Novel nasal formulation of xylometazoline with hyaluronic acid: In vitro ciliary beat frequency study.

Acute viral rhinosinusitis (viral ARS), or commonly referred to as the "common cold", is caused by respiratory viruses that cause disruption of the airway epithelial barrier and mucociliary dysfunction. Treatment of ARS is mainly symptomatic, with xylometazoline, a direct-acting α-adrenoceptor agonist, commonly used as a nasal decongestant. Unfortunately, this treatment does not resolve the epithelial dysfunction observed in ARS, and its use might negatively impact the nasal mucosa causing issues such as dryness, stinging, burning, rebound congestion, as well as atrophy. In light of this, a novel nasal spray formulation containing both xylometazoline and hyaluronic acid (HA) was developed to provide a more effective and safer treatment for viral ARS. HA is a natural polysaccharide known to hydrate and moisturise the upper respiratory tract, maintain the integrity of the nasal mucosa, and promote mucociliary clearance and wound healing. To investigate the potential of this combination, this study was conducted using the nasal MucilAirTMin vitro model and high-speed phase-contrast microscopy to examine the effect of xylometazoline and HA on ciliary function by measuring ciliary beat frequency and their cytotoxicity by morphological, histological and ultrastructural analysis. This research is the first to assess the effects of a specific dose and molecular weight of HA as an active pharmaceutical ingredient in nasal spray formulations. The combination of a fast-acting decongestant and an additional active agent targeting nasal epithelial dysfunction has the potential to provide an improved, reliable and safe treatment for viral ARS, and may serve as the basis for future clinical studies.

A randomized controlled trial on the effects of oxymetazoline nasal spray after dacryocystorhinostomy among adult patients.

OBJECTIVES: The study aimed to determine the effect of oxymetazoline nasal spray on the patency of the fistula created after dacryocystorhinostomy, specifically: to compare the success of fistula formation with oxymetazoline versus placebo, and to compare the incidence of post-operative congestion, pain and bleeding with oxymetazoline versus placebo. RESULTS: The study was a single-center, randomized controlled, triple-masked study involving the patients of the Plastic-Lacrimal service of a national university hospital. Block randomization was done. Dacryocystorhinostomy was performed by a single-masked surgeon. The intervention group used oxymetazoline. The placebo group used sodium chloride. The data were collected by another masked investigator. The study showed no significant difference in terms of congestion, pain and epistaxis between the two groups at day 2 post-operation. The patency, presence of silicone tube, granuloma formation, and presence of bleeding on both day 2 and day 16 post-operation had no difference between the two groups. This study doesn't support the use of oxymetazoline nasal spray after DCR, since it does not decrease the symptoms of congestion, pain and epistaxis after DCR. Aside from being an additional expense for patients, it also does not affect fistula formation and success rate of the surgery. Trial registration Australian New Zealand Clinical Trial Registry: ACTRN12619001394134, Date registered 10/11/2019, Retrospectively Registered.

Local field potential power spectra and locomotor activity following treatment with pseudoephedrine in mice.

The efficacy of pseudoephedrine (PSE) as a nasal decongestant has been well­demonstrated; however, PSE is strictly prescribed as a control substance due to its controversial psychostimulant effects. Although standard stimulatory drugs increase exploratory behavior and stimulate the dopamine system, the exact effects of PSE on locomotion and electrical activity in the striatum have not been determined. This study aimed to examine and compare the locomotor activities, local field potential (LFP) and sleep­wake patterns produced by PSE and morphine, which is a standard drug used to promote psychomotor activity. Male Swiss albino mice were anesthetized and implanted with an intracranial electrode into the striatum. Animals were divided into four groups, which received either saline, PSE or morphine. Locomotor activity and LFP signals were continuously monitored following pseudoephedrine or morphine treatment. One­way ANOVA revealed that locomotor count was significantly increased by morphine, but not PSE. Frequency analyses of LFP signals using fast Fourier transform also revealed significant increases in spectral powers of low­ and high­gamma waves following treatment with morphine, but not PSE. Sleep­wake analysis also confirmed significant increases in waking and decreases in both non­rapid eye movement and rapid eye movement sleep following morphine treatment. Sleep­wakefulness did not appear to be disturbed by PSE treatment. These findings indicate that acute PSE administration, even at high doses, does not have psychostimulatory effects and may be relatively safe for the treatment of non­chronic nasal congestion.

The effect of topical xylometazoline on Eustachian tube function.

BACKGROUND: Topical nasal decongestants are frequently used as part of the medical management of symptoms related to Eustachian tube dysfunction. OBJECTIVE: This study aimed to assess the effect of topical xylometazoline hydrochloride sprayed in the anterior part of the nose on Eustachian tube active and passive opening in healthy ears. METHODS: Active and passive Eustachian tube function was assessed in healthy subjects before and after intranasal administration of xylometazoline spray, using tympanometry, video otoscopy, sonotubometry, tubo-tympano-aerodynamic-graphy and tubomanometry. RESULTS: Resting middle-ear pressures were not significantly different following decongestant application. Eustachian tube opening rate was not significantly different following the intervention, as measured by all function tests used. Sonotubometry data showed a significant increase in the duration of Eustachian tube opening following decongestant application. CONCLUSION: There remains little or no evidence that topical nasal decongestants improve Eustachian tube function. Sonotubometry findings do suggest that further investigation with an obstructive Eustachian tube dysfunction patient cohort is warranted.

Effect of Intranasal Vasoconstrictors on Blood Pressure: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Treatment for epistaxis includes application of intranasal vasoconstrictors. These medications have a precaution against use in patients with hypertension. Given that many patients who present with epistaxis are hypertensive, these warnings are commonly overridden by clinical necessity. OBJECTIVE: Our aim was to determine the effects of intranasal vasoconstrictors on blood pressure. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial from November 2014 through July 2016. Adult patients being discharged from the emergency department (ED) at Mayo Clinic (Rochester, Minnesota) were recruited. Patients were ineligible if they had a contraindication to study medications, had a history of hypertension, were currently taking antihypertensive or antidysrhythmic medications, or had nasal abnormalities, such as epistaxis. Subjects were randomized to one of four study arms (phenylephrine 0.25%; oxymetazoline 0.05%; lidocaine 1% with epinephrine 1:100,000; or bacteriostatic 0.9% sodium chloride [saline]). Blood pressure and heart rate were measured every 5 min for 30 min. RESULTS: Sixty-eight patients were enrolled in the study; of these, 63 patients completed the study (oxymetazoline, n = 15; phenylephrine, n = 20; lidocaine with epinephrine, n = 11; saline, n = 17). We did not observe any significant differences in mean arterial pressure over time between phenylephrine and saline, oxymetazoline and saline, or lidocaine with epinephrine and saline. The mean greatest increases from baseline in mean arterial pressure, systolic and diastolic blood pressure, and heart rate for each treatment group were also not significantly different from the saline group. CONCLUSIONS: Intranasal vasoconstrictors did not significantly increase blood pressure in patients without a history of hypertension. Our findings reinforce the practice of administering these medications to patients who present to the ED with epistaxis, regardless of high blood pressure.

Effects of common cold and concomitant administration of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in otherwise healthy participants: A randomized clinical trial.

AIMS: Nasal glucagon (NG) is a nasally-administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant. MATERIALS AND METHODS: This was a single-centre, open-label study. Cohort 1 participants (N = 18) received 2 doses of NG: one while experiencing nasal congestion and another after recovery from cold symptoms. Cohort 2 participants (N = 18), who also had colds with nasal congestion, received a single dose of NG 2 hours after treatment with the decongestant oxymetazoline. Total symptoms score and other safety measures were assessed before and after NG administration. RESULTS: NG was well tolerated, without serious adverse events. Common adverse events (transient lacrimation, nasal discomfort, rhinorrhea and nausea) were more frequent in both Cohorts 1 and 2 during nasal congestion. Glucagon levels peaked 18 minutes post-dose and glucose levels peaked 30 to 42 minutes post-dose in all groups. Nasal congestion, with or without concomitant nasal decongestant, did not significantly affect PK of NG. Although glucose AUECs0-t was different between Cohort 1 with nasal congestion and Cohort 2, glucose concentrations at 30 minutes appeared similar in all groups. CONCLUSIONS: There were no clinically relevant differences in safety or PK/PD of NG associated with nasal congestion or concomitant administration of nasal decongestant, suggesting that NG can be used to treat severe hypoglycaemia in individuals experiencing nasal congestion.

[The possibility of using соformulated intranasal drugs after surgical correction of nasal breathing].

One of the major causes of chronic nasal obstruction is the nasal septum deformation and increase of the lower nasal turbinates. The number of septoplasty--operations ranges from 14% to 44,2% of all ENT-operations. The results of surgery are swelling of the tissues and damaged ciliar epithelium, that leads to the inparament of the mucociliar transport. In the postoperati e period the nasal cavity should be cleaned. Drugs, that are used, should reduce swelling, improve regeneration and should not supress ciliar activity. The results of supervisory, non-interventional study have shown, that application of Nasiс after septoplasty and submucose vasotomy of inferior nasal turbinates increases reparative process and leads to more rapid recovery of respiratory function of nasal cavity.

Effects of benzalkonium chloride on histamine H1 receptor mRNA expression in nasal epithelial cells.

OBJECTIVE: To better understand the causes of the exacerbation of rhinitis medicamentosa (RM) induced by oxymetazoline (OMZ) or benzalkonium chloride (BKC), we examined the impact of pretreatment with OMZ or BKC on cultured human nasal epithelial cells. We also examined the effect of mometasone furoate (MF) on the cultured human nasal epithelial cells treated with OMZ or BKC. METHODS: Cells of the human nasal epithelial cell line HNEpC were treated with OMZ or BKC, and the OMZ- and BKC-induced expression of histamine H1 receptor (H1R) mRNA was assayed using real-time polymerase chain reaction. In some experiments, 1.0×10(-5)M MF was added to the HNEpC cells for 24h before treatment with OMZ or BKC. RESULTS: Treatment with OMZ slightly increased the expression level of H1R mRNA in HNEpC cells. This enhanced expression was not significantly reduced by pretreatment with MF. In contrast, treatment with BKC remarkably increased the expression level of H1R mRNA in HNEpC cells. In addition, this enhanced expression was significantly reduced by pretreatment with MF. CONCLUSION: These results suggest that the increased expression of H1R mRNA due to treatment with OMZ or BKC might be one of the factors underlying the exacerbation of symptoms in patients with RM and those complicated with allergic rhinitis. The concomitant use of a nasal steroid might reduce the exacerbation of symptoms caused by BKC, although there remains a risk of developing histamine hypersensitivity from the long-term use of a topical steroid-containing BKC.

Magnetic resonance imaging reveals the complementary effects of decongestant and Breathe Right Nasal Strips on internal nasal anatomy.

OBJECTIVES/HYPOTHESIS: This magnetic resonance imaging (MRI) study of 26 subjects with nasal congestion was performed to assess in the complete nasal passage both the anatomical effect of the marketed Breathe Right Nasal Strip (BRNS) relative to placebo and the potential adjunctive effect of using a decongestant in combination with the BRNS. STUDY DESIGN: Randomized, crossover study. METHODS: The study consisted of two parts, the first involving application of either the BRNS or the placebo strip in a randomized, crossover design with evaluator blinding, and repeated MRI scanning; and the second a sequential process of decongestant administration, MRI scanning, application of the BRNS, and repeated MRI. The same anatomical MRI protocol was used throughout. Nasal patency was assessed in the whole nasal passage and eight subregions (by inferior-superior, anterior-posterior division). Numerical response scores representing subjective nasal congestion were also obtained. RESULTS: Results demonstrate significant anatomical enlargement with the BRNS relative to placebo (P < .001), as well as an additive effect of using a decongestant in combination with the BRNS; both supported by a strong and significant negative correlation with the subjective nasal response measures of nasal congestion (r = -0.98, P = .002). Furthermore, analysis of the nasal subregions indicates that this adjunctive effect arises from a partially localized action of the complementary products: the BRNS acting primarily anteriorly in the nose and the decongestant mainly posteriorly. CONCLUSIONS: The BRNS alone significantly increases nasal patency and alleviates perceived nasal congestion, and additional relief of symptoms can be obtained with simultaneous use of a decongestant. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:2205-2211, 2016.

Evaluating the Effect of Sinex® (0.05% Oxymetazoline) Nasal Spray on Reduction of Nasal Congestion Using Computational Fluid Dynamics.

Computational fluid dynamics (CFD) was used to simulate air flow changes in reconstructed nasal passages based on magnetic resonance imaging (MRI) data from a previous clinical study of 0.05% Oxymetazoline (Vicks Sinex Micromist®). Total-pressure boundary conditions were uniquely applied to accommodate low patency subjects. Net nasal resistance, the primary simulation outcome, was determined using a parallel-circuit analogy and compared across treatments. Relative risk (RR) calculations show that for a 50% reduction in nasal resistance, subjects treated with Sinex® are 9.1 times more likely to achieve this after 8 hr, and 3.2 times more likely after 12 hr compared to Sham.

Effects of oxymetazoline on nasal flow and maximum aerobic exercise performance in patients with inferior turbinate hypertrophy.

OBJECTIVES/HYPOTHESIS: To determine the effect of topical intranasal oxymetazoline on nasal resistance and aerobic exercise performance in patients with nasal congestion caused by inferior turbinate hypertrophy. STUDY DESIGN: Individual randomized controlled trial. METHODS: Eight patients with inferior turbinate hypertrophy performed a set of exercise tests to exhaustion 1 week apart. They were given oxymetazoline or a placebo before each of the two test sessions according to a random pattern. Changes in nasal airflow were measured as peak nasal flow and ventilatory efficiency parameters, ventilatory equivalents, end-expiratory pressure, oxygen consumption, cardiac efficiency, rate of perceived exertion, and maximal and submaximal mechanical power. RESULTS: Ten minutes after use of the drug or placebo, improvements in maximum nasal airflow were seen in the oxymetazoline group (P < 0.05). However, exercise tests showed improvements in both groups (P < 0.05). After exertion, there was no difference between the two groups in maximum nasal airflow (P > 0.05). There were no differences between groups in oxygen consumption, rate of perceived exertion, respiratory exchange ratio, ventilation, or ventilatory equivalents for oxygen. CONCLUSION: Oxymetazoline increased nasal airflow in patients with turbinate hypertrophy, but this change did not translate into gains in physical exercise parameters or perceived exertion. LEVEL OF EVIDENCE: 1b.

Acoustic impedance rhinometry (AIR): a technique for monitoring dynamic changes in nasal congestion.

We describe a simple and inexpensive method for monitoring nasal air flow resistance using measurement of the small-signal acoustic input impedance of the nasal passage, similar to the audiological measurement of ear drum compliance with acoustic tympanometry. The method requires generation of a fixed sinusoidal volume-velocity stimulus using ear-bud speakers, and an electret microphone to monitor the resultant pressure fluctuation in the nasal passage. Both are coupled to the nose via high impedance silastic tubing and a small plastic nose insert. The acoustic impedance is monitored in real-time using a laptop soundcard and custom-written software developed in LabView 7.0 (National Instruments). The compact, lightweight equipment and fast time resolution lends the technique to research into the small and rapid reflexive changes in nasal resistance caused by environmental and local neurological influences. The acoustic impedance rhinometry technique has the potential to be developed for use in a clinical setting, where the need exists for a simple and inexpensive objective nasal resistance measurement technique.

Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion.

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

[Ciliary epithelium and topical decongestants: how to minimize the undesirable events?].

The objective of the present study was to evaluate the influence of the combination of 0.1% xylometazoline with seawater (Rinomaris, "Jadran", Croatia) on the state and functional activity of the ciliary epithelium of the nasal cavity. The results of the study confirm the safety of this treatment and the possibility of its application in routine clinical practice.

Nasal flow, volumes, and minimal cross sectional areas in asthmatics.

BACKGROUND: The Unified Airways hypothesis suggests an involvement of the upper airways in asthma. Critical parameters of the nasal airway can be quantified objectively with acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF). OBJECTIVE: We aimed to investigate nasal airway patency in asthmatics compared to non-asthmatic controls. Nasal volume, cross sectional area and flow were measured using acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF) in 87 asthmatics and 93 non-asthmatic controls before and after decongestion with xylometazoline. Nasal congestion index (NCI) was calculated, and allergy status was assessed by skin prick test or specific IgE. RESULTS: We found significantly smaller minimum cross sectional area and nasal cavity volume in asthmatics than controls, and the cross sectional area is at its minimum at 2-3 cm from the nasal orifice in both groups. AR and PNIF measurements are not different in allergic and non allergic subjects in either group. The effect of xylometazoline is not significantly different between the 2 groups with regard to AR, but there is a significant improvement in PNIF for the asthmatics when assessed by the NCI. CONCLUSION: The present study demonstrates a significantly smaller nasal airway when assessed by minimum cross sectional area and nasal cavity volume in asthmatics than controls, and these findings apply to asthmatics and controls irrespective of allergy status.

SPRIX (ketorolac tromethamine) nasal spray: a novel nonopioid alternative for managing moderate to moderately severe dental pain.

In summary, SPRIX is a nonopioid alternative for the management of moderate to moderately severe pain. SPRIX offers dentists, physicians, and patients a new non-opioid option to control acute moderate to moderately severe pain in situations in which use of an IM or IV access is not feasible or not wanted. SPRIX is a valuable treatment option for patients with nausea or vomiting, those unable to take oral medications, and those unable to tolerate the side effects of opioids. In ambulatory acute pain settings, use of SPRIX will allow patients who need to remain alert to receive effective pain control. Currently, there are no nonopioid alternatives for the treatment of moderate to moderately severe pain other than ketorolac. In patients with more severe pain states, the combination of opioids and SPRIX provides unique advantages in maximizing analgesia while minimizing the unwanted adverse effects of both classes of drugs (referred to as multimodal or "balanced analgesia").

The relationship between nasal index and nasal airway resistance, and response to a topical decongestant.

The differences in the shape and size of the nose have been proposed to be an adaptation to climate with broad noses (platyrrhine) evolving in a warm humid environment where there was little need for air conditioning and narrow noses (leptorrhine) evolving in colder climates where the air needed more warming. The main aim of this research was to determine if there was any relationship between the shape of the nose as expressed in terms of nasal height and width (nasal index) and total nasal airway resistance (NAR), as one would predict that the narrower leptorrhine noses would have a greater resistance to air flow than the broader platyrrhine noses. It was also proposed that the narrow leptorrhine nose would have better developed vascular tissue than the broad platyrrhine nose in order to condition cold air, and would exhibit a greater response to nasal decongestion. No correlation was found between nasal index and NAR (r = -0.09) and similarly no correlation was found between nasal index and response to a topical nasal decongestant (r = 0.02). The absence of any physiological differences between the different nose types may be due to acclimatisation of participants to the area of recruitment.

Nasal inspiratory flow: at rest and sniffing.

BACKGROUND: This study quantifies the time-varying flow rate during inspiration at rest and in sniffing, both predecongestion and postdecongestion. It aims to provide a better understanding of nasal airflow mechanics, for application to the physiological modeling of nasal respiration and to therapeutic drug delivery. METHODS: The temporal profiles of nasal inspiration were measured at high fidelity in 14 healthy individuals using simultaneous bilateral hot-wire anemometry. Peak nasal inspiratory flow (PNIF) rate, acoustic rhinometry (AR), and the sinonasal outcome test (SNOT) provided complementary clinical measurements. The impact of decongestion was also investigated. RESULTS: In the initial phase of inspiration, a rapid rise in flow rate was observed. Flow first exceeded 150 mL/second in either passage within a median time of approximately 120 ms for inspiration at rest and approximately 60 ms in sniffing (∼20 ms in the fastest sniffs). The mean sustained flow rate attained and the overall period of each measured inspiratory profile were analyzed. AR showed a significant change in nasal volume with decongestion, although these change were not manifest in the temporal profiles of inspiratory flow (barring a weak effect associated with the most vigorous sniffs). CONCLUSION: Novel methods were applied to investigate the temporal profiles of nasal inspiration. Characteristic features of the profile were identified and found to be significantly different between inspiration at rest and sniffing. Decongestion was found to have little effect on the temporal profiles for the flow regimes studied.