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.

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.

[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.

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.

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.

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.

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.

Empirical vs natural weighting in random effects meta-analysis.

This article brings into serious question the validity of empirically based weighting in random effects meta-analysis. These methods treat sample sizes as non-random, whereas they need to be part of the random effects analysis. It will be demonstrated that empirical weighting risks substantial bias. Two alternate methods are proposed. The first estimates the arithmetic mean of the population of study effect sizes per the classical model for random effects meta-analysis. We show that anything other than an unweighted mean of study effect sizes will risk serious bias for this targeted parameter. The second method estimates a patient level effect size, something quite different from the first. To prevent inconsistent estimation for this population parameter, the study effect sizes must be weighted in proportion to their total sample sizes for the trial. The two approaches will be presented for a meta-analysis of a nasal decongestant, while at the same time will produce counter-intuitive results for the DerSimonian-Laird approach, the most popular empirically based weighted method. It is concluded that all past publications based on empirically weighted random effects meta-analysis should be revisited to see if the qualitative conclusions hold up under the methods proposed herein. It is also recommended that empirically based weighted random effects meta-analysis not be used in the future, unless strong cautions about the assumptions underlying these analyses are stated, and at a minimum, some form of secondary analysis based on the principles set forth in this article be provided to supplement the primary analysis.

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.

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 effects of inhaled L-methamphetamine on athletic performance while riding a stationary bike: a randomised placebo-controlled trial.

OBJECTIVE: L-methamphetamine (the non-abused isomer of methamphetamine) is banned in athletic competition because it may improve athletic performance, but there are no studies assessing its effects on performance. In the United States L-methamphetamine is formulated in the non-prescription Vick's Vapor Inhaler (VVI) nasal decongestant. VVIs sold elsewhere (we used ones from the UK) contain similar inactive ingredients (menthol, camphor and Siberian pine oil) but no L-methamphetamine. This study tested the effects of inhaled L-methamphetamine delivered from a widely available non-prescription product on athletic performance. DESIGN: In a 2-session double-blind placebo-controlled study 12 participants (ages 14-17) were dosed with 4 (session 1) and 12 (session 2) inhalations from VVIs with (USA) or without (UK) L-methamphetamine and then performed two 20 minute rides on a stationary bike with rides separated by a 30 minute rest. OUTCOME MEASURE: The main outcome measure was miles travelled during each 20 minute ride. Secondary outcome measures included postride urine toxicology; heart rate and blood pressure before, 1, 5 and 10 minutes postride; energy, performance, endurance, and ability to breathe; and VVI preference. Data were analysed using Excel statistical macros. RESULTS: After approximately 16 microg L-methamphetamine distance travelled was 5.26 (SD 0.53) miles vs 5.30 (0.55) with placebo; p = 0.81. After approximately 48 microg L-methamphetamine distance travelled was 5.30 (0.51) vs 5.35 (0.43) with placebo; p = 0.85. The approximately 16 microg dose increased systolic blood pressure from 72.6 (4.3) to 79.6 (6.6) mm Hg (p = 0.03) at 5 minutes postride but there were no other differences in outcomes. CONCLUSIONS: Modest doses of inhaled L-methamphetamine probably do not improve athletic performance but do minimally raise diastolic blood pressure.

Intraoperative dilated pupil during nasal polypectomy.

In endoscopic sinus surgery, it is often desirable to prepare the nasal mucosa with a nasal decongestant to minimise blood loss and enhance the operative field during surgery. A widely used commercially available preparation for such a purpose is a solution containing 5% Lidocaine Hydrochloride and 0.5% Phenylepherine Hydrochloride. We report a case of a unilateral dilated pupil occurring during nasal polypectomy. A dilated pupil during sinus surgery is associated with an intraorbital injury but many commonly used nasal decongestive agents can also cause mydriasis and this knowledge may prevent some anxiety for the unwary ENT surgeon undertaking sinonasal surgery.

Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats.

BACKGROUND: Pseudoephedrine is a drug commonly prescribed as a nasal decongestant and bronchodilator and is also freely available in cold remedies and medications. The structural and pharmacological similarity of pseudoephedrine to amphetamine has led to evaluation of its psychomotor stimulant properties within the central nervous system. Previous investigations have shown that the acute responses to pseudoephedrine were similar to those of amphetamine and other psychostimulants. RESULTS: This study examined the effect of chronic administration of pseudoephedrine in rat nucleus accumbens and striatum and identified three further similarities to amphetamine. (i) Chronic exposure to pseudoephedrine reduced the c-Fos response to acute pseudoephedrine treatment suggesting that pseudoephedrine induced tolerance in the animals. (ii) In animals chronically treated with amphetamine or pseudoephedrine the acute c-Fos response to pseudoephedrine and amphetamine was reduced respectively as compared to naïve animals indicating cross-tolerance for the two drugs. (iii)The known involvement of the dopamine system in the response to amphetamine and pseudoephedrine was further confirmed in this study by demonstrating that pseudoephedrine similarly to amphetamine, but with lower potency, inhibited [3H]dopamine uptake in synaptosomal preparations. CONCLUSION: This work has demonstrated further similarities of the effect of pseudoephedrine to those of amphetamine in brain areas known to be associated with drug addiction. The most significant result presented here is the cross tolerance effect of amphetamine and pseudoephedrine. This suggests that both drugs induce similar mechanisms of action in the brain. Further studies are required to establish whether despite its considerable lower potency, pseudoephedrine could pose health and addiction risks in humans similar to that of known psychostimulants.

A randomized, controlled trial of nasal phenylephrine in infants hospitalized for bronchiolitis.

OBJECTIVE: To examine the hypothesis that pharmacologic treatment of nasal obstruction, specifically alpha-adrenergic nose drops, will decrease objective signs of respiratory distress in infants with bronchiolitis. STUDY DESIGN: Forty-one infants aged 3 weeks to 12 months hospitalized for viral bronchiolitis were enrolled in this double-blinded, placebo-controlled trial of topical 0.5% phenylephrine drops. The primary outcome measure was change in oxygen saturation. Secondary outcomes were changes in respiratory scores and vital signs. RESULTS: There were no statistical differences in any of the outcome measures between groups. No adverse events were observed. Overall, participants showed an average 1.6 percentage point increase in their oxygen saturations (P = .002) and a 0.5-point improvement in respiratory score (P = .003) over the 30 minutes of the study. CONCLUSIONS: Topical nasal phenylephrine did not produce significant short-term improvements in clinical status in infants hospitalized for acute bronchiolitis.

Over-the-counter cough and cold medication use in young children.

During a 2-year period from 2004 and 2005, emergency departments treated over 1,500 children under the age of 2 years for adverse events related to over-the-counter (OTC) cough and cold medication use; these incidents include 3 infant deaths. The risk of overdose, incorrect dosing and adverse events is increased in young children due to the greater number of colds they acquire each year. Lack of evidence to support the use of OTC medications in young children is well documented in the literature; however, people continue to use OTC medications with young children. The common cold is generally a mild, self-limited illness that usually improves with time. Recommended care and treatment for the common cold includes symptomatic treatment. This article presents and reviews the available evidence regarding the use of OTC cough and cold medications for pediatric healthcare providers. This review of the evidence will be helpful for healthcare providers to minimize risks to young children who intentionally or unintentionally ingest these medications and to educate child caregivers regarding proper use of OTC cough and cold medications with children.

Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524).

The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.