Implementation and review of the care ecosystem in an integrated healthcare system.

BACKGROUND AND OBJECTIVES: The University of California, San Francisco Memory and Aging Center (UCSF-MAC) led the development and tested a collaborative care model delivered by lay care team navigators (CTNs) with support from a multidisciplinary team known as the Care Ecosystem (CE). We evaluated outcomes related to the feasibility of the CE in a non-academic healthcare system, including acceptability, adoption, and fidelity to the original UCSF model. RESEARCH DESIGN AND METHODS: The CE team at HealthPartners consisted of two CTNs, a social worker, an RN, a program coordinator, and a behavioral neurologist. Intake forms were developed to collect demographic, baseline, and annual data at one year related to dementia severity and caregiver status. Experience surveys were completed at 6 and 12 months by participating caregivers. All data was entered into REDCap. RESULTS: A total of 570 PWD-caregiver dyads were recruited into the CE: 53% PWDs female, average age 75.2 ± 9.43, 19% living within rural communities. Of the 173 dyads assessed at one year, 30% responded to the annual intake forms and 58% of responded to experience surveys. At one year, PWDs progressed in disease severity and functional impairment, although caregiver burden and mood remained unchanged. We observed a significant reduction in caregiver reported emotional challenges associated with caregiving, sleep problems, and obtaining caregiver help at one year. 86% of caregivers reported feeling supported by their CTN nearly always or quite frequently, and 88% rated the CTN as highly responsive to what was important to them. DISCUSSION AND IMPLICATIONS: The CE was feasible and well-received within a non-academic healthcare system.

A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease.

BACKGROUND: Intranasal insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose uptake, reduce amyloid plaques, and improve verbal memory in cognitively impaired as well as healthy adults. Investigations have suggested rapid-acting insulins such as glulisine may result in superior cognitive benefits compared with regular insulin. OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of rapid-acting intranasal glulisine in subjects with amnestic mild cognitive impairment (MCI) or mild probable Alzheimer's disease (AD). METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of intranasal glulisine 20 IU twice daily versus saline placebo in 35 memory-impaired (MCI/AD) subjects using the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating (CDR) global score, and Functional Assessment Questionnaire (FAQ) were measured at baseline and 3 and 6 months. Secondary outcome measures included digit span forward/backwards, Trail Making Test Parts A/B, Controlled Oral Word Association Test (COWAT), and Weschler Memory Scale (WMS)-IV logical memory. Adverse effects (AEs) and serious adverse effects (SAEs) were measured along with blood glucose/insulin levels. RESULTS: No significant difference in ADAS-Cog13, CDR Sum of Boxes (CDR-SOB), or FAQ scores were found between treatment groups at 3 and 6 months. Subjects in the saline group were significantly older than those in the glulisine group (p = 0.022). No significant differences in sex, education, apolipoprotein E4 (ApoE4) status, and Montreal Cognitive Assessment (MoCA) score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24; p = 0.824), although subjects receiving intranasal glulisine had higher rates of nasal irritation (25.0% vs. 13.9%) and respiratory symptoms (15.9% vs. 8.3%) compared with placebo. There were no differences in blood sugar or rate of hypoglycemia between the treatment and placebo groups. CONCLUSIONS: Intranasal glulisine was relatively safe and well-tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of intranasal glulisine on cognition, function, or mood, but the ability to detect significance was limited by the number of subjects successfully enrolled and the study duration. CLINICALTRIALS. GOV REGISTRATION: NCT02503501.

Double-Blind Placebo-Controlled Pilot Investigation of the Safety of a Single Dose of Rapid-Acting Intranasal Insulin in Down Syndrome.

BACKGROUND: Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer's disease dementia by the ages of 35-40 years. Intranasal insulin is a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin. OBJECTIVES: The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome. METHODS: A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test. RESULTS: Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed. CONCLUSIONS: Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population. CLINICALTRIALS. GOV ID: NCT02432716.

Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement.

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.

Quantifying Intranasally Administered Deferoxamine in Rat Brain Tissue with Mass Spectrometry.

Deferoxamine, a metal chelator, has been shown to be neuroprotective in animal models of ischemic stroke, traumatic brain injury and both subarachnoid and intracerebral hemorrhage. Intranasal deferoxamine (IN DFO) has also shown promise as a potential treatment for multiple neurodegenerative diseases, including Parkinson's and Alzheimer's. However, there have been no attempts to thoroughly understand the dynamics and pharmacokinetics of IN DFO. We developed a new high-performance liquid-chromatography electrospray-tandem mass spectrometry (HPLC/ESI-MS2) method to quantify the combined total levels of DFO, ferrioxamine (FO; DFO bound to iron), and aluminoxamine (AO; aluminum-bound DFO) in brain tissue using a custom-synthesized deuterated analogue (DFO-d7, Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method toward understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 min to 4 h after delivery. We found that IN delivery successfully targets DFO to the brain to achieve concentrations of 0.5-15 µM in various brain regions within 15 min, and decreasing though still detectable after 4 h. Systemic exposure was minimized as assessed by concentration in blood serum. Serum concentrations were 0.02 µM at 15 min and no more than 0.1 µM at later time points. Compared to blood serum, brain region-specific drug exposure (as measured by area under the curve) ranged from slightly under 10 times exposure in the hippocampus to almost 200 times exposure in the olfactory bulb with IN DFO delivery. These findings represent a major step toward future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic.

Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats.

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.

Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model.

The ability of a novel intranasally delivered amnion cell derived biologic to suppress inflammation, prevent neuronal damage and preserve neurologic function in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis was assessed. Currently, there are no existing optic nerve treatment methods for disease or trauma that result in permanent vision loss. Demyelinating optic nerve inflammation, termed optic neuritis, induces permanent visual dysfunction due to retinal ganglion cell damage in multiple sclerosis and experimental autoimmune encephalomyelitis. ST266, the biological secretome of Amnion-derived Multipotent Progenitor cells, contains multiple anti-inflammatory cytokines and growth factors. Intranasally administered ST266 accumulated in rodent eyes and optic nerves, attenuated visual dysfunction, and prevented retinal ganglion cell loss in experimental optic neuritis, with reduced inflammation and demyelination. Additionally, ST266 reduced retinal ganglion cell death in vitro. Neuroprotective effects involved oxidative stress reduction, SIRT1-mediated mitochondrial function promotion, and pAKT signaling. Intranasal delivery of neuroprotective ST266 is a potential novel, noninvasive therapeutic modality for the eyes, optic nerves and brain. The unique combination of biologic molecules in ST266 provides an innovative approach with broad implications for suppressing inflammation in autoimmune diseases, and for preventing neuronal damage in acute neuronal injury and chronic neurodegenerative diseases such as multiple sclerosis.

Food consumption and activity levels increase in rats following intranasal Hypocretin-1.

Hypocretin-1 (HC, orexin-A) is a neuropeptide involved in regulating physiological functions of sleep, appetite and arousal, and it has been shown that intranasal (IN) administration can target HC to the brain. Recent clinical studies have shown that IN HC has functional effects in human clinical trials. In this study, we use rats to determine whether IN HC has an immediate effect on food consumption and locomotor activity, whether distribution in the brain after IN delivery is dose-dependent, and whether MAPK and PDK1 are affected after IN delivery. Food intake and wheel-running activity were quantified for 24h after IN delivery. Biodistribution was determined 30min after IN delivery of both a high and low dose of 125I-radiolabelled HC throughout the brain and other bodily tissues, while Western blots were used to quantify changes in cell signaling pathways (MAPK and PDK1) in the brain. Intranasal HC significantly increased food intake and wheel activity within 4h after delivery, but balanced out over the course of 24h. The distribution studies showed dose-dependent delivery in the CNS and peripheral tissues, while PDK1 was significantly increased in the brain 30min after IN delivery of HC. This study adds to the growing body of evidence that IN administration of HC is a promising strategy for treatment of HC related behaviors.

Intranasal administration of CNS therapeutics to awake mice.

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.

Intranasal delivery of insulin via the olfactory nerve pathway.

OBJECTIVES: Intranasal delivery has been shown to target peptide therapeutics to the central nervous system (CNS) of animal models and induce specific neurological responses. In an investigation into the pathways by which intranasal administration delivers insulin to the CNS, this study has focused on the direct delivery of insulin from the olfactory mucosa to the olfactory bulbs via the olfactory nerve pathway. METHODS: Nasal and olfactory tissues of mice were imaged with fluorescent and electron microscopy 30 min following intranasal administration. KEY FINDINGS: Macroscopic analysis confirmed delivery to the anterior regions of the olfactory bulbs. Confocal microscopy captured delivery along the olfactory nerve bundles exiting the nasal mucosa, traversing the cribriform plate and entering the bulbs. With electron microscopy, insulin was found within cells of the olfactory nerve layer and glomerular layer of the olfactory bulbs. CONCLUSIONS: These results demonstrated that intranasal administration of labelled insulin targeted the CNS through the olfactory nerve pathway in mice.

Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice.

Intranasal administration, which bypasses the blood-brain barrier and minimizes systemic exposure, is a non-invasive alternative for targeted drug delivery to the brain. While identification of metal dysregulation in Alzheimer's brain has led to the development of therapeutic metal-binding agents, targeting to the brain has remained an issue. The purpose of this study was to both determine concentrations of deferoxamine (DFO), a high-affinity iron chelator, reaching the brains of mice after intranasal administration and to determine its efficacy in a mouse model of spatial memory loss. Intranasal administration of DFO (2.4 mg) labeled with (59)Fe (75 µCi) to C57 mice resulted in micromolar concentrations at 30 min within brain parenchyma. After 3 months of intranasal DFO treatment, 2.4 mg three times per week, 48-week-old APP/PS1 mice had significantly reduced escape latencies in Morris water maze compared to vehicle-treated mice. This is the first report that intranasal DFO improves spatial memory in a mouse model of Alzheimer's disease and demonstrates that intranasal DFO reaches the brain in therapeutic doses.

Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice.

Intranasal administration is emerging as a reliable and non-invasive method to bypass the blood-brain barrier and deliver drugs to the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. However, intranasal administration could also be used to create animal models of brain disease. Beta-amyloid peptide (Aß) accumulation is a key feature of Alzheimer's disease (AD), and the most common models of AD are transgenic mice expressing mutant human genes linked to familial AD. An alternative model of amyloidosis utilizes intracerebroventricular infusion of thiorphan or phosphoramidon to block the activity of key Aß degrading enzymes (NEP, NEP2) resulting in accumulation of Aß. Here, we demonstrate that intranasal administration of phosphoramidon produces significantly elevated cerebral Aß levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also showed increased levels of Aß(40). These data show that intranasal delivery of drugs can be used to model AD and suggest that other phosphoramidon-sensitive peptidases are degrading Aß in NEP/NEP2-deficient mice.

Inhibition of ligand binding to G protein-coupled receptors by arachidonic acid.

Arachidonic acid (AA), released in response to muscarinic acetylcholine receptor (mAChR) stimulation, previously has been reported to function as a reversible feedback inhibitor of the mAChR. To determine if the effects of AA on binding to the mAChR are subtype specific and whether AA inhibits ligand binding to other G protein-coupled receptors (GPCRs), the effects of AA on ligand binding to the mAChR subtypes (M1, M2, M3, M4, and M5) and to the micro-opioid receptor, beta2-adrenergic receptor (beta2-AR), 5-hydroxytryptamine receptor (5-HTR), and nicotinic receptors were examined. AA was found to inhibit ligand binding to all mAChR subtypes, to the beta2-AR, the 5-HTR, and to the micro-opioid receptor. However, AA does not inhibit ligand binding to the nicotinic receptor, even at high concentrations of AA. Thus, AA inhibits several types of GPCRs, with 50% inhibition occurring at 3-25 MuM, whereas the nicotinic receptor, a non-GPCR, remains unaffected. Further research is needed to determine the mechanism by which AA inhibits GPCR function.

Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer's brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants.

Oxidative stress has been implicated as a contributing factor to neurodegeneration in Alzheimer's disease. An endogenous, low molecular weight (LMW) inhibitor from Alzheimer's brain inactivates the human brain muscarinic acetylcholine receptor (mAChR). The inhibitor prevents agonist and antagonist binding to the mAChR as assessed by radioligand binding studies. The LMW endogenous inhibitor, which has components with molecular weights between 100 and 1000 Da, requires dissolved oxygen and glutathione. Prevention of inactivation of the mAChR with peroxidase suggests that the LMW endogenous inhibitor generates peroxide. Heme, previously shown to be present in the LMW endogenous inhibitor, also inactivates the mAChR in the presence of peroxide. Free radical damage to the muscarinic receptor by the endogenous inhibitor can be prevented through the use of naturally occurring antioxidants including bilirubin, biliverdin, carnosol, myricetin and quericetin. In addition, pyrophosphate, imidodiphosphate, bisphosphonates and related compounds also protect the muscarinic receptor from free radical damage. Inactivation of the mAChR by the LMW endogenous inhibitor is likely to be a factor in the continual decline of Alzheimer's patients, even those taking acetylcholinesterase inhibitors. Natural antioxidants and pyrophosphate analogs may improve the effectiveness of acetylcholinesterase inhibitors and prove useful in the treatment and prevention of Alzheimer's disease since the muscarinic acetylcholine receptor is required for memory, and decreased cholinergic function is a critical deficit in Alzheimer's disease.