Intranasal Application Research Articles

Physico-Chemical and In Vitro Characterization of Chitosan-Based Microspheres Intended for Nasal Administration.

The absorption of non-steroidal anti-inflammatory drugs (NSAIDs) through the nasal epithelium offers an innovative opportunity in the field of pain therapy. Thanks to the bonding of chitosan to the nasal mucosa and its permeability-enhancing effect, it is an excellent choice to formulate microspheres for the increase of drug bioavailability. The aim of our work includes the preparation of spray-dried cross-linked and non-cross-linked chitosan-based drug delivery systems for intranasal application, the optimization of spray-drying process parameters (inlet air temperature, pump rate), and the composition of samples. Cross-linked products were prepared by using different amounts of sodium tripolyphosphate. On top of these, the micrometric properties, the structural characteristics, the in vitro drug release, and the in vitro permeability of the products were studied. Spray-drying resulted in micronized chitosan particles (2–4 μm) regardless of the process parameters. The meloxicam (MEL)-containing microspheres showed nearly spherical habit, while MEL was present in a molecularly dispersed state. The highest dissolved (>90%) and permeated (~45 µg/cm2) MEL amount was detected from the non-cross-linked sample. Our results indicate that spray-dried MEL-containing chitosan microparticles may be recommended for the development of a novel drug delivery system to decrease acute pain or enhance analgesia by intranasal application.

Comparison of Intranasal Steroid Application Using Nasal Saline Irrigation and a Mucosal Atomization Device to Treat Chronic Rhinosinusitis.

Introduction: Chronic rhinosinusitis (CRS) is a disease that can significantly reduce patients' quality of life (QoL). Intranasal steroid therapy is the most commonly used treatment for CRS. There are many evaluation tools dedicated to assessing CRS patients' QoL, but none of them evaluates QoL during local steroid therapy. Mucosal atomization devices (MADs) and nasal saline irrigation (NSI) are effective and safe methods of applying intranasal steroids for CRS patients. Materials and Methods: The sample population for this prospective study comprised 43 CRS patients. Following endoscopic sinus surgery, all participants received intranasal steroids administered via an MAD, followed by NSI for 1.5 months. Each participant completed the SNOT-22 (22-item Sino-Nasal Outcomes Test) score and a new questionnaire, the Complementary Topical Nasal Drug Delivery Questionnaire (the Complementary Questionnaire), at the end of 3 months of intranasal steroid therapy. Results: The patients' responses in both the SNOT-22 score and the Complementary Questionnaire revealed significant differences in their adverse experiences. The patients who received intranasal steroid treatment using NSI experienced more frequently delayed nasal drainage, higher frequency of ear symptoms, and facial pain/pressure, while those whose therapy was administered using an MAD reported complaints such as nasal irritation, nasal dryness, and postnasal drip with unpleasant taste/smell. Conclusion: We used the Complementary Questionnaire as an effective tool for assessment of the QoL of CRS patients. The SNOT-22 score and the Complementary Questionnaire make it possible to select an intranasal applicator tailored to a CRS patient's specific complaints.

Intranasal levosimendan prevents cognitive dysfunction and apoptotic response induced by repeated isoflurane exposure in newborn rats.

Anesthetic-induced toxicity in early life may lead to risk of cognitive decline at later ages. Notably, multiple exposures to isoflurane (ISO) cause acute apoptotic cell death in the developing brain and long-term cognitive dysfunction. This study is the first to investigate whether levosimendan (LVS), known for its protective myocardial properties, can prevent anesthesia-induced apoptotic response in brain cells and learning and memory impairment. Postnatal day (P)7 Wistar albino pups were randomly assigned to groups consisting of an equal number of males and females in this laboratory investigation. We treated rats with LVS (0.8 mg/kg/day) intranasally 30 min before each ISO exposure (1.5%, 3 h) at P7+9+11. We selected DMSO as the drug vehicle. Also, the control group at P7+9+11 received 50% O2 for 3 h instead of ISO. Neuroprotective activity of LVS against ISO-induced cognitive dysfunction was evaluated by Morris water maze. Expression of apoptotic-related proteins was detected in the whole brain using western blot. LVS pretreatment significantly prevented anesthesia-induced deficit in spatial learning (at P28-32) and memory (at P33, P60, and P90). No sex-dependent difference occurred on any day of the training and probe trial. Intranasal LVS was also found to significantly prevent the ISO-induced apoptosis by reducing Bax and cleaved caspase-3, and by increasing Bcl-2 and Bcl-xL. Our findings support pretreatment with intranasal LVS application as a simple strategy in daily clinical practice in pediatric anesthesia to protect infants and children from the risk of general anesthesia-induced cell death and cognitive declines.

Comparative pharmacodynamics of intranasal and enteral administration of captopril for uncomplicated hypertensive crises

Uncomplicated hypertensive crises without acute or progressive damage to the target organs pose a potential threat to the patient’s life and require rapid reduction of arterial pressure within hours or days in an outpatient setting. The existing protocol for the treatment of this pathology is not entirely perfect, as it does not offer the primary physician a clear and unambiguous description of the use of effective and complementary drugs. The use in these cases of nasal transport of antihypertensive active pharmaceutical ingredients in appropriate dosage forms makes it possible to ensure their rapid delivery to the bloodstream and perivascular structures of the brain.
 Based on previous experience, and taking into account biopharmaceutical research on pharmacodynamics and pharmacokinetics of captopril innovative captopril dosage form has been developed and put into practice for trasmucosal administration as 2.5 % intranasal gel with controlled releasing of captopril substance in Zaporizhzhia State Medical University.
 The aim of the research was to study the pharmacodynamics of captopril gel in patients with arterial hypertension with uncomplicated hypertensive crises.
 Materials and methods. 58 outpatients with stage 2 arterial hypertension with uncomplicated cardiac crises were surveyed, an experienced group had 30 patients aged from 38 to 69 years (average age 52.60 ± 5.03 years) with average duration of disease 11.50 ± 2.72 years, obtained the intranasal application into two nasal routes 0.5 ml 2.5 % captopril gel with a dose syringe. Comparison group had 28 patients with stage 2 arterial hypertension with uncomplicated cardiac crises aged from 37 to 65 years with duration of arterial hypertension 10.8 ± 2.63 years, obtained peroral captopril in equivalent dose. Captopril tablets 0.025 g were used as a reference drug. In the course of treatment, the indicators of office blood pressure and heart rate in the crisis state were determined after 60, 120 and 240 minutes after the use of captopril. Because of asymmetric distribution, the non-parametric method – the Wilcoxon signed-rank test – was used.
 Results. There has been a significant reduction in systolic and diastolic arterial pressure one hour after the gel’s intranasal application by 19.9 % and 23.8 % respectively, whereas, after the use of captopril in tablets, there is only a tendency to decrease systolic and diastolic pressures by 8.8 % and 11.6 % respectively. Two hours after the use of the gel, systolic and diastolic blood pressure decreased by 23.5 % and 23.5 % respectively, reaching the level recommended by the leading cardiologists of Ukraine. After oral administration of the captopril tablets, systolic arterial pressure decreased by 13 %, diastolic arterial pressure, and heart rate showed only a downward trend. Four hours after the use of the captopril gel, there was a gradual increase in systolic arterial pressure, and the level of diastolic arterial pressure remained almost the same. After application of captopril gel, the heart rate in the treatment dynamics remained unchanged, with a trend of acceleration in the first time of treatment, and decreased by 4 hours by 12.4 %.
 Conclusions. A randomized, controlled study of nasal captopril pharmacodynamics in the form of 2.5 % hydrophilic gel compared to its tableted dosage form in patients with arterial hypertension with uncomplicated hypertensive crises was carried out. It has been established that the nasal dosage form of captopril provides for the reduction of the arterial pressure to the level recommended in the case of uncomplicated hypertensive crises for 4 hours more efficiently than the oral agent. Captopril nasal gel has been shown to have good tolerance and there are practically no side effects from its use.

Intranasal administration of the chemotherapeutic perillyl alcohol results in selective delivery to the cerebrospinal fluid in rats

Perillyl alcohol (POH) has been extensively studied for the treatment of peripheral and primary brain tumors. The intranasal route of administration has been preferred for dosing POH in early-stage clinical trials associated with promising outcomes in primary brain cancer. However, it is unclear how intranasal POH targets brain tumors in these patients. Multiple studies indicate that intranasally applied large molecules may enter the brain and cerebrospinal fluid (CSF) through direct olfactory and trigeminal nerve-associated pathways originating in the nasal mucosa that bypass the blood–brain barrier. It is unknown whether POH, a small molecule subject to extensive nasal metabolism and systemic absorption, may also undergo direct transport to brain or CSF from the nasal mucosa. Here, we compared CSF and plasma concentrations of POH and its metabolite, perillic acid (PA), following intranasal or intravascular POH application. Samples were collected over 70 min and assayed by high-performance liquid chromatography. Intranasal administration resulted in tenfold higher CSF-to-plasma ratios for POH and tenfold higher CSF levels for PA compared to equal dose intravascular administration. Our preclinical results demonstrate POH undergoes direct transport from the nasal mucosa to the CSF, a finding with potential significance for its efficacy as an intranasal chemotherapeutic for brain cancer.

Chitinase-Induced Airway Hyperreactivity and Inflammation in a Mouse Model of Nonallergic Asthma

Introduction: Environmental exposure to mites and fungi has been proposed to critically contribute to the development of IgE-mediated asthma. A common denominator of such organisms is chitin. Human chitinases have been reported to be upregulated by interleukin-13 secreted in the context of Th2-type immune responses and to induce asthma. We assessed whether chitin-containing components induced chitinases in an innate immune-dependent way and whether this results in bronchial hyperresponsiveness. Materials and Methods: Monocyte/macrophage cell lines were stimulated with chitin-containing or bacterial components in vitro. Chitinase activity in the supernatant and the expression of the chitotriosidase gene were measured by enzyme assay and quantitative PCR, respectively. Non-sensitized mice were stimulated with chitin-containing components intranasally, and a chitinase inhibitor was administered intraperitoneally. As markers for inflammation leukocytes were counted in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness was assessed via methacholine challenge. Results: We found both whole chitin-containing dust mites as well as the fungal cell wall component zymosan A but not endotoxin-induced chitinase activity and chitotriosidase gene expression in vitro. The intranasal application of zymosan A into mice led to the induction of chitinase activity in the BAL fluid and to bronchial hyperresponsiveness, which could be reduced by applying the chitinase inhibitor allosamidin. Discussion: We propose that environmental exposure to mites and fungi leads to the induction of chitinase, which in turn favors the development of bronchial hyperreactivity in an IgE-independent manner.

S-ketamine and intranasal application: alternatives for the castration of male suckling piglets?

BackgroundThe intramuscular injection of ketamine and azaperone was proposed as a suitable anaesthesia for male suckling piglets for surgical castration. However, this can be opposed by massive defensive movements, hypothermia and tachycardia during castration and a long recovery period. The aim of the present study was to test whether the use of S-ketamine and/or a change in the route of application from intramuscular to intranasal could reduce stress responses and the duration of recovery compared to the intramuscular route and the use of racemic ketamine. Seventy-eight healthy, five-day-old male piglets were randomized to six treatment groups in a blinded experimental study, matched by litter and weight. Experimental groups were A (15 mg kg-1 S-ketamine + 2 mg kg-1 azaperone, i.m., surgical castration), B (15 mg kg-1 R/S-ketamine racemate + 2 mg kg-1 azaperone, i.m., surgical castration), C (30 mg kg-1 S-ketamine + 2 mg kg-1 azaperone, i.n., surgical castration), D (15 mg kg-1 R/S-ketamine racemate + 2 mg kg-1 azaperone, i.m.; not castrated), E (positive control group; no anesthesia, surgical castration) and F (negative control group; no anesthesia, not castrated).ResultsS-ketamine reduced the defensive movement score during castration to a similar extent to racemic ketamine when administered intramuscularly but not via the intranasal route. However, the effects of S-ketamine (both routes) on the increase in cortisol levels and decrease in body temperature were similar to those induced by racemic ketamine. A reduction of the long recovery time known for ketamine-azaperone anaesthesia could not be achieved with S-ketamine in the given dosage, regardless of the route of application. The intranasal administration of ketamine was difficult with the available formulation as the necessary amount exceeded the capacity of the nose cavity.ConclusionsNeither the use of S-ketamine nor intranasal administration can be suitable alternatives for the anaesthesia of male suckling piglets for castration.

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice.

Simple SummaryThe concept of utilizing mesenchymal stem cells for the treatment of central nervous system disorders has progressed from preclinical studies to clinical trials. While promising, the effectiveness of cell therapy is hampered by the route used to deliver cells into the brain. In this context, intranasal cell administration has boomed over the past few years as an effective cell delivery method. However, comprehensive safety studies are required before translation to the clinic. Our study shed light on how intranasally administrated mesenchymal stem cells may be used to safely treat neurological disorders.Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.

Immunopathogenesis and perspectives for immunotherapy of coronavirus infection

Highly pathogenic coronavirus SARS-CoV-2 is the cause of COVID-19 in humans sometimes with severe clinical manifestations and death. COVID-19 immunopathogenesis is linked with dysregulated immune response with decreased interferon synthesis at the beginning of infection followed by inflammatory cytokines hyperproduction, resulting in an exuberant lung inflammation and respiratory distress syndrome. Perspective immunotherapy directions for COVID-19 could be: intranasal recombinant interferon application in the initial stage of disease, anticytokine therapy at the stage of severe pneumonia and cytokine storm development, passive immunization with blood plasma of recovered patients or therapeutic monoclonal antibodies, prophylactic vaccination.

Effects of Virus Specific Short-Interfering RNAs on Enterovirus D68 Induced Lung Injury

Enterovirus D68 (EV-D68) is an emerging respiratory pathogen. We previously described siRNAs targeting the EV-D68 RNA dependent RNA polymerase, which were able to suppress EV-D68 replication and cytopathic effect in vitro. We sought to assess the effects of intranasal application of these siRNAs in vivo, utilizing a previously established animal model of EV-D68 infection.

Качество распыления комбинированного препарата для лечения инфекций верхних дыхательных путей

Local pharmacotherapy plays an important role in the treatment of inflammatory diseases of the throat in children. Metereddose aerosols and sprays are very popular among both doctors and patients. One of such medicines is sold under the ‘Kameton’ brand. ‘Kameton’ is a combination local drug with anti-inflammatory, antiseptic, and moderate ‘distracting’ effects ensured by its components, namely hlorobutanol, camphor, levomentholum, and eucalyptus oil. This medicine is characterized by low systemic absorption, while the combination of synthetic and natural components makes it an effective and mild-acting agent with a minimum of side effects. ‘Kameton’ is one of the few ENT medications used not only for the treatment of inflammatory diseases of the throat, but also allows intranasal application; it is recommended for children aged 5 years and older. Objective. To compare the spraying quality of ‘Kameton’ aerosols and sprays produced by different manufacturers to find an additional criterion to choose an optimal medicine of this brand. Materials and methods. We analyzed 5 medicines (metered-dose sprays or aerosols) under the ‘Kameton’ brand produced by different manufacturers. We compared the following parameters: homogeneity of the dose mass (pharmacopoeial test), reproducibility of the dose mass (relative error of the mean dose mass), and spray width. The assessment of homogeneity and reproducibility of the dose mass was performed using the Electronic Balance B2104 electronic scale. To evaluate the spray width, we used planar simulation models (paper filters impregnated with Dragendorf reagent). The spray width was estimated as the print area obtained by spraying of one dose on a planar simulation model. Results. All medicines studied met the requirements of the pharmacopoeial test for aerosols and sprays in terms of their homogeneity of the dose mass. Using the Student's t-test, we found that the relative error of the mean dose mass was approximately the same in all drugs analyzed (≈ 1%). The maximum print area and the most homogenous distribution of the medicine on the model was demonstrated by the spray produced by ‘VIPS-MED’ LLC. Conclusion. Our findings on the quality of spraying allow us to recommend ‘Kameton’ produced by ‘VIPS-MED’ LLC as the most effective drug in terms of its active component delivery to the upper respiratory tract mucosa. Key words: Kameton, spray nozzle, homogeneity of dosing, reproducibility of the dose mass, print area

Профилактика ОРВИ у новорожденных детей и их матерей в условиях пандемии новой коронавирусной инфекции

Objective. To study the prophylactic effectiveness of the intranasal application of VIFERON®, the gel for external and local use (interferon α-2b) 36,000 IU/g, against ARVI in newborns and their mothers during the COVID-19 pandemic. Patients and methods. A total of 227 mother–newborn couples were examined, randomized into three groups: Group 1 (n = 63) – the VIFERON® gel was used according to the instructions; Group 2 (n = 50) – the VIFERON® gel was used in violation of the recommended scheme; Group 3 (control, n = 114) – did not use the medication. The main criteria for the effectiveness of prevention were: the incidence of ARVI in a mother–child couple for 3 months after inclusion in the study; the duration and severity of clinical symptoms of the disease; evaluation of the frequency of adverse events associated with the use of the drug under study. Results. The use of the VIFERON® gel led to a decrease in the number of ARVI cases in mothers (11.1 and 14.9%) and newborns (7.9 and 20.2%; p = 0.034) in Group 1 compared with Group 3, respectively, as well as to a significant reduction in the duration of the disease (p = 0.001), a decrease in the severity of clinical symptoms: the level of hyperthermia (p = 0.015), the duration of febrile (p = 0.021), cough (p = 0.032), rhinitis (p = 0.033). There were no statistically significant differences between these indicators in Groups 2 and 3, which requires to follow drug instructions in order to achieve the maximum effect. The timing of onset of diseases in Group 1 in the third month of observation from the beginning of drug administration makes it possible to justify the need for repeated courses of prophylaxis at high risk of respiratory diseases. In 100% of cases, the drug was well tolerated, and there were no adverse effects. Conclusion. The high preventive efficacy and safety of interferon α-2b with antioxidants in the form of gel for external and local use (VIFERON®, gel) in newborns and their mothers against ARVI were proved, which makes it possible to recommend its use to prevent the new coronavirus infection COVID-19 in newborns and confirms the validity of its inclusion in clinical guidelines for the treatment of COVID-19 in children. Key words: prevention, ARVI, interferon α-2b with antioxidants, VIFERON® gel, mother–newborn, COVID-19

Intranasal applications in Alzheimer's treatment

Intranasal applications in Alzheimer's treatment

A method of intranasal application of a live vaccine against pasteurellosis waterfowl

A method of intranasal application of a live vaccine against pasteurellosis waterfowl

Nasal povidone-iodine implementation for preventing surgical site infections: Perspectives of surgical nurses.

Preoperative nasal decolonization of surgical patients with nasal povidone-iodine (PI) has potential to eliminate pathogenic organisms responsible for surgical site infections. However, data on implementation of PI for quality improvement in clinical practice is limited. The purpose of this study was to evaluate the implementation feasibility, fidelity and acceptability of intranasal PI solution application by surgical nurses using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) conceptual framework. Using the i-PARIHS framework to frame questions and guide interview content areas, we conducted 15 semi-structured interviews of pre- and post-operative care nurses in two facilities. We analyzed the data using deductive content analysis to evaluate nurses' experience and perceptions on preoperative intranasal PI solution decolonization implementation. Open coding was used to analyze the data to ensure all relevant information was captured. Each facility adopted a different quality improvement implementation strategy. The mode of facilitation, training, and educational materials provided to the nurses varied by facility. Barriers identified included lack of effective communication, insufficient information and lack of systematic implementation protocol. Action taken to mitigate some of the barriers included a collaboration between the study team and nurses to develop a systematic written protocol. The training assisted nurses to systematically follow the implementation protocol smoothly to ensure PI administration compliance, and to meet the goal of the facilities. Nurses' observations and feedback showed that PI did not cause any adverse effects on patients. We found that PI implementation was feasible and acceptable by nurses and could be extended to other facilities. However further studies are required to ensure standardization of PI application.

Human β-defensin-2 suppresses key features of asthma in murine models of allergic airways disease.

Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy. To elucidate the therapeutic potential of human β-defensins (hBD), such as hBD2 mild to moderate and severe asthma. We investigated the role of hBD2 in a steroid-sensitive, house dust mite-induced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with Cmuridarum (Cmu) respiratory infection. In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge. These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.

Identification of a large repetitive RTX immunogen in a highly virulent Rodentibacter heylii strain

Rodentibacter (R.) heylii is frequently detected in laboratory rodents. Repeats in toxin (RTX) toxins are considered important virulence factors of this major murine pathogen. We evaluated the virulence of a R.heylii strain negative for all known RTX toxin genes and Muribacter (M.) muris, a commensal in mice, in experimental infections of C57BL/6 and BALB/c mice. Experimental intranasal infection with 108 CFU of the pnxI-, pnxII- and pnxIII- R. heylii strain resulted in 75% and 100% mortality in C57BL/6 and BALB/c mice, respectively. In early losses, multiple internal organs were infected and purulent bronchopneumonia was the main pathology. Intranasal application of M. muris did not result in mortality or severe weight loss. Immunoproteomics led to the identification of a surface-associated and specific immunogen, which was designated as R. heylii immunogen A (RhiA) and which was exclusively recognised by sera obtained from mice infected with this R. heylii pathotype. RhiA is a 262.6 kDa large protein containing long imperfect tandem repeats and C-terminal RTX consensus sequences. Immunohistochemical analysis confirmed that this R.heylii pathotype expresses RhiA in the lower respiratory tract. In summary, this study describes a specific immunogen in a virulent R. heylii, strain which is an excellent antigen for pathotype-specific serological screenings and which might carry out RTX-related functions.

Oxytocin and Three Kinds of Dangerous Behaviors in a Romantic Relationship: Playing, Suffering, and Stalking.

Romantic relationships are an essential element of healthy living. Although difficulties in love are encountered often, it seems that three kinds of behaviors in a romantic relationship are more susceptible to physical or psychiatric disorders: playing (sexually transmitted disease), suffering (major depressive disorder or suicide), and stalking (violence or homicide). Oxytocin plays an important role in pair-bonding. Elevated plasma oxytocin concentrations have been observed in new lovers when compared with singles. It is hypothesized that those who display these dangerous behaviors in a romantic relationship might possess specific oxytocin receptor gene aberrancy and the resultant deviant pair-bonding pattern is likely to recur in successive relationships. It is postulated that a blunted oxytocin surge might be observed in playing, whereas exaggerated oxytocin surge might be observed in suffering and stalking. The distinction between suffering and stalking might stem from the difference in their aggression tendencies. Those who suffer displays aggression toward self, while those who stalk displays aggression toward others. The exaggerated oxytocin concentrations in people who suffer and people who stalk might not be suppressed by the discouraging attitudes of their partners and might be maintained by rumination. Considering the whole-body influence of oxytocin, intranasal oxytocin application or gene therapy should be used exclusively for those who display these dangerous behaviors and not for the general population. Future research is warranted to confirm this hypothesis with analysis of modifiers such as gender.

Intranasal mesenchymal stem cell therapy to boost myelination after encephalopathy of prematurity.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future.

Intranasal Application of Lactococcus lactis W136 Is Safe in Chronic Rhinosinusitis Patients With Previous Sinus Surgery.

Objective: Modulation of the dysbiotic gut microbiome with “healthy” bacteria via a stool transplant or supplementation is increasingly practiced, however this approach has not been explored in the nasal passages. We wished to verify whether Lactococcus lactis W136 (L. lactis W136) bacteria could be safely applied via irrigation to the nasal and sinus passages in individuals with chronic rhinosinusitis (CRS) with previous undergone endoscopic sinus surgery, and whether this was accompanied by bacterial community flora modification.Study Design: Prospective open-label pilot trial of safety and feasibility.Setting: Academic tertiary hospital center.Subjects and Methods: Twenty-four patients with CRS refractory to previous medical and surgical therapy received a 14-day course of BID sinus irrigations containing 1.2 × 109 CFU live L. lactis W136. Patients were monitored for safety using questionnaire, sinus endoscopy, otoscopy, UPSIT-40 smell testing, and endoscopically-obtained conventional sinus culture and a swab for 16S microbiome profiling.Results: All 24 patients receiving at least one treatment successfully completed treatment. L. lactis W136 probiotic treatment was safe, with no major adverse events or new infections. Treatment was associated with improvement in sinus symptoms, QOL, and mucosal scores, which remained improved during the subsequent 14-day observation period. Microbiome changes associated with treatment were limited to an increase of the pathobiont Dolosigranulum pigrum, a bacteria identified as potentially beneficial in the upper airways. Subgroup analysis suggested differences in microbiomes and responses for CRSsNP and CRSwNP phenotypes, but these did not attain significance.Conclusion: Intranasal irrigation of live L. lactis W136 bacteria to patients with refractory chronic rhinosinusitis was safe, and was associated with effects on symptoms, mucosal aspect and microbiome composition. Intranasal bacteria may thus find a role as a treatment strategy for CRS.Clinical Trials Registration: www.ClinicalTrials.gov. identifier: NCT04048174.