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INTRODUCTION: This study described, in routine clinical practice in Japan, the patient characteristics, treatment patterns, and outcomes of female patients with HR + /HER2- metastatic breast cancer (MBC) who started abemaciclib treatment. METHODS: Clinical charts were reviewed for patients starting abemaciclib in 12/2018-08/2021 with a minimum of 3 months follow-up data post-abemaciclib initiation regardless of abemaciclib discontinuation. Patient characteristics, treatment patterns, and tumor response were descriptively summarized. Kaplan-Meier curves estimated progression-free survival (PFS). RESULTS: 200 patients from 14 institutions were included. At abemaciclib initiation, median age was 59 years, and the Eastern Cooperative Oncology Group performance status score was 0/1/2 for 102/68/5 patients (58.3/38.9/2.9%), respectively. Most had an abemaciclib starting dose of 150 mg (92.5%). The percentage of patients receiving abemaciclib as 1st, 2nd, or 3rd line treatment was 31.5%, 25.8%, and 25.2%, respectively. The most frequent endocrine therapy drugs used with abemaciclib were fulvestrant (59%) and aromatase inhibitors (40%). Evaluation of tumor response was available for 171 patients, 30.4% of whom had complete/partial response. Median PFS was 13.0 months (95% CI 10.1-15.8 months). CONCLUSIONS: In a routine clinical practice setting in Japan, patients with HR + , HER2- MBC appear to benefit from abemaciclib treatment in terms of treatment response and median PFS, with the results broadly reflecting the evidence demonstrated in clinical trials.
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Neoplasias de la Mama , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/patología , Japón , Aminopiridinas/efectos adversos , Fulvestrant/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2RESUMEN
Affinity chromatography of crude human urinary proteins on either human rIL-6, human rIFN-gamma, or anti-IFN-gamma-R mAb yielded the two respective soluble receptors in significant quantities. A single sequence of 30 amino acid residues was obtained by NH2-terminal microsequencing of the protein peak purified in tandem by affinity chromatography on an IL-6 column and reversed-phase HPLC. This sequence was identical to the predicted NH2-terminal sequence of IL-6-R as previously reported. Analysis of the eluted proteins from both IFN-gamma and anti-IFN-gamma-R columns by inhibition of solid phase RIA, ELISA, SDS-PAGE, and Western blotting proved the existence of soluble IFN-gamma-R in normal urine. Our finding, together with the already known presence of urinary TNF binding proteins and a soluble IL-2-R both in plasma and in urine, indicates that release of soluble cytokine receptors into body fluids is a general phenomenon that occurs under normal physiological conditions.
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Interferón gamma/metabolismo , Interleucina-6/metabolismo , Receptores Inmunológicos/orina , Secuencia de Aminoácidos , Western Blotting , Cromatografía de Afinidad , Humanos , Datos de Secuencia Molecular , Peso Molecular , Receptores de Interferón , Receptores de Interleucina-6 , Proteínas Recombinantes , SolubilidadRESUMEN
The soluble interleukin 6 receptor (sIL-6R) circulates at elevated levels in various diseases. This suggests that inflammatory mediators control sIL-6R release. Through examination of human neutrophils, it was found that the acute phase reactant C-reactive protein (CRP) activates a threefold increase in sIL-6R production. Maximal release occurred after 30-60 min exposure to CRP (50 micrograms/ml), and was mimicked by peptides corresponding to amino acid residues 174- 185 and 201-206 of native CRP. A third peptide fragment (77-82) had no effect. Differential mRNA splicing did not account for the CRP-mediated release of sIL-6R, since this isoform was not detected in conditioned media. Furthermore, stimulation of neutrophils with CRP or with peptides 174-185 or 201-206 promoted a loss of membrane-bound IL-6R, suggesting release by proteolytic shedding. The metalloprotease inhibitor TAPI had only a marginal effect on CRP-mediated sIL-6R release, suggesting that shedding occurs via a mechanism distinct from that previously reported. It well established that IL-6 stimulates the acute phase expression of CRP. Our current findings demonstrate a novel relationship between these two mediators, since CRP may affect IL-6-mediated inflammatory events by enabling formation of the sIL-6R/IL-6 complex.
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Proteína C-Reactiva/farmacología , Mediadores de Inflamación/metabolismo , Neutrófilos/efectos de los fármacos , Receptores de Interleucina-6/metabolismo , Reacción de Fase Aguda , Proteína C-Reactiva/inmunología , Relación Dosis-Respuesta a Droga , Humanos , Ácidos Hidroxámicos/farmacología , Neutrófilos/inmunología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Inhibidores de Proteasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Empalme del ARN/efectos de los fármacos , SolubilidadRESUMEN
INTRODUCTION: This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. METHODS: EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. RESULTS: Of 1,831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline DISCUSSION: Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach.
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Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Cumplimiento de la Medicación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Antimaníacos/efectos adversos , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/diagnóstico , Estudios de Cohortes , Comorbilidad , Quimioterapia Combinada , Femenino , Humanos , Compuestos de Litio/efectos adversos , Masculino , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Trastornos Relacionados con Sustancias , Resultado del TratamientoRESUMEN
INTRODUCTION: The number needed to treat (NNT) for all-cause medication discontinuation in large, industry-sponsored, non-randomized, observational studies conducted across world geographies was compared with NNTs from CATIE, an 18-month, NIMH-sponsored, randomized study. METHODS: NNTs (with 95% confidence intervals) were calculated using data from 3 large Lilly-sponsored, non-randomized, observational studies (EU-SOHO, IC-SOHO, and US-SCAP, n=20 957). Group differences at medication initiation were adjusted by Cox regression modeling. These NNTs were compared with published NNTs for CATIE (phase 1). RESULTS: NNTs for olanzapine vs. risperidone and for olanzapine vs. quetiapine were similar across the observational studies and similar to those of CATIE. The NNTs for olanzapine vs. oral typical antipsychotics were similar across the observational studies but demonstrated a somewhat stronger effect size than the NNT reported for olanzapine vs. perphenazine in CATIE. DISCUSSION: NNTs for all-cause treatment discontinuation (a proxy measure of a medication's effectiveness from patients' and clinicians' perspectives) appear to be consistent across study designs (non-interventional, observational vs. RCT), study sponsorship (industry vs. independent), and across world geographies, suggesting that antipsychotics differ in this measure.
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Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Diseño de Investigaciones Epidemiológicas , Perfenazina/uso terapéutico , Esquizofrenia , Geografía , Humanos , National Institute of Mental Health (U.S.) , Olanzapina , Ensayos Clínicos Controlados Aleatorios como Asunto , Apoyo a la Investigación como Asunto , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/epidemiología , Resultado del Tratamiento , Estados UnidosRESUMEN
INTRODUCTION: In the present study, we examined the levels of the pro-inflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of Wegener's granulomatosis (WG) patients at various stages of the disease. PATIENTS AND METHODS: Sera from eight consecutive biopsy-proven systemic WG patients (four men and four women; age at diagnosis 58.4 +/- 13.8 years) were obtained longitudinally with a follow-up period of 55.2 +/- 30 months. Sera obtained from 50 healthy subjects were used as controls. RESULTS AND DISCUSSION: Serum levels of IL-18, IL-18BP, and free IL-18 obtained during an active phase of the disease (Birmingham Vasculitis Activity Score, BVAS > 10) were more than twofold higher than levels in the same patients during inactive disease stages (BVAS < 5; P < 0.002; P < 0.006, and P < 0.03 for IL-18, IL-18BP, and free IL-18, respectively). During inactive stages, the levels of these markers were comparable to those of healthy controls. The elevated levels of IL-18 and IL-18BP in sera during active stages of disease suggest a possible role in the pathogenesis and course of the WG. CONCLUSION: Despite the elevated IL-18BP levels during active disease, free IL-18 remained higher than in the inactive disease stages, suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active WG.
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Granulomatosis con Poliangitis/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Interleucina-18/sangre , Anciano , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Granulomatosis con Poliangitis/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
Leptin mediates its effects on food intake through the hypothalamic form of its receptor OB-R. Variants of OB-R are found in other tissues, but their function is unknown. Here, an OB-R variant was found in human hepatic cells. Exposure of these cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals.
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Proteínas Adaptadoras Transductoras de Señales , Insulina/farmacología , Proteínas/farmacología , Receptores de Superficie Celular , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Receptores ErbB/metabolismo , Proteína Adaptadora GRB2 , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Glucosa/metabolismo , Humanos , Antagonistas de Insulina , Proteínas Sustrato del Receptor de Insulina , Leptina , Hígado/citología , Hígado/metabolismo , Fosfatidilinositol 3-Quinasas , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotirosina/metabolismo , Proteínas/metabolismo , Receptor de Insulina/metabolismo , Receptores de Leptina , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Interferons, which induce several intracellular antiviral proteins, also induce an extracellular soluble protein that inhibits vesicular stomatitis virus (VSV) infection. This 28-kilodalton soluble protein was purified to homogeneity and identified by protein sequencing as the ligand-binding domain of the human 160-kilodalton low density lipoprotein receptor (LDLR). The existence of an antiviral soluble LDLR was confirmed by immunoaffinity chromatography with monoclonal antibody to LDLR. This soluble receptor mediates most of the interferon-triggered antiviral activity against VSV, apparently by interfering with virus assembly or budding, and not by inhibiting virus attachment to cells.
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Antivirales/biosíntesis , Interferón gamma/farmacología , Receptores de LDL/biosíntesis , Secuencia de Aminoácidos , Antivirales/química , Antivirales/aislamiento & purificación , Línea Celular , Células Cultivadas , Cromatografía de Afinidad , Medio de Cultivo Libre de Suero , Efecto Citopatogénico Viral , Células HeLa , Humanos , Interferón beta/farmacología , Datos de Secuencia Molecular , Peso Molecular , Receptores de LDL/química , Receptores de LDL/aislamiento & purificación , Solubilidad , Virus de la Estomatitis Vesicular Indiana/crecimiento & desarrolloRESUMEN
INTRODUCTION: Antipsychotic treatment dose adjustments may influence treatment outcomes in patients with schizophrenia. METHODS: We analysed data from 4,247 outpatients with schizophrenia who started olanzapine monotherapy in the 3-year, prospective, observational SOHO study to determine factors associated with olanzapine dose adjustments and how these impact on treatment effectiveness and tolerability. RESULTS: Regression analyses showed an association between changes in the Clinical Global Impression (CGI) and olanzapine dose changes: patients with a lack of effectiveness were more likely to have their dose increased, whereas patients with good treatment response were more likely to have a dose decrease. Improvement in tardive dyskinesia was associated with dose increase or no change (p=0.034) and worsening of sexual problems was associated with dose decrease (p=0.001). Conversely, an increase in olanzapine dose was associated with subsequent clinical improvement (CGI), but dose adjustment had no significant effects on tolerability outcomes. DISCUSSION: These results indicate that psychiatrists tend to modify olanzapine dose according to treatment response. Dose increases seem to be associated with a better response to treatment and not with a worsening of side-effects.
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Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Atención Ambulatoria , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Benzodiazepinas/administración & dosificación , Benzodiazepinas/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Discinesias/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Oportunidad Relativa , Olanzapina , Estudios Prospectivos , Análisis de Regresión , Disfunciones Sexuales Fisiológicas/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVES: The aim of this study was to compare the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a randomised controlled trial (RCT) assessing the same treatments. METHODS: EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with the treatment of mania. Severity of mania and depression were assessed at baseline and 6 weeks using the YMRS and the 5-item version of the HAMD, respectively. RESULTS: 621 patients were analysed (n=107 valproate, n=514 olanzapine). Both groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with greater mean improvements in the olanzapine compared with the valproate group. Olanzapine was associated with more weight gain and less gastrointestinal difficulties than valproate. DISCUSSION: The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy seems to be more effective than valproate monotherapy in the treatment of acute mania.
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Antimaníacos/uso terapéutico , Benzodiazepinas/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Adulto , Antidepresivos/uso terapéutico , Antimaníacos/efectos adversos , Benzodiazepinas/efectos adversos , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Masculino , Olanzapina , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Ácido Valproico/efectos adversos , Aumento de Peso/efectos de los fármacosRESUMEN
OBJECTIVE: To describe the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO) patient population at study entry, focusing on illness burden and prescribing practices across regions. METHODS: The SOHO study was a 3-year, prospective, observational study designed to assess costs and outcomes associated with antipsychotic use in outpatients initiating or changing antipsychotic (with an emphasis on olanzapine compared with other antipsychotics). SOHO was conducted in 10 European countries and 27 other countries as Intercontinental SOHO (IC-SOHO). Data from all countries have been pooled to produce the W-SOHO dataset. MAIN OUTCOMES MEASURES: Clinical Global Impression-Schizophrenia (CGI-SCH) severity scores, psychotropic medication use, adverse events, social interaction, housing and employment status, self-perceived health state (EuroQoL EQ-5D scale and Visual Analogue Scale, EQ-VAS), and reasons for initiation/change of antipsychotic. RESULTS: The W-SOHO database comprises 17,384 patients from six regions; East Asia (n = 1223), Central and Eastern Europe (n = 2175), Northern Europe (n = 4291), Southern Europe (n = 5788), Latin America (n = 2566), North Africa and the Middle East (n = 1341). Overall, patients were 38 +/- 13 years old (mean +/- SD), moderately ill (mean CGI-SCH overall score of 4.4 +/- 1.0) with a median duration of illness of 7 years (interquartile range 1-16 years); 43% were female, 10% were receiving antipsychotic medication for the first time. Adverse events were prevalent across all regions; on average, 50% (range 41-59%) of patients taking antipsychotics exhibited extrapyramidal symptoms at baseline, and 62% (34-67%) of patients reported sexual dysfunction in the previous month. On average, only 19% (16-23%) of patients were in paid employment and as many as 69% were living in dependent housing. CONCLUSIONS: Despite inherent diversity in these patients and the health care systems supporting them, there are striking cross-regional similarities in baseline characteristics for most measures. Not all countries are represented; regional comparisons may not be valid outside of the countries studied.
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Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adulto , Atención Ambulatoria/economía , Antipsicóticos/economía , Femenino , Humanos , Masculino , Estudios Prospectivos , Salud Rural , Esquizofrenia/economía , Resultado del Tratamiento , Salud UrbanaRESUMEN
The course of schizophrenia includes a combination of periods of remission and relapse. Previous studies focused on simple dichotomous outcomes and did not take into account the complexity of the course. Using data from a large 3-year follow-up study of schizophrenia, we described the different courses of schizophrenia. Of the 5950 patients with complete 3-year data, 38.7% never achieved remission (prolonged course), 15.7% achieved remission but relapsed and 45.7% achieved and maintained remission (persistent remission). Females, patients with better social functioning at baseline (living independently, in paid employment, socially active or having a spouse or partner) and with a shorter duration of illness had a more favourable course. Patients prescribed risperidone, quetiapine or depot typicals at the baseline visit were more likely to have a prolonged course than patients who started olanzapine. The results show that description of the long-term outcome of schizophrenia cannot be summarized with just one outcome variable.
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Antipsicóticos/uso terapéutico , Evaluación de Resultado en la Atención de Salud , Pacientes Ambulatorios , Esquizofrenia/tratamiento farmacológico , Intervalos de Confianza , Femenino , Humanos , Estudios Longitudinales , Masculino , Oportunidad Relativa , Escalas de Valoración Psiquiátrica , Recurrencia , Esquizofrenia/epidemiología , Esquizofrenia/fisiopatologíaRESUMEN
OBJECTIVE: Few studies have prospectively examined remission and recovery as well as their predictors in schizophrenia simultaneously. Aims of the study were to identify remission and recovery rates as well as their predictors in schizophrenia. METHOD: 392 never-treated patients with schizophrenia were assessed over 3 years. Combined remission and recovery required concurrent achievement of symptomatic and functional remission as well as adequate quality of life for at least 6 and 24 months respectively. Predictors were analysed using stepwise logistic regression models. RESULTS: At 3 years, remission rates for symptoms, functioning and subjective wellbeing were 60.3%, 45.4% and 57.0%; recovery rates were 51.7%, 35.0% and 44.3%. Of those, 28.1% were in combined remission and 17.1% in combined recovery. Predictors mainly included the baseline functional status and early remission within the first 3 months. CONCLUSION: The proportion of patients who met combined remission or recovery criteria is low. Early treatment adaptations in case of early non-remission are mandatory.
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Esquizofrenia/epidemiología , Adulto , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Empleo/psicología , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Olanzapina , Valor Predictivo de las Pruebas , Estudios Prospectivos , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Calidad de Vida , Remisión Espontánea , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Conducta Social , Resultado del Tratamiento , Adulto JovenRESUMEN
By using a sandwich ELISA, soluble human IL-6 receptor (sIL-6 R) levels were measured in the sera of 20 healthy children and of 25 patients with systemic juvenile rheumatoid arthritis (JRA). In patients with systemic JRA, serum sIL-6 R levels (114.6 +/- 37.7 ng/ml) were significantly lower (P < 0.01) than those of healthy children (161.2 +/- 45.5 ng/ml). Serum sIL-6 R levels were negatively correlated (r = -0.610, P < 0.001) with serum IL-6 levels measured with the B9 cells. The serum IL-6/sIL-6 R complex was detected using an ELISA based on a monoclonal antibody to IL-6 for capture and on a monoclonal antibody to human sIL-6 R for detection. Healthy controls had little, if any, detectable serum IL-6/sIL-6 R complex (OD 0.024 +/- 0.027), while the majority of patients with systemic JRA presented measurable serum IL-6/sIL-6 R complex (OD 0.492 +/- 0.546). IL-6 levels estimated in the circulating IL-6/sIL-6 R complexes were in the range of nanograms per milliliter and approximately 20-fold higher than those measured by the B9 cells. Since serum C-reactive protein concentrations were much more correlated with serum levels of IL-6/sIL-6 R complexes (r = 0.713, r2 = 0.51, P < 0.0001) than with the serum IL-6 levels measured with the B9 cells (r = 0.435, r2 = 0.19, P = 0.05), the large quantities of serum IL-6 present in IL-6/sIL-6 R complexes appear to be biologically relevant in vivo, at least as far as the induction by IL-6 of acute phase protein production.