Identifying Racial and Ethnic Disparities in Acute Inpatient Rehabilitation.

OBJECTIVE: To investigate whether racial, ethnic, and linguistic disparities exist at discharge from an acute inpatient rehabilitation facility (IRF) by examining change in Functional Independence Measure (FIM) scores and discharge destination. DESIGN: This is a retrospective study using our IRF's data from the Uniform Data System for Medical Rehabilitation from 2013-2019. FIM scores and discharge destination were compared between race, language, and ethnic groups, with adjustment for patient characteristics. SETTING: An urban hospital with a level 1 trauma center, comprehensive stroke center, and IRF with Commission on Accreditation of Rehabilitation Facilities (CARF) certification. PARTICIPANTS: 2518 patients admitted to the IRF from 2013-2019 (N=2518). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in FIM score and discharge destination. RESULTS: After adjusting for covariates, non-White patients and patients with limited English proficiency had significantly lower functional recovery, as measured by smaller changes in FIM scores from IRF admission to discharge. Additionally, both groups were more likely to be discharged home with home health care than to a skilled nursing facility, compared with White and English-speaking patients. Disparities in discharge destination persisted within patients with noncommercial insurance (Medicaid or Medicare) and a stroke diagnosis but not within those who had commercial insurance or a nonstroke diagnosis. CONCLUSIONS: Racial and linguistic disparities were identified within our CARF certified IRF; however, the organization is committed to reducing health care disparities. Next steps will include investigating interventions to reduce disparities.

Improving Access to Yoga for Chronic Pain in a Spanish-Speaking Community: A Quality Improvement Initiative.

BACKGROUND: The recent increase in opioid misuse and overdose among the Hispanic population signifies the need for an initiative to increase efforts in pain management in the Hispanic population. Yoga is an evidence-based therapeutic intervention that is effective for several pain-associated disorders. However, in the United States, it is primarily taught in English and not always accessible. This quality improvement (QI) project aimed to assess the outcome of implementing a yoga program on pain and quality of life in the Hispanic population. METHODS: Twenty Spanish-speaking community center members participated in a linguistically-tailored yoga program over the course of 10 weeks that included educational, demonstration, and practice videos. Outcome measures of the QI program included changes in pain interference, physical function, opioid medication use, the overall impression of change in pain, satisfaction with the program, and the likelihood of continuation of yoga practice. RESULTS: Data collected from participants (n = 16) after the 10-week period indicated that nearly 60% experienced an improvement in their overall impression of change in pain; their reported likelihood of continuation of yoga practice at home or another location were 6.8 and 7.4, respectively, on a 10-point scale. While pain interference was unaffected, there was an improvement in markers of physical function, including a two-fold improvement in general activity without limitations. The mean average intensity of pain decreased by 33%. CONCLUSION: The use of a linguistically-tailored yoga program improved self-reported overall pain, physical function, average intensity of pain, and initiated an interest in participants in utilizing yoga practice for self-management of pain. This QI project provides results that can be used for further implementation initiatives at other sites and consideration of use in diverse populations.

Implementation of a Clinic-Based Yoga Program for Chronic Pain.

PURPOSE: Although many integrative therapies exist, studies increasingly demonstrate yoga can help change the negative neuroplastic effects experienced by people living with chronic pain. Despite encouraging findings, a gap exists in accessible yoga programs designed to meet the individual needs of those experiencing limitations from chronic pain. This study evaluated a yoga program designed for people living with chronic pain delivered in a health care setting. Although yoga began as a spiritual practice thousands of years ago, it is now widely practiced for its physical and mental well-being aspects achieved through movement and breathing techniques. DESIGN: This was a piolt study that did not include a control group. METHODS: Twenty-one people with chronic pain participated in an in-person group yoga program for 8 weeks that included an educational program and yoga practice. A prepost design was used to measure effectiveness of the program on pain interference (Brief Pain Inventory), physical function, opioid medication use, overall impression of change in pain, satisfaction with the program, and likelihood of continuation of yoga practice. RESULTS: Data collected from participants demonstrated a decrease in pain interference as measured by the Brief Pain Inventory subscale between pre- and postintervention (5.6 ± 2.2 to 4.0 ± 2.3). In addition, the proportion of respondents with a pain interference rating of severe decreased by 15.4% (38.1% to 22.7%) between the pre- and postintervention time point. On follow-up from a survey 3 months after the completion of the study, more than 25% (N = 5) of participants were still practicing yoga daily. CONCLUSIONS: Despite yoga being practiced for thousands of years, studies evaluating the neural effects of yoga show possible reversal of persistent patterns leading to chronic pain, leading to new interest in an ancient practice. This study helps fill the gap in research findings addressing the benefits of yoga programs designed to meet the needs of people living in chronic pain and provides an accessible option. This program provides pain management nurses an innovative nonpharmacological intervention to consider for people living with chronic pain. CLINICAL IMPLICATIONS: Evidence supporting the use of yoga in the treatment of chronic pain is growing, yet it remains an underutilized approach in a comprehensive treatment plan. Yoga can not only improve self-agency, but also reduces social isolation. Pain management nurses can play an important role in promoting the application of yoga for chronic pain and advocating for yoga programs that are focused on accessibility for people living with pain.

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.

Correction to: The AGING Initiative experience: a call for sustained support for team science networks.

After publication of the original article [1], it came to the authors' attention that a funding source was omitted. This Correction article shows the updated Funding section.

Feasibility Trial of a 10-Week Adaptive.

BACKGROUND: This study assessed the feasibility of implementing a yoga intervention adapted for participants diagnosed with chronic pain in a large Midwest neuroscience pain clinic. Although conducted using a small convenience sample, this was a novel program in that it was led by an advanced practice nurse certified in pain management and to teach yoga. She was therefore uniquely qualified to tailor the yoga practice to suit individual needs of study participants. DESIGN: The intervention consisted of a weekly 1-hour class for 10 weeks. Feasibility measures included patient recruitment, program adherence, patient satisfaction, global impression of change, and likelihood of continuing yoga practice. In addition, it was hypothesized that the program would positively affect participants' pain interference, physical function, pain intensity, pain behavior, mood, sleep, and pain medication usage. METHODS: Survey measurements were conducted 10 weeks before class start, immediately before the first class, and immediately after the last class. CONCLUSIONS: Although there is a strong body of research supporting the benefits of yoga for chronic pain conditions, our experience highlights some of the challenges of implementing an adaptive yoga program. Our study found that recruitment of patient through physician referral was highly feasible; however, retention rates for participants were very low. Program adherence is a barrier for research on yoga in chronic pain, as well as for clinical practice. A slight reduction in pain interference and physical function over time and trend toward improvement in all exploratory outcomes was identified. None of these trends were statistically significant, likely because of small sample size.

Screening Positive for Cognitive Impairment: Impact on Healthcare Utilization and Provider Action in Primary and Specialty Care Practices.

BACKGROUND: Alzheimer's disease, the most common cause of dementia, goes unrecognized in half of patients presenting to healthcare providers and is associated with increased acute care utilization. Routine cognitive screening of older adults in healthcare settings could improve rates of dementia diagnosis and patterns of healthcare utilization. OBJECTIVE: To evaluate the impact of screening positive for cognitive impairment on provider action in primary and specialty care practices and patient healthcare utilization. DESIGN: Individuals asymptomatic for cognitive impairment completed cognitive screening with the Mini-Cog (MC). Outcomes included MC screen-positive rates, provider follow-up actions, and healthcare utilization for all participants over a period of 36 months (18 months prior to and following MC screening). Data were extracted from the electronic medical record (EMR). Healthcare provider interventions and healthcare utilization for screen-positive and -negative groups, before and after screening, were compared. PARTICIPANTS: Primary and specialty care patients (n = 787) aged ≥ 65 without history of cognitive impairment seen in HealthPartners, an integrated healthcare system in Minnesota and Western Wisconsin. KEY RESULTS: In primary care and neurology practices combined, over the entire 36-month study window, individuals screening positive showed 32% higher rates of ED visits (p < 0.05) pre and post-screening compared to those screening negative. Screen positive also showed 39% higher rates of hospitalizations pre-screening (p < 0.05) and 58% higher rates post-screening (p < 0.01). While screen-detected cognitive impairment was associated with some relevant provider follow-up action in 32% of individuals, subsequent healthcare utilization did not change between the 18-month pre- and post-screening periods. CONCLUSION: Despite being associated with higher rates of healthcare utilization, screening positive on the MC led to a change in provider action in a minority of cases and did not reduce post-screening healthcare utilization. Screening for cognitive impairment alone is not sufficient to alter patterns of provider practice or patient healthcare utilization.

Rescue therapies for seizure emergencies: New modes of administration.

A subgroup of patients with drug-resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility. Alternate routes of administration have been used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intramuscular, and intranasal. The objective of this narrative review is to describe the (1) anatomical, physiologic, and drug physicochemical properties that need to be considered when developing therapies for seizure emergencies and (2) products currently in development. New therapies must consider parameters of Fick's law such as absorptive surface area, blood flow, membrane thickness, and lipid solubility, because these factors affect both rate and extend of absorption. For example, the lung has a 50 000-fold greater absorptive surface area than that associated with a subcutaneous injection. Lipid solubility is a physicochemical property that influences the absorption rate of small molecule drugs. Among drugs currently used or under development for rescue therapy, allopregnanolone has the greatest lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam, lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility correlates with lower water solubility, complicating formulation of rescue therapies. One approach to overcoming poor aqueous solubility involves the use of a water-soluble prodrug coadministered with a converting enzyme, which is being explored for the intranasal delivery of diazepam. With advances in seizure prediction technology and the development of drug delivery systems that provide rapid onset of effect, rescue therapies may prevent the occurrence of seizures, thus greatly improving the management of epilepsy.

The AGING Initiative experience: a call for sustained support for team science networks.

Team science, defined as collaborative research efforts that leverage the expertise of diverse disciplines, is recognised as a critical means to address complex healthcare challenges, but the practical implementation of team science can be difficult. Our objective is to describe the barriers, solutions and lessons learned from our team science experience as applied to the complex and growing challenge of multiple chronic conditions (MCC). MCC is the presence of two or more chronic conditions that have a collective adverse effect on health status, function or quality of life, and that require complex healthcare management, decision-making or coordination. Due to the increasing impact on the United States society, MCC research has been identified as a high priority research area by multiple federal agencies. In response to this need, two national research entities, the Healthcare Systems Research Network (HCSRN) and the Claude D. Pepper Older Americans Independence Centers (OAIC), formed the Advancing Geriatrics Infrastructure and Network Growth (AGING) Initiative to build nationwide capacity for MCC team science. This article describes the structure, lessons learned and initial outcomes of the AGING Initiative. We call for funding mechanisms to sustain infrastructures that have demonstrated success in fostering team science and innovation in translating findings to policy change necessary to solve complex problems in healthcare.

Stroke Characteristics in a Cohort of Hmong American Patients.

Background Prior studies have indicated high rates of vascular risk factors, but little is known about stroke in Hmong. Methods and Results The institutional Get With The Guidelines (GWTG) database was used to identify patients discharged with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage between 2010 and 2019. Hmong patients were identified using clan names and primary language. Univariate analysis was used to compare Hmong and White patients. A subarachnoid hemorrhage comparison was not conducted because of the small sample size. We identified 128 Hmong patients and 3084 White patients. Hmong patients had more prevalent hemorrhagic stroke (31% versus 15%; P<0.0016). In the acute ischemic stroke cohort, compared with White patients, Hmong patients were younger (60±13 versus 71±15 years; P<0.0001), presented to the emergency department almost 4 hours later; and had a lower thrombolysis usage rate (6% versus 14%; P=0.03496), worse lipid profile, higher hemoglobin A1C, similar stroke severity, and less frequent discharge to rehabilitation facilities. The most common ischemic stroke mechanism for Hmong patients was small-vessel disease. In the intracerebral hemorrhage cohort, Hmong patients were younger (55±13 versus 70±15 years; P<0.0001), had higher blood pressure, and had a lower rate of independent ambulation on discharge (9% versus 30%; P=0.0041). Conclusions Hmong patients with stroke were younger and had poorer risk factor control compared with White patients. There was a significant delay in emergency department arrival and low use of acute therapies among the Hmong acute ischemic stroke cohort. Larger studies are needed to confirm these observations, but action is urgently needed to close gaps in primary care and stroke health literacy.

Potentially Preventable Readmissions After Acute Inpatient Rehabilitation.

OBJECTIVE: The aim of the study is to identify causes and risk factors for potentially preventable readmissions of patients discharged from an inpatient rehabilitation facility. DESIGN: Our hospital billing database was used to identify patients discharged from our inpatient rehabilitation facility between 2013 and 2018 and experienced a potentially preventable readmission within 90 days ( n = 75). Retrospective chart review was completed to obtain clinical data. Of the patients discharged from the inpatient rehabilitation facility who did not experience a potentially preventable readmission, a group of age- and sex-matched controls ( n = 75) was randomly selected. The two study groups were compared using univariate and multivariate analyses. RESULTS: Our study found that individuals who discharged from acute inpatient rehabilitation were more likely to be readmitted with a potentially preventable readmission if they have a greater number of comorbidities, were admitted initially with a spinal cord injury, or have lower admission or discharge Functional Independence Measure motor scores. The most common potentially preventable readmission diagnoses were sepsis, renal failure, respiratory problems, and urinary tract infection. CONCLUSIONS: Identifying patients with the common causes for potentially preventable readmissions, in addition to the noted risk factors, is an important consideration for inpatient rehabilitation discharge planning.

Subacute intranasal administration of tissue plasminogen activator increases functional recovery and axonal remodeling after stroke in rats.

As a thrombolytic agent, application of recombinant tissue plasminogen activator (tPA) to ischemic stroke is limited by the narrow time window and side effects on brain edema and hemorrhage. This study examined whether tPA, administered by intranasal delivery directly targeting the brain and spinal cord, provides therapeutic benefit during the subacute phase after stroke. Adult male Wistar rats were subjected to permanent right middle cerebral artery occlusion (MCAo). Animals were treated intranasally with saline, 60 µg or 600 µg recombinant human tPA at 7 and 14days after MCAo (n=8/group), respectively. An adhesive-removal test and a foot-fault test were used to monitor functional recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticorubral tract (CRT) and the corticospinal tract (CST). Naive rats (n=6) were employed as normal control. Animals were euthanized 8 weeks after stroke. Compared with saline treated animals, significant functional improvements were evident in rats treated with 600 µg tPA (p<0.05), but not in 60 µg tPA treated rats. Furthermore, 600 µg tPA treatment significantly enhanced both CRT and CST sprouting originating from the contralesional cortex into the denervated side of the red nucleus and cervical gray matter compared with control group (p<0.01), respectively. The behavioral outcomes were highly correlated with CRT and CST axonal remodeling. Our data suggest that delayed tPA intranasal treatment provides therapeutic benefits for neurological recovery after stroke by, at least in part, promoting neuronal remodeling in the brain and spinal cord.

Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states.

BACKGROUND: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα2δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects. RESULTS: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα2δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα2δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα2δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation. CONCLUSIONS: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα2δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.

Lysosomal enzyme can bypass the blood-brain barrier and reach the CNS following intranasal administration.

Here we provide the first evidence that therapeutic levels of a lysosomal enzyme can bypass the blood-brain barrier following intranasal administration. α-L-iduronidase (IDUA) activity was detected throughout the brains of IDUA-deficient mice following a single intranasal treatment with concentrated Aldurazyme® (laronidase) and was also detected after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These results suggest that intranasal routes of delivery may be efficacious in the treatment of lysosomal storage disorders.

Brain Glucose Hypometabolism and Iron Accumulation in Different Brain Regions in Alzheimer's and Parkinson's Diseases.

The aim of this study was to examine the relationship between the presence of glucose hypometabolism (GHM) and brain iron accumulation (BIA), two potential pathological mechanisms in neurodegenerative disease, in different regions of the brain in people with late-onset Alzheimer's disease (AD) or Parkinson's disease (PD). Studies that conducted fluorodeoxyglucose positron emission tomography (FDG-PET) to map GHM or quantitative susceptibility mapping-magnetic resonance imaging (QSM-MRI) to map BIA in the brains of patients with AD or PD were reviewed. Regions of the brain where GHM or BIA were reported in each disease were compared. In AD, both GHM and BIA were reported in the hippocampus, temporal, and parietal lobes. GHM alone was reported in the cingulate gyrus, precuneus and occipital lobe. BIA alone was reported in the caudate nucleus, putamen and globus pallidus. In PD, both GHM and BIA were reported in thalamus, globus pallidus, putamen, hippocampus, and temporal and frontal lobes. GHM alone was reported in cingulate gyrus, caudate nucleus, cerebellum, and parietal and occipital lobes. BIA alone was reported in the substantia nigra and red nucleus. GHM and BIA are observed independent of one another in various brain regions in both AD and PD. This suggests that GHM is not always necessary or sufficient to cause BIA and vice versa. Hypothesis-driven FDG-PET and QSM-MRI imaging studies, where both are conducted on individuals with AD or PD, are needed to confirm or disprove the observations presented here about the potential relationship or lack thereof between GHM and BIA in AD and PD.

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease.

Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.

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.

Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations.

There is evidence of the therapeutic potential of intranasal oxytocin for the treatment of pain and various psychiatric disorders, however, there is scant evidence that oxytocin reaches the brain. We quantified the concentration and distribution pattern of [125I]-radiolabeled oxytocin in the brains and peripheral tissues of rats after intranasal delivery using gamma counting and autoradiography, respectively. Radiolabel was detected in high concentrations in the trigeminal and olfactory nerves as well as in brain regions along their trajectories. Considerable concentrations were observed in the blood, however, relatively low levels of radiolabel were measured in peripheral tissues. The addition of a mucoadhesive did not enhance brain concentrations. These results provide support for intranasal OT reaching the brain via the olfactory and trigeminal neural pathways. These findings will inform the design and interpretation of clinical studies with intranasal oxytocin.

Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer's Mice.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer's disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aß) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aß plaques and soluble Aß42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aß reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aß-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures.

Intranasal delivery has been shown to noninvasively deliver drugs from the nose to the brain in minutes along the olfactory and trigeminal nerve pathways, bypassing the blood-brain barrier. However, no one has investigated whether nasally applied drugs target orofacial structures, despite high concentrations observed in the trigeminal nerve innervating these tissues. Following intranasal administration of lidocaine to rats, trigeminally innervated structures (teeth, temporomandibular joint (TMJ), and masseter muscle) were found to have up to 20-fold higher tissue concentrations of lidocaine than the brain and blood as measured by ELISA. This concentration difference could allow intranasally administered therapeutics to treat disorders of orofacial structures (i.e., teeth, TMJ, and masseter muscle) without causing unwanted side effects in the brain and the rest of the body. In this study, an intranasally administered infrared dye reached the brain within 10 minutes. Distribution of dye is consistent with dye entering the trigeminal nerve after intranasal administration through three regions with high drug concentrations in the nasal cavity: the middle concha, the maxillary sinus, and the choana. In humans the trigeminal nerve passes through the maxillary sinus to innervate the maxillary teeth. Delivering lidocaine intranasally may provide an effective anesthetic technique for a noninvasive maxillary nerve block. Intranasal delivery could be used to target vaccinations and treat disorders with fewer side effects such as tooth pain, TMJ disorder, trigeminal neuralgia, headache, and brain diseases.