmacocinética , Inyecciones Subcutáneas , Masculino , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/farmacocinética , Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Glucagón/agonistas , Receptores de Glucagón/genética , Anticuerpos de Dominio Único/administración & dosificación , Anticuerpos de Dominio Único/sangre , Ponzoñas/farmacología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
This meeting report presents the 2022 Annual Meeting of the cluster for Integrative Structural Biology at the University of Copenhagen (ISBUC) and discusses the cluster approach to interdisciplinary research management. This approach successfully facilitates cross-faculty and inter-departmental collaboration. Innovative integrative research collaborations ignited by ISBUC, as well as research presented at the meeting, are showcased.
Asunto(s)
Biología , Investigación InterdisciplinariaRESUMEN
Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.
Asunto(s)
COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Neoplasias , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Estudios Clínicos como Asunto , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunidad , SARS-CoV-2RESUMEN
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.
RESUMEN
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/inmunología , Neoplasias/complicaciones , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/inmunología , Estudios Prospectivos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto JovenRESUMEN
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Asunto(s)
Vacuna BNT162/inmunología , COVID-19/prevención & control , ChAdOx1 nCoV-19/inmunología , Neoplasias/inmunología , SARS-CoV-2/inmunología , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacuna BNT162/administración & dosificación , COVID-19/sangre , COVID-19/inmunología , ChAdOx1 nCoV-19/administración & dosificación , Femenino , Humanos , Inmunidad Celular , Inmunogenicidad Vacunal , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/complicaciones , Estudios Prospectivos , Linfocitos T/inmunologíaRESUMEN
CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.
Asunto(s)
Inmunidad Adaptativa/inmunología , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Carcinoma de Células Renales/complicaciones , Neoplasias Renales/complicaciones , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162/administración & dosificación , Vacuna BNT162/inmunología , COVID-19/complicaciones , COVID-19/epidemiología , Vacunas contra la COVID-19/administración & dosificación , ChAdOx1 nCoV-19/administración & dosificación , ChAdOx1 nCoV-19/inmunología , Femenino , Humanos , Inmunogenicidad Vacunal/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Estudios Prospectivos , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Linfocitos T/virología , Vacunación/métodosRESUMEN
The apelin receptor is a potential target in the treatment of heart failure and pulmonary arterial hypertension where levels of endogenous apelin peptides are reduced but significant receptor levels remain. Our aim was to characterise the pharmacology of a modified peptide agonist, MM202, designed to have high affinity for the apelin receptor and resistance to peptidase degradation and linked to an anti-serum albumin domain antibody (AlbudAb) to extend half-life in the blood. In competition, binding experiments in human heart MM202-AlbudAb (pKi = 9.39 ± 0.09) bound with similar high affinity as the endogenous peptides [Pyr1 ]apelin-13 (pKi = 8.83 ± 0.06) and apelin-17 (pKi = 9.57 ± 0.08). [Pyr1 ]apelin-13 was tenfold more potent in the cAMP (pD2 = 9.52 ± 0.05) compared to the ß-arrestin (pD2 = 8.53 ± 0.03) assay, whereas apelin-17 (pD2 = 10.31 ± 0.28; pD2 = 10.15 ± 0.13, respectively) and MM202-AlbudAb (pD2 = 9.15 ± 0.12; pD2 = 9.26 ± 0.03, respectively) were equipotent in both assays, with MM202-AlbudAb tenfold less potent than apelin-17. MM202-AlbudAb bound to immobilised human serum albumin with high affinity (pKD = 9.02). In anaesthetised, male Sprague Dawley rats, MM202-AlbudAb (5 nmol, n = 15) significantly reduced left ventricular systolic pressure by 6.61 ± 1.46 mm Hg and systolic arterial pressure by 14.12 ± 3.35 mm Hg and significantly increased cardiac contractility by 533 ± 170 mm Hg/s, cardiac output by 1277 ± 190 RVU/min, stroke volume by 3.09 ± 0.47 RVU and heart rate by 4.64 ± 2.24 bpm. This study demonstrates that conjugating an apelin mimetic peptide to the AlbudAb structure retains receptor and in vivo activity and may be a new strategy for development of apelin peptides as therapeutic agents.
Asunto(s)
Receptores de Apelina/agonistas , Apelina/farmacología , Albúmina Sérica/farmacología , Animales , Receptores de Apelina/metabolismo , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , Contracción Miocárdica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas GRESUMEN
We have used phage display to isolate a range of human domain antibodies (dAbs) that bind to mouse, rat and/or human serum albumin (SA) and can be expressed at very high levels in bacterial, yeast or mammalian cell culture. In contrast to non-SA-binding dAbs, which have terminal half-lives of less than 45 min, the half-lives of these 12 kDa 'AlbudAbs' can match the half-life of SA itself. To demonstrate the use of AlbudAbs for extending the half-lives of therapeutic drugs, we created a fusion of the interleukin-1 receptor antagonist (IL-1ra) with an AlbudAb. Soluble IL-1ra is potent inhibitor of IL-1 signalling that is approved for the treatment of rheumatoid arthritis but has a relatively short in vivo half-life. Here we show that although the AlbudAb/IL-1ra fusion has a similar in vitro potency, its in vivo efficacy can be dramatically improved due to its extended serum half-life. AlbudAbs could potentially be used to generate a range of long half-life versions of many different drugs in order to improve their dosing regimen and/or clinical effect.
Asunto(s)
Albúminas/química , Química Farmacéutica/métodos , Industria Farmacéutica/métodos , Ingeniería de Proteínas/métodos , Secuencia de Aminoácidos , Animales , Colágeno/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Proteína Antagonista del Receptor de Interleucina 1/química , Ratones , Datos de Secuencia Molecular , Biblioteca de Péptidos , Ratas , Homología de Secuencia de AminoácidoAsunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Neoplasias Hematológicas/inmunología , Inmunización Secundaria , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/complicaciones , COVID-19/epidemiología , Neoplasias Hematológicas/complicaciones , Humanos , Inmunogenicidad Vacunal , Neoplasias/complicaciones , Neoplasias/inmunología , Evaluación de SíntomasRESUMEN
OBJECTIVE: The current study sought to explore how, if at all, people construct an understanding of the origin and maintenance of their experience of hearing voices. METHOD: A social constructionist grounded theory method was adopted throughout the research process. Eight voice hearers, who were distressed by this experience, were recruited and interviewed. RESULTS: Three overarching descriptive categories were constructed regarding participants' understanding of the development and maintenance of hearing voices; search for meaning, view of self, and framework for understanding voices. The "essence" of the developing grounded theory was that individuals actively searched for meaning of their voices through different frameworks, but the relative "success" of this pursuit, and potential usefulness of an understanding, is influenced by the individual's perceptions of agency, stigma, and hope(lessness). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This research illustrates how voice hearers actively searched for meaning in relation to their voices and the challenges they encountered during this process. One clinical implication from this study emphasizes the potential role of psychological formulation in generating a shared understanding of the voices. Future research is warranted to explore voice hearers from a wider range of cultural, religious, and spiritual backgrounds.
Asunto(s)
Alucinaciones/psicología , Trastornos Psicóticos/psicología , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Adulto , Femenino , Alucinaciones/etiología , Humanos , Masculino , Persona de Mediana Edad , Teoría Psicológica , Trastornos Psicóticos/complicaciones , Esquizofrenia/etiologíaRESUMEN
Occurring naturally in "heavy chain" immunoglobulins from camels, and now produced in fully human form, domain antibodies (dAbs) are the smallest known antigen-binding fragments of antibodies, ranging from 11 kDa to 15 kDa. dAbs are the robust variable regions of the heavy and light chains of immunoglobulins (VH and VL respectively). They are highly expressed in microbial cell culture, show favourable biophysical properties including solubility and temperature stability, and are well suited to selection and affinity maturation by in vitro selection systems such as phage display. dAbs are bioactive as monomers and, owing to their small size and inherent stability, can be formatted into larger molecules to create drugs with prolonged serum half-lives or other pharmacological activities.
Asunto(s)
Anticuerpos/farmacología , Región Variable de Inmunoglobulina/farmacología , Animales , Anticuerpos/química , Anticuerpos/genética , Anticuerpos/uso terapéutico , Especificidad de Anticuerpos , Clonación Molecular , Humanos , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/uso terapéutico , Biblioteca de Péptidos , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologíaRESUMEN
PURPOSE: The purpose of this review was to identify, appraise, and synthesize the current peer-reviewed qualitative literature which explores the phenomenon of hearing voices from a first person perspective. METHODS: A comprehensive systematic search of the literature was conducted. Seven studies utilizing various qualitative methodologies met the criteria to be included in the synthesis. An appraisal tool (Walsh & Downe, 2005, J. Adv. Nurs., 50, 204-211) was used to assess their quality. A meta-ethnographic approach was used to synthesize the data extracted from them. RESULTS: The interpretation of the findings suggested five key themes: identity of the voice(s), power of the voice(s), impact of hearing voices on relationships, relationship with the voice(s), and the distinction between thoughts and voices. The identity of the voices seemed inextricably linked to the perceived power the voice(s) wielded over the voice hearer. The quality of the studies included in the synthesis varied greatly. CONCLUSIONS: The findings of this synthesis highlight the importance of the voice hearer's individual frame of reference for understanding their experience. Clinical implications include the need for mental health professionals to explore an individual's understanding of their experience of hearing voices and address the perceived power of the voice(s). Further research is indicated in this area with a focus of improving the quality of qualitative research studying this phenomenon. PRACTITIONER POINTS: There are multiple frames of reference in which to understand an individual's experience of hearing voices. Mental health professionals should attend to the meaning and understanding voice hearers give to the experience.
Asunto(s)
Antropología Cultural/métodos , Alucinaciones/psicología , HumanosRESUMEN
Increasing serum residence time of drugs by means of fusing them to albumin-binding domain antibodies (AlbudAbs™) has previously been documented. AlbudAbs™ provide a valuable method for increasing the efficacy of drugs by extending the time for which therapeutic levels of drug are present in the body and also for increasing the convenience to the patient by reducing the need for frequent dosing. Here, we describe methods that could be used preclinically to determine the suitability of drug-AlbudAbs™ for development. Particular focus is given to suggested in vivo study design which could enable the fitting of accurate PK parameters, assay methods for concentration determination of AlbudAbs™ in blood samples, and to the protocols used to fit PK parameters to AlbudAb™ concentration data. Whilst the examples cited here are focussed on the AlbudAb™ technology, similar methods could be used for assessing the success of other half-life extension technologies (drug Fc fusions, PEGylated drugs).
Asunto(s)
Portadores de Fármacos/farmacocinética , Anticuerpos de Dominio Único/metabolismo , Administración Intravenosa , Albúminas/química , Albúminas/inmunología , Animales , Anticuerpos/sangre , Anticuerpos/inmunología , Portadores de Fármacos/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Mediciones Luminiscentes , Masculino , Proteínas Proto-Oncogénicas c-myc/química , Proteínas Proto-Oncogénicas c-myc/inmunología , Conejos , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/farmacocinética , Anticuerpos de Dominio Único/administración & dosificación , Anticuerpos de Dominio Único/inmunologíaRESUMEN
Serum albumin-binding domain antibodies (AlbudAbs) have previously been shown to greatly extend the serum half-life of the interleukin-1 receptor antagonist IL-1ra. We have subsequently extended this approach to look at the in vitro activity, in vivo efficacy and pharmacokinetics of an agonist molecule, interferon (IFN)-alpha2b, fused to an AlbudAb. Here we describe this molecule and show that in this format AlbudAb half-life extension technology displays significant advantages in comparison with other methods of half-life extension, in particular genetic fusion to serum albumin. When compared directly IFN-alpha2b fused to an Albudab shows higher potency, increased serum half-life and greater efficacy than human serum albumin fused to IFN-alpha2b. AlbudAbs are therefore an ideal platform technology for creation of therapeutics with agonist activity and long serum half-lives.
Asunto(s)
Anticuerpos/genética , Interferón-alfa/farmacocinética , Albúmina Sérica/inmunología , Anticuerpos/química , Anticuerpos/inmunología , Humanos , Interferón alfa-2 , Interferón-alfa/química , Interferón-alfa/farmacología , Ingeniería de Proteínas/métodos , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes , Albúmina Sérica/química , Resonancia por Plasmón de Superficie , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To investigate the effectiveness of an educational Quality Use of Medicines program, delivered at the level of general practice, on medicines use, falls and quality of life in people aged > or = 65 years. DESIGN: Cluster randomised controlled trial conducted in 2002. SETTING: General practices in the Hunter Region, New South Wales, Australia. PARTICIPANTS: Twenty general practitioners recruited 849 patients to participate in the study. INTERVENTION: Education (academic detailing, provision of prescribing information and feedback); medication risk assessment; facilitation of medication review; financial incentives. PRIMARY MEASURES: a composite score reflecting use of benzodiazepines, non-steroidal anti-inflammatory drugs (NSAIDs) and thiazide diuretics; secondary measures: use of medication reviews, occurrence of falls, quality of life (as assessed by SF-12 and EQ-5D survey scores. RESULTS: Compared with the control group, participants in the intervention group had increased odds of having an improved medication use composite score (odds ratio [OR], 1.86; 95% CI, 1.21-2.85) at 4-month follow-up but not at 12 months. At 4-month follow-up, the intervention group had reduced odds of using NSAIDs (OR, 0.62; 95% CI, 0.39-0.99) and showed a non-significant reduction in use of benzodiazepines (OR, 0.51; 95% CI, 0.20-1.30) and thiazide diuretics (OR, 0.70; 95% CI, 0.48-1.01). Changes in drug use were not significant at 12-month follow-up. At 12 months, intervention-group participants had lower adjusted ORs (AORs) for having a fall (AOR, 0.61; 95% CI, 0.41-0.91), injury (AOR, 0.56; 95% CI, 0.32-0.96), and injury requiring medical attention (AOR, 0.46; 95% CI, 0.30-0.70). Quality-of-life scores were unaffected by the intervention. CONCLUSION: Education and systems for medication review conducted by GPs can be used to improve use of medicines. These interventions are associated with a reduction in falls among older people, without adverse effects on quality of life.