Intranasal Therapy Research Articles

Intranasal therapy and COVID-19: A comprehensive literature review

Intranasal therapy and COVID-19: A comprehensive literature review

The role of intranasal steroid therapy in the treatment of chronic sinusitis with nasal polyps

Polypoid rhinosinusitis (PRS) is a form of chronic rhinosinusitis (CRS), which is a heterogeneous group of pathological conditions based on a chronic inflammatory process of the nasal cavity and paranasal sinuses (PNS), leading to polypoid tissue formation. In most cases, T2-inflammation underlies the pathogenetic mechanism of PRS. In the presence of T2-associated conditions, the course of PRS is usually severe. The main aim of PRS treatment is to control symptoms, prolong the recurrence-free period, and restore the aeration of the PNS. The basic therapy of PRS involves the use of intranasal glucocorticosteroids (InGCS), which have a nonspecific anti-inflammatory effect by acting on different points of the pathological inflammatory process. The level of evidence for the use of InGCS is Ia: the drugs are included in Russian and foreign clinical guidelines for the treatment of polypoid rhinosinusitis. InGCS have high topical activity at low steroid doses. Mometasone furoate has an important place among this group of drugs because of its high efficacy, long-lasting therapeutic effect and optimal safety profile. The drug is officially registered for the treatment of PRS. Long-term use of mometazone furoate has been clinically observed to cause almost no atrophic nasal mucosal changes. It can be administered as monotherapy and in combination therapy over long periods of time in all phases of the treatment of PRS.

Primary Hyperparathyroidism From Ectopic Parathyroid Adenoma in a Patient With Bilateral Slipped Capital Femoral Epiphysis

Background: Primary hyperparathyroidism has been reported in 13 pediatric patients presenting with slipped capital femoral epiphysis (SCFE), but never in patients with ectopic parathyroid adenoma [1]. Case report: A 12-year-old boy with obesity (BMI 99th percentile) and autism spectrum disorder presented with a limp and was found to have bilateral SCFE. Calcium was elevated to 12.3 mg/dL (reference range 8.0–10.5) with phosphorus of 3.2 mg/dL (3.0–5.7), alkaline phosphatase 775 units/L (40–360), tubular reabsorption of phosphorus 89% (> 95%), 25OH-vitamin D 12.1 ng/mL (30–80), 1,25OH-vitamin D 246.6 pg/mL (19.9–79.3), and PTH 1191 pg/mL (10–65). He had significant neuropsychiatric agitation but denied constipation, polyuria, and other symptoms of hypercalcemia. He had in situ pinning of the SCFE bilaterally and was hyperhydrated with minimal improvement in his calcium level. Neck ultrasound revealed no parathyroid adenoma. He was discharged on cholecalciferol 1000 IU daily with plans for outpatient Tc-99m Sestamibi scintigraphy. Following discharge, he developed significant nausea, did not tolerate the cholecalciferol, and was non-weight bearing. Repeat labs and imaging 5 days later demonstrated calcium had risen to 16.7 mg/dL with phosphorus of 2.2 mg/dL. He was admitted and calcium improved transiently to less than 12 mg/dL with intranasal calcitonin therapy. Sestamibi and subsequent CT scan revealed a 2.7x1.6x1.9 cm ectopic parathyroid adenoma in the upper anterior mediastinum. He had thoracoscopic resection of the mass, which was revealed to be intrathymic, and PTH levels fell from 1613 pg/mL pre-operatively to 76 pg/mL 30 minutes post-resection. Post-operatively, he developed hungry bone syndrome with a calcium nadir of 7.6 mg/dL and phosphorus nadir of 1.6 mg/dL, which required oral calcium and calcitriol for 10 days. With normalization of his calcium, his neuropsychiatric symptoms improved. Pathology revealed a parathyroid adenoma. Conclusion: Primary hyperparathyroidism can be associated with SCFE and should be considered even in patients with traditional risk factors for SCFE, especially with bilateral disease. Pediatric patients with primary hyperparathyroidism and negative neck imaging should be further evaluated for ectopic parathyroid adenomas.

Transcranial and Intranasal Photobiomodulation for Treating Dementia Symptoms

There is currently no cure for dementia. Moreover, the available pharmacological medications for dementia only offer limited symptomatic relief and have considerable side effects. Photobiomodulation (PBM) is a therapeutic modality that uses radiant light energy to modify biological functions. The goal of this study was to replicate and build upon a previously published case series report describing improved cognitive function in five patients with mild-to-moderate dementia after 12 weeks of transcranial and intranasal PBM therapy.

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.

A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19.

BackgroundCoronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.MethodsWe conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1–4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.FindingsThe trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.InterpretationUNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.FundingThe study was funded by Innovationsfonden Denmark and UNION therapeutics.

Regulation of Metabolic Health by an “Olfactory-Hypothalamic Axis” and Its Possible Implications for the Development of Therapeutic Approaches for Obesity and T2D

The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.

Allergic rhinitis as a comorbid disease with Covid-19 infection

Allergic rhinitis (AR) is the most common disease (28.3%) among allergic pathology. Coronavirus disease 2019 (Covid-19) is characterized by a variety of clinical conditions ranging from mild symptoms to severe pneumonia and death. Nasal and ocular manifestations are included in the number of possible manifestations of Covid-19, therefore differential diagnosis of AR and coronavirus infection is important. The penetration of the Sars-CoV-2 virus occurs through the nasal and oral mucosa; scientists have paid close attention to the local immunity of these mucous membranes. Respiratory allergies have not been reported as risk factors for SARS- CoV-2 infection. Intranasal corticosteroids have a dose- dependent suppression of the expression of both ACE2 and the transmembrane protease, serine 2. Respiratory allergy (AR, asthma) and controlled exposure to allergens are associated with a significant decrease in ACE2 expression. Patients with Covid-19 infection need to continue intranasal corticosteroid treatment at the recommended dose for AR, as more frequent sneezing after cessation means more spread of SARS-CoV-2 infection. The importance of adhering to inhaled and intranasal corticosteroid therapy, which will achieve optimal control of upper and lower respiratory tract diseases, and may also provide protection against viral triggers, including SARS-CoV-2. Allergic rhinitis is not a contraindication for Covid-19 vaccination.

Efficacy of intranasal olopatidine hydrochloride as an add on therapy in mild to moderate allergic rhinitis

Background: Treatment with intranasal olopatidine hydrochloride spray is proposed for patients with chronic perennial and seasonal rhinitis. Hence we compared the efficacy of intranasal mometasone furoate as an add-on therapy with existing standard treatment in a randomized, open label comparative study.Methods: A prospective, randomized, single blinded, comparative study in patients with chronic perennial and seasonal rhinitis. Patients were divided into two groups to receive intranasal olopatidine therapy and intranasal saline plus existing standard treatment with levocetrizine and vitamin C orally. Improvement in symptoms like nasal obstruction, nasal discharge, sneezing, nasal itching, itching of eyes, watering of eyes were assessed by a questionnaire at 2, 4, 6 and 8 weeks and by a reduction of eosinophil count in blood and nasal smear examination at baseline and 8 weeks.Results: At the end of 8 weeks the percentage reduction of nasal obstruction in olopatidine hydrochloride and saline were 93.1% and 36.07% respectively, rhinorrhoea was 90.34% and 36.42%, nasal itching was 85.76% and 41.37% sneezing symptoms were 89.6% and 37.86%, itching in the eyes was 94.6% and 44.05% and watering in the eyes were 87.1% in group A and 38.07% in group B. At the end of 8 weeks, there was reduction in absolute eosinophil count and it attributed to 57.5% in olopatidine hydrochloride and 11.9% in saline group and reduction in nasal smear count scoring was 60.7% and 18.2% respectively.Conclusions: Intranasal olopatidine hydrochloride is highly effective, in the treatment of allergic rhinitis.

Association of intranasal desmopressin therapy with overcorrection of severe hyponatremia: A retrospective, propensity score-based, single-center cohort study.

Severe hyponatremia, defined as serum sodium concentration ([sNa]) ≤ 120 mEq/L, requires aggressive treatment to prevent potentially fatal cerebral edema, seizures, and other sequelae, but overcorrection can also result in life-threatening cerebral hemorrhage and demyelination. We compared the safety and efficacy of nasal desmopressin to conventional management for the prevention of [sNa] overcorrection. This retrospective analysis compared 47 patients treated with desmopressin to 17 patients treated conventionally at a university hospital ICU in Japan between 2013 and 2018 using propensity score-based approaches. The primary outcome was safe [sNa] correction, defined as a ≤ 8 mEq/L difference between baseline and follow-up [sNa] at any time within 24h of diagnosis. The 24-h safe correction rate was significantly greater in the desmopressin group than the conventional treatment group (68% [32/47] vs. 41% [7/17], P = 0.039), and dose-response analysis indicated a positive association between cumulative 24-h desmopressin dose and safe correction at 24 h (P = 0.003). Few overcorrections precluded reliable assessment at 48 h. Exacerbation of hyponatremia was comparable in the two treatment groups. Intranasal desmopressin therapy increased the safe correction of severe hyponatremia. Large prospective trials are warranted to confirm this result.

Chronic rhinitis in children is not a local problem

Allergic rhinitis is the most common pathology among all allergic diseases. The article presents the epidemiologic and pathogenetic issues of the allergic rhinitis. The underdiagnosis of allergic rhinitis and its underestimation as a systemic pathology were observed in various countries. The importance of allergic rhinitis in paediatric practice, its impact on the quality of life, studies, and cognitive abilities is considered. The extranasal manifestations of the disease, as well as the role of allergic rhinitis in the development of increased respiratory viral morbidity are assessed. The differences between allergic and vasomotor rhinitis (non-allergic non-infectious rhinopathy) are analysed. Frequent interdependence and interaction of the allergic and vasomotor rhinitis are stressed. The signs of nonspecific hyperreactivity of the upper respiratory tract affected by the allergic rhinitis are presented. The role and importance of decongestants in the treatment of both allergic and vasomotor rhinitis are discussed in detail. Vasoconstrictors would help reduce hyperemia and nasal mucosa oedema, reduce the level of mucus secretion, improve the drainage of paranasal sinuses, normalizing the pressure in them. The use of a combination drug – a sympathomimetic combined with a local antihistamine agent would be the most appropriate treatment for patients with AR. The use of intranasal combination therapy for allergic rhinitis is justified: a sympathomimetic phenylephrine combined with a blocker of H1-histamine receptors dimethindene. The insights into the safety and efficacy of above drug combination in paediatric practice are presented. The use of a combination intranasal drug based on phenylephrine and dimethindene in patients with allergic rhinitis is justified in paediatric practice as both symptomatic and pathogenetic treatment. It is also advisable to administer it to treat acute respiratory viral diseases, in the post-viral period with situational exacerbations of the vasomotor component.

A Herbal Formula in the Therapy of Acute Postviral Rhinosinusitis.

Objective:To assess the effects and adverse events of preparation Sinulan forte® containing extracts of five medicinal plants in comparison to mometasone furoate nasal spray (MFNS) in therapy of acute postviral rhinosinusitis (APRS).Methods:We included 46 APRS patients in this prospective investigation and randomized to two groups. The patients in group 1 (n=23) received MFNS 200 μg two times/day for ten days, and patients in group 2 (n=23) received Sinulan forte®, tablets 225 mg per os, two times/day also for ten days. We evaluated the total symptom score (TSS), the separate scores for individual symptoms (nasal congestion, rhinorrhea, postnasal discharge, facial pain, impaired sense of smell), the quality-of-life outcome, and the findings from nasal endoscopy (edema of the nasal mucosa, nasal secretion) prior and after the therapy.Results:Significantly lower absolute post-treatment scores and better relative improvement were identified for TSS, nasal congestion, facial pain, loss of the sense of smell, edema of the mucosa and nasal secretion in patients receiving herbal preparation (group 2). However, lower absolute post-treatment score and better relative improvement were found for rhinorrhea and postnasal drip in group 1. Clinically important differences were found regarding the TSS and endoscopic findings, with no adverse effects in group 2, but in group 1 two patients had mild nasal bleeding and two had sensation of dryness in the nasal mucosa.Conclusion:Herbal product Sinulan forte® can be a safe and effective treatment for APRS. Our results suggest no adverse events of this herbal preparation in comparison to intranasal corticosteroid spray therapy.

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.

Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity.

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP.

코로나바이러스감염증-19에서 나타나는 후미각손상의 특성과 한의학적 분석

Besides respiratory infection, COVID-19 has many neurological symptoms not only loss of smell and taste but also fatigue and brain fog. But it is a challenge to treat the neurological symptoms especially of anosmia and ageusia. In order to search for the therapeutic methods, the geographical diversity and pathological mechanisms of the COVID-19 and two symptoms were investigated from the latest clinical studies. Because the environmental conditions of the monsoon climate zone of East Asia and the Mediterranean and Oceanic climate zone of Italy, Britain, United States and tropical Brazil are different, each of diverse etiology and internal milieu should be considered differently in the treatment. SARS-CoV-2 exhibits the dampness-like characteristics and the olfactory and gustatory disorders are particularly more common than other flu or cold. and it tends to show features of damaging the lung qi of olfaction and heart-spleen qi of gustation. The mechanisms of olfactory and gustatory loss are various according to precursory, inflammatory, non-inflammatory and sequelar forms, so the therapeutic method should be designed for each period and pathology. If the process of inflammation arises from nasal and respiratory, olfactory epithelium to the central nervous structure by way of blood brain barrier, the treatment should be corresponded with the stage and depth of pathogen place. And if the olfactory loss is asymptomatic or in the initial stage, it can be applied intranasal topical scent therapy to relieve temporary locking of qi movement, but maybe also used in parallel together with herbs of relieving dampness toxin latent in the lung parenchyma.

Enhanced Mesenchymal Stromal Cells or Erythropoietin Provide Long-Term Functional Benefit After Neonatal Stroke.

Perinatal stroke is a common cause of life-long neurobehavioral compromise. Mesenchymal stromal cells (MSCs) and EPO (erythropoietin) have each demonstrated short-term benefit with delayed administration after stroke, and combination therapy may provide the most benefit. The purpose of this study is to determine the long-term histological and functional efficacy of enhanced, intranasal stem cell therapy (MSC preexposed to EPO) compared with standard MSC or multidose systemic EPO. Transient middle cerebral artery occlusion or sham surgery was performed in postnatal day (P) 10 Sprague-Dawley rats, who were treated with single-dose intranasal MSC, MSC preexposed to EPO (MSC/EPO), multidose systemic EPO (EPO3; 1000 u/kg per dose×3 every 72 hours), or cell-conditioned media on P13 (day 3 [P13-P19] for EPO), or on P17 (day 7 [P17-P23] for EPO). At 2 months of age, animals underwent novel object recognition, cylinder rearing, and open field testing to assess recognition memory, sensorimotor function, and anxiety in adulthood. MSC, MSC/EPO, and EPO3 improved brain volume when administered at 3 or 7 days after middle cerebral artery occlusion. MSC/EPO also enhanced long-term recognition memory with either day 3 or day 7 treatment, but EPO3 had the most long-term benefit, improving recognition memory and exploratory behavior and reducing anxiety. These data suggest that single-dose MSC/EPO and multidose systemic EPO improve long-term neurobehavioral outcomes even when administration is delayed, although EPO was the most effective treatment overall. It is possible that EPO represents a final common pathway for improved long-term repair, although the specific mechanisms remain to be determined.

Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models

Autism spectrum disorder (ASD) is a continuum of neurodevelopmental disorders and needs new therapeutic approaches. Recently, oxytocin (OXT) showed potential as the first anti-ASD drug. Many reports have described the efficacy of intranasal OXT therapy to improve the core symptoms of patients with ASD; however, the underlying neurobiological mechanism remains unknown. The OXT/oxytocin receptor (OXTR) system, through the lateral septum (LS), contributes to social behavior, which is disrupted in ASD. Therefore, we selectively express hM3Dq in OXTR-expressing (OXTR+) neurons in the LS to investigate this effect in ASD mouse models developed by environmental and genetic cues. In mice that received valproic acid (environmental cue), we demonstrated successful recovery of impaired social memory with three-chamber test after OXTR+ neuron activation in the LS. Application of a similar strategy to Nl3R451C knock-in mice (genetic cue) also caused successful recovery of impaired social memory in single field test. OXTR+ neurons in the LS, which are activated by social stimuli, are projected to the CA1 region of the hippocampus. This study identified a candidate mechanism for improving core symptoms of ASD by artificial activation of DREADDs, as a simulation of OXT administration to activate OXTR+ neurons in the LS.

The role of topical therapy in the treatment of acute otitis media in children

Acute otitis media is a common disease in children and accounts for about 2% of the total child morbidity. In the largest percentage of cases, acute otitis is usually successfully resolved, but its relapses increase the possibility of complications and lead to higher treatment costs, as well as lower quality of life for both the patient and his or her family in general. Therapy of acute otitis media depends on the stage of disease development and clinical manifestations and is aimed at early resolution of inflammatory process and prevention of disease progress and complications development. Pathogenetic therapy is shown at the 1 st and 2 nd stages of development of acute otitis media and is based on restoration of auditory tube function and normalization of nasal breathing (unloading – intranasal therapy). As a local analgesic therapy for acute otitis media in children, ear drops containing non-opioid analgesic antipyretic drug phenazone and lidocaine, consisting of a combination of phenazone (40 mg) and lidocaine hydrochloride (10 mg), are most commonly used. Phenazone is a nonsteroidal anti-inflammatory drug and has an anti-inflammatory effect, typical for non-selective inhibitors of cyclooxygenase, while lidocaine has a local analgesic effect. Based on the clinical trials conducted, it was recommended to include combined topical drugs as a local analgesic and anti-inflammatory drug with effective action and good tolerability in all age groups into the combined therapy of acute preperforative otitis media.

Adjuvant effect of low-carbohydrate diet on outcomes of patients with recurrent glioblastoma under intranasal perillyl alcohol therapy.

Background: Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.Methods: To investigate LCD’s effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients. This study involved 29 individuals and evaluated, over a period of 1 year, the adjuvant effect of LCD associated with POH therapy in terms of toxicity, extent of peritumoral edema, reduced corticosteroid use, seizure frequency, and overall survival. POH group (n = 14) received solely intranasal POH without specific diet regimen, whereas POH/LCD group (n = 15) received intranasal POH in combination with nutritional intervention. Patients’ assessment was based on clinical reviews and magnetic resonance data.Results: In the 1-year follow-up, the POH/LCD group showed a 4.4-fold decrease in the proportion of patients who needed treatment with corticosteroids, as well as a reduction in tumor size and peritumoral edema, as compared to the POH group. While 75% of patients undergoing POH treatment experienced seizures, this fraction was reduced to 56% in the POH/LCD group. A 2.07-fold increase in the proportion of patients with stable disease, along with a 2.8-fold decrease in the proportion of patients with TP, was seen in the POH/LCD group.Conclusion: The results presented in this study show that the LCD associated with intranasal POH therapy may represent a viable option as adjunctive therapy for rGB to improve survival without compromising patients’ quality of life. Prospective cohort studies are needed to confirm these findings and validate the efficacy of this novel therapeutic strategy.

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.