RESUMEN
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.
Asunto(s)
Aminopiridinas/química , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Administración Oral , Aminopiridinas/metabolismo , Aminopiridinas/uso terapéutico , Animales , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/antagonistas & inhibidores , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Eliminación de Gen , Semivida , Humanos , Unión Proteica , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published. Here, the theory and design of a 3-stage single pass diafiltration step is presented. Buffer exchange greater than 99.75% was experimentally demonstrated. Several critical design aspects were incorporated to minimize system complexity and reduce the buffer volume requirements. Lastly, single pass diafiltration was demonstrated in a pilot scale continuous process with uninterrupted flow from the bioreactor through the formulation step. This work illustrates the feasibility of incorporating a single pass diafiltration step into an end-to-end continuous protein purification process. This article is protected by copyright. All rights reserved.
RESUMEN
The concept of continuous manufacturing has gained significant interest from the biopharmaceutical industry over the past several years. Benefits include increased manufacturing productivity, improved quality control, reduction in plant footprint, and more flexible management of facility capacity. There are several technologies currently available that enable continuous processing for chromatography and ultrafiltration. However, a single pass diafiltration design that meets the required small molecule clearance and has been integrated into a fully continuous monoclonal antibody purification process has not been previously published. Here, the theory and design of a 3-stage single pass diafiltration step is presented. Buffer exchange greater than 99.75% was experimentally demonstrated. Several critical design aspects were incorporated to minimize system complexity and reduce the buffer volume requirements. Lastly, single pass diafiltration was demonstrated in a pilot scale continuous process with uninterrupted flow from the bioreactor through the formulation step. This work illustrates the feasibility of incorporating a single pass diafiltration step into an end-to-end continuous protein purification process.
Asunto(s)
Anticuerpos Monoclonales/aislamiento & purificación , Biotecnología/métodos , Filtración/métodos , Factores Inmunológicos/aislamiento & purificación , Tecnología Farmacéutica/métodos , Antígenos HelmínticosRESUMEN
Dementia care environments are now home to thousands of people who have complex mental and physical health needs. Many of these people have lost capacity or have fluctuating capacity to make decisions about their care. There can be times when restrictive physical interventions are necessary to protect a person's wellbeing and to administer required treatment and care. However, nurses working in care settings may not be aware of their rights and liabilities, and those of care staff, when such interventions are used for therapeutic purposes. This article seeks to address areas of uncertainty and clarify the legal responsibilities of care teams by exploring the issues raised through a fictitious case vignette.
RESUMEN
OBJECTIVES: This study investigated the therapeutic alliance (TA) between clients and therapists involved in a telephone-based cognitive behaviour therapy (CBT) oriented psychological intervention for individuals experiencing psychosis. DESIGN: The telephone intervention involved recovery-focused CBT with use of a self-help guide and group intervention co-facilitated by colleagues with personal experience of psychosis. It was delivered as part of a Participant Preference Trial. METHODS: Twenty-one client/therapist dyads were examined within this study. In addition to a measure of TA, clients completed measures of depression, social functioning, symptom severity, and strength of treatment preference, while therapists completed measures related to the level of shared formulation, therapist confidence, and therapeutic change estimates. RESULTS: Therapeutic alliance levels were comparable to previously reported face-to-face psychosis intervention studies. Clients consistently reported significantly higher TA ratings compared to therapists. Depression scores and the strength of preference for treatment were significantly associated with client TA. Greater therapist perceived change was associated with higher therapist rated TA, while higher numbers of missed therapy sessions associated with lower therapist ratings. CONCLUSIONS: Telephone-based psychosis interventions may support the formation of positive relationships that are comparable to the quality of relationships developed between therapists and clients during face-to-face CBT therapy. Methodological limitations including low participant numbers and heightened risk of a Type I error necessitate caution when interpreting findings. Further research into therapist and client variables associated with TA is required. PRACTITIONER POINTS: Telephone delivered interventions to support people with psychosis-related difficulties can result in the development of a good quality TA between therapists and clients. There is a significant difference between therapist and client ratings of TA. Clients tend to score the quality of the TA significantly more highly than therapists. Providing clients with choice when participating in therapeutic interventions could potentially contribute towards improved TA reporting by clients.