DRUGS AND THE PHARMACEUTICAL SCIENCES
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`M0780} [siee)
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`Nasal Systemic
`ea
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`Yie W. Chien
`Kenneth S.E. Su
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`Nasal Systemic
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`Drug Delivery
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`YIE W. CHIEN
`Controlled Drug-Delivery Research Center
`College of Pharmacy, Rutgers University
`Piscataway, New Jersey
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`KENNETHS. E. SU
`Pharmaceutical Research Department
`Eli Lilly and Company
`Indianapolis, Indiana
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`SHYI-FEU CHANG
`Department of Pharmaceutics/Drug Delivery
`Amgen Incorporated
`Thousand Oaks, California
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`MARCELDEKKER, INC.
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`New York « Basel
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` Library of Congress Cataloging-in-Publication Data
`
`Nasal systemic drug delivery / [edited by] Yie W. Chien, Kenneth S. E.
`Su, Shyi-Feu Chang.
`p.
`cm. ~(Drugs and the pharmaceutical sciences; v. 39)
`Includesbibliographies and index.
`ISBN 0-8247-8093-0 (alk. paper)
`1. Intranasal medication.
`I. Chien, Yie W.
`Kenneth S. E.
`II. Chang, Shyi-Feu
`RM160.N37
`615’.6--dc20
`
`Il. Su,
`IV. Series.
`
`89-12007
`CIP
`
`1989
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`'
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`
`
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`This bookis printed on acid-free paper.
`
`Copyright © 1989 by MARCEL DEKKER, INC.
`
`All Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying, micro-
`filming, and recording, or by any information storage andretrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Currentprinting (last digit).
`
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`10987654321 PRINTED IN THE UNITED STATES OF AMERICA
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` 4
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`Anatomyand Physiology of the Nose
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`The bioavailability of a drug and hence its therapeutic effectiveness are often
`influenced by the route selected for administration. For a medication to
`achieve its maximal efficacy, a drug should be able to be administered easily
`so better patient compliance can be achieved; andit should be capable of
`being absorbedefficiently so greater bioavailability can be accomplished. The
`nasal route appears to be an ideal alternative to the parenterals for adminis-
`tering drugs intended for systemic effect in view of the rich vascularity of
`the nasal membranes and the ease of intranasal administration.
`Several advantages can be achieved from delivering drugsintranasally:
`(a) avoidance of hepatic “first-pass” elimination, gut wall metabolism, and/or
`destruction in gastrointestinal tracts; (b) the rate and extent of absorption
`and the plasma concentration vs. time profile are relatively comparable to
`that obtained by intravenous medication; and (c) the existence of a rich vas-
`culature and a highly permeable structure in the nasal membranes for absorp-
`tion. These advantages have made the nasal mucosa a feasible and desirable
`site for systemic drug delivery.
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`However, there are somefactors that should also be considered for opti-
`mizing the intranasal adminstration of drugs: (a) methods and techniques of
`administration; (b) thesite of disposition; (c) the rate of clearance; and (d)
`the existence of any pathological conditions which may affect the nasal
`functions. These factors could potentially influence the efficiency of nasal
`absorption ofdrugs.
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`To study the intranasal delivery of drugs for systemic medication,it is im-
`portantto first gain some fundamental understanding of the anatomy and
`physiology of the nose.
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`1.1. NASAL PASSAGE
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`The upperrespiratory tract is constantly influenced by the inspiredair.
`The nasal modification of the inspired air by filtration, humidification, and/
`or warming are considered to be prime functions of the nose in man (1). To
`carry out its functions, the nose must control the rate of air flow, remove
`noxious agents, and introduce large quantities of fluid into the air stream.
`The nasal passage which runs from thenasal vestibule(i.e., nasal valve)
`to the nasopharynx has a depth of approximately 12-14 cm (2) (Figure 1.1).
`In this passage, the nasal cellular apparatus is in close contact with mucus
`which protects the mucosa from the inspired air. There are three distinct
`functional zones in the nasal cavities (3,4); namely, vestibular, respiratory,
`and olfactory areas, which are arranged anteroposteriorly in this sequence
`of order (Figure 1.2). (a) The vestibular area serves as a baffle system, and
`its surface is covered by a common pseudostratified epithelium where the
`long hairs may provide the functionoffiltering airborneparticles. (b) The
`respiratory area has a surface lined by a pseudostratified columnar epithel-
`ium, and is normally covered by a dense layer of mucusthatis constantly
`moving toward the posterior apertures of the nasal cavity by a powerful
`system of motile cilia. (c) The olfactory region is about 10 cm?, as com-
`pared to 170 cm? in the German shepherd dog. Theolfactory airwaylies
`above the middle turbinate between the nasal septum andthelateral wall
`of the main nasal passage. The airway here is only about 1-2 mm wide and
`is contiguousto the cribriform plate above. This region is generally free of
`inspiratory air flow.
`The nasal passage is composedof a horizontally skin-lined vestibule with
`the passages being directed upward and backward, andis separated by a car-
`tilaginous, bony nasal septum (5). The lateral wall is convoluted with stra-
`tegically placed turbinates that mold the air stream to their configurations
`and changing dimensions.
`The anterior nares mark the beginning of the double nasal airway, which
`extends from the entranceat the nostrils to the beginning ofciliated mucosa
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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`(Left) The upper airways seen from the midline. The dashed line
`Figure 1.1
`just beyondthe nostril marks the beginning of the nasal valve, whereas the
`dotted line shows approximately the beginning of the ciliated epithelium re-
`gion. The dashed line near the nasopharynx indicates the posterior termina-
`tion of the nasal septum. (Right) Section through the main nasal passage
`showing the nasal septum, folds of the turbinates, and airway. The stippled
`area indicates the olfactory region, which is generally free of inspriatory air
`flow. The hatched areas mark the meatal spaces, through which there is very
`little air flow, but in which there exist the communications with the paranasal
`sinuses and nasolacrimal duct. The clear areas represent the main nasalair-
`way for inspiratory airflow and the region lined with richly vascular erectile
`tissue. This is the site primarily reached by the medications applied intra-
`nasally as nose dropsor fine aerosol sprays. (From Ref. 1, reproduced with
`permission of Elsevier.)
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`nasal passage extends backward by approximately 6-8 cm to the posterior
`ends ofthe turbinates and the arch of the septum.
`Its crosssectionis large,
`but the width of the convoluted air stream is narrow. The liningis ciliated,
`highly vascular, and rich in mucous glands and gobletcells. The septum
`ends at the nasopharynx and the airways merge into one (7).
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`4
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`CHAPTER 1
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`Figure 1.2 Diagram showingthelateral wall of the nasal cavity. A, nasal
`vestibule, B, internal ostium, C, inferior turbinate; D, middle turbinate, E,
`superior turbinate. The hatchedareas indicate the olfactory region. (From
`Ref. 3, reproduced with permission of Elsevier.)
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`1.2 NASAL EPITHELIUM
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`The nasal membrane can beclassified into olfactory and nonolfactory epi-
`thelia (5). The olfactory epithelium is a pseudostratified columnain type,
`and consists of specialized olfactory cells, supporting cells, and both serous
`and mucousglands, whereas the nonolfactory epithelium is a highly vascular
`tissue covered by a ciliated pseudostratified columnar epithelium (Figure
`1.3). The olfactory cells are bipolar neurons andact as peripheral receptors
`and first-order ganglion cells.
`There are two types of mucuscovering the surface of the mucous mem-
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`Pseggott
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`brane: one adheresto thetips ofcilia, and the otherfills the space among the
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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`Figure 1.3. Transmission electron microscopic view of variouscell types in
`the nasal epithelium.
`I, nonciliated columnarcell with microvilli, II, goblet
`cell with mucousgranules and Golgi apparatus,III, basal cell, IV,ciliated
`columnar cell with mitochondria in the apical part, DM, double membrane,
`CTM,connective tissue membrane. (From Ref. 125, reproduced with permis-
`sion of Blackwell.)
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`cilia. Numerousgroupsof microvilli can be seen microscopically among the
`groups ofcilia. All microvilli are of short clublike appearance andthere are
`approximately 500 microvilli on the surface of each ciliated cell. These cells
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`with microvilli are called goblet cell. Another type of epithelial cell is ob-
`served in the free surface of the mucous membrane. They are rounded or
`elonged in shape and rough on the surface. These cells are defined as squa-
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`mouscells. However, some polygonalor elonged cells apparently have
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`numerous microvillilike processes on their outer surface. These basal cells of
`the lining epithelium havea looser intercellular connection and a wider inter-
`cellular space than in the ciliated cells. Furthermore, the subepithelial layer
`is seen to be packed with fibrils and covered with a homogeneous gelatinlike
`substance. Theindividual fine fibrils form bundles, but they are separated
`from each other with branches connecting the adjacentfibril to form net-
`works.
`Adequate moisture is required to maintain the normal functions of the
`nasal mucosa (8). Dehydration of the mucousblanketincreases the viscosity
`of the secretions and reducestheciliary activity. Thus, the recovery of heat
`and moisture from the expired air by the nasal membranesis of fundamental
`importancefor retaining its normal functions.
`In many animal species, including man, pronounced respiratory and car-
`diovascular responses associated with primary reflex from the nose can be
`elicited by appropriate stimulation of the nasal mucous membrane(9).
`Histamine has been detected in the nasal mucosa andalso in the nasal secre-
`tions ofallergic rhinitis (10). Another smooth muscle-stimulating substance,
`probably an unsaturatedacid, has also been found in the nasal mucosa of
`the dog and sheep.
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`1.3 NASAL SECRETIONS
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`The composition of nasal secretions is complex and consists of a mixture
`of secretory materials from the gobletcells, nasal glands, and lacrimal glands
`and a transudate from plasma(11,12).
`Ina clean, noninfected, nonallergic, and nonirritated nose, the mucosa is
`covered by a thin layer of clear mucuswhichis secreted from the mucousand
`serous glands in the nasal mucosa and submucosa (13). This mucous blanket
`is moved posteriorly by theciliary beat at a rate of about 1 cm/min, so that
`the nasal mucusis renewed approximately every 10 min. A total of approxi-
`mately 1500-2000 ml of mucus is produced daily, which contains 90-95%
`water, 1-2% salt, and 2-3% mucin. The mucushas a two-layer composition:
`The watery (sol) layer is located immediately adjacent to the mucosalsur-
`face, and the mucous(gel) layer, which is more superficial. Normal nasal
`secretions contain about 150 mEq/L of sodium, 40 mEq/L of potassium,
`and 8 mEq/Lofcalcium aswell as about 600 mg% of proteins,including 57
`mg% of albumins and 133 and 50 mg% of immunoglobulins A (IgA) and G
`(IgG), respectively (14).
`In addition to mucousglycoproteins, nasal secretions contain a variety
`of other proteins:
`lysozymes (15,16), enzymes (17), IgA, IgE, IgG, and al-
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`bumins (14-18); kallikrein-like substance (19), protease inhibitor (20,21),
`prostaglandins (22-24), reagenic and antibacterial antibody (25), influenza
`virus-neutralizing activity, and hemagglutination-inhibiting activity (16,26)
`as well as serum proteinslike gamma A-globulin, gamma G-globulin, albumin,
`and siderophilin (27,28).
`The functions of mucusinclude:
`(a) acts as a retainer for the substances
`in the nasal duct; (b) behaves as an adhesive; (c) has water-holding capacity;
`(d) transports particulate matter; (e) exhibits surface electrical activity; (f)
`protects the mucosa; (g) acts as a mesh with permeability; and (h) allows
`heat transfer (13). Both experimentally and clinically, it has been reported
`that the nasal epithelium maybealtered to produce excess mucusbydif-
`ferent agents, including gases,viruses, bacteria, and certain diseases, such as
`allergic rhinitis (11). In addition, parasympathetic stimulation from metha-
`cholin, histamine, or SRS-A (slow-reacting substance of anaphylaxis) will
`also stimulate the secretion of mucous glycoproteins.
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`1.4 NASAL MUCOCILIARY CLEARANCE
`Nasal ciliary clearance is one of the most important physiological defense
`mechanismsofthe respiratory tract to protect the body against any noxious
`materials inhaled. There are approximately five ciliated cells for each mucous
`cell, with an average of 200cilia extending from every ciliated cell on the sur-
`face of psuedostratified columnar epithelium. An individual cilium is approx-
`imately 5 yw in length and 0.2 p in diameter (29), which moves at a frequency
`of about 20 beats/sec (30). Thefine structure of the cilum consists of a
`ring of nine outer doublets surrounding a central pair (31) (Figure 1.4).
`Each doublet contains an A and B subfibril with both an inner and an outer
`dynein (a complex protein with adenosine triphosphatase [ATPase] activ-
`ity) arm located on the A subfibril with a radial spoke extending toward the
`central doublet. The microtubules are surrounded by a cell membrane which
`is an extension from the body ofthe respiratory epithelial cell. Cilia beat in
`a synchronized fashion in a highly complicated manner. The motion of the
`cilia is dependent upon the microtubules sliding past one another with the
`dynein providing the needed ATPase activity. The bending oftheciliais
`thought to be caused by the radial spokes detaching and reattaching onto
`the central microtubules (32). Their coordination may be associated with
`neutral innervation, chemical pacemakingstimulation from hormones (e.g.,
`epinephrine, serotonin), and the effects of ions (e.g., calcium, potassium)
`(33).
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`SUBFIBER A
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`Le CILIARY MEMBRANE
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`SUBFIBER B
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`AXONEME
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`CENTRAL
`MICROTUBULE
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`DOUBLET
`MICROTUBULE
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`RADIAL SPOKE
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`CENTRAL SHEATH
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`INTERDOUBLET LINK
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`SPOKE HEAD
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`Figure 1.4 Diagram of cilium cross section, viewed from base toward tip. A
`ring of nine doublet microtubules surrounds two single central microtubules.
`Each doublet microtubule has two subfibers, A and B: Dynein armsproject
`from subfiber A toward the next microtubule’s subfiber B. (From Ref. 126,
`reproduced with permission of Sci, Am.)
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`In general nasal mucociliary clearance carries the airway secretions back-
`ward to the nasopharynx (34). This material is dispatched by a wiping action
`of the palate to the stomach periodically through swallowing. However, there
`is an area in the anterior nares of the inferior turbinate from which muco-
`ciliary clearance moves material forward, andthis provides a clearance of de-
`posited foreign materials from the body by nose blowing and wiping (35).
`Nasal clearance proceedsat an average rate of about 5-6 mm/min (36-39).
`The nasal mucociliary function can be impaired by certain air pollutants,
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`but not be relative humidity or temperature of the ambientair (36,37 ,40-42). QUESTIVE EXHIBIT 1082 Page 0011
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`In patients with pathological conditions, their mucociliary function may be im-
`paired. Slow mucociliary clearance is associated with nasal polyposis, or an
`injury to the nasal mucosaasa resultofviral infections and other environ-
`mental insults occurring during childhood (37). Drying of the nasal mucous
`membrane will cause the cessation of ciliary activity, whereas prompt moist-
`ening will restore its normalactivity (42). The optimum temperature range
`for mucociliary activity is 28-30°C. Hypotonic saline solutions tend to inhibit
`mucociliary activity, whereas hypertonicsaline solutionswill cause it to stop.
`A highlysignificant correlation between nasal ciliary beat frequency andlog
`MTT(mucustransport time) was recently established in human volunteers,
`The data suggest that nasal ciliary beat frequencyis the main factor in the
`nasal mucociliary clearance in healthy volunteers (43). The transport times,
`as measured by saccharin sodium, ranged from 2.5 to 20.0 min.
`The arrest ofciliary mobility by drugs has been studied. The nasal admin-
`istration of propranolol solution (0.1%) was reportedto arrest the ciliary
`movement of both human adenoids and chicken embryo tracheas within 20
`min (44) (Table 1.1). Cocaine solution yielded an immediate and complete
`paralysis of cilia at 10%, caused the arrest of ciliary activity after 2-3 min
`at 5%, and stoppedciliary activity at 2.5% after 1 h of continuousapplication
`(45). However, a 25% cocaine paste is an effective and safe local anesthetic,
`since sufficient cilia escape direct contact with cocaine crystals, allowing
`the mucous blanketto continue to be swept backward. Lidocaine and
`pontocaine werestudied as to their effect on the mucus clearance ability
`of the humannasal ciliated epithelium (46). Lidocaine at the concentration
`of 4% did not impair mucus flow, whereas 2% pontocaine caused an immedi-
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`Table 1.1 The Decreasing Effect of Propranolol on the Ciliary Beat Fre-
`quency of Chicken Embryo Tracheal Epithelium and Human Adenoid
`Epithelium
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`Frequency@ (%)
`Time (min)
`20
`10
`2
`Species
`Concentration
`Compound
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`Propranolol HCl
`1%
`Chicken
`0
`0
`0.1%
`Chicken
`70
`8
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`Human 77 250.1% 0
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`4Frequency as a percentage of the initial frequency.
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`ate and complete cessation of bothciliary activity and mucusflow. Xylo-
`metazoline was also reported to diminish the mucociliary transport signifi-
`cantly (47). In another study,the use of xylometazoline at the concentra-
`tion of 1 mg/ml over a 6-week period did not induce any major functional
`and structural changes in normal nasal mucosa (48). In subjects with com-
`moncolds, a prolonged recovery in the mucociliary transport time was ob-
`served during the continued use of nose drops. A very diluted solution of
`adrenocorticotropic hormone (ACTH)esterase inhibitors was foundto accel-
`erate the nasal ciliary movement, whereashigher concentration slowedit
`down (49). Atropine was observed to slow thecilia beat, whereas morphine
`inhibited it. All of these effects are reversible. Tween 20 was reported to
`facilitate the nasal mucociliary clearance in the frog, which may be due to
`the reduction in adhesiveness caused by the surface-active agent(50).
`Normal mucociliary transport is dependent upon the optimal interac-
`tion between the cilia and mucus, which was reportedly influenced by thein-
`gredients in hair spray (51). The depression wassignificantat 15-60 min
`after exposure anddid not regain normal values until 1.5 hr later. The alco-
`hol content of the hair spray mayalso have affected the rheological proper-
`ties of the mucus.
`It has been reported that a gas which rapidly affects ciliary activity at
`low concentration andis relatively resorbed in the nasal cavity will be more
`toxic than a gas which is not resorbedin the nose andhaslittle influence
`on thecilia.
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`1.5 NASAL BLOOD FLOW
`The blood vessels in the nasal mucosaare of importance in the functions
`of the nose for thermal regulation and humidification of the inhaledair,
`and for controlling the lumen of the nasal passage.
`The nasal mucosais highly vascular. The surface of epithelium is sup-
`plied with a dense network of erectile carvernoustissue, whichis particu-
`larly well developed over the turbinates and septum (52,53). The vascular
`bed provides a rich surface for drug absorption. Constriction of the blood
`vessels would decrease blood flow and blood contentin the nasal mucosa,
`whereas vasodilation would yield the opposite response. The penetration of
`drug through the sinus mucosa is partly influenced by the blood flow in the
`region under normal and pathological conditions.
`The arterial supply to the nose is derived from both the external and the
`internal carotid arteries. The terminal branch of the maxillary artery, which
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`is a branch of the external carotid, supplies the sphenopalatine artery, which
`in turn supplies blood to the lateral and medial wall of the nasal chamber
`(54). On the other hand, the anterior and posterior ethmoid branches from
`the ophthalmic artery , which is a branch of the internal carotid artery. These
`yessels supply the anterior portion of the nose. The porosity of the endo-
`thelial basement membraneseemstofacilitate the exposure of the contractile
`elementsin the blood wall to agents carried by the blood. The nasal vascular
`bedis so designed that rapid exchange can be made forfluid and dissolved
`substances between the blood vessels and the nasal tissues (55). The capillary
`flow in the nasal mucosa wasreported to be about 0.5 mi/g/min, whereas
`the anteriovenous shunt flow was found to be 60% of the total blood flow in
`the cat. Sympathetic stimulation was reported to producea greater reduction
`in shunt flow than in capillary flow (56).
`Manydifferent factors, both local and general, have been identified to
`affect the vasomotor reaction of the nose. Thelocal factors include the
`changes in the ambient temperature and humidity, the nasal administration
`of vasoactive drugs, the external compressionoflarge veins in the neck,
`trauma, and inflammation (52). The general factors that affect nasal blood
`flow include emotion,fear, frustration, humiliation, anxiety, changes in en-
`vironmental temperature, hyperventilation, and exercise (57,58). Nasal air-
`way resistance wasreportedto increase at rest in the supine position and to
`decrease during exercise owing to some changesin the thickness of nasal
`mucosa as regulated by the capacitance vessels (58). The data suggest that the
`blood flow and the blood content of the human nasal mucosa are not affected
`in the same way by exercise.
`The blood flow in the maxillary sinus mucosa in humanswasreported to
`be in the range of 0.58-1.25 ml/g/min, as measured by microspheres (59-61),
`0.09-0.77 mi/g/min, as measured by the Ry,* Cl technique (62), or 34-44
`ml/min, as measured by '°? Xe technique (63).
`Nasal mucosal blood vessels are surrounded by adrenergic nerves, in which
`alpha-adrenoceptors show a functional predominance. Stimulation of these
`receptors produces a decrease in both blood content and blood flow in the
`nasal mucosa of both animals (64-66) and humans,(67,68).
`The nasal blood flow is very sensitive to a variety of agents applied topi-
`cally or systemically. The drugs that were reported to increase the blood
`flow in humansincluded histamine (63), fenoterol (69,70), isoproterenol
`(71), phenylephrine (72), and albuterol (72). The administration of oxymet-
`azoline (63,73) or clonidine (73) in humans was foundto decrease the nasal.
`blood flow.
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`areasernieeeneyraeeanetSeenea
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`Table 1.2 Response of the Nasal Airway to Some Vasoactive Agents
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` Increased patency Decreased patency
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`Beta agonists, e€.g.,
`Isoproterenol
`Nylidrin
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`Alphaantagonists, e.g.,
`Phenoxybenzamine
`Phentolamine
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`Alpha agonists, e.g.,
`Norepinephrine
`Epinephrine
`Methoxamine
`Phenylephrine
`Serotonin
`Dopamine
`Prostaglandins
`Cocaine
`Antihistamines
`Tyramine
`Vasopressin
`
`Acetylcholine
`Histamine
`Papaverine
`Aminophylline
`Reserpine
`Kt
`
`Source: From Ref. 74, reproduced with permission.
`
`Prostaglandins (PGE, , PGE, , PGA, and PGF, a) are generally considered
`to be vasodilating agents. However, they were observed to induce a constric-
`tion of the nasal blood vessels in the dog (74). While PGE, and PGE, were
`found to be equipotent to epinephrine,their duration of action was observed
`to last more than seven times longer in normal humansubjects (75). A partial
`list of drugs and their general effect on nasal patency is shown in Table 1.2.
`
`1.6 NASAL NERVE SUPPLY
`The nasal blood vessels and glandshave a rich nerve supply both from the
`autonomic system and from the somatic system. The nasal mucous mem-
`brane derivesits sensory supply from the cranial nerve and contains sympa-
`thetic and parasympathetic fibers of the autonomic nervous system (76).
`Figure 1.5 showsthe origin of the autonomic innervation of the nose.
`The autonomic innervation of aboutthree-quarters of the nasal mucous
`membranereaches the nose via the vidian nerve and follows the distribution
`of the second division of the trigeminal nerve to the nose (77,78). The
`vidian nerve may consist of parasympathetic and also sympathetic cholin-
`ergic fibers (78). The capillary vessels (or resistance vessels) receive the
`primary alpha-adrenergic sympathetic fibers (constrictor), but may also
`
`
`
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`AQUESTIVE EXHIBIT 1082 Page 0015
`QUESTIVE EXHIBIT 1082 Page 0015
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`

`

`
`
`
`GENICULATE
`een
`= = . .
`277 SUPERFICIAL ~s_
`PETROSAL
`NERVE
`dp VIDIAN NERVE
`
`SPHENOPALATINE
`GANGLION
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`SUPERIOR
` SALIVATORY 3
`NUCLEUS
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`ANATOMY AND PHYSIOLOGY OF THE NOSE
`
`TYMPANIC
`PLEXUS
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`pi
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`CERVICAL
`SYMPATHETIC
`GANGLION
`
`NASAL
`GLANDS
`
`NASAL
`VESSELS
`
`SYMPATHE T/C
`
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`
`PARASYMPATHETIC
`
`Figure 1.5 Autonomic nasal innervation. Origin of sympathetic and para-
`sympathetic fibers to the nasal mucosa. (From Ref. 76, reproduced with
`permission of the Ear Nose Throat J.)
`
`receive a small beta-adrenergic innervation (dilators). There is a rich para-
`sympathetic innervation of the glands. Nervous stimulation of the glandular
`cholinoceptorscausesa significant hypersecretion and vasodilation (Figures
`1.6 and 1.7). When the cholinergic nerveis stimulated, the arterioles in the
`conchadilate, permeability through the capillary wall changes, the uptake of
`serum constituents through the basement membranesinto the gland in-
`creases, and secretion is formed and then squeezed outof the nasal gland
`(79). Therefore, the cholinergic innervation is dominant in the functioning
`of the nasal glands, whereas adrenergic innervation is predominantin the
`functioning of the vascular system of the nasal mucosa. Stimulation of the
`vidian nerve in the case for 3 min wasnoted to induce nasalsecretions,
`whereas stimulation for 15 sec produced a vasoconstriction in the nasal
`cavity.
`While the arterioles of the inferior concha are richly endowed with adre-
`nergic nerves, the nasal gland is almost devoid of adrenergic nerve fibers
`(79). Electrical stimulation of the sympathetic nerves, using lower impulse
`
`
`
` Page 0016
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`AQUESTIVE EXHIBIT 1082 Page 0016
`AQUESTIVE EXHIBIT 1082
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`

`
`
`ORDINARY
`EXOGENOUS
`STIMULATION
`
`CHAPTER 1
`
`
`
`VIP (?)
`
`
`
`w
`YC, VIP?
`
`=|PTERYGO- PTERYGO-
`
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`BY&PALATINE PALATINE
`
`AGANGLION
`GANGLION
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`* ". CENTRAL NERVOUSSYSTEM © ..
`
`«
`
`Figure 1.6 Stimulation of sensory nerves, ¢.g., by the unconditioned inhaled
`air, initiates parasympathetic reflexes, which cause significant hypersecretion,
`andslight, transient vasodilation. C, cholinoceptor, VIP, vasoactive intestinal
`polypeptide. (From Ref. 127, reproduced with permission of J. Allergy Clin.
`Immunol.)
`
`AQUESTIVE EXHIBIT 1082 Page 0017
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
`
`
`
`
`STELLATE
`GANGLION
`
`
`
`
` |. |S CENTRAL NERVOUS ‘SYSTEM. >.” <e
`
`
`Figure 1.7 Sympathetic innervation of blood vessels. There is a continuous
`impulse traffic in efferent sympathetic fibers to the blood vessels, keeping
`them partially constricted. Action on alpha-1-adrenoceptors causes marked
`vasoconstriction, and stimulation of beta-2-adrenoceptors causes slight vaso-
`dilation. (From Ref. 127, reproduced with permission of J. Allergy Clin.
`Immunol.)
`
`frequencies, was reported to affect mainly the capacitance vessels (80). At
`minimal effective frequency of 2-5 Hz, the sympathetic activity-induced
`stimulation of vidian nerve was noted to increase nasal secretion and also
`induce vasoconstriction in the nasal cavity (81).
`The adrenergic transmitter, norepinephrine, , was found to be present in the
`typical nasal adrenergic nerve terminals(82). In all studies with mammals,
`the nasal mucosa ofthe inferior concha was observed to be dominated by a
`
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`
`
`CHAPTER 1
`
`16
`
`rich adrenergic plexus surrounded by a thin muscle layer of the wide veins
`of the erectile tissue. This adrenergic plexus is considered to be of great
`importancein regulating the blood flow through the nasal mucosa. The
`alpha-1, beta, and muscarinic receptors were reported to be present in human
`mucosa (83). Both isoprenaline andterbutaline, beta-receptor-stimulating
`agents, were found to decrease nasal blood flow resistance and nasal potency;
`ie., dilation of resistance and capacitance vessels (84). However, propranolol,
`a beta-receptor-blocking agent, was noted to reducetheeffect of isoprenaline
`and terbutaline on the resistance vessels. Therefore, it is evident that the
`effects of isoprenaline andterbutaline in the nasal vascular bedofthe cat are
`mediatedvia beta-adrenergic receptors,at least in the resistance vessels (85).
`It has been suggested that vasomotorrhinitis is a result of increased para-
`sympathetic activity in the nasal mucosa (78). Following parasympathetic
`stimulation of the nasal mucosa in the cat, the secretory and vascular re-
`sponses were reportedly blocked by atropine (86,87).
`
`1.7 NASAL ENZYMES
`
`Many enzymesexist in nasal secretions. These are cytochrome P-450-depen-
`dent monooxygenases (88-92); lactate-dehydrogenase (93); oxidoreductases
`(94); hydrolases, acid phosphatase andesterase (95), NAD*-dependentfor-
`maldehyde dehydrogenase and aldehyde dehydrogenase (96); leucine amino-
`peptidase (97); phosphoglucomutase, glucose-6-phosphate dehydrogenase,
`aldolase, lactic dehydrogenase, isocitric dehydrogenase, malic enzymes,
`glutamic oxaloacetic transaminase, glutamic pyruvic transaminase (98);
`NAD?*-dependent 15-hydroxyprostaglandin dehydrogenase (99); carboxyl-
`esterase (100), lysosomal proteinases and their inhibitors (101); B-gluco-
`sidase, a-fucosidase, and w-galactosidase (102); succinic dehydrogenase (103);
`lysozyme (104); and steroid hydroxylases (105).
`Cytochrome P-450-dependent monooxygenase has been reported tocata-
`lyze the metabolism ofdifferent xenobiotics (88-93). It has also been ob-
`served to metabolize many compoundsin the nasal mucosa, suchas nasal
`decongestants, nicotine, and cocaine (89); phenacetin (106); N-nitroso-di-
`ethylamine (107,108); N-nitrosonornicotine (109); nitrosoamine (110);
`aminopyrine (111); and progesterone (112).
`Insulin (zinc-free) was found to be hydrolyzed slowly by leucine amino-
`peptidase (97). The aminoacids, released from zinc-free insulin in the in
`vitro studies, were estimated by ion-exchange chromatography. The results
`are shown in Table 1.3. Prostaglandins of the E series were observed to be
`inactivated by the nasal mucosal 15-hydroxyprostaglandin dehydrogenase
`
`
`
`
`
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`

` ANATOMY AND PHYSIOLOGY OF THE NOSE
`
`
`
`
`
`Fes=P=a
`arnt
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`Table 1.3 Amino Acids Released from Insulin By Leucine Aminopeptidase
`
`Moles/Mole
`Moles/Mole
`Moles/Mole
`Amino acid
`insulin Aminoacid insulin
`Amino acid
`insulin
`
`
`1.36
`Ser + AspNH,
`0.99
`His
`0.72
`Phe
`$
`Cys-S-Cy
`1.43
`Leu
`1.63
`Val
`0.0
`Arg
`0.48
`Ala
`0.40
`leu
`
`
`
`Gly
`1.09 4 Glu 1