Allergy 2000: 1!2: 6-11
`Primed;, UK All n'gltl.\' resened
`
`ALLERGY
`/SSN fJJ08-J67J
`
`A comparison of the anti-inflammatory properties of intranasal
`corticosteroids and antihistamines in allergic rhinitis
`
`P. H. Howarth
`Division of Respiratory Cell and Molecular Biology
`Research. University of Southampton School of
`Medicine. Southampton, UK
`
`Allergic rhinitis manifests itself clinically due to the local release of mediators
`from activated cells within the nasal mucosa. Treatment strategies aim either to
`reduce the effects of these mediators on the sensory neural and vascular end
`organs, or to reduce the tissue accumulation of the activated cells that generate
`them. C01ticosteroids intervene at a number of steps in the inflammatory
`pathway, and, by reducing the release of cytokines and chemokines, inhibit cell
`recruitment and activation. These effects are evident both in vivo and in vitro.
`While antihistamines also have some anti-inflammatory effects in vitro, these
`require higher concentrations than with corticosteroids and are not consistently
`reproduced in vivo. In addition, although antihistamines and corticosteroids
`might appear to have complementary mechanisms of action, clinical trials
`suggest that their co-administration does not confer any additional long-term
`benefits compared with that achieved with corticosteroids alone. Topical
`corticosteroids are therefore the preferred anti-inflammatory therapy for
`persistent allergic rhinitis.
`
`In trod ucti on
`Allergic rhinitis is the clinical manifestation of the local
`release, within the nasal mucosa, of mediators from
`activated infiamm~ tory cells (l ). Immunohistochemical
`studies of nasal biopsies taken from patients with
`allergic rhinitis show an accumulation within
`the
`epithelium of eosinophils, basophils, and mast cells
`(2- 4), which are believed to be the primary effector cells
`in this condition, while nasal lavage reveals elevated
`levels of eosinophil cationic protein and tryptasc in
`seasonal and perennial allergic rhinitis, indicative of cell
`activation (5).
`Treatment for allergic rhinitis is directed toward
`reducing either
`the
`tissue accumulation of these
`activated cells or the end-organ effects of the released
`mediators. The two most important classes of pharma(cid:173)
`cologic agents used
`to achieve
`these aims are,
`respectively, topical corticosteroids ~nd H 1-antihista(cid:173)
`mines. While H 1-antihistamines are clearly effective in
`relieving symptoms, particularly those associated with
`sensory neural stimulation, it has been proposed that
`many drugs within this class have more extensive
`actions, modifying the inflammatory process in addi(cid:173)
`tion to inhibiting the H 1-receptor-mcdiated end-organ
`effects of histamine. As such, H 1-antihistamines might
`be potentially considered an alternative prophylactic
`therapy to topical corticosteroids in rhinitis. To address
`the
`this paper briefly reviews
`this consideration,
`mechanisms
`involved
`in airways
`inflammation
`in
`
`6
`
`allergic rhinitis and examines the in vitro and in vivo
`evidence for the rdevant anti-inflammatory potential
`and effects of these two classes of pharmacologic
`agents.
`
`Allergic airways inflammation
`in allergic airways
`Tht: major pathways
`involved
`inflammation are shown in Fig. 1. In addition to lgE(cid:173)
`dcpcndcnt ~ctivation of mast cells inducing mediator
`release, ~ctivated mast cells and T cells produce TH2
`cytokines, which, in turn , activate both endothelial and
`epithelial cells (1). Endothelial activation results in the
`expression of endothelial adhesion molecules such as
`intercellular adhesion molecule-1 (ICAM-1) and, more
`importantly,
`vascular
`cell
`adhesion molecule-!
`(VCAM-1). While both these adhesion rnolt:cules are
`potentially involved in tissue-cell recruitment (6), the
`interaction between VCAM-1 and the ligand VLA -4 is
`more speci!ic for allergic inflammation, being involved
`not only in eosinophil adherence but also in basophil
`and lymphocyte endothelial interactions. The directed
`movement of cells through the tissue toward the nasal
`lumen, once tr~nsendothclial migration has taken place,
`is dependent upon cell-cell contact and the local rele~se
`of chemokines. Epithelial activation is associated with
`the generation and release of a number of chemokines -
`such as regulatt:d on activation, normal T-cell expressed
`and secreted (RANTES), macrophage inflammatory
`protein
`(MIP)- La, monocyte chemotactic protein
`
`PLAINTIFFS'
`TRIAL EXHIBIT
`PTX0337
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`APOTEX_AZFL 0060403
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`PTX0337 -00001
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`1
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`CIP2041
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`CorticosteroidS and antihistamines as anti-inflammatories
`
`e~ssociated with cell recruitment and activation, and,
`ultimately. clinical disease expression.
`The glucocorticoid molecule enters the cell and binds
`to the cytoplasmic glucocorticoid receptor, displacing
`the associated heat-shock proteins. The glucocorticoid/
`glucocorticord receptor complex can either bind to the
`transcription factors tht:mselves within the cytoplasm,
`thereby preventing their interaction with DNA and thus
`indirectly blocking their etl"ects on gene expression, or
`translocate to the nucleus and bind ::~s a dimer to the
`DNA. This direct interaction with DNA modifies gene
`transcription, down-regulating the production of pro(cid:173)
`inflammatory proteins or up-regulating the generation
`of anti-inflammatory ones. This latter action may
`require higher concentrations than the down-regulatory
`activity. Corticosteroids thus have both direct and
`indirect effects
`in
`inhibiting
`transcription
`factor(cid:173)
`induced gene expression.
`
`In vitro studies
`Studies with corticosteroids in l'itro have shown that
`this class of drug has potent effects on T cells, inhibiting
`their stimulated proliferation and synthesis of TH2
`cytokines at low concentrations ( 11-13). In this respect,
`the most potent of the
`fl.uticasone propionate is
`currently available topical corticosteroids. having an
`IC50 (inhibitory concentration producing a soo;,, reduc(cid:173)
`tion in the stimulated response) in the range of w-to M
`(13, 14). In addition to this inhibitory effect on T cells,
`fluticasone propionate inhibits the release of IL-4, IL-6,
`IL-8. and TNF-:x from stimulated masl cells with an
`IC50 of <I nM (15). The TC50 for inhibiting the release
`ofTNF-a and GM-CSF from the stimulated epithelium
`are 0.1 and 1.0 nM, respectively (16). Epithelium(cid:173)
`generated [ L-6 and IL-8 are less sensitive to the effects
`of Hulicasone, with IC50 of" 5 and 10 nM, rt:spectively
`(16).
`
`Figure 2. Influence of lluticasone propionate on mucosal JL-4
`mRNA in nasal biopsies in seasonal allergic rhinitis (Cameron
`et al. [17]).
`
`7
`
`Figure 1. Allergic airways inflammation.
`
`(MCP)-1, intt:rleukin-8 (IL-8), and eotaxin - whil:h art:
`chemoattractants for eosinophils, mast cells, lympho(cid:173)
`cytes. neutrophils, and basophils, and direct
`the
`migration of thes~:: l:ells toward the epithdium and
`nasal airway lumen (7). Epithelial activation can thus
`account for the specific accumulation of mast cells.
`eosinophils, basophils, and T cells within the epithelium
`in allergic rhinitis.
`It tallows that therapy which reduces either the
`the cytokines
`expression of tht:se chemokint:s or
`associated with endothelial and epithelial activation
`will diminish the recruitment of these efft:ctor cells and
`thus decrease the availability of mediators to induce
`symptom expression.
`Cytokinc and chcmokine expression is regulated by
`transcription factors such as nuclear factor kappa B
`<NFKB), AP-1, and NF-AT (8). In the unactivated celL
`transcription factors exist in an inactive form, and cell
`stimulation results in their m.:tivation with a resultant
`upregulated expression of cytokine and chwwkine
`messenger RNA (mRNA). For examph::, NFKB exists
`as a dimer bound to an inhibitory protein, I kappaS
`(h:B). within the cytoplasm (9). When exposed to an
`activation stimulus, phosphorylation of the inhibitory
`protein leads
`to
`loss of binding, and
`the dimer
`dissociates from the inhibitory protein and translocates
`to the nucleus. Once there, it interacts with the DNA,
`resulting in a directed increase in gene expression and
`upregulation of specific cytokine (e.g., IL-l and TNF-a)
`and chemokine (t:.g., RANTES ami eolaxin) synthesis.
`The transcription factor NFKB also controls the
`synthesis of adhesion molecules (such as VCAM-1)
`and enzymes (such as inducible nitric oxide synthase
`[iN OS]) of relevance to allergic nasal inflammation.
`
`Corticosteroids
`Corticosteroids act by modifying the ability of tran(cid:173)
`scription factors to up-regulate gene expression (10).
`Thus, by acting very early in the inllammatory pathway,
`corticosteroids can prevent the cascade of events
`
`APOTEX_AZFL 0060404
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`

`Howarth
`
`In vivo studies
`Topic<:~! corticosteroid therapy inJiuences m<:~ny aspects
`of the allergic mucosal response. Much of the published
`literature concerns fluticasone propionate, and, to a
`lesser extent, budesonide. Fluticasone propionate sig(cid:173)
`nificantly blunts the seasonal increases in the expression
`of mRNA for both IL-4 (Fig. 2) (17) and IL-5 (18), in
`nasal mucosal biopsies in seasonal allergic rhinitis. In
`addition, prophylactic treatment with !luticasone pro(cid:173)
`pionate, as compared to placebo, prevents the pericel(cid:173)
`lular expression of the activated and secreted form of
`IL-4 (as demonstrated by the number of immunoreac(cid:173)
`tive 3H4 + cells) on nasal mucosal mast cells in s~;:asonal
`rhinitis (Fig. 3) (19). Thus, fluticasone propionate
`downregulatcs both TL-4 and JL-5 gene expression as
`well as the active secretion of IL-4 within the nasal
`mucosa. These are key cytokines in regulating endothe(cid:173)
`lial VCAM-1 expression and, consistent with this,
`tluticasone propionate has also been shown to inhibit
`the seasonal increase in endothelial VCAM-1 expres(cid:173)
`sion (20). This action, along with a redt1ction in JL-5, a
`cytokine known to stimulate the proliferation and
`diffen:ntiation of eosinophil progenitor cells within the
`bone marrow, can account for
`the dccrease
`in
`cosinophils within the nasal mucosa and lumen with
`topical corticosteroid therapy in rhinitis (20, 21 ).
`This inhibitory effect on inflammatory cell accumula(cid:173)
`tion in allergic rhinitis will also be promoted by the
`downregulation, by corticosteroids, of chemokine
`synthesis by the epithelium. Fluticasone propionate
`has been shown to reduce significantly the levels of IL(cid:173)
`l~. MIPb::, RANTES, and GM-CSF recovered from
`nasal lavage after allergen challenge (Fig. 4) (22),
`indicating inhibition of epithelial activation. This action
`inhibitory effect of t:luticasone
`may underlie
`the
`propionate in preventing the seasonal accumulation
`of mast cells within the epithelium in grass pollenosis
`(Fig. 5).
`
`Fig11re 3. lnflueuce of prophylactil·. tluticasone propionate on TL-4
`secretion by mast cells in seasonal allergic rhinitis (Bradding et al.
`[J 9]).
`
`8
`
`Figure 4. Nasal lavage chemokine levels: in!luence of fluticasone
`propionate (Weido et al. [22]).
`
`Thus, fiuticasone propionate modifies a number of
`steps in the inflammatory pathway: it blocks cytokine
`and chemokine generation, endothelial and epithelial
`cell activation, and the tissue recruitment and activation
`of mast cells and eosinophils. It follows that the fewer
`the number of these primary effector cells, the lower the
`amount of inilammatory mediators produced and, as a
`cons~;:quenct:, the fewer the nasal symptoms.
`
`Antihistamines
`Since many rhinitis symptoms are mediated by
`histamine, antihistamines offer a therapeutic alternative
`to corticosteroids. With short-term therapy, H 1-anti(cid:173)
`histamines are most effective at reducing the neurally
`mediated symptoms of itch, sneeze, and rhinorrhoea
`(23). This can be attributed to end-organ receptor
`blockade. There is, however, an indication that a
`number of these agents also have the potential for
`antiallergic activity that, theoretically, may increase
`their spectrum of clinical effectiveness.
`
`In vitro studies
`Studies undertaken in vitro show that H 1-antihistamines
`modify mediator release from mast cells and basophils
`(24, 25). These investigations reveal that, for most
`traditional antihistamines,
`the antiallergic activity
`requires higher concentrations than the H 1-antihista(cid:173)
`minic activity. For example, the pA2 value to inhibit
`anti-IgE induced mast cell degranulation is about 21ogs
`lower: i.e., the dose required to abolish the allergic
`response is approximately 100-fold higher than for
`the Ht·antihistaminic activity (24). The exception is
`oxatomide, which has similar antiallergic and anti(cid:173)
`histamines pA2 values (26). Thus, for these effects to be
`fully evident in vivo, most H 1-antihistamines would
`have to be administered al doses higher than generally
`tolerated, due to their sedative effects.
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`Corticosteroids and antihistamines as anti-inflammatories
`
`subsequent eosinophil accumulation in the allergen
`challenge model (40). The interpretation of these
`findings is also complicated by the report that factors,
`including histamine, which increase plasma protein
`exudation, incre{(se mediator recovery in nasal lavage
`( 41 ). Thus, inhibition of a histamine-related increase in
`vascular permeability after allergen challenge, due to
`the H 1-receptor blockade on the endothdial surface,
`could reduce mediator recovery in nasal lavage and be
`interpreted as reflecting an ''anti-allergic" effect.
`An antihistamine that decreased h.:ukotriene produc(cid:173)
`tion might be expected to have a broader clinical profile
`than one with antihistamine activity alone. In clinical
`that
`inhibit
`leukotriene
`studies, however, agents
`production in the allergen challenge test have similar
`clinical benefits to those lha L do not ( 42. 43), raising
`some doubt about the interpretation of the allergen(cid:173)
`challenge findings. Also unknown is whether or not the
`inhibition of mast-cell mediator release occurs
`in
`parallel to an inhibition of cytokinc release "nd thus
`cell recruitment. There is conflicting evidence for
`cetirizinc. For example, cetirizine appears not to
`affect eosinophil recruitment in
`the nasal allergen
`ch<~llenge model (40) but does have such an ctfect in
`some other challenge models. such as skin blisler (44).
`Lavage studies also have produced contradictory
`findings (45, 46). In our own studies in naturally
`occurring seasonal rhinitis, cetirizine failed to show a
`clear anti-inflammatory effect, at least as indicated by
`tissue eosinophil accumulation (47). Cetirizine, how(cid:173)
`ever, has been found to reduce nasal epithelial ICAM-1
`expression in !l{(turally occurring disease (48).
`Moreover.
`if cetirizine does prevent eosinophil
`accumulation, greaLer clinical bcnelil would be expected
`with prophylactic than with short-term use, but this
`does not appear to be the case. The effect of active
`prophylactic therapy of H 1-antihistamines on nasal
`congestion is also not significantly superior to that of
`placebo (49), in contrast to that with corticosteroids. A
`study of prophylactic Aunisolide and beclomethasone in
`patients with ragweed-sensitive rhinitis found that both
`prevented the development of seasonal rhinitis (50).
`
`Comparative and combination clinical studies
`In clinic"! comparisons, wnicosteroids are signifi(cid:173)
`cantly more efTective than H 1-antihistamines (51). The
`in vitro findings with the two classes of compounds
`suggest a complementary mechanism of action; i.e.,
`that there is a potential for inhibition both of mast(cid:173)
`cell and basophil degranulation and of cell activation
`and eosinophil recruitment. If corticosteroids and
`antihist{(mines were used concomitantly, this might be
`translated into addition"! clinical benefit. The limited
`studies avail"ble, however, do nol support a superior
`effect with
`long-term
`regular
`therapy with
`the
`
`9
`
`Figure 5. Epithelial eosinophil and mast-cell accumulation in
`seasonal allergic rhinitis: influence of prophylactic fluticasone
`propionate. 200 ftg once daily (Bradding ct al. [19]).
`
`For some more recently introduced non-sedating
`antihistamines, including terfenadine. cetirizine. and
`loratadine, IC50 values for inhibition of anti-IgE- or
`alkrgen-induced histamine release are in the 10 ~M
`range (27. 28). In other words,
`the inhibition of
`histamine release by these agents requires a concentra(cid:173)
`tion at least 1000 times higher than that those of
`Duticasone propionate required to inhibit cytokine or
`chcmokinc release. The "antiallergic" effects arc
`to be independent of the H 1-receptor
`considered
`antagonistic activity and to be related to nonspecific
`cell membrane stabilization due to ionic association
`with cell membranes. This leads to modification of ion
`lransporl and membrane-associated enzyme aclivily
`(29- 31).
`In addition, several H 1-antihistamines haw been
`shown to modify in vitro the epithelial expression of the
`adhesion molecule ICAM-1. Both terfcnadinc "nd
`cetirizinc have been found to reduce the expression of
`!CAM-I on epithelial cdl lines in vitro (32).
`
`In vivo studies
`Antihistamines may exert their effects either directly, by
`inhibiting end-organ effects, or indirectly by inhibiting
`mast cell degranulation. This has been investigated in
`allergen-challenge models in vivo. with nasal lavage to
`measure postchallenge mediator levels. Pretreatment
`with standard doses or <mtihistamines, as compared to
`placebo, has bl!en shown Lo decrt:ase the il!cowry of
`mediators following allergen challenge (33). Overall.
`however, the effects of the various agents appear to be
`somewhat variable. Thus , azclastine, cetirizine, and
`ketotifcn (34- 36) have no effect on histamine release,
`although a decreased recovery of leukotrienes has been
`reported with both azelastine and cctirizine (34, 35).
`Conversely, several studies show decreased histamine
`release with loratadine and terfenadine (37-39). but no
`change in the recovery of leukoLrienes. None of these
`drugs appear to have a consistent effect on the
`
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`

`Howarth
`
`combination compared with
`alone (52. 53).
`
`topical corticosteroid
`
`Conclusions
`The broad effet;l of lopit;al corticosteroid therapy in
`reducing the mucosal accumulation of the major
`effector cells of the disease. mast cells and eosino(cid:173)
`phils, accounts for their substantial clinical benefit.
`The lack of additional clinical benefit when anti(cid:173)
`histamines are used in combine1tion with corticoster(cid:173)
`oids indicates that,
`the anti-inflammatory
`in vivo,
`effects on the airway of corticosteroids overlap those
`of the H 1-antihistamines, making the action of the
`
`latter redundant. An alternative explanation is that
`the in vilro effects of antihistamines are not evident in
`l'ivo, possibly due to inadequate potency at the dose
`used.
`Thus, first-line therapy for rhinitis based on anti(cid:173)
`inflammatory activity
`is a
`topical corticosteroid
`such as fiuticasone propionate. A better understand(cid:173)
`ing of those properties of H 1-antihistamine molecules
`that are relevant
`to cell activation and accumu(cid:173)
`lation may allow the development of other molecules
`with appropriate potency at standard oral doses.
`the profile of antihistamines
`This would extend
`beyond their inhibition of the end-organ effects of
`histamine.
`
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