A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis.

Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.

Synthesis and characterization of fullerene-based nanocarrier for targeted delivery of quercetin to the brain.

Aim: Preparation of quercetin fullerene conjugate (QFC) for nose-to-brain delivery and their in vitro and ex vivo characterizations.Methods: Carboxylated fullerene was converted into acetylated fullerene and quercetin was conjugated and physically adsorbed on acetylated fullerene.Results: The particle size and zeta potential of QFC and chitosan-coated QFC (CC-QFC) were found to be 179.2 ± 1.10, 293.4 ± 2.757, -5.28 ± 1.43 and 11.6 ± 0.4 respectively. The entrapment efficiency, loading efficiency of QFC were found to be 85.55% and 42.77%. The MTT assay revealed 80.69% SH-SY5Y cell viability at a concentration of 50 µg/ml. CC-QFC showed remarkable (89.20%) ex vivo mucoadhesive properties compared with QFC (66.67%). Further study showed no significant ciliotoxicity by CC-QFC.Conclusion: The obtained results suggested the potential of CC-QFC for treatment in Alzheimer's disease.

In our study, we developed a new method to deliver a natural substance called quercetin into the brain for the treatment of Alzheimer's disease. Quercetin is known for its health benefits, especially in protecting brain cells. We combined quercetin with a tiny carbon-based material called fullerene, which looks like a soccer ball, to create a new compound called quercetin fullerene conjugate (QFC). This QFC was designed to help quercetin reach the brain more effectively. To make it even better at reaching the brain, we coated QFC with a substance called chitosan. Coating it with chitosan can help to adhere it to nasal cavity for longer time for the delivery of quercetin to the brain. Importantly, our studies showed that this modified form of quercetin did not harm brain cells or the lining of the nose.Overall, our findings suggest that this new approach could be a promising way to develop treatments for Alzheimer's disease.

Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates.

A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2.

Therapeutic efficacy of JEW-M449, an anti-TCTP monoclonal antibody, administered via the nasal route in a BALB/c mouse model of ovalbumin-induced acute asthma.

Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.

Effect of intranasal administration of Granulocyte-Macrophage Colony-Stimulating Factor on pulmonary Cryptococcus gattii infection.

Cryptococcosis, caused by infections with C. neoformans and C. gattii, presents a serious threat to global health and necessitates effective treatment strategies. Granulocyte-Macrophage Colony-Stimulating Factor, GM-CSF, is an immune-modulating cytokine that has been utilized clinically to improve host defense against infection; however, the impact of GM-CSF treatment in C. gattii infection has not been elucidated. Our current study aimed to investigate the effect of GM-CSF treatment on pulmonary immune response during C. gattii infection. In response to C. gattii infection, GM-CSF-expressing T helper cells and CD11b+ myeloid were enhanced in the lungs. The intranasal administration of GM-CSF during C. gattii infection significantly reduced pulmonary cryptococcal load, promoted an increase in pulmonary Th17 cells, as well as neutrophil infiltration in the lungs. Exposure of neutrophils to C. gattii in the presence of GM-CSF resulted in an increased neutrophil phagocytosis and fungal killing capacity, generation of reactive oxygen species (ROS), and upregulation of inflammatory cytokines and anti-microbial peptides. Although GM-CSF treatment in C. neoformans-infected mice had a comparable impact on the reduction of lung fungal burden, it resulted in the enhancement of Th1-type cytokine IFN-γ and the activation of M1 macrophages. Altogether, this study demonstrated that the intranasal delivery of GM-CSF has distinct effects on promoting the protection against C. gattii and C. neoformans by activating neutrophil/type-17 immune response and stimulating M1 macrophage/type-1 immunity, respectively.

Antibodies to Glutamate Reduce the IL-6 Content in Cerebral Structures in Mice with Age-Related Memory Impairment.

Intranasal administration of antibodies to glutamate for 14 days improved passive avoidance conditioning and reduces the content of IL-6 within 7 days after their withdrawal in the prefrontal cortex and hippocampus of aging C57BL/6 mice.

Chiral Intranasal Nanovaccines as Antivirals for Respiratory Syncytial Virus.

This study aimed to develop an intranasal nanovaccine by combining chiral nanoparticles with the RSV pre-fusion protein (RSV protein) to create L-nanovaccine (L-Vac). The results showed that L-NPs increased antigen attachment in the nasal cavity by 3.83 times and prolonged its retention time to 72 h. In vivo experimental data demonstrated that the intranasal immunization with L-Vac induced a 4.86-fold increase in secretory immunoglobulin A (sIgA) secretion in the upper respiratory tract, a 1.85-fold increase in the lower respiratory tract, and a 20.61-fold increase in RSV-specific immunoglobin G (IgG) titer levels in serum, compared with the commercial Alum Vac, while the neutralizing activity against the RSV authentic virus is 1.66-fold higher. The mechanistic investigation revealed that L-Vac activated the tumor necrosis factor (TNF) signaling pathway in nasal epithelial cells (NECs), in turn increasing the expression levels of interleukin-6 (IL-6) and C-C motif chemokine ligand 20 (CCL20) by 1.67-fold and 3.46-fold, respectively, through the downstream nuclear factor kappa-B (NF-κB) signaling pathway. Meanwhile, CCL20 recruited dendritic cells (DCs) and L-Vac activated the Toll-like receptor signaling pathway in DCs, promoting IL-6 expression and DCs maturation, and boosted sIgA production and T-cell responses. The findings suggested that L- Vac may serve as a candidate for the development of intranasal medicine against various types of respiratory infections.

Thermosensitive chitosan-based hydrogel: A vehicle for overcoming the limitations of nose-to-brain cell therapy.

Cell therapy is a promising strategy for treating neurological pathologies but requires invasive methods to bypass the blood-brain barrier restrictions. The nose-to-brain route has been presented as a direct and less invasive alternative to access the brain. The primary limitations of this route are low retention in the olfactory epithelium and poor cell survival in the harsh conditions of the nasal cavity. Thus, using chitosan-based hydrogel as a vehicle is proposed in this work to overcome the limitations of nose-to-brain cell administration. The hydrogel's design was driven to achieve gelification in response to body temperature and a mucosa-interacting chemical structure biocompatible with cells. The hydrogel showed a < 30 min gelation time at 37 °C and >95 % biocompatibility with 2D and 3D cultures of mesenchymal stromal cells. Additionally, the viability, stability, and migration capacity of oligodendrocyte precursor cells (OPCs) within the hydrogel were maintained in vitro for up to 72 h. After the intranasal administration of the OPCs-containing hydrogel, histological analysis showed the presence of viable cells in the nasal cavity for up to 72 h post-administration in healthy athymic mice. These results demonstrate the hydrogel's capacity to increase the residence time in the nasal cavity while providing the cells with a favorable environment for their viability. This study presents for the first time the use of thermosensitive hydrogels in nose-to-brain cell therapy, opening the possibility of increasing the delivery efficiency in future approaches in translational medicine. STATEMENT OF SIGNIFICANCE: This work highlights the potential of biomaterials, specifically hydrogels, in improving the effectiveness of cell therapy administered through the nose. The nose-to-brain route has been suggested as a non-invasive way to directly access the brain. However, delivering stem cells through this route poses a challenge since their viability must be preserved and cells can be swept away by nasal mucus. Earlier attempts at intranasal cell therapy have shown low efficiency, but still hold promise to the future. The hydrogels designed for this study can provide stem cells with a biocompatible environment and adhesion to the nasal atrium, easing the successful migration of viable cells to the brain.

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.

Intranasal HD-Ad-FS vaccine induces systemic and airway mucosal immunities against SARS-CoV-2 and systemic immunity against SARS-CoV-2 variants in mice and hamsters.

The outbreak of coronavirus disease 19 (COVID-19) has highlighted the demand for vaccines that are safe and effective in inducing systemic and airway mucosal immunity against the aerosol transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we developed a novel helper-dependent adenoviral vector-based COVID-19 mucosal vaccine encoding a full-length SARS-CoV-2 spike protein (HD-Ad-FS). Through intranasal immunization (single-dose and prime-boost regimens), we demonstrated that the HD-Ad-FS was immunogenic and elicited potent systemic and airway mucosal protection in BALB/c mice, transgenic ACE2 (hACE2) mice, and hamsters. We detected high titers of neutralizing antibodies (NAbs) in sera and bronchoalveolar lavages (BALs) in the vaccinated animals. High levels of spike-specific secretory IgA (sIgA) and IgG were induced in the airway of the vaccinated animals. The single-dose HD-Ad-FS elicited a strong immune response and protected animals from SARS-CoV-2 infection. In addition, the prime-boost vaccination induced cross-reactive serum NAbs against variants of concern (VOCs; Beta, Delta, and Omicron). After challenge, VOC infectious viral particles were at undetectable or minimal levels in the lower airway. Our findings highlight the potential of airway delivery of HD-Ad-FS as a safe and effective vaccine platform for generating mucosal protection against SARS-CoV-2 and its VOCs.

An intranasally administered adenovirus-vectored SARS-CoV-2 vaccine induces robust mucosal secretory IgA.

BACKGROUNDThe level of nasal spike-specific secretory IgA (sIgA) is inversely correlated with the risk of SARS-CoV-2 Omicron infection. This study aimed to evaluate the safety and immunogenicity of intranasal vaccination using Ad5-S-Omicron (NB2155), a replication-incompetent human type 5 adenovirus carrying Omicron BA.1 spike.METHODSAn open-label, single-center, investigator-initiated trial was carried out on 128 health care workers who had never been infected with SARS-CoV-2 and had previously received 2 or 3 injections of inactivated whole-virus vaccines, with the last dose given 3-19 months previously (median 387 days, IQR 333-404 days). Participants received 2 intranasal sprays of NB2155 at 28-day intervals between November 30 and December 30, 2022. Safety was evaluated by solicited adverse events and laboratory tests. The elevation of nasal mucosal spike-specific sIgA and serum neutralizing activities were assessed. All participants were monitored for infection by antigen tests, disease symptoms, and the elevation of nucleocapsid-specific sIgA in the nasal passage.RESULTSThe vaccine-related solicited adverse events were mild. Nasal spike-specific sIgA against 10 strains had a mean geometric mean fold increase of 4.5 after the first dose, but it increased much higher to 51.5 after the second dose. Serum neutralizing titers also increased modestly to 128.1 (95% CI 74.4-220.4) against authentic BA.1 and 76.9 (95% CI 45.4-130.2) against BA.5 at 14 days after the second dose. Due to the lifting of the zero-COVID policy in China on December 7, 2022, 57.3% of participants were infected with BA.5 between days 15 and 28 after the first dose, whereas no participants reported having any symptomatic infections between day 3 and day 90 after the second dose. The elevation of nasal nucleocapsid-specific sIgA on days 0, 14, 42, and 118 after the first dose was assessed to verify that these 2-dose participants had no asymptomatic infections.CONCLUSIONA 2-dose intranasal vaccination regimen using NB2155 was safe, was well tolerated, and could dramatically induce broad-spectrum spike-specific sIgA in the nasal passage. Preliminary data suggested that the intranasal vaccination may establish an effective mucosal immune barrier against infection and warranted further clinical studies.TRIAL REGISTRATIONChinese Clinical Trial Registry (ChiCTR2300070346).FUNDINGNatural Science Foundation of China, Guangzhou Laboratory, The First Affiliated Hospital of Guangzhou Medical University.

The interaction of oxytocin and nicotine addiction on psychosocial stress: an fMRI study.

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.

Effect of intranasal insulin on perioperative cognitive function in older adults: a randomized, placebo-controlled, double-blind clinical trial.

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-ß 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-ß 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.

Effective cerebral tuberculosis treatment via nose-to-brain transport of anti-TB drugs using mucoadhesive nano-aggregates.

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.

Comparing the Sedative Effects of Intranasal Dexmedetomidine, Midazolam, and Ketamine in Outpatient Pediatric Surgeries: A Randomized Clinical Trial.

Background: The management of preoperative anxiety in pediatric patients, as well as its implications, has remained challenging for anesthesiologists. In this study, we compared the safety and efficacy of intranasal dexmedetomidine, midazolam, and ketamine as surgical premedication in children. Methods: This double-blinded randomized clinical trial was conducted at two tertiary hospitals in January 2014, on 90 children aged between 2-7 years old. The participants' American Society of Anesthesiologists (ASA) physical status was I or II, and they were scheduled for elective unilateral inguinal herniorrhaphy. Using the block randomization method, the patients were randomly assigned to three groups, each receiving intranasal dexmedetomidine (2 µg/Kg), midazolam (0.2 mg/Kg), and ketamine (8 mg/Kg) 60 min before induction of anesthesia. Anxiety and sedation state were evaluated before drug administration, and then every 10 min for the next 50 min. Parental separation anxiety, mask acceptance, postoperative agitation, pain, nausea, and vomiting were also recorded and compared between these groups. All the statistical analyses were performed using SPSS software (version 21.0). P<0.05 was considered statistically significant. Results: Ketamine indicated the strongest sedative effect 10, 20, and 30 min after administration of premedication (P<0.001, P=0.03, P=0.01, respectively). However, dexmedetomidine was more effective than other drugs after 40 and 50 min (P<0.001). Other variables indicated no statistically significant difference. Conclusion: In case of emergencies, intranasal ketamine, with the shortest time of action, could be administered. Intranasal dexmedetomidine, which was revealed to be the most potent drug in this study, could be administrated 40-50 min before elective pediatric surgeries.Trial registration number: IRCT2013081614372N1.

Intranasal administration of insulin on the incidence of postoperative delirium in middle-aged patients undergoing elective on-pump cardiac surgery (INIPOD-MOPS): a prospective double-blinded randomized control study protocol.

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.

Understanding the molecular basis of anti-fibrotic potential of intranasal curcumin and its association with mitochondrial homeostasis in silica-exposed mice.

Silicosis is an occupational disease of the lungs brought in by repeated silica dust exposures. Inhalation of crystalline silica leads to persistent lung inflammation characterized by lung lesions due to granuloma formation. The specific molecular mechanism has not yet been identified, though. The Present study investigated the impact of silica-exposed lung fibrosis and probable molecular mechanisms. Here, Curcumin, derived from Curcuma longa shown to be an effective anti-inflammatory and anti-fibrotic molecule has been taken to investigate its therapeutic efficacy in silica-induced lung fibrosis. An experimental model of silicosis was established in mice where curcumin was administered an hour before intranasal silica exposure every alternate day for 35 days. Intranasal Curcumin treatment reduced silica-induced oxidative stress, inflammation marked by inflammatory cell recruitment, and prominent granuloma nodules along with aberrant collagen repair. Its protective benefits were confirmed by reduced MMP9 activities along with EMT markers (Vimentin and α-SMA). It has restored autophagy and suppressed the deposition of damaged mitochondria after silica exposure. Intranasal Curcumin also inhibited oxidative stress by boosting antioxidant enzyme activities and enhanced Nrf2-Keap1 expressions. Higher levels of PINK1, PARKIN, Cyt-c, P62/SQSTM, and damaged mitochondria in the silicosis group were significantly lowered after curcumin and dexamethasone treatments. Curcumin-induced autophagy resulted in reduced silica-induced mitochondria-dependent apoptosis. We report that intranasal curcumin treatment showed protective properties on pathological features prompted by silica particles, suggesting that the compound may constitute a promising strategy for the treatment of silicosis in the near future.

Addition of Mucoadhesive Agent to Enzymatically Polymerized Caffeic Acid-Based Nasal Vaccine Formulation Attenuates Antigen-Specific Antibody Responses in Mice.

Mucosal vaccination is a promising strategy for combating infectious diseases caused by pathogenic microbes, as it can generate antigen-specific immune responses in both systemic and mucosal compartments. In our recent study, we developed a nasal vaccine system for Streptococcus pneumoniae infections in mice using enzymatically polymerized polyphenols such as caffeic acid. However, the efficacy of this mucosal vaccine system is approximately 70%, indicating a need for improvement. To address this issue, we hypothesized that incorporating a mucoadhesive agent that enhances mucosal absorption into a polyphenol-based mucosal vaccine system would improve vaccine efficacy. Contrary to our expectations, we found that adding a mucoadhesive agent, hydrophobically modified hydroxypropylmethylcellulose, to the vaccine system reduced the stimulation of antigen-specific antibody responses in both the mucosal (more than 90% reduction; P < 0.05) and systemic compartments (more than 80% reduction; P < 0.05). Although the addition of the mucoadhesive agent may have interfered with the interaction between the mucosal epithelium and the vaccine system, the underlying mechanism remains unclear, and further research is needed to fully understand the mechanisms involved.

[Modern approaches to rational combination pharmacotherapy of allergic rhinitis]. / Sovremennye podkhody k ratsional'noi kombinirovannoi farmakoterapii allergicheskogo rinita.

Allergic rhinitis (AR) can significantly reduce the quality of life of patients leading to increased fatigue, mood changes, cognitive impairment, and depression. In clinical practice, insufficient effectiveness of initial AR monotherapy is often noted, and a significant proportion of patients referring for medical care have moderate-severe AR. In this regard, the issues of optimization of combined pharmacological treatment of AR are becoming more and more urgent. This paper provides analysis of the opportunities of combined pharmacotherapy within the framework of current management strategy of AR. Based on the results of some studies and known pharmacological properties of medications it is being discussed the advantages of combined use of intranasal corticosteroids and leukotriene receptor antagonists, in particular mometasone furoate and montelukast, in the therapy of AR, including such comorbidities as bronchial asthma, chronic polyposis rhinosinusitis and pharyngeal tonsil hyperplasia. Some aspects of combination therapy with montelukast and second-generation systemic antihistamines as an alternative approach in case of inability to take intranasal corticosteroids, including the reasonability of using a fixed combination of montelukast and levocetirizine, are analyzed from the perspective of rational pharmacotherapy. The problem of interchangeability of brand-name and generic drugs for the treatment of AR is discussed, considering the almost complete absence of studies of their therapeutic equivalence.