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1.
Ann Neurol ; 93(5): 1023-1028, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36897287

RESUMEN

OBJECTIVE: This study was undertaken to examine the association between montelukast use, ß2-adrenoreceptor (ß2AR) agonist use, and later Parkinson disease (PD). METHODS: We ascertained use of ß2AR agonists (430,885 individuals) and montelukast (23,315 individuals) from July 1, 2005 to June 30, 2007, and followed 5,186,886 PD-free individuals from July 1, 2007 to December 31, 2013 for incident PD diagnosis. We estimated hazard ratios and 95% confidence intervals using Cox regressions. RESULTS: We observed 16,383 PD cases during on average 6.1 years of follow-up. Overall, use of ß2AR agonists and montelukast were not related to PD incidence. A 38% lower PD incidence was noted among high-dose montelukast users when restricted to PD registered as the primary diagnosis. INTERPRETATION: Overall, our data do not support inverse associations between ß2AR agonists, montelukast, and PD. The prospect of lower PD incidence with high-dose montelukast exposure warrants further investigation, especially with adjustment for high-quality data on smoking. ANN NEUROL 2023;93:1023-1028.


Asunto(s)
Enfermedad de Parkinson , Quinolinas , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Acetatos/efectos adversos , Ciclopropanos , Quinolinas/efectos adversos
2.
Synapse ; 77(4): e22269, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36951466

RESUMEN

Corticobasal syndrome (CBS) is associated with 4-repeat tauopathy and/or Alzheimer's disease pathologies. To examine tau and amyloid-ß (Aß) deposits in CBS patients using positron emission tomography (PET). Eight CBS patients and three healthy individuals lacking amyloid pathology underwent PET with [11 C]PBB3 for tau imaging, and [11 C]AZD2184 for Aß. Subcortical and cortical binding of [11 C]PBB3 was compared between Aß(-) and Aß(+) CBS patients and reference group. Postmortem analysis was done in one CBS patient. Three CBS patients were considered Aß(+). Total binding was higher in all patients compared to the reference group. Similar regional binding profiles of [11 C]PBB3 in Aß(+) and Aß(-) CBS patients were found. Elevated [11 C]PBB3 binding in pallidum was observed in all CBS patients. Cortical [11 C]PBB3 binding was higher in Aß(+) compared to Aß(-) patients. Postmortem analysis of a CBS patient revealed corticobasal degeneration neuropathology and [11 C]PBB3 autofluorescence in some tau-positive structures. [11 C]PBB3 is elevated in CBS patients with binding in relevant areas capturing some, but not all, 4-repeat tauopathy in CBS.


Asunto(s)
Enfermedad de Alzheimer , Degeneración Corticobasal , Tauopatías , Humanos , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Tauopatías/patología , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones/métodos
3.
Lancet ; 397(10277): 892-901, 2021 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-33676628

RESUMEN

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma de Células B/patología , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Resultado del Tratamiento
4.
Int J Mol Sci ; 22(11)2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-34070609

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder where misfolded alpha-synuclein-enriched aggregates called Lewy bodies are central in pathogenesis. No neuroprotective or disease-modifying treatments are currently available. Parkinson's disease is considered a multifactorial disease and evidence from multiple patient studies and animal models has shown a significant immune component during the course of the disease, highlighting immunomodulation as a potential treatment strategy. The immune changes occur centrally, involving microglia and astrocytes but also peripherally with changes to the innate and adaptive immune system. Here, we review current understanding of different components of the PD immune response with a particular emphasis on the leukotriene pathway. We will also describe evidence of montelukast, a leukotriene receptor antagonist, as a possible anti-inflammatory treatment for PD.


Asunto(s)
Acetatos/uso terapéutico , Antiinflamatorios/uso terapéutico , Ciclopropanos/uso terapéutico , Antagonistas de Leucotrieno/uso terapéutico , Enfermedad de Parkinson , Quinolinas/uso terapéutico , Sulfuros/uso terapéutico , Astrocitos/metabolismo , Astrocitos/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Cuerpos de Lewy/metabolismo , Cuerpos de Lewy/patología , Microglía/metabolismo , Microglía/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Receptores de Leucotrienos/metabolismo
5.
Oncologist ; 24(9): e930-e942, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30833489

RESUMEN

BACKGROUND: The purpose of this nonrandomized, open-label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer. MATERIALS AND METHODS: This was a multicenter, nonrandomized, open-label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four-cohort dose-confirmation study (part B) and subsequently a four-part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts. RESULTS: The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease. CONCLUSION: This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation. IMPLICATIONS FOR PRACTICE: Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.


Asunto(s)
Colangiocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Indazoles/administración & dosificación , Niacinamida/análogos & derivados , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Proliferación Celular/efectos de los fármacos , Cetuximab/administración & dosificación , Colangiocarcinoma/patología , Cisplatino/administración & dosificación , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Gemcitabina , Ramucirumab
6.
J Pharmacol Exp Ther ; 366(1): 96-104, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29691287

RESUMEN

Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterize tumor growth dynamics and also optimize upcoming experiments. To the best of our knowledge, this is the first report where unperturbed growth of a large set of tumor cell lines (n = 28) has been systematically analyzed using a previously proposed model of nonlinear mixed effects (NLME). Exponential growth was identified as the governing mechanism in the majority of the cell lines, with constant rate values ranging from 0.0204 to 0.203 day-1 No common patterns could be observed across tumor types, highlighting the importance of combining information from different cell lines when evaluating drug activity. Overall, typical model parameters were precisely estimated using designs in which tumor size measurements were taken every 2 days. Moreover, reducing the number of measurements to twice per week, or even once per week for cell lines with low growth rates, showed little impact on parameter precision. However, a sample size of at least 50 mice is needed to accurately characterize parameter variability (i.e., relative S.E. values below 50%). This work illustrates the feasibility of systematically applying NLME models to characterize tumor growth in drug discovery and development, and constitutes a valuable source of data to optimize experimental designs by providing an a priori sampling window and minimizing the number of samples required.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Modelos Estadísticos
7.
Clin Lung Cancer ; 23(4): 300-310, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35400584

RESUMEN

INTRODUCTION: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. PATIENT AND METHODS: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%). RESULTS: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). CONCLUSION: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Clorhidrato de Erlotinib , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Mutación/genética , Estudios Retrospectivos
8.
Ther Drug Monit ; 33(6): 663-72, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22105583

RESUMEN

BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h(-1)·kg(-0.75) immediately after transplantation, increasing to a maximum of 1.37 L·h(-1)·kg(-0.75). Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.


Asunto(s)
Rechazo de Injerto/prevención & control , Inmunosupresores/farmacocinética , Trasplante de Hígado/efectos adversos , Modelos Biológicos , Tacrolimus/farmacocinética , Adolescente , Teorema de Bayes , Niño , Preescolar , Simulación por Computador , Esquema de Medicación , Monitoreo de Drogas , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Lactante , Absorción Intestinal , Masculino , Registros Médicos , Tasa de Depuración Metabólica , Periodo Posoperatorio , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Tacrolimus/sangre , Tacrolimus/uso terapéutico
9.
Environ Health ; 10: 96, 2011 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-22074398

RESUMEN

BACKGROUND: While environmental research addresses scientific questions of possible societal relevance, it is unclear to what degree research focuses on environmental chemicals in need of documentation for risk assessment purposes. METHODS: In a bibliometric analysis, we used SciFinder to extract Chemical Abstract Service (CAS) numbers for chemicals addressed by publications in the 78 major environmental science journals during 2000-2009. The Web of Science was used to conduct title searches to determine long-term trends for prominent substances and substances considered in need of research attention. RESULTS: The 119,636 journal articles found had 760,056 CAS number links during 2000-2009. The top-20 environmental chemicals consisted of metals, (chlorinated) biphenyls, polyaromatic hydrocarbons, benzene, and ethanol and contributed 12% toward the total number of links- Each of the top-20 substances was covered by 2,000-10,000 articles during the decade. The numbers for the 10-year period were similar to the total numbers of pre-2000 articles on the same chemicals. However, substances considered a high priority from a regulatory viewpoint, due to lack of documentation, showed very low publication rates. The persistence in the scientific literature of the top-20 chemicals was only weakly related to their publication in journals with a high impact factor, but some substances achieved high citation rates. CONCLUSIONS: The persistence of some environmental chemicals in the scientific literature may be due to a 'Matthew' principle of maintaining prominence for the very reason of having been well researched. Such bias detracts from the societal needs for documentation on less well known environmental hazards, and it may also impact negatively on the potentials for innovation and discovery in research.


Asunto(s)
Bibliometría , Contaminantes Ambientales/toxicidad , Toxicología , Contaminantes Ambientales/clasificación , Factor de Impacto de la Revista , Análisis de Regresión , Proyectos de Investigación
10.
J Clin Epidemiol ; 133: 24-31, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33359253

RESUMEN

OBJECTIVE: Medline/PubMed is often first choice for health science researchers when doing literature searches. However, Medline/PubMed does not cover the health science research literature equally well across specialties. Embase is often considered an important supplement to Medline/PubMed in health sciences. The present study analyzes the coverage of Embase as a supplement to PubMed, and the aim of the study is to investigate if searching Embase can compensate for low PubMed retrieval. STUDY DESIGN AND SETTING: The population in this study is all the included studies in all Cochrane reviews from 2012 to 2016 across the 53 Cochrane groups. The analyses were performed using two units of analysis (study and publication). We are examining the coverage in Embase of publications and studies not covered by PubMed (25,119 publications and 9,420 studies). RESULTS: The results showed that using Embase as a supplement to PubMed resulted in a coverage of 66,994 publications out of 86,167 and a coverage rate of 77.7, 95% CI [75.05, 80.45] of all the included publications. Embase combined with PubMed covered 48,326 out of 54,901 studies and thus had a coverage rate of 88.0%, 95% CI [86.2, 89.9] of studies. The results also showed that supplementing PubMed with Embase increased coverage of included publications by 6.8 percentage points, and the coverage of studies increased by 5.5 percentage points. Substantial differences were found across and within review groups over time. CONCLUSION: The included publications and studies in some groups are covered considerably better by supplementing with Embase, whereas in other groups, the difference in coverage is negligible. However, due to the variation over time, one should be careful predicting the benefit from supplementing PubMed with Embase to retrieve relevant publications to include in a review.


Asunto(s)
Bases de Datos Bibliográficas/estadística & datos numéricos , Almacenamiento y Recuperación de la Información/métodos , MEDLINE/estadística & datos numéricos , PubMed/estadística & datos numéricos , Informe de Investigación , Revisiones Sistemáticas como Asunto/métodos , Humanos
11.
J Immunother ; 44(7): 264-275, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-33928928

RESUMEN

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60-600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non-small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Indolamina-Pirrol 2,3,-Dioxigenasa , Neoplasias Pulmonares , Neoplasias de la Mama Triple Negativas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/sangre , Quinurenina/sangre , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo
12.
J Thorac Oncol ; 15(1): 80-90, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31622732

RESUMEN

INTRODUCTION: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC. METHODS: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. RESULTS: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]). CONCLUSIONS: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.


Asunto(s)
Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico
13.
BMJ Open ; 10(12): e042142, 2020 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-33372078

RESUMEN

OBJECTIVES: The overall study aim was to synthesise understandings and experiences regarding the concept of spiritual care (SC). More specifically, to identify, organise and prioritise experiences with the way SC is conceived and practised by professionals in research and the clinic. DESIGN: Group concept mapping (GCM). SETTING: The study was conducted within a university setting in Denmark. PARTICIPANTS: Researchers, students and clinicians working with SC on a daily basis in the clinic and/or through research participated in brainstorming (n=15), sorting (n=15), rating and validation (n=13). RESULTS: Applying GCM, ideas were identified, organised and prioritised online. A total of 192 unique ideas of SC were identified and organised into six clusters. The results were discussed and interpreted at a validation meeting. Based on input from the validation meeting a conceptual model was developed. The model highlights three overall themes: (1) 'SC as an integral but overlooked aspect of healthcare' containing the two clusters SC as a part of healthcare and perceived significance; (2) 'delivering SC' containing the three clusters quality in attitude and action, relationship and help and support, and finally (3) 'the role of spirituality' containing a single cluster. CONCLUSION: Because spirituality is predominantly seen as a fundamental aspect of each individual human being, particularly important during suffering, SC should be an integral aspect of healthcare, although it is challenging to handle. SC involves paying attention to patients' values and beliefs, requires adequate skills and is realised in a relationship between healthcare professional and patient founded on trust and confidence.


Asunto(s)
Terapias Espirituales , Espiritualidad , Adulto , Actitud del Personal de Salud , Femenino , Personal de Salud , Humanos , Masculino , Persona de Mediana Edad
14.
Ther Drug Monit ; 31(4): 457-66, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19531982

RESUMEN

The population pharmacokinetics of tacrolimus was described in 22 pediatric hematopoietic stem cell transplant recipients, and a model-based dosage adjustment tool that may assist with therapy in new patients was developed. Patients received tacrolimus by continuous intravenous (IV) infusion (0.03 mg x kg(-1) x d(-1)) starting 2 days before transplantation, with conversion to oral therapy 2-3 weeks after transplant. Population pharmacokinetic analysis was performed using NONMEM. A Bayesian dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counterbalanced by the final population model, was created in Excel. Typical clearance was 106 mL x h(-1) x kg(-0.75), typical distribution volume was 3.71 L/kg, and typical bioavailability was 15.7%. Tacrolimus clearance decreased with increasing serum creatinine, and bioavailability decreased with postoperative day. A Bayesian dosage adjustment tool capable of suggesting an initial infusion rate based on patient covariate values and devising a further individualized dosage regimen as drug concentration measures become available was developed. Predictions from the model showed that current IV dose recommendations of 0.03 mg x kg(-1) x d(-1) may potentially produce toxic drug concentrations in this patient population, whereas current oral conversion of 4 times the adjusted IV dose may lead to subtherapeutic concentrations. A more suitable infusion rate to obtain a steady state concentration of 12 ng/mL was predicted to be 0.035 mg x kg(-0.75) x (-1)d. An additional loading dose of 0.07 mg x kg(-1) x d(-1) (total dose: 0.07 mg x kg(-1) x d(-1) + 0.035 mg x kg(-0.75) x d(-1)) during the first 24 hours of therapy should allow rapid achievement of steady state concentrations. A conversion factor of 6 from IV to enteric therapy may be more suitable. Such dosage recommendations may be site specific. The appropriateness of targets was not investigated in this study. The Bayesian dosing adjustment tool and suggested dose recommendations need to be evaluated in a prospective study before they can be applied in the clinical setting.


Asunto(s)
Relación Dosis-Respuesta a Droga , Inmunosupresores/farmacocinética , Tacrolimus/farmacocinética , Adolescente , Disponibilidad Biológica , Niño , Rechazo de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Pediatría , Grupos de Población , Estudios Prospectivos , Factores de Tiempo
15.
Clin Cancer Res ; 12(18): 5481-90, 2006 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-17000683

RESUMEN

PURPOSE: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs. EXPERIMENTAL DESIGN: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made. RESULTS: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha1-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction. CONCLUSIONS: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Neutropenia/inducido químicamente , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Docetaxel , Interacciones Farmacológicas/inmunología , Etopósido/efectos adversos , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Persona de Mediana Edad , Modelos Teóricos , Neutrófilos/efectos de los fármacos , Paclitaxel/efectos adversos , Caracteres Sexuales , Taxoides/efectos adversos , Topotecan/efectos adversos
16.
Clin Pharmacokinet ; 56(5): 505-514, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27696220

RESUMEN

Necitumumab is a second-generation, recombinant, human immunoglobulin G1, epidermal growth factor (EGFR) receptor antibody that specifically blocks the ligand binding site of EGFR. Necitumumab potentially acts by blocking ligand epidermal growth factor (EGF) binding-mediated activation of the EGFR signaling pathway, inhibiting tumor growth, angiogenesis, and anti-apoptotic mechanisms. Necitumumab inhibited the interaction of EGF and EGFR with a concentration that inhibits binding by 50 % of approximately 0.9 nM (0.13 mg/L) and demonstrated antitumor activity during in vivo experiments associated with trough plasma concentrations of approximately 40 mg/L. This work describes the population pharmacokinetics of necitumumab in cancer patients when administered with or without concomitant chemotherapy and evaluates patient characteristics that may guide dosing. Nonlinear mixed-effects modeling of serum concentration data across five clinical studies (phases I-III) indicated that necitumumab exhibited target-mediated drug disposition, commonly observed with monoclonal antibodies, and that pharmacokinetics were expected to be linear in the studied dose ranges when administered as repeated infusions. No age, sex, race, or concomitant medication factors were found influential, while weight was a statistically significant factor for both distribution and elimination. Simulations from the final model indicated that only a limited reduction in patient drug exposure variability would be achieved by weight- or body surface area-based dosing. Necitumumab effective half-life was estimated to approximately 2 weeks, and steady state was achieved within three to four cycles of treatment. The phase III dosing schedule of 800 mg dosed on days 1 and 8 of a 21-day schedule resulted in serum concentrations that exceeded the 40-mg/L threshold indicated by preclinical experiments.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Modelos Biológicos , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Factor de Crecimiento Epidérmico/metabolismo , Femenino , Humanos , Inmunoglobulina G/metabolismo , Masculino , Persona de Mediana Edad , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Adulto Joven
17.
Neurosci Lett ; 399(1-2): 85-90, 2006 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-16469445

RESUMEN

Substantial evidence has established that activation of the NMDA receptor in the spinal dorsal horn is essential for central sensitization-a phenomenon which comprises various pathophysiological mechanisms underlying neuropathic pain-like signs in animal models. In the present study, a partial sciatic nerve ligation in the rat was used to produce a model of nerve injury-induced pain represented by hypersensitivity to innocuous stimuli ("allodynia"). The aim was to assess whether alteration of NMDA receptor expression correlates with the presence of neuropathic signs. Our approach was to compare spinal NMDA receptor subunit expression and especially subunit 1 phosphorylation, assessed with immunohistochemistry and Western blot at late postoperative times, between nerve-injured rats with marked signs of neuropathy in terms of mechanical and cold hypersensitivity and nerve-injured rats that lacked robust behavioral signs of neuropathy. Quantification of receptor expression was based on comparisons between the dorsal horns ispi- and contralateral to the nerve lesion. The phosphorylated NR1 subunit of the NMDA receptor was found to be significantly increased in the ipsilateral dorsal horn in hypersensitive, but not in non-hypersensitive nerve-injured rats. We did not detect any differences in immunoreactivity in any of the non-phosphorylated NR1, NR2A, NR2B, NR2C or the NR2D subunits. These data suggest that phosphorylation of the NMDA receptor 1 subunit is correlated to the presence of signs of neuropathy (stimulus evoked pain-like behavior) and possibly also to persistent pain following nerve injury. This may represent a mechanism involved in spinal sensitization.


Asunto(s)
Dolor/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Médula Espinal/metabolismo , Animales , Frío , Inmunohistoquímica , Masculino , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Fosforilación , Células del Asta Posterior/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/biosíntesis , Nervio Ciático/lesiones , Tacto
19.
Cancer Chemother Pharmacol ; 78(2): 271-80, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27312733

RESUMEN

PURPOSE: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors. METHODS: Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations. RESULTS: Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration-QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation. CONCLUSIONS: The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Electrocardiografía , Síndrome de QT Prolongado/inducido químicamente , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología
20.
Basic Clin Pharmacol Toxicol ; 97(5): 261-75, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16236137

RESUMEN

Bibliometric studies are increasingly being used for research assessment. Bibliometric indicators are strongly methodology-dependent but for all of them, various types of data normalization are an indispensable requirement. Bibliometric studies have many pitfalls; technical skill, critical sense and a precise knowledge about the examined scientific domain are required to carry out and interpret bibliometric investigations correctly.


Asunto(s)
Bibliometría , Bases de Datos Bibliográficas , Publicaciones Periódicas como Asunto/normas , MEDLINE , Investigación
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