EuropeanfJournal
`Ophthalmology
`
`0
`
`Vol. 13 No.2, 2003
`CONTENTS
`
`'l'
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`[3
`
`I
`
`9(- .
`1133610“ cytology on conjunctiva and cornea in dry eye patients establishes a correlation
`ngween squamous metapiasia and dry eye clinical severityl115
`J_ Murube, l_. Rivas
`K. _.
`Tl e anll'a'lf'ngc effects of a cromolyn sodium-chlorpheniramine combination compared to ketotifen
`l .
`'n1the conjunctival allergen challengemodel [4/66 OW (44/6 128
`:4. Leonaro'r. F. Buses, M. Tavofai‘o, A. G. Secchi
`Factors influencing visual outcome after penetrating keratoplasty combined with intraocular lens implantation .................................. 134
`J B: Jonas, RM. Rank, WM. Budde, G. Sauder
`
`Complications of laser in'situ keratomileusis (LASlK) .............................................................................................................................. 139
`K.F. Tabbara, H.F. El-She/kh, C.L. Vera-Crista
`
`Visually significant cpacification of hydrophilic acrylic intraocular lenses - a clinico-pathological analySIS 147
`“Ky Yong, FEA. Netto, W-J. Heng, E.-Y. Yap, H.-M. Lee, M.M.L. Ng, K.-G. Au Eong
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`Prevention of posterior capsule opacification using capsular tension ring for zonular defects in cataract surgery
`D, D’E/iseo, B. Pastena, L. Longanesi, F. Grisanti, V. Negrini
`
`151
`
`The effects of some antibiotics on sheep lens glucose 6—phosphate dehydrogenase inwtro 155
`$. Beydemir. D. N. Ku/acog/u, M. Qiftci, O. I. KUfreviog/u
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`Four years later: A clinical update on latanoprost ................................................................................................................................... 162
`E. Ravinet, A. Mermoud, R. Brignoli
`
`Endotoxins in ophthalmic viscosurgical devices ..................................................................................................................................... 176
`H. Burkhard Dick, A.J. Augustin, I Paku/a, N. Pfeiffer
`Immunological effects of allopurinol in the treatment of experimental autoimmune uveitis (EAU) after onset of the disease ................ 185
`F.H. Grus, A.J. Augustin, K. Loefllei: J. Lutz, N. Pfeiffer
`
`Thenmanagement of giant retinal tears with silicone oil ........................................................................................................................... 192
`N. Unlu, H. Kocaogian, M.A. Acar, M. Sargin, 8.8. Asian, 8. Duman
`
`Magnetic resonance imaging analysis of anterior and posterior eye segment displacement during ocular gaze shifts 196
`N. Eter, S. Gar/0e, D. Pau/eit, 77 SchUttoff, H. SchL‘i/ler
`
`Autogenous versus allograft fascia lata in frontal sling surgery - long-term results 202
`C. Gurdei, U. Erdener, M. Orhan, M. lrkec
`
`SHORT COMMUNICATIONS
`
`209
`
`215
`
`I
`
`givergent Strabismus fixus - A case report .............................................................................................................................................. 207
`‘K- Shanna, J.S. Grewal, M. MacDonald
`BEUIBrfindings in cerebrO-oculo—facial-ske|etal syndrome (Pena—Shokeir—ll syndrome)
`'
`- JONES. U. Mayei; WM. Budde
`Minggement of free floating iris cysts in the anterior chamber - A case report 212
`'
`-
`ner, S. Kaynak, N. Kocak, G. Qingil
`grganized vitreous hemorrhage masquerading as an optic disc melanocytoma
`C- W, S. Prasad, I.G. Rennie
`T-hharfgidnlneovascularization secondary to vitrectomy for idiopathic epiretinal membrane: Report of an unusual case ....................... 218
`C
`ell.- f‘EITarr. R. Dammacco, G. M. Ouaranta. N. Cardascia, F. Bose/a, C. Sborgia
`affifignrficular edema associated with latanoprost therapy in a pseudophakic vitrectomized patient
`M. Jé
`<>val of Silicone orl endotamponade........................................................................................................................................... 221
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`lPR2018—01020 and lPR2018—01021, Exhibit 1028, Page 1
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`—
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`IPR2018-01020 and IPR2018-01021, Exhibit 1028, Page 1
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`

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`European Journal of Ophthalmology / Vol. 13 no. 2, 2003 / pp. 128-133
`
`The anti-allergic effects of a cromolyn
`sodium-chlorpheniramine combination
`compared to ketotifen in the conjunctival
`allergen challenge model
`
`A. LEONARDI, F. BUSCA, M. TAVOLATO, A.G. SECCHI
`
`Department of Neuroscience, Ophthalmology and Ocular Inflammation Unit, University of Padova - Italy
`
`PURPOSE. To compare the inhibitory effects of a topical combination product, cromolyn sodi-
`um (DSCG) 4% with the antihistamine, chlorpheniramine, with those of topical ketotifen
`0.05% on the clinical allergic reaction induced by the conjunctival allergen challenge (CAC).
`METHODS. Ten allergic but non-active patients were challenged in both eyes with increasing
`doses of specific allergen to obtain a positive bilateral reaction (visit 1). They were then
`rechallenged after 1 week to confirm the allergic threshold dose response (visit 2). After 2
`weeks, a third CAC was performed bilaterally 30 minutes after topical application of DSCG-
`chlorpheniramine in one eye and ketotifen in the contralateral eye in a double-masked fash-
`ion (visit 3). Clinical signs and symptoms were registered 5, 10, 15, and 20 minutes after
`challenge using the standard scoring system. Tear cytology was performed 30 minutes af-
`ter challenge.
`RESULTS. Comparing the two drug effects at visit 3, DSCG-chlorpheniramine was shown to
`be superior to ketotifen at all time points for itching (p<0.01) and at 5 minutes for redness
`(p<0.01). For the total signs score, DSCG-chlorpheniramine was shown to be superior to
`ketotifen at all time points (p<0.01), and at 10 and 15 minutes for the total symptoms score
`(p<0.05). Compared to visit 2, DSCG-chlorpheniramine significantly lowered itching
`(p<0.001) and redness (p<0.05) at 5, 10, 15, and 20 minutes after challenge. Ketotifen sig-
`nificantly lowered itching at 5 and 10 minutes (p<0.001) and redness at 5, 10, and 15 min-
`utes (p<0.05). Both drugs reduced the total number of cells evaluated by tear cytology dur-
`ing the early-phase reaction (p<0.05).
`CONCLUSIONS. DSCG-chlorpheniramine was found to be more effective than ketotifen at pre-
`venting itching and redness in the CAC model. (Eur J Ophthalmol 2003; 13: 128-33)
`
`KEY WORDS. Allergic conjunctivitis, Conjunctival allergen challenge, Chlorpheniramine, Sodi-
`um cromolyn, Ketotifen
`
`Accepted: January 20, 2003
`
`INTRODUCTION
`
`Itching, redness, and lid swelling are the typical in-
`flammatory signs and symptoms of seasonal allergic
`conjunctivitis (SAC), and are the result of single or re-
`
`1120-6721/128-06$03.00/0
`
`peated natural challenges by environmental allergens
`(1). The reaction induced by specific conjunctival al-
`lergen challenge (CAC) accurately reproduces the signs
`and symptoms of an acute seasonal allergic reaction.
`In the CAC model, a single episode is induced in a
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1028, Page 2
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`

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`Leonardi et al
`
`standardized manner that allows for a homogeneous
`baseline for all patients in the study independent of
`the type of allergen sensitization (2). This model is a
`reliable method for quantifying and comparing the ef-
`ficacy of various therapies in the prophylactic treat-
`ment of allergic conjunctivitis. As in SAC, the reac-
`tion in the CAC model is characterized by mast cell
`activation and the release of preformed and newly formed
`mediators such as histamine, tryptase, prostaglandins,
`leukotrienes, and cytokines (3, 4), as well as subse-
`quent activation of vascular endothelial cells, expression
`of adhesion molecules (5), and inflammatory cell in-
`filtration. In the acute allergic reaction, either induced
`by environmental allergen exposure or by the CAC,
`most of the signs and symptoms are related to hist-
`amine release from mast cells (6). In fact, histamine
`accounts for 98% of the material released by mast
`cell degranulation (7). Several topical mast cell sta-
`bilizers and antihistamines have been shown to sig-
`nificantly reduce the ocular allergic symptoms in both
`the SAC and CAC models (8, 9).
`The combination product investigated, 4% cromolyn
`sodium–0.2% chlorpheniramine (DSCG-chlorpheniramine),
`is an anti-allergic ophthalmic solution that combines
`the mast cell stabilizing effect of cromolyn sodium
`(DSCG) with the antihistaminic effect of the H1-re-
`ceptor antagonist chlorpheniramine. Mast cell stabi-
`lizers prevent calcium influx across cell membranes,
`thereby preventing mast cell degranulation and me-
`diator release (10). Chlorpheniramine is a first-gen-
`eration anti-H1 alkylamine compound with high H1
`receptor affinity (11). Topical application of chlor-
`pheniramine is rapidly effective in reducing itching
`without systemic side effects (12). Ketotifen fumarate
`0.05% ophthalmic solution is a cyproheptadine de-
`rived anti-allergic drug that possesses both a mast
`cell stabilizing effect and H1-receptor antagonistic ac-
`tivity (13). The commercial combination of DSCG-chlor-
`pheniramine has been widely used in Italy since 1985.
`The efficacy of this combination, however, has not
`been compared to that of one of the new anti-aller-
`gic products that combine in one drug the pharma-
`cologic properties of two, such as ketotifen.
`The current study was performed to determine the
`protective effect of two dual action anti-allergic top-
`ical preparations – DSCG-chlorpheniramine and ke-
`totifen – on the onset of the allergic conjunctival re-
`action induced by the CAC model.
`
`MATERIALS AND METHODS
`
`Ten patients (age range 18–47 years; 6 men, 4 women)
`with a clinical history of SAC were included in this
`randomized, double-masked study. All patients were
`asymptomatic and had positive results on a prick test
`(wheal diameter >3 mm) as confirmation of their al-
`lergic medical history. The allergen that gave the great-
`est response by prick test and/or that was most clin-
`ically correlated with seasonal symptoms was cho-
`sen for challenge: seven patients were challenged with
`rye grass and three with Parietaria officinalis. The CAC
`was performed according to the standardized proce-
`dure described by Abelson et al (2).
`At visit 1, demographic data, medical and medica-
`tion history, and informed consent were obtained. Base-
`line slit-lamp examination and visual acuity (Snellen)
`were also recorded at each visit before challenge. The
`allergen threshold dose that induced a positive con-
`junctival reaction was determined by challenging both
`eyes with one 20-µL drop of allergen in serial dilu-
`tions (10–50–100–200–300 Allergen Unit RAST [AUR]
`/ml), increasing the dose every 15 minutes until a clin-
`ical reaction with a score of 2+ itching and redness
`was obtained. Seven days later (visit 2), a second chal-
`lenge with the last threshold dose identified at visit 1
`was repeated to confirm the conjunctival reaction. Af-
`ter 2 more weeks (visit 3: drug evaluation day), pa-
`tients were administered a single dose of ketotifen
`0.05% in one eye and DSCG-chlorpheniramine 4% in
`the contralateral eye in a double-masked fashion 30
`minutes prior to CAC using the threshold dose.
`Conjunctival signs
`(redness, chemosis, eyelid
`swelling) were assessed by the investigators and symp-
`toms (itching, burning, foreign body sensation, tear-
`ing) by the patients using a score of 0 (none) to 4 (se-
`vere) for each eye before drug administration (time
`0), immediately before allergen challenge, and 5, 10,
`15, and 20 minutes after challenge.
`Tear samples (2 µL) were collected from both eyes
`with a capillary tube 1 hour before CAC and within 30
`minutes after CAC to determine inflammatory cell num-
`ber. Tears were placed on pre-colored slides (Test-
`simplets, Roche, Germany) and the numbers of neu-
`trophils, eosinophils, and lymphocytes were immedi-
`ately counted in five consecutive microscopic fields
`at 250x magnification power.
`The primary efficacy variables were itching and red-
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`DSCG-chlorpheniramine and ketotifen in CAC
`
`ness. Secondary efficacy variables were the sum scores
`of signs and symptoms, and tear cytology. The mean
`change from baseline itching and redness between
`visit 3 (eyes pretreated with drug and then challenged)
`and visit 2 (the baseline challenge reaction) provided
`a measure of clinical efficacy of a drug treatment. Dif-
`ferences in clinical scores between the two active treat-
`ments were also determined. The nonparametric
`Wilcoxon signed-rank test was performed on itching,
`redness, and total sign and symptom scores at each
`time point, with significance set at p<0.05. Data are
`presented as mean and standard deviation (±SD). In
`addition, clinical significance was defined as at least
`a one-unit difference in the mean score of itching and
`redness from visit 3 to visit 2.
`
`RESULTS
`
`All the enrolled subjects completed the study and
`were evaluable for efficacy. No adverse events were
`reported in this study. There were no significant changes
`between visual acuity or baseline slit-lamp parame-
`ters between visits. The conjunctival signs and symp-
`toms induced by challenge were not statistically dif-
`ferent between contralateral eyes of the same sub-
`ject, and were reproducible from visit 1 to visit 2.
`For the efficacy variable itching (Fig. 1), DSCG-chlor-
`pheniramine was statistically significantly superior to
`ketotifen at all time points (5, 10, 15, and 20 minutes)
`(p<0.01), whereas for redness, DSCG-chlorpheniramine
`was statistically significantly superior to ketotifen at
`5 minutes after challenge (p<0.01) (Fig. 2). DSCG-chlor-
`pheniramine eyes demonstrated statistically signifi-
`cantly lower mean itching (p<0.01) and redness
`scores (p<0.05) at all time points compared to non-
`treated eyes (visit 2, the baseline challenge reaction)
`(Figs. 1 and 2). Ketotifen showed statistically signif-
`icantly lower mean scores at 5 and 10 minutes for
`itching (p<0.01), and at 10 and 15 minutes for red-
`ness (p<0.05) (Figs. 1 and 2).
`Both DSCG-chlorpheniramine and ketotifen showed
`a clinically significant reduction in itching after chal-
`lenge at 5 and 10 minutes (Tab. I), whereas only DSCG-
`chlorpheniramine showed a clinically significant re-
`duction in conjunctival redness at 10 and 15 minutes
`(Tab. II).
`The mean sum score of signs (Fig. 3) was signifi-
`cantly lower in DSCG-chlorpheniramine–treated eyes
`
`130
`
`Fig. 1 - Mean score of the primary variable, itching, after bilateral
`conjunctival allergen challenge at visit 2, and after pretreatment at
`visit 3 with either cromolyn sodium (DSCG)-chlorpheniramine in one
`eye or ketotifen in the contralateral eye. At visit 3, DSCG-chlorpheni-
`ramine was statistically superior to ketotifen at all time points
`(‡p<0.01). Both drugs significantly reduced itching compared to the
`respective reaction obtained at visit 2 (** p<0.01).
`
`Fig. 2 - Mean score of the primary variable, redness, after conjuncti-
`val allergen challenge. At visit 3, cromolyn sodium (DSCG)-chlor-
`pheniramine was statistically superior to ketotifen at 5 minutes
`(‡p<0.01). Both drugs significantly reduced redness compared to the
`respective reaction obtained at visit 2 (*p<0.05).
`
`than ketotifen-treated eyes at all time points (p<0.01),
`whereas the mean sum score of symptoms (Fig. 4) was
`significantly lower in DSCG-chlorpheniramine versus
`ketotifen eyes at 10 and 15 minutes (p<0.05). DSCG-
`chlorpheniramine demonstrated significantly lower mean
`scores at all time points compared to visit 2, where-
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`Leonardi et al
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`TABLE I - MEAN ± STANDARD DEVIATION (SD) OF ITCHING SCORES AT VISIT 2 (no pretreatment) AND VISIT 3
`(pretreatment with drugs) AND MEAN DIFFERENCE (D) BETWEEN VISIT 2 AND VISIT 3
`
`Minutes
`after challenge
`
`DSCG + chlorpheniramine
`Visit
`3±SD
`
`Visit
`2±SD
`
`∆
`
`5
`10
`15
`20
`
`1.5±0.7
`2±0
`1.3±0.3
`0.8±0.6
`
`0.2±0.4
`0.6±0.5
`0.6±0.6
`0.1±0.3
`
`1.3±0.8*
`1.4±0.5*
`0.7±0.4
`0.7±0.4
`
`Visit
`2±SD
`
`1.5±0.7
`2±0
`1.4±0.5
`0.8±0.6
`
`Ketotifen
`Visit
`3±SD
`
`0.3±0.4
`0.8±0.6
`0.9±0.9
`0.4±0.6
`
`∆
`
`1.2±0.6*
`1.2±0.6*
`0.5±0.6
`0.4±0.5
`
`*Clinically significant (>1-unit difference in itching)
`
`TABLE II - MEAN ± STANDARD DEVIATION (SD) OF REDNESS SCORES AT VISIT 2 (no pretreatment) AND VISIT 3
`(pretreatment with drugs) AND MEAN DIFFERENCE (D) BETWEEN VISIT 2 AND VISIT 3
`
`Minutes
`after challenge
`
`DSCG + chlorpheniramine
`Visit
`3±SD
`
`Visit
`2±SD
`
`∆
`
`5
`10
`15
`20
`
`1±0
`2.1±0.3
`2.2±0.4
`1.8±0.7
`
`0.2±0.4
`1±0.4
`1±0.6
`1±0.8
`
`0.8±0.4
`1.1±0.5*
`1.2±0.6*
`0.8±0.6
`
`Visit
`2±SD
`
`1±0
`2.1±0.3
`2.2±0.4
`1.8±0.7
`
`Ketotifen
`Visit
`3±SD
`
`0.5±0.7
`1.5±0.6
`1.6±0.6
`1.6±0.9
`
`∆
`
`0.5±0.5
`0.6±0.5
`0.6±0.5
`0.2±0.5
`
`*Clinically significant (>1-unit difference in redness)
`
`Fig. 3 - Mean sum score of signs (redness, chemosis, eyelid swelling)
`after challenge in eyes pretreated with either cromolyn sodium
`(DSCG)-chlorpheniramine or ketotifen compared with the respective
`reaction at visit 2 (**p<0.01, *p<0.05). At visit 3, DSCG-chlorpheni-
`ramine was statistically superior to ketotifen at all time points
`(‡p<0.01).
`
`Fig. 4 - Mean sum score of symptoms (itching, burning, foreign body
`sensation, tearing) after challenge in eyes pretreated with either cro-
`molyn sodium (DSCG)-chlorpheniramine or ketotifen compared with
`the respective control reaction without pretreatment at visit 2
`(**p<0.005, *p<0.05). At visit 3, DSCG-chlorpheniramine was statisti-
`cally superior to ketotifen at 10 and 15 minutes (‡p<0.05).
`
`131
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`DSCG-chlorpheniramine and ketotifen in CAC
`
`as these scores in ketotifen-treated eyes were signif-
`icantly lower only at 5 and 10 minutes after challenge.
`Tear cytology performed 30 minutes after CAC showed
`a statistically significant reduction in the total num-
`ber of inflammatory cells in the eyes pretreated with
`each drug (visit 3) compared to visit 2 (DSCG-chlor-
`pheniramine: 12.5±19 versus no pretreatment,
`27±35, p<0.05; ketotifen: 11±22 versus no pretreat-
`ment, 28±30, p<0.05). The numbers of single cell pop-
`ulations of eosinophils, neutrophils, and lymphocytes
`were also reduced at visit 3 compared to visit 2; how-
`ever, these differences were not statistically signifi-
`cant because of the high SD around the mean (data
`not shown).
`
`DISCUSSION
`
`The clinical hallmarks of allergic conjunctivitis are
`ocular itching and conjunctival redness. The CAC mod-
`el allows for the precise evaluation of itching and red-
`ness in a controlled environment (14). In this study,
`DSCG-chlorpheniramine was statistically significant-
`ly superior to ketotifen in the prevention of itching and
`redness. Efficacy scores of both agents were clinically
`equivalent up to the first 10 minutes of the reaction.
`DSCG-chlorpheniramine appeared to be clinically
`more effective than ketotifen at 15 and 20 minutes af-
`ter challenge. These results indicate that the antihis-
`taminic effect of the two drugs immediately after chal-
`lenge is of equal potency; however, DSCG-chlorpheniramine
`may have a longer duration of action.
`In a previous CAC study, ketotifen was reported to
`be as effective as another topical antihistamine,
`emedastine, for inhibition of itching (15). The antihis-
`taminic compounds chlorpheniramine and ketotifen have
`been proven to have an equal H1-receptor affinity in
`an in vitro receptor binding study (16). The present re-
`sults suggest that the first-generation histamine-re-
`ceptor antagonist chlorpheniramine is highly effective
`in reducing not only ocular itching but also redness in
`the allergic conjunctivitis model. However, it is also
`possible that the effect on redness was a result of mast
`cell stabilization provided by cromolyn. Sodium cro-
`molyn has been proven to interfere with the influx of
`calcium and to inhibit mast cell degranulation and his-
`tamine release (10,17,18). Mast cell stabilizers may al-
`so act through other mechanisms. Cromolyn sodium
`
`132
`
`is known to inhibit chemotaxis, activation, degranu-
`lation, and cytotoxicity of neutrophils, eosinophils, and
`monocytes (19, 20). Similar properties have also been
`shown for ketotifen (13, 21). DSCG-chlorpheniramine
`has been shown to prevent tear histamine release in
`a CAC model, with a 2-week pretreatment before chal-
`lenge (22). Results of the present study suggest some
`effect on mast cell stabilization, even after only one
`drop. In fact, both drugs also reduced the total num-
`ber of inflammatory cells 30 minutes after challenge,
`suggesting an inhibitory effect of other chemotactic
`mediators besides histamine.
`In conclusion, one would expect the dual mast cell
`stabilization and antihistaminic properties of ketotifen
`to be superior in anti-allergic efficacy compared to
`an older combination product such as DSCG with the
`first-generation
`antihistamine
`chlorpheniramine.
`However, this was not the case. In the present mod-
`el, DSCG-chlorpheniramine and ketotifen were both
`effective at preventing the onset of the clinical re-
`sponse, and reducing the cytologic reaction, but DSCG-
`chlorpheniramine was more effective in reducing itch-
`ing and redness.
`
`Reprint requests to:
`Andrea Leonardi, MD
`Department of Ophthalmology
`University of Padova
`Via Giustiniani 2
`35128 Padova, Italy
`andrea.leonardi@unipd.it
`
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