Efficacy and safety of an oral formulation of cetirizine and prolonged-release pseudoephedrine versus xylometazoline nasal spray in nasal congestion.

The aim of this study was to compare the decongestant properties and tolerability of the sympathomimetic xylometazoline hydrochloride 0.1% (CAS 1218-35-5, XMZ) and an oral formulation of cetirizine hydrochloride 5 mg and pseudoephedrine hydrochloride 120 mg (CAS 83881-51-0 and 90-82-4, CTZ/PSE; Cirrus). Thirty-six asymptomatic patients suffering from perennial allergic rhinitis from house dust mite were randomized to this open two-period crossover study. Patients received the study medications for four days each. In each period, treatments were taken twice a day. On day 1 in each period, immediately after the first dose of medication, patients were challenged with Dermatophagoides pteronyssinus extract 1 in the Vienna Challenge Chamber for 5 h. Primary efficacy parameters were nasal congestion evaluated by digital analysis of nasal cavity photographs and nasal airflow. Furthermore amounts of nasal secretions, nasal and ocular symptoms were recorded. In addition, 5 independent Ear-Nose-Throat specialists also assessed nasal cavity photographs. Statistical analyses were conducted at the 5% level of significance. Digital analysis of the nasal cavity photographs as well as nasal airflow measurements did not differentiate XMZ from CTZ/PSE. Ratings of the photographs of the nasal cavity emphasized the rapid onset of XMZ. No clinically relevant adverse events were recorded. This rapid onset of action but short-lived effect of topical xylometazoline 0.1% should be balanced against the consistent and prolonged effect of systemic cetirizine/pseudoephedrine combination in the treatment of perennial allergic rhinitis as no significant differences between these 2 medications were noted regarding their decongestant properties. With the exception of nasal obstruction, all subjective symptoms as well as the global condition were significantly better under CTZ/PSE. Amounts of nasal secretions during these sessions were significantly lower with CTZ/PSE.     

Computer-assisted video measurement of inhibition of ciliary beat frequency of human nasal epithelium in vitro by xylometazoline.

The effect of xylometazoline, an alpha-adrenergic agonist, on ciliary beat frequency (CBF) was tested on samples of human nasal epithelium in vitro. Ciliated tissue was obtained from the inferior nasal turbinates of five normal individuals. CBF was measured from video recordings of ciliary activity using a computer-assisted photometric technique. The mean CBF of cells from the five subjects, followed for 40 min without xylometazoline, was 12.0 +/- 1.1 Hz. All concentrations of xylometazoline significantly decreased ciliary beat frequency. After a 10-min exposure, the mean CBF dropped to 3.8 +/- 0.4 with 0.1% xylometazoline, 4.9 +/- 1.0 with 0.05%, and 8.1 +/- 0.9 with 0.025%. Washing with control culture medium at least partially reversed the inhibition within 10 min. Phentolamine (10(-3) M), an alpha-adrenergic antagonist, did not alter CBF significantly when used alone, but partially blocked the strong cilioinhibitory effect of xylometazoline. This action of xylometazoline is similar to that of several commercially prepared decongestants that contain potentially ciliotoxic preservatives in addition to alpha-adrenergic agonists and supports the view that alpha-adrenergic agonists act directly on ciliated cells to inhibit ciliary activity.     

Comparison of the clinical efficacy of standard and mucoadhesive-based nasal decongestants

AIMS: To compare two xylometazoline 0.1% preparations: reference commercial solution (RS) and test mucoadhesive solution (TS). METHODS: Twenty subjects with perennial allergic rhinitis (age range 18-69 years, 5 atopic, 7 men) applied randomly in turn TS and RS for 5 days in a double-blind crossover clinical trial. Nasal airflow resistance (NAR), nasal symptoms (6 grade scoring), frequency of application (times/day), and side-effects were recorded. RESULTS: Mean ratio TS/RS of areas under the resistance/time curves for NAR +/- 90% CI: 3.56 +/- 0.92; mean TS-RS differences +/- 95% CI: for congestion: -1.12 +/- 0.59, for frequency of application: -1.10 +/- 0.20. Subjects experienced fewer side-effects with TS. CONCLUSIONS: A mucoadhesive solution with a decongestant had a greater and longer lasting effect on nasal congestion in subjects with perennial allergic rhinitis than the commercially available decongestant solution. It also caused fewer side effects.     

Nasal decongestion with imidazoline derivatives: acoustic rhinometry measurements

Objective: The objective of this single-blind study was to establish whether there are any differences between conventional imidazoline-containing nasal drops with regard to duration of action and decongestion potential. Methods: Six different substances were each administered to 108 healthy volunteers (nine groups of 12 adults), respectively, in the concentration recommended for adults (and two also in that recommended for infants) over a period of 8 h in comparison with 0.9% NaCl. The volumetric measurement of the nasal lumen was conducted by means of acoustic rhinometry (Rhinoklack). Results: The decongestive effect of all imidazoline preparations set in relatively uniformly, without any appreciable differences. After 20 min all the products exhibited approximately 60% of their maximum decongestive effect, which was achieved after approximately 40 min, having produced an increase in volume of approximately 20%. In contrast, in terms of duration of action, considerable differences between the individual products were to be discerned: indanazoline 0.118%, naphazoline 0.02% and tetryzoline 0.1% had no effect whatsoever after 4 h. Oxymetazoline 0.05% and 0.01%, xylometazoline 0.025% and 0.1%, and tramazoline 0.1264% still had an appreciable effect after 4 h, while after 8 h only oxymetazoline 0.05% and 0.01% still had a relevant decongestive effect. A rebound effect associated with reactive hyperaemia was observed after 8 h in all short-acting products (indanazoline, naphazoline, tetryzoline and tramazoline), which in the case of indanazoline was even associated with a reduction in the nasal lumen. Interestingly, there were no differences between the xylometazoline and oxymetazoline concentrations recommended for adults and those for infants in terms of efficacy. The low-dose concentrations of the preparations for infants appear to be sufficient to produce a satisfactory therapeutic effect. Received: 13 July 1998 / Accepted in revised form: 17 November 1998     

Scopolamine nasal spray in motion sickness: a randomised, controlled, and crossover study for the comparison of two scopolamine nasal sprays with oral dimenhydrinate and placebo.

Scopolamine has been used successfully for treatment of motion sickness for almost a century and the nasal administration was first studied 50 years ago. However, there never appeared a nasal dosage form. Finally, after finding a stable and suitable formulation for scopolamine, a study to investigate efficacy, safety, and tolerability was conducted, with a randomised, double-blind, double-dummy, crossover, Latin square design including placebo control and a placebo/placebo control for internal validity at the German Air Force Institute of Aviation Medicine. To assess the efficacy of a new, stable and well-tolerated formulation of scopolamine nasal spray the reproducible induction of whole body vibrations by a rotating chair was chosen and a validated seasickness score (SKS). The reduction of SKS showed that scopolamine nasal spray at a concentration of 0.2% was statistically superior to both placebo and dimenhydrinate (P=0.003 and 0.004, respectively). There were no signs for a nasal or epipharyngeal irritation of the mucous membrane. Scopolamine nasal spray was found to be an effective and safe treatment in motion sickness, with a fast onset of action within 30 min after administration.     

Preliminary studies on nasal decongestant activity from the seed of the shea butter tree, Butyrospermum parkii.

1 The seed of Butyrospermum parkii yields shea butter which according to local traditional healers relieves inflammation of the nostrils. 2 Since there is as yet no absolutely satisfactory nasal decongestant in clinical use, it was decided to investigate the effects of shea butter in nasal congestion. The substance was prepared in the laboratory. 3 The human subjects used were those suffering from rhinitis with moderate to severe nasal congestion. They were divided into the test group which received shea butter, the control group which was treated with xylometazoline and the 'placebo' group which received white petroleum jelly B.P. 4 The results showed that nasal congestion was relieved more satisfactorily in the test group than in the other two groups. 5 It is concluded that shea butter may prove more efficacious in nasal congestion than conventional nasal drops.     

Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant

The relative bioavailability of nicotine from a nasal spray was assessed in 15 smokers suffering a common cold and rhinitis according to generally accepted criteria. The patients were given a single dose of 2 mg nicotine from the nasal spray with and without concurrent administration of a nasal vasoconstrictor decongestant, xylometazoline, in randomised order. Control session measurements were made in the disease-free state.Applying strict bioequivalence criteria, we found that common cold/rhinitis slightly reduced the bioavailability of nicotine, both in its rate and extent; the geometric mean of the ratio of C_max, AUC and t_max were 0.81, 0.93 and 1.36, respectively. The nasal vasoconstrictor, xylometazoline, normalised the extent of the bioavailability of nicotine, but further prolonged the time for absorption to almost twice that measured in the disease-free state, increasing the t_max ratio to 1.72.The results suggest that a minor proportion of people stopping smoking with the help of a nicotine nasal spray may experience a minor reduction in the effect of the spray during common cold/rhinitis. However, the nicotine self-titration behaviour found with most smoking cessation products (except the nicotine patch) will automatically lead to an adjustment of the dosage to achieve the desired effect.     

Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse

The aim of this review was to investigate the rationale for replacing the nasal decongestant pseudoephedrine (PDE) with phenylephrine (PE) as a means of controlling the illicit production of methamphetamine. A literature search was conducted in electronic databases and use of textbooks. Restrictions have been placed on the sale of PDE in the USA in an attempt to control the illicit production of methamphetamine. This has caused a switch from PDE to PE in many common cold and cough medicines. PE is a poor substitute for PDE as an orally administered decongestant as it is extensively metabolized in the gut and its efficacy as a decongestant is unproven. Both PDE and PE have a good safety record, but the efficacy of PDE as a nasal decongestant is supported by clinical trials. Studies in the USA indicate that restricting the sale of PDE to the public as a medicine has had little impact on the morbidity and number of arrests associated with methamphetamine abuse. Restricting the sale of PDE in order to control the illicit production of methamphetamine will deprive the public of a safe and effective nasal decongestant and force the pharmaceutical industry to replace PDE with PE, which may be an ineffective decongestant. Restrictions on sales of PDE to the public may not reduce the problems associated with methamphetamine abuse.     

Thiomers in noninvasive polypeptide delivery: in vitro and in vivo characterization of a polycarbophil-cysteine/glutathione gel formulation for human growth hormone

This study was aimed at investigating the potential of a new polycarbophil-cysteine (PCP-Cys)/glutathione (GSH) gel formulation to enhance the permeation of the model drug human growth hormone (hGH) across nasal mucosa in vitro and in vivo. The aqueous nasal gel contained PCP-Cys, GSH, and hGH in a final concentration of 0.3%, 0.5%, and 0.6% (m/v), respectively. In vitro permeation studies were performed in Ussing chambers on freshly excised bovine nasal mucosa using fluorescence-labeled dextran (molecular mass: 4.3 kDa; FD-4) and hGH (FITC-hGH). The release profile of FITC-hGH from the gel formulation and an unmodified PCP control formulation was determined. Furthermore, in vivo studies in rats were performed comparing the PCP-Cys/GSH/hGH gel with PCP/hGH control gel and physiological saline. The permeation of FD-4 and FITC-hGH across the nasal mucosa was improved two-fold and three-fold, respectively, in the presence of PCP-Cys/GSH. The PCP-Cys/GSH/hGH gel and the PCP/hGH control gel showed the same biphasic and matrix-controlled drug release. The nasal administration of the PCP-Cys/GSH/hGH gel formulation to rats resulted in a significantly increased and prolonged hGH plasma concentration-time profile versus unmodified PCP gel and physiological saline. According to these results, PCP-Cys gels might represent a promising new strategy for systemic nasal polypeptide delivery.     

Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor

Acetazolamide, a carbonic anhydrase inhibitor is used orally (no topical formulation being available in the market) for the reduction of intraocular pressure (IOP) in patients suffering from glaucoma. Two major reasons responsible for the failure to develop a topically effective formulation of acetazolamide are its low solubility (0.7mg/ml) and its low permeability coefficient. It is generally recognized that topical acetazolamide formulation possessing efficacy similar to that achieved upon oral administration would be a significant advancement in the treatment of glaucoma. In order to enhance the bioavailability of acetazolamide by topical route and to improve the corneal permeability of the drug, the niosomes of acetazolamide were prepared (by reverse phase evaporation method) and coated with Carbopol for the latter's bioadhesive effect. The pharmacodynamic studies showed 33% fall in IOP with the developed formulation, and the effect was sustained for 6h after instillation. The effect compared well with a four times higher concentration of dorzolamide (Dorzox, a topical CAI available in the market. In the present study, the aqueous humor disposition of the drug from the developed bioadhesive coated niosomal formulation (ACZREVbio) is compared with the aqueous suspension of the drug (containing 1% (w/v) Tween 80 as a dispersing agent) at similar concentrations. The concentration of acetazolamide absorbed in the aqueous humor at various times from the control suspension and from ACZREVbio was determined by microdialysis in male albino rabbits. Microdialysis provides a complete concentration versus time profile and hence is an important advance to the regional sampling of tissues. The peak concentration of drug absorbed in the aqueous humor from the ACZREVbio formulation (14.94microg/ml) was almost two times of that obtained with the equivalent amount of acetazolamide control suspension (6.93microg). The results show a significant broadening of peak from 80 to 120min with the concentration of more than 13microg being maintained at these times, for the bioadhesive coated niosomal formulation (ACZREVbio). An important observation was the fact that a high drug concentration of 12.02microg reached immediately, i.e., 20min after instillation of ACZREVbio indicating a high penetration being achieved, while a meagre concentration of only 3.53microg is obtained at 60min after instillation of the control suspension. The aqueous humor disposition indicates peaks and troughs in drug concentration which may be related to the decrease in aqueous humor formation, such that the drug concentration/volume increased at these points.     

A new nasal decongestant, A-57219: a comparison with oxymetazoline

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.     

Pharmacological characterization of a noninvasive,chronic, experimental dog model of nasal congestion

INTRODUCTION: The present experiments were undertaken to pharmacologically characterize a noninvasive, chronic, experimental dog model of nasal congestion with the overall goal of developing an effective tool for studying the mechanism of action of nasal decongestant drugs. METHODS: Nasal patency was measured using acoustic rhinometry with chlorpheniramine and d-pseudoephedrine used as test agents. Solubilized compound 48/80 was administered as an intranasal mist to a single naris, to elicit nasal congestion in five conscious beagle dogs. Effects of localized degranulation of mast cells on nasal cavity volume, with and without pretreatment with oral decongestant drugs, were measured before and after compound 48/80 administration. Each series of experiments were repeated with a minimum 2-week rest period between trials. RESULTS: Compound 48/80 caused a decrease of nasal cavity volume (to about 50% of control). Maximal responses were seen at 90-120 min after 48/80 administration and were of similar magnitude when trials were repeated. Oral administration of the adrenergic agonist, d-pseudoephedrine (3 mg/kg), as well as the histamine H(1) receptor antagonist, chlorpheniramine (10 mg/kg), reduced compound 48/80-induced nasal congestion with the greater effect seen with alpha-adrenoceptor blockade. DISCUSSION: These results demonstrate the utility of using acoustic rhinometry to measure parameters of nasal patency in the conscious dog, and suggest that this model may provide an effective tool with which to study the actions of decongestant drugs in preclinical investigations using conscious preparations. As this technology is noninvasive, replicate determinations can be made in the same experimental subjects. Both alpha-adrenoceptor agonism and, to a lesser extent, histamine H(1) receptor antagonism appear to block compound 48/80-induced nasal congestion in this model.     

The addition of calcium ions to starch/Carbopol mixtures enhances the nasal bioavailability of insulin.

To evaluate the influence of calcium poly(acrylates) on the nasal absorption of insulin in rabbits, starch/poly(acrylic acid) (ratio 25/75) (SD 25/75) was neutralised with NaOH and/or Ca(OH)(2). After neutralisation, a mixture of sodium and/or calcium carboxylate was formed depending on the Ca(OH)(2) concentration in the formulation. IR spectroscopy confirmed that most of the calcium molecules in the formulation interacted with acid groups of the acrylic acid polymer. Addition of Ca(OH)(2) to aqueous dispersions containing starch/poly(acrylic acid) yielded powders with an enhanced absorption of insulin after nasal delivery to rabbits in comparison with the equivalent powder without Ca(OH)(2). A mixture of SD 25/75 and Ca(OH)(2) at a ratio of 90/10 neutralised to pH 7.4 with NaOH induced the highest absorption of insulin, obtaining a bioavailability of +/-29% (vs. 19% for an equivalent formulation without Ca(OH)(2)). This increase in nasal delivery was possibly due to a higher elasticity after dispersing this formulation in nasal fluid and to a higher water absorbing capacity. Furthermore, after nasal delivery of (SD 25/75)/Ca(OH)(2) 90/10, a decrease in t(max) was observed, possibly due to a progressive dissociation of Ca(2+)-ions after hydration of the powder resulting in the closing of the tight junctions.     

苯甲酸利扎曲普坦原位凝胶鼻喷剂的制备

目的：一种新型治疗偏头痛的鼻喷剂——苯甲酸利扎曲普坦（RZTB）原位凝胶鼻喷剂的制备。方法：经大鼠的鼻腔灌流试验来筛选最佳浓度的吸收促进剂;通过测定胶凝温度确定原位凝胶材料泊洛沙姆407（P407）和泊洛沙姆188（P188）的合适比例;利用胶凝温度、黏度、粒径分布、喷射角度和每喷主药含量来调整处方中各组分的比例,确定RZTB原位凝胶鼻喷剂的最优处方。结果：羧甲基壳聚糖（CMCS）具有较好的吸收促进效果,制备的RZTB原位凝胶鼻喷剂的最佳处方为：20% P407、2% P188、0.1% CMCS和0.5% RZTB。结论：本实验所得的RZTB原位凝胶鼻喷剂,制备工艺简单可行,为曲坦类药物新剂型的研发提供了依据。     

Efficacy and safety of intranasally applied dimetindene maleate solution. Multicenter study in children under 14 years suffering from seasonal allergic rhinitis

The aim of this study was to investigate the efficacy and tolerability of intranasally applied dimetindene (CAS 3614-69-5) 0.1% spray in children suffering from seasonal allergic rhinitis. A total of 100 children under 14 years with acute seasonal allergic rhinitis participated in this randomised, single-blind, reference-controlled, multi-center, parallel group study with two treatment groups. The study took place between 2nd April and 16th September 1996 during the pollen season. Patients were examined at enrollment (day 1), day 8 and day 15. Patients kept diary throughout the 2-week treatment phase. Patients were randomised to receive either dimetindene 0.1% (Fenistil Nasal Spray) or a levocabastine (CAS 79516-68-0) 0.05% solution as reference medication. Both medications were supplied in similar outer packages. A single-blind approach was chosen, because the reference medication levocabastine requires two spray puffs per nostril as a single dose, whereas for dimetindene maleate solution a single spray puff per nostril is sufficient. Dimetindene 0.1% was applied with 1 spray puff (= 0.14 mg dimetindene) in each nostril and levocabastine with 2 spray puff (= 0.10 mg levocabastine) in each nostril every day in the morning before leaving the house and in the evening before going to bed. Additional administration of the spray was allowed up to 4 times a day if needed. Efficacy was assessed as change in severity of characteristic symptoms associated with pollen rhinitis: nasal rhinorrhea, nasal itching, nasal sneezing and nasal congestion. In addition, changes in ocular symptoms, lacrimation, ocular itching and red eyes, global physician's assessment of efficacy at the end of treatment were assessed. The primary criterion change of total nasal symptom severity score between day 1 and day 3 resulted in a statistically equivalent and therapeutically relevant symptom reduction for the two treatments. All secondary criteria showed a similar reduction in symptoms, thus underlining the consistency of the findings. Both nasal sprays were well tolerated. It is concluded from these results that dimetindene 0.1% nasal spray solution is a safe and efficient treatment option for children under 14 years suffering from seasonal allergic rhinitis.     

Tolerability comparison of adapalene gel, 0.3% versus tazarotene cream, 0.05% in subjects with healthy skin

BACKGROUND: Topical retinoids, including adapalene and tazarotene, are a primary treatment choice for patients with acne. Adapalene is currently marketed in a 0.1% concentration in gel and cream formulation. A new gel containing a higher concentration (0.3%) of adapalene has been developed. In clinical studies, adapalene 0.1% concentration has proven to be better tolerated than other retinoids in skin treatment. However, the tolerability of adapalene gel 0.3% has yet to be compared to other topical retinoids. PURPOSE: The purpose of this study was to compare the local cutaneous tolerability of adapalene gel 0.3% once daily versus tazarotene cream 0.05% once daily. METHODS: Subjects reported to the investigative site each day Monday through Friday, cleansed the faced and then applied adapalene 0.3% gel to one side of the face and tazarotene 0.05% cream to the other in the presence of study personnel. For the weekends, subjects were instructed to apply the treatment at home according to the same procedure. Tolerability was assessed during each weekday visit. The study lasted for 3 weeks. RESULTS: Tolerability results for adapalene 0.3% gel and tazarotene 0.05% cream were statistically similar throughout the study. Investigator-assessed overall tolerability was in favor of adapalene at days 19 and 22 (P=.043). A cosmetic acceptability survey also showed results were better for adapalene 0.3% gel. CONCLUSION: Adapalene gel 0.3% is very well-tolerated with good cosmetic acceptability.     

In vitro and in vivo evaluation of a sulfobutyl ether beta-cyclodextrin enabled etomidate formulation

In this study, we report the formulation and in vivo evaluation of etomidate in an aqueous solution using sulfobutyl ether-7 beta-cyclodextrin (SBE-CD, Captisol) as a solubilizing agent. The phase-solubility behavior of etomidate as a function of SBE-CD concentration was evaluated, and accelerated solution stability studies of 2 mg/mL etomidate in a 5% w/v SBE-CD solution were conducted. The intravenous administration of the SBE-CD etomidate formulation in dogs was compared with Amidate, the commercial etomidate drug product formulated with propylene glycol as a cosolvent. The etomidate plasma concentration-time data were fit to a three-compartment mamillary model and the derived standard pharmacokinetic parameters were not statistically different between the two formulations (n = 4, p > 0.050). Concurrent pharmacodynamic analysis provided statistically equivalent maximum effects and median inhibitory concentrations for the two formulations. In vivo hemolysis after intravenous administration of Amidate was 10-fold higher than the SBE-CD formulation. Whereas Amidate cannot be given subcutaneously because of the cosolvent in the formulation, a 12 mg/mL aqueous solution of etomidate in 20% (w/v) SBE-CD was well tolerated by this route. The results suggest that the SBE-CD formulation is a viable clinical drug product with a reduced side-effect profile.     

Trapping of adrenergic decongestant drugs into cellular endomembrane compartments: toxicological and pharmacological consequences

Rhinitis of allergic and viral origin is often self-treated by patients with locally applied vasoconstrictor decongestant drugs. In turn, prolonged use of these agents produce an inflammatory condition termed rhinitis medicamentosa. Cationic drugs are sequestered into cells via various mechanisms, including mitochondrial concentration and V-ATPase-driven trapping in vacuoles that swell by an osmotic mechanism. We hypothesized that receptor-independent endomembrane sequestration of topically applied concentrated alpha-adrenoceptor agonists (decongestants, mydriatics) could contribute to their toxicity and prolonged duration of action. The morphological and functional effects of phenylephrine and xylometazoline on rabbit aortic smooth muscle cells were examined and their possible sequestration evaluated using the contractility of rabbit aorta rings. Synthetic agonists produced V-ATPase-dependent cell vacuolization (prevented by bafilomycin A1; xylometazoline 250 microM, phenylephrine 2.5 mM). V-ATPase-mediated cytotoxicity was slow (24 h; phenylephrine only, 5-10 mM); a rapid xylometazoline-induced cytotoxicity (> or =500 microM, 4 h) correlated to mitochondrial functional alterations. Xylometazoline had slower contraction and relaxation kinetics than the other alpha-adrenoceptor agonists in the aorta; bafilomycin pre-treatment influenced its kinetics (accelerated contraction and relaxation) and concentration-effect relationship (potentiation). V-ATPase-driven sequestration contributed to a component of the tissue reservoir of both phenylephrine and xylometazoline as assessed by aortic rings contracted with the concentrated agonists and subsequently washed. Phenylephrine and xylometazoline caused the V-ATPase-dependent cytopathology at a fraction of the usual topical concentrations; this form of sequestration influenced the toxicity and pharmacology of individual agents.     

Pharmacokinetics and relative bioavailability of a new chewable, buffered acetylsalicylic acid tablet formulation in comparison to a conventional plain tablet.

The pharmacokinetics of acetylsalicylic acid (ASA) and its main metabolite salicylic acid (SA) following single dose administration of a new chewable, buffered ASA tablet formulation and a conventional plain ASA tablet formulation were investigated in 12 healthy male subjects. The volunteers received in a randomized, crossover design two pharmaceutical units of both formulations containing 500 mg ASA each after an overnight fast on an empty stomach. ASA and SA in the collected plasma and urine samples were determined using an internally standardized validated HPLC method. Regarding the normalized extent parameters for ASA, an increase of about 114% for the maximum concentration (Cmax,norm) and about 16% for the area under the curve (AUC0----infinity,norm) was found for the new chewable, buffered tablet formulation as compared to the plain tablet. Comparing the corresponding parameters for the main metabolite, both formulations were statistically equivalent. The quotient of normalized areas (QAUC0-20min, norm/AUC0----infinity,norm) for ASA was higher by about 124% for the new formulation, indicating an increased and faster absorption during the first 20 min after administration. The time of the concentration maximum did not differ statistically. These data indicate that the new chewable, buffered ASA tablet formulation shows a significant benefit as compared to the plain ASA tablet. The new tablet produced higher plasma ASA concentrations in a shorter time, which is clinically important since higher ASA concentrations are assumed to be related to an improved analgesic efficacy.     

An In Vitro Study of the Diclofenac Delivery Properties of Hyaluronan in Human Skin

Previous in vitro studies have indicated that hyaluronan, when compared to buffer controls, effects a controlled and sustained release of diclofenac through the skin by the formation of a reservoir of the drug around the basement membrane. The aim of this study was to further characterize the drug delivery properties of hyaluronan by comparing it with other gel-forming materials and another glycosaminoglycan, chondroitin sulphate. The results show that neither NaCMC (at a weight or rheologically equivalent concentration) nor chondroitin sulphate (at a weight equivalent concentration) exert the controlled release effect seen for the hyaluronan formulationin fullthickness skin. A significant difference is seen between the cumulative amounts of labelled diclofenac diffused from the controls at times where sink conditions for the hyaluronan formulation are reached (p 0.05). Mass balance calculations from each experiment show that significantly more activity is retained in the skin when applied in 2.5% HA, compared to 2.5% NaCMC (p 0.02), 3.2% NaCMC (p 0.05) and 2.5% chondroitin sulphate (p 0.02). This study supports the hypothesis that the controlled release and epidermal retention of diclofenac is a characteristic specific to the hyaluronan formulation and does not appear to be observed with another rheologically equivalent gel,such as NaCMC or an alternative glycosaminoglycan, chondroitin sulphate.