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The over-the-counter nasal decongestant oxymetazoline (eg, Afrin) is used in the pediatric population for a variety of conditions in the operating room setting. Given its vasoconstrictive properties, it can have cardiovascular adverse effects when systemically absorbed. There have been several reports of cardiac and respiratory complications related to use of oxymetazoline in the pediatric population. Current US Food and Drug Administration approval for oxymetazoline is for patients ≥6 years of age, but medical professionals may elect to use it short-term and off label for younger children in particular clinical scenarios in which the potential benefit may outweigh risks (eg, active bleeding, acute respiratory distress from nasal obstruction, acute complicated sinusitis, improved surgical visualization, nasal decongestion for scope examination, other conditions, etc). To date, there have not been adequate pediatric pharmacokinetic studies of oxymetazoline, so caution should be exercised with both the quantity of dosing and the technique of administration. In the urgent care setting, emergency department, or inpatient setting, to avoid excessive administration of the medication, medical professionals should use the spray bottle in an upright position with the child upright. In addition, in the operating room setting, both monitoring the quantity used and effective communication between the surgeon and anesthesia team are important. Further studies are needed to understand the systemic absorption and effects in children in both nonsurgical and surgical nasal use of oxymetazoline., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Jatana is a stockholder for Tivic Health Systems; Drs Cartabuke and Tobias have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Introduction: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites., Methods: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis., Results: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis., Discussion: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The subject matter of the investigation is to compare the metered dose nasal sprays containing the long-acting decongestant oxymetazoline from the different manufacturers according to the dispersion quality: the dose quantity in one packing, the dose mass reproducibility, imprint area on the planar imitation model. The tests were conducted: «The number of doses per package», «Mass uniformity of the dose», «Irrigated area (on the planar imitation model)». The analysis of nine oxymetazoline nasal sprays demonstrates that the optimal result is achieved while usingVicks Sinex.

Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed., (Copyright © 2018. Published by Elsevier Inc.)

The primary objective of the current investigation was to establish the pharmacokinetic characteristics of oxymetazoline and tetracaine's primary metabolite, para-butylaminobenzoic acid (PBBA), after the intranasal administration of oxymetazoline/tetracaine. Thirty-six subjects contributing a total of 1791 plasma concentration results from 2 open-label trials were utilized. Model development was achieved using data from the second trial (N = 24) in which 0.3 mg oxymetazoline/18 mg tetracaine was administered. External model validation utilized data from the first trial (N = 12), which included doses of 0.3 mg oxymetazoline/18 mg tetracaine and 0.6 mg oxymetazoline/36 mg tetracaine. Oxymetazoline and PBBA dispositions were described by a 2-compartment model with first-order absorption. An allometric model for body weight was included on volumes and clearances to describe unexplained between-subject variability. The final oxymetazoline parameter estimates were k a 4.41 h -1 ; peripheral volume 418 L; clearance 66.4 L/h; central volume 6.97 L; and intercompartmental clearance 419 L/h for a 70-kg subject. The final PBBA parameter estimates were k a 8.51 h -1 ; peripheral volume 32.0 L; clearance 16.7 L/h; central volume 29.8 L; and intercompartmental clearance 2.43 L/h for a 70-kg subject. Between-subject variability ranged from 14% to 39% for oxymetazoline and from 10% to 94% for PBBA., (© 2016, The American College of Clinical Pharmacology.)

The efficacy of phenylephrine (PE) is controversial due to its extensive pre-systemic metabolism through sulfation to form phenylephrine-3-O-sulfate (PES). Hence quantitation of PES is important in order to study the metabolism of PE. There are no published methods available for direction detection of PES. We have developed and validated a hydrophilic interaction liquid chromatography (HILIC) method for the direct detection of PES and simultaneous detection of PE to study the enzyme kinetics and metabolism of PE to enable approaches to reduce the presystemic metabolism of PE. This is the first method which facilitates direct detection of PES and simultaneous detection of PE using a zwitterionic HILIC column with improved sensitivity in a single short run. The observed quantitative ranges of our method for PE and PES were 0.39-200μM and 0.0625-32μM (respectively) with a run time of 6.0min. The method was applied to the determination of PE and PES in LS180 human intestinal cell line, recombinant enzymes and human intestinal cytosol (HIC)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Over-the-counter (OTC) medications are among the most commonly used products in pregnancy. Similar to prescription medications, for many products there is a lack of adequate data on safety of use in pregnancy. Assumptions of safety for these products based on long experience and OTC status, in the absence of data, may be ill founded. Examples of four OTC products used to treat common conditions in pregnancy are described. Potential links to adverse short- and long-term infant outcomes for these products are reviewed, and the strengths and limitations of data to support these. Research to detect or rule out these risks is essential., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

Objectives: The primary objective of this study was to compare the bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a new oral syrup with an established oral reference product. The secondary objective was to compare the safety of the new syrup and the reference product., Methods: This was a single-centre, open-label, randomized, reference-replicated, crossover study. Healthy adult volunteers received one dose of syrup and two separate doses of a reference oral liquid formulation in a randomized sequence over three study periods, with a washout interval of ≥ 7 days between study periods. Blood samples were taken regularly postdose and analysed for paracetamol, phenylephrine hydrochloride and guaifenesin concentrations; adverse events were recorded., Results: This study enrolled 45 subjects. For paracetamol and guaifenesin, the syrup and reference product were considered to be bioequivalent. Bioequivalence was not shown for phenylephrine hydrochloride. All adverse events were mild or moderate, most of which were considered formulation related., Conclusions: The syrup did not reach bioequivalence with the reference product, as bioequivalence could not be shown for phenylephrine hydrochloride. This may be due to differences in the excipients between the two products. Both the syrup and the reference product had a good safety profile and were well tolerated.

In urine drug testing, enantiomer analysis is used to determine whether a positive methamphetamine result could be due to use of an over-the-counter (OTC) nasal inhaler containing L-methamphetamine. D-methamphetamine at more than 20% of the total is considered indicative of a source other than an OTC product. This interpretation is based on a 1991 Department of Health and Human Services (HHS) Technical Advisory. We performed studies to verify the methamphetamine enantiomer content of current OTC nasal inhalers and to evaluate current laboratory testing capabilities. This study demonstrated that OTC inhalers contain less than 1% D-methamphetamine. A proficiency testing (PT) set for HHS-certified laboratories performing methamphetamine enantiomer testing found D-methamphetamine percentages that were consistently 1 to 3% higher than theoretical due to optical impurity of the derivatizing reagent N-trifluoroacetyl-L-prolyl chloride (L-TPC). The PT results also demonstrate that laboratories can accurately determine 20% D-methamphetamine in samples with total methamphetamine concentrations down to 250 ng/mL. Based on these studies, the guideline of >20% D-methamphetamine is appropriate for interpreting results obtained using current laboratory methods.

Eucalyptol (1,8-cineole) is a common active agent in non-prescription pharmaceutical products that is employed to clear the airways during mucus blockages. Following ingestion of a eucalyptol-containing capsule, the capsule dissolves in the gut and transfers eucalyptol into the blood, which is subsequently expelled via the lungs, thus exposing this decongesting and inflammation-abating compound to the airways. The breath gas concentrations of eucalyptol in 11 healthy adult volunteers were monitored at regular intervals after capsule ingestion using on-line proton-transfer-reaction mass spectrometry (PTR-MS). Eucalyptol appeared in exhaled breath gas at varying times following ingestion, with its onset ranging from 1 h and 6 min to 4 h and 48 min (mean ± SD: 2.1 ± 0.5 h). Maximum concentrations also varied greatly, with peak eucalyptol levels between 106 and 1589 ppb(v) (mean ± SD: 489 ± 319 ppb(v)). These variations were not only inter-subject, but also intra-subject, i.e. repeated tests with the same participant yielded different onset times and a broad range of concentration maxima. A considerable contribution to these variations from infrequent sampling and analysis is discussed. This study characterized the temporal transfer of eucalyptol via the blood into the airways by examining exhaled breath and thereby demonstrated the suitability of on-line breath gas analyses, particularly PTR-MS, for certain pharmacokinetic investigations.

The objectives of these studies were to characterize the pharmacokinetics (PK) of the nasal decongestant pseudoephedrine (PSE) in rats, dogs, and monkeys, and to evaluate its lower gastrointestinal tract regional bioavailability in rats. An LC-MS/MS assay with a lower limit of quantification (LLOQ) of 0.4 ng/mL of plasma was developed for the analysis of PSE in animal plasma. The total body clearance (CL) was the highest in rats (78 mL/min/kg), lowest in monkeys (15 mL/min/kg) and the dog averaged in between (33 mL/min/kg). The volume of distribution at steady state (Vdss) ranged from 3-5 L/kg in all species. In rats and dogs, the mean half-lives (t1/2) was ≈1.5 hr, while in monkeys the mean t1/2 was 4.6 hr, comparable to that observed in adult humans (4-8 hr). The oral bioavailability was 38, 58 and 78% in rats, dogs and monkeys. The bioavailability following intra-ileum or intra-colonic administration in rats was superior to that following oral dosing (66% and 78%, respectively) suggesting that colonic absorption may be compensating for the short half-life, thus enabling successful QD sustained release formulations of PSE. The pharmacokinetic/pharmacodynamic relationship (PK/PD) of PSE was also investigated in a feline model of nasal congestion to establish efficacious trough concentrations in cats for a comparison with that in humans. The PK/PD in the cat model followed a sigmoid Emax model with an EC50 (plasma concentration that elicits 50% of the maximum response) of 0.32 ±0.05 (SD) µM consistent with human plasma concentrations required for efficacy.

Purpose: To develop a simple and inexpensive method to visualize and quantify droplet deposition patterns., Methods: Deposition pattern was determined by uniformly coating the nose model with Sar-Gel (a paste that changes from white to purple on contact with water) and subsequently discharging sprays into the nose model. The color change was captured using a digital camera and analyzed using Adobe Photoshop. Several tests were conducted to validate the method. Deposition patterns of different nasal sprays (Ayr, Afrin, and Zicam) and different nasal drug delivery devices (Afrin nasal spray and PARI Sinustar nasal nebulizer) were compared. We also used the method to evaluate the effect of inhaled flow rate on nasal spray deposition., Results: There was a significant difference in the deposition area for Ayr, Afrin, and Zicam. The deposition areas of Afrin nasal spray and PARI Sinustar nasal nebulizer (2 min and 5 min) were significantly different. Inhaled flow rate did not have a significant effect on the deposition pattern., Conclusions: Lower viscosity formulations (Ayr, Afrin) provided greater coverage than the higher viscosity formulation (Zicam). The nebulizer covered a greater surface area than the spray pump we evaluated. Aerosol deposition in the nose model was not affected by air flow conditions.

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.

Nasal decongestants are the most powerful drugs in the reduction of nasal obstruction. Despite their large use, local and systemic adverse reactions are frequent. The authors focus on the pharmacology of these kinds of drugs in light of the most recent knowledge on nasal pathophysiology. The ultrastructural anatomy of nasal mucosa explains the complexity of the possible interactions between the sympathomimetics and imidazoles derivates, and the submucosal layer. Nasal obstruction is one of the most frequent clinical problems that otorhinolaryngologists encounter daily, both in adults and children. All possible predisposing conditions to nasal obstruction are documented along with the better ways to diagnose them through nasal functionality tests. Active anterior rhinomanometry, acoustic rhinometry and the determination of mucociliary transport time represent, together with nasal endoscopy, the gold standard for an accurate diagnosis and the follow-up of the patient to cure. An updated review of the most significant works in this field and the best treatment protocol to avoid adverse effects, such as rhinitis medicamentosa, are reported.

The distribution of topical nasal sprays is suboptimal, the main obstruction to adequate delivery in normal volunteers being the nasal valve. We aimed to test the hypothesis that, in patients with rhino-sinusitis, hypertrophy of the inferior turbinate also limits the distribution of administered drug to the middle meatus. We modelled the effect of inferior turbinate hypertrophy and reduction by effecting congestion (by ipsilateral isometric exercise) and decongestion (topical oxymetazoline) in normal volunteers. The method chosen to estimate drug delivery to the middle meatus used endoscopic photography after the administration of dyed aqueous spray. A randomized cross-over study design was used and 20 nasal cavities were studied. The congestion/decongestion manoeuvres significantly altered nasal airflow, as measured by peak inspiratory nasal flow (P < 0.001). Congestion diminished significantly drug delivery to the middle meatus, as compared with decongestion (P = 0.026). This may support a clinical role for inferior turbinate reduction to improve the efficacy of topical nasal therapy, as well as improving nasal airflow.

Dipotassium beta-glycyrrhizinate (GK2) is a saponin originated from "kanzo" plant. We studied such two functions of GK2 as a drug carrier and a penetration enhancer on the eye mucosa. The interactions of GK2 with various drugs were investigated using the 1-octanol/water partition method. GK2 increased the partition of cationic drugs, i.e., antihistamines (chlorpheniramine maleate (CM), diphenhydramine hydrochloride (DH)), as well as decongestants (naphazoline hydrochloride (NA), tetrahydrozoline hydrochloride (TH)). The carrier effect of GK2 is remarkable at its concentration above critical miceller concentration (CMC) and, especially at its pH value of between 4 to 5, resulting that transfers of drugs increased 2 to 10 times as compared to drugs without GK2. In vivo experiments were carried out using rats and rabbits. The effect of GK2 on the inhibition efficiency by CM was evaluated using experimental conjunctivitis formed by injection of histamine on rat upper eyelid. The Inhibition efficiency of edema by CM with GK2 was 4 times stronger than that without GK2. Cornea permeability of TH increased 1.8 times by the addition of GK2. These results indicated that GK2 is applicable as a carrier of cationic drugs on the eye mucosa and cornea.

The influence of time of administration on the serum levels of phenylpropanolamine when administered alone and in combination with chlorpheniramine maleate at two different times of a day was studied in healthy human volunteers in a randomized 4 x 4 Latin square crossover design with a washout period of ten days. Blood samples were collected at predetermined time intervals and serum samples were analysed for unchanged phenylpropanolamine using high performance liquid chromatography. The various pharmacokinetic parameters of phenylpropanolamine were calculated using model independent methods. There was a significant (P < 0.05) decrease in the rate of absorption of phenylpropanolamine following its administration in combination with chlorpheniramine maleate at 2200 hours. However, such a change was not observed for treatment at 1000 hours. The observed change may be due to the time dependent gastrointestinal effect of these drugs.

Pharmacokinetics of a single oral dose of phenylpropanolamine (CAS 154-41-6) was investigated by administering 50 mg of the drug at 10.00 and 22.00 h to 8 healthy male volunteers in a crossover design with a wash-out period of 10 days. Serum samples were analysed for phenylpropanolamine using high performance liquid chromatography. Pharmacokinetic parameters were calculated using model independent method. A significant (p < 0.05) elevation in Cmax (227.45 versus 181.98 micrograms/l) was observed following the drug administration at 22.00 h as compared to 10.00 h. These variations may be due to circadian changes in gastric pH contributing to the time dependent changes in the absorption of the drug.

Background: There is little published, objective information about pseudoephedrine and phenylpropanolamine in the treatment of children. Our goal was to determine the pharmacokinetics of these medications in young subjects., Methods: In two sequential double-blind, parallel-group, single-dose studies, 21 children received either pseudoephedrine, 30 or 60 mg, or placebo, and 20 children received either phenylpropanolamine, 20 or 37.5 mg, or placebo. Before dosing and at intervals up to 7 hours after dosing, serum pseudoephedrine or phenylpropanolamine concentrations were measured, and pulse and blood pressure were recorded. In two children receiving each drug, these tests were also performed at 12 and 24 hours, and urine was collected from 0 to 12 and from 12 to 24 hours., Results: In children, the mean (+/-SEM) terminal elimination half-life values for pseudoephedrine, 3.1 +/- 0.5 hours, and for phenylpropanolamine, 2.6 +/- 0.6 hours, were significantly shorter than those found by other investigators in adults. Pharmacokinetics were not dose dependent in the dose ranges studied., Conclusion: Further studies of pseudoephedrine and phenylpropanolamine should be performed in children with the use of objective measurements. The widespread use of these medications in young subjects should be reevaluated.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylephrine (PE, CAS 59-42-7) after single dose administration of a retard capsule (Rhinopront) containing 20 mg PE hydrochloride and 4 mg CA maleate, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects according to a standard crossover design with a one-week wash-out. The pharmacokinetic profile of the active ingredients of the retard capsule was also investigated in the same subjects under repeated dosing conditions (one capsule b.i.d. during 4 days). Blood samples were collected before each administration and up to 36 h after the first and last doses. CA and total PE (free + conjugated) were assayed in the plasma samples by HPLC with coulometric detection and by gas chromatography with electron-capture detection, respectively. The pharmacokinetic parameters obtained after single dose administration indicated an effective slow release of PE and CA with the retard capsule, compared to the solution. Significantly dampened Cmax, delayed tmax and prolonged plateau time were observed. Despite the clear decrease in absorption rate, the two formulations yielded a similar extent of absorption for CA (90% confidence interval of AUC ratio: 61-111%), but not for PE (90% confidence interval of AUC ratio: 56-69%). At steady-state, accumulation of the two active principles apparently followed simple superposition (accumulation index R = 1.6 for PE and 3.9 for CA). The slow absorption pattern of the formulation was maintained at steady-state with tmax and plateau time similar to single dose conditions.

Only three drugs are commonly used as oral decongestants--phenylpropanolamine (PPA), pseudoephedrine (PDE), and phenylephrine (PE). They are all chiral drugs that exist as stereoisomers. It is possible that each enantiomer can reflect significant enantioselective differences with regard to both pharmacokinetic and pharmacodynamic effects. Both PPA and PDE are readily and completely absorbed, whereas PE, with a bioavailability of only approximately 38%, is subject to gut wall metabolism and is thought to be absorbed erratically. Peak concentrations are reached between 0.5 and 2 hours after administration. All three drugs are extensively distributed into extravascular sites (apparent volume of distribution between 2.6 and 5.0 L/kg). No protein-binding data in humans are available. Whereas PPA and PDE are not substantially metabolized, PE undergoes extensive biotransformation in the gut wall and the liver. Elimination of PPA and PDE is predominantly renal, with urinary excretion being pH dependent. Half-lives are relatively short, approximately 2.5 hours for PE, 4 hours for PPA, and 6 hours for PDE. Elimination of PPA and PDE may be rapid in children, and the agents should be used with caution in patients with renal impairment. In addition, PPA increases caffeine plasma levels and decreases theophylline clearance. Reduced metabolism of PE occurs with concurrent administration of monoamine oxidase inhibitors. No direct relationship between nasal decongestant effect and plasma concentration has been established.

2-(4-Amino-3,5-dichlorobenzyl)imidazoline hydrochloride (A-57219), has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.