RESUMEN
Inflammatory bowel disease (IBD) is an incurable disease of the gastrointestinal tract with a lack of effective therapeutic strategies. The proinflammatory microenvironment plays a significant role in both amplifying and sustaining inflammation during IBD progression. Herein, biocompatible drug-free ceria nanoparticles (CeNP-PEG) with regenerable scavenging activities against multiple reactive oxygen species (ROS) were developed. CeNP-PEG exerted therapeutic effect in dextran sulfate sodium (DSS)-induced colitis murine model, evidenced by corrected the disease activity index, restrained colon length shortening, improved intestinal permeability and restored the colonic epithelium disruption. CeNP-PEG ameliorated the proinflammatory microenvironment by persistently scavenging ROS, down-regulating the levels of multiple proinflammatory cytokines, restraining the proinflammatory profile of macrophages and Th1/Th17 response. The underlying mechanism may involve restraining the co-activation of NF-κB and JAK2/STAT3 pathways. In summary, this work demonstrates an effective strategy for IBD treatment by ameliorating the self-perpetuating proinflammatory microenvironment, which offers a new avenue in the treatment of inflammation-related diseases.
Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Animales , Colitis/tratamiento farmacológico , Colon/metabolismo , Citocinas/metabolismo , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND CONTEXT: Opioid use is prevalent in the management of pre- and postoperative pain in patients undergoing spinal fusion. There is evidence that opioids downregulate osteoblasts in vitro, and a previous study found that morphine delays the maturation and remodeling of callus in a rat femur fracture model. However, the effect of opioids on healing of spinal fusion has not been investigated before. Isolating the effect of opioid exposure in humans would be limited by the numerous confounding factors that affect fusion healing. Therefore, we have used a well-established rabbit model to study the process of spinal fusion healing that closely mimics humans. PURPOSE: The objective of this work was to study the effect of systemic opioids on the process of healing of spinal fusion in a rabbit posterolateral spinal fusion model. STUDY DESIGN/SETTING: This is a preclinical animal study. MATERIALS AND METHODS: Twenty-four adult New Zealand white rabbits were studied in two groups after approval from the Institutional Animal Care and Use Committee (IACUC). The opioid group (n=12) received 4 weeks' preoperative and 6 weeks' postoperative transdermal fentanyl. Serum fentanyl levels were measured just before surgery and 4 weeks postoperatively to ensure adequate levels. The control group (n=12) received only perioperative pain control as necessary. All animals underwent a bilateral L5-L6 posterolateral spinal fusion using iliac crest autograft. Animals were euthanized at the 6-week postoperative time point, and assessment of fusion was done by manual palpation, plain radiographs, microcomputed tomography (microCT), and histology. RESULTS: Twelve animals in the control group and 11 animals in the opioid group were available for analysis at the end of 6 weeks. The fusion scores on manual palpation, radiographs, and microCT were not statistically different. Three-dimensional microCT morphometry found that the fusion mass in the opioid group had a lower bone volume (p=.09), a lower trabecular number (p=.02), and a higher trabecular separation (p=.02) compared with the control group. Histologic analysis found areas of incorporation of autograft and unincorporated graft fragments in both groups. In the control group, there was remodeling of de novo woven bone to lamellar organization with incorporation of osteocytes, formation of mature marrow, and relative paucity of hypertrophied osteoblasts lining new bone. Sections from the opioid group showed formation of de novo woven bone, and hypertrophied osteoblasts were seen lining the new bone. There were no sections showing lamellar organization and development of mature marrow elements in the opioid group. Less dense trabeculae on microCT correlated with histologic findings of relatively immature fusion mass in the opioid group. CONCLUSIONS: Systemic opioids led to an inferior quality fusion mass with delay in maturation and remodeling at 6 weeks in this rabbit spinal fusion model. These preliminary results lay the foundation for further research to investigate underlying cellular mechanisms, the temporal fusion process, and the dose-duration relationship of opioids responsible for our findings.
Asunto(s)
Analgésicos Opioides/efectos adversos , Fusión Vertebral/métodos , Cicatrización de Heridas/efectos de los fármacos , Analgésicos Opioides/uso terapéutico , Animales , Trasplante Óseo/efectos adversos , Trasplante Óseo/métodos , Vértebras Lumbares/cirugía , Conejos , Fusión Vertebral/efectos adversos , Trasplante Autólogo/efectos adversos , Trasplante Autólogo/métodosRESUMEN
Purpose: To determine the intravitreal pharmacokinetic properties and to study the systemic biodistribution characteristics of I-124-labeled bevacizumab, ranibizumab, and aflibercept with positron emission tomography-computed tomography (PET/CT) imaging in a nonhuman primate model. Methods: Three groups with four owl monkeys per group underwent intravitreal injection with 1.25 mg/0.05 mL I-124 bevacizumab, 0.5 mg/0.05 mL I-124 ranibizumab, or 2.0 mg/0.05 mL I-124 aflibercept in the right eye of each subject. All subjects were imaged using PET/CT on days 0, 1, 2, 4, 8, 14, 21, 28, and 35. Serum blood draws were performed at hours 1, 2, 4, 8, 12 and days 1, 2, 4, 8, 14, 21, 28, and 35. Radioactivity emission measurements were used to determine the intravitreal half-lives of each agent and to study the differences of radioactivity uptake in nonocular organs. Results: The intravitreal half-lives were 3.60 days for I-124 bevacizumab, 2.73 days for I-124 ranibizumab, and 2.44 days for I-124 aflibercept. Serum levels were highest and most prolonged for bevacizumab as compared to both ranibizumab and aflibercept. All agents were primarily excreted through the renal and mononuclear phagocyte systems. However, bevacizumab was also found in significantly higher levels in the liver, heart, and distal femur bones. Conclusions: Among the three anti-VEGF agents used in clinical practice, bevacizumab demonstrated the longest intravitreal retention time and aflibercept the shortest. Significantly higher and prolonged levels of bevacizumab were found in the serum as well as in the heart, liver, and distal bones. These differences may be considered by clinicians when formulating treatment algorithms for intravitreal therapies with these agents.
Asunto(s)
Bevacizumab/farmacocinética , Ranibizumab/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Enfermedades de la Retina/tratamiento farmacológico , Cuerpo Vítreo/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Animales , Aotidae , Bevacizumab/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Inyecciones Intravítreas , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ranibizumab/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/metabolismo , Distribución Tisular , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Cuerpo Vítreo/diagnóstico por imagenRESUMEN
Although inflammatory bowel disease (IBD) has been extensively studied, the pathogenesis is still not completely understood. As a result, the treatment options remain unsatisfactory and nonspecific. With the rapid advancement of diagnostic imaging techniques, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are playing a more important role in IBD diagnosis and evaluation. Recent developments in nanotechnology utilize an interdisciplinary approach to specifically target molecular or cellular IBD pathological process thereby generating nanoparticles (NPs) with high specificity and diagnostic and/or therapeutic efficacy. Nano-based imaging, which incorporates nanotechnology and imaging modalities, may allow for the early detection of IBD, the monitoring of disease activity, and may be used to monitor the therapeutic response at cellular and/or molecular level. In this review, we highlight issues related to nano-based imaging and its application in IBD field.