RESUMEN
BACKGROUND: Management of diabetes mellitus (DM) remains a challenge in the US, as almost half of patients with diabetes are uncontrolled with a hemoglobin A1c (HbA1c) >7%. Over the last decade there has been increasing evidence supporting the integration of Clinical Pharmacy Specialists (CPSs) to multidisciplinary medical teams which have demonstrated improved glycemic control and better clinical outcomes in the primary care setting. OBJECTIVES: The primary objective of this study was to evaluate the change in HbA1c levels in patients with diabetes followed by a CPS. The secondary objectives of this study were to evaluate the percent of patients who reached American Diabetes Association (ADA) goal HbA1c (<7%) by study conclusion and evaluate documentation of hypoglycemic events in progress notes. METHODS: A retrospective chart review evaluating glycemic control was conducted on patients with DM managed by a CPS at a large Veterans Affairs Medical Center. Patients with a diagnosis of Type 1 or Type 2 DM with a baseline HbA1c ≥9% and at least three CPS visits over twelve months were included in this study. Patients with cognitive impairment as documented by ICD-9 codes or with less than three CPS visits over twelve months were excluded. RESULTS: A sample of 79 patients was identified. The mean HbA1c declined by 1.5 percentage points (from 10.6%, SD=1.4 to 9.1%, SD=1.5) after one year. No patients reached ADA goal of HbA1c <7% at study conclusion, however 23% of patients reached a less stringent goal of <8%. All CPS progress notes assessed episodes of hypoglycemia and provided education, and no hospitalizations were related to hypoglycemic events. CONCLUSIONS: Integration of a CPS into a veteran's diabetes care was associated with improved outcomes and enhanced hypoglycemic education. Our results advance the existing literature by demonstrating a positive association between CPS intervention and improved glycemic control in a complex veteran population.
RESUMEN
Background: Management of diabetes mellitus (DM) remains a challenge in the US, as almost half of patients with diabetes are uncontrolled with a hemoglobin A1c (HbA1c) >7%. Over the last decade there has been increasing evidence supporting the integration of Clinical Pharmacy Specialists (CPSs) to multidisciplinary medical teams which have demonstrated improved glycemic control and better clinical outcomes in the primary care setting. Objectives: The primary objective of this study was to evaluate the change in HbA1c levels in patients with diabetes followed by a CPS. The secondary objectives of this study were to evaluate the percent of patients who reached American Diabetes Association (ADA) goal HbA1c (<7%) by study conclusion and evaluate documentation of hypoglycemic events in progress notes. Methods: A retrospective chart review evaluating glycemic control was conducted on patients with DM managed by a CPS at a large Veterans Affairs Medical Center. Patients with a diagnosis of Type 1 or Type 2 DM with a baseline HbA1c ≥9% and at least three CPS visits over twelve months were included in this study. Patients with cognitive impairment as documented by ICD-9 codes or with less than three CPS visits over twelve months were excluded. Results: A sample of 79 patients was identified. The mean HbA1c declined by 1.5 percentage points (from 10.6%, SD=1.4 to 9.1%, SD=1.5) after one year. No patients reached ADA goal of HbA1c <7% at study conclusion, however 23% of patients reached a less stringent goal of <8%. All CPS progress notes assessed episodes of hypoglycemia and provided education, and no hospitalizations were related to hypoglycemic events. Conclusions: Integration of a CPS into a veteran's diabetes care was associated with improved outcomes and enhanced hypoglycemic education. Our results advance the existing literature by demonstrating a positive association between CPS intervention and improved glycemic control in a complex veteran population
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Asunto(s)
Humanos , Hiperglucemia/prevención & control , Servicios Farmacéuticos/métodos , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemia/prevención & control , Hospitales de Veteranos/estadística & datos numéricos , Servicio de Farmacia en Hospital/métodos , Estudios Retrospectivos , Grupo de Atención al Paciente/organización & administración , Evaluación de Eficacia-Efectividad de Intervenciones , Atención Ambulatoria/tendencias , Administración del Tratamiento Farmacológico/organización & administraciónRESUMEN
OBJECTIVE: TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis. METHODS AND RESULTS: The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells. CONCLUSIONS: These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Activinas Tipo I/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Administración Oral , Animales , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/metabolismo , Sitios de Unión , Traumatismos de las Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/fisiopatología , Línea Celular , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibrosis , Humanos , Masculino , Mioblastos del Músculo Liso/efectos de los fármacos , Mioblastos del Músculo Liso/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Tipo I de Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
The authors assess the equivalence of 2 assays and put forward a general approach for assay agreement analysis that can be applied during drug discovery. Data sets generated by different assays are routinely compared to each other during the process of drug discovery. For a given target, the assays used for high-throughput screening and structure-activity relationship studies will most likely differ in their assay reagents, assay conditions, and/or detection technology, which makes the interpretation of data between assays difficult, particularly as most assays are used to measure quantitative changes in compound potency against the target. To better quantify the relationship of data sets from different assays for the same target, the authors evaluated the agreement between results generated by 2 different assays that measure the activity of compounds against the same protein, ALK5. The authors show that the agreement between data sets can be quantified using correlation and Bland-Altman plots, and the precision of the assays can be used to define the expectations of agreement between 2 assays. They propose a scheme for addressing issues of assay data equivalence, which can be applied to address questions of how data sets compare during the lead identification and lead optimization processes in which assays are frequently added and changed.
Asunto(s)
Receptores de Activinas Tipo I/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Receptores de Factores de Crecimiento Transformadores beta/química , Tecnología Farmacéutica/métodos , Adenosina Trifosfato/química , Interpretación Estadística de Datos , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Modelos Estadísticos , Preparaciones Farmacéuticas , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas , Receptor Tipo I de Factor de Crecimiento Transformador beta , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Equivalencia TerapéuticaRESUMEN
We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TbetaRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TbetaRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target.