Intranasal Deferoxamine Provides Increased Brain Exposure and Significant Protection in Rat Ischemic Stroke

Abstract

Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the bloodbrain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9 -18.5 M) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 M, p Ͻ 0.05).Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p Ͻ 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p Ͻ 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.

Inhalation of growth factors and apo-transferrin to protect and repair the hypoxic-ischemic brain

“…Several reports confirm the positive outcome of nose-to-brain delivery not only for drug molecules with various molecular weights [11,12] but also for living cells [13,14]. Hanson et al (2009) [11,12] reported that INA targets deferoxamine to the brain and reduces systemic exposure, and that intranasal deferoxamine prevents and treats stroke damage after middle cerebral artery occlusion in rats.…”

“…Hanson et al (2009) [11,12] reported that INA targets deferoxamine to the brain and reduces systemic exposure, and that intranasal deferoxamine prevents and treats stroke damage after middle cerebral artery occlusion in rats. On the other hand, Danielyan and collaborators (2001) [13,14] have revealed noninvasive intranasal delivery of stem cells to the rat brain for the first time,…”

Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting

“…Recent reports confirm the positive outcome of noseto-brain delivery not only for drug molecules with various molecular weights (Hanson et al, 2009;Yang et al, 2009), but also for living cells (Danielyan et al, 2009;Danielyan et al, 2011). Nanoemulsion (NE) formulation offers an improvement to nose-to-brain drug delivery since they are able to protect the encapsulated drug from biological and/or chemical degradation, and extracellular transport by P-gp efflux proteins.…”

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

“…Nasal tissues from two untreated control rats were processed in the same manner as the treated tissues. Three driving pressures (10,20, and 30 psi) of the POD device were tested. Within 5 min of dosing, the animal was euthanized.…”

“…A variety of nasal delivery methods are typically used in studies investigating nose-tobrain delivery in rodents, but very few studies specifically and consistently deposit drug on the olfactory epithelium. The most commonly used nasal administration modes are nose drops (18)(19)(20)(21), in which the animal is placed on its back in a supine position while liquid drops are snorted into the nasal cavity, or inserting a soft catheter connected to a microsyringe into the nasal cavity and applying a volume of drug a set distance into the nasal cavity from the naris (11,22). These methods may effectively deliver drug to the nasal cavity; however, they tend to involve a large dose volume resulting in saturation of both the respiratory and olfactory epithelium.…”