RESUMEN
Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.
Asunto(s)
Calidad de Vida , Sialorrea , Adulto , Niño , Humanos , Voluntarios Sanos , Sialorrea/tratamiento farmacológico , Área Bajo la Curva , Soluciones Oftálmicas/efectos adversos , Derivados de Atropina , Administración OralRESUMEN
BACKGROUND: Budesonide high-volume saline irrigations (HVSIs) are routinely used to treat chronic rhinosinusitis (CRS) due to improved sinonasal delivery and efficacy compared to intranasal corticosteroid sprays. The off-label use of budesonide is assumed to be safe, with several studies suggesting the systemically absorbed dose of budesonide HVSI is low. However, the actual budesonide dose retained in the sinonasal cavity following HVSI is unknown. The objective of this study was to quantify the retained dose of budesonide after HVSI. METHODS: Adult patients diagnosed with CRS who had undergone endoscopic sinus surgery (ESS) and were prescribed budesonide HVSI were enrolled into a prospective, observational cohort study. Patients performed budesonide HVSI (0.5â mg dose) under supervision in an outpatient clinic, and irrigation effluent was collected. High-performance liquid chromatography was employed to determine the dose of budesonide retained after HVSI. RESULTS: Twenty-four patients met inclusion criteria. The average corrected retained dose of budesonide across the cohort was 0.171 ± 0.087â mg (37.9% of administered budesonide). Increased time from ESS significantly impacted the measured retained dose, with those 3 months post-ESS retaining 27.4% of administered budesonide (P = .0004). CONCLUSION: The retained dose of budesonide in patients with CRS after HVSI was found to be significantly higher than previously estimated and decreased with time post-ESS. Given that budesonide HVSI is a cornerstone of care in CRS, defining the retained dose and the potential systemic implications is critical to understanding the safety of budesonide HVSI.
Asunto(s)
Rinitis , Rinosinusitis , Sinusitis , Adulto , Humanos , Budesonida/uso terapéutico , Estudios Prospectivos , Rinitis/cirugía , Rinitis/tratamiento farmacológico , Sinusitis/cirugía , Sinusitis/tratamiento farmacológico , Solución Salina/uso terapéutico , Resultado del Tratamiento , Enfermedad CrónicaRESUMEN
Chronic rhinosinusitis (CRS) is a chronic health condition affecting the sinonasal cavity. CRS-associated mucosal inflammation leads to sinonasal epithelial cell death and epithelial cell barrier disruption, which may result in recurrent bacterial infections and biofilm formation. For patients who fail medical management and elect endoscopic sinus surgery for disease control, bacterial biofilm formation is particularly detrimental, as it reduces the efficacy of surgical intervention. Effective treatments that prevent biofilm formation in post-operative patients in CRS are currently limited. To address this unmet need, we report the controlled release of silver nanoparticles (AgNps) with silk-elastinlike protein-based polymers (SELPs) to prevent bacterial biofilm formation in CRS. This polymeric network is liquid at room temperature and forms a hydrogel at body temperature, and is hence, capable of conforming to the sinonasal cavity upon administration. SELP hydrogels demonstrated sustained AgNp and silver ion release for the studied period of three days, potent in vitro antibacterial activity against Pseudomonas aeruginosa (**** p < 0.0001) and Staphylococcus aureus (**** p < 0.0001), two of the most commonly virulent bacterial strains observed in patients with post-operative CRS, and high cytocompatibility with human nasal epithelial cells. Antibacterial controlled release platform shows promise for treating patients suffering from prolonged sinonasal cavity infections due to biofilms.
RESUMEN
Chronic rhinosinusitis (CRS) is a chronic inflammatory condition affecting the nasal and paranasal sinuses of approximately 11.5% of the United States adult population. Oral corticosteroids are effective in controlling sinonasal inflammation in CRS, but the associated adverse effects limit their clinical use. Topical budesonide has demonstrated clinical efficacy in patients with CRS. Herein, we investigated the systemic delivery of liposomes tethered with poly(ethylene glycol) (PEG) and loaded with budesonide in a murine model of CRS. PEGylated liposomes encapsulated with budesonide phosphate (L-BudP) were administered via tail vein injection, and the feasibility of L-BudP to reduce sinonasal inflammation was compared to that of free budesonide phosphate (F-BudP) and topical budesonide phosphate (T-BudP) treatment over a 14-day study period. Compared to a single injection of F-BudP and repeat T-BudP administration, a single injection of L-BudP demonstrated increased and prolonged efficacy, resulting in the significant improvement of sinonasal tissue histopathological scores (p < 0.05) with decreased immune cell infiltration (p < 0.05). Toxicities associated with L-BudP and T-BudP treatment, assessed via body and organ weight, as well as peripheral blood liver enzyme and differential white blood cell analyses, were transient and comparable. These data suggest that systemic liposomal budesonide treatment results in improved efficacy over topical treatment.
Asunto(s)
Rinitis , Sinusitis , Adulto , Humanos , Animales , Ratones , Budesonida/uso terapéutico , Liposomas/uso terapéutico , Rinitis/tratamiento farmacológico , Rinitis/inducido químicamente , Sinusitis/tratamiento farmacológico , Sinusitis/inducido químicamente , Inflamación/tratamiento farmacológico , Enfermedad Crónica , Polietilenglicoles/uso terapéuticoRESUMEN
Osteosarcoma (OS) is the most common form of primary malignant bone cancer in adolescents. Over the years, OS prognosis has greatly improved due to adjuvant and neoadjuvant (preoperative) chemotherapeutic treatment, increasing the chances of successful surgery and reducing the need for limb amputation. However, chemotherapeutic treatment to treat OS is limited by off-target toxicities and requires improved localization at the tumor site. Collagen, the main constituent of bone tissue, is extensively degraded and remodeled in OS, leading to an increased availability of denatured (monomeric) collagen. Collagen hybridizing peptides (CHPs) comprise a class of peptides rationally designed to selectively bind to denatured collagen. In this work, we have conjugated CHPs as targeting moieties to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to target OS tumors. We demonstrated increased accumulation of collagen-targeted HPMA copolymer-CHP conjugates compared to nontargeted HPMA copolymers, as well as increased retention compared to both nontargeted copolymers and CHPs, in a murine intratibial OS tumor model. Furthermore, we used microcomputed tomography analysis to evaluate the bone microarchitecture and correlated bone morphometric parameters (porosity, bone volume, and surface area) with maximum accumulation (Smax) and accumulation at 168 h postinjection (S168) of the copolymers at the tumor. Our results provide the foundation for the use of HPMA copolymer-CHP conjugates as targeted drug delivery systems in OS tumors.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Ratones , Humanos , Animales , Adolescente , Microtomografía por Rayos X , Sistemas de Liberación de Medicamentos/métodos , Metacrilatos , Péptidos , Colágeno , PolímerosRESUMEN
The extracellular matrix (ECM) is dynamically involved in many aspects of cell growth and survival, and it plays an active role in cancer etiology. In comparison to healthy ECM, tumor associated ECM shows high collagen deposition and remodeling activity, which results in an increased amount of denatured collagen strands in tumor tissues. Capitalizing on this distinguishing feature, we developed tumor-localizing polymeric carriers that selectively bind to denatured collagen in the tumor ECM. We synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with their side chains conjugated to collagen hybridizing peptides (CHPs). HPMA copolymer-CHP conjugates exhibited selective affinity to denatured collagen and localized to tumors in an orthotopic MDA-MB-231 murine breast cancer model. The conjugates had increased tumor localization compared to copolymers with scrambled peptides in the side chains, as well as increased retention compared to free CHPs. Such conjugates show promise as carriers for ECM-acting drugs and imaging agents in the management of diseases characterized by high ECM remodeling activity.
Asunto(s)
Neoplasias de la Mama , Sistemas de Liberación de Medicamentos , Humanos , Animales , Ratones , Femenino , Sistemas de Liberación de Medicamentos/métodos , Metacrilatos , Péptidos , Colágeno , Matriz Extracelular , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Chronic rhinosinusitis (CRS) is a debilitating inflammatory disorder of the sinonasal mucosa that substantially diminishes patient quality of life. Progress surrounding management of this disease has been crippled by a lack of therapeutic innovation. It has been posited that increased vascularity within the diseased sinuses of patients with CRS may allow for improved systemic drug delivery via nanoscale liposomal carriers. Such a system could enhance drug distribution, accumulation, and retention within the sinuses, ultimately leading to improved patient outcomes. PEGylated liposomes loaded with indocyanine green (ICG) were synthesized, characterized and systemically administered in a mouse model of CRS. Accumulation and retention of ICG in sinonasal tissue were evaluated. Compared to healthy controls, CRS mice showed significant sinonasal tissue accumulation and retention of PEGylated liposomal ICG for up to 21â¯days (Pâ¯<â¯0.001). Conversely, free ICG was eliminated from the body after 24â¯h in both groups.