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AIM: The purpose of the study was to investigate whether course transformation teaching strategies using repetitive quizzing and peer-tutor supplemental instruction help enhance students' learning experiences and learning outcomes based on self-determination theory. BACKGROUND: Undergraduate baccalaureate pharmacology and pathophysiology courses were redesigned as part of a campus-wide course transformation program to promote students' perceptions of learning and academic achievement. METHOD: Students in the nursing pathopharmacology course participated in the two-time online perception survey (pretest and posttest) and knowledge-based exams. RESULTS: Results revealed that the course transformation implemented to support students' basic psychological needs was significantly associated with both learning outcomes and students' feelings of competence while also decreasing attrition rates. CONCLUSION: Considering the depth and breadth of pathopharmacology content, the teaching intervention using repetitive quizzing and peer-tutor supplemental instruction may contribute to improving students' understanding of the course content while promoting their competence.
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Bachillerato en Enfermería , Estudiantes de Enfermería , Humanos , Bachillerato en Enfermería/métodos , Estudiantes de Enfermería/psicología , Aprendizaje , Curriculum , Encuestas y CuestionariosRESUMEN
Supported work internship programmes for young adults with disability are an evidence-based model, leading to greater employment outcomes. This mixed methods pilot study evaluated the experiences of students, supervisors and a project coordinator, who participated in an Integrated Practical Placement (IPP) programme for students with disability in Australia. Intervention students (n = 10) completed 3, 9-week rotations, and accessed personal placement support and employment coaches. Comparison students (n = 38) completed 3, 2-week placements without additional support. Intervention students perceived significantly greater initial changes in work skills (p < 0.01) and work readiness (p < 0.05). Intervention students reported development of communication and self-organisational skills and stressed the value of staff support. Post programme 70% of intervention students gained employment, compared with 15.4% of comparison students. The findings suggest an evidence-based supported employment programme emphasising personalised assessment and training, could provide individuals with disability the required skills to enable successful employment.
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Personas con Discapacidad , Discapacidad Intelectual , Adulto Joven , Humanos , Proyectos Piloto , Estudiantes , AustraliaRESUMEN
BACKGROUND: Theory-based and qualitative evaluations in pilot trials of complex clinical interventions help to understand quantitative results, as well as inform the feasibility and design of subsequent effectiveness and implementation trials. AIM: To explore patient, family, clinician and volunteer ('stakeholder') perspectives of the feasibility and acceptability of a multicomponent non-pharmacological delirium prevention intervention for adult patients with advanced cancer in four Australian palliative care units that participated in a phase II trial, the 'PRESERVE pilot study'. DESIGN: A trial-embedded qualitative study via semi-structured interviews and directed content analysis using Michie's Behaviour Change Wheel and the Theoretical Domains Framework. SETTING/PARTICIPANTS: Thirty-nine people involved in the trial: nurses (n = 17), physicians (n = 6), patients (n = 6), family caregivers (n = 4), physiotherapists (n = 3), a social worker, a pastoral care worker and a volunteer. RESULTS: Participants' perspectives aligned with the 'capability', 'opportunity' and 'motivation' domains of the applied frameworks. Of seven themes, three were around the alignment of the delirium prevention intervention with palliative care (intervention was considered routine care; intervention aligned with the compassionate and collaborative culture of palliative care; and differing views of palliative care priorities influenced perspectives of the intervention) and four were about study processes more directly related to adherence to the intervention (shared knowledge increased engagement with the intervention; impact of the intervention checklist on attention, delivery and documentation of the delirium prevention strategies; clinical roles and responsibilities; and addressing environmental barriers to delirium prevention). CONCLUSION: This theory-informed qualitative study identified multiple influences on the delivery and documentation of a pilot multicomponent non-pharmacological delirium prevention intervention in four palliative care units. Findings inform future definitive studies of delirium prevention in palliative care.Australian New Zealand Clinical Trials Registry, ACTRN12617001070325; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373168.
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Delirio , Neoplasias , Adulto , Australia , Delirio/prevención & control , Humanos , Neoplasias/complicaciones , Cuidados Paliativos , Proyectos PilotoRESUMEN
Background: Delirium is a common debilitating complication of advanced cancer. Objective: To determine if a multicomponent nonpharmacological delirium prevention intervention was feasible for adult patients with advanced cancer, before a phase III (efficacy) trial. Design: Phase II (feasibility) cluster randomized controlled trial. All sites implemented delirium screening and diagnostic assessment. Strategies within sleep, vision and hearing, hydration, orientation, mobility, and family domains were delivered to enrolled patients at intervention site admission days 1-7. Control sites then implemented the intervention ("waitlist sites"). Setting: Four Australian palliative care units. Measurements: The primary outcome was adherence, with an a priori endpoint of at least 60% patients achieving full adherence. Secondary outcomes were interdisciplinary care delivery, delirium measures, and adverse events, analyzed descriptively and inferentially. Results: Sixty-five enrolled patients (25 control, 20 intervention, and 20 waitlist) had 98% delirium screens and 75% diagnostic assessments completed. Nurses (67%), physicians (16%), allied health (8.4%), family (7%), patients (1%), and volunteers (0.5%) delivered the intervention. There was full adherence for 5% patients at intervention sites, partial for 25%. Both full and partial adherence were higher at waitlist sites: 25% and 45%, respectively. One-third of control site patients (32%) became delirious within seven days of admission compared to one-fifth (20%) at both intervention and waitlist sites (p = 0.5). Mean (standard deviation) Delirium Rating Scale-Revised-1998 scores were 16.8 + 12.0 control sites versus 18.4 + 8.2 (p = 0.6) intervention and 18.7 + 7.8 (p = 0.5) waitlist sites. The intervention caused no adverse events. Conclusion: The intervention requires modification for optimal adherence in a phase III trial.
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Delirio , Neoplasias , Adulto , Australia , Delirio/prevención & control , Hospitalización , Humanos , Neoplasias/complicaciones , Proyectos PilotoRESUMEN
BACKGROUND: Life expectancy in patients with end-stage kidney disease treated with hemodialysis (HD) is limited, and as such, the presence of an advanced care directive (ACD) may improve the quality of death as experienced for patients and families. Strategies to discuss and implement ACDs are limited with little being known about the status of Do Not Resuscitate (DNR) orders in the Canadian HD population. OBJECTIVES: Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), we set out to (1) examine the variability in DNR orders across Canada and its largest province, Ontario and (2) identify clinical and functional status measures associated with a DNR order. DESIGN: We conducted a retrospective cohort study using data from the DOPPS Canada Phase 4 to 6 from 2009 to 2017. SETTING: DOPPS facilities in Canada. PATIENTS: All adults (>18 years) who initiated chronic HD with a documented ACD were included. MEASUREMENTS: ACD and DNR orders. METHODS: Descriptive statistics were compared for baseline characteristics (demographics, comorbidities, medications, facility characteristics, and patient functional status) and DNR status. The crude proportion of patients per facility with a DNR order was calculated across Canada and Ontario. Functional status was determined by activities of daily living and components of the Kidney Disease Quality of Life (KDQOL)-validated questionnaire. We used generalized estimating equations (GEEs) to create sequential multivariable models (demographics, comorbidities, and functional status) of variables associated with DNR status. RESULTS: A total of 1556 (96% of total) patients treated with HD had a documented ACD and were included. A total of 10% of patients had a DNR order. The crude variation of DNR status differed considerably across facilities within Canada, between Ontario and non-Ontario, and within Ontario (interprovince variation = 6.3%-17.1%, Ontario vs non-Ontario = 8.2% vs 11.7%, intraprovincial variation [Ontario] = 1%-26%). Patients with a DNR order were more commonly older, white, with cardiac comorbidities, with less or shorter predialysis care compared with those without a DNR order. Patients with a DNR order reported lower energy, more difficulty with transfers, meal preparation, household tasks, and financial management. In a multivariate model, age, cardiac disease, stroke, dialysis duration, and intradialytic weight gain were associated with DNR status. LIMITATIONS: Relatively small number of events or measures in certain categories. CONCLUSIONS: A large inter- and intraprovincial (Ontario) variation was observed regarding DNR orders across Canada highlighting areas for potential quality improvement. While functional status did not appear to have a bearing on the presence of a DNR order, the presence of various comorbidities was associated with the presence of a DNR order.
CONTEXTE: L'espérance de vie des patients atteints d'insuffisance rénale terminale (IRT) traités par hémodialyse (HD) est limitée et, de ce fait, la présence de directives médicales anticipées (DMA) peut améliorer la qualité du décès tel qu'il sera vécu par les patients et leurs proches. Les stratégies de discussion et de mise en Åuvre de DMA sont limitées et on en sait peu sur le statut des ordonnances de non-réanimation (statut des ONR) dans la population des patients canadiens hémodialysés. OBJECTIFS: À partir des données de l'étude DOPPS (Dialysis Outcomes and Practice Patterns Study), nous avons analysé la variabilité du statut des ONR à travers le Canada et au sein de sa plus grande province, l'Ontario, puis nous avons défini des mesures des états cliniques et fonctionnels associés à une ONR. TYPE D'ÉTUDE: Étude de cohorte rétrospective. SOURCE: Les données canadiennes des phases 4 à 6 de l'étude DOPPS. PARTICIPANTS: Ont été inclus tous les adultes ayant amorcé un traitement d'HD chronique entre 2009 et 2017 et qui avaient rédigé des DMA. MESURES: La non-réanimation (statut de l'ONR) et le statut fonctionnel selon les activités de la vie quotidienne et les composantes du questionnaire validé KDQOL (Kidney Disease Quality of Life) sur la qualité de vie des personnes dialysées. MÉTHODOLOGIE: Les statistiques descriptives ont été comparées sur la base des caractéristiques à l'inclusion (données démographiques, comorbidités, médicaments, caractéristiques de l'établissement de santé et statut fonctionnel du patient) et du statut de l'ONR. La proportion brute de patients par établissement avec une ONR a été calculée pour l'ensemble du Canada et pour l'Ontario seulement. Nous avons utilisé des équations d'estimation généralisées (EEG) pour créer des modèles multivariés séquentiels (données démographiques, comorbidités et statut fonctionnel) des variables associées au statut de l'ONR. RÉSULTATS: Au total, nous avons inclus 1 556 patients hémodialysés (96 % des patients répertoriés) qui avaient des DMA documentées, et 10 % d'entre elles contenaient une ONR. La variation brute du statut de l'ONR différait considérablement d'un établissement à l'autre au Canada, entre l'Ontario et les autres provinces et entre les établissements ontariens (variation entre provinces: 6,3 à 17,1 %; Ontario par rapport aux autres provinces: 8,2 contre 11,7 %; variation intraprovinciale [Ontario]: 1 à 26 %). Les patients avec une ONR étaient généralement de race blanche et plus âgés, présentaient des comorbidités cardiaques et avaient reçu moins de soins de prédialyse et sur une plus courte durée comparativement aux patients sans ONR. Les patients ayant une ONR ont signalé des pertes d'énergie et une plus grande difficulté avec les transferts, la préparation des repas, les tâches ménagères et la gestion financière. Dans un modèle multivarié, l'âge, la maladie cardiaque, les accidents vasculaires cérébraux, la durée de la dialyse et une perte de poids intradialyse ont été associés à l'existence d'une ONR. LIMITES: Un nombre limité d'événements dans certaines catégories; les mesures de l'état fonctionnel étaient transversales. CONCLUSIONS: Une importante variation inter et intraprovinciale (Ontario) a été observée quant au statut des ONR à travers le Canada, ce qui met en évidence les domaines d'amélioration potentielle de la qualité. Bien que l'état fonctionnel du patient n'ait pas semblé avoir d'incidence sur l'existence ou non d'une ONR, on a noté une association entre la présence de comorbidités et l'existence d'une ONR.
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INTRODUCTION: Delirium is a significant medical complication for hospitalised patients. Up to one-third of delirium episodes are preventable in older inpatients through non-pharmacological strategies that support essential human needs, such as physical and cognitive activity, sleep, hydration, vision and hearing. We hypothesised that a multicomponent intervention similarly may decrease delirium incidence, and/or its duration and severity, in inpatients with advanced cancer. Prior to a phase III trial, we aimed to determine if a multicomponent non-pharmacological delirium prevention intervention is feasible and acceptable for this specific inpatient group. METHODS AND ANALYSIS: The study is a phase II cluster randomised wait-listed controlled trial involving inpatients with advanced cancer at four Australian palliative care inpatient units. Intervention sites will introduce delirium screening, diagnostic assessment and a multicomponent delirium prevention intervention with six domains of care: preserving natural sleep; maintaining optimal vision and hearing; optimising hydration; promoting communication, orientation and cognition; optimising mobility; and promoting family partnership. Interdisciplinary teams will tailor intervention delivery to each site and to patient need. Control sites will first introduce only delirium screening and diagnosis, later implementing the intervention, modified according to initial results. The primary outcome is adherence to the intervention during the first seven days of admission, measured for 40 consecutively admitted eligible patients. Secondary outcomes relate to fidelity and feasibility, acceptability and sustainability of the study intervention, processes and measures in this patient population, using quantitative and qualitative measures. Delirium incidence and severity will be measured to inform power calculations for a future phase III trial. ETHICS AND DISSEMINATION: Ethical approval was obtained for all four sites. Trial results, qualitative substudy findings and implementation of the intervention will be submitted for publication in peer-reviewed journals, and reported at conferences, to study sites and key peak bodies. TRIAL REGISTRATION NUMBER: ACTRN12617001070325; Pre-results.
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Delirio/prevención & control , Pacientes Internos , Neoplasias/psicología , Australia , Ensayos Clínicos Fase II como Asunto , Delirio/diagnóstico , Delirio/etiología , Humanos , Incidencia , Estudios Multicéntricos como Asunto , Neoplasias/terapia , Cuidados Paliativos , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores de TiempoAsunto(s)
Ceguera/genética , Atrofia Óptica Hereditaria de Leber/genética , Adolescente , Humanos , Masculino , Adulto JovenAsunto(s)
Enfermedades Mitocondriales , Anestesia General/efectos adversos , Diagnóstico Diferencial , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/fisiopatología , Enfermedades Mitocondriales/terapia , Educación del Paciente como Asunto , Relaciones Profesional-Paciente , Apoyo SocialRESUMEN
OBJECTIVE: To determine whether individualized nursing case management can decrease stress among pregnant women at risk for or in abusive relationships. DESIGN: A multisite randomized controlled trial. SETTING: Two prenatal clinics in the Pacific Northwest and rural Midwest. PARTICIPANTS: 1,000 women who spoke English and were 13 to 23 weeks pregnant at time of recruitment. INTERVENTION: All intervention group women (N = 499) were offered an abuse video and had access to a nurse case manager 24/7. Additionally, participants at risk for or in abusive relationships received individualized nursing care management throughout the pregnancy. RESULTS: The most frequent nursing care management activities were providing support (38%) and assessing needs (32%). The nursing care management group received an average of 22 contacts, most (80%) by telephone and had a significant reduction in stress scores as measured by the Prenatal Psychosocial Profile. Compared to the control group, the differences were in the predicted direction, but not statistically different. A major finding was the choice by abused women to focus on basic needs and their pregnancies rather than the abuse, although all received safety planning. CONCLUSIONS: Pregnant women at risk for or in abusive relationships experience very stressful and complex lives. Nurses need to focus on the needs they identify, which may not be the abusive relationship.
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Manejo de Caso/organización & administración , Enfermería Maternoinfantil/organización & administración , Complicaciones del Embarazo/prevención & control , Maltrato Conyugal/prevención & control , Estrés Psicológico/prevención & control , Adolescente , Adulto , Mujeres Maltratadas/educación , Mujeres Maltratadas/psicología , Femenino , Humanos , Persona de Mediana Edad , Medio Oeste de Estados Unidos , Evaluación de Necesidades , Noroeste de Estados Unidos , Rol de la Enfermera , Evaluación en Enfermería , Investigación en Evaluación de Enfermería , Educación del Paciente como Asunto/organización & administración , Embarazo , Complicaciones del Embarazo/psicología , Resultado del Embarazo , Mujeres Embarazadas/psicología , Atención Prenatal/organización & administración , Medición de Riesgo , Maltrato Conyugal/psicología , Estrés Psicológico/diagnóstico , Estrés Psicológico/psicologíaRESUMEN
Functional tasks using real-life objects in an enriched environment provide a multidimensional approach to treatment. Functional tasks are therapeutic for stroke survivors, because they require the simultaneous use of motor control, cognition, visual perception, sensation, and motor planning. Therapists utilizing functional tasks as treatment modalities must also be multidimensional in their implementation. This article provides a systematic approach to guide therapists in developing a functional upper extremity training program for stroke survivors.
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Actividades Cotidianas , Brazo/fisiopatología , Desempeño Psicomotor/fisiología , Rehabilitación de Accidente Cerebrovascular , Humanos , Estimulación Física , Práctica Psicológica , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/psicologíaRESUMEN
Alkaptonuria is an autosomal recessive disease involving a deficiency of the enzyme homogentisate dioxygenase, which is involved in the tyrosine degradation pathway. The enzymatic deficiency results in high concentrations of homogentisic acid (HGA), which results in orthopedic and cardiac complications, among other symptoms. Nitisinone (NTBC) has been shown to effectively treat alkaptonuria by blocking the conversion of 4-hydroxyphenylpyruvate to HGA, but there have been concerns that using doses higher than about 2 mg/day could cause excessively high levels of tyrosine, resulting in crystal deposition and corneal pathology. We have enrolled seven patients in a study to determine whether higher doses of NTBC were effective at further reducing HGA levels while maintaining tyrosine at acceptable levels. Patients were given varying doses of NTBC (ranging from 2 to 8 mg/day) over the course of between 0.5 and 3.5 years. Urine HGA, plasma tyrosine levels, and plasma NTBC were then measured longitudinally at various doses. We found that tyrosine concentrations plateaued and did not reach significantly higher levels as NTBC doses were increased above 2 mg/day, while a significant drop in HGA continued from 2 to 4 mg/day, with no significant changes at higher doses. We also demonstrated using untargeted metabolomics that elevations in tyrosine from treatment resulted in proportional elevations in alternative tyrosine metabolic products, that of N-acetyltyrosine and γ-glutamyltyrosine.
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Background. The treatment of pancreatic cancer and other periampullary neoplasms is complex and challenging. Major high-volume cancer centers can provide excellent multidisciplinary care of these patients but almost two-thirds of pancreatic cancer patients are treated at low volume centers. There is very little published data from low volume community cancer programs in regards to the treatment of periampullary cancer. In this study, a review of comprehensive periampullary cancer care at two low volume hospitals with comparison to national standards is presented. Methods. This is a retrospective review of 70 consecutive patients with periampullary neoplasms who underwent surgery over a 5-year period (2006-2010) at two community hospitals. Results. There were 51 successful resections of 70 explorations (73%) including 34 Whipple procedures. Mortality rate was 2.9%. Comparison of these patients to national standards was made in terms of operative mortality, resectability rate, administration of adjuvant therapy, clinical trial participation and overall survival. The results in these patients were comparable to national standards. Conclusions. With adequate commitment of resources and experienced surgical and oncologic practitioners, community cancer centers can meet national tertiary care standards in terms of pancreatic and periampullary cancer care.
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Epigenetic therapy with hypomethylating drugs is now the standard of care in myelodysplastic syndrome (MDS). Response rates remain low, and mechanism-based dose optimization has not been reported. We investigated the clinical and pharmacodynamic results of different dose schedules of decitabine. Adults with advanced MDS or chronic myelomonocytic leukemia (CMML) were randomized to 1 of 3 decitabine schedules: (1) 20 mg/m2 intravenously daily for 5 days; (2) 20 mg/m2 subcutaneously daily for 5 days; and (3) 10 mg/m2 intravenously daily for 10 days. Randomization followed a Bayesian adaptive design. Ninety-five patients were treated (77 with MDS, and 18 with CMML). Overall, 32 patients (34%) achieved a complete response (CR), and 69 (73%) had an objective response by the new modified International Working Group criteria. The 5-day intravenous schedule, which had the highest dose-intensity, was selected as optimal; the CR rate in that arm was 39%, compared with 21% in the 5-day subcutaneous arm and 24% in the 10-day intravenous arm (P < .05). The high dose-intensity arm was also superior at inducing hypomethylation at day 5 and at activating P15 expression at days 12 or 28 after therapy. We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS.
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Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/análogos & derivados , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Teorema de Bayes , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Metilación de ADN/efectos de los fármacos , Decitabina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Inducción de Remisión , Riesgo , Resultado del TratamientoRESUMEN
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
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Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Disclosure of abuse by pregnant women can vary depending on whether the woman is assessed directly by a trained interviewer versus written questionnaires, and if she is asked repeatedly during the course of pregnancy. One thousand pregnant women were enrolled in a randomized clinical trial designed to assess the effects of a nursing case management intervention on the mental and physical well-being of pregnant women experiencing or at risk for abuse. Thirteen percent of the total study participants reported current abuse and/or abuse within the past year, with only 2% of those reporting that the abuse occurred during pregnancy. The incidence of reported abuse was much higher among Medicaid-funded women (28.9%) than privately insured women (8.7%). Regardless of source of payment, women reporting abuse were significantly younger, less educated, nonwhite with lower income, and had significantly higher stress and lower self-esteem than women not reporting abuse. A high incidence of women reporting intimate partner violence described being choked on the Danger Assessment Screen (34%). We strongly urge that choking be added to routine screening questions used during pregnancy and that the Danger Assessment tool is used for further evaluation of women who screen positive. In addition, we believe another barrier to reporting abuse was fear of being reported to child protective services, contributing to the overall low rate of abuse disclosure.
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Revelación/estadística & datos numéricos , Seguro de Salud/estadística & datos numéricos , Partería/métodos , Rol de la Enfermera , Sector Privado/estadística & datos numéricos , Sector Público/estadística & datos numéricos , Maltrato Conyugal/estadística & datos numéricos , Revelación de la Verdad , Factores de Edad , Femenino , Humanos , Incidencia , Seguro de Salud/economía , Tamizaje Masivo/estadística & datos numéricos , Investigación Metodológica en Enfermería , Embarazo , Mujeres Embarazadas/psicología , Atención Prenatal/estadística & datos numéricos , Sector Privado/economía , Sector Público/economía , Apoyo Social , Factores Socioeconómicos , Maltrato Conyugal/diagnóstico , Estados Unidos/epidemiologíaRESUMEN
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).
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Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Receptores de Somatostatina/antagonistas & inhibidores , Unión Competitiva/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Piperidinas/química , Pirrolidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
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Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
BACKGROUND: Chronic heart failure (HF) is the only heart condition increasing in prevalence and is primarily a condition of aging. This condition has outcomes worse than many cancers; however, patients are often denied the benefits of palliative care with its important emphasis on symptom management, spirituality, and emotional health and focus on family issues. AIM: To describe the development of a model of an integrated, consultative, palliative care approach within a comprehensive HF community-focussed disease management program. METHOD: A collaborative model was developed following a systematic needs assessment and documentation of local resources. Principles underpinning this model were based upon fostering of communication, consultancy, and skill development. Within this model a health care system, based upon universal coverage, supported co-management of patients and their families. The place of death, level of social support available at home, and degree of palliative care involvement was documented in 121 consecutive deaths from 1999-2002. FINDINGS: Following a period of skill sharing and program development, only 8.3% of HF patients in the collaborative program required specialized palliative care intervention for complex symptom management, carer support, and issues related to spirituality. Twenty percent of this cohort died in nursing homes underscoring the importance of supporting our nursing colleagues in this setting. CONCLUSIONS: In spite of well-documented difficulties in determining prognosis, it is the St George experience that key principles of a palliative care strategy can be implemented in a HF disease management program with support and consultancy from expert palliative care services.
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Servicios de Salud Comunitaria/organización & administración , Prestación Integrada de Atención de Salud/organización & administración , Insuficiencia Cardíaca/terapia , Hospitales de Enseñanza/organización & administración , Relaciones Interinstitucionales , Cuidados Paliativos/organización & administración , Continuidad de la Atención al Paciente/organización & administración , Conducta Cooperativa , Manejo de la Enfermedad , Investigación sobre Servicios de Salud , Insuficiencia Cardíaca/epidemiología , Hospitales con más de 500 Camas , Humanos , Modelos Organizacionales , Evaluación de Necesidades , Nueva Gales del Sur , Enfermeras Clínicas/organización & administración , Grupo de Atención al Paciente/organización & administración , Rol Profesional , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Gestión de la Calidad Total/organización & administraciónRESUMEN
BACKGROUND AND OBJECTIVES: Early studies have suggested that increasing doses of anthracycline improve outcome in younger patients with acute myelogenous leukemia (AML), but dose escalation has been precluded by the acute and chronic toxicities of these agents. Amifostine is a cytoprotective compound that has been shown to protect against the acute cytotoxicities of anthracyclines in animal models. We report the results of a phase I study of dose escalation of idarubicin with amifostine and high-dose ara-C in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS). DESIGN AND METHODS: The continuous reassessment method was used to predict the probability of toxicity. RESULTS: Five patients were treated at an idarubicin dose of 18 mg/m2/day x 3, three of whom developed grade 3 diarrhea or mucositis. Subsequently, three additional patients were treated at a dose of 15 mg/m2 x 3 days, all of whom experienced grade 3 diarrhea or mucositis. One patient achieved complete remission (CR rate 12.5%, 95% CI 0-0.52%). INTERPRETATION AND CONCLUSIONS: The addition of amifostine does not allow dose escalation of idarubicin when combined with high-dose ara-C.