Improving the precision of intranasal oxytocin research.

The neuropeptide oxytocin has been popularized for its role in social behaviour and nominated as a candidate treatment for several psychiatric illnesses due to promising preclinical results. However, these results so far have failed to reliably translate from animal models to human research. In response, there have been justified calls to improve intranasal oxytocin delivery methodology in terms of verifying that intranasal administration increases central levels of oxytocin. Nonetheless, improved methodology needs to be coupled with a robust theory of the role of oxytocin in behaviour and physiology to ask meaningful research questions. Moreover, stringent methodology based on robust theory may yield interesting results, but such findings will have limited utility if they are not reproducible. We outline how the precision of intranasal oxytocin research can be improved by the complementary consideration of methodology, theory and reproducibility.

A narrative review on trans-nasal pulmonary aerosol delivery.

The use of trans-nasal pulmonary aerosol delivery via high-flow nasal cannula (HFNC) has expanded in recent years. However, various factors influencing aerosol delivery in this setting have not been precisely defined, and no consensus has emerged regarding the optimal techniques for aerosol delivery with HFNC. Based on a comprehensive literature search, we reviewed studies that assessed trans-nasal pulmonary aerosol delivery with HFNC by in vitro experiments, and in vivo, by radiolabeled, pharmacokinetic and pharmacodynamic studies. In these investigations, the type of nebulizer employed and its placement, carrier gas, the relationship between gas flow and patient's inspiratory flow, aerosol delivery strategies (intermittent unit dose vs continuous administration by infusion pump), and open vs closed mouth breathing influenced aerosol delivery. The objective of this review was to provide rational recommendations for optimizing aerosol delivery with HFNC in various clinical settings.

Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial.

Importance: Previous unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose. Objective: To test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose. Design, Setting, and Participants: A double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo). Interventions: Clients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 µg per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 µg per 1 mL and intranasal administration of placebo 1 mL. Main Outcomes and Measures: The primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 µg) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13. Results: A total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group. Conclusions and Relevance: This trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority. Trial Registration: anzctr.org.au Identifier: ACTRN12611000852954.

How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods.

Nasal delivery offers many benefits over other conventional routes of delivery (e.g. oral or intravenous administration). Benefits include, among others, a fast onset of action, non-invasiveness and direct access to the central nervous system. The nasal cavity is not only limited to local application (e.g. rhinosinusitis) but can also provide direct access to other sites in the body (e.g. the central nervous system or systemic circulation). However, both the anatomy and the physiology of the nose impose their own limitations, such as a small volume for delivery or rapid mucociliary clearance. To meet nasal-specific criteria, the formulator has to complete a plethora of tests, in vitro and ex vivo, to assess the efficacy and tolerance of a new drug-delivery system. Moreover, depending on the desired therapeutic effect, the delivery of the drug should target a specific pathway that could potentially be achieved through a modified release of this drug. Therefore, this review focuses on specific techniques that should be performed when a nasal formulation is developed. The review covers both the tests recommended by regulatory agencies (e.g. the Food and Drug Administration) and other complementary experiments frequently performed in the field.

The Intranasal Route as an Alternative Method of Medication Administration.

Intranasal drug administration is a less invasive method of drug delivery that is easily accessible for adult and pediatric patients. Medications administered by the intranasal route have efficacy comparable to intravenous administration and typically have superior efficacy to subcutaneous or intramuscular routes. The intranasal route is beneficial in emergent situations when the intravenous route is not available. The intranasal route is safe and effective in various indications, and therapeutic systemic concentrations of medication can be attained via this route. As the evidence for and comfort with intranasal administration continue to grow, guidance on correct technique, medications, and dosing is vital for appropriate use. This article reviews the process and practices of appropriate intranasal medication administration.

Seizing the Opportunity: Exploring Barriers to Use of Transmucosal Midazolam in Hospice Patients.

BACKGROUND: Status epilepticus seizures are distressing events for hospice and palliative care patients. Currently, rectal diazepam is the only abortive therapy approved by the U.S. Food and Drug Administration for seizures occurring out of hospital. However, transmucosal (buccal and intranasal) midazolam hydrochloride is a less expensive, equally effective, and a more socially acceptable alternative. OBJECTIVE: To explore the use of transmucosal midazolam in out-of-hospital hospice patients in the State of Alabama. DESIGN: A cross-sectional survey was used explore hospice providers' knowledge and use of transmucosal midazolam in clinical practice within Alabama. Setting Subjects: Hospice providers (physicians, nurses, and administrators) in the State of Alabama (n = 27). MEASUREMENTS: An electronic survey was used to elicit transmucosal midazolam use among hospice providers. RESULTS: Transmucosal midazolam has been documented throughout the literature and reported by expert clinicians as an efficacious, safe, and appropriate pharmaceutical intervention for the abortive treatment of seizures in adult and pediatric out-of-hospital patients. However, barriers to the use of transmucosal midazolam with hospice patients included unfamiliarity with transmucosal route and lack of provider orders. None of the participants reported transmucosal midazolam use in out-of-hospital hospice settings. CONCLUSION: Evidence in the literature supports the use of transmucosal midazolam; however, further research is necessary to understand and address barriers in a more diverse and generalizable population.

Intranasal Fentanyl and Quality of Pediatric Acute Care.

BACKGROUND: Changes in the manner in which medications can be delivered can have significant effects on the quality of care in the acute care setting. OBJECTIVE: The objective of this study was to evaluate the change in three Institute of Medicine quality indicators (timeliness, safety, and effectiveness) in the pediatric emergency department (ED) after the introduction of the Mucosal Atomizer Device Nasal™ (MADn) for opioid analgesia. METHODS: This was a retrospective review of patients receiving opioid analgesia for certain conditions over a 5-year period. We compared patients receiving intravenous opioid (IVO) to those receiving intranasal fentanyl (INF). Timeliness outcomes include time from medication order to administration, time from dose to discharge, overall time to analgesia, and ED length of stay. Effectiveness outcomes include change in pain score and frequency of repeat dosing. Safety outcomes were the frequency of reversal agent administration or a documented oxygen desaturation of < 90%. Sensitivity analyses were performed to evaluate the effect of moderate sedation on all three outcomes. RESULTS: During the study period, 1702 patients received opioid analgesia, 744 before and 958 after MADn introduction, of whom, 233 (24%) received INF. After MADn introduction, patients receiving INF had a shorter time to discharge from dose (109 vs. 203 min; p < 0.05) and shorter ED length of stay (168 vs. 267 min; p < 0.05). There was no difference in pain score reduction; however, repeat dosing was less frequent for patients receiving INF (16% vs. 27%). There was no use of reversal medication and no difference in the frequency of oxygen desaturations. When patients undergoing moderate sedation were removed from the analysis, there was no difference in the direction of findings for all three outcomes. CONCLUSIONS: INF is associated with improved timeliness and equivalent effectiveness and safety when compared to IVO in the setting of the pediatric ED.

Taking the alternative route: Women's experience of intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia.

OBJECTIVE: To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. DESIGN: A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire. SETTING: A tertiary and regional maternity unit in South Australia. FINDINGS: Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement. KEY CONCLUSIONS: Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects. IMPLICATIONS FOR PRACTICE: For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine.

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability.

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl ß cyclodextrin inclusion complex (AM-HPßCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29-34 °c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120 min (99.1 ± 0.44%w/v). Dissolution in simulated nasal fluid was 92.33 ± 0.15%w/v at the end of 120 min. Locomotor activity was improved with nasal gel containing AM-HPßCD as compared to AM and AM-HPßCD oral solution in rats. Cmax for nasal gel was found to be more (9 ng/ml) as compared to AM-HPßCD (5.5 ng/mL) and oral standard solution (2 ng/ml). Tmax was found to be 1.5 h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.

Nanopartículas poliméricas de administración intranasal para la liberación de activos en el sistema nervioso centra / Polymeric Nanoparticles for Drug Delivery to the Central Nervous System Via Nasal Route

Objetivos. Analizar la situación actual de las investigaciones relacionadas con las nanopartículas poliméricas como sistemas de liberación de fármacos, así como los estudios que muestran las aplicaciones de fármacos incorporados en dichos sistemas y liberados en el sistema nervioso central mediante la administración intranasal. Métodos. Se utilizó, entre otras, como principal fuente la base de datos de la National Library of Medicine, Washington, DC (MEDLINE: PubMed) para realizar la búsqueda de artículos de investigación más importantes publicados sobre el tema. Resultados. Muchos de los fármacos utilizados para el tratamiento de enfermedades neurodegenerativas no son capaces de atravesar la barrera hematoencefálica (BHE) y llegar al cerebro en concentraciones suficientes para ejercer su efecto terapéutico. Es por ello que surge la idea de desarrollar nanopartículas poliméricas para ser administradas por vía nasal. Gracias a la utilización de dichos sistemas, numerosos estudios han puesto de manifiesto una mejora en la utilidad clínica del fármaco, permitiendo reducir la dosis y la frecuencia de dosificación a la vez que se reducen los efectos secundarios. Conclusiones. Pese a los avances realizados, demostrándose un aumento de la concentración de fármacos incorporados en sistemas nanoparticulados que llegan al cerebro, aún son necesarias investigaciones que solventen los problemas de toxicidad presentados por estos sistemas y su variabilidad de dosis absorbida

Objectives. The main objective of this study is to analyse the current researches related to polymeric nanoparticles as a system of drug delivery, as well as the studies that show the different ways in which the drugs included in this system and delivered into the central nervous system are apply through intranasal delivery. Methods. The elaboration of this study has required the exhaustive analysis of different scientific articles related to polymeric nanoparticles and drug delivery systems. The National Library of Medicine, Washington, DC (MEDLINE: PlubMed) has been the main source of information from which the scientific articles used to carry out this study have been selected. Results. Many of the drugs employed for the treatment of neurodegenerative diseases are not capable of going through the blood-brain-barrier (BBB) and reach the brain with enough concentration, being unable to apply their therapeutic effect. That is why the idea of developing polymeric nanoparticles to be delivered through nasal delivery come out. Thanks to the use of this system, many researches have shown an improvement in the clinical utility of the drug, reducing the dose and the frequency of dosing as well as the side effects. Conclusions. Despite the improvements in this field that demonstrate an increase in the concentration of drugs, included in the nanoparticles systems, that reaches the brain, it is still necessary to carry out researches in order to solve issues related to the toxicity and the variability in the absorbed dose that these systems present

Resultados en salud y eficiencia del fentanilo intranasal en pectina en el dolor irruptivo en la práctica clínica habitual / No disponible

OBJETIVO: Conocer la efectividad y eficiencia del fentanilo intranasal en pectina comparado con otros tratamientos empleados en el dolor irruptivo oncológico a través de un análisis farmacoeconómico. RESULTADOS Y CONCLUSIONES: En la evaluación farmacoeconómica realizada, todas las opciones analizadas fueron coste-efectivas para una disposición a pagar (invertir) de 30.000 € por AVAC ganado (ratio coste/efectividad < 30.000 €). La opción más eficiente (mayor efectividad y menor coste) en todos los casos analizados es el espray intranasal de fentanilo en pectina (FPNS). En el análisis incremental, FPNS fue la opción dominante sobre todas las demás evaluadas: FST, OTFC, FBT e INFS. Del análisis de los datos de nuestro estudio de modelización de coste/efectividad del espray intranasal de fentanilo en pectina FPNS se concluye: - INFS sin proporcionar más eficacia ha demostrado ser significativamente más caro (+15 %). - FST, OTFC, FBT han demostrado una efectividad un 18 % menor que FPNS y además ser significativamente más caros (+9 %; +15 %; +10 %, respectivamente). Abreviaturas: AVAC: años ganados con buena calidad de vida. FPNS: PecFent®. FST: Abstral®. OTFC: Actiq®. FBT: Effentora®. INFS: Instanyl®

OBJECTIVE: Determine, with a pharmacoeconomic evaluation, the effectiveness and efficiency of fentanyl pectin intranasal spray for BTPc versus other indicated treatments. RESULTS AND CONCLUSIONS: All the treatments analyzed in the pharmacoeconomic evaluation were cost-effective in terms of a willingness to pay (invest) of € 30,000 per AVAC gained (cost / effectiveness ratio < € 30,000). The most efficient option (greater effectiveness and lower cost) of all the treatments analyzed was the fentanyl pectin nasal spray (FPNS). In the incremental analysis FPNS was the dominant treatment option over all the others evaluated: FST, OTFC, FBT and INFS. From the analysis of the data of our cost/effectiveness modeling study of the fentanyl pectin nasal spray, FPNS, we can conclude: - INFS without providing greater effectiveness has been shown to be significantly more expensive (+15 %). - FST, OTFC, FBT have demonstrated -18 % less effectiveness and also been shown to be significantly more expensive than FPNS (+9 %; +15 %; +10 %, respectively). Abbreviations: AVAC: Years gained with good quality of life. FPNS: PecFent®. FST: Abstral®. OTFC: Actiq®. FBT: Effentora®. INFS: Instanyl®

Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research.

A series of studies have reported on the salubrious effects of oxytocin nasal spray on social cognition and behavior in humans, across physiology (e.g., eye gaze, heart rate variability), social cognition (e.g., attention, memory, and appraisal), and behavior (e.g., trust, generosity). Findings suggest the potential of oxytocin nasal spray as a treatment for various psychopathologies, including autism and schizophrenia. There are, however, increasing reports of variability of response to oxytocin nasal spray between experiments and individuals. In this review, we provide a summary of factors that influence transmucosal nasal drug delivery, deposition, and their impact on bioavailability. These include variations in anatomy and resultant airflow dynamic, vascularisation, status of blood vessels, mode of spray application, gallenic formulation (including presence of uptake enhancers, control release formulation), and amount and method of administration. These key variables are generally poorly described and controlled in scientific reports, in spite of their potential to alter the course of treatment outcome studies. Based on this review, it should be of no surprise that differences emerge across individuals and experiments when nasal drug delivery methods are employed. We present recommendations for researchers to use when developing and administering the spray, and guidelines for reporting on peptide nasal spray studies in humans. We hope that these recommendations assist in establishing a scientific standard that can improve the rigor and subsequent reliability of reported effects of oxytocin nasal spray in humans.

Effects of localized hydrophilic mannitol and hydrophobic nelfinavir administration targeted to olfactory epithelium on brain distribution.

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = -3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.