Swimming short fibrous nasal drops achieving intraventricular administration.

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.

A comprehensive review of mechanistic insights into formaldehyde-induced nasal cavity carcinogenicity.

According to the International Agency for Research on Cancer classification, formaldehyde is a human carcinogen that targets the nasal cavity. In humans and rats, inhaled formaldehyde is primarily deposited in the nasal cavity mucosa, metabolized to the less toxic formic acid, and finally excreted into the urine or exhaled. Thus, formaldehyde-induced nasal carcinogenicity may be a direct effect of formaldehyde itself, although the underlying mechanisms remain unclear. With regard to cytotoxicity, degeneration and necrosis of nasal respiratory cells occur in rats after short exposure to formaldehyde. Cell proliferation is increased in the damaged cells, suggesting its critical roles both in the early stages and throughout the entire process of nasal carcinogenicity. Hyperplasia, squamous metaplasia, and dysplasia of the damaged epithelium frequently appear as morphological precursor lesions. With regard to genotoxicity, in addition to DNA-protein crosslinks, oxidative DNA damage also occurs in the exposed nasal mucosal cells. Sustained exposure to formaldehyde may cause nasal carcinogenicity through cytotoxicity and auxiliary genotoxicity. In this review, we discuss adverse outcome pathways through which cytotoxicity can lead to carcinogenicity and the development of integrated approaches for testing and assessment for nongenotoxic carcinogens.

New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.

C407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4-NBD1 interface.

Overcoming the challenges of developing an intranasal diazepam rescue therapy for the treatment of seizure clusters.

Seizure clusters must be treated quickly and effectively to prevent progression to prolonged seizures and status epilepticus. Rescue therapy for seizure clusters has focused on the use of benzodiazepines. Although intravenous benzodiazepine administration is the primary route in hospitals and emergency departments, seizure clusters typically occur in out-of-hospital settings, where a more portable product that can be easily administered by nonmedical caregivers is needed. Thus, other methods of administration have been examined, including rectal, intranasal, intramuscular, and buccal routes. Following US Food and Drug Administration (FDA) approval in 1997, rectal diazepam became the mainstay of out-of-hospital treatment for seizure clusters in the United States. However, social acceptability and consistent bioavailability present limitations. Intranasal formulations have potential advantages for rescue therapies, including ease of administration and faster onset of action. A midazolam nasal spray was approved by the FDA in 2019 for patients aged 12 years or older. In early 2020, the FDA approved a diazepam nasal spray for patients aged 6 years or older, which has a different formulation than the midazolam nasal product and enhances aspects of bioavailability. Benzodiazepines, including diazepam, present significant challenges in developing a suitable intranasal formulation. Diazepam nasal spray contains dodecyl maltoside (DDM) as an absorption enhancer and vitamin E to increase solubility in an easy-to-use portable device. In a Phase 1 study, absolute bioavailability of the diazepam nasal spray was 97% compared with intravenous diazepam. Subsequently, the nasal spray demonstrated less variability in bioavailability than rectal gel (percentage of geometric coefficient of variation of area under the curve = 42%-66% for diazepam nasal spray compared with 87%-172% for rectal gel). The diazepam nasal spray safety profile is consistent with that expected for rectal diazepam, with low rates of nasal discomfort (≤6%). To further improve the efficacy of rescue therapy, investigation of novel intranasal benzodiazepine formulations is underway.

Clinical efficacy of high-flow nasal oxygen in patients undergoing ERCP under sedation.

Hypoxemia can occur during endoscopic retrograde cholangiography (ERCP) and it is difficult to achieve adequate ventilation with the prone position. High-flow nasal oxygen (HFNO) has been recommended to be more effectively help ventilation than conventional low flow oxygen. The aim of this study was to evaluate the effect of HFNO during sedated ERCP and to identify predictors of desaturation during ERCP. The investigated variables were age, gender, American Society of Anesthesiologists classes (ASA), duration of exam, and sedative used for midazolam or/and propofol of 262 patients with sedated ERCP. The differences between categorical and continuous variables were analyzed using the Student's t test and the chi-square test. Desaturation (SpO2 ≤ 90%) occurred in 9(3.4%) patients among 262 patients during sedated ERCP. The variables found to predict desaturation were older age (p < 0.01), higher sedation dose for midazolam or propofol (p < 0.01), and use of midazolam (p < 0.01). Desaturation rate was lower during sedated ERCP with HFNO compared to the preliminary study with conventional low flow nasal oxygen. Patients with older age, higher sedation dose, or the use of midazolam might require close monitoring for desaturation and hypoventilation by nursing staff. The study shows the use of high-flow nasal oxygen reduces the incidence of desaturation during ERCP.

A Comparison between Mygind and Kaiteki positions in administration of drops to the olfactory cleft.

OBJECTIVES: Topical nasal steroids are a common treatment intervention for olfactory dysfunction. Penetration of topical treatment to the olfactory cleft (OC), such as nasal drops, is greatly dependent on the position of the head when the treatment is administered. We aimed to examine the penetrance of nasal drops to the OC in two different head positions: the Mygind (lying head back) position and the Kaiteki position. DESIGN AND SETTING: The specimens were firstly positioned in Mygind, and thereafter in Kaiteki positions. Nasal drops mixed with blue food dye were administered into the nostrils in each of the head position. Endoscopic videos were recorded, and two blinded observers scored the extent of olfactory cleft penetration (OCP) using a 4-point scale (0 = none, 3 = heavy). PARTICIPANTS: Twelve fresh-frozen cadaver specimens. MAIN OUTCOME MEASURES: Penetration of the dye into the OC. RESULTS: The mean score of nasal drops penetrance to the OC in the Mygind position was 1.34 (standard deviation, SD = 0.92), as compared to 1.76 (SD = 0.65) in the Kaiteki position. The difference in the OCP score between the two groups was not statistically significant (P > .05). CONCLUSION: Both Mygind and Kaiteki head positions are reasonable options for patients considering topical nasal drops for olfaction impairment. The preference of one position over the other should be determined by patient's preference and comfort.

Influence of nasal mucosa irritants on the occurrence of chronic rhinosinusitis without /and with polyps.

<b>Introduction: </b>The aim of the study was to assess the effect of nasal mucosa irritants on the occurrence of chronic rhinosinusitis without/and with nasal polyps. <br><b>Material and methods:</b> The study involved 100 adult participants, including 39 women and 61 men, aged 21-68, diagnosed and treated at the Department of Otolaryngology, ENT Oncology, Audiology and Phoniatrics at the University Clinical Hospital WAM in Lódz. Based on the otorhinolaryngological and imaging (CT) tests they were divided into two groups: I - 50 patients, including 23 women and 27 men, aged 21-64 - with chronic rhinosinusitis without nasal polyps, II - 50 patients, including 16 women and 34 men, aged 22-68 - with chronic rhinosinusitis with nasal polyps. The control group consisted of 50 people (group III), including 25 women and 25 men, aged 18-30, students of the Faculty of Military Medicine at the Medical University of Lodz. All respondents completed a prepared questionnaire consisting of 17 questions addressed in the form of an anonymous interview among patients treated in the Department of Otolaryngology, ENT Oncology, Audiology and Phoniatrics. <br><b>Results:</b> The conducted surveys indicate the impact of the following factors in pathogenesis of chronic rhinosinusitis without/ with nasal polyps: exogenous factors (viruses, bacteria, fungi, drugs, injuries, toxic substances, environmental pollution), general endogenous factors (allergy, hypersensitivity to acetylsalicylic acid and its derivatives, hormonal disorders, supraesophageal reflux disease, granulation disease, immunity disorders, local endogenous factors. <br><b>Conclusions:</b> In the examined material, patients with chronic rhinosinusitis without/and nasal polyps in most cases are in the age range 51-60 years and over 60 years, they most often live in large cities over 250 thousand inhabitants, suffer from allergic rhinorhinitis in 38.0% in group I and 36.0% in group II, rapid temperature changes and dry air have a negative impact on comfort of breathing. The conducted surveys confirm that the cause of chronic rhinosinusitis with polyps is multifactorial, but a significant factor affecting typical tissue remodeling in this disease is long-term breathing of polluted atmospheric air.

Bilateral multiple serous retinal detachments after treatment with nivolumab: a case report.

BACKGROUND: Immune checkpoint inhibitors have recently been widely used for advanced cancers and are known to cause ocular complications. We herein report a case developing bilateral serous retinal detachments, without ocular inflammation, after starting nivolumab treatment. CASE PRESENTATION: A 73-year-old man was referred to our hospital, having become aware of metamorphopsia 2 months after starting nivolumab (anti-programmed cell death protein 1 monoclonal antibody) for malignant melanoma of the nasal cavity. The initial corrected visual acuity of the right eye was 20/20, and that of the left eye was 20/16. There were no inflammatory findings in the anterior segment or the vitreous. Vitelliform lesions were found in the macular area of both ocular fundi, consistent with serous retinal detachment and subretinal deposits. Swept source optical coherence tomography showed diffuse thickening of the outer photoreceptor segment and thickening of the choroid. Two months after the initial diagnosis, multiple vitelliform lesions were noted, and the fundus findings had worsened. Indocyanine green fluorescein angiography showed delayed inflow in the peripapillary and posterior pole regions in the early phase of imaging. Fundus autofluorescence showed hyperautofluorescence consistent with most of the vitelliform lesions on color fundus photography. CONCLUSIONS: Nivolumab may have impaired the pumping and phagocytosis functions of retinal pigment epithelial cells, resulting in bilateral serous retinal detachments and thickening of the photoreceptor outer segment. This is the first case report, to our knowledge, describing multiple bilateral serous retinal detachments and outer segment thickening without inflammation in a patient treated with nivolumab.

World Trade Center Dust induces airway inflammation while promoting aortic endothelial dysfunction.

Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.

Histomorphological Study of a New Nasal Spray with Anti-inflammatory Properties Efficacy in Rabbits with Rhinosinusitis.

INTRODUCTION: The high world prevalence of rhinosinusitis (RS) initiates the ways of a favorable search for effective and safe medicines for its pathogenetic treatment. The important part of this process is the choice of the most comfortable dosage form, which will enhance therapeutic compliance and ensure the appropriate medicine efficacy and safety. AIM: To substantiate the efficacy of a new nasal spray with anti-inflammatory properties containing Enisamium Iodide (EI) at a concentration of 10 mg/mL by histomorphological study of the nasal cavity and paranasal sinuses mucosal in rabbits with experimental rhinosinusitis (ERS). METHODS: EI (nasal spray) was a test object. Sinupret® was a reference drug. ERS was induced in rabbits on the first day of the study by tamponade of the right half of the nasal cavity under general anesthesia. The study was performed using 24 rabbits (4 groups, 6 rabbits in each group). The histomorphological examination was performed on the 25th day of the study by the standard light microscopy methods. RESULTS: The histomorphological examination of EI 10 mg/mL (nasal spray) impact on RS in rabbits, which administered during 10 days intranasally, revealed the significant therapeutic effect presented by reduced inflammation signs in the epithelium of the nasal cavities and paranasal sinuses mucosal. Besides, the EI impact was not inferior to the reference drug Sinupret® in tablets. The study of the pharmacological properties of the EI (nasal spray) on ERS showed the high rate of onset of EI actions when used intranasally which was superior to the rate of actions of the reference drug Sinupret® (tablets) administered intragastrically. CONCLUSION: The EI (nasal spray) is a promising drug for a pathogenetic therapy of acute RS, which demands further pre-clinical and clinical studies aiming to substantiate its implementation to the clinical practice.

Effects of oral isotretinoin therapy on the nasal cavities / Efeitos nasais da terapia com isotretinoína oral

Abstract Introduction Isotretinoin (13 cis-retinoic acid) is the most effective treatment for acne vulgaris and is the only treatment option that can provide either remission or a permanent cure. Objective The aim of this study was to use both subjective and objective methods to assess the nasal complaints of patients with severe acne who received oral isotretinoin therapy. Methods Fifty-four subjects were enrolled in the study. All the subjects were assessed with subjective (NOSE and VAS questionnaires) and objective (rhinomanometry and saccharine) tests to determine the severity of their nasal complaints. Results The mean severity scores (min: 0; max: 100) for nasal dryness/crusting and epistaxis were 0.47 ± 1.48 (0-5); 0.35 ± 1.30 (0-5) at admission, 3.57 ± 4.45 (0-10); 2.26 ± 4.71 (0-20) at the first month, and 4.28 ± 6 (0-20); 2.26 ± 4.71 (0-20) at the third month of the treatment respectively. Total nasal resistance of 0.195 ± 0.079 (0.12-0.56) Pa/cm3/s at admission, 0.21 ± 0.084 (0.12-0.54) Pa/cm3/s at the first month, and 0.216 ± 0.081 (0.14-0.54) Pa/cm3/s at the third month. Conclusion Oral isotretinoin therapy can cause the complaint of nasal obstruction. In addition, nasal complaints, such as dryness/crusting and epistaxis, significantly increase in patients during the therapy schedule.

Resumo Introdução A isotretinoína (ácido-13 cis-retinóico) é o tratamento por via oral mais eficaz para acne vulgar e é a única opção de tratamento que pode produzir remissão ou cura permanente. Objetivo Usar métodos subjetivos e objetivos para avaliar as queixas nasais de pacientes com acne grave que receberam terapia com isotretinoína oral. Método Foram incluídos no estudo 54 indivíduos. Todos os indivíduos foram avaliados por meio de testes subjetivos (questionários NOSE e escala EVA) e objetivos (rinomanometria e teste de sacarina) para determinar a gravidade de suas queixas nasais. Resultados Os escores médios de gravidade (min: 0; max: 100) para ressecamento/crostas e epistaxe nasal foram de 0,47 ± 1,48 (0-5); 0,35 ± 1,30 (0-5) no início, 3,57 ± 4,45 (0-10); 2,26 ± 4,71 (0-20) no primeiro mês e 4,28 ± 6 (0-20); 2,26 ± 4,71 (0-20) no terceiro mês do tratamento, respectivamente. A resistência nasal total foi de 0,195 ± 0,079 (0,12 a 0,56) Pa/cm3/s no início, 0,21 ± 0,084 (0,12 a 0,54) Pa/cm3/s no primeiro mês e 0,216 ± 0,081 (0,14 a 0,54) Pa/cm3/s no terceiro mês. Conclusão A terapia com isotretinoína por via oral pode resultar em queixa de obstrução nasal. Além disso, queixas nasais, tais como ressecamento/formação de crostas e epistaxe, aumentam significativamente nos pacientes durante o esquema terapêutico.

Assessment of respiratory and systemic toxicity of Benzalkonium chloride following a 14-day inhalation study in rats.

BACKGROUND: Although biocides at low concentrations have been used to control pests, they can be more harmful than industrial chemicals as humans are directly and frequently exposed to such biocides. Benzalkonium chloride (BAC or BKC) is a non-toxic substance used to control pests. Recently, BAC has been increasingly used as a component in humidifier disinfectants in Korea, raising a serious health concern. Moreover, it poses significant health hazards to workers handling the chemical because of direct exposure. In the present study, we aimed to evaluate the respiratory toxicity of BAC due to its inhalation at exposure concentrations of 0.8 (T1 group), 4 (T2 group) and 20 (T3 group) mg/m3. RESULTS: In our previous study on the acute inhalational toxicity of BAC, bleeding from the nasal cavity was observed in all the rats after exposure to 50 mg/m3 BAC. Therefore, in this study, 20 mg/m3 was set as the highest exposure concentration, followed by 4 and 0.8 mg/m3 as the medium and low concentrations for 6 h/day and 14 days, respectively. After exposure, recovery periods of 2 and 4 weeks were provided. Additionally, alveolar lavage fluid was analyzed in males of the BAC-exposed groups at the end of exposure and 2 weeks after exposure to evaluate oxidative damage. In the T3 group exposed to BAC, deep breathing, hoarseness, and nasal discharge were observed along with a decline in feed intake and body weight, and nasal discharge was also observed in the T1 and T2 groups. ROS/RNS, IL-1ß, IL-6, and MIP-2 levels decreased in a concentration-dependent manner in the bronchoalveolar lavage fluid. Histopathological examination showed cellular changes in the nasal cavity and the lungs of the TI, T2, and T3 groups. CONCLUSIONS: As a result, it was confirmed that the target organs in the respiratory system were the nasal cavity and the lungs. The adverse effects were evaluated as reversible responses to oxidative damage. Furthermore, the no observed adverse effect level was found to be less than 0.8 mg/m3 and the lowest benchmark dose was 0.0031 mg/m3. Accordingly, the derived no-effect level of BAC was calculated as 0.000062 mg/m3.

Effects of oral isotretinoin therapy on the nasal cavities.

INTRODUCTION: Isotretinoin (13 cis-retinoic acid) is the most effective treatment for acne vulgaris and is the only treatment option that can provide either remission or a permanent cure. OBJECTIVE: The aim of this study was to use both subjective and objective methods to assess the nasal complaints of patients with severe acne who received oral isotretinoin therapy. METHODS: Fifty-four subjects were enrolled in the study. All the subjects were assessed with subjective (NOSE and VAS questionnaires) and objective (rhinomanometry and saccharine) tests to determine the severity of their nasal complaints. RESULTS: The mean severity scores (min: 0; max: 100) for nasal dryness/crusting and epistaxis were 0.47±1.48 (0-5); 0.35±1.30 (0-5) at admission, 3.57±4.45 (0-10); 2.26±4.71 (0-20) at the first month, and 4.28±6 (0-20); 2.26±4.71 (0-20) at the third month of the treatment respectively. Total nasal resistance of 0.195±0.079 (0.12-0.56)Pa/cm3/s at admission, 0.21±0.084 (0.12-0.54)Pa/cm3/s at the first month, and 0.216±0.081 (0.14-0.54)Pa/cm3/s at the third month. CONCLUSION: Oral isotretinoin therapy can cause the complaint of nasal obstruction. In addition, nasal complaints, such as dryness/crusting and epistaxis, significantly increase in patients during the therapy schedule.

Impact of physicochemical properties of nasal spray products on drug deposition and transport in the pediatric nasal cavity model.

The study is focused on the analysis of physicochemical properties of selected nasal sprays of mometasone furoate, and the influence of these properties on aerosol quality and penetration in the pediatric nose. After the determination of drugs surface tension and viscosity, spray geometry and size distribution of aerosol droplets, the topical delivery of each drug to different parts of the pediatric model of the nose with the flexible vestibule was evaluated by colorimetric visualization. All tested drugs are pseudo-plastic liquids, showing some differences in flow consistency constant k (range 714-1422) and flow behavior index n (range 0.16-0.31). At no-flow conditions, all sprays are deposited mainly in the anterior of the nasal cavity and the septum (2-3 cm from the nostril), as a result of inertial impaction of large droplets. The deposition range is slightly influenced by the geometry of the aerosol cloud, which, in turn, depends both on drug properties and the type of the spraying nozzle. Deposition experiments accompanied by the airflow show an enhancement of drug transport to deeper parts of the nasal cavity (up 4-6 cm from the vestibule), and this effect can be attributed to the secondary effects of spreading of the deposited liquid layer along the narrow air passages in the nose. Plume geometry, dose volume and rheological properties of the drug were shown to be important factors in the spray penetration pattern in the pediatric nose. The deepest delivery can be expected for drugs of low viscosity and short aerosol plumes.

Approximate Weight of 1:1000 Topical Epinephrine on Wrung-Out Epinephrine-Soaked Pledgets.

OBJECTIVE: Topical 1:1000 epinephrine solution is commonly applied intranasally with cottonoid pledgets in endoscopic sinonasal surgery for local vasoconstriction and hemostasis. Pledgets are typically submerged in epinephrine solution and applied without measurement. Hemodynamic complications have been reported when pledgets have been saturated and not wrung out. The amount of epinephrine absorbed per pledget has not been studied methodically. The purpose of this study was to determine the amount of topical 1:1000 epinephrine remaining on a cottonoid pledget after wringing out the pledget, to simulate intraoperative application. STUDY DESIGN: Cohort study. SETTING: Tertiary care center. SUBJECTS AND METHODS: Sixty 0.5-in × 3-in cottonoid pledgets were submerged in canisters filled with 1:1000 epinephrine solution (1 mg/mL). Weights of the epinephrine-filled canisters were measured before submerging the pledgets and then after removing and wringing out the pledgets. Measurements were recorded for each pledget after being submerged for 0, 1, and 5 minutes and then wrung out. Mean weights were calculated and compared between the submersion durations. RESULTS: The mean overall weight of epinephrine on a wrung-out pledget was 0.931 mg. Mean weights of epinephrine absorbed onto wrung-out pledgets after submersion for 0, 1, and 5 minutes were 0.914, 0.913, and 0.967 mg, respectively. There were no significant differences in weights based on submersion duration (P = .296). CONCLUSION: Approximately 1 mg of epinephrine was absorbed onto 0.5-in × 3-in cottonoid pledgets when pledgets were wrung out after being submerged in 1:1000 epinephrine, whether being removed from solution immediately or after up to 5 minutes.

Nasal Cavity Administration of Melanin-Concentrating Hormone Improves Memory Impairment in Memory-Impaired and Alzheimer's Disease Mouse Models.

Melanin-concentrating hormone (MCH) is a highly conserved neuropeptide known to exhibit important functions in the brain. Some studies have reported that MCH improves memory by promoting memory retention. However, the precise molecular mechanisms by which MCH enhances memory impairment have yet to be fully elucidated. In this study, MCH was administered to the scopolamine-induced memory-impaired mice via the nasal cavity to examine the acute effects of MCH and Alzheimer's disease (AD) mouse models to evaluate the chronic effects of MCH. MCH improved memory impairment in both models and reduced soluble amyloid beta in the cerebral cortex of APP/PS1 transgenic mice. In vitro assays also showed that MCH inhibits amyloid beta-induced cytotoxicity. Furthermore, MCH increased long-term potentiation (LTP) in the hippocampus of wild-type and 5XFAD AD mouse model. To further elucidate the mechanisms of the chronic effect of MCH, the levels of phosphorylated CREB and GSK3ß, and the expression of BDNF, TrkB and PSD95 were examined in the cerebral cortex and hippocampus. Our findings indicate that MCH might have neuroprotective effects via downstream pathways associated with the enhancement of neuronal synapses and LTP. This suggests a therapeutic potential of MCH for the treatment of neurodegenerative diseases such as AD.

Nasal Delivery Devices: A Comparative Study on Cadaver Model.

Nasal nebulization is a more effective method of delivering topical medication than nasal spray. The purpose of this study was to assess the deposition patterns of nebulization in delivering topical agents to the nasal cavities in the human cadaveric model using a color-based method. We have compared these following nasal devices: single-dose vial irrigation, syringe-irrigation, common nasal spray, Spray-sol, MAD nasal, and Rinowash nasal douche. Endoscopic images were recorded at six anatomical regions prior to and following each nasal device application and four reviewers evaluated the amount of surface area staining. At the nasal vestibule, the blue dye distribution achieved with Spray-sol was more extensive than nasal sprays. At inferior turbinate and nasal cavity floor, single dose vial, syringe, MAD nasal, Spray-sol, and Rinowash demonstrated a greater extent of dye distribution than nasal spray. At the middle turbinate, the average score of both Spray-sol and MAD nasal was significantly higher than other nasal investigated devices. At the nasopharynx, Spray-sol nebulization covers a surface significantly greater than other devices. Compared to traditional sprays, Spray-sol and MAD nasal provided a more effective method of delivering topical agents to the deeper and higher portions of the nasal cavities.

The Endothelin-A Receptor Antagonist Zibotentan Induces Damage to the Nasal Olfactory Epithelium Possibly Mediated in Part through Type 2 Innate Lymphoid Cells.

Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory click. Human side effects have been reported in the nasal cavity, so we hypothesized that the nasal cavity is a target for toxicity in mice receiving zibotentan. Lesions in the nasal cavity predominantly targeted olfactory epithelium in treated mice and were more pronounced in castrated animals. Minimal lesions were present in vehicle control animals, which suggested possible gavage-related reflux injury. The incidence, distribution, and morphology of lesions suggested direct exposure to the nasal mucosa and a possible systemic effect targeting the olfactory epithelium, driven by a type 2 immune response, with group 2 innate lymphoid cell involvement. Severe nasal lesions may have resulted in recurrent upper airway obstruction, leading to aerophagia and associated clinical morbidity. These data show the nasal cavity is a target of zibotentan when given by gavage in athymic nude mice, and such unanticipated and off-target effects could impact interpretation of research results and animal health in preclinical studies.

Menthol-induced facilitation of cerebrocortical excitatory propagation induced by air puff stimulation of the nasal cavity in the rat: An optical imaging study.

Temperature plays a critical role in the sensation of airflow in the nasal mucosa. Neural activities of the ethmoidal nerve, a trigeminal afferent, responding to airflow are suppressed by warm airflow, whereas cold airflow enhances the ethmoidal nerve activities, which is mimicked by application of menthol, a cold-sensitive TRPM8 receptor agonist. However, it has been an open issue how menthol modulates the spatiotemporal profiles of neural activities of somatosensory cortical neurons. In this study, we assessed neural responses to an air puff stimulation (100 ms) to the nasal cavity in the absence or presence of l-menthol using an optical imaging technique with a voltage-sensitive dye in the primary cortex (S1) of urethane-anesthetized rats. A weak air puff application (15 psi) without l-menthol induced neural excitation in a part of the contralateral S1. The air puff stimulation with l-menthol significantly increased the optical signal intensity, expanded the activated area, and shortened the latency, compared to those in the absence of l-menthol. These results suggest that activation of cold-sensitive TRPM8 receptors sharpens airflow sensation in the nasal cavity and expands the receptive field, especially toward the pharynx, which may contribute to enhanced flavor perception.