Clinical and Experimental Allergy, 1996. Volume 26, Supplement 3. pages II 17
`
`Antihistamines: topical vs oral administration
`
`R. J. DAVIES, A. C. BAGNALL, R. N. McCABE. M. A. CALDERON and
`J. H. WANG
`
`Department of Respiratory Medicine and Allergy. St Bartholomew's Hospital. London. UK
`
`I
`
`Summarv
`
`The pathogenesis of allergic rhinitis is complex, involving not only histamine and mast
`cell-derived tryptase. but also eosinophii- and neutrophil-derived mediators, cytokines,
`and intercellular cell adhesion molecules (ICAM-I). It is surprising that antihistamines,
`which block only one component of the process, have proved so effective in the
`management of allergic rhinitis. Research has therefore focused on whether antihista-
`mines have additional pharmacological activities. In vitro studies have shown that high
`concentrations of second generation antihistamines can block inflammatory mediator
`release from basophils and mast cells, and reduce ICAM-I expression in epithelial cell
`lines. In vivo studies have also shown an effect on the allergen-induced inflammatory
`reaction; both oral and intranasal antihistamines cause a reduction in nasal symptoms
`and inflammatory cell influx. Oral terfenadine and cetirizine and intranasai levoca-
`bastine and azelastine have also demonstrated a lowering of ICAM-1 expression on
`epithelial cells. With regard to clinical efficacy, topical levocabastine (0-5 mg/mL eye
`drop solution and 0-5 mg/mL nasal spray) was shown to be more effective than oral
`terfenadine (60 mg twice daily) in relieving ocular itch {P = 0-02) and reducing nasal
`symptoms in allergic rhinoconjunctivitis, In a further study. levocabastine eye drops
`were as effective and well tolerated as sodium cromoglycate in seasonal allergic rhinitis.
`Intranasal azelastine (0-28 mg twice daily) showed a trend for superior relief of
`rhinorrhoea and nasal obstruction compared with oral terfenadine (60 mg twice
`daily). In addition, intranasal azelastine (0-28 mg twice daily) resulted in significant
`reductions in sneezing, nasal obstruction, rhinorrhoea and itching in perennial rhinitis,
`compared with the lower efficacy of beclomethasone dipropionate (0-1 mg twice daily).
`As well as benefits in efficacy, topical adtninistration is associated with improved
`safety. Some antihistamines, particularly those metabolized in the liver, are associated
`with occasional reports of severe side-effects. It is therefore logical to administer
`antihistatnines directly to the target organ.
`
`The pathogenesis of allergic rhinitis
`
`The pathogenesis of allergic rhinitis is complex, invol-
`ving many different cell types, inflatnmatory mediators,
`cytokines and adhesion molecules. Indeed, a recent study
`including 30 adults with seasonal allergic
`rhinitis
`recruited during the pollen season showed that in addi-
`tion to mast cell-derived tryptase (MCT) and histamine,
`eosinophil cationic protein (ECP), myeloperoxidase
`(MPO), prostaglandin Dj (PGDj) and leukotriene C4
`
`Correspondence: Professor R, J. Davies. Deparlment of Respiratory
`Medicine. Si Bartholomew's Hospital. West Smithfleld. London ECIA
`7BE. UK.
`
`© 1996 Blackwell Science Ltd
`
`(LTC4) were detected in the nasal lavage fluid, indicating
`the involvement of eosinophils and neutrophils. Inter-
`leukin-8 (IL-8) and RANTES. and soluble-intercellular
`adhesion molecule (sICAM-l) were also present in nasal
`lavage fluid, underlining the importance of chemokines
`and adhesion molecules (Fig. I).
`Mast cell- and eosinophil-derived mediators increase
`in nasal lavage fluid after direct allergen challenge and
`can be influenced further by exposure to air pollutants,
`such as nitrogen dioxide, which acts by priming eosino-
`phils [i] (Eig. 2).
`the
`in
`to be involved
`likely
`Epithelial cells are
`pathogenesis of allergic rhinitis through production of
`
`!
`
`11
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 001
`
`

`

`IL-8 and tumour necrosis factor-o (TNFa) released into
`the culture medium by these cells. Cell cultures from the
`atopic individuals released significantly greater amounts
`of IL-8. TNFo and GM-CSF than cell cultures from
`non-atopic individuals {P < 005). Of the atopic indivi-
`duals, cell cultures from those with rhinitis released the
`highest quantity of these cytokines. IL-8 release was the
`greatest and GM-CSF the least, irrespective of whether
`the cell cultures were derived from atopic or non-atopic
`subjects [2]. Importantly, the conditioned medium from
`atopic rhinitic patients in particular showed chemotactic
`activity for human eosinophils, probably due to the
`presence of RANTES (Fig. 3).
`
`The actions of histamine
`
`Histamine released from mast cells and basophils causes
`the symptoms of itch, pain and sneezing through stimu-
`lation of the afferent cutaneous nerve endings of the
`trigeminal nerve situated in the nasal epithelium. Of
`particular importance is the action of histamine on the
`subepithelial blood vessels, causing vasodilatation.
`hyperaemia and oedema
`through plasma exudation,
`which contribute to the symptoms of nasal blockage
`and rhinorrhoea. Contrary to findings from previous in
`vivo experimental work, histamine does not directly
`influence epithelial permeability
`[3]; exudation of
`plasma into the nasal cavity is due to extravasated fluid
`from postcapiilary venuies exerting lateral pressure on
`epithelial cells, causing temporary and reversible separa-
`tion of the tight junctions [4.51 (F'g- 4).
`
`Antihistamines
`
`It is perhaps surprising, given the many mediators and
`cytokines involved in the pathogenesis of allergic rhinitis,
`that drugs such as antihistamines are so effective in the
`management of this disorder, since they block only one
`component of the process. This has led to a considerable
`research effort to explore other pharmacological activities
`of this group of drugs.
`
`Anti-allergic and anti-inflammatory actions
`
`In vitro studies have shown that high concen-
`In vitro
`trations of histamine (H)) antagonists are able to block
`mediator release from basophils and human mast cells.
`At concentrations ranging from I to 50/iM, loratadinc
`blocks the release of histamine from basophils [6] and
`terfenadine inhibits the release of cicosanoids from mast
`cells and macrophages [7]. The mechanisms involved are
`not completely understood, though Berthon et ai [8]
`have shown that loratadine impairs the increase in
`
`12
`
`R.J. Davies
`
`Tryptase
`
`PGD.,
`
`IL-8
`
`si CAM-1
`
`Histamine
`
`ECP
`
`MPO
`
`1 0r
`
`0-8
`
`06
`
`0-4
`
`0-2
`
`12
`
`10
`
`4 2 0
`
`14
`
`12
`
`10
`
`RANTES
`Fig. 1. The levels of inflammatory mediators, cytokines and
`adhesion molecules in the nasal lavage Ruld of adults with
`seasonal allergic rhinitis during the pollen season.
`
`LTC,
`
`cytokines which are chemoattractant for both mast cells
`and eosinophiis. We have cultured nasal epithelial cells
`from biopsies of the inferior turbinates of well characterized
`atopic rhinitic. atopic non-rhinitic and non-atopic non-
`rhinitic subjects and measured the amount of granulo-
`cyle macrophage colony stimulating factor (GM-CSF),
`
`1996 Blackwell Science Lid, Clinical and Experimental
`
`Allergy.
`
`26, Supplement 3, 1 1 - 17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 002
`
`

`

`Topical vs oral antihistamines
`
`13
`
`P < 0.02
`
`P<0.05
`
`P < 0.05
`
`o
`
`Pre
`
`Post
`
`Air + Allergen
`
`Pre
`
`Post
`
`NO2 + Allergen
`
`Pre
`
`Post
`
`Air + Allergen
`
`Pre
`
`Post
`
`NO2 + Allergen
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Pre
`
`Post
`
`Air + Allergen
`
`Pre
`
`Post
`
`N02 + Allergen
`
`Pre
`
`Post
`
`Air + Allergen
`
`Pre
`
`Post
`
`NO2 + Allergen
`
`Fig. 2. The eflect of 6 h pre-exposure to air or 400 ppb nitrogen dioxide (NO,) on ECP. MCT, MPO and IL-8 concentration in the
`nasal lavage fluid coflected 30min after allergen challenge. From [I] with kind permission.
`
`intracellular Ca2+ following cell activation, by decreas-
`ing the influx of extracellular Ca2+ and inhibiting the
`release of Ca2+ from intracellular stores. Loratadine has
`also been shown to inhibit the release of LTC4 and
`histamine from cloned murine cells [9] and cetirizine has
`been shown to inhibit platelet activating factor (PAF)-
`induced migration of eosinophils in vitro and in vivo [10].
`Azelastine inhibits both histamine release from human
`basophils and LTC4/LTD4 from neutrophils, while the
`stabilizing action on lung mast cells requires
`long
`preincubation [II]. Terfenadine and cetirizine are cap-
`able of reducing the in vitro expression of ICAM-I on
`epithelial cell lines [12], These actions are thought to be
`separate from the H] receptor blocking activity of the
`antihistamines.
`
`t'n vivo studies have been
`In vivo A number of
`performed to assess the clinical effectiveness of anti-
`histamines in inhibiting the allergen-induced infiamma-
`
`tory process in the nasal mucosa and the conjunctiva. In
`a double-blind, crossover study, Bousquel et al. [13]
`demonstrated the clinical efficacy of terfenadine (60 mg
`twice daily) and loratadine (lOnig once daily) on nasal
`allergen challenge and also showed that there was a
`significant reduction in the release of PGD, in nasal
`secretions in the loratadine-treated group. In addition,
`Ciprandi et al. [14.15] demonstrated
`that
`loratadine
`exerted a significant protective effect both on the early
`and late-phase allergen-induced reactions in the con-
`junctiva, reducing cellular infiltration.
`The higher concentrations of antihistamines achiev-
`able by topical as opposed to oral administration should
`enhance any anti-allergic or anti-infiammatory activity
`possessed by these drugs. Pazdrak et al. [16] showed thai
`treatment with
`levocabastine
`(0 5 mg/mL
`solution)
`caused a significant reduction in nasal symptoms and
`inflammatory cell influx of eosinophils and neutrophils
`after allergen challenge, as compared with placebo
`
`1996 Blackwell Science Ltd, Clinical and Experimental
`
`Allergy, 26, Supplement 3. 11-17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 003
`
`

`

`14
`
`R. J. Davies et al.
`
`100
`
`P<005
`
`Non-atopic
`non-rhinitic
`
`Eczema
`(atopic non-rhinitic)
`
`Atopic
`rhinitic
`
`P<005
`
`cB2 (
`
`0
`•3
`
`Fig. 3. Synthesis of IL-8, GM-CSF and TNFa by cultured human nasal epithelial cells. From 12] with kind permission.
`
`I Methacholine:
`
`Vasodilatation
`
`Transudation
`
`Gland & gobiet
`cell secretion
`
`Fig. 4. The effects of histamine and methacholine on the nasal
`mucosa. From [5] with kind permission.
`
`administration. Van Wauwe [17], using histamine as well
`as aiiergen provocation, showed a marked decrease in
`vascular permeability after
`the use of topical levo-
`cabastine compared with placebo.
`Recently, atlenlion has focused on the effects of both
`orally and topically administered antihistamines with
`regard to expression ofthe adhesion molecule ICAM-l
`on epithelial cells in the conjunctiva and the nose.
`ICAM-I plays a key role in the capture of infiammatory
`cells in the epithelium through binding with its counter-
`receptors, LFA-I and Mac-1 (CDlib). on eosinophils
`and neulrophils. Indeed, intravenous treatment with an
`anti-ICAM-l monoclonal antibody has been shown lo
`attenuate allergen-induced airway eosinophilia and
`associated bronchial hyperresponsiveness in a primate
`model of asthma 1181. In a recent study, the effect of
`cetirizine (20 mg daily for 3 days) on the early and late
`responses induced by conjunctival allergen provocation
`testing was assessed in a double-blind, randomized,
`placebo-con I rolled study. Compared with placebo.
`
`1996 Blackwell Science Ltd, Clinical and Experimeniai AUergy, 26, Supplement 3, 11-17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 004
`
`

`

`Topical vs oral antihistamines
`
`15
`
`cetirizine treatment led to significantly lower symptom
`scores, infiammatory cell infiltration, and expression of
`ICAM-1 on epithelial cells after allergen provocation. In
`a similarly designed study, terfenadine. administered at a
`dose of I20mg/day for 7 days, reduced infiltration into
`the nasal mucosa and expression of epithelial ICAM-1
`when compared with placebo in 20 patients with allergic
`rhinitis studied during the pollen season [19]. The same
`group studied the effects of topically applied levoca-
`bastine (one drop to each eye 30 min before allergen
`challenge) and azelastine (one spray. 014mg into each
`nostril 30 min before allergen challenge) in double-blind,
`randomized, placebo-controlled trials. Bolh antihista-
`mines significantly reduced inflammatory cell inliltration
`and epithelial cell ICAM-1 expression compared with
`placebo [20,21]. However, from the published results to
`date, there does not appear to be any advantage of
`topically applied over systemic anlihistamines in terms
`of the extent of inhibition of ICAM-l expression, infiam-
`matory cell infiltration, or clinical efficacy.
`
`Onset of action
`
`The second generation antihistamines are well absorbed
`when taken orally, with peak plasma concentrations
`being achieved within 30 min to 4h. There is evidence
`that the clinical onset of action of antihistamines may be
`faster than is indicated by the time needed to reach
`maximum plasma concentration. In a recent placebo-
`controlled, randomized, double-blind, i-day Held study,
`the efficacy and onset of action of aerivastine (8 mg) were
`evaluated in 42 patients suffering from allergic rhino-
`conjunctivitis elicited by natural grass pollen exposure.
`The time of onset ofclinical efiectiveness (inhibition of
`nasal symptoms) using an exponential decay model was
`19 min [22]. This remarkably rapid onset of clinical
`effectiveness parallels the speed of action of topically
`applied antihistamines.
`Janssens and Vanden Bussche [23] found that 73% of
`patients reported symptom relief within 30 min of topical
`administration of levocabastine to the nasal mucosa.
`Janssens [24] also found levocabastine to be effective in
`the treatment of ocular symptoms, with 94yo of patients
`experiencing symptom relief within 15 min after the first
`instillation of levocabastine eye drops. In our study,
`topical azelastine O28mg applied to each nostril had
`a rapid (within 30min) and long-acting (up to lOh)
`inhibitory effect on allergen-induced sneezing [25].
`
`Efficacy
`
`Conjunctival and nasal provocation studies have been
`carried out in order to assess the efficacy of topical and
`
`oral preparations of antihistamines. In a randomized,
`double-blind, double-dummy, parallel-group
`study,
`Bahmer and Ruprecht 126] compared the safety and
`efficacy of topical levocabastine (0 5 mg/mL eye drop
`solution — one drop in each eye twice daily; and
`0-5 mg/mL nasal spray solulion — two sprays in each
`nostril twice daily) and oral terfenadine (60 mg twice
`daily). It was demonstrated
`that
`levocabastine was
`significantly more effective than lerfenadine in relieving
`ocular itch (P - 0 02). The patients' symptom scores also
`yielded better results with levocabastine, particularly
`with respect to nasal symptoms. In conclusion, the
`authors reported that topical levocabastine was a well
`tolerated and ciTcctive alternative to oral terfenadine for
`the treatment of allergic rhinoconjunctivitis. In a double-
`blind, randomized study. Wih! et al. [27] compared
`levocabastine eye drops and sodium cromoglycate in
`seasonal allergic conjunctivitis. Levocabastine eye
`drops applied twice daily were as effective and well
`tolerated as sodium cromoglycate eye drops applied
`four times daily.
`The efficacy and toierability of intranasal azelastine
`has also been evaluated in a number of clinical tHals.
`Gastpar et al. 128] compared the efficacy of intranasal
`azelastine (0 28 mg twice daily) with that of oral terfena-
`dine (60 mg twice daily) in a double-blind, parallel group
`study in patients with perennial rhinitis. Azelastine
`showed a trend towards superior relief of rhinorrhoea
`and nasal obstruction, whereas terfenadine showed a
`trend
`towards better control of sneezing and nasal
`itching. However, no clinically relevant statistically
`significant differences between the active
`treatments
`were observed in this study. We compared azelastine
`nasal spray (0-28 mg twice daily) with beclomethasone
`dipropionate (01 mg twice daily) in a double-blitid,
`randomized, parallel-group, placebo-controlled study
`involving 130 patients, to assess the elTect of 6 weeks'
`treatment on the symptoms of perennial rhinitis [29].
`Efficacy was assessed by patients recording the severity
`ofthe symptoms of rhinitis daily on lOcm visual analo-
`gue scales. Analysis of the diary data showed significant
`reductions in sneezing, nasal obstruction, rhinorrhoea,
`and itching during azelastine treatment. Patients on
`beclomethasone dipropionate
`recorded a consistent
`reduction in rhinitis symptoms, but these reductions
`were significant only for sneezing on treatment day 7.
`
`Safety
`
`\
`
`\
`
`Ofthe second generation antihistamines. terfenadine and
`astemizole are the least sedative. Terfenadine has been
`evaluated extensively in psyehomotor tests of visual and
`motor ability, mathematical ability, driving performance.
`
`1996 Blackwcll Science Ltd, Clinical and Experimeniat Atlergy. 26. Supplement 3, 11-17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 005
`
`

`

`16
`
`R. J. Davies efd\.
`
`electroencephalogram (EEG) response, reaction time and
`choice reaction time, and sleep latency, and has been
`shown not to differ significantly frotn placebo [30]. Simi-
`larly, the second generation antihistamines loratadine,
`aerivastine and cetirizine. are generally non-sedating in
`the recommended therapeutie doses., but may cause signs
`of sedation when administered in higher doses [31,32]. Of
`greatest concern are reports ofthe development of cardiac
`arrhythmias in a very small number of patients taking
`astemizole or terfenadine. often when used at doses higher
`than recommended or when taken concurrently with
`ketoconazole or erythromycin.
`The topical administration of levoeabastine to the
`nasal mucosa or to the eye does not cause significant
`sedation [33]. Tlie most frequently reported side-effects
`associated with the use of topical levoeabastine include
`nasai and ocular iriitation in 5-10% of patients, though
`this was not significantly different from placebo [24,34].
`The incidence of reported side-effects associated with
`the use of topical azelastine is low. and includes head-
`ache, somtiolence. taste perversion and nasal irritation at
`the site of application [35].
`
`C'onelusion
`
`There are clear advantages for the use of antihistamines
`applied topically to the nose and the eyes. Topical
`levoeabastine and azelastine are as effective as oral
`antihistamines and may be more beneficial in relieving
`nasal obstruetion. Although there is little difference with
`regard to speed of onset of eiinieai activity, unwanted
`effeets are reduced and the preparations ean be pre-
`scribed without risk of interactions with any concomi-
`tant medications.
`
`References
`
`1 Wang JH, Devalia JL. Duddle JM, Hamilton SA, Davies
`RJ. Effect of six hour exposure to nitrogen dioxide on early-
`phase nasal response to allergen challenge in patients with a
`history of seasonal allergic rhinitis. J Allergy Clin Immunol
`1995; 96:669 76.
`2 Calderon MA, E)evalia JL. Sapsford RJ. Davies RJ. Cytokine
`profiles ofeiilturcd na.sal epithelial cells from atopie rhinitic,
`atopic non-rhinitic and non-atopic non-rhinitic subjeets. J
`Allergy Clin Immunol 1995; 95(1 part 2): {abstr) 257.
`3 Devalia JL. Godfrey RWA. Sapsford RJ et al. No effect of
`histamine on human bronchial epithelial cell permeability
`and tight junctional integrity in-vitro. Eur Respir J 1994;
`7:1958-65.
`4 Persson CGA. Erjefalt I. Alkner U et al. Plasma exudation
`as a first line respiratory mucosal defence. Clin Exp Allergy
`1991; 21:17-24.
`5 Davies RJ. Trigg C. Rhinitis: pathophysiology and
`
`etassifieation. In: Holgate ST. Church M. eds.. Allergy.
`London: Gower Medical Publications. 1993:17. 7.
`6 Miadonna A. Milazzo N. Lorini M, Marchesi E. Tcdesehi
`A. Inhibitory elTeet of the H| antagonist loratadine on
`histamine release from human basophils. Int Areh Allergy
`Immunol 1994; 105:12 7.
`7 Campbell AM. Chanez P. Marty-Ane C et al. Modulation
`of eicosanoid and histamine release from human dispersed
`lung cells by terfenadine. Ailergy 1993; 48:125-9.
`8 Berthon B. Taudou G. Combettes L et al. In-vitro inhibi-
`tion by loratadine and desearboxyethoxyloratadine, of
`histamine release from human basophils and of histamine
`release and intraeellular ealeium fluxes in rat basophilic
`leukaemia cells. Biochem Pharmacol 1994; 47:789 94.
`9 Kreutner W. Chapman RW. Gulbcklan A. Siegel Ml.
`Antiallergic activity of loratadine. a non-sedating anti-
`histamine. Allergy 1987; 42:57-63.
`10 Fadel R, Herpin-Richard M. Rihoux JP, Henocq E. Inhi-
`bitory eflcet ofcetirizine 2HCi on eosinophil migration in-
`vivo. Clin Allergy 1987; 17:373-9.
`11 Little MM. Casale TB. Azelastine inhibiLs Ig-E mediated
`human basophils histamine release. J Allergy Clin Immunol
`1989; 83:862-5.
`12 Cunoniea GW. Ciprandi G, Buscaglia S. Pesce G. Bagnasco
`M. Adhesion molecules of allergic inflammation: rceent
`insights into their funetional roles. Allergy 1994; 49:135 41.
`13 Bousquet J. Lebel B. Chanal I. Morel A. Michel FB.
`Antiallergic activity of H| receptor antagonists assessed
`by nasal ehallenge. J Allergy Clin Immunol 1988; 82:881 7.
`14 Ciprandi G. Buseaglia S. Pesce GP. Marchesi E, Canoniea
`GW. Protective effect of loratadine on specific conjunctival
`provocation test. Int Arch Allergy AppI Immunol 1991;
`96:344-7.
`15 Ciprandi G. Buscaglia S. Marehesi E ei al. Protective elTect
`of loratadine in late phase reaction induced by conjunctival
`provocation test. Int Arch Allergy Appi Immunol 1993;
`100:185-9.
`16 Pazdrak K. Gorski P, Ruta U. Inhibitory effeet of levoea-
`bastine on allergen-indueed increase of nasal reactivity to
`histamine and eell influx. Allergy 1993; 48:598-601.
`17 Van Wauwe JP. Animal pharmacology of levoeabastine: a
`new
`type of H|-antihistamine wel! suited for topieal
`application. In: Mygind N. Naelerio RM. eds. Rhino-
`conjunetivitis: new perspectives
`in
`topical
`treatment.
`Toronto: Hogrefe & Huber. 1989:27-34.
`18 Wegner CD. Gundel RH. Reilly P et al. Intercellular
`adhesion molecule-1 (ICAM-1) in Ihe pathogenesis of
`aslhma. Science 1990: 247:456 9.
`19 Bagnaseo M. Canoniea GW. Influcnee of H,-receptor
`antagonists on adhesion molecules and cellular traltie.
`Allergy 1995; 50:17-23.
`20 Buscaglia S. Calrullo A. Ciprandi G et al. Levoeabastine
`eye drops reduce ICAM-I expression bolh In-vitro and in-
`vivo. Allergy 1995; 50(suppl): (abstr)79.
`21 Pronzato G. Ricea V. Varese P et al. Evaluation of anti-
`allergic activity of azelasline nasal spray. Allergy 1995; 50
`(suppl): (abstr)69.
`
`1996 Blackwell Science Ltd, Clinical and Experimental Allergy, 26, Supplement 3, 11-17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 006
`
`

`

`Topical vs oral antihistamines
`
`17
`
`22 Nielsen L, Johnsen CR, Bindsley-Jensen C, Poulsen LK.
`Eflicacy of aerivastine in the treatment of allergic rhinitis
`during natural pollen exposure: onset of action. Allergy
`1994; 49:630 6.
`23 Janssens MM-L, Vanden Bussche G. Levocabastine: an
`effective topical treatment of allergic rhinoconjunctivitis.
`Clin Exp Allergy 1991; 2l(suppl 2):29-36.
`24 Janssens MM-L. Levoeabastine: a new topieal approach for
`the treatment of paediatric allergic rhinoconjunctivitis.
`Rhinology 1992: l3(suppl):39-49.
`25 Thomas KE, Oilier S. Ferguson H, Davies RJ. The effect of
`intranasal azelastine. Rhinolast, on nasal airways obstruc-
`tion and sneezing following provocation
`testing with
`histamine and allergen. Clin Exp Allergy 1992; 22:642-7.
`26 Bahmer FA. Ruprecht KW. Safety and eflicacy of topical
`levocabastine compared with oral terfenadine. Ann Allergy
`1994; 72:429-34.
`27 Wihl JA. Rudbiad S, Kjellen H, Blychert LA. Levoea-
`bastine eye drops versus sodium cromoglycate in seasonal
`aliergic conjunctivitis. Clin Exp Allergy 199I(suppl 2):37-
`8.
`28 Gastpar H.. Nolte D. Aurich R et al. Comparative efficacy
`of azelastine nasal spray and terfenadine in seasonal and
`perennial rhinitis. Allergy 1994; 49:152-8.
`
`29 Davies RJ. Lund VJ. Harten-Ash VJ. The effeet of intra-
`nasal azelastine and beclomethasone on the symptoms and
`signs of nasal aUergy in patienis with perennial allergic
`rhinitis. Rhinology 1993; 31:159-64.
`30 Nicholson AN. Stone BM. Performance studies with the H,
`antagonists, astemizole and terfenadine. Br J Clin Pharma-
`col 1982; 13:199.
`31 Weiler JM. Donnelley A. Campbell BH et al. Multieentre
`double-blind, multiple dose, parallel grouping efficacy and
`safety trial of azelastine. chlorpheniramine and plaeebo in
`the treatment of spring allergic rhinitis. J Allergy Clin
`Immunol 1988; 82:801.
`32 Falliers CJ. Brandon M, Buchman E et al. Cetirizine
`therapy in seasonal allergic rhinitis: a dose response study.
`Ann Allergy 1988:60:166.
`33 Arriaga F. Rombaut N. Absenee of central efTects with
`levocabastine eye drops. Allergy 1990; 45:552-4.
`34 Deehant KL. Goa KL. Levocabastine: a review of Its
`pharmacological properties and tiierapeutic potential as a
`topical antihistamine in allergic rhinitis and conjunctivitis.
`Drugs 1991; 41:202 24.
`35 Grossman J. Halverson PC, Meltzer EO et al. Double-blind
`assessment of azelastine in the treatment of perennial
`allergic rhinitis. Ann Allergy 1994; 73:141-6.
`
`1996 Blackwell Science Ltd. Clinical and Experimental Ailergy, 26. Supplement 3. 11-17
`
`Apotex, Inc. (IPR2019-00400), Ex. 1012, p. 007
`
`