Comparative pathogenicity of influenza virus-induced pneumonia mouse model following intranasal and aerosolized intratracheal inoculation.

BACKGROUND: Infection of mice with mouse-adapted strains of influenza virus has been widely used to establish mouse pneumonia models. Intranasal inoculation is the traditional route for constructing an influenza virus-induced pneumonia mouse model, while intratracheal inoculation has been gradually applied in recent years. In this article, the pathogenicity of influenza virus-induced pneumonia mouse models following intranasal and aerosolized intratracheal inoculation were compared. METHODS: By comparing the two ways of influenza inoculation, intranasal and intratracheal, a variety of indices such as survival rate, body weight change, viral titer and load, pathological change, lung wet/dry ratio, and inflammatory factors were investigated. Meanwhile, the transcriptome was applied for the initial exploration of the mechanism underlying the variations in the results between the two inoculation methods. RESULTS: The findings suggest that aerosolized intratracheal infection leads to more severe lung injury and higher viral loads in the lungs compared to intranasal infection, which may be influenced by the initial site of infection, sialic acid receptor distribution, and host innate immunity. CONCLUSION: Intratracheal inoculation is a better method for modelling severe pneumonia in mice than intranasal infection.

Preclinical/clinical trials of thrice-weekly administration of a combination of tegafur/gimeracil/oteracil (TS-1) and toceranib phosphate in dogs with intranasal tumors.

Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia®) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.

Nasal immature teratoma in an elderly patient: Clinicopathological and epigenetic analogies with central nervous system counterparts, alongside genomic divergences.

Germ cell tumors (GCTs) are categorized as gonadal or extra-gonadal, based on the origin. Extra-gonadal GCTs predominantly manifest within the central nervous system (CNS), mediastinum, retroperitoneum, and sacrococcygeal region. These malignancies are most frequently diagnosed in the pediatric, adolescent, and young adult demographics. Incidences of GCT within the nasal cavity are notably scarce, with only six cases documented. This report details the case of a 70-year-old man who presented with a left nasal mass ultimately diagnosed as immature teratoma. A remarkable aspect of this case was the detection of SMARCA4 (BRG1) loss through immunohistochemical analysis. In addition, methylation profiling aligned this case with CNS GCTs, specifically those classified as non-germinomatous GCTs. This molecular characterization informed a tailored therapeutic strategy incorporating carboplatin and etoposide, alongside localized irradiation. This individualized treatment regimen achieved favorable outcomes, with the patient remaining recurrence free for over three years. This highlights the need for precise therapeutic approaches in the management of extragonadal GCTs, particularly those arising in atypical anatomical locations. The present case accentuates the significance of thorough diagnostic evaluations and customized treatment plans for rare GCT presentations. Further empirical and clinical investigations are warranted to enhance our understanding of and refine therapeutic protocols for such exceptional cases.

Recent opportunities and application of gellan gum based drug delivery system for intranasal route.

OBJECTIVES: In the recent years, in-situ hydrogel based on gellan gum has been investigated for delivery of various drug molecules particularly to treat neurological disorders via intranasal route. The major objective of the present manuscript is to review the recent research studies exploring gellan gum as ionic triggered in-situ gel for intranasal administration to enhance absorption of drugs and to increase their therapeutic efficacy. METHODS: This review include literature from 1982 to 2023 and were collected from various scientific electronic databases like Scopus, PubMed and Google Scholar to review source, chemistry, ionotropic gelation mechanism, and recent research studies for gellan gum based in-situ hydrogel for intransasl administration.Keywords such as gellan gum, in-situ hydrogel, intranasal administration and brain targeting were used to search literature. The present review included the research studies which explored gellan gum based in-situ gel for intranasal drug delivery. RESULTS: The findings have shown enhanced biavailability of various drugs upon intranasal administration using gellan-gum based in-situ hydrogel.Moreover, the review indicated that intranasal administration of in-situ hydrogel facilitate to overcome blood brain barrier effectively. Hence, significantly higher drug concentration was found to be achieved in brain tissues upon intranasal administration than that of other routes like oral and intravenous. CONCLUSION: The present work conducted a comprehensive review for gellan gum based in-situ hydrogel particularly for intransal administration to overcome BBB. The study concluded that gellan gum based in-situ hydrogel could be potential promising delivery system for intranasal administration to improve bioavailability and efficacy of drugs specifically to treat neurological disorders.

Uptake of Mesenchymal Stem Cell-Derived Exosomes in Mouse Brain through Intranasal Delivery.

INTRODUCTION: Exosomes are nanoscale extracellular vesicles that widely participate in intercellular communication. An increasing number of studies have reported on the neuroprotective effects of stem cell-derived exosomes in brain diseases through various delivery methods. However, only a few reports are available on the delivery and uptake of stem cell-derived exosomes in the brains of mice of different ages. METHODS: PKH-26-labelled mesenchymal stem cell-derived exosomes were collected, and their uptake was investigated in the brains of mice aged 2 weeks, 2 months, and >6 months, 24 hours after intranasal delivery. RESULTS: No exosomes were distributed in the whole brains of 2-week-old mice after 24 hours of intranasal delivery. However, a small number of exosomes were found in the olfactory bulb, cortex, and hippocampus of 2-month-old mice, with no exosomes observed in the cerebellum. In contrast, a large number of exosomes were ingested in all brain regions, including the olfactory bulb, cortex, hippocampus, and cerebellum, of >6-month-old mice. CONCLUSION: Exosomes can enter the brains of adult mice through intranasal administration, but there are differences in the uptake rate among mice of different ages. These findings provide a theoretical basis for the future clinical administration of exosomes for treating brain disorders.

A Dual-Adjuvanted Parenteral-Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS-CoV-2 in Mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters can overcome the shortcomings of parenteral vaccines and enhance pre-existing systemic immunity. Here, a new protein subunit nanovaccine is developed by utilizing dual-adjuvanted (RIG-I: PUUC RNA and TLR-9: CpG DNA) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) along with SARS-CoV-2 S1 trimer protein, that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL subunit nanovaccine, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lungs and showed robust systemic humoral immunity. Interestingly, as a purely intranasal subunit vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. The data suggest that PUUC+CpG PAL subunit nanovaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

Early, robust mucosal secretory IgA but not IgG response to SARS-CoV-2 spike in oral fluid is associated with faster viral clearance and COVID-19 symptom resolution.

BACKGROUND: High priority efforts are underway to support the development of novel mucosal COVID-19 vaccines, such as the US Government's Project NextGen and the Center for Epidemic Preparedness Innovations' goal to respond to the next pandemic with a new vaccine in 100 days. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how to evaluate immunogenicity of mucosal vaccines. This study investigated the role of oral mucosal antibody responses in viral clearance and COVID-19 symptom duration. METHODS: Participants with PCR-confirmed SARS-CoV-2 infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for RT-PCR and symptom information at up to eight follow-ups from April 2020 to February 2022. RESULTS: High and moderate oral fluid anti-spike (S) secretory IgA (SIgA) post infection was associated with significantly faster viral clearance and symptom resolution across age groups with effect sizes equivalent to having COVID-19 vaccine immunity at the time of infection. Those with high and moderate anti-S SIgA cleared the virus 14 days (95% CI: 10-18) and recovered 9-10 days (95% CI: 6-14) earlier. Delayed and higher anti-S IgG was associated with significantly longer time to clearance and recovery. Experiencing symptoms longer than four weeks was associated with lower anti-RBD SIgA 15-30 days after infection onset (p<0.001). CONCLUSION: Robust mucosal SIgA early post infection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new mucosal vaccines.

Sedative and behavioral effects of atomized intranasal midazolam in comparison with nebulized midazolam for children undergoing dental treatment: A randomized clinical trial.

BACKGROUND: Fear and anxiet are significant barriers of dental care in children. Sedation emerged as a valuable behaviour guidance technique to manage uncooperative children. AIM: To evaluate the sedative and behavioral effectiveness of midazolam administered via nebulizer in comparison with intranasal atomizer in the behavior management of anxious children during dental treatment. STUDY DESIGN: Two-arm randomized clinical trial with 68 children (3-5 years) assigned to receive nebulized midazolam (NEB MDZ) and atomized intranasal midazolam (AIN MDZ) during dental treatment. The onset time, sedation levels, and behavior of children were documented. The data were analyzed using the Wilcoxon signed-rank test and Mann-Whitney U tests. RESULTS: Significant differences between the two groups in terms of onset time, sedation level, and behavior of children during the dental treatment. AIN MDZ was associated with a significantly faster onset time compared with NEB MD, (p < .001). Children who received NEB MDZ exhibited deeper levels of sedation compared with AIN MDZ group (p = .02). During the administration of local anesthesia, notable statistical differences were observed between the behavior of the two groups (p = .02). CONCLUSIONS: Midazolam administered via either nebulizer or intranasal atomizer was the effective route of administration and proved effective in the management of anxious children undergoing dental treatment. AIN MDZ, however, exhibited a faster onset time, whereas children receiving NEB MDZ demonstrated superior behavior compared with those receiving AIN MDZ.

Brain-targeted intranasal delivery of protein-based gene therapy for treatment of ischemic stroke.

Gene therapy using a protein-based CRISPR system in the brain has practical limitations due to current delivery systems, especially in the presence of arterial occlusion. To overcome these obstacles and improve stability, we designed a system for intranasal administration of gene therapy for the treatment of ischemic stroke. Methods: Nanoparticles containing the protein-based CRISPR/dCas9 system targeting Sirt1 were delivered intranasally to the brain in a mouse model of ischemic stroke. The CRISPR/dCas9 system was encapsulated with calcium phosphate (CaP) nanoparticles to prevent them from being degraded. They were then conjugated with ß-hydroxybutyrates (bHb) to target monocarboxylic acid transporter 1 (MCT1) in nasal epithelial cells to facilitate their transfer into the brain. Results: Human nasal epithelial cells were shown to uptake and transfer nanoparticles to human brain endothelial cells with high efficiency in vitro. The intranasal administration of the dCas9/CaP/PEI-PEG-bHb nanoparticles in mice effectively upregulated the target gene, Sirt1, in the brain, decreased cerebral edema and increased survival after permanent middle cerebral artery occlusion. Additionally, we observed no significant in vivo toxicity associated with intranasal administration of the nanoparticles, highlighting the safety of this approach. Conclusion: This study demonstrates that the proposed protein-based CRISPR-dCas9 system targeting neuroprotective genes in general, and SIRT1 in particular, can be a potential novel therapy for acute ischemic stroke.

Safety and efficacy of a novel dexmedetomidine nasal spray for pre-anesthetic sedation in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Off-label intranasal administration of injectable dexmedetomidine has been widely applied in the pediatric sedation setting. However, the development of an improved drug delivery system that is easy to use is needed. We developed a novel dexmedetomidine nasal spray that can be administered directly without dilution or configuration for pediatric pre-anesthetic sedation. This nasal spray has a fixed dose and is stable during storage. To the best of our knowledge, this is the first licensed nasal spray preparation of dexmedetomidine worldwide. OBJECTIVE: To evaluate the pre-anesthetic sedation efficacy and safety of the novel dexmedetomidine nasal spray in children. METHODS: The study was conducted at 11 sites in China between 24 November 2021 and 20 May 2022 and was registered in ClinicalTrials.gov (NCT05111431, first registration date: 20/10/2021). Subjects (n = 159) between 2 and 6 years old who were to undergo elective surgery were randomized to the dexmedetomidine group (n = 107) or the placebo group (n = 52) in a 2:1 ratio. The dosage was 30 µg or 50 µg based on the stratified body weight. The primary outcome measure was the proportion of subjects who achieved the desired child-parent separation and Ramsay scale ≥ 3 within 45 min of administration. Safety was monitored via the assessments of adverse events, blood pressure, heart rate, respiratory rate and blood oxygen saturation. RESULTS: The proportion of subjects achieving desired parental separation and Ramsay scale ≥ 3 within 45 min was significantly higher in the dexmedetomidine group (94.4%) vs the placebo group (32.0%) (P < 0.0001). As compared with placebo, dexmedetomidine treatment led to more subjects achieving Ramsay scale ≥ 3 or UMSS ≥ 2, and shorter time to reach desired parental separation, Ramsay scale ≥ 3 and UMSS ≥ 2 (all P < 0.0001). Adverse events were reported in 90.7% and 84.0% of subjects in the dexmedetomidine and placebo groups, respectively, and all the events were mild or moderate in severity. CONCLUSIONS: This novel dexmedetomidine nasal spray presented effective pre-anesthetic sedation in children with a tolerable safety profile.

Hemagglutinin and neuraminidase of a non-pathogenic H7N7 avian influenza virus coevolved during the acquisition of intranasal pathogenicity in chickens.

Polybasic amino acid residues at the hemagglutinin (HA) cleavage site are insufficient to induce the highly pathogenic phenotype of avian influenza viruses in chickens. In our previous study, an H7N7 avian influenza virus named "Vac2sub-P0", which is nonpathogenic despite carrying polybasic amino acids at the HA cleavage site, was passaged in chick air sacs, and a virus with high intravenous pathogenicity, Vac2sub-P3, was obtained. Intranasal infection with Vac2sub-P3 resulted in limited lethality in chickens; therefore, in this study, this virus was further passaged in chicken lungs, and the resultant virus, Vac2sub-P3L4, acquired high intranasal pathogenicity. Experimental infection of chickens with recombinant viruses demonstrated that mutations in HA and neuraminidase (NA) found in consecutive passages were responsible for the increased pathogenicity. The HA and NA functions of Vac2sub-P3L4 were compared with those of the parental virus in vitro; the virus growth at 40 °C was faster, the binding affinity to a sialic acid receptor was lower, and the rate of release by NA from the cell surface was lower, suggesting that these changes enabled the virus to replicate efficiently in chickens with high intranasal pathogenicity. This study demonstrates that viruses that are highly pathogenic when administered intranasally require additional adaptations for increased pathogenicity to be highly lethal to intranasally infected chickens.

The assessment of pharmacokinetics and neuroprotective effect of berberine hydrochloride-embedded albumin nanoparticles via various administration routes: comparative in-vivo studies in rats.

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles.

Beta Spike-Presenting SARS-CoV-2 Virus-like Particle Vaccine Confers Broad Protection against Other VOCs in Mice.

Virus-like particles (VLPs) are non-infectious and serve as promising vaccine platforms because they mimic the membrane-embedded conformations of fusion glycoproteins on native viruses. Here, we employed SARS-CoV-2 VLPs (SMEN) presenting ancestral, Beta, or Omicron spikes to identify the variant spike that elicits potent and cross-protective immune responses in the highly sensitive K18-hACE2 challenge mouse model. A combined intranasal and intramuscular SMEN vaccine regimen generated the most effective immune responses to significantly reduce disease burden. Protection was primarily mediated by antibodies, with minor but distinct contributions from T cells in reducing virus spread and inflammation. Immunization with SMEN carrying ancestral spike resulted in 100, 75, or 0% protection against ancestral, Delta, or Beta variant-induced mortality, respectively. However, SMEN with an Omicron spike provided only limited protection against ancestral (50%), Delta (0%), and Beta (25%) challenges. By contrast, SMEN with Beta spikes offered 100% protection against the variants used in this study. Thus, the Beta variant not only overcame the immunity produced by other variants, but the Beta spike also elicited diverse and effective humoral immune responses. Our findings suggest that leveraging the Beta variant spike protein can enhance SARS-CoV-2 immunity, potentially leading to a more comprehensive vaccine against emerging variants.

Chronic nasal inflammation early in life induces transient and long-term dysbiosis of gut microbiota in mice.

The gut microbiota begins to colonize the host body following birth, develops during the suckling period and changes to the adult type after weaning. The early gut microbiota during the suckling period is thought to have profound effects on the host physiology throughout life but it is still unclear whether early dysbiosis is retained lifelong. Our previous study indicated that chronic nasal inflammation induces dysbiosis of gut microbiota in adult mice. In the present study, we addressed the question as to whether early exposure to chronic nasal inflammation induces dysbiosis, and if so, whether the dysbiosis is retained until adulthood and the sex differences in this effect. Male and female mice received repeated intranasal administration of lipopolysaccharide (LPS) or saline twice a week from P7 to P24 and were weaned at P24. The cecal contents were obtained for 16S rRNA analysis at 2 time points: at 4 weeks (wks), just after weaning, and at maturation to adulthood at 10 wks. The body weight did not differ between saline- and LPS-treated mice till around weaning, suggesting that the mothers' milk was given similarly to all mice. At 4 wks, the beta diversity was significantly different between saline- and LPS-treated male and female mice and the composition of the gut microbiota changed in LPS-treated mice. The abundance of phylum Bacteroidota tended to decrease and that of Firmicutes increased in LPS-treated male mice, while the abundance of Deferribacterota increased in LPS-treated female mice. At 10 wks, the beta diversity was not different between saline- and LPS-treated mice, but the abundance of family Lachnospiraceae significantly decreased in LPS-treated male and female mice by LEfSe analysis. Together, chronic nasal inflammation early in life caused transient and long-term dysbiosis of gut microbiota, which may contribute to the onset and progress of metabolic and neuropsychiatric disorders.

Intranasal Insulin Eases Autism in Rats via GDF-15 and Anti-Inflammatory Pathways.

In rat models, it is well-documented that chronic administration of propionic acid (PPA) leads to autism-like behaviors. Although the intranasal (IN) insulin approach is predominantly recognized for its effects on food restriction, it has also been shown to enhance cognitive memory by influencing various proteins, modulating anti-inflammatory pathways in the brain, and reducing signaling molecules such as interleukins. This study seeks to explore the potential therapeutic benefits of IN insulin in a rat model of autism induced by PPA. Thirty male Wistar albino rats were categorized into three cohorts: the control group, the PPA-induced autism (250 mg/kg/day intraperitoneal PPA dosage for five days) group, treated with saline via IN, and the PPA-induced autism group, treated with 25 U/kg/day (250 µL/kg/day) insulin via IN. All treatments were administered for 15 days. After behavioral testing, all animals were euthanized, and brain tissue and blood samples were collected for histopathological and biochemical assessments. Following insulin administration, a substantial reduction in autism symptoms was observed in all three social behavior tests conducted on the rats. Moreover, insulin exhibited noteworthy capabilities in decreasing brain MDA, IL-2, IL-17, and TNF-α levels within autism models. Additionally, there is a notable elevation in the brain nerve growth factor level (p < 0.05) and GDF-15 (p < 0.05). The assessment of cell counts within the hippocampal region and cerebellum revealed that insulin displayed effects in decreasing glial cells and inducing a significant augmentation in cell types such as the Purkinje and Pyramidal cells. The administration of insulin via IN exhibits alleviating effects on autism-like behavioral, biochemical, and histopathological alterations induced by PPA in rats. Insulin-dependent protective effects show anti-inflammatory, anti-oxidative, and neuroprotective roles of insulin admitted nasally.

Development of Glycerosomal pH Triggered In Situ Gelling System to Ameliorate the Nasal Delivery of Sulpiride for Pediatric Psychosis.

Sulpiride (Sul) is a medication that blocks dopamine D2 receptors. It is used to treat gastrointestinal disturbances and has antipsychotic effects depending on the dose given. Sulpiride is subject to P-glycoprotein efflux, resulting in limited bioavailability and erratic absorption. Hence, the aim of this study was to generate a glycerosomal in situ gel of sulpiride for intranasal administration, specifically targeting children with schizophrenia who may have difficulty swallowing traditional solid medications, for enhancing its bioavailability. This study aimed to demonstrate the efficacy of intranasal administration of glycerin-encapsulated lipid-nanovesicles (glycerosomes) mixed with in situ gels for prolonged release of anti-psychotic medication. A Box-Behnken design was utilized to create sulpiride-loaded glycerosomes (Sul-GMs), with the lipid amount (A), glycerin concentration (B), and sonication time (C) acting as independent variables. Their impact on the entrapment efficiency, EE% (Y1), and in vitro drug release (Y2) were evaluated. The sulpiride EE% showed an increase when the glycerin concentration was raised to 25% v/v. Nevertheless, when the glycerin concentration was raised to 40% v/v, there was a notable decrease in the EE%. The optimized glycerosome was added to pH triggered carbopol 974P in situ gel formulations including HPMC K15M with different concentrations. The in situ gel formulation (G3) comprising 0.6% carbopol 974P and 0.6% hydroxypropyl methyl cellulose-K15M (HPMC K15M) demonstrated suitable pH, viscosity, desired gel strength, spreadability, and mucoadhesive strength. Consequently, it was selected for in vitro study, ex vivo permeation investigation, and in vivo evaluations. The glycerosomal in situ gel exhibited favorable ex vivo permeability of SU when applied to the nasal mucosa. The pharmacokinetic investigation revealed that the optimized Sul-loaded glycerosomal in situ gel exhibited a significant fourfold and twofold enhancement in systemic bioavailability compared to both the control gel and the commercially available formulation. Finally, the intranasal administration of Sul-loaded glycerosomal in situ gel is a promising alternative to oral treatment for pediatric patients with psychosis.

Sinonasal Outcomes Obtained after 2 Years of Treatment with Benralizumab in Patients with Severe Eosinophilic Asthma and CRSwNP: A "Real-Life" Observational Study.

BACKGROUND/OBJECTIVES: Benralizumab is a monoclonal antibody that targets the interleukin-5 receptor (IL-5Rα), leading to the rapid depletion of blood eosinophils. RCTs have demonstrated efficacy in patients with severe eosinophilic asthma (SEA). The aim of this study was to assess the efficacy of benralizumab on sinonasal outcomes in a real-life setting in patients with SEA and concomitant chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: We included 25 patients (mean age: 57.47 years, range: 35-77, F/M = 12:13) who were prescribed 30 mg benralizumab every month for the first three administrations and then every 2 months. The primary endpoint was to evaluate changes in the SinoNasal Outcome Test-22 (SNOT-22) and nasal polyp score (NPS) over a 24-month treatment period. Secondary endpoints included measuring the effects on nasal obstruction and impaired sense of smell. RESULTS: The mean NPS score decreased significantly from 5.11 ± 1.84 at baseline to 2.37 ± 1.96 at 24 months. The mean SNOT-22 decreased from 57 ± 15.30 at baseline to 26 ± 16.73 at 24 months. The SSIT-16 mean score improved with an increase in olfactory performance from 5.23 ± 2.58 at baseline to 7 ± 3.65 at 24 months. Moreover, 8/25 patients (32%) required rescue treatment with systemic steroids and 2 patients required endoscopic sinus surgery. CONCLUSIONS: While the improvement may not seem optimal at 12 months, a progressive enhancement was noted during the second year of treatment. Despite our data showing an improvement in quality of life and a reduction in the size of nasal polyps, no significant improvement in olfactory sensitivity was observed. In addition, in several patients, rescue treatments were required to maintain control of nasal and sinus symptoms. A careful risk-benefit assessment is therefore needed when deciding to continue treatment, weighing the potential for further improvement against the risks of complications. Such decisions should always be made in the context of a multidisciplinary team.

Review of Intranasal Active Pharmaceutical Ingredient Delivery Systems.

In recent decades, there has been an increased interest in the development of intranasal delivery systems for active pharmaceutical ingredients (APIs) not only for treating local nasal diseases but also for treating systemic diseases, central nervous system (CNS) disorders, and vaccine delivery. The nasal cavity possesses a unique set of anatomical characteristics for delivering active pharmaceutical ingredients, but there are several limitations that recent research in the field of the intranasal administration of APIs aims to overcome. For the effective delivery of nasal preparations, active pharmaceutical ingredients are incorporated into various micro- and nanosystems. Some of the most commonly encountered API delivery systems in the scientific literature include liposomal systems, polymer particles with mucoadhesive properties, in situ gels, nano- and microemulsions, and solid lipid particles. This article provides a review of research on the development of nasal preparations for treating local nasal cavity diseases (in particular, for antibiotic delivery), systemic diseases (analgesics, drugs for cardiovascular diseases, antiviral and antiemetic drugs), CNS disorders (Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, depression), and vaccine delivery. The literature data show that active research is underway to reformulate drugs of various pharmacotherapeutic groups into a nasal form.

Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation.

Recently, ribavirin has demonstrated effectiveness in treating glioblastoma through intranasal administration utilizing the nose-to-brain delivery route. Enhancing ribavirin's bioavailability can be achieved by utilizing intranasal stimuli-responsive systems that create a gel on the nasal mucosa. The research examined thermosensitive, pH-sensitive, and ion-selective polymers in various combinations and concentrations, chosen in line with the current Quality by Design (QbD) approach in pharmaceutical development. Following a thorough assessment of key parameters, the optimal composition of gellan gum at 0.5%, Poloxamer 124 at 2%, and purified water with ribavirin concentration at 100 mg/mL was formulated and subjected to in vivo testing. Through experiments on male rats, the nose-to-brain penetration mechanism of the active pharmaceutical ingredient (API) was elucidated, showcasing drug accumulation in the olfactory bulbs and brain.

Astodrimer Sodium Nasal Spray versus Placebo in Non-Hospitalised Patients with COVID-19: A Randomised, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND/OBJECTIVES: Dendrimer-based astodrimer sodium nasal spray was assessed for its ability to reduce SARS-CoV-2 load in outpatients with COVID-19, which remains a severe illness for vulnerable groups. METHODS: This was a randomised, double-blind, placebo-controlled clinical investigation evaluating the efficacy of astodrimer nasal spray in reducing SARS-CoV-2 viral burden in the nasopharynx of outpatients with COVID-19. Non-hospitalised adults with SARS-CoV-2 infection were randomised 1:1 to astodrimer or placebo four times daily from Day 1 to Day 7. Nasopharyngeal swabs for SARS-CoV-2 load determination were self-obtained daily from Day 1 to Day 8. The primary endpoint was an area under the curve of SARS-CoV-2 RNA copies/mL through Day 8 (vAUCd1-8). The primary analysis population was the modified intent-to-treat population (mITT: all randomised participants exposed to the study treatment who had at least one post-baseline viral load determination). Safety analyses included all randomised participants exposed to the study treatment. STUDY REGISTRATION: ISRCTN70449927; Results: 231 participants were recruited between 9 January and 20 September 2023. The safety population comprised 109 and 113 participants randomised to astodrimer and placebo, respectively, with 96 and 101 participants in the mITT. Astodrimer sodium nasal spray reduced the SARS-CoV-2 burden (vAUCd1-8) vs. placebo in non-hospitalised COVID-19 patients aged 16 years and over (-1.2 log10 copies/mL × Day). The reduction in SARS-CoV-2 load was statistically significant in those aged 45 years and older (-3.7, p = 0.017) and the effect increased in older age groups, including in those aged 65 years and older (-7.3, p = 0.005). Astodrimer sodium nasal spray increased the rate of viral clearance and helped alleviate some COVID-19 symptoms, especially loss of sense of smell. Overall, 31 participants (14%) had ≥1 adverse event (AE). Four AEs were deemed possibly related to treatment. Most AEs were of mild severity and occurred at similar rates in both treatment arms. CONCLUSIONS: Astodrimer nasal spray reduces viral burden and accelerates viral clearance, especially in older populations, and is well tolerated.