RESUMEN
INTRODUCTION: Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of Alzheimer's and Parkinson's disease. METHODS: In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline-treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing. RESULTS: We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non-disease-specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK-3ß activity and increased HIF-1α activity. CONCLUSIONS: These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.
Asunto(s)
Encéfalo/efectos de los fármacos , Deferoxamina/administración & dosificación , Memoria a Corto Plazo/efectos de los fármacos , Sideróforos/administración & dosificación , Administración Intranasal , Animales , Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , RatonesRESUMEN
Emerging evidence continues to demonstrate that disrupted insulin signaling and altered energy metabolism may play a key role underpinning pathology in neurodegenerative conditions. Intranasally administered insulin has already shown promise as a memory-enhancing therapy in patients with Alzheimer's and animal models of the disease. Intranasal drug delivery allows for direct targeting of insulin to the brain, bypassing the blood brain barrier and minimizing systemic adverse effects. In this study, we sought to expand upon previous results that show intranasal insulin may also have promise as a Parkinson's therapy. We treated 6-OHDA parkinsonian rats with a low dose (3 IU/day) of insulin and assessed apomorphine induced rotational turns, motor deficits via a horizontal ladder test, and dopaminergic cell survival via stereological counting. We found that insulin therapy substantially reduced motor dysfunction and dopaminergic cell death induced by unilateral injection of 6-OHDA. These results confirm insulin's efficacy within this model, and do so over a longer period after model induction which more closely resembles Parkinson's disease. This study also employed a lower dose than previous studies and utilizes a delivery device, which could lead to an easier transition into human clinical trials as a therapeutic for Parkinson's disease.
Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Hipoglucemiantes/farmacología , Insulina/farmacología , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Administración Intranasal , Adrenérgicos/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Movimiento/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/patología , Ratas , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% ± 6.0%, 112% ± 10%, and 114% ± 7% bioavailability; maximum plasma concentrations 71.5 ± 9.3, 388 ± 31, and 355 ± 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 ± 0.0080 minutes-1 for diazepam and 0.122 ± 0.022 minutes-1 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Diazepam/administración & dosificación , Dipéptidos/administración & dosificación , Profármacos/administración & dosificación , Administración Intranasal , Aminopeptidasas/química , Aminopeptidasas/metabolismo , Animales , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Disponibilidad Biológica , Diazepam/farmacocinética , Dipéptidos/efectos adversos , Dipéptidos/farmacocinética , Composición de Medicamentos , Masculino , Cavidad Nasal/citología , Cavidad Nasal/metabolismo , Profármacos/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To clarify the effect of progressively increasing intra-abdominal pressure on esophageal pressure, transpulmonary pressure, and functional residual capacity. DESIGN: Controlled application of increased intra-abdominal pressure at two positive end-expiratory pressure levels (1 and 10 cm H2O) in an anesthetized porcine model of controlled ventilation. SETTING: Large animal laboratory of a university-affiliated hospital. SUBJECTS: Eleven deeply anesthetized swine (weight 46.2 ± 6.2 kg). INTERVENTIONS: Air-regulated intra-abdominal hypertension (0-25 mm Hg). MEASUREMENTS: Esophageal pressure, tidal compliance, bladder pressure, and end-expiratory lung aeration by gas dilution. MAIN RESULTS: Functional residual capacity was significantly reduced by increasing intra-abdominal pressure at both positive end-expiratory pressure levels (p ≤ 0.0001) without corresponding changes of end-expiratory esophageal pressure. Above intra-abdominal pressure 5 mm Hg, plateau airway pressure increased linearly by ~ 50% of the applied intra-abdominal pressure value, associated with commensurate changes of esophageal pressure. With tidal volume held constant, negligible changes occurred in transpulmonary pressure due to intra-abdominal pressure. Driving pressures calculated from airway pressures alone (plateau airway pressure--positive end-expiratory pressure) did not equate to those computed from transpulmonary pressure (tidal changes in transpulmonary pressure). Increasing positive end-expiratory pressure shifted the predominantly negative end-expiratory transpulmonary pressure at positive end-expiratory pressure 1 cm H2O (mean -3.5 ± 0.4 cm H2O) into the positive range at positive end-expiratory pressure 10 cm H2O (mean 0.58 ± 1.2 cm H2O). CONCLUSIONS: Despite its insensitivity to changes in functional residual capacity, measuring transpulmonary pressure may be helpful in explaining how different levels of positive end-expiratory pressure influence recruitment and collapse during tidal ventilation in the presence of increased intra-abdominal pressure and in calculating true transpulmonary driving pressure (tidal changes of transpulmonary pressure). Traditional interpretations of respiratory mechanics based on unmodified airway pressure were misleading regarding lung behavior in this setting.
Asunto(s)
Hipertensión Intraabdominal/fisiopatología , Respiración con Presión Positiva , Animales , Esófago/fisiopatología , Espiración/fisiología , Capacidad Residual Funcional/fisiología , Inhalación/fisiología , Modelos Lineales , Pulmón/fisiopatología , Modelos Animales , Porcinos , Volumen de Ventilación Pulmonar/fisiología , Vejiga Urinaria/fisiopatologíaRESUMEN
Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials. Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models and deferoxamine in Alzheimer's mouse models. The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible.