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This review aims to provide an overview and update of current literature on the use of intranasal (IN) drug delivery in pediatric emergency medicine (PEM), in terms of the anatomy, physiology, pharmacokinetics, limitations, drug delivery methods, necessary training, safety, contraindications, effectiveness, current indications and trends, and implications for clinical practice and future developments in IN drug administration. We evaluate how IN medication use in PEM has recently evolved, what recent research has revealed about the utility of IN drug delivery in PEM, and what the future of IN drug delivery might look like.

Background: Intranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived fromLactococcus lactishave the potential to serve as a vaccine adjuvant.This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®)., Methods: This was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18-49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additionalelderly cohort (>65 years)., Results: Ninty participants were included. Intranasal FluGem®was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly., Conclusions: Intranasal vaccination of FluGEM®was safe and tolerable in healthy adult volunteers aged 18-49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose-response relationship.More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants., Competing Interests: Declaration of competing interest Kees Leenhouts and Bert-Jan Haijema were former employees of Mucosis BV. The study was sponsored by Mucosis BV. For the other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mucosal vaccines have the potential to elicit protective immune responses at the point of entry of respiratory pathogens, thus preventing even the initial seed infection. Unlike licensed injectable vaccines, mucosal vaccines comprising protein subunits are only in development. One of the primary challenges associated with mucosal vaccines has been identifying and characterizing safe yet effective mucosal adjuvants that can effectively prime multi-factorial mucosal immunity. In this study, we tested NanoSTING, a liposomal formulation of the endogenous activator of the stimulator of interferon genes (STING) pathway, cyclic guanosine adenosine monophosphate (cGAMP), as a mucosal adjuvant. We formulated a vaccine based on the H1 antigen (fusion protein of Ag85b and ESAT-6) adjuvanted with NanoSTING. Intranasal immunization of NanoSTING-H1 elicited a strong T-cell response in the lung of vaccinated animals characterized by (a) CXCR3 + KLRG1 - lung resident T cells that are known to be essential for controlling bacterial infection, (b) IFNγ-secreting CD4 + T cells which is necessary for intracellular bactericidal activity, and (c) IL17-secreting CD4 + T cells that can confer protective immunity against multiple clinically relevant strains of Mtb. Upon challenge with aerosolized Mycobacterium tuberculosis Erdman strain, intranasal NanoSTING-H1 provides protection comparable to subcutaneous administration of the live attenuated Mycobacterium bovis vaccine strain Bacille-Calmette-Guérin (BCG). Our results indicate that NanoSTING adjuvanted protein vaccines can elicit a multi-factorial immune response that protects from infection by M. tuberculosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Navin Varadarajan reports financial support was provided by National Institutes of Health. Navin Varadarajan reports financial support was provided by AuraVax Therapeutics. Navin Varadarajan reports a relationship with AuraVax Therapeutics and CellChorus that includes: equity or stocks., (Copyright © 2024. Published by Elsevier Ltd.)

Abstract: Esketamine, the s(+) enantiomer of ketamine, was approved in 2019 as the first rapid-acting intranasal spray medication for treatment-resistant depression; the drug is given in combination with an antidepressant. The treatment is self-administered in a clinical setting under the supervision of a healthcare provider and usually is well tolerated. Many of its adverse reactions are mild, temporary, and dose-dependent, and they improve with subsequent treatments. Although the prescribing information lists difficulty remembering or thinking as possible adverse reactions, a neurocognitive evaluation is not part of the initial patient evaluation. This case report focuses on a patient whose neurocognitive symptoms worsened with esketamine treatment, necessitating treatment discontinuation., (Copyright © 2024 American Academy of Physician Associates.)

Background: Postoperative cognitive impairment are common neural complications in older surgical patients and exacerbate the burden of medical care on families and society., Methods: A total of 140 older patients who were scheduled for elective orthopaedic surgery or pancreatic surgery with general anaesthesia were randomly assigned to Group S or Group I with a 1:1 allocation. Patients in Group S and Group I received intranasal administration of 400 μL of normal saline or 40 IU/400 μL of insulin, respectively, once daily from 5 minutes before anaesthesia induction until 3 days postoperatively. Perioperative cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Basic (MoCA-B) at 1 day before and 3 days after surgery and postoperative delirium (POD) incidence was assessed using the 3-minute Diagnostic Interview for CAM (3D-CAM) on postoperative days 1-3. Serum levels of interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), S100-β and C-reactive protein (CRP) were measured on the first day after surgery., Results: Insulin treatment significantly increased postoperative MMSE and MoCA-B scores in group I than in group S (P < 0.001, P = 0.001, respectively), decreased the incidence of POD within the 3-day postoperative period in Group I than in Group S (10.9% vs 26.6%, P = 0.024), and inhibited postoperative IL-6 and S100-β levels in Group I compared to Group S (P = 0.034, P = 0.044, respectively)., Conclusions: Intranasal insulin administration is thus suggested as a potential therapy to improve postoperative cognition in older patients undergoing surgery. However, a more standardized multi-centre, large-sample study is needed to further validate these results., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Benzodiazepines are the recommended first-line treatment of acute seizures. We wished to compare the efficacy, side effects, and satisfaction after midazolam administration by the buccal, intranasal, or intramuscular route in the treatment of acute seizures in children at homes and in emergency room (ER)., Methods: A prospective, randomized, controlled trial was performed in children aged one month to 17 years with acute seizures lasting longer than five minutes. The primary end point was seizure cessation within 10 minutes of drug administration and no seizure recurrence within 30 minutes., Results: In the home group, 67 patients received midazolam via buccal route, 60 via intranasal route, and 69 via intramuscular route, whereas in the ER group, 37 patients received buccal, 34 received intranasal, and 34 received intramuscular midazolam. The primary end point was achieved in 94.2% and 85.3% after intramuscular midazolam in the home and ER groups, respectively. The intranasal midazolam was successful in stopping seizures in 93.3% in the home group and 88.2% in the ER group. The buccal route was effective in 91% in the home group and 78.4% in the ER group. There were no significant differences in efficacy between all groups (P = 0.763 and P = 0.509) among the home and ER groups, respectively. There were no significant cardiorespiratory events in all groups., Conclusions: Intramuscular, intranasal, and buccal doses of midazolam resolved most seizures in prehospital and emergency settings. Our results indicate that there is no statistically significant difference detected between different routes of midazolam. Intranasal route showed the highest satisfaction rate among caregivers., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chitosan and its derivatives are ideal nasal vaccine adjuvant to deliver antigens to immune cells. Previously, we successfully used a chitosan derivative, O-(2-Hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (O-HTCC), and a β-glucan derivative, curdlan sulfate (CS), to prepare a nanoparticle adjuvant CS/O-HTCC which could deliver ovalbumin to antigen presenting cells (APCs) through nasal inhalation. In this article, we used SARS-CoV-2 spike receptor binding domain (S-RBD) as the antigen and CS/O-HTCC nanoparticles as the adjuvant to develop a nasal mucosal protein subunit vaccine, CS/S-RBD/O-HTCC. The humoral immunity, cell-mediated immunity and mucosal immunity induced by vaccines were evaluated. The results showed that CS/S-RBD/O-HTCC could induce desirable immunization with single or bivalent antigen through nasal inoculation, giving one booster vaccination with mutated S-RBD (beta) could bring about a broad cross reaction with ancestral and different mutated S-RBD, and vaccination of the BALB/c mice with CS/S-RBD/O-HTCC containing S-RBD mix antigens (ancestral and omicron) could induce the production of binding and neutralizing antibodies against both of the two antigens. Our results indicate that CS/O-HTCC is a promising nasal mucosal adjuvant to prepare protein subunit vaccine for both primary and booster immunization, and the adjuvant is suitable for loading more than one antigen for preparing multivalent vaccines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To investigate fear of hypoglycemia (FoH) in parents of children with type 1 diabetes (T1D) before and after undergoing training to learn intranasal (IN) glucagon administration., Method: In this pre-test/post-test uncontrolled study 364 caregivers of patients with T1D (6-18 years) completed questionnaires measuring sociodemographic characteristics, diabetes-related factors (e.g., type of insulin therapy, glycemic control), and parents' trait anxiety. Parents' FoH was assessed at baseline (T0, training) and after nine months (T1). Two repeated-measure mixed analyses of covariance (ANCOVA) compared the FoH at T0 and at T1 and analyzed the moderating roles of anxiety proneness and type of insulin therapy, as well as of anxiety proneness and use of sensor. Age, T1D duration, HbA1c values, and SES were included as covariates., Results: Parental FoH at T1 (M = 1.72; SE = 0.06/M = 1.57; SE = 0.09) was significantly lower than parental FoH at T0 (M = 1.89; SE = 0.06/M = 1.77; SE = 0.09). The group with high trait-anxiety had a higher level of FoH (M = 2.05; SE = 0.08/M = 1.89; SE = 0.12) than the group with low trait-anxiety (M = 1.57; SE = 0.08/M = 1.46; SE = 0.09) at both time points. SES was negatively associated with FoH at T0 (t = -2.87; p = .004/t = -2.87; p = .005). No other significant effects were found., Conclusions: Training and educating parents on IN glucagon use can help them effectively manage hypoglycemic episodes and alleviate the fear that generally accompany such events., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A Phase II trial was conducted to determine if nasal disinfection with a commercial Good Manufacturing Practice-manufactured 0.5% povidone-iodine nasal spray (Nasodine®) may be a useful adjunct in the management of COVID-19 by reducing viral shedding and prevention of transmission of SARS-CoV-2. The aim was to confirm the results from a human single-dose pilot study by assessing repeated and frequent doses on nasal shedding of SARS-CoV-2 from adult subjects with confirmed COVID-19., Methods: A multicenter, randomized, double-blinded, placebo-controlled Phase II clinical trial involving adults with early COVID-19 symptoms. Baseline nasal swabs were collected to quantify pretreatment SARS-CoV-2 nasal viral load, followed by Nasodine treatment eight times daily over 3 calendar days. Daily nasal swabs were collected post-dose to assess the impact of treatment on nasal viral load, measured by log10 TCID50 in quantitative culture., Results: Nasodine subjects exhibited significantly improved reduction in viral load (log10 TCID50) on Days 2-4 compared to placebo recipients (p = 0.028), rate of nasal clearance of viable virus (p = 0.032), and complete (100%) nasal and throat clearance of the virus by Day 5. No difference was seen in antigen shedding as measured by time transition from Rapid Antigen Test (RAT) positivity to RAT negativity., Conclusion: A total of 20 doses of Nasodine® nasal spray administered over 2.5 days significantly reduced the titers of viable SARS-CoV-2 virus in the nasal passages of COVID-19 subjects. This is the first study demonstrating the efficacy of a tolerable intranasal formulation of povidone-iodine on viral shedding in COVID-19 subjects. Nasal disinfection may diminish viral transmission to others., Level of Evidence: 2 Laryngoscope, 134:3947-3952, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Ketamine is a safe and widely used sedative and analgesic in children. The purpose of this study is to evaluate the response to sedoanalgesia for painful procedures in the pediatric emergency department., Methods: A retrospective study was conducted in children younger than 16 years who underwent painful procedures with intravenous/intranasal ketamine between January 2016 and December 2022. We collected demographic variables, effectiveness, route of administration, indication, dose, sedation strategy, duration of procedure, and associated adverse effects., Results: A total of 671 ketamine sedation procedures (411 males/260 females) were included, with a mean age of 7.2 years. Closed reduction was the most common painful procedure (53.8%), followed by burn healing (24.6%). Ketamine was administered intravenously in 93.4% of procedures and intranasally in 6.6%. The result of sedoanalgesia was satisfactory in 84.9% and unsatisfactory in 15.1%. The percentage of cases with unsatisfactory analgesia was higher with intranasal administration (36.4%; P < 0.001). In the intravenous group, the percentage of cases with unsatisfactory effectiveness (28.7%) was higher for patients younger than 2 years of age ( P < 0.001). Arthrocentesis procedures were associated with the highest percentage of unsatisfactory sedoanalgesia failures among patients receiving intravenous ketamine (39.3%; P < 0.001). Intranasal ketamine patients who received a dose between 3.6 and 4 mg/kg had a significantly higher percentage of unsatisfactory sedoanalgesia (66.7%; P = 0.048). Patients receiving intravenous ketamine had significantly higher rates of unsatisfactory sedoanalgesia when the initial dose interval was 1.6 to 2 mg/kg (11.8%; P = 0.002) and when the final total dose was also 1.6 to 2 mg/kg (17.6%; P = 0.002)., Conclusions: This study concludes that intravenous/intranasal ketamine can provide safe and successful analgesia in pediatric patients in the ED. At intravenous doses of 1-1.5 mg/kg, good effectiveness was achieved in almost 90% of cases. Arthrocentesis had the highest percentage of unsatisfactory results. Repeat dosing should be considered for procedures longer than 20 minutes., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials., Background: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®)., Methods: The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria., Results: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs., Conclusion: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications., (© 2024 American Headache Society.)

Aging and interactions between genetic and environmental factors are believed to be involved the chronic development of Parkinson's disease (PD). Among PD patients, abnormally aggregated α-synuclein is a major component of the Lewy body. Generally, the intranasal route is believed to be a gate way to the brain, and it assists environmental neurotoxins in entering the brain and is related to anosmia during early PD. The current study applies the chronic intranasal application of lipopolysaccharides (LPS) in 4-, 8-, 12- and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice at 2-day intervals for a 2-month period, for evaluating the behavioral, pathological, and biochemical changes and microglial activation in these animals. According to our results, after intranasal administration of LPS, A53T-α-Syn mice showed severe progressive anosmia, hypokinesia, selective dopaminergic (DAergic) neuronal losses, decreased striatal dopamine (DA) level, and enhanced α-synuclein accumulation within the substantia nigra (SN) in an age-dependent way. In addition, we found obvious NF-кB activation, Nurr1 inhibition, IL-1β, and TNF-α generation within the microglia of the SN. Conversely, the wild-type (WT) mice showed mild, whereas A53T-α-Syn mice had moderate PD-like changes among the old mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD development. Its underlying mechanism may be associated with Nurr1 inhibition within microglia and the amplification of CNS neuroinflammation. The mice with multiple factors, including aging, neuroinflammation, and α-synuclein mutation, have played a significant role in enhancing our understanding of how inflammation and α-synuclein mutation contribute to the neurodegeneration observed in PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R 2 : 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Cryptococcal meningitis is a deadly disease with few treatment options. Its incidence is still high and closely linked to the HIV/AIDS epidemic. This study aimed to develop a mucoadhesive microsphere delivery system for fluconazole for the intranasal route., Method: Microspheres of mucoadhesive fluconazole formulation variables such as different amounts of drug concentration and polymer concentration were prepared by a simple emulsion-crosslinking method. The prepared microspheres' surface was characterised by SEM (Scanning electron microscopy) and evaluated for particle size, entrapment efficiency, production yield, infrared spectroscopic study, in-vitro muco-adhesion, and in-vitro drug release., Results: The results showed that formula 1 is the optimal mucoadhesive microsphere preparation, with a particle size of 56.375m, a spherical surface shape, an entrapment efficiency of 99.96%, and a greater mucoadhesive capability during 6-hour evaluation. Furthermore, wash-off examination revealed that the mucoadhesive ability of this delivery system has a long duration and may release the active material at the right time., Conclusion: The result of the researches suggesting that the formulation of mucoadhesive microspheres of fluconazole could be used to treat cryptococcal meningitis infection in HIV/AIDS patients., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated., Methods: This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 μg and 20-40 μg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated., Results: A total of 60 participants completed the study. PA9159 doses of up to 80 μg in the SAD and up to 40 μg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8 % (368/880) of the samples in all treatment groups, including 25.2 % (105/416) of the SAD and 56.7 % (263/464) of the MAD. The majority (>80.0 %) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC 0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t 1/2 ) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUC ss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t 1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median T max was approximately 6 h in both the SAD and MAD cohorts., Conclusions: The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Evidence supporting topical steroids for the treatment of chronic rhinosinusitis without nasal polyposis (CRSsNP) is unclear. Recent trials describe alternative topical steroid delivery modalities, including rinses and exhalation delivery system (EDS), necessitating a re-examination of the current literature., Methods: Cochrane Library, CINAHL, PubMed, and Scopus databases were searched from inception to February 13, 2024 for placebo-controlled randomized control trials on topical steroids used to treat CRSsNP, including topical spray, nasal irrigation, sinonasal catheter, and EDS modalities. Primary outcome measures included total symptom scores (TSS) (Δ) and response rates (odds ratio)., Results: Ten trials (N = 751) were included for meta-analysis, with a mean age of 47.5 years (range: 18-80 years; 95% confidence interval [CI]: 43.9-51.2 years). Topical steroids delivered by any method significantly improved TSS in CRSsNP patients (Δ0.4; 95% CI: 0.3-0.6; p < 0.0001). When stratified by allergy status, CRSsNP patients without allergy had significantly improved TSS when treated with EDS (Δ0.4; 95% CI: 0.1-0.7; p = 0.01), but not with topical spray (Δ0.04; 95% CI: -0.9 to 1.0; p = 0.94). Patients treated with EDS or sinonasal catheter responded significantly better compared to placebo (odds ratio [OR]: 3.4; 95% CI: 1.9-6.0; p < 0.0001; OR: 12.4; 95% CI: 1.8-83.8; p < 0.01), whereas patients treated with topical spray had no significant difference (OR: 1.8; 95% CI: 0.9-4.0; p = 0.12)., Conclusions: Topical steroids are effective in treating CRSsNP, especially when delivered via EDS or sinonasal catheter. Future trials comparing steroid delivery mechanisms using validated outcome measures in CRSsNP populations are needed., (© 2024 ARS‐AAOA, LLC.)

About 30% of patients with major depressive disorder have treatment-resistant depression (TRD). Recently, intranasal esketamine was approved as a treatment option after the failure of two antidepressant trials. We report a patient with multiresistant depression that was successfully and safely treated with esketamine nasal spray. This 31-year-old inpatient with severe, chronic, and multi-TRD received an acute course of intranasal esketamine (84 mg). Previously, 14 different antidepressants, alone or in potentiation, and several neurostimulation techniques had been unsuccessful. Over 20 bi-weekly sessions, she had no significant adverse effects and was stabilized into remission. During the maintenance phase and 1 year after, she continues to be stable. This case report provides an example of a patient with severe TRD that showed significant improvement after treatment with intranasal esketamine., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of - 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine ( 131 I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain., (© 2024. The Author(s).)

Key Points: PVP-I is a widely used antiseptic but only recently proposed for intranasal use. The extent of iodine absorption from available PVP-I nasal products is unknown. Iodine absorption from use of Nasodine (0.5% PVP-I nasal spray) is not clinically significant., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Glucocorticoids are widely used for treating allergic rhinitis, but conventional intranasal administration encounters unfavorable nasal cilia clearance and nasal mucosal barrier. Herein, a bilateral microneedle patch is fabricated for delivering cyclodextrin-based metal-organic frameworks (CD-MOF) encapsulating dexamethasone (DXMS) and paeonol (Pae), while NaH particles are mounted on the basal part of each microneedle. By intranasal administration, the microneedles are propelled into the nasal mucosa by NaH-generated hydrogen and then swell to form a hydrogel for sustainedly releasing drugs. The DXMS/Pae combination is demonstrated to be superior to more than the twofold dose of DXMS alone for improving allergic rhinitis in rats. It involves reducing mast cell degranulation and modulating Treg/Th17 cell homeostasis, whereas inhibiting Th1 to Th2 differentiation is associated with regulating the GATA3/T-bet pathway, as well as repairing epithelial barrier function by increasing MUC1 and downregulating periostin. In addition, this delivery system modulates the lipid metabolism of the nasal mucosa. Notably, the newly designed device significantly enhances the drug's therapeutic effect, and NaH-generated hydrogen may have the potential adjunctive therapeutic effect. Collectively, such an emerging microneedle-mediated nasal drug delivery creates a new form for alleviating immune inflammation and contributes a promising solution to reduce clinical glucocorticoid abuse., (© 2024 Wiley‐VCH GmbH.)

The anxiolytic effect of oxytocin (OXT) on psychosocial stress has been well documented, but the effectiveness under the interference of other factors still requires in-depth research. Previous studies have shown that nicotine addiction interacts with OXT on psychosocial stress on the behavioral level. However, the underlying neural mechanism of interaction between OXT and nicotine addiction on psychosocial stress has not been examined, and we conducted two experiments to reveal it. Firstly, after intranasal administration of randomized OXT or placebo (saline), a group of healthy participants (n = 27) and a group of smokers (n = 26) completed the Montreal Imaging Stress Task (MIST) in an MRI scanner. Secondly, a group of smokers (n = 22) was recruited to complete a transcranial direct current stimulation (tDCS) experiment, in which anodal tDCS was applied on subjects' anterior right superior temporal gyrus (rSTG). In both experiment, subjective stress ratings, salivary cortisol samples and the amount of daily cigarette consumption were obtained from each participant. Analysis of variance were applied on both behavioral and neural data to examine the effects of OXT and nicotine addiction, and correlation analysis were used to examine relationships between neural and behavioral data. In first fMRI experiment, analysis of variance (ANOVA) revealed an interaction of OXT and nicotine addiction on subjective stress. In smokers, OXT failed to suppress the elevation of subjective stress and craving ratings after psychosocial stress. A voxel-wise ANOVA of fMRI data identified an interaction between OXT and nicotine addiction in anterior rSTG, and its functional connectivity with right middle frontal gyrus. Correlations between this functional connectivity and subjective psychosocial stress were also found abnormal in smokers. In second tDCS experiment, we found that under tDCS, OXT successfully suppressed the elevation of subjective stress and craving ratings after stress. In summary, we found that nicotine addiction blocked OXT's anxiolytic on psychosocial stress, which was related to abnormalities in anterior rSTG. By applying anodal tDCS on anterior rSTG, OXT's anxiolytic effect was restored in smokers. These findings will support further development on oxytocin's intervention of psychosocial stress in nicotine addiction, and provides essential information for indicating OXT's effectiveness., (© 2024. The Author(s).)

Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance., Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research., Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations., Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients., (© 2024. The Author(s).)

Background: Delirium, marked by acute cognitive decline, poses a life-threatening issue among older individuals, especially after cardiac surgery, with prevalence ranging from 15 to 80%. Postoperative delirium is linked to increased morbidity and mortality. Although clinical trials suggest preventability, there is limited research on intranasal insulin (INI) for cardiac surgery-related delirium. INI has shown promise in managing cognitive disorders. It rapidly elevates brain hormone levels, enhancing memory even in non-impaired individuals. While effective in preventing delirium in gastrointestinal surgery, its impact after cardiac surgery remains understudied, especially for middle-aged patients., Method: This is a prospective randomized, double-blind, single-center controlled trial. A total of 76 eligible participants scheduled for elective on-pump cardiac surgery will be enrolled and randomly assigned in a 1:1 ratio to either receive Intranasally administered insulin (INI) or intranasally administered normal saline. The primary outcome of our study is the incidence of postoperative delirium (POD). Secondary outcomes include duration of ICU, postoperative hospital length of stay, all in-hospital mortality, the change in MMSE scores pre- and post-operation, and incidence of postoperative cognitive dysfunction at 1 month, 3 months, and 6 months after operation. Moreover, we will subjectively and objectively evaluate perioperative sleep quality to investigate the potential impact of nasal insulin on the development of delirium by influencing sleep regulation., Discussion: Our study will aim to assess the impact of intranasal administration of insulin on the incidence of postoperative delirium in middle-aged patients undergoing on-pump elective cardiac surgery. If intranasal insulin proves to be more effective, it may be considered as a viable alternative for preventing postoperative delirium., Trial Registration: ChiCTR ChiCTR2400081444. Registered on March 1, 2024., (© 2024. The Author(s).)

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery ( R 2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.

Objectives : The aim of the present study was to study the potential therapeutic effects of quercetin in protection against repeated intranasal exposure of an amyloid-beta-induced mouse model. Methods : Mice received intranasal Aβ 1-42 (5 μg/10 μL) exposure once daily for seven consecutive days. Quercetin was orally administered to them at 30 mg kg -1 and 100 mg kg -1 doses for one week starting from day five following Aβ 1-42 peptide administration. Following this, the animals were evaluated for neurobehavioral parameters using a Morris water maze test and a novel object recognition test. Further to this, the biomarkers for neuroinflammation and neurodegeneration were evaluated in the hippocampus and cortex regions of the brain in these animals. Results : Multiple exposures to intranasal Aβ led to a significant decline in the learning and cognitive memory of the animals, whereas oral treatment with quercetin at dosages of 30 and 100 mg kg -1 alleviated Aβ-induced effects. Quercetin treatment significantly reduced Aβ accumulation, oxidative stress and proinflammatory cytokine biomarkers in the brain. In addition, it also alleviated the activation of astrocytic biomarkers, amyloid precursor protein and phosphorylated-tau proteins in the brain. Conclusion : Quercetin was found to be a potent antioxidant, anti-inflammatory compound with protection against neurodegenerative damage and improved learning and cognitive memory in a repeated Aβ-exposure model of AD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive. We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization. Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2. Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motoneuron degeneration, and effective clinical treatments are lacking. In this study, we evaluated whether intranasal delivery of mesenchymal stem cell-derived small extracellular vesicles (sEVs) is a strategy for ALS therapy using SOD1 G93A mice. In vivo tracing showed that intranasally-delivered sEVs entered the central nervous system and were extensively taken up by spinal neurons and some microglia. SOD1 G93A mice that intranasally received sEV administration showed significant improvements in motor performances and survival time. After sEV administration, pathological changes, including spinal motoneuron death and synaptic denervation, axon demyelination, neuromuscular junction degeneration and electrophysiological defects, and mitochondrial vacuolization were remarkably alleviated. sEV administration attenuated the elevation of proinflammatory cytokines and glial responses. Proteomics and transcriptomics analysis revealed upregulation of the complement and coagulation cascade and NF-ĸB signaling pathway in SOD1 G93A mouse spinal cords, which was significantly inhibited by sEV administration. The changes were further confirmed by detecting C1q and NF-ĸB expression using Western blots. In conclusion, intranasal administration of sEVs effectively delays the progression of ALS by inhibiting neuroinflammation and overactivation of the complement and coagulation cascades and NF-ĸB signaling pathway and is a potential option for ALS therapy., (© 2024. The Author(s).)

Rift Valley fever (RVF) is an important zoonotic viral disease affecting several species of domestic and wild ruminants, causing major economic losses and dozens of human deaths in various geographical areas of Africa, where it is endemic. Although it is not present in Europe, there is a risk of its introduction and spread linked to globalisation and climate change. At present, the only measure that could help to prevent the disease is vaccination of flocks in areas at risk of RVF. Available live attenuated vaccines are an effective means of controlling the disease, but their use is often questioned due to residual virulence, particularly in susceptible hosts such as pregnant sheep. On the other hand, no vaccine is currently licensed for use in humans. The development of safe and effective vaccines is therefore a major area of research. In previous studies, we selected under selective mutagenic pressure a highly attenuated RVFV 56/74 virus variant called 40Fp8. This virus showed an extremely attenuated phenotype in both wild-type and immunodeficient A129 (IFNARKO) mice, yet was still able to induce protective immunity after a single inoculation, thus supporting its use as a safe, live attenuated vaccine. To further investigate its safety, in this work we have analysed the attenuation level of 40Fp8 in immunosuppressed mice (A129) when administered by the intranasal route, and compared it with other attenuated RVF viruses that are the basis of vaccines in use or in development. Our results show that 40Fp8 has a much higher attenuated level than these other viruses and confirm its potential as a candidate for safe RVF vaccine development., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: INIA-CSIC (BB and AB) has filed an international patent application (code # WO2021/245313A1) for 40-FP8 based RVF vaccines. The authors declare that the research was conducted in the absence of any commercial, financial, personal, or professional relationships that could be construed as a potential conflict of interest., (Copyright: © 2024 Borrego et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Despite vaccination, influenza and otitis media (OM) remain leading causes of illness. We previously found that the human respiratory commensal Haemophilus haemolyticus prevents bacterial infection in vitro and that the related murine commensal Muribacter muris delays OM development in mice. The observation that M muris pretreatment reduced lung influenza titer and inflammation suggests that these bacteria could be exploited for protection against influenza/OM., Methods: Safety and efficacy of intranasal H haemolyticus at 5 × 107 colony-forming units (CFU) was tested in female BALB/cARC mice using an influenza model and influenza-driven nontypeable Haemophilus influenzae (NTHi) OM model. Weight, symptoms, viral/bacterial levels, and immune responses were measured., Results: Intranasal delivery of H haemolyticus was safe and reduced severity of influenza, with quicker recovery, reduced inflammation, and lower lung influenza virus titers (up to 8-fold decrease vs placebo; P ≤ .01). Haemophilus haemolyticus reduced NTHi colonization density (day 5 median NTHi CFU/mL = 1.79 × 103 in treatment group vs 4.04 × 104 in placebo, P = .041; day 7 median NTHi CFU/mL = 28.18 vs 1.03 × 104; P = .028) and prevented OM (17% OM in treatment group, 83% in placebo group; P = .015)., Conclusions: Haemophilus haemolyticus has potential as a live biotherapeutic for prevention or early treatment of influenza and influenza-driven NTHi OM. Additional studies will deem whether these findings translate to humans and other respiratory infections., Competing Interests: Potential conflicts of interest. P. C. R. has served on vaccine scientific advisory boards and together with L. S. K. has received institutional funding for investigator-initiated grants from GlaxoSmithKline, Pfizer, and MSD that are unrelated to this work. L. S. K., P. C. R., and C. M. G. are coinventors on patents filed in 2020 for using Pasteurellaceae species, including H haemolyticus, for prevention of respiratory infections: United States Patent and Trademark Office Application number: 17/337052 and Australian Patent Office Application number: 2020203634 (“Treating or preventing respiratory infection”; priority date: 2 June 2020; inventors: L. S. K., P. C. R., C. M. G.). K. R. S. is a consultant for Sanofi, Roche, and Novo Nordisk. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic 16-amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides. A 6-amino acid linear peptide fragment of LAT8881, LAT9997, was investigated as a potential influenza therapy., Methods: LAT9997 was evaluated for its potential to limit disease in a preclinical mouse model of severe influenza infection., Results: Intranasal treatment of mice with either LAT8881 or LAT9997 from day 1 following influenza infection significantly improved survival outcomes. Initiating LAT9997 treatment at the onset of severe disease also significantly improved disease severity. Greater disease resistance in LAT9997-treated mice correlated with reduced lung immunopathology, damage markers, vascular leak, and epithelial cell death. Treatment reduced viral loads, cytokines, and neutrophil infiltration in the airways yet maintained protective alveolar macrophages in a dose-dependent manner. Sequential trimming of N- and C-terminal amino acids from LAT9997 revealed a structure-activity relationship., Conclusions: These findings provide preclinical evidence that therapeutic LAT9997 treatment limits viral burden and characteristic features of severe influenza, including hyperinflammation and lung damage., Summary: Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT9997 is a linear peptide fragment derived from human growth hormone. This study provides preclinical evidence that therapeutic LAT9997 treatment limits viral burden, hyperinflammation, and lung damage., Competing Interests: Potential conflicts of interest. M. D. T. received research funding from Lateral Pharma Pty Ltd. A. J. G. receives consultancy fees from Lateral Pharma Pty Ltd and has patent ownership. L. K. E. is an employee of Lateral Pharma Pty Ltd. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Mucosal vaccination presents a promising complement to parenteral vaccination. Bacterium-like particles (BLPs), peptidoglycan structures prepared from lactic acid bacteria, are explored as potential nasal vaccine adjuvants for respiratory infections. To date, studies on BLP-adjuvanted nasal vaccines against intestinal infections have remained limited. In this study, we demonstrated the efficacy of intranasal BLP-adjuvanted vaccination in controlling intestinal infections using the Citrobacter rodentium (C. rodentium) model in C57BL/6 mice. Intranasal vaccination of Intimin, an adhesin critical for intimate bacterial adhesion to colonic epithelial cells, combined with BLP (BLP+I) elicited robust Intimin-specific intestinal secretory IgA production, reduced bacterial load in feces and almost completely inhibited colonic hyperplasia, a characteristic symptom of C. rodentium infection in mice. Conversely, parenteral vaccination with Alhydrogel-adjuvanted Intimin failed to induce intestinal Intimin-specific IgA production, resulting in poor protection against C. rodentium infection. This underscores the pivotal role of mucosal IgA responses elicited by intranasal immunization in its protective efficacy. As this study did not delineate the precise protective mechanism conferred by BLP+I intranasal immunization against C. rodentium infection, further elucidation of the mechanisms underlying intranasal BLP+I immunization is required., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin., (© 2024. The Author(s).)

Influenza virus infection remains a major global health problem and requires a universal vaccine with broad protection against different subtypes as well as a rapid-response vaccine to provide immediate protection in the event of an epidemic outbreak. Here, we show that intranasal administration of probiotic Escherichia coli Nissle 1917 activates innate immunity in the respiratory tract and provides immediate protection against influenza virus infection within 1 day. Based on this vehicle, a recombinant strain is engineered to express and secret five tandem repeats of the extracellular domain of matrix protein 2 from different influenza virus subtypes. Intranasal vaccination with this strain induces durable humoral and mucosal responses in the respiratory tract, and provides broad protection against the lethal challenge of divergent influenza viruses in female BALB/c mice. Our findings highlight a promising delivery platform for developing mucosal vaccines that provide immediate and sustained protection against respiratory pathogens., (© 2024. The Author(s).)

Live-attenuated influenza vaccines (LAIV) offer advantages over the commonly used inactivated split influenza vaccines. However, finding the optimal balance between sufficient attenuation and immunogenicity has remained a challenge. We recently developed an alternative LAIV based on the 2009 pandemic H1N1 virus with a truncated NS1 protein and lacking PA-X protein expression (NS1(1-126)-ΔPAX). This virus showed a blunted replication and elicited a strong innate immune response. In the present study, we evaluated the efficacy of this vaccine candidate in the porcine animal model as a pertinent in vivo system. Immunization of pigs via the nasal route with the novel NS1(1-126)-ΔPAX LAIV did not cause disease and elicited a strong mucosal immune response that completely blocked replication of the homologous challenge virus in the respiratory tract. However, we observed prolonged shedding of our vaccine candidate from the upper respiratory tract. To improve LAIV safety, we developed a novel prime/boost vaccination strategy combining primary intramuscular immunization with a haemagglutinin-encoding propagation-defective vesicular stomatitis virus (VSV) replicon, followed by a secondary immunization with the NS1(1-126)-ΔPAX LAIV via the nasal route. This two-step immunization procedure significantly reduced LAIV shedding, increased the production of specific serum IgG, neutralizing antibodies, and Th1 memory cells, and resulted in sterilizing immunity against homologous virus challenge. In conclusion, our novel intramuscular prime/intranasal boost regimen interferes with virus shedding and transmission, a feature that will help combat influenza epidemics and pandemics., Competing Interests: RA, GZ, and AS filed a patent related to the intramuscular prime/intranasal boost vaccine described in this work. All other authors declare no competing interests., (Copyright: © 2024 Avanthay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na + , K + -ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na + , K + -ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 μg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na + , K + -ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na + , K + -ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.

Background: Alzheimer's disease results in neurodegeneration and is characterized by an accumulation of abnormal neuritic lesions and intracellular aggregates of hyperphosphorylated Tau proteins in the cerebrum. That leads to progressive decline in memory, thinking, and learning skills. Oxidative stress has been shown to play a significant role in the pathogenesis of Alzheimer's disease. Antioxidants are identified as part of therapeutic strategy to prevent or reduce the disease. Idebenone is a synthetic analogue of coenzyme Q 10 with potent antioxidant properties, originally developed for the treatment of Alzheimer's disease and other cognitive disorders. After oral administration idebenone undergoes excessive first-pass metabolism and has a very low bioavailability of only about 1%. The use of an alternative route of administration such as the nasal and its incorporation into a novel carrier (nanocomposite microspheres) will eliminate the problems associated with reduced absorption, stability, and rapid biotransformation and will increase the opportunity for idebenone to realize its therapeutic potential in Alzheimer's disease., Methods: Idebenone-loaded nanocomposite microspheres were obtained by spray drying. The structures were characterized using laser diffraction, scanning electron microscopy, high-performance liquid chromatography, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The ability of nanocomposite microspheres to bind human serum albumin was investigated by fluorescence spectroscopy. The mucoadhesive properties of the carrier were also determined., Results: Bioadhesive nanocomposite microparticles with spherical shape, smooth surface, size of 7.37 ± 2.4 μm, and with high production yield, good drug entrapment efficiency, and loading values were obtained. Infrared spectra demonstrated no chemical interactions between idebenone and structure-forming polymers. The ability of particles to bind to human serum albumin depends on their drug loading., Conclusions: Nanocomposite microspheres were developed as the novel delivery system of idebenone for target nose-to-brain delivery. The obtained carrier may increase the therapeutic potential of idebenone by providing higher concentrations in brain tissue and reducing systemic exposure and side effects.

Background: Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year., Methods: This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks., Results: Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal., Conclusions: One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated. Trial registration: Clinicaltrials.gov: NCT04408794., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KM serves as a consultant, advisory board member, or has received honoraria from Amgen, Teva, Theranica, Vorso, Biohaven, electroCore, and Eli Lilly.RC was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd, was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC which has had consulting agreements with Pfizer, Actio Biosciences, Inc., Aptose Biosciences Inc., Manistee Therapeutics, and Vida Ventures Management Co., LLC.LM and TF are employed by Pfizer Inc. JM was employed by Biohaven Pharmaceuticals at the time the study was conducted. JM and LM own stock in Biohaven Pharmaceuticals. LM owns stock in Pfizer Inc.RBL serves on the editorial board of Neurology and as senior advisor to Headache but is not paid for his roles on these journals. He has received research support from the NIH. He also receives support from the National Headache Foundation. He receives research grants from Allergan/AbbVie, Amgen, Dr. Reddy's Laboratories, and Novartis. He has reviewed for the NIA and NINDS and serves as consultant, advisory board member, or has received honoraria from Allergan/AbbVie, Amgen, Biohaven, Dr. Reddy's Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. He receives royalties from Wolff's Headache (8th Edition, Oxford University Press, 2009) and Informa. He holds stock options in Biohaven Pharmaceuticals and Manistee.

Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens 1 , yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear 2 . Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs) 3 . Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA + B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Exposure to ionizing radiation leads to oxidative stress and neuroinflammation, resulting in neurocognitive impairments. Adverse effects are also associated with glutamate-induced excitotoxicity due to alterations in the composition of glutamate receptors. Ketamine, which is a noncompetitive NMDA glutamate receptor antagonist, has been stated to exert an impact on glutamatergic receptors. This study aims to reveal the possible alleviating or preventive effects of ketamine, which maintains glutamate homeostasis and decreases neurodegeneration, in a radiation-induced neurotoxicity model. Twenty-one female Wistar Queryrats were included in the study and 14 of these underwent whole brain irradiation (IR) with a 20 Gray single dose. Animals were allocated into three groups. Group 1: Normal control; Group 2: Placebo / IR + Saline; Group 3: IR + Ketamine. Ketamine was administered in addition to IR to rats in Group 3. The one-way ANOVA statistical test was used to compare groups. The value of p < 0.05 was considered statistically significant. When administered in addition to irradiation, ketamine treatment significantly increased scores in the three-chamber sociability test, open field test, and passive avoidance learning test. It also raised neuron counts in the hippocampal CA1 and CA3 regions as well as in Purkinje cells, and enhanced levels of brain-derived neurotrophic factor and tyrosine receptor kinase-B. Furthermore, ketamine administration resulted in decreased levels of glial fibrillary acidic protein, malondialdehyde, and tumor necrosis factor-alpha, indicating a reduction in neuroinflammation and oxidative stress. Ketamine exerted a significant protective impact on radiation-induced neurocognitive impairments and enhanced social-memory capacity by reducing neuronal loss, oxidative stress, and neuroinflammation. Our findings suggest that ketamine is beneficial in the treatment or prevention of neurodegeneration via the regulation of the BDNF/TrkB signaling pathway besides decreasing neuroinflammation and blocking NMDA receptors., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Coxsackievirus B3 (CVB3) triggers viral myocarditis, with no effective vaccine yet. This fecal-oral transmitted pathogen has prompted interest in mucosal immunization strategies to impede CVB3 spread. We developed a new attenuated vaccine strain, named CVB3(mu). The potential of CVB3(mu) to stimulate mucosal immune protection remains to be elucidated. This study evaluates the attenuation characteristics of CVB3(mu) via a rapid evolution cellular model and RNA sequencing. Its temperature sensitivity and safety were evaluated through in vitro and in vivo experiments. The mucosal immunity protection of CVB3(mu) was assessed via intranasal immunization in Balb/c mice. The results indicate that CVB3(mu) exhibits temperature sensitivity and forms smaller plaques. It sustains fewer genetic mutations and still possesses certain attenuated traits up to the 25th passage, in comparison to CVB3(WT). Intranasal immunization elicited a significant serum neutralizing antibodies, and a substantial sIgA response in nasal washes. In vivo trials revealed CVB3(mu) protection in adult mice and passive protection in suckling mice against lethal CVB3(WT) challenges. In conclusion, CVB3(mu), a live attenuated intranasal vaccine, provides protection involving humoral and mucosal immunity, making it a promising candidate to control CVB3 spread and infection., (© 2024 Wiley Periodicals LLC.)

Abstract: INTRODUCTION: Nurses have a central role in educating patients and families about treatment options and how to integrate them into action plans for neurologic conditions. In recent years, a growing number of intranasal formulations have become available as rescue therapy for neurologic conditions or symptoms including migraine, opioid overdose, and seizures. Rescue therapies do not replace maintenance medications or emergency care but are designed to enable rapid treatment of urgent or disabling conditions in community settings. Yet, discussion of rescue therapies for neurologic conditions remains limited in nursing literature. CONTENT: Intranasal formulations are specifically formulated for delivery and absorption in the nose and have several characteristics that are well suited as rescue therapies for neurologic conditions. Intranasal formulations include triptans for migraine, naloxone and nalmefene for opioid overdose, and benzodiazepines for seizure clusters in patients with epilepsy. Therapeutic attributes discussed here include ease of use in community settings by nonmedical professionals, relatively rapid onset of action, and favorable safety profile and patient experience. This information is critical for nurses to make informed decisions about rescue therapy options, incorporate these into plans of care, and educate patients, care partners, and other healthcare providers. CONCLUSION: Rescue therapies are increasingly important in the care of people with neurologic conditions. Various formulations are available and continue to evolve, offering easy and quick ways for nurses, patients, and nonmedical care partners to administer critical rescue medications. For nurses overseeing medication management, the attributes of intranasal rescue therapies should be considered in the context of providing patients with the right care at the right time., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Aim: Vitamin B 12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B 12 dosage regimens in elderly vitamin B 12 -deficient patients., Methods: Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 μg cobalamin. Total vitamin B 12 , holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90., Results: Both dosage regimens resulted in a rapid increase of vitamin B 12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B 12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B 12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B 12 of 717 pmol/L after 90 days., Conclusions: Intranasal vitamin B 12 administration is an effective and suitable way to replenish and sustain vitamin B 12 levels in elderly patients., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: We aimed to compare the analgesic effectiveness of intranasal tapentadol nasal spray 44.5 mg and intravenous (IV) paracetamol 1 gm during the postoperative period in patients undergoing lower limb orthopedic surgeries under spinal anesthesia., Methods: This prospective, randomized, single-blind clinical trial was carried out in a tertiary care teaching hospital. Patients aged between 18 and 60 years of physical status ASA grade 1-3 were included in the study. Postoperative pain scores were measured using the visual analog scale (VAS) in centimeters (cm) every 12 hours in 37 patients per group. The patients were administered either intranasal tapentadol or IV paracetamol every 6 hours for 72 hours, beginning 3 hours after surgery., Results: There was a significant group by intervention effect favoring intranasal tapentadol, suggesting a greater reduction in VAS pain scores after the intervention at 72 hours (estimate: -1.58 cm; SE:0.2; P<0.001). Group by time effect for all the measured time frames, except for 36 hours, favored intranasal tapentadol with estimated values for greater reduction in VAS pain scores ranging from -0.8 cm to -1.6 cm., Discussion: The results of the present study suggests that intranasal tapentadol results in a greater reduction of postoperative pain compared with IV paracetamol in lower limb orthopedic surgeries. The ease of administration of tapentadol may make it a preferred option over IV paracetamol in such surgeries., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Allergic rhinitis (AR) is a prevalent disease in childhood and adolescence. A type 2 inflammation characterizes AR and, mainly, sustains nasal obstruction. Budesonide aqueous nasal spray (BANS) is an intranasal corticosteroid (INCS) available since the early 1980s. BANS is indicated for treating allergic rhinitis. There is evidence about its efficacy in treating children and adolescents with seasonal and perennial AR. In addition, BANS is safe with negligible local and systemic side effects. Recent guidelines for patients with AR recommend the use of INCS as first line in many situations. In particular, AR patients (and their parents) may assess the perception of symptoms' severity using the Visual Analog Scale (VAS). A score ≥5/10 means uncontrolled symptoms and requires adequate treatment. BANS could appropriately be used in patients with uncontrolled symptoms and/or moderate/severe nasal obstruction. In conclusion, BANS represents a valuable option in managing children and adolescents with AR.

Restricted by synaptic plasticity, dopamine receptor (DR) upregulation takes a long time to work. Moreover, the impact of the blood-brain barrier (BBB) on delivery efficiency restricts the development of drugs. Taking inspiration from snuff bottles, a convenient, fast-acting, and nonaddictive nasal drug delivery system has been developed to rapidly reshape the balance of synaptic transmitters. This optical and magnetic response system called CFs@DP, comprised of carbonized MIL-100 (Fe) frameworks (CFs) and domperidone (DP), which can enter the brain via nasal administration. Under dual stimulation of near-infrared (NIR) irradiation and catecholamine-induced complexation, CFs@DP disintegrates to release iron ions and DP, causing upregulation of the dopamine type 1 (D 1 ), type 2 (D 2 ) receptors, and brain-derived neurotrophic factor (BDNF) to achieve a therapeutic effect. In vivo experiments demonstrate that the DR density of mice (postnatal day 50-60) increased in the prefrontal cortex (PFC) and the hippocampus (HPC) after 10 days of therapy, resulting in antidepressant-like and cognitive enhancement effects. Interestingly, the cognitive enhancement effect of CFs@DP is even working in noniron deficiency (normal fed) mice, making it a promising candidate for application in enhancing learning ability., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes. In this pre-registered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional MRI. One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief. Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. Functional MRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects. In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)