Conjunctival Allergen Challenge:
`Models in the Investigation of
`Ocular Allergy
`Mark B. Abelson, MD, andOliverLoeffler
`
`Address
`Ophthalmic Research Associates, 863 Turnpike Street, North Andover,
`MA 01845, USA.
`E-mail: mbabelson@oraclinical.com
`Current Allergy and Asthma Reports 2003, 3:363-368
`Current Science Inc. ISSN 1529-7322
`Copyright © 2003 by Current Science Inc.
`
`Recently, the number of agents to treat ocularallergy has
`increased dramatically, from three (pheniramine, antazoline,
`cromolyn) to more than a dozen. A general increase in the
`incidence of atopy in recent years andthefact that patients
`are becomingless tolerant of bothersome signs and symp-
`toms have been driving forcesin this increase: As-visual
`tasking, such as reading and working on a computer, has
`become moreprevalent, there is an increased awareness of
`ocularallergy and the impact it has on quality oflife and
`productivity at work and school. With the need for more
`effective medications, the development of models, such as
`the conjunctival allergen challenge (CAC), has made the
`identification of new agents moreefficient. In this article,
`wereview the relevant background on the science behind
`allergen challenges in the eye, how models are designed,
`and how models are used in the field today.
`
`Introduction
`It
`is estimated that as many as 50 million Americans are
`affected by ocular allergy—almost 25% of the population
`1]. Of the four types ofallergic conjunctivitis (atopic
`
`keratoconjunctivitis, vernal keratoconjunctivitis, sea-
`sonal/perennial allergic conjunctivitis (SAC/PAC), and
`drug-induced allergic conjunctivitis), the most prevalent
`forms are SAC,triggered by pollens, and PAC triggered by
`dust or dander. The bothersome signs and symptoms
`causedbyocularallergy will cause significant decreases in
`quality oflife and ability to function, sleep problems,
`decreasedability to visual task, andeffects on social inter-
`actions, all leading to missed timeat work, owing tovisits
`to the doctor's office, and decreased productivity. There-
`fore, it
`is important not onlythat therapeutic modalities
`be developedfor ocularallergic sufferers, but alsothat the
`model or methads by which these treatments are identi-
`
`fied and tested be accurate and reliable. In the pursuit of
`effective therapies,
`the conjunctival allergen challenge
`(CAC) model has been developed. This model has
`allowedprecise control of confounding factors that are
`present in the typical environmental studyand has
`helped to evaluate and bring to market effective medica-
`tions for ocularallergy. The model has also been very
`useful in elucidating the allergic and inflammatory mech-
`anisms of the ocular surface,
`in identifying thecells and
`mediators that are involved, andin identifying targets for
`novel therapies. In this article, we review the CAC model,
`compareit with the environmental design, and look at
`howit has helped contribute further understanding to
`ocular disease andtherapy.
`
`Basic Science of the Conjunctival
`Challenge Model
`Ofthose who suffer fromocularallergic conditions, at
`least 90%suffer from SAC/PAC. Thesediseases aretrig-
`gered when an allergen comes in contact with conjunctival
`mastcells containing IgE molecules boundto the cytoplas-
`
`mic membrane. Thecross-linking of pairs of IgE molecules
`with allergen initiates a cascade of intercellular changes
`that result in mast-cell degranulation. Understanding the
`host of substances released, and howtheyinteract, has
`been driven byuseof challenge models.
`Various mediators and cytokines are released from the
`mast cell during degranulation, leading to theclinical signs
`and symptoms of allergy, and the propagation ofthe reaction
`(Table 1). The primary inflammatory mediator released
`during this process is histamine, as confirmedbyaseries of
`studies [2—-5,6¢e]. Instillation of histamineinto the eye repro-
`duces in a dose-dependent fashion thesigns and symptoms
`ofallergic conjunctivitis: itching, redness, chemosis, tearing,
`andlid swelling. In fact, histamineis the only mediatorthat
`can reproducethe entire clinical allergic condition in the eye
`[2]. Furthermore, instillation of substances known to induce
`degranulation of mast cells (secretagogues) andthe release of
`histamine also producethe allergic condition in both animal
`and human eyes [3]. The collection of histamineintears is
`difficult, however, because the enzyme histaminase is also
`released during mast-cell degranulation and works to break
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`364 OcularAllergy
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`ES
`Table |. Mediators released by the mastcell
`
`
`eeEEE
`
`Preformed mediators
`Histamine
`Chymases
`Heparin
`Proteoglycans
`Newly formed mediators
`Leukotriene B4
`Leukotriene C4, D4, E4
`Prostaglandin D2
`Platelet-activating factor
`Mast-cell-derived cytokines/
`chemokines
`TNF-c
`IL-loy, IL-1, IL-3, IL-4, IL-5,
`IL-6, IL-10
`MCP
`Interferon-y
`Granulocyte-macrophage
`Macrophage-inhibitory
`
`protein colony-stimulating factor
`HETE—hydroxyeicosatetraenoic acid; HHT—hydroxyheptadeca-
`trienoic acid; HPETE-hydroperoxyeicosatetraenoic acid;
`IL—interleukin; MCP—monocyte chemoattractant protein;
`RANTES—regulated on activation, normal T-cell expressed and
`secreted; TNF—tumor necrosis factor.
`
`Conjunctival challenges have also been used to identify
`other mediators that are present in allergic patients.
`Tryptase is a good marker for mast-cell degranulationas the
`mast cell is the onlycell in the bodythat contains this neu-
`ropeptidase. Tryptase levels were found to be increased in
`patients who were symptomatic with SAC and in patients
`after challenging the conjunctiva withallergens, compound
`48/80, and mechanical rubbing [10]. Implications of this
`study were twofold: it showedthat tryptase is a good
`indicator of mast-cell degranulation, and it showedthat
`conjunctival challenges can be used to induce mast-cell
`degranulation. Studies in which the conjunctiva was chal-
`lenged with allergen have shownincreases in histamine,
`kinins, prostaglandins, albumin, and TAME-esterase (tolu-
`ene-sulfo-trypsin-arginine methyl ester) [11]; leukotrienes
`B4, C4, D4, and E4 [12]; eosinophil cationic protein (ECP)
`[13]; and histaminase [14]. An understanding of the release
`of histaminase, the enzymethat breaks downthe released
`histamine, following a conjunctival challenge is especially
`important in understanding the time course ofsigns and
`symptoms. The challenge models have also been usedto
`studyeffects that occur on the epitheliuminallergic dis-
`eases. For example, it has been shownthat conjunctival epi-
`thelium expresses intracellular adhesion molecules (ICAM-
`1) following challenge[15].
`During the acute allergic reaction, there are many
`chemotactic factors released from the mast cell; the actual
`cellularinfiltrate that would be expected to subsequently
`occurin the eye is more ambiguous. Some ofthe mediators
`released from the mastcell, such as PAR interleukin-5,
`LTB4, PGD2, and tumornecrosis factor (TNF), will help to
`recruit leukocytes, lymphocytes, and more mast cells in the
`conjunctiva. However, usually only high doses of allergen
`ina challengetest will provoke cellular infiltrate of eosino-
`phils, neturophils, basophils, lymphocytes, and mast cells
`in selected patients [16], with ranges of 20 minutes to 6 to
`24 hoursfollowingchallenge. Furthermore, not all patients
`havecellular infiltrate in their environment, and SACgener-
`ally occurs in the absenceofcellular rectuitment [17¢¢, 18].
`A secondpeak(or continuation of the acute phase) in
`symptoms has been demonstrated duringthis late phase at
`6 h [19] following a conjunctival challenge with high doses
`of allergen. This reaction at 6 h was accompanied by
`increased histamine and eosinophil cationic protein levels
`(ECP-released from eosinophils), and upregulated adhe-
`sion molecules, as comparedwith pre-challenge baseline
`values [20¢]. Although mast-cell numbers were increased in
`this latterstudy, interestinglytryptase levels were not during
`this late time point, indicating a potential role forcells
`other than mastcells (such as basophils) during this late
`phase. However, it is important to mention that infiltrate in
`general is not correlated with anincrease in clinical signs
`and symptoms, and althoughan increase might be seenfol-
`lowing CACsonthe cellularlevel, this does not necessarily
`reachtheclinical threshold necessary to induce signs and
`symptoms. Nonetheless, the study ofcellular infiltrate is
`
`<=
`
`Tryptases
`Serine proteases
`Carboxypeptidase A
`
`Thromboxanes
`HHT
`HPETE/HETE
`
`Eotaxin
`RANTES
`
`downthe released histamine, which peaks at 3 minutes. His-
`taminase levels were foundto be lowerin patients with vernal
`keratoconjunctivits resulting in chronically elevatedhista-
`minelevels, indicating that this conditionis allergic in nature
`[4]. Inactivation ofhistaminase allows the collection and
`measurement oftear histaminelevels followinginstillation of
`allergen in the humaneye. Fourhistamine receptors have
`beenidentified in the humanbody, although two, H, and H5,
`have beenidentified in the eye [5]. The binding of histamine
`to the H, receptors on nerve endingsleadstoitch, andbind-
`ing to H, andFl, receptors on endothelial vascular smooth
`muscle leads to dilation (redness) and endothelial gaping
`(swelling). The blocking of these receptors withselective
`antagonists results in a decrease in itching andredness. Fur-
`thermore, morerecentlyit has been shownthatbyinstilling a
`potent mast-cell stabilizer into humaneyes priorto allergen
`challenge, histamine levels are reduced, which correlates with
`reduced signs and symptoms [6ee].
`Theeffects of manyofthe mediators wereinvestigated by
`instilling each of themontothe eye andobservingeffects clin-
`ically andhistologically. For example, platelet activating factor
`(PAF) was foundto be a potent chemoattractant for eosino-
`phils and neutrophils, leadingto intravascular margination in
`the conjunctiva [7]; prostaglandin D) resulted in redness,
`conjunctival chemosis, mucus discharge, and eosinophil infil-
`trate [8]; and in the humaneye leukotriene B4 (LTB4) did not
`produce vasodilation; however, biopsy revealedinfiltration of
`polymorphonuclearinfiltrates (1 Inpublisheddata), whereas
`L'TE4 and LIC4 [9] elicited no observableeffect. PAF, leukot-
`rienes, and prostaglandinsare all newly formed mediators
`producedin the arachidonic acid pathway during the break-
`downofphospholipids from the mast-cell membrane.
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`Conjunctival Allergen Challenge © Abelson and Loeffler
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`very important in the complete understandingofthealler-
`gic mechanisms, for severe chronic conditions, andasasur-
`rogate endpoint forthe release of chemotacticfactors from
`mast cells (ie, mast-cell degranulation).
`The earlier discussion was not intendedtogivea full
`reviewofthe allergic mechanismsin the eye; however, the
`compilationofresearch highlights ways in which conjunc-
`tival challenge models have been used to understand the
`pathophysiologyof the ocular surface. The clinical rele-
`vance ofthe conjunctival challengeis validated bythe sim-
`ilarities seen betweenthereactions following a challenge
`with the reactions seen in symptomatic atopic patients
`with allergic conjunctivitis,
`
`Environmental Model for Studying
`Allergic Conjunctivitis
`The environmental model for testing the effectiveness of
`anti-allergy agents has been usedextensively throughout the
`world, andwas theoriginal mannerin whichocularallergy
`was studied. In fact, the “environmental” concept is used
`throughout the medical research field to study almost all dis-
`eases. Theideais that a patient can be given the medication
`to use at homeandeither maintains adiary, or returns to the
`office for followupvisits. A study using the environmental
`model might be conducted during the course ofseveral
`weeks to months. In ocular allergy, the patient ‘car-be given a
`diaryto record severity of symptoms(itching) and perceived
`signs (redness) on a daily basis. Generally, patients are given
`scales to use as a reference in grading. At predeterminedtime
`intervals, the patients returntothe office for examinations by
`the investigator. Theseoffice visits serve as safetyvisits—to
`determineefficacy and to review compliancewith dosing
`and record keeping in the diary. Compliance can also be
`monitoredutilizing telephonecontacts madebystudystaff
`betweenofficevisits.
`
`Factors Affecting Data in the
`Environmental Model
`Althoughthis type of study design most accuratelyreflects
`what wouldoccurin a clinical setting in the individual
`patient, several confounding factors might interfere with
`the analysis and combinationofdata from patients within
`the sameoffice and thoseseen at different sites in multi-
`centerstudies. Particularly in studying an acute condition
`such as allergic conjunctivitis, the viability andvariabilityof
`the results andinterpretation ofthe data might bedifficult.
`Theseissues relate to five main concepts: 1) enrollment of
`sensitized atopic individuals; 2) exposure to offending
`allergens; 3) reliance on subjective data and compliance;
`and4) placeboeffect.
`Theenvironmental model relies on the fact that the
`patients enrolled suffer from the conditionthat is being
`studied. Therefore, patients enrolled in environmental
`ocularallergy studies need to be atopic, andspecifically
`
`allergic in the eye. If they are not, there is no way to ensure
`that the individual will be allergic to theparticularaller-
`gens that are in season. Often, skin testing is performedto
`qualify patients, andit is assumedthey will have ocular
`allergy. However, in our experience, we have found an
`approximately 60%to 70%correlation between positive
`skin tests andpositive reactiontoallergen instilled in the
`eye; therefore, if skin testing is solely relied on, some
`patients will be enrolled who might not haveallergy to the
`pollen in season. Others have also seen a similar correla-
`tion [21]. Often, entry criteria require a patient to present
`in the office with a positive skin test and positive clinical
`signs and symptoms ofocular allergy. In this case,
`it is
`important to ensure that standard diagnosticcriteria are
`being followed.
`The second, and most obvious, problem associated
`with the environmental model is the inability to regulate
`each participant's exposure tovarious allergens. Each indi-
`vidual is exposed to various degrees and types of allergens
`owing to differences in work habits; life style; natural varia-
`tion in pollen counts between homeand workplace;
`indoorpets or plants; use ofair conditioning, fans, or ven-
`tilation ducts that would moveairborne allergens through-
`out the home/office; density of plants outside; and natural
`variations in pollen counts. Additionally, some behavioral
`modifications, such as avoidanceofallergen during the
`allergy season, might further complicate the issue. If the
`patient is not experiencing significant signs and symptoms,
`it is moredifficult to identify a drug effect. Alternatively, if
`a patient reports to theoffice with fewsigns or symptoms,
`it could be dueto alack of exposure to offending allergens.
`The scheduledoffice visits that are includedin the
`study design to ensure a degree ofobjectivity are problem-
`atic owing to the unlikelihood of having patients whose
`worstallergic symptomsare timed synchronouslywith the
`predetermined scheduledvisit. Patient diaries can be used
`to track signs and/or symptoms daily, and thepatient's
`assessment of exposureto the outdoors and pollen counts
`are recorded within the geographic areaofthe studysite by
`a pollen-countingstation. But, patients might beallergic to
`indoorallergens or exposedto other irritants. It is ques-
`tionable, therefore, whether a regional pollen count (or
`patient-recorded exposure) is a true measure of personal
`allergen exposure. Interestingly, clinical signs and symp-
`toms are not always exactly correlated with the absolute
`values of pollen counts [22]. Pollen counts can vary even
`within the samearea andwill differ based on the exact
`location ofthe counteritself. Perhaps the fact that pollen-
`counting stations are not validated by standardcriteria
`betweensites might also playarole.
`The thirdissueis the reliance on patient's diaries to deter-
`minedrugefficacy. The diaries contain a highlevel of subjec-
`tivity owing todifferences in symptominterpretation among
`people. Although standardizedscales can be used, environ-
`mental studies rely on data recordedforprimaryefficacy vari-
`ables ofitching and redness bythe patients themselves.
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`Complianceissues affect the quality of results, as one must
`assumethat in somecases subjects will neglect to enter data
`inatimely fashion, andthen later “back-fill” prior to the next
`office visit.
`Anotherissue involved with the use ofthe environmental
`modelis the high rate of placeboeffect seen. A placebo drop,
`manytimesanartificial tear, caneffect allergy treatment. They
`dothis by acting as a barrier to preventallergen fromattack-
`ing the conjunctival surface, helping to dilute allergen and
`mediators in thetearfilm, and acting as an eyewash. Such
`environmental studies are known to have placeboeffect rat-
`ings as high as 50%and 60%[23,24]. Althoughit is difficult
`to completelyeliminate, the placeboeffectis a significantfac-
`tor, andit can be expectedtoplay a largerrole in environmen-
`tal studies in which it acts as an eyewash, compared with
`single-dropstudies in the CAC model.
`
`The Conjunctival Allergen Challenge Model for
`Studying Allergic Conjunctivitis
`‘To evaluate anti-allergic agents in a more controlled manner,
`CACs have been developed. Histamine produces a dose-
`dependent response wheninstilled in the eye, and thus has
`been used as a model for screening anti-allergic drugs.
`Although such an agent can helpevaluate drugs with antihis-
`taminic properties [25], and drugs that actively reduce red-
`ness, such as vasoconstrictors [26], this challenge is not
`directlystimulating mast-cell degranulation, as happens with
`allergen. Substances such as compound 48/80, whichis a
`secretagogue that induces mast-cell degranulation, have also
`beenusedin humanchallengetests [10]. However, because
`the secretagogues do not induce an immunologic reaction
`via an IgE-mediated pathway, they might not be appropriate
`for evaluating agents with mast-cell stabilizing activities. The
`CAC [27] was developed as the most accuratereplication of
`thetrue allergic reaction, becauseit is IgE mediated, and
`results in mast-cell degranulation.
`The standard controlled CAC studydesign includes two
`baselinevisits. The first is a titration visit, and a selected
`allergenis instilled into botheyes ofthe patient. Signs and
`symptomsarethengradedonstandardizedscales. Allergen
`is instilled into the eyes at increasing concentrations until a
`prespecified thresholdofclinical responseis achieved. The
`threshold scores, however, needto be set considering the
`reaction that resembles a natural allergic reaction—in
`other words, one that provides sufficient improvement of
`drug over placebo, but does not stimulate such alarge reac-
`tion that it cannot be modulatedbythe drug. The intent of
`thestudyalso needs to be considered whenevaluating this
`thresholdandallergen used. For example, a high dose of
`allergen is generally requiredtostimulatea significantcel-
`lularinfiltrate andto correlate this infiltrate withclinical
`signs and symptoms. However, this reaction might be
`higher than that usually seen in the environment. When
`critically evaluating data from astudy, the methodology
`andallergen dose used should be considered in determin-
`ing clinical relevance.
`
`Oncethe thresholdallergen dose is determinedin the
`patient, the patient returns for a confirmationvisit. At this
`visit, the dose that elicited a sufficient reactionat thefirst
`visit is instilled in both eyes. This secondvisit confirms the
`consistency and reproducibility of the reaction in the
`patient. Patients who demonstratea sufficient and reproduc-
`ible responseproceedtoathirdvisit.
`Both onset and durationofaction ofthe agent can be
`evaluated using the CAC model. The patient can be dosed
`with the study treatment (placebo in one eye and drug in
`the other; drug in both; or drug A in one anddrug Bin the
`contralateral eye) and then challenged with the appropri-
`ate dose ofallergen in botheyes. The eyes are then evalu-
`atedfor signs and symptoms, andthe appropriate analysis
`is performed. To evaluate duration of action, the challenge
`can beperformedat a specific time followinginstillation of
`treatment. For example, if the patient is challenged 6 hours
`followinginstillation ofthe drug, thenit is clear that the
`drug effects last at least 6 hours. Onset and duration of
`action are evaluatedat separateoffice visits.
`Safety during allergen challenge cannot be emphasized
`enough, because conjunctivalinstillation can producesignifi-
`cant nasal, throat, and respiratoryreactions. Having trained
`medical personnel and appropriate emergency equipment
`on-site is critical.
`
`Advantages of the Conjunctival Allergen
`Challenge Model
`The CAC model mimicsthe signs and symptomsofan ocular
`allergic response accuratelyin a controlledsetting [28¢¢].
`Theinstillation of the threshold dose in the subject's eyes
`consistently results in itching and redness.
`Byenrolling patients based on their responseto a CAC,
`only those patients whoactually haveocularallergy are
`being enrolled. Thetitration ofallergen during thefirst visit
`provides a methodforobtaining the threshold dose needed
`for adequatereactivity. The coupling ofthetitration with
`the secondvisit for confirmation ensures reproducibility.
`The CAC model contains alevel of internal control that is
`not seen in the environmental model becausethebilateral
`instillation of drug and placeboserves as a highly reproduc-
`ible internal control.
`The patient's exposure to offending allergens and
`certainty that the drug is being tested in anallergic eye is
`controlled bypreciselyinstilling allergen in theoffice, in
`patients who are asymptomatic at baseline when theyenter
`the office. Therefore, variable exposure patterns to allergens
`typically seen between patients in environmentaldesignsis
`controlled. By completing the study in the “off-season”(ie,
`not during the pollen season) with allergens that the
`patients are allergic to,
`it can be further ensured that any
`environmental exposure will not confoundtheresults.
`By inducingthe allergic reactionin theoffice, a trained,
`masked examinercan be usedtoevaluate the primarysigns
`(redness and chemosis). The primary symptomscan also
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`Conclusions
`We can see how the CAC model has been a useful tool for the
`development of newagents for ocularallergy, andto help fur-
`ther our understanding of the pathophysiology of ocular
`allergy. The controls afforded bythe use ofthis type of model
`lead to morereliable results and help to mitigate manyofthe
`issues wesee with standard environmentalstudies.
`Challengetests have been used for years in thefields of
`asthmaandallergic rhinitis. The ophthalmic division at the
`FDAhas been aleader in accepting the CAC model, andhas
`helpedour field tremendously bygiving us anefficient study
`design in whichto evaluate the condition andto pave the way
`for the development of novel pharmaceuticals. With therec-
`ognition of the significance of using the model for the drug
`development process, as a pathwayfor drug approval, weare
`actually nowseeing agents being developedfirst specifically
`for theeye, as a proofof conceptfor other indications. A thor-
`ough understanding of the model is required to ensure that
`accurate interpretations are made fromthe results, andthat
`the studyis still designed appropriately, matching the phar-
`macologyof the agent, clinically relevant mechanisms ofthe
`disease process, andthe objectives ofthe study.
`
`References and Recommended Reading
`Papers ofparticular interest, published recently, have been
`highlighted as:
`°
`Ofimportance
`ee
`Ofmajor importance
`
`be evaluated by the patients using standardizedscales in
`the office while being observedbystudystaff, ensuring
`grading is done properly andthat the patients correctly
`understandthe scales. The CACallows a timely and con-
`cise evaluationfor the effects of the investigational drug.
`Also, with the instillation of the study treatments in the
`office, complianceis ensured.
`
`Use of the Conjunctival Allergen Challenge
`Model for Evaluation of Drugs
`Owingto the CAC model's high level of internal control, sen-
`sitivity, and reproducibility, it can be usedin several ways.
`The CAC model is very applicable for studies involving a
`comparisonof efficacy between drug and placebo
`[29,30,31¢] The CAC model canalso be used to compare a
`drug with an active control. This has been done by many
`groups using various agents available for eyeallergy
`[32,33,34¢,35¢e,36e]. Llsing the CAC, precise comparisons
`of onset of action and duration of action can be measured,
`which cannotbeaccurately evaluated in environmental stud-
`ies. It
`is important to notethat in the challenge studies, in
`which standardizedscales are used, a specified unit change
`between drug andplacebo on that scale can be defined as
`being clinically significant. This is different from showing
`statistical significance, which can occur withoutclinical sig-
`nificance. For example, typically on the 0-4 scale, a unit
`change is considered by the FDAtobeclinically significant.
`However, even if a drug might not producea clinically signif-
`icant response ofone full unit, the CAC model is still very
`useful for evaluating efficacy and in helpingto select agents
`for furthertesting (eg, dose ranging).
`Environmental and CAC models can be combined. In
`this design, patients arefirst exposed to a CAC. Patients
`whorespond sufficiently to an initial CAC are enrolled
`into the study with an environmental design. This model
`helps to ensure that patients whoare enrolled are atopic
`and, more specifically, are sensitive in the eye to thealler-
`gen currently in-season, during which the study is con-
`ducted. This hybrid model has successfully been used to
`studythe mast-cell stabilizer pemirolast [35¢¢].
`A unique useofthe CACis to studyeffects of drugs on
`nasal signs and symptoms. Inflammatory mediators,
`released during theallergic reaction in the conjunctiva,
`and/orallergenitself, can drain through the nasolacrimal
`duct into the inferior turbinate of the nose and produce
`clinically significant nasal itching, sneezing, congestion,
`and rhinorrhea. Similar to mediators, topical drugs can
`also drain from the eye into the nose. Infact, we have seen
`an effect of potent allergy eye drops on nasal signs and
`symptoms, in both challenge models and environmental
`studies |36¢,37e].
`
`1.
`
`2,
`
`>,
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`Abelson MB, Chapin MJ: Current andfuture topical treatments
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`Abelson MB, Smith LM. Levocabastine: evaluationin thehis-
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`6,.¢¢ Leonardi A, Abelson M: Mast cell stabilizing effects of
`olopatadine following allergen challenge in humans
`[abstract].ARVO 2003, in press.
`This is thefirst studycorrelating clinical effects and the indices of mast
`cell stabilizing properties, including decreased histaminelevels, for a
`therapeutic agent with multiple actions in ocularallergic subjects.
`7.
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`tor induced inflammation following topical ocular challenge
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`Abelson MB, Madiwale NA, Weston JH: The roleof prostaglandin
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`nor GR, Chandler JW. NewYork: Masson; 1985:163-166.
`9. Weston JH, Abelson MB: Leukotriene C4 in rabbit and human
`eyes [abstract]. Invest Ophthalmol Vis Sci 1981, 26(Suppl):191.
`Butrus $I, Ochsner KI, Abelson MB, Schwartz LB: The level of
`tryptase in humantears: an indicatorofactivation of con-
`junctival mast cells. Ophthalmology 1990, 97:1678-1683.
`
`8.
`
`10.
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`368 OcularAllergy
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`Bisgaard H, Ford-Hutchinson AW, Charleson §, et al.: Produc-
`tion of leukotrienes in humanskin and conjunctival mucosa
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`Horak § Toth J, Hirschwehr R, et al.: Effect of continuous aller-
`gen challenge on clinical symptoms and mediator releasein
`dust-mite-allergic patients. Allergy 1998, 53:68-72
`14. Abelson MB, Leonardi AA, Smith LM, et al.: Histaminaseactiv-
`ity in patients with vernal keratoconjunctivitis. Ophthalmology
`1995, 102:1958-1963.
`Ciprandi G, Buscaglia S, Pesce G, et al.: Allergic subjects
`express intercellular adhesion molecule-1 (ICAM-1 or CD54)
`on epithelial cells of conjunctiva after allergen challenge. |
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`gic conjunctivitis is accompaniedbyincreased mast cell
`numbers in the absenceof leukocyte infiltration. Clin Exp
`Allergy 1997, 27:1060- 1066.
`Results of this study showthat infiltrate of eosinophils and neutro
`phils was not seen in more than 50% of subjects with seasonal aller-
`gic conjunctivitis. This suggested the absenceof aclinically relevant
`late-phasereaction in the eyes of most patients.
`18.
`Abelson MB, Madiwale N, Weston JH: Conjunctival eosino-
`phils in allergic ocular disease. Arch Ophthalmol 1983,
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`Leonardi A, Papa V, Milazzo G, Secchi AG: Efficacy and safety
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`might not be degranulating during this time.
`2i
`Leonardi A, Fregona IA, Gismondi M, et al.: Correlation
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`Abelson MB, Smith LM: Levocabastine: evaluation in the
`histamine and compound48/80 models ofocular allergyin
`humans. Ophthalmology 1988, 95:1494-1497
`Abelson MB, Yamamoto GK, Allansmith MR: Effects of ocular
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`A review paper evaluating the challenge model versus environ-
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`29. Abelson MB, George MA, Schaefer K, Smith LM: Evaluation of
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