ABSTRACT
Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 µm well. In comparison to γ-CD and ß-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils.
Subject(s)
Administration, Intranasal , Drug Carriers , Drug Delivery Systems , Eugenol , Metal-Organic Frameworks , Powders , Metal-Organic Frameworks/chemistry , Powders/chemistry , Humans , Eugenol/chemistry , Eugenol/administration & dosage , Eugenol/pharmacology , Administration, Intranasal/methods , Drug Delivery Systems/methods , Drug Carriers/chemistry , Particle Size , Cell Survival/drug effects , Molecular Docking Simulation/methods , gamma-Cyclodextrins/chemistry , Drug Stability , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cyclodextrins/chemistry , Nasal Cavity/metabolismABSTRACT
Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.
Subject(s)
Administration, Intranasal , Blood-Brain Barrier , Brain , Drug Delivery Systems , Administration, Intranasal/methods , Humans , Drug Delivery Systems/methods , Brain/metabolism , Blood-Brain Barrier/metabolism , Animals , Drug Carriers/chemistry , Pharmaceutical Preparations/administration & dosage , Nasal Mucosa/metabolismABSTRACT
Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.
Subject(s)
Administration, Intranasal , Brain , Drug Delivery Systems , Drug Liberation , Glycerides , Nasal Mucosa , Particle Size , Verapamil , Administration, Intranasal/methods , Animals , Brain/metabolism , Brain/drug effects , Drug Delivery Systems/methods , Verapamil/administration & dosage , Verapamil/pharmacokinetics , Tissue Distribution , Glycerides/chemistry , Nasal Mucosa/metabolism , Biological Availability , Rats , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/administration & dosage , Poloxamer/chemistry , Male , Chemistry, Pharmaceutical/methods , Rats, Wistar , Nanoparticles/chemistryABSTRACT
Adequate drug delivery across the blood-brain barrier (BBB) is a critical factor in treating central nervous system (CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization, the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2 (LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine (PLL) and negatively charged surface of fibers; this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.
Subject(s)
Administration, Intranasal , Nasal Mucosa , Animals , Administration, Intranasal/methods , Nasal Mucosa/metabolism , Nasal Mucosa/drug effects , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effects , Drug Delivery Systems/methods , Mice , Nasal Cavity/drug effects , Nasal Cavity/metabolism , Polylysine/chemistry , Polylysine/analogs & derivatives , Swimming , Male , Brain/metabolism , Brain/drug effects , Brain/pathology , Mucociliary Clearance/drug effects , Microglia/drug effects , Microglia/metabolism , HumansABSTRACT
The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 µg/mL), Cmax (368.07 ± 0.23 µg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.
Subject(s)
Administration, Intranasal , Biological Availability , Brain , Fluoxetine , Fluoxetine/pharmacokinetics , Fluoxetine/administration & dosage , Fluoxetine/chemistry , Administration, Intranasal/methods , Animals , Brain/metabolism , Blood-Brain Barrier/metabolism , Drug Liberation , Rats , Nasal Mucosa/metabolism , Male , Gels/chemistry , Rats, Wistar , Drug Compounding/methodsABSTRACT
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly characterized by deficient sociability and repetitive behaviors. Effective treatment for the core symptoms of ASD is still lacking. Behavioral interventions show limited effectiveness, while pharmacotherapy focuses on the amelioration of secondary symptomatology. Oxytocin (OXT) is a neuropeptide known for its prosocial impact, making it a candidate drug for ASD treatment. Its alleviating effect has been and still is widely researched, but outcomes reported by clinical studies are ambiguous. We examined the effect of daily intranasal OXT (0.8 IU/kg) administration for 4 weeks on the ASD-like phenotype in Shank3-/- adult mice. Animals treated with OXT spent twice as much time interacting with the social partner as early as after 2 weeks of treatment. Furthermore, OXT-treated mice exhibited reduced explorative behavior by 50%, after 4 weeks of treatment, and a 30% reduction in repetitive behavior, 4 weeks after treatment termination. One-fold higher sociability and 30% reduced exploration due to OXT lasted up to 4 weeks following the treatment termination. However, social disinterest was elevated by roughly 10% as well, indicating a form of social ambivalence. Obtained results support the therapeutic potential of intranasally administered OXT in alleviating social shortfalls in a genetic model of ASD. Subsequent research is necessary to elucidate the benefits and risks of the long-term OXT administration, as well as its applicability in other ASD models and the potential treatment effect on social communication, which was not measured in the present study.
Subject(s)
Administration, Intranasal , Autism Spectrum Disorder , Disease Models, Animal , Mice, Knockout , Oxytocin , Social Behavior , Animals , Oxytocin/administration & dosage , Oxytocin/pharmacology , Administration, Intranasal/methods , Mice , Male , Autism Spectrum Disorder/drug therapy , Autism Spectrum Disorder/genetics , Nerve Tissue Proteins/genetics , Autistic Disorder/genetics , Autistic Disorder/drug therapy , Exploratory Behavior/drug effects , Microfilament Proteins/genetics , Behavior, Animal/drug effects , Mice, Inbred C57BLABSTRACT
El Trastorno Depresivo Mayor es la causaprincipal de discapacidad a nivel mundial. La depresión resistente al tratamiento ocurre en un subgrupo de pacientes con trastorno depresivo mayor, y consiste en una falta de respuesta a dos o más antidepresivos diferentes en dosis y duración adecuadas, con una adherencia óptima al tratamiento. En 2019 tanto la FDA como la EMA aprobaron la indicación de esketamina intranasal (esketamina in-) en el Trastorno Depresivo Mayor, cuyo mecanismo de acción se basa en el antagonismo del receptor NMDA. En este artículo exponemos el caso de una paciente con Trastorno Depresivo Mayor, que fue tratada con esketamina en uso compasivo, los efectos secundarios presentados y el manejo de los mismos. Los resultados fueron espectaculares, ya que, a partir de la tercera administración, se observó una respuesta clínica muy favorable, evidenciándose la remisión completa a las 5 semanas. El uso de esketamina intranasal ha demostrado ser muy efectivo y con una gran rapidez de acción, siendo el único antidepresivo capaz de lograr la remisión completa en esta paciente tan compleja y grave, además de conseguir ajustar a la baja la medicación concomitante. Los efectos secundarios fueron de fácil manejo, transitorios y autolimitados al momento de la administración. Tal y como se describe en la ficha técnica y en el informe de posicionamiento terapeútico de esketamina intranasal, el tratamiento debe ser administrado en un entorno clínico adecuado, que podría ser bien el hospital o el ambulatorio, ya que ambos contienen los recursos necesarios para la sesión de administración y posterior periodo de observación del paciente. (AU)
Mayor depressive disorder is the main cause of disability in the world. Treatment resistant depression occurs in a subgroup of patients with mayor depressive disorder and consists of a lack of response to two or more different antidepressants in adequate doses and duration, with optimal adherence to treatment. In 2019, both the FDA and the EMA approved the indication of intranasal esketamine in Major Depressive Disorder, whose mechanism of action is based on NMDA receptor antagonism. In this article we present the case of a patient with Major Depressive Disorder, who was treated with esketamine in compassionate use, secondary effects presented and their management. The results were dramatic, since from the third administration a very favorable clinical response was observed, showing complete remission at five weeks. The use of intranasal esketamine has proved to be very effective and rapid over time, being the only antidepressant able of achieving complete remission in this very complex and severe patient, in addition to achieving downward adjustment of the concomitant medication. The treatment may be administered in a suitable clinical environment, so both hospital and outpatient resources may be suitable places for administration. (AU)
Subject(s)
Humans , Administration, Intranasal/methods , Depression/therapy , Antidepressive Agents/therapeutic useABSTRACT
La rinitis alérgica ha ido en aumento en los países latinoamericanos, dando lugar a una creciente población de pacientes que necesitan tratamiento médico para esta afección respiratoria. Su similitud con la COVID-19 en cuanto a síntomas y la posibilidad de concurrencia con esta, hacen que la rinitis alérgica sea de particular interés para los sistemas de salud. Los países de América Latina y el Caribe han sido particularmente vulnerables por múltiples desafíos, entre estos, las altas tasas de pobreza, el acceso limitado a la atención médica y las limitaciones en la prestación de servicios básicos de salud, así como la ausencia de guías de tratamiento para la rinitis alérgica en situación de pandemia. Con el objetivo de proporcionar orientación esencial para los equipos multidisciplinarios de América Latina y el Caribe con respecto a la evaluación y el tratamiento de la rinitis alérgica durante la pandemia de COVID-19, se revisó literatura científica publicada sobre tratamiento de la rinitis alérgica y COVID-19, y se consideró la opinión de profesionales líderes de sociedades científicas de la región. Se analizaron las diferentes medidas para evitar contagios, y las diferentes estrategias de tratamiento con énfasis en la terapia intranasal y el tratamiento con vacunas contra la alergia. Se formuló una declaración de posicionamiento con la intención de mantener la continuidad del servicio médico en el contexto de una pandemia y minimizar la propagación, infección y complicación asociada con el coronavirus tipo 2 del síndrome respiratorio agudo severo en pacientes con seguimiento o comenzando tratamiento para la rinitis alérgica(AU)
Allergic rhinitis has been increasing in Latin American countries, leading to a growing population of patients who need medical treatment for this respiratory condition. Its similarity to COVID-19 in terms of symptoms and the possibility of concurrence with it, make allergic rhinitis of particular interest to health systems. The countries of Latin America and the Caribbean have been particularly vulnerable due to multiple challenges, including high poverty rates, limited access to medical care and limitations in the provision of basic health services, as well as the absence of guidelines of treatment for allergic rhinitis in a pandemic situation. With the aim of to provide essential management for multidisciplinary teams in Latin America and the Caribbean regarding the evaluation and treatment of allergic rhinitis during the COVID-19 pandemic, published scientific literature on the treatment of allergic rhinitis and COVID-19 was reviewed, and the opinion of leading professionals from scientific societies in the region was considered. The different measures to avoid infections and the different treatment strategies were analyzed, with an emphasis on intranasal therapy and treatment with allergy vaccines. A position statement was formulated with the intention of maintaining continuity of medical service in the context of a pandemic and minimizing the spread, infection and complication associated with severe acute respiratory syndrome coronavirus 2 in patients undergoing or starting treatment for allergic rhinitis(AU)
Subject(s)
Humans , Male , Female , Administration, Intranasal/methods , Rhinitis, Allergic/drug therapy , Rhinitis, Allergic/epidemiology , COVID-19 Vaccines/therapeutic use , Caribbean Region , COVID-19/epidemiology , Latin AmericaABSTRACT
Effective vaccines are essential for the control of the coronavirus disease 2019 (COVID-19) pandemic. Currently developed vaccines inducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-antigen-specific neutralizing antibodies (NAbs) are effective, but the appearance of NAb-resistant S variant viruses is of great concern. A vaccine inducing S-independent or NAb-independent SARS-CoV-2 control may contribute to containment of these variants. Here, we investigate the efficacy of an intranasal vaccine expressing viral non-S antigens against intranasal SARS-CoV-2 challenge in cynomolgus macaques. Seven vaccinated macaques exhibit significantly reduced viral load in nasopharyngeal swabs on day 2 post-challenge compared with nine unvaccinated controls. The viral control in the absence of SARS-CoV-2-specific NAbs is significantly correlated with vaccine-induced, viral-antigen-specific CD8+ T cell responses. Our results indicate that CD8+ T cell induction by intranasal vaccination can result in NAb-independent control of SARS-CoV-2 infection, highlighting a potential of vaccine-induced CD8+ T cell responses to contribute to COVID-19 containment.
Subject(s)
Administration, Intranasal/methods , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Animals , COVID-19/epidemiology , COVID-19/virology , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Coronavirus Envelope Proteins/immunology , Coronavirus M Proteins/immunology , Coronavirus Nucleocapsid Proteins/immunology , Disease Models, Animal , Female , Macaca fascicularis , Male , Pandemics/prevention & control , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Treatment Outcome , Vero Cells , Viral LoadABSTRACT
The inflammasome NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) is closely associated with exacerbation of asthma as endotoxin (lipopolysaccharide, LPS) is one of its activators present in the environment. Present study is undertaken to investigate anti-inflammatory effects of a well known phytochemical, curcumin, which might regulate LPS exposed asthma exacerbations by modulating NLRP3 activation if given through intranasal route. Balb/c mice were sensitized with intraperitoneal injection of OVA (Ovalbumin; 100 µg of OVA with alum) from day 1 to 8 and exposed to LPS with 1% OVA aerosol from day 9 to 15. LPS (0.1 µg) was given an hour before sensitization and OVA-aerosol challenge. Significant decrease in inflammatory cell recruitment and restoration of structural changes in lungs, alterations in mRNA and protein expressions of TLR-4, NF-κB, NLRP3, Caspase-1, IL-1ß, MMP-9, IL-5 and IL-17 in intranasal curcumin alone and corticosteroid combined pretreatment group.
Subject(s)
Asthma/drug therapy , Curcumin/pharmacology , Dexamethasone/pharmacology , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Administration, Intranasal/methods , Animals , Asthma/chemically induced , Asthma/metabolism , Caspase 1/metabolism , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Lung/drug effects , Lung/metabolism , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Ovalbumin/pharmacology , Transcription Factor RelA/metabolismABSTRACT
Asthma being an inflammatory disease of the airways lead to structural alterations in lungs which often results in the severity of the disease. Curcumin, diferuloylmethane, is well known for its medicinal properties but its anti-inflammatory potential via Histone deacetylase inhibition (HDACi) has not been revealed yet. Therefore, we have explored here, anti-inflammatory and anti-fibrotic potential of intranasal curcumin via HDAC inhibition and compared its potential with Sodium butyrate (SoB), a known histone deacetylase inhibitor of Class I and II series. Anti-inflammatory potential of SoB, has been investigated in cancer but not been studied in asthma before. MATERIALS AND METHODS: In present study, ovalbumin (OVA) was used to sensitize Balb/c mice and later exposed to (1%) OVA aerosol. Curcumin (5 mg/kg) and Sodium butyrate (50 mg/kg) was administered through intranasal route an hour before OVA aerosol challenge. Efficacies of SoB and Curcumin as HDAC inhibitors were evaluated in terms of different inflammatory parameters like, total inflammatory cell count, reactive oxygen species (ROS), histamine release, nitric oxide and serum IgE levels. Inflammatory cell recruitment was analyzed by H&E staining and structural alterations were revealed by Masson's Trichrome staining of lung sections. RESULTS: Enhanced Matrix Metalloproteinase-2 and 9 (MMP-2 and MMP-9) activities were observed in bronchoalveolar lavage fluid (BALF) of asthmatic mice by gelatin zymography which was inhibited in both treatment groups. Protein expressions of MMP-9, HDAC 1, H3acK9 and NF-kB p65 were modulated in intranasal curcumin and SoB pretreatment groups. CONCLUSION: This is the first report where intranasal curcumin inhibited asthma severity via affecting HDAC 1 (H3acK9) leading to NF-kB suppression in mouse model of allergic asthma.
Subject(s)
Asthma/diet therapy , Butyric Acid/administration & dosage , Curcumin/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Inflammation/diet therapy , Lung/drug effects , Administration, Intranasal/methods , Animals , Anti-Inflammatory Agents/administration & dosage , Asthma/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Disease Models, Animal , Fibrosis/diet therapy , Fibrosis/metabolism , Immunoglobulin E/metabolism , Inflammation/metabolism , Lung/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Ovalbumin/pharmacologyABSTRACT
BACKGROUND: Anesthesia studies using high-flow, humidified, heated oxygen delivered via nasal cannulas at flow rates of more than 50 l · min-1 postulated a ventilatory effect because carbon dioxide increased at lower levels as reported earlier. This study investigated the increase of arterial partial pressure of carbon dioxide between different flow rates of 100% oxygen in elective anesthetized and paralyzed surgical adults before intubation. METHODS: After preoxygenation and standardized anesthesia induction with nondepolarizing neuromuscular blockade, all patients received 100% oxygen (via high-flow nasal oxygenation system or circuit of the anesthesia machine), and continuous jaw thrust/laryngoscopy was applied throughout the 15-min period. In this single-center noninferiority trial, 25 patients each, were randomized to five groups: (1) minimal flow: 0.25 l · min-1, endotracheal tube; (2) low flow: 2 l · min-1, continuous jaw thrust; (3) medium flow: 10 l · min-1, continuous jaw thrust; (4) high flow: 70 l · min-1, continuous jaw thrust; and (5) control: 70 l · min-1, continuous laryngoscopy. Immediately after anesthesia induction, the 15-min apnea period started with oxygen delivered according to the randomized flow rate. Serial arterial blood gas analyses were drawn every 2 min. The study was terminated if either oxygen saturation measured by pulse oximetry was less than 92%, transcutaneous carbon dioxide was greater than 100 mmHg, pH was less than 7.1, potassium level was greater than 6 mmol · l-1, or apnea time was 15 min. The primary outcome was the linear rate of mean increase of arterial carbon dioxide during the 15-min apnea period computed from linear regressions. RESULTS: In total, 125 patients completed the study. Noninferiority with a predefined noninferiority margin of 0.3 mmHg · min-1 could be declared for all treatments with the following mean and 95% CI for the mean differences in the linear rate of arterial partial pressure of carbon dioxide with associated P values regarding noninferiority: high flow versus control, -0.0 mmHg · min-1 (-0.3, 0.3 mmHg · min-1, P = 0.030); medium flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.002); low flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.003); and minimal flow versus control, -0.1 mmHg · min-1 (-0.4, 0.2 mmHg · min-1, P = 0.004). CONCLUSIONS: Widely differing flow rates of humidified 100% oxygen during apnea resulted in comparable increases of arterial partial pressure of carbon dioxide, which does not support an additional ventilatory effect of high-flow nasal oxygenation.
Subject(s)
Administration, Intranasal/methods , Apnea/blood , Apnea/therapy , Carbon Dioxide/blood , Oxygen Inhalation Therapy/methods , Administration, Intranasal/adverse effects , Adult , Aged , Female , Humans , Male , Middle Aged , Oxygen Inhalation Therapy/adverse effects , Partial PressureABSTRACT
Natural polysaccharides have shown promising effects on the regulation of immunity in animals. In this study, we examined the immune stimulatory effect of intranasally administered Codium fragile polysaccharides (CFPs) in mice. Intranasal administration of CFPs in C57BL/6 mice induced the upregulation of surface activation marker expression in macrophages and dendritic cells (DCs) in the mediastinal lymph node (mLN) and the production of interleukin-6 (IL-6), IL-12p70, and tumor necrosis factor-α in bronchoalveolar lavage fluid. Moreover, the number of conventional DCs (cDCs) was increased in the mLNs by the upregulation of C-C motif chemokine receptor 7 expression, and subsets of cDCs were also activated following the intranasal administration of CFP. In addition, the intranasal administration of CFPs promoted the activation of natural killer (NK) and T cells in the mLNs, which produce pro-inflammatory cytokines and cytotoxic mediators. Finally, daily administration of CFPs inhibited the infiltration of Lewis lung carcinoma cells into the lungs, and the preventive effect of CFPs on tumor growth required NK and CD8 T cells. Furthermore, CFPs combined with anti-programmed cell death-ligand 1 (PD-L1) antibody (Ab) improved the therapeutic effect of anti-PD-L1 Ab against lung cancer. Therefore, these data demonstrated that the intranasal administration of CFP induced mucosal immunity against lung cancer.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Antineoplastic Agents/administration & dosage , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/therapy , Chlorophyta/chemistry , Immunity, Mucosal , Immunotherapy/methods , Lung Neoplasms/immunology , Lung Neoplasms/therapy , Phytotherapy/methods , Plant Extracts/administration & dosage , Polysaccharides/administration & dosage , Administration, Intranasal/methods , Animals , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Dendritic Cells/immunology , Disease Models, Animal , Female , Killer Cells, Natural/immunology , Lung Neoplasms/pathology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BLABSTRACT
The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989-1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.
Subject(s)
Administration, Intranasal/methods , Critical Care/methods , Glucagon/analogs & derivatives , Hypoglycemia/drug therapy , Adult , Child , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucagon/administration & dosage , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Injections, Subcutaneous , Insulin/adverse effects , Insulin, Regular, Human/therapeutic use , Powders/administration & dosage , Sulfonylurea Compounds/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: Molecular mechanisms of depression remain unclear. The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Rats were exposed to chronic ultrasound stress and treated with intranasal and intraperitoneal clomipramine. We then analyzed 28 metabolites in the frontal cortex and hippocampus. METHODS: Rats' behavior was identified in such tests: social interaction, sucrose preference, forced swim, and Morris water maze. Metabolic analysis was performed with liquid chromatography. RESULTS: After ultrasound stress pronounced depressive-like behavior, clomipramine had an equally antidepressant effect after intranasal and intraperitoneal administration on behavior. Ultrasound stress contributed to changes of the metabolomic pathways associated with pathophysiology of depression. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should also be evaluated from this point of view.
Subject(s)
Clomipramine/pharmacology , Depression/drug therapy , Administration, Intranasal/methods , Animals , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Clomipramine/administration & dosage , Depression/physiopathology , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Metabolome/physiology , Metabolomics/methods , Motor Activity/drug effects , Rats , Rats, Wistar , Stress, Psychological/drug therapyABSTRACT
Sesamol is a sesame seed constituent with reported activity against many types of cancer. In this work, two types of nanocarriers, solid lipid nanoparticles (SLNs) and polymeric nanoparticles (PNs), were exploited to improve sesamol efficiency against the glioma cancer cell line. The ability of the proposed systems for efficient brain targeting intranasally was also inspected. By the aid of two docking programs, the virtual loading pattern inside these nanocarriers was matched to the real experimental results. Interactions involved in sesamol-carrier binding were also assessed, followed by a discussion of how different scoring functions account for these interactions. The study is an extension of the computer-assisted drug formulation design series, which represents a promising initiative for an upcoming industrial innovation. The results proved the power of combined in silico tools in predicting members with the highest sesamol payload suitable for delivering a sufficient dose to the brain. Among nine carriers, glyceryl monostearate (GMS) and polycaprolactone (PCL) scored the highest sesamol payload practically and computationally. The EE % was 66.09 ± 0.92 and 61.73 ± 0.47 corresponding to a ΔG (binding energy) of -8.85 ± 0.16 and -5.04 ± 0.11, respectively. Dynamic light scattering evidenced the formation of 215.1 ± 7.2 nm and 414.25 ± 1.6 nm nanoparticles, respectively. Both formulations demonstrated an efficient cytotoxic effect and brain-targeting ability compared to the sesamol solution. This was evidenced by low IC50 (38.50 ± 10.37 µM and 27.81 ± 2.76 µM) and high drug targeting efficiency (7.64 ± 1.89-fold and 13.72 ± 4.1-fold) and direct transport percentages (86.12 ± 3.89 and 92.198 ± 2.09) for GMS-SLNs and PCL-PNs, respectively. The results also showed how different formulations, having different compositions and characteristics, could affect the cytotoxic and targeting ability.
Subject(s)
Administration, Intranasal/methods , Antineoplastic Agents/administration & dosage , Benzodioxoles/administration & dosage , Brain Neoplasms/drug therapy , Nanoparticle Drug Delivery System/administration & dosage , Phenols/administration & dosage , Animals , Antineoplastic Agents/therapeutic use , Benzodioxoles/therapeutic use , Cell Line, Tumor , Computer Simulation , Glioma/drug therapy , In Vitro Techniques , Male , Molecular Docking Simulation , Phenols/therapeutic use , RatsABSTRACT
BACKGROUND: There has been a great interest in developing strategies for enhancing antigen delivery to the mucosal immune system as well as identifying mucosal active immunostimulating agents. To elevate the potential of O-2'-Hydroxypropyl trimethyl ammonium chloride chitosan (O-2'-HACC) as an adjuvant and mucosal immune delivery carrier for DNA vaccine, we prepared the O-2'-HACC loaded with Newcastle disease virus (NDV) F gene plasmid DNA and C3d6 molecular adjuvant (O-2'-HACC/pFDNA microparticles). RESULTS: The O-2'-HACC/pFDNA exhibited a regular spherical morphology with a particle size of 202.3 ± 0.52 nm, a zeta potential of 50.8 ± 8.21 mV, encapsulation efficiency of 90.74 ± 1.10%, and a loading capacity of 49.84 ± 1.20%. The plasmid DNA could be sustainably released from the O-2'-HACC/pFDNA after an initial burst release. Intranasal vaccination of chickens immunized with O-2'-HACC/pFDNA not only induced higher anti-NDV IgG and sIgA antibody titers but also significantly promoted lymphocyte proliferation and produced higher levels of IL-2, IL-4, IFN-γ, CD4+, and CD8 + T lymphocytes compared with the NDV commercial live attenuated vaccine. Intranasal delivery of the O-2'-HACC/pFDNA enhanced humoral, cellular, and mucosal immune responses and protected chickens from the infection of highly virulent NDV compared with the intramuscular delivery. CONCLUSIONS: Collectively, our findings indicated that the O-2'-HACC could be used as a vaccine adjuvant and delivery system for mucosal immunity and have an immense application promise.
Subject(s)
Administration, Intranasal/methods , Ammonium Chloride/chemistry , Chitosan/chemistry , Immunization/methods , Newcastle Disease/immunology , Vaccination , Adjuvants, Vaccine/chemistry , Animals , Chickens , Immunity, Mucosal/immunology , Newcastle Disease/prevention & control , Newcastle disease virus/immunology , Particle Size , Vaccines, DNA/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/chemistryABSTRACT
Despite the availability of vaccines that efficiently reduce the severity of clinical symptoms, influenza viruses still cause substantial morbidity and mortality worldwide. In this regard, nasal influenza vaccines-because they induce virus-specific IgA-may be more effective than traditional parenteral formulations in preventing infection of the upper respiratory tract. In addition, the neuraminidase (NA) of influenza virus has shown promise as a vaccine antigen to confer broad cross-protection, in contrast to hemagglutinin (HA), the target of most current vaccines, which undergoes frequent antigenic changes, leading to vaccine ineffectiveness against mismatched heterologous strains. However, the usefulness of NA as an antigen for nasal vaccines is unclear. Here, we compared NA and HA as antigens for nasal vaccines in mice. Intranasal immunization with recombinant NA (rNA) plus adjuvant protected mice against not only homologous but also heterologous virus challenge in the upper respiratory tract, whereas intranasal immunization with rHA failed to protect against heterologous challenge. In addition, intranasal immunization with rNA, but not rHA, conferred cross-protection even in the absence of adjuvant in virus infection-experienced mice; this strong cross-protection was due to the broader capacity of NA-specific antibodies to bind to heterologous virus. Furthermore, the NA-specific IgA in the upper respiratory tract that was induced through rNA intranasal immunization recognized more epitopes than did the NA-specific IgG and IgA in plasma, again increasing cross-protection. Together, our findings suggest the potential of NA as an antigen for nasal vaccines to provide broad cross-protection against both homologous and heterologous influenza viruses. IMPORTANCE Because mismatch between vaccine strains and epidemic strains cannot always be avoided, the development of influenza vaccines that induce broad cross-protection against antigenically mismatched heterologous strains is needed. Although the importance of NA-specific antibodies to cross-protection in humans and experimental animals is becoming clear, the potential of NA as an antigen for providing cross-protection through nasal vaccines is unknown. We show here that intranasal immunization with NA confers broad cross-protection in the upper respiratory tract, where virus transmission is initiated, by inducing NA-specific IgA that recognizes a wide range of epitopes. These data shed new light on NA-based nasal vaccines as powerful anti-influenza tools that confer broad cross-protection.
Subject(s)
Influenza Vaccines/immunology , Neuraminidase/pharmacology , Orthomyxoviridae/immunology , Adjuvants, Immunologic , Administration, Intranasal/methods , Animals , Antibodies, Viral/immunology , Cross Protection , Female , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinins/immunology , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza Vaccines/administration & dosage , Influenza Vaccines/metabolism , Influenza, Human/virology , Male , Mice , Mice, Inbred C57BL , Neuraminidase/immunology , Neuraminidase/metabolism , Orthomyxoviridae Infections/virology , Vaccination/methodsABSTRACT
Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (â¼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core-shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.
