Eur Arch Otorhinolaryngol (2006) 263: 827–832
`DOI 10.1007/s00405-006-0071-5
`
`RHINOLOGY
`
`Paul Merkus Æ Fenna A. Ebbens Æ Barbara Muller
`Wytske J. Fokkens
`Influence of anatomy and head position on intranasal drug deposition
`
`Received: 23 August 2005 / Accepted: 10 April 2006 / Published online: 29 June 2006
`Ó Springer-Verlag 2006
`
`Abstract The objective of this study was to determine the
`influence of individual anatomical differences on intra-
`nasal drug deposition. The data of a comparison of se-
`ven different administration techniques in ten healthy
`volunteers was used in this single-blind crossover pilot
`study. After intranasal administration of a dyed test
`formulation, endoscopic video imaging was done on
`seven non-sequential days. The deposition pattern per
`individual around the head of the middle turbinate was
`analyzed for each technique and correlated with the
`individual anatomy. Decreased deposition of dyed test
`formulation in the target area around the head of the
`middle turbinate was observed in the presence of minor
`septal deviations, narrow nasal valve areas, or inferior
`turbinate hypertrophy; a lateral head position helps to
`bypass a minor septal deviation. Although results are
`preliminary, we conclude that anatomy and head posi-
`tion are important factors in the deposition of topical
`nasal drugs and may be the key to improving individual
`local nasal (steroid) treatment.
`
`Keywords Nasal drug delivery Æ Nasal polyposis Æ
`Rhinosinusitis Æ Anatomy Æ Distribution Æ
`Head position
`
`Introduction
`
`A recent thorough review shows that only eight studies
`have proven the efficacy of topical intranasal cortico-
`
`P. Merkus (&)
`Department of Otorhinolaryngology & Head and Neck Surgery,
`VU University Medical Center, KNO 1D-116, P.O. Box 7057,
`1007 MB Amsterdam, The Netherlands
`E-mail: P.Merkus@VUmc.nl
`Tel.: +31-20-4443690
`Fax: +31-20-4443688
`
`F. A. Ebbens Æ B. Muller Æ W. J. Fokkens
`Department of Otorhinolaryngology & Head and Neck Surgery,
`Academic Medical Center, Amsterdam, The Netherlands
`
`steroids in the treatment of patients with chronic rhi-
`nosinusitis (five studies) and nasal polyposis (three
`studies) [6]. Although this treatment is often successful,
`topical corticosteroids sometimes fail to reduce polyp
`size effectively or to decrease rhinosinusitis complaints.
`Many factors determine the outcome of topical nasal
`drug treatment:
`formulation characteristics, delivery
`device, delivery technique, site of deposition, anatomy,
`pathophysiology, and compliance, for example. This
`means that there are many uncertainties confronting the
`ENT surgeon when optimizing treatment for individual
`patients.
`It seems rational to aim for the middle meatus when
`treating nasal polyposis and chronic rhinosinusitis [22].
`Several studies have looked at the best way to reach this
`area but, remarkably, the American Academy of Oto-
`laryngology–Head and Neck Surgery Foundation has
`failed, on the basis of a review of these studies, to draw
`definitive conclusions regarding the best technique for
`topical nasal treatment [3]. An explanation could be the
`underestimation of the influence of individual anatomy.
`If anatomical obstructions reduce the delivery to the
`middle meatus of topical nasal drugs, it would seem
`unlikely that there is a single administration technique
`appropriate for all patients. In a recent publication [14],
`we confirmed the absence of a ‘‘best technique’’ for
`topical nasal drug delivery; in the present pilot study, we
`correlate the drug deposition data with the individual
`anatomical differences. Ten volunteers and seven tech-
`niques of drug delivery were used to determine whether
`anatomical obstructions influence drug deposition and
`whether obstructions can be avoided by changing the
`technique of administration.
`
`Materials and methods
`
`Healthy volunteers
`
`symptoms were
`Healthy volunteers without nasal
`recruited through an advertisement. Volunteers with
`
`AQUESTIVE EXHIBIT 1114 Page 0001
`
`

`

`828
`
`frequent epistaxis, a history of smoking, an absent
`middle turbinate, a history of sino-nasal operations, or a
`severe septal deviation (defined as severe enough to
`prevent visualization of the anterior end of the middle
`turbinate without decongestion) were excluded. All
`anatomical differences were carefully described and re-
`corded prior to inclusion. Patients with various ana-
`tomical differences (except for extreme septal deviations
`as described above) were included. Volunteers taking
`medication (prednisone, antibiotics) known to interfere
`with nasal mucosa and volunteers with difficulties in
`assuming the different head positions for administration
`were excluded. All subjects were required to read and
`sign an informed consent form. The Medical Ethical
`Committee of the Amsterdam University Medical Cen-
`ter approved this study.
`
`Test drug formulation for sprays and drops
`
`The same dyed formulation was used in each test. The
`test formulation selected was fluticasone nasal drops
`[Flixonase nasulesÒ (1 mg/ml), GlaxoSmithKline, Zeist,
`Netherlands]. It was dyed with 0.1% methylene blue
`(methylthionin chloride 1 mg/ml of pharmaceutical
`grade). In order to ensure a comparable volume of test
`formulation in all test situations, the usual daily dose for
`fluticasone in a metered atomizing nasal spray (Flixon-
`ase, GlaxoSmithKline, Zeist, Netherlands, two puffs
`each nostril, approximately 0.18 ml) was used as the
`standard test volume.
`
`Nasal sprays
`
`Metered atomizing nasal spray for fluticasone (further
`referred to as ‘‘container spray’’) was emptied and filled
`with dyed test formulation. This device delivers 0.089 ml
`during each spray. After priming, two puffs per nostril
`were administered (equals approximately 0.18 ml per
`nostril) to each volunteer seated with the head in upright
`position (HUR).
`The manufacturer adapted a single-unit dose spray
`(Bidose MK3Ò, Valois, France) to deliver 0.18 ml of test
`formulation per nostril (fill volume 0.203 ml). This sin-
`gle-unit dose spray is, unlike the container spray, capa-
`ble of delivering drugs in different head positions. Three
`different head positions were tested (see below and
`Table 1).
`
`Nasal drops
`
`Nasal drops were administered using nasules (Flixonase
`nasules). Each nasule was filled with 0.20 ml dyed test
`formulation in order to deliver 0.18 ml after one firm
`squeeze (0.18 ml dose volume, 0.02 ml residual volume).
`This resembles the prescribed dosage of ‘‘half a nasule’’
`and is similar to the daily dose of the container spray.
`Three different head positions were tested (see below and
`Table 1).
`
`Study design
`
`A blind randomized crossover study using seven different
`nasal drug-delivery techniques (Table 1) was conducted.
`Each volunteer was tested on seven non-sequential days.
`The correlation between dye deposition and individual
`anatomy was analyzed.
`
`Head positions
`
`Head upright (HUR) This position is widely used for
`all multidose container sprays. The three other head
`positions are explained below and shown in Fig. 1.
`
`Lying head back (LHB) Lying down in supine posi-
`tion with the head just off the bed in hyperextension, so
`that the chin is the highest point of the head. This head
`position was described first by Proetz [19, 20] in 1926
`and modified by Mygind [16] in 1979.
`
`Lateral head low (LHL) [17 , 18 , 21] Lying on the side
`with the parietal eminence resting on the bed (no pillow
`or a pillow under the shoulders). The nasal formulation
`is administered in the lower nostril.
`
`Head down and forward (HDF), (Praying to Mecca) [4 ,
`13 ] Kneeling down with the top of the head on the
`ground and the forehead close to the knees with the
`nostrils facing upward.
`
`Protocol
`
`Three ENT physicians reviewed and graded the ana-
`tomical differences between the selected individuals.
`All healthy volunteers received instructions during the
`first visit. Subsequently, and at all later visits, an ENT
`
`Table 1 Summary of the seven techniques used. Figure 1 shows the head positions
`
`Device
`
`Sprays
`
`Multi-dose
`container
`HUR
`
`Single-unit dose
`
`LHB
`
`LHL
`
`HDF
`
`Drops
`
`Nasules
`
`LHB
`
`LHL
`
`HDF
`
`Head
`position
`
`Head
`upright
`
`Lying head
`back
`
`Lateral head
`low
`
`Head down
`forward
`
`Lying head
`back
`
`Lateral head
`low
`
`Head down
`forward
`
`AQUESTIVE EXHIBIT 1114 Page 0002
`
`

`

`829
`
`Endoscopic investigation
`
`A 2.7 mm, 0° Storz rigid nasendoscope was used and
`images were captured using digital video registration
`(StroboviewÒ 2000, Alphatron medical & microwave
`systems BV, Rotterdam, Netherlands). The endoscope
`was placed near the anterior end of the middle turbinate
`and subsequently retracted slowly while recording the
`images. This procedure was based on a combination of
`the photo analysis described by Weber and Keerl [25]
`and the endoscopic evaluation described by Homer and
`Raine [9]. No local anesthetic or decongestant was used.
`
`Video analysis
`
`Three independent ENT specialists analyzed the video
`images. Deposition of dyed formulation was scored as
`either ‘‘head of the middle turbinate insufficiently seen’’
`(not on the video), ‘‘absence of dye’’, or ‘‘presence of
`dye.’’ Presence of dye was scored at several pre-defined
`locations (Table 2) and dye scoring was rehearsed to
`diminish inter-observer variability. Observer consen-
`sus—with at least two observers independently agreeing
`about deposition scoring—was used in analysis. This is a
`statistically valid method often used in histological
`grading [23].
`‘‘Non-consensus videos’’ were excluded
`from analysis. The videos in which the middle turbinate
`was not visible were also excluded from analysis.
`
`Results
`
`Ten volunteers were included in the study: two males
`and eight females, median age 23 (19–28) years. Nostrils
`were evaluated separately (n=20). Seven different drug-
`delivery techniques were compared and a total of 140
`videos were analyzed. Anatomical differences were
`defined as ‘‘narrow valve area’’ (three volunteers/six
`
`Table 2 Deposition of dyed test formulation. Results of 140 inde-
`pendently reviewed nasal deposition videos. Nine pre-defined
`locations were assessed. Only ‘‘valid’’ observations (videos in which
`the location was visible) were assessed and scored as ‘‘dye present’’
`or ‘‘dye absent.’’ A decreased amount of dye is observed when
`going from the vestibulum (97%) to postero-cranial
`locations
`(above the middle turbinate, 17%)
`
`Location
`
`Dye (%)
`
`Vestibulum
`Inferior turbinate head
`Inferior turbinate tail
`Septum
`Lateral wall
`Lateral of middle turbinate
`Middle turbinate head
`Medial of middle turbinate
`Superior of middle turbinate
`Median
`
`97
`83
`83
`68
`36
`28
`45
`30
`17
`45
`
`AQUESTIVE EXHIBIT 1114 Page 0003
`
`Fig. 1 Three head positions: a Lying head back (LHB, chin as
`highest point), b lateral head low (LHL, lying on one side), and
`c head down and forward (HDF, ‘‘praying to Mecca’’)
`
`physician administered the test formulation using one
`of the techniques described in the study design (Ta-
`ble 1 and Fig. 1). After administration, the volunteer
`remained in the same position for 60 s. Vigorous
`sniffing and nose blowing were not allowed during the
`test (this was only allowed prior to administration and
`after endoscopy). In the next room, a second ENT
`physician, who was not informed of the technique
`used for drug administration, performed a nasal
`endoscopy within three minutes after administration.
`The technique used for drug delivery was revealed
`after scoring of three independent observers and after
`closing of the database.
`
`

`

`830
`
`nostrils), ‘‘hypertrophic or congested inferior turbinate’’
`(ten nostrils), and ‘‘septal deviation/slight septal devia-
`tion’’ (five volunteers/five narrow nostrils and five con-
`tralateral
`‘‘open’’ nostrils). Three ENT physicians,
`proceeding without objective measurements and without
`selection, independently agreed upon the interpretation
`of these anatomical differences. The results are presented
`in Table 2. Values counted as ‘‘head of the middle tur-
`binate
`insufficiently
`seen’’ or without
`consensus
`(minority) were excluded from analysis (16% of all
`observations, mainly observations in narrow cephalic
`regions, only 10% in the head of the middle turbinate
`region). Positive scores for the overall presence of dye
`were found in 45% of observations, with 55% of
`observations resulting in negative scores (median val-
`ues). On and around the middle turbinate, the number of
`observations without dye (55–72%) exceeded those with
`dye (28–45%).
`Looking at anatomical differences between individu-
`als, a trend emerges indicating that anatomy affects the
`site of deposition. Figure 2a–c shows the cumulative
`deposition pattern in three individuals after testing all
`seven techniques. Only in a few techniques did the
`deposition reach the area around the middle turbinate,
`in volunteers with a narrow valve area or hypertrophic
`inferior turbinate (Fig. 2a). Dye deposition was good at
`all sites and with all techniques in volunteers with an
`‘‘open’’ nose (Fig. 2b). A mild septal deviation caused a
`decrease in the amount of dye present in the area around
`the middle turbinate on the obstructing convex side and
`an increase or ‘‘normal’’ amount of dye on the concave
`side (Fig. 2c).
`Head position (read: gravity) seems to have a sub-
`stantial influence on drug delivery to the middle meatus.
`Increased amounts of dye are present in more lateral
`locations (this is especially important when challenging
`septal deviations) when using the LHL head position
`(Fig. 3) and in the superior region when using the HDF
`head position (data not shown). These results support
`the idea that gravity affects drug deposition.
`In general, the different techniques of topical nasal
`drug administration were easily accepted, although most
`volunteers mentioned some discomfort associated with
`the HDF head position. This confirms the findings of
`Kayarkar et al. [11] The test formulation was tolerated
`well, but some volunteers noticed some discomfort
`(sneezing and itching). No adverse effects were observed.
`
`Discussion
`
`When the literature fails to provide definitive conclu-
`sions about the best technique for administering topical
`nasal drugs, it is difficult to investigate ‘‘a best tech-
`nique,’’ even supposing that one exists. In a recent re-
`view, Aggarwal et al. [1] clearly point out why topical
`nasal drug deposition is hard to investigate. Individual
`anatomical differences, different head positions, and the
`use of sprays or drops all affect topical nasal drug
`
`Right Nostril
`
` Left Nostril
`
`Case 1
`
`Vestibulum
`
`Inferior turbinate head
`
`Inferior turbinate (tail)
`
`Septum
`
`Lateral wall
`
`Lateral of middle turbinate
`
`Middle turbinate head
`
`Medialof middle turbinate
`
`Superior of middle turbinate
`
`100% 0 100%
`number of observations
`
`Right Nostril
`
` Left Nostril
`
`Case 2
`
`Vestibulum
`
`Inferiorturbinate head
`
`Inferiorturbinate (tail)
`
`Septum
`
`Lateral wall
`
`Lateral of middle turbinate
`
`Middle turbinate head
`
`Medialof middle turbinate
`
`Superior of middle turbinate
`
`100% 0 100%
`number of observations
`
`Right Nostril
`
` Left Nostril
`
`Case 3
`
`Vestibulum
`
`Inferior turbinate head
`
`Inferior turbinate (tail)
`
`Septum
`
`Lateral wall
`
`Lateral of middle turbinate
`
`Middle turbinate head
`
`Medialof middle turbinate
`
`Superiorof middle turbinate
`
`100% 0 100%
`number of observations
`
`Fig. 2 Individual deposition (cases 1–3) and anatomical correla-
`tion. Deposition of dye at various locations shown for both left and
`right nostrils of three individuals after administration using seven
`techniques. The presence or absence of dye per technique is
`cumulatively represented by a bar on the X-axis (100% = seven
`techniques). Bar length = amount of videos scored. The white
`dotted bar shows the number of videos scored as ‘‘absence of dye.’’
`The black bar shows the number of videos scored as ‘‘presence of
`dye.’’ The anatomical
`locations are on the Y-axis. Each bar
`represents the percentage of observations. A clear correlation
`between observed deposition and anatomy can be seen. a Case 1:
`septal deviation to the right, narrow valve area; b case 2: an ‘‘open
`nose’’; c case 3: septal deviation to the right and an ‘‘open’’ valve
`region
`
`administration. Moreover, the wide variety of research
`methods used renders comparison between studies dif-
`ficult. In that perspective, we have gathered data in a
`standardized manner relating to techniques with drops
`and sprays and different head positions. We studied ten
`
`AQUESTIVE EXHIBIT 1114 Page 0004
`
`

`

`831
`
`position. A crossover efficacy study in patients with
`minor effect with one head position could maybe
`establish the value of changing the head position. Until
`then it seems plausible to advise a different head position
`when treatment fails.
`In a small study (n=5) of Homer et al. [8], it is sug-
`gested that there is an optimal delivery technique for
`each individual; some volunteers do better on nasal
`drops whereas others are best treated with nasal sprays.
`In our study, we also investigated both techniques, and
`we conclude from our data that individual anatomical
`variations are the most important factor in determining
`the outcome of topical nasal drug treatment. In 1985,
`Hardy et al. [7] concluded that nasal drops are superior
`to nasal sprays in penetrating the nasal valve area. From
`our data, we conclude that considerable amounts of dye
`fail to penetrate the nasal valve area with all techniques
`and that nasal sprays are superior, albeit not signifi-
`cantly, to nasal drops for bypassing the valve area. The
`decrease in deposition toward the cephalic nasal regions
`(Table 2) supports the idea that the middle meatus area
`is difficult to reach and that most of the administrated
`formulation will never reach this area [9, 15, 26]. It is
`possible that a narrow valve and vestibule hair area can
`be bypassed using a longer nasal-spray tip and high-
`velocity administration, increasing drug delivery to the
`head of the middle turbinate. This spray advantage is in
`contrast to the efficacy study of fluticasone drops of
`Aukema et al. [2], which seems to be more effective in the
`treatment of nasal polyposis when comparing the results
`to treatment with fluticasone spray as studied by Lund
`et al. [12] An explanation for this can be the question-
`able predictive value of healthy volunteers in our study.
`Although we were able to investigate several aspects
`of nasal drug delivery, our study has several limitations:
`video imaging simplifies the nose to a 2D structure, it is
`not a quantitative measure, and the rigidity of the
`endoscope occasionally prevents assessment of every
`area of the nose. The nasal cycle (changing turbinate
`congestion) has not been seperately taken into account.
`Furthermore, it is not known whether the test solution
`reaches the area of the middle turbinate later as a result
`of mucociliary clearance. This is especially important in
`the case of nasal drops, because droplets do not neces-
`sarily reach the target area of the middle turbinate at the
`same time and in the same way as nasal sprays [7]. By
`comparison with a recommended, more quantitative,
`assessment [1, 8], we did not alter nasal physiology by
`using a decongestant and local anesthetic. As our tech-
`nique is well tolerated, repeated testing is possible,
`making the comparison between different techniques in
`one subject possible.
`Although our results reveal differences in topical
`nasal drug deposition associated with ‘‘normal’’ ana-
`tomical variations, they are not statistically significant.
`Furthermore, in this pilot study, we did not select the
`patients for their nasal anatomy; we investigated whe-
`ther there were correlations between anatomy and
`deposition in the nose. Extrapolation of our data of
`
`Lateral nasal wall
`
`20
`18
`16
`14
`12
`10
`
`20468
`
`Observations
`
`Unit Dose Spray HDF
`Nasal Drops HDF
`Unit Dose Spray LHL
`Nasal Drops LHL
`UnitDose Spray LHB
`Nasal Drops LHB
`Container spray HUR
`
`Dye Present Dye Absent
`
`Fig. 3 Deposition lateral nasal wall. The number of valid obser-
`vations per technique is around 16/20 (84%). Dye was present on
`the lateral nasal wall in about 6/20 observations (36%) of these
`observations. The most favorable head position during adminis-
`tration for reaching the lateral nasal wall is lateral head low (LHL)
`(ten observations with dye present using the single-unit dose nasal
`spray and eight observations with dye present using nasal drops)
`
`volunteers in an intra-individual and inter-individual
`comparison [14].
`This pilot study establishes that individual anatomi-
`cal differences, even though seeming trivial upon first
`inspection, explain the impossibility of identifying a
`single ‘‘best technique’’ for topical nasal corticosteroid
`administration [14]. The outcome of topical nasal drug
`treatment is even harder to predict when there are
`pathological changes. Obstruction by either a hyper-
`trophic inferior turbinate or a narrow nasal valve area
`confines delivery of topical nasal drugs to the head of the
`middle turbinate (Fig. 2). These findings confirm the
`results of Dowley et al. [5], who showed that congestion
`of
`the inferior turbinate significantly reduced drug
`delivery to the middle meatus. Weber suggested that a
`septal deviation may affect nasal drug deposition [26],
`but we are not aware of any other study that investigates
`this suggestion. In concordance with most drug delivery
`studies, we excluded patients with severe septal devia-
`tions in order to ensure adequate observation of the
`head of the middle turbinate [5, 8–10, 24]. In spite of this
`exclusion criterion, we show that even slight septal
`deviations can have major consequences on nasal drug
`deposition. Only five volunteers with ‘‘minor’’ septal
`deviations were included in our study; still we were able
`to show that their drug deposition patterns (70 obser-
`vations) are remarkably similar. Furthermore, adminis-
`trating topical nasal drugs in certain head positions
`(LHL, LHB) bypasses
`septal deviations,
`thereby
`increasing the amount of drug delivered to the head of
`the middle turbinate. Improving nasal drug deposition
`to the middle meatus when the individual’s anatomy is
`unfavorable may therefore be a matter of changing head
`
`AQUESTIVE EXHIBIT 1114 Page 0005
`
`

`

`832
`
`healthy volunteers to patients suffering from rhinosi-
`nusitis with or without nasal polyposis is difficult,
`especially since intranasal deposition and distribution
`patterns are presumed to be different in these diseases.
`Investigating patients with pathological conditions like
`nasal polyposis should therefore be the next step in nasal
`drug delivery studies.
`Although these results are still preliminary, we
`recommend taking even ‘‘minor’’ anatomical differences
`into account when trying to optimize topical nasal drug
`treatment for individual patients. Head position during
`administration should be adapted to individual ana-
`tomical characteristics. The single-unit dose spray seems
`to present potential advantages for topical nasal drug
`delivery and it therefore merits additional testing.
`
`Acknowledgment We wish to thank Valois (France) for their sup-
`port with the single-unit dose device.
`
`References
`
`1. Aggarwal R, Cardozo A, Homer JJ (2004) The assessment of
`topical nasal drug distribution. Clin Otolaryngol 29:201–205
`2. Aukema AA, Mulder PG, Fokkens WJ (2005) Treatment of
`nasal polyposis and chronic rhinosinusitis with fluticasone
`propionate nasal drops reduces need for sinus surgery. J Al-
`lergy Clin Immunol 115(5):1017–1023
`3. Benninger MS, Hadley JA, Osguthorpe JD, Marple BF, Leo-
`pold DA, Derebery MJ, Hannley M (2004) Techniques of
`intranasal steroid use. Otolaryngol Head Neck Surg 130:5–24
`4. Chalton R, Mackay I, Wilson R, Cole P (1985) Double-blind,
`placebo-controlled trial of betamethasone nasal drops for nasal
`polyposis. Br Med J 291:788
`5. Dowley AC, Homer JJ (2001) The effect of inferior turbinate
`hypertrophy on nasal spray distribution to the middle meatus.
`Clin Otolaryngol 26:488–490
`6. Fokkens WJ, Lund V, Bachert C, Clement P, Helllings P,
`Holmstrom M, Jones N, Kalogjera L, Kennedy D, Kowalski
`M, Malmberg H, Mullol J, Passali D, Stammberger H, Stierna
`P (2005) EAACI position paper on rhinosinusitis and nasal
`polyps executive summary. Allergy 60(5):583–601
`7. Hardy JG, Lee SW, Wilson CG (1985) Intranasal drug delivery
`by sprays and drops. J Pharm Pharmacol 37:294–297
`8. Homer JJ, Maughan J, Burniston M (2002) A quantitative
`analysis of the intranasal delivery of topical nasal drugs to the
`middle meatus: spray versus drop administration. J Laryngol
`Otol 116:10–13
`
`9. Homer JJ, Raine CH (1998) An endoscopic photographic
`comparison of nasal drug delivery by aqueous spray. Clin Ot-
`olaryngol 23:560–563
`10. Karagama YG, Lancaster JL, Karkanevatos A, O’Sullivan G
`(2001) Delivery of nasal drops to the middle meatus: which is
`the best head position? Rhinology 39:226–229
`11. Kayarkar R, Clifton NJ, Woolford TJ (2002) An evaluation of
`the best head position for instillation of steroid nose drops. Clin
`Otolaryngol 27:18–21
`12. Lund VJ, Flood J, Sykes AP, Richards DH (1998) Effect of
`fluticasone in severe polyposis. Arch Otolaryngol Head Neck
`Surg 124:513–518
`13. Mackay I (1997) Infective rhinitis and sinusitis. In: Scott
`Browne, Otolaryngology 6th edn. Butterworth Heinemann,
`Oxford, p 4/8/24
`14. Merkus P, Ebbens FA, Muller B, Fokkens WJ (2006) The ‘‘best
`method’’ of topical nasal drug delivery: a comparison of seven
`techniques. Rhinology 44:102–110
`15. More´ n F, Bjornek K, Klint T, Wagner ZG (1988) A compar-
`ative distribution study of two procedures for administration of
`nose drops. Acta Otolaryngol 106:286–290
`16. Mygind N (1979) Conventional medical treatment. In: Nasal
`allergy, 2nd edn. Blackwell Scientific Publications, Oxford,
`pp257–270
`17. Parkinson SN (1933) A lateral head-low position for nasal and
`sinus treatment. Arch Otolaryngol 17:787–788
`18. Parkinson SN (1939) Non-traumatic ventilation treatment of
`the nose and sinuses. J Laryngol Otol 54:611–620
`19. Proetz AW (1926) Displacement irrigation of nasal sinuses.
`Arch Otolaryngol 4:1–13
`20. Proetz AW (1927) Further data on the displacement method in
`sinuses. Ann Otol Rhinol Laryngol 36:297–323
`21. Raghavan U, Logan BM (2000) New method for the effective
`instillation of nasal drops. J Laryngol Otol 114:456–459
`22. Stammberger H (1986) Endoscopic endonasal surgery: con-
`cepts in treatment of recurring rhinosinusitis. Part I. Anatomic
`and pathophysiologic considerations. Otolaryngol Head Neck
`Surg 94:143–147
`23. Tabor MP, Braakhuis BJ, van der Wal JE, van Diest PJ,
`Leemans CR, Brakenhoff RH, Kummer JA (2003) Compara-
`tive molecular and histological grading of epithelial dysplasia
`of the oral cavity and the oropharynx. J Pathol 199(3):354–360
`24. Tsikoudas A, Homer JJ (2001) The delivery of topical nasal
`sprays and drops to the middle meatus: a semiquantitative
`analysis. Clin Otolaryngol 26:294–297
`25. Weber R, Keerl R (1996) Einsatz moderner Bilddatenverar-
`beitung in der klinisch-rhinologischen Forschung. Eur Arch
`Otorhinolaryngol Suppl 1:271–296
`26. Weber R, Keerl R, Radziwill R, Schick B, Jaspersen D,
`Dshambazov, Mlynski G, Draf W (1999) Videoendoscopic
`analysis of nasal steroid distribution. Rhinology 37:69–73
`
`AQUESTIVE EXHIBIT 1114 Page 0006
`
`