Topical Nasal Decongestant Oxymetazoline: Safety Considerations for Perioperative Pediatric Use.

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.

[A COMPARATIVE ANALYSIS OF THE DISPERSION QUALITY OF NASAL SPRAYS OXYMETAZOLINE].

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 package¼, «Mass uniformity of the dose¼, «Irrigated area (on the planar imitation model)¼. The analysis of nine oxymetazoline nasal sprays demonstrates that the optimal result is achieved while usingVicks Sinex.

Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

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.

An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.

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.

Direct detection of phenylephrine 3-O-sulfate in LS180 human intestinal cells using a novel hydrophilic interaction liquid chromatography (HILIC) assay.

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).

Population Pharmacokinetics of an Intranasally Administered Combination of Oxymetazoline and Tetracaine in Healthy Volunteers.

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 ka 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 ka 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.

Over-the-counter medications: Risk and safety in pregnancy.

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.

Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product.

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.

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.

Evaluation of the 20% D-methamphetamine requirement for determining illicit use of methamphetamine in urine.

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.

Characterization of mucoadhesive nasal gels containing midazolam hydrochloride prepared from Linum usitatissimum L. mucilage

Nasal drug delivery systems prepared from natural materials are gaining importance in the field of pharmaceutical technology. Mucilage isolated from Linum usitatissimum L. (LUM) seeds was reported to be an effective natural mucoadhesive agent. The present study deals with a comparison of various characteristics of nasal gels containing midazolam hydrochloride (HCl) prepared from mucoadhesive agent extracted from Linum usitatissimum L. seeds and synthetic polymers like HPMC and Carbopol 934P in terms of texture profile analysis, mucoadhesive strength, and in vivo drug absorption profiles. It was observed that gels formulated with the natural mucilage showed better results than the synthetic gels in all aspects like hardness, adhesiveness, cohesiveness and mucoadhesive strength. The absolute bioavailability of midazolam hydrochloride from the natural gel was 97.55 percent whereas that of synthetic gels was 57.33 percent and 76.81 percent respectively.

Sistemas de liberação nasal preparados com produtos naturais estão ganhando importância no campo da tecnologia farmacêutica. A mucilagem isolada de sementes de Linum usitatissimum L. (LUM) mostrou-se agente mucoadesivo eficaz. O presente estudo trata da comparação de várias características de géis nasais contendo cloridrato de midazolam preparados com agente mucoadesivo extraído das sementes de Linum usitatissimum L. e com polímeros sintéticos, como HPMC e Carbopol 943P, com relação ao perfil de textura, força mucoadesiva e perfis de absorção do fármaco in vivo. Observou-se que os géis formulados com mucilagem natural apresentam melhores resultados do que os sintéticos em todos os aspectos, como dureza, adesão, coesão e força mucoadesiva. A biodisponibilidade absoluta do cloridrato de midazolam a partir do gel natural foi de 97,55 por cento, enquanto que nos géis sintéticos foi de 57,33 por cento e 76,81 por cento, respectivamente.

Pharmacokinetics of pseudoephedrine in rats, dogs, monkeys and its pharmacokinetic-pharmacodynamic relationship in a feline model of nasal congestion.

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.

Real-time breath gas analysis for pharmacokinetics: monitoring exhaled breath by on-line proton-transfer-reaction mass spectrometry after ingestion of eucalyptol-containing capsules.

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.

Assessment of nasal spray deposition pattern in a silicone human nose model using a color-based method.

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.

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.

Nasal decongestants in the treatment of chronic nasal obstruction: efficacy and safety of use.

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 effect of inferior turbinate hypertrophy on nasal spray distribution to the middle meatus.

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.

[Effect of beta-glycyrrhizinate on eye mucosa absorption of drugs].

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.