Mechanisms and solutions for nasal drug delivery - a narrative review.

The aim of this paper is to review mechanisms and solutions for nasal drug delivery. Literature survey was performed via PubMed, Google Scholar, Google, and ProQuest Central database of Kirikkale University. The nasal lining presents a large area of endothelium of variable permeability and with a rich vascular supply. Advantages of this route include eliminating first-pass metabolism and being easily accessible. The nasal route enables some agents which are otherwise difficult to administer to enter the systemic circulation, for example, low molecular mass compounds with high polarity, peptides, or proteins. There are three principal factors that influence the extent to which drugs can be absorbed through the nasal lining, namely the physico-chemical characteristics of the drug molecule itself, the action of the mucociliary system within the nose, and the presence of any factors increasing nasal absorption. A key factor limiting the use of the intranasal route of administration is insufficient absorption through the nasal mucosa. A number of drugs in development cannot be administered intranasally because their bioavailability following nasal administration is too low. There has been considerable research focus on methods to enhance absorption via the nasal mucosa. In this chapter, we review the literature related to this problem and discuss potential solutions.

Lactoferrin: a potential candidate to fight respiratory infections in the pandemic COVID-19 era.

Respiratory infections are a significant burden at any age, but especially in childhood and aging. The COVID-19 pandemic has worsened the issue since there is no specific treatment and vaccine is not available. Moreover, respiratory symptoms cause social stigma in subjects suffering from an infection of any kind. As new drugs require a very long time to be marketed, a natural compound's interest is growing. In this regard, lactoferrin is a multifunctional protein present in secretions, mainly in breast milk. Lactoferrin has marked antimicrobial activity, including antibacterial, antiviral, antiparasitic, and antifungal. Moreover, lactoferrin strongly affects immune response and cellular control activity. Therefore, this natural component could provide a promising effect in preventing respiratory infections and potentially also for COVID-19.

Can Pseudomonas aeruginosa growth be modulated by natural compounds?

Pseudomonas aeruginosa is an opportunistic human pathogen that frequently induces antibiotic resistance, as it mainly tends to form biofilms. Iron chelation may be an intriguing strategy to contrast bacterial growth. Lactoferrin is a natural compound able to chelate iron. A new multi-component medical device also contains lactoferrin. This study analyzed this compound investigating the in vitro capacity to inhibit Pseudomonas aeruginosa growth. In conclusion, this study demonstrated that a multicomponent medical device (Saflovir), also containing lactoferrin, could inhibit the in vitro growth of P. aeruginosa. This activity could be positively used in the prevention of respiratory nasal infections.

The impact of Allergic Rhinitis in clinical practice: An International Survey.

Allergic rhinitis (AR) is a frequent disease caused by an IgE-mediated inflammation of the nose and characterized by typical symptoms. Diagnostic workup is directed to document the production of specific IgE (sensitization). Clinical management aims to relieve symptoms, resolve allergic inflammation, use medications, and potentially induce allergen tolerance, using allergen immunotherapy (AIT). The current survey was conducted in 17 International ear nose throat experts using a questionnaire with 20 questions concerning the practical management of AR patients. It was administered in the 2020 summer. The large majority (94%) of participants use the ARIA classification in clinical practice. On average, subjects with suspected AR represent half of the patients who turn to the ENT experts; 80% have the confirmed diagnosis. Most of the experts use both cutaneous and serum assay to document IgE production. Antihistamines are prescribed in 59% of AR patients, intranasal corticosteroids in 69%, non-adrenergic decongestants in 88%, nasal lavage in 88%, and AIT in 22%. About 68% of AR patients had turbinate hypertrophy, which requires surgery in 62% (mostly surgical decongestion). In conclusion, the current International Survey demonstrated that AR is a common disorder worldwide, the diagnostic workup is mainly based on IgE assessment, and the therapeutic approach is also based on non-pharmacological remedies.

The management of chronic rhinosinusitis in clinical practice: An International Survey.

Chronic rhinosinusitis (CRS) is a common disease and is currently classified in two main phenotypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). A panel of international experts conducted the present survey. A questionnaire, containing 25 questions, was completed by each member of the panel. About half of patients with suspected CRS had confirmed diagnosis. CRSwNP affected 31% of CRS patients. Endoscopy and CT were ever performed. Rhinitis and asthma were frequent comorbidities. Intranasal corticosteroids were prescribed on average in 86% of patients. Nonadrenergic compounds were prescribed by 71% of experts. Surgery for CRSwNP was performed in about half of patients; repeated intervention occurred in about one/third. In conclusion, the current survey demonstrated that CRS requires thorough diagnostic work-up, and the most common therapeutic approach is mainly based on intranasal corticosteroids, non-adrenergic decongestants, and surgery.

Laryngopharyngeal reflux management in clinical practice.

Laryngopharyngeal reflux (LPR) is an inflammatory reaction of the mucosa of the pharynx, larynx, and other associated upper respiratory organs, caused by a reflux of stomach contents outside the esophagus. LPR is considered a relatively new clinical entity with a vast number of clinical manifestations that are sometimes treated empirically and without a correct diagnosis. Alginate is a reasonable therapeutic option as a first-line or add-on option. A survey included 35 Italian otorhinolaryngologists. The survey considered ten practical queries. LPR is a common disease in clinical practice. History and fiber-optic endoscopy constitute the main diagnostic tools. Alginates represent a frequent medication to treat LPR both as first-line and add-on. The mean effectiveness rate is 44% for first-line choice and 76% for the add-on. In conclusion, the current survey provided exciting information about the management of LPR in clinical practice.

The efficacy and tolerability of Streptococcus salivarius 24SMB and Streptococcus oralis 89a administered as nasal spray in the treatment of recurrent upper respiratory tract infections in children.

OBJECTIVE: Nasal administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a has been proposed to reduce the risk of new episodes of adenoiditis, tonsillitis and acute rhinosinusitis in children. PATIENTS AND METHODS: We enrolled 202 children with a recent diagnosis of recurrent upper respiratory tract infection. All the patients were treated twice daily for 7 days each month for 3 consecutive months with a nasal spray whose active agents were two specific bacterial strains: Streptococcus salivarius 24SMB and Streptococcus oralis 89a. Evaluation was performed at the end of treatment and at follow-up at 3, 6, and 12 months. RESULTS: Patients who completed the entire 90-day course of bacteriotherapy and the follow-up period showed a 64.3% reduction in their episodes of upper respiratory tract infections compared to the number of episodes recorded in the previous year. Treatment decreased the reported incidence of infection events by 52.4% in the first 3 months, 31.2% at 6-month follow-up, and 20.8% after 12 months. Enrolled patients tolerated the product well, and there were no dropouts. CONCLUSIONS: Prophylactic bacteriotherapy by administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a in children with a history of recurrent upper respiratory tract infection could reduce the number of episodes of otolaryngologic infections. Bacteriotherapy can be even more clinically important due to increasing difficulty in finding new effective antibiotic compounds. New alternative therapeutic approaches must be found with, in comparison to antibiotics, greater specificity and safety with respect to patients' native beneficial flora; lack of drug interactions; the ability to leverage complementary systemic modes of action; and drastically reduced risk of developing resistance within the patient population and the environment.

Obstructive sleep apnea syndrome in the pediatric age: the role of the pneumologist.

OBJECTIVE: This review paper aims to summarize the current state of knowledge on the role of the pneumologist in the diagnosis and respiratory treatment of children affected by obstructive Sleep Disordered Breathing (SDB). MATERIALS AND METHODS: A literature review has been performed on the following topics: obstructive SDB and its clinical entities, indications for respiratory treatment of pediatric SDB, and Continuous Positive Airway Pressure (CPAP) and Noninvasive Positive Pressure Ventilation (NIPPV) treatment approach to obstructive SDB. RESULTS: OSDB is related to obesity, craniofacial pathologies, neuromuscular disorders and, most commonly, oadenotonsillar hypertrophy. Adenotonsillectomy is the first-choice treatment in children with obstructive apnea secondary to adenotonsillar hypertrophy. CPAP and NIPPV are recommended in cases where Obstructive Sleep Apnea (OSA) persists after surgery or when surgery is contraindicated. Treatment interventions are usually implemented gradually by separately addressing each abnormality that would predispose to obstructive SDB, then reevaluating after each intervention to detect any residual disease and to assess the need for additional treatment. CONCLUSIONS: Many pediatric patients continue to experience problems and symptoms such as hypersomnia and apnea after adenotonsillectomy and need CPAP/NIPPV treatment. Current knowledge is still incomplete, especially with regard to the mechanisms of pathogenesis of pediatric OSA, the factors affecting pediatric OSA, and the phenotypic variability of the disease. A better understanding of these aspects would contribute to the development of new therapies.

The role of bacteriotherapy in the prevention of adenoidectomy.

OBJECTIVE: Adenoidectomy is a surgical procedure with potential adverse events. Effective nonsurgical therapy could reduce patient risk and harm. The aim of this study was to evaluate the role of bacteriotherapy to reduce the necessity of adenoid surgery. PATIENTS AND METHODS: This experimental study was conducted as an open study in 44 children (30 males and 14 females, mean age 4.9 years) who were candidates for adenoidectomy and tympanocentesis as treatment for adenoidal hypertrophy and otitis media with effusion. Twenty-two children were treated with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray, administered as 2 puffs per nostril twice a day for a week for 3 months (study group). The other half of the children was treated with hypertonic saline nasal lavage on the same schedule (control group). Tympanometry and adenoid size assessment were evaluated throughout the intervention period. RESULTS: In the study group, 6/22 children required surgery, compared to 20/22 children in the study group (p<0.0001). The clinical change in the treated children was a significant reduction of adenoid size (p<0.0001) and improvement of middle ear effusion measured with tympanometry (p<0.0001). CONCLUSIONS: Bacteriotherapy with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray could significantly reduce the need for adenoid surgery.

Bromelain's penetration into the blood and sinonasal mucosa in patients with chronic rhinosinusitis.

SUMMARY: The aim of this research is to investigate penetration of Bromelain into sinonasal mucosa in patients with chronic rhinosinusitis (CRS) versus a control group. Bromelain is derived from pineapple (Ananas comosus) and has various pharmacological effects. 40 patients (20 patients and 20 controls) were enrolled in the study. Bromelain 500 mg tablet twice daily was administered for 30 days. We scored bromelain presence in turbinate and ethmoid mucosas and in the serum of both the groups. Bromelain has an excellent distribution from blood to rhinosinusal mucosa. Its diffusion ability may allow the use of bromelain as an anti-inflammatory agent in paranasal sinus pathologies.

Glycyrrhetinic acid suppressed hmgb1 release by up-regulation of Sirt6 in nasal inflammation.

To extend our understanding of previous studies on the pathogenesis and mechanism of high mobility group box 1 (HMGB1) in chronic rhinosinusitis with nasal polyps (CRSwNP), here we show that Sirtuin 6 (Sirt6), one of the Sirtuin family members which are widely studied in aging, DNA repair, metabolism, inflammation and cancer, was expressed in normal nasal mucosa using immunohistochemical staining and Western blot assay. Sirt6 expression levels were decreased in CRSwNP tissue. Sirt6 expression levels were modulated by small interfering RNA transfection in human nasal epithelial cells (HNE). We found that depletion of Sirt6 suppressed the number of human nasal epithelial cell cilia, and dramatically induced HMGB1 translocation from nucleus to cytoplasm in the HNE cells. Glycyrrhizic acid (GA) and glycyrrhetinic acid (GTA) are specific chemical compounds that may be isolated from the licorice plant. GTA has been shown to have anti-inflammatory and anti-allergic activity: it binds selectively to HMGB1 protein released extra-cellularly and inhibits its cytokine activities through a scavenger mechanism on the protein accumulation. In an in vitro study we used the 18-ß-stereoisomer of GTA to enhance Sirt6 expression levels, inhibiting through this mechanism the translocation of HMGB1 protein from nucleus and reversing its extracellular accumulation stimulated by lipopolysaccharides. These findings reveal a previously unknown role for nasal mucosa steady-state conditions in the control of Sirt6 activity, and provide evidence for a relationship between HMGB1 and Sirt6 in CRSwNP, and promising benefits of glycyrrhetinic acid for CRSwNP patients.

Salivary biomarkers and proteomics: future diagnostic and clinical utilities.

Saliva testing is a non-invasive and inexpensive test that can serve as a source of information useful for diagnosis of disease. As we enter the era of genomic technologies and -omic research, collection of saliva has increased. Recent proteomic platforms have analysed the human salivary proteome and characterised about 3000 differentially expressed proteins and peptides: in saliva, more than 90% of proteins in weight are derived from the secretion of three couples of "major" glands; all the other components are derived from minor glands, gingival crevicular fluid, mucosal exudates and oral microflora. The most common aim of proteomic analysis is to discriminate between physiological and pathological conditions. A proteomic protocol to analyze the whole saliva proteome is not currently available. It is possible distinguish two type of proteomic platforms: top-down proteomics investigates intact naturally-occurring structure of a protein under examination; bottom-up proteomics analyses peptide fragments after pre-digestion (typically with trypsin). Because of this heterogeneity, many different biomarkers may be proposed for the same pathology. The salivary proteome has been characterised in several diseases: oral squamous cell carcinoma and oral leukoplakia, chronic graft-versus-host disease Sjögren's syndrome and other autoimmune disorders such as SAPHO, schizophrenia and bipolar disorder, and genetic diseases like Down's Syndrome and Wilson disease. The results of research reported herein suggest that in the near future human saliva will be a relevant diagnostic fluid for clinical diagnosis and prognosis.

Position paper on olfactory dysfunction.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

New olfactometric findings in Parkinson's disease.

OBJECTIVES: To investigate in Parkinson's disease-affected patients a correlation between hyposmia and gastrointestinal dysfunction and their possible identical etiopathogenesis. DESIGN: Retrospective cohort study. SETTING: ENT and neurology departments (Gemelli Hospital, Rome, Italy). PARTICIPANTS: A total of 78 patients with diagnosis of PD according to the UK Brain Bank criteria. INCLUSION CRITERIA: informed consent and olfactory testing executed; exclusion criteria: signs of dementia according to the DSM-IV criteria; Mini Mental State Examination score ≤26; head trauma; central neurological disorders, nasal or systemic diseases potentially affecting olfactory function. Motor condition was assessed by means of Hoehn and Yahr staging and by section III of the Unified PD Rating Scale, performed off and on medications. MAIN OUTCOME MEASURES: The patients underwent olfactory evaluation (TDI score), after rhinomanometry with nasal decongestion. A total of 25 non-motor symptoms were evaluated through an interview. RESULTS: Olfactory dysfunction was objectively found in 91.0% of patients, a percentage higher than the subjective hyposmia reported (55.1%) P = 0.0001. Seven patients (9.0%) were normosmic, 49 (62.8%) hyposmic and 22 (28.2%) anosmic. Subjective hyposmia, constipation, bloating and dyspepsia differed across groups, being higher in anosmic and hyposmic ones than in the normosmic group. P value was ≤0.05 for each symptom. Despite the original results, this study has the limitation of being based on subjective ratings by a relatively limited group of patients. CONCLUSIONS: Hyposmia and gastrointestinal symptoms are correlated, and this would support a possible common origin; the CNS could be reached through two different pathways, both starting in the peripheral nervous system.

Values of SP-A protein in the nasal mucosa.

The paranasal sinus epithelium is exposed to the environment and therefore to a variety of biological, chemical and mechanical insults. Surfactant protein A (SP-A) is a 34-36 kD pulmonary surfactant-associated protein that appears to play an important role in mammalian first-line host defence. Recent studies have reported the possibility of local production of SP-A in the extrapulmonary organs and tissues of the human body. However, the presence of SP-A in the human paranasal sinus mucosa is not well known. The purpose of this study was to investigate the expression of SP-A protein in human turbinate mucosa and to compare the expression of SP-A mRNA in normal turbinate mucosa and turbinate mucosa of chronic rhinosinusitis patients. Reverse transcriptase polymerase chain reaction was used to detect SP-A mRNA. Student's t test was used for statistical comparison of the SP-A/GAPDH-mRNA ratio (GAPDH: glycerinaldehyde-3-phosphate dehydrogenase) of cases and controls. We found expression of SP-A mRNA in mucosa lining the inferior turbinates of healthy patients and its up-regulation in mucosa lining the inferior turbinates of patients with chronic rhinosinusitis. These results may provide targets for new therapies for chronic rhinosinusitis.

Radiofrequency volumetric inferior turbinate reduction: long-term clinical results.

The aim of our study was to assess long-term results of radiofrequency volumetric tissue reduction of inferior turbinates (RVTR). We performed a prospective long-term longitudinal evaluation of 305 patients affected by rhinitis (114 allergic and 191 non-allergic) who were unresponsive to medical treatment and underwent RVTR (January 2004 - December 2010). Subjects were followed for a mean period of 39.70 ± 19.41 months (range 24-60). Patients completed the NOSE-scale questionnaire pre- and post-operatively after 1 month and yearly for 5-years. Recurrence was assumed if the post-operative total NOSE score increased by at least 75% during follow-up and the patient restarted medical treatments. Estimation of relapse over time was performed by Kaplan-Meyer analyses. We documented overall good satisfaction of patients regarding the procedure, with a good rate of pain control and a low rate of complications. Post-operatively there was a significant improvement in nasal stuffiness, nasal obstruction and mouth breathing (p < 0.05). We observed a worsening trend for symptoms after 36 months with progressive increasing rate of recurrences that were significantly higher in allergic than non-allergic patients (p < 0.05). We also observed a slight worsening trend of global satisfaction of patients. Our study confirms the minor discomfort and low risk of side effects of RVTR. Our data showed good efficacy of the procedure in the majority of patients for at least 36 months after surgery, and in fact in this time period the cumulative probability to remain relapse-free was up to 0.8. In the following 2 years, we observed a worse temporal trend in term of recurrence rate, and in particular in allergic patients with a significant difference vs non-allergic individuals (p < 0.05).

Managing turbinate hypertrophy: coblation vs. radiofrequency treatment.

The role of inferior turbinate hypertrophy in the reduction of nasal airflow is well established. Although chronic nasal obstruction is not life- threatening, it significantly impairs patients' quality of life, affecting many aspects of daily activities; therefore, patients seek medical intervention. 40 patients were selected (27 males and 13 females) between 27 and 64 years of age with a symptom of nasal obstruction. The patients were divided in two groups: Group 1: coblation, 25 patients (18 males and 7 females); Group 2: radiofrequency, 15 patients (7 males and 6 females). These 40 patients were followed for 3 years. Patients were analyzed using both subjective and objective methods. The visual analog scale (VAS) subjective data and objective data including both active anterior rhinomanometry and acoustic rhinometry were recorded and analyzed. Data were collected pre-operatively and at 1 and 3 years post-operatively. According to our data, both coblation and radiofrequency turbinate reduction benefit patients with good results. The complications, found during the follow-up, are limited to minimal bleeding and crusting. Coblation and radiofrequency were significantly less painful than others procedures during the early post-operative period. In our study, both coblation and radiofrequency provide an improvement in nasal airflow with a reduction in nasal obstructive symptoms in the short term, but their efficacy tended to decrease within 3 years.

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Oxidative stress in patients with obstructive sleep apnoea syndrome.

Obstructive sleep apnoea syndrome (OSAS) is a disorder that leads to metabolic abnormalities and increased cardiovascular risk. The aim of this study was to identify early laboratory markers of cardiovascular disease through analysis of oxidative stress in normal subjects and patients with OSAS. A prospective study was designed to compare outcomes of oxidative stress laboratory tests in 20 adult patients with OSAS and a control group of 20 normal subjects. Laboratory techniques for detecting and quantifying free radical damage must be targeted to assess the pro-oxidant component and the antioxidant in order to obtain an overall picture of oxidative balance. No statistical differences in age, sex distribution, or BMI were found between the two groups (p>0.05). There were significant differences in the apnoea/hypopnoea index (AHI) between OSAS patients and the control group (p<0.05). Statistically significant differences in isoprostane, advanced oxidation protein products (AOPP) and non-protein bound iron (NPBI) levels were found between the study and control groups. No significant difference in the levels of thiol biomarkers was found between the two groups. The main finding of the present study was increased production of oxidative stress biomarkers in OSAS patients. The major difference between thiols and other oxidative stress biomarkers is that thiols are antioxidants, while the others are expressions of oxidative damage. The findings of the present study indicate that biomarkers of oxidative stress in OSAS may be used as a marker of upper airway obstructive episodes due to mechanical trauma, as well as a marker of hypoxaemia causing local oropharyngeal inflammation.