DRUGS AND THE PHARMACEUTICAL SCIENCES
`
`VOLUME 39
`
`Yie W Chien
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`Nasal svsjemic
`[Iruullelwerv
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`Kenneth S. E. Su
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`Shyi-Feu Chang
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`Nasal Systemic
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`Drug Delivery
`*
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`YlEVV. CHIEN
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`Control/ed Drug-Delivery Research Center
`College of Pharmacy, Rutgers University
`Piscataway, New jersey
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`KENNETH S. E. SU
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`Pharmaceutical Research Department
`Eli Lilly and Company
`Indianapolis, Indiana
`
`SHYl-FEU CHANG
`
`'-
`:
`'
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`Department of Pharmaceutics/Drug Delivery
`Amgen Incorporated
`Thousand Oaks, California
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`I
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`MARCEL DEKKER, INC.
`
`New York 0 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)
`Includes bibliographies and index.
`ISBN 0-8247-8093-0 (alk. paper)
`1. Intranasal medication.
`I. Chien,Yie W.
`Kenneth S. E.
`III. Chang, Shyi-Feu
`RM160.N37
`615’.6--dc20
`
`II. Su,
`IV. Series.
`
`89-12007
`CIP
`
`i
`
`_
`
`,
`
`1989
`
`
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`
`
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`This book is 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 and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit).
`10 9 8 7 6 5 4 3 2 l
`
`
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`
`
`
`PRINTED IN THE UNITED STATES OF AMERICA
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`'1
`Anatomy and Physiology of the Nose
`
`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; and it should be capable of
`being absorbed efficiently 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 drugs intranasally:
`(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.
`1
`However, there are some factors that should also be considered for opti-
`mizing the intranasal adminstration of drugs: (a) methods and techniques of
`administration; (b) the site 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 of drugs.
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` CHAPTE R 1
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`To study the intranasal delivery of drugs for systemic medication, it is im-
`portant to first gain some fundamental understanding of the anatomy and
`physiology of the nose.
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`1.1 NASAL PASSAGE
`
`The upper respiratory tract is constantly influenced by the inspired air.
`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 the nasal 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 function of filtering airborne particles. (b) The
`respiratory area has a surface lined by a pseudostratified columnar epithel—
`ium, and is normally covered by a dense layer of mucus that is constantly
`moving toward the posterior apertures of the nasal cavity by a powerful
`system of motile cilia. (c) The olfactory region is about 10 cm2, as com-
`pared to 170 cm2 in the German shepherd dog. The olfactory airway lies
`above the middle turbinate between the nasal septum and the lateral wall
`of the main nasal passage. The airway here is only about 1-2 mm wide and
`is contiguous to the cribriform plate above. This region is generally free of
`inspiratory air flow.
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`The nasal passage is composed of a horizontally skin-lined vestibule with
`the passages being directed upward and backward, and is 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 entrance at the nostrils to the beginning of ciliated mucosa
`at the anterior ends of the nasal septum and turbinates (5,6). The main
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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`nasal passage extends backward by approximately 6-8 cm to the posterior
`ends of the turbinates and the arch of the septum.
`Its cross section is large,
`but the width of the convoluted air stream is narrow. The lining is ciliated,
`highly vascular, and rich in mucous glands and goblet cells. The septum
`ends at the nasopharynx and the airways merge into one (7).
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`(Left) The upper airways seen from the midline. The dashed line
`Figure 1.1
`just beyond the 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 nasal air-
`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 drops or fine aerosol sprays. (From Ref. 1, reproduced With
`permission of Elsevier.)
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`1xii-'3;-
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`4
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`CHAPTER 1
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`Figure 1.2 Diagram showing the lateral wall of the nasal cavity. A, nasal
`vestibule, B, internal ostium, C, inferior turbinate; D, middle turbinate, E,
`superior turbinate. The hatched areas 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 be classified into olfactory and nonolfactory epi-
`thelia (5). The olfactory epithelium is a pseudostratified columna in type,
`and consists of specialized olfactory cells, supporting cells, and both serous
`and mucous glands, 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 and act as peripheral receptors
`and first-order ganglion cells.
`There are two types of mucus covering the surface of the mucous mem-
`brane: one adheres to the tips of cilia, and the other fills the space among the
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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`II
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`III
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`IV
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`Figure 1.3 Transmission electron microscopic view of various cell types in
`the nasal epithelium.
`I, nonciliated columnar cell with microvilli, II, goblet
`cell with mucous granules and Golgi apparatus, III, basal cell, IV, ciljated
`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. Numerous groups of microvilli can be seen microscopically among the
`groups of cilia. All microvilli are of short clublike appearance and there 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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`mous cells. However, some polygonal or elonged cells apparently have
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`CHAPTER 1
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`numerous microvillilike processes on their outer surface. These basal cells of
`the lining epithelium have a 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. The individual fine fibrils form bundles, but they are separated
`from each other with branches connecting the adjacent fibril to form net-
`works.
`
`Adequate moisture is required to maintain the normal functions of the
`nasal mucosa (8). Dehydration of the mucous blanket increases the viscosity
`of the secretions and reduces the ciliary activity. Thus, the recovery of heat
`and moisture from the expired air by the nasal membranes is of fundamental
`importance for retaining its normal functions.
`In many animal species, including man, pronounced respiratory and car-
`di0vascular 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 and also in the nasal secre-
`tions of allergic rhinitis (10). Another smooth muscle-stimulating substance,
`probably an unsaturated acid, has also been found in the nasal mucosa of
`the dog and sheep.
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`1.3 NASAL SECRETIONS
`
`The composition of nasal secretions is complex and consists of a mixture
`of secretory materials from the goblet cells, nasal glands, and lacrirnal glands
`and a transudate from plasma (11,12).
`In a clean, noninfected, nonallergic, and nonirritated nose, the mucosa is
`covered by a thin layer of clear mucus which is secreted from the mucous and
`serous glands in the nasal mucosa and submucosa (13). This mucous blanket
`is moved posteriorly by the ciliary beat at a rate of about 1 cm/min, so that
`the nasal mucus is renewed approximately every 10 min. A total of approxi-
`mately 1500-2000 m1 of mucus is produced daily, which contains 90-95%
`water, 1-2% salt, and 2-3% mucin. The mucus has a two-layer composition:
`The watery (sol) layer is located immediately adjacent to the mucosal sur-
`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/ L of calcium as well 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 mucous glycoproteins, nasal secretions contain a variety
`of other proteins:
`lysozymes (15,16), enzymes (17), IgA, IgE, IgG, and al-
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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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 proteins like gamma A—globulin, gamma G-globulin, albumin,
`and siderophilin (27,28).
`The functions of mucus include: (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 may be altered to produce excess mucus by dif-
`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.
`
`1.4 NASAL MUCOCILIARY CLEARANCE
`Nasal ciliary clearance is one of the most important physiological defense
`mechanisms of the 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 200 cilia extending from every ciliated cell on the sur-
`face of psuedostratified columnar epithelium. An individual cilium is approx-
`imately 5 ,u in length and 0.2 y in diameter (29), which moves at a frequency
`of about 20 beats/sec (30). The fine 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 of the 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 of the cilia is
`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 pacemaking stimulation from hormones (e.g.,
`epinephrine, serotonin), and the effects of ions (e .g., calcium, potassium)
`(33).
`
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`CHAPTER 1
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`SUBFIBER A
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`SUBFIBER B
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`AXONEME
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`CENTRAL
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`MICROTUBULE
`RADIAL SPOKE
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`DOUBLET
`SPOKE HEAD
`MICROTUBULE
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`CENTRAL SHEATH
`INTER DOUBLET LINK
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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 arms project
`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-
`cih‘ary clearance moves material forward, and this provides a clearance of de-
`posited foreign materials from the body by nose blowing and wiping (35).
`Nasal clearance proceeds at an average rate of about 5-6 mm/min (36-39).
`The nasal mucociliary function can be impaired by certain air pollutants,
`but not be relative humidity or temperature of the ambient air (36,37,40—42).
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` ANATOMY AND PHYSIOLOGY OF THE NOSE
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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 mucosa as a result of viral 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 normal activity (42). The optimum temperature range
`for mucociliary activity is 28-30°C. Hypotonic saline solutions tend to inhibit
`mucociliary activity, whereas hypertonic saline solutions will cause it to stop.
`A highly significant correlation between nasal ciliary beat frequency and log
`MTT (mucus transport time) was recently established in human volunteers.
`The data suggest that nasal ciliary beat frequency is 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 of ciliary mobility by drugs has been studied. The nasal admin-
`istration of propranolol solution (0.1%) was reported to 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 stopped ciliary activity at 2.5% after 1 h of continuous application
`(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 blanket to continue to be swept backward. Lidocaine and
`pontocaine were studied as to their effect on the mucus clearance ability
`of the human nasal 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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`Frequencya (%)
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`Time (min)
`
`Compound
`Concentration
`Species
`2
`10
`2 0
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`Propranolol HCl
`1%
`Chicken
`0
`0
`O
`0. l %
`Chicken
`7 0
`8
`0
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`7 7 25Human0. l % 0
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`aFrequency as a percentage of the initial frequency.
`Source: From Ref. 44, used with permission.
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`CHAPTER 1
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`ate and complete cessation of both ciliary activity and mucus flow. 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-
`mon colds, 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 found to accel-
`erate the nasal ciliary movement, whereas higher concentration slowed it
`down (49). Atropine was observed to slow the cilia 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 the in-
`gredients in hair spray (51). The depression was significant at 15-60 min
`after exposure and did not regain normal values until 1.5 hr later. The alco-
`hol content of the hair spray may also have affected the rheological proper-
`ties of the mucus.
`It has been reported that a gas which rapidly affects ciliary activity at
`low concentration and is relatively resorbed in the nasal cavity will be more
`toxic than a gas which is not resorbed in the nose and has little influence
`on the cilia.
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`1.5 NASAL BLOOD FLOW
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`The blood vessels in the nasal mucosa are of importance in the functions
`of the nose for thermal regulation and humidification of the inhaled air,
`and for controlling the lumen of the nasal passage.
`The nasal mucosa is highly vascular. The surface of epithelium is sup-
`plied with a dense network of erectile carvernous tissue, which is particu-
`larly well developed over the turbinates and septum (52,5 3). The vascular
`bed provides a rich surface for drug absorption. Constriction of the blood
`vessels would decrease blood flow and blood content in 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
`vessels supply the anterior portion of the nose. The porosity of the endo-
`thelial basement membrane seems to facilitate the exposure of the contractile
`elements in the blood wall to agents carried by the blood. The nasal vascular
`bed is so designed that rapid exchange can be made for fluid and dissolved
`substances between the blood vessels and the nasal tissues (55). The capillary
`flow in the nasal mucosa was reported to be about 0.5 ml/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 produce a greater reduction
`in shunt flow than in capillary flow (56).
`Many different factors, both local and general, have been identified to
`affect the vasomotor reaction of the nose. The local factors include the
`
`changes in the ambient temperature and humidity, the nasal administration
`of vasoactive drugs, the external compression of large 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 was reported to increase at rest in the supine position and to
`decrease during exercise owing to some changes in 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 humans was reported to
`be in the range of 0.58-1.25 ml/g/min, as measured by microspheres (59-61),
`0.09-0.77 ml/g/min, as measured by the Rb“C1 technique (62), or 34-44
`ml/min, as measured by 133 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 humans included histamine (63), fenoterol (69,70), isoproterenol
`(71), phenylephrine (72), and albuterol (72). The administration of oxymet-
`azoline (63,73) or clonidine (7 3) in humans was found to decrease the nasal.
`blood flow.
`
`"nu-m—a—«m-m—
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`AQUESTIVE EXHIBIT 1082 Page 0014
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`CHAPTER 1
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`Table 1.2 Response of the Nasal Airway to Some Vasoactive Agents
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`
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` Increased patency Decreased patency
`
`Beta agonists, e.g.,
`Isoproterenol
`Nylidrin
`
`Alpha antagonists, e.g.,
`Phenoxybenzamine
`Phentolamine
`
`Alpha agonists, e.g.,
`Norepinephrine
`Epinephrine
`Methoxamine
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`Phenylephrine
`Serotonin
`Dopamine
`Prostaglandins
`Cocaine
`Antihistamines
`Tyramine
`Vasopressin
`
`Acetylcholine
`Histamine
`Papaverine
`Aminophylline
`Reserpine
`K+
`
`Source: From Ref. 74, reproduced with permission.
`
`Prostaglandins(PGE1 , PGE2 , PGA, and PGF1 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 PGEl and PGE; were
`f0und to be equipotent to epinephrine, their duration of action was observed
`to last more than seven times longer in normal human subjects (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 glands have a rich nerve supply both from the
`autonomic system and from the somatic system. The nasal mucous mem-
`brane derives its sensory supply from the cranial nerve and contains sympa-
`thetic and parasympathetic fibers of the autonomic nervous system (76).
`Figure 1.5 shows the origin of the autonomic innervation of the nose.
`The autonomic innervation of about three-quarters of the nasal mucous
`membrane reaches the nose via the vidian nerve and follows the distribution
`of the second division of the trigeminal nerve to the nose (77,7 8). 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
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`ANATOMY AND PHYSIOLOGY OF THE NOSE
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`TYMPANIC
`PLEXUS
`
`GENICUL ATE
`
`@LION
`\ \
`
`if
`
`7"
`
`
`
`SPHENOPALATINE
`GANGLION
`
`
`
`, x' SUPERFICIAL ‘ ‘ c ‘
`PETROSAL
`NERVE
`... vxomrv NERVE
`
`\ ..
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`‘.
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`
`
`
`--.
`
`SUPERIOR
`SALIVATORY ,
`NUCLEUS
`
`anatssm
`
`CERVICAL
`
`CAROTID
`PLEX US
`
`are. L/
`
`I
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`‘.
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`@333th
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`;
`
`SY/MPA THE T/C
`
`.
`
`'.
`
`PA/‘F‘ASY/MPA THEf/C
`
`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.)
`
`
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`'47:515-131v-rr-2‘
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`receive a small beta-adrenergic innervation (dilators). There is a rich para-
`sympathetic innervation of the glands. Nervous stimulation of the glandular
`cholinoceptors causes a significant hypersecretion and vasodilation (Figures
`1.6 and 1.7). When the cholinergic nerve is stimulated, the arterioles in the
`concha dilate, permeability through the capillary wall changes, the uptake of
`serum constituents through the basement membranes into the gland in-
`creases, and secretion is formed and then squeezed out of the nasal gland
`(79). Therefore, the cholinergic innervation is dominant in the functioning
`of the nasal glands, whereas adrenergic innervation is predominant in the
`functioning of the vascular system of the nasal mucosa. Stimulation of the
`vidian nerve in the case for 3 min was noted to induce nasal secretions,
`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
`
`
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`AQUESTIVE EXHIBIT 1082 Page 0016
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`CHAPTERl
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`ORDINARY
`EXDGENOUS
`STIMULATION
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`H>
`
`C
` VIP ('2)
`
`u
`‘ C,VIP?
`E
`PTERYGO—
`PTERYGO-
`
`g
`PALATINE
`PALATINE
`E
`GANGLION
`GANGLION
`
`3+
`+
`
`
`
`
`‘~
`
`I.CENIRAh Nngq s SYSTEM 3 I-
`
`
`
`Figure 1.6 Stimulation of sensory nerves, e.g., by the unconditioned inhaled
`air, initiates parasympathetic reflexes, which cause significant hypersecretion,
`and slight, transient vasodilation. C, cholinoceptor, VIP, vasoactive intestinal
`polypeptide. (From Ref. 127, reproduced with permission of J. Allergy Clin.
`Immunol.)
`
`
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`AQUESTIVE EXHIBIT 1082 Page 0017
`QUESTIVE EXHIBIT 1082 Page 0017
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`ANATOMYANDPHYEOLOGYOFTHENOSE
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` fli
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`STELLATE
`GANGLION
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`+ +
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`‘
`‘
`.
`:‘1 QE-NTRAL'NERYOIUSFYST'EM' 3-;
`'.
`
`
`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-l-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 of the inferior concha was observed to be dominated by a
`
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` ‘ QUESTIVE EXHIBIT 1082 Page 0018
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`16
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`CHAPTER 1
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`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
`importance in 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 and terbutaline, beta-receptor-stimulating
`agents, were found to decrease nasal blood flow resistance and nasal potency;
`i.e., dilation of resistance and capacitance vessels (84). However, propranolol,
`a beta-receptor-blocking agent, was noted to reduce the effect of isoprenaline
`and terbutaljne on the resistance vessels. Therefore, it is evident that the
`effects of isoprenaline and terbutaljne in the nasal vascular bed of the cat are
`mediated via beta-adrenergic receptors, at least in the resistance vessels (85).
`It has been suggested that vasomotor rhinitis 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 enzymes exist in nasal secretions. These are cytochrome P-450-depen-
`dent monooxygenases (88-92); lactate-dehydrogenase (93); oxidoreductases
`(94); hydrolases, acid phosphatase and esterase (95), NAD+-dependent for-
`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-hydroxyprostag1andin dehydrogenase (99); carboxyl-
`esterase (100), lysosomal proteinases and their inhibitors (101); B—gluco-
`sidase, oz-fucosidase, and oc-galactosidase (102); succinic dehydrogenase (103);
`lysozyme (104); and steroid hydroxylases (105).
`Cytochrome P-450-dependent monooxygenase has been reported to cata-
`lyze the metabolism of different xenobiotics (88-93). It has also been ob-
`served to metabolize many compounds in the nasal mucosa, such as nasal
`decongestants, nicotine, and cocaine (89); phenacetin (106); N-nitroso-di-
`ethylamine (107,108); N-nitrosonornicotine (109); nitrosoamine (110);
`aminopyrine (111);