By Rosenwasser, Lanny J; O’Brien, Terrence; Weyne, Jonathan
Key words: Anti-histamines * Mast cell stabilizer * Olopatadine * Ocular allergy
ABSTRACT
Background: Histamine receptor activation and degranulation of mast cells are the mechanisms by which the ocular itching, hyperemia, chemosis, eyelid swelling, and tearing of seasonal allergic conjunctivitis are induced. Some of the topical solutions available as anti-allergy therapies are intended to interfere with these mechanisms, and the body of research regarding the capabilities of these therapeutic molecules continues to expand.
Objective.-Jo review the currently available literature regarding one topical ophthalmic antiallergy agent, olopatadine (Patanol*), and its antihistaminic and mast cell stabilizing actions, both in pre-clinical and clinical settings.
Design and methods: Relevant research of laboratory, animal model, and clinical trial studies performed using olopatadine was reviewed. MEDLINE literature searches were conducted and supplemented by additional reports which furthered relevant discussion or were necessary to verify the information resulting from original searches.
Results: Olopatadine demonstrates unique properties both pre- clinically and clinically which differentiate it from other therapeutic molecules in its class of dual action mast cell stabilizer/antihistamine. Its non-perturbation of cell membranes, human conjunctival mast cell stabilization in vivo and in vitro, and superior efficacy as compared to other topical anti-allergic medications including mast cell stabilizers, anti-histamines, and dual action agents, all contribute to olopatadine’s profile.
Conclusions: Peer-reviewed literature suggests that Olopatadine is clinically superior to the other anti-allergic molecules because of its strong antihistaminic qualities and its unique ocular mast cell stabilizing properties.
Introduction
Since the discovery of histamine in 19101, and the development of the first anti-histamine compound in 19372, much has been learned about the complex nature of the allergic reaction. The evolution of anti-histamines has provided medicine with agents that act more specifically and for a longer duration, such as levocabastine and emadastine.
However, advances in immunology have demonstrated that blocking the action of histamine alone does not completely suppress the allergic reaction, as it is released from the mast cell along with numerous other allergic mediators3. This realization led to the birth of a new class of drugs: the mast cell stabilizers. The original mast cell stabilizer molecules, such as cromolyn sodium, were at first tested in allergic models, based on non-ocular tissues, not representative of the clinical pharmacology of the allergic eye. These compounds, also including nedocromil, pemirolast, and lodoxamide in addition to cromolyn, have for the most part been supplanted in ocular allergy therapy by newer therapeutic molecules.
The most recently developed class is that of the dual action agents, which are more precisely aimed at the mast cell. Though there are also several less-frequently prescribed anti-allergy options available including products such as corticosteroids (loteprednol etabonate) and non-steroidal anti-inflammatory drugs (ketorolac), the dual action molecules have become the standard therapy of use for seasonal allergic conjunctivitis. Dual action molecules are classified as such based upon pharmacological testing which revealed their inhibition of H^sub 1^-receptors as well as ability to stabilize mast cells. Drugs included in this class are olopatadine, ketotifen, epinastine, and azelastine, though olopatadine is the only one of this class to have shown human conjunctival mast cell stabilization in vitro and in vivo.
The present review asks how pre-clinical findings correspond to the clinical effects, thus discussing a possible pre-clinical rationale which explains olopatadine’s clinical effects, as seen across many peer-reviewed studies. These include evaluations of allergic mediators at the molecular level, as well as clinical comparisons with other anti-allergy medications, including topical eye drops of various mechanisms, as well as systemic and nasal spray anti-allergy therapies. The distinctiveness of olopatadine, both clinically and pharmacologically, with respect to the other drugs in this class will also be discussed.
Design and methods
Database searches of the literature were conducted from 1966- June 2005. Searches for in vitro, cell membrane, and clinical study of the olopatadine molecule were conducted using the search terms Olopatadine and in vitro’, Olopatadine and cell membrane’, and Olopatadine and clinical’ on the MEDLINE online searchable database. From the results of literature searches, articles were selected for inclusion based upon their applicability to the central question of this review: that of determining the relationship between olopatadine’s effects at the molecular level and those observed clinically. Additional original reports were referenced at the authors’ discretion if it was determined that the data presented was relevant to the discussion on the topics of this review or if further support was necessary to verify the information resulting from original searches.
Results
Initial in vitro and in vivo characterization of Olopatadine
Olopatadine hydrochloride is the active ingredient in the currently marketed anti-allergy treatment, Patanol (Alcon Laboratories Inc, Fort Worth, TX, USA). The molecule is a selective H1-receptor antagonist and human conjunctival mast cell stabilizer. In the ophthalmic solution currently available, olopatadine exists as an aqueous solution containing 0.1% olopatadine.
Olopatadine was the focus of many in vitro and in vivo animal studies designed initially to identify its potential clinical value. It was shown in various screening models to both inhibit the binding of histamine to H!-receptors4″6 and to stabilize mast cells in the conjunctiva and other tissues7″9. The exceptionally high binding affinity of olopatadine for H^sub 1^-receptors was first demonstrated in rodent brain homogenates; affinities for H2 and H3 receptors were also observed9. The high selectivity of olopatadine has been proposed as being due to a unique binding pocket containing the aspartate residue and other sites within the H^receptor10. Studies have since demonstrated that the H j-receptor selectivity of olopatadine is superior to other anti-histamines formulated for use in the eye such as levocabastine, pheniramine, and antazoline3, as determined through histamine receptor subtype binding assays as well as assays for non-histamine receptors. Olopatadine’s high level of selectivity is further defined by its lack of interaction with alpha- adrenergic, muscarinic, dopaminergic and numerous other receptors. Taken together, the authors of these studies noted that these findings indicate olopatadine as having a relatively high affinity, high potency antagonism, specifically of the H ^receptor, which suggests that this compound has advantages over other topical ocular antiallergic medications5,9.
Olopatadine was shown to inhibit, in a dose-dependent fashion, the immunologically-stimulated release of histamine from rat basophilic leukemia cells and from human conjunctival mast cells in vitro4. Greater than 90% inhibition was achieved without observable histamine release even at 10 times the clinically maximally effective dose. Results obtained with the comparative drug, ketotifen, gave a first glimpse at the divergent activity of olopatadine compared to other drugs in this class. Ketotifen elicited a clearly biphasic response: at low concentrations, exhibiting suppression of histamine release, but as concentration was increased, histamine release was stimulated4. This disparity was an early indication that olopatadine has a potentially broader margin of efficacy and safety than ketotifen.
Two in vivo models of passive conjunctival anaphylaxis confirmed these in vitro findings. Olopatadine elicited an 80% inhibition of allergic conjunctivitis in passively sensitized guinea pigs, with significant activity noted after 8 hours. Its anti-histaminic properties were then defined in vivo by measuring changes in histamineinduced conjunctival vascular permeability. This activity was of rapid onset and prolonged duration, evident from 5 minutes to 24 hours after drug administration4.
With regard to determining mast cell stabilizing activity, it is first important to understand the heterogeneity of mast cell populations. This heterogeneity translates into variability in mast cell properties, such as differences in reactivity to pharmaceutical molecules, among species, and even among tissues within the same species”’12. It is of note that olopatadine was shown to be specifically effective at the cellular level in human conjunctival mast cells. One study was aimed at defining and comparing the effects of nedocromil, olopatadine, and pemirolast on mediator release from human conjunctival mast cell cultures and comparing these effects with those obtained with cromolyn sodium as an historical point of reference8. The affinity of these compounds for the Hj-receptor was also investigated. Interestingly, findings indicated that cromolyn and pemirolast failed to significantly inhibit histaminerelease from human conjunctival mast cells while nedocromil elicited only a 28% inhibition of histamine release even at higher than customary doses8. In this study, only olopatadine inhibited histamine release from human conjunctival mast cells in a dose-dependent fashion, as well as inhibiting H^sub 1^-receptor binding at clinically relevant concentrations. The lack of efficacy of the other antiallergic agents to act on human conjunctival mast cells, after they had been shown to exert efficacy in rodent models, underscores the importance of evaluating these drugs in the appropriate model and species.
Further definition of the mechanisms of olopatadine activity
The role of conjunctival epithelial cells in allergy has gained interest in recent years, and these cells are considered a potential site for pharmacological intervention. Epithelial cells produce cytokines following a number of stimuli13; and are known to have functional Hj-receptors14. Exposure of human conjunctival epithelial cells (HCEC) to histamine has been shown to stimulate interleukin (IL)-G and IL-8 production, and treatment with H^sub 1^ antagonists prevents this stimulus15. Blocking these effects of histamine on the epithelium accounts, in large part, for the anti-inflammatory effects of many common anti-histaminic agents15,16.
Olopatadine has been shown to significantly downregulate the effects of mast cell-mediated intercellular adhesion molecule-1 (ICAM-1) on HCEC after anti-immunoglobulin E (IgE) antibody challenge, although it did not decrease ICAM-1 directly. ICAM-1, a mediator important to promotion of the allergic reaction, contributes to the recruitment of migrating pro-inflammatory mediators. It is not known if this effect is related to H^sub 1^ antagonism, though it is known that ICAM-1 expression is upregulated by mediators released from the mast cell. Inhibition of mast cell tumor necrosis factor-alpha (TNF-α) and epithelial cell ICAM-1 by olopatadine is a measure which contributes to limiting the attraction of migrating cells such as eosinophils to the site of allergic reaction17’18. The long duration of action of olopatadine has been proposed by some to be at least in part due to shutting down of this ripple effect: a blocking of TNF-α-mediated upregulation of inflammatory marker expression on conjunctival epithelial cells may lead to generalized suppression of inflammatory cell migration and recruitment on the ocular surface18. This supporting anti-inflammatory role of olopatadine may render it appropriate therapy to use, as an adjunct to the primary therapy of steroids, for chronic inflammatory diseases such as allergic keratoconjunctivitis or vernal keratoconjunctivitis, where a damaging cellular infiltrate is a significant component of the disease.
Cell membrane effects of anti-allergic agents: pre-clinical differences and clinical implications
Marked differences in the mast cell stabilization capabilities of ketotifen and olopatadine have been demonstrated4, yet there is still an incomplete knowledge of how these compounds behave transcellularly. Recent research has focused on the interaction of these drugs with model and biological membranes19. Surface activity can regulate the biological activity of a drug, as well as a drug’s tendency to first stabilize and then permeabilize biological membranes. One study evaluated the functional consequences of these interactions using several assessments: natural membranes by leakage of 6-carboxyfluorescein (small molecules) and hemoglobin (large molecules) from intact erythrocytes and ghosts, and by lactate dehydrogenase (LDH) (i.e. cytoplasmic) and histamine release (i.e. intracellular granules) from human conjunctival mast cells (HCMC) and corneal epithelial cells. Compounds tested were: desloratadine, clemastine, azelastine, ketotifen, diphenhydramine, pyrilamine, emedastine, epinastine, and olopatadine19.
Results of this set of tests indicated that all anti-histamines except olopatadine had a negative impact on mast cell surface membranes. Intrinsic surface activity, as measured using an argon- buffer interface, resulted in measurements of surface activity ranging from highly surface active to weakly surface active in the following order: desloratadine > clemastine > azelastine = ketotifen > diphenhydramine > pyrilamine > emedastine > epinastine ≥ olopatadine. In further tests assessing the functional consequences of these surface activities, olopatadine showed the lowest intrinsic surface activity, as measured by cell-based assays (hemoglobin leakage from erythrocytes, LDH release from HCMC, 6- carboxyfluorescein release from erythrocyte ghosts), and was the only compound tested to inhibit release of histamine from the human mast cell at the marketed concentration.
In natural membranes, olopatadine was the only agent that did not promote membrane perturbation. Assessment of the degranulation potential of marketed concentrations of ketotifen (0.025%), azelastine (0.05%), and epinastine (0.05%) revealed significant membrane perturbation of HCMC and, importantly, human corneal epithelial cells. This was in contrast to the marketed concentration of olopatadine (0.1%), which maintained normal mast cell and corneal epithelial cell membrane function. Thus, ketotifen, azelastine, and epinastine, the other dual action drugs approved for use in the eye, all behave similarly: the suppression of histamine release at low concentrations is followed by membrane perturbation and histamine release after achieving a threshold concentration. This effect was seen at the marketed concentrations, was independent of histamine receptor antagonism, and was a direct consequence of interaction of these agents with the human conjunctival mast cell membrane. Thus, we suggest that these data contribute to explaining how these compounds can demonstrate a certain level of clinical efficacy (via anti-histaminic activity) while actually causing mast cell degranulation after an initial mast cell stabilization. An illustration of the divergent effects of the commercially available compounds on histamine release can be seen in Figure 1. Olopatadine’s restricted interaction with membrane phospholipids, limiting membrane perturbation and release of intracellular constituents, including histamine, LDH and hemoglobin19, represent a novel property of this molecule, which we hypothesize may contribute to the superior efficacy and patient tolerability that have been observed with its use in clinical trials.
Figure 1. Effects of the commercially available concentrations of olopatadine, ketotifen, azelastine and epinastine ophthalmic solutions on histamine release from immunologically stimulated human conjunctival mast cells in vitro. Only olopatadine did not elicit a biphasic reaction (i.e. initial inhibition at low concentrations/ stimulation of response at marketed concentrations)19
Clinical experience with olopatadine
Placebo-controlled trials
The clinical efficacy of anti-allergic compounds is ideally evaluated in the conjunctival allergen challenge model (CAC), which has been accepted as a valid clinical model for drug registration trials in the United States20. The CAC model controls allergen exposure, inducing an ocular allergic reaction in a reproducible manner and has been used for the standardized evaluation of criteria including ocular itching, redness, hyperemia, chemosis, and eyelid swelling. Signs and symptoms are graded on standardized scales and the onset and duration of action of drugs can be accurately determined by modifying the time of drug administration in relation to the time of challenge. The standard CAC design can also be modified to induce a clinically evident late phase of allergy in a subgroup of predisposed patients by challenging with high doses of allergen.
A combined analysis of two CAC placebocontrolled trials evaluated the efficacy, safety, optimal concentration, onset and duration of action of olopatadine (n = 169)21. The onset of action was determined to be within five minutes of challenge, and the duration of action over 8 hours. Both 0.5% and 0.1% concentrations of olopatadine were the strongest candidates for drug formulation, significantly inhibiting peak ocular itching and hyperemia (p
A human clinical trial has researched olopatadine’s effects on specific cellular mediators involved in the ocular allergic reaction. This study was performed in a subset of patients who experienced a late phase of allergy when challenged with high doses of allergen22. Contralateral olopatadine and placebo treatment in challenged allergic patients (n = 10) verified the mast cell stabilizing effects previously observed in vitro with olopatadine. In olopatadine-treated eyes, itching and hyperemia were significantly reduced as compared to placebo (p
The significant effects of olopatadine against both ocular itching and hyperemia have been comprehensively researched and validated21-30. In addition, the effects of olopatadine on the recalcitrant sign of eyelid swelling have also been investigated. Eyelid swelling is difficult to treat since it is a lingering, residual consequence of the vascular permeability changes wrought by mediator release. In a single visit, randomized placebo-controlled CAC trial, an ocular allergic reaction was induced and only those patients who experienced lid swelling as a component of the allergic reaction were continued in the study (n = 56). In addition to the usual subjective measurement of eyelid swelling provided by the patient, scanning and imaging technology was used to objectively measure pre- and post-challenge changes in the volume of the skin around the eyes with a sensitivity of 0.5 mm. The imager indicated that 15 minutes after challenge, lid swelling was 5.65 times greater, and after 30 minutes, 1.76 times greater in placebo- versus olopatadine-treated eyes23. These changes were statistically and clinically significant (p
An additional study has evaluated the effect of olopatadine on chemosis of the conjunctiva which, like eyelid swelling, results from the increases in vascular permeability induced by histamine and other vasoactive mediators during an ocular allergic reaction. This randomized, double-masked study evaluated the effects of olopatadine on chemosis in 20 individuals with a history of allergic conjunctivitis. There was significantly less chemosis evident in olopatadine treated eyes at 3, 10, and 20 minutes following allergen challenge as compared to placebo treated eyes (p
Comparative trials
Olopatadine has been compared to many anti-allergic/ anti- inflammatory agents: topical anti-histamines, mast cell stabilizers, and corticosteroids, in controlled, randomized, masked clinical studies. Olopatadine has also been paired with nasal corticosteroids and with systemic anti-histamines in CAC studies to identify appropriate modalities for multi-allergy sufferers. In the clinical comparisons reviewed here, olopatadine consistently performs significantly more favorably than its comparators in terms of both efficacy and comfort.
One of the first comparative trials evaluated olopatadine versus ketorolac 0.5%, a nonsteroidal anti-inflammatory eye drop approved for the relief of ocular itching associated with seasonal allergic conjunctivitis24. This was a randomized, double-masked, contralaterally placebo controlled, crossover design, CAC study which evaluated ocular itching, hyperemia, and comfort in allergic conjunctivitis patients (n = 36). Medication dosing took place 27 minutes prior to allergen challenge. Evaluations of ocular itching and hyperemia were performed at 3, 10, and 20 minutes following allergen challenge. Patients evaluated comfort, using a standardized discomfort scale immediately following instillation. Olopatadine significantly reduced ocular itching and hyperemia versus placebo at all three evaluation time points, both statistically (p
Subsequently, in separate studies, olopatadine was demonstrated to be superior to nedocromil25 and ketotifen26,32-34 in the CAC model. One study compared olopatadine to ketotifen in a prospective, doublemasked, contralaterally controlled design (n = 32)26. The primary efficacy variables were ocular itching and subject satisfaction. Drop comfort was assessed immediately after eye drop instillation, efficacy at 12 hours duration (i.e. medication dosing occurred at 12 hours prior to CAC), and satisfaction following the efficacy analysis.
In a more recent comparative study of olopatadine and ketotifen, in which 100 patients used both medications over a two week period, 81% of patients with seasonal or perennial allergic conjunctivitis preferred olopatadine based on its comfort and superior efficacy (p
In a single-center, randomized, double-masked, contralaterally controlled, CAC model evaluation of olopatadine and nedocromil, comfort and efficacy were evaluated (n = 49). One drop of olopatadine was shown to be statistically and clinically, significantly more effective in controlling itching than a 2-week (29 drop) load of nedocromil (p
A comparison of cromolyn with olopatadine was also carried out in a parallel group seasonal allergic conjunctivitis study (n = 185; mean age 35, range 4-77), confirming the superiority of olopatadine in controlling itching and hyperemia, as well as better local tolerability in children less than 11 years of age; specifically the ocular hyperemia scores were two times lower in pediatric subjects who received olopatadine as compared to those who received cromolyn (p = 0.002)27.
Azelastine, a compound approved for the relief of itching due to allergic conjunctivitis, was interestingly compared to olopatadine as both of these compounds are dual-action anti-histamine/mast cell stabilizers28. Olopatadine was found to be more effective in this controlled, randomized, double-masked study (n = 111), in the management of itching (p
Corticosteroids such as loteprednol etabonate 0.2% are potent anti-inflammatory agents. Since steroids are known to have a longer onset of action, a 14-day loading period was incorporated into the study for loteprednol (n = 50). Results demonstrated that one drop of olopatadine was significantly more effective than a 57 drop, 2- week loading of loteprednol for the relief of ocular allergic itching and hyperemia (p
A recent comparative trial investigated epinastine, an agent that was originally approved for rhinitis, in comparison to olopatadine in the CAC model in a placebo controlled, randomized, double-masked study (n = 66). Olopatadine was shown to be superior to epinastine in inhibition of itching, hyperemia, and chemosis. In this study, epinastine was statistically equivalent to placebo in the ocular redness assessment at 20 minutes post challenge, suggesting initial mast cell stabilization is followed later by mast cell degranulation and the release of histamine30. This relates to the preclinical data on the non-specific degranulation effects of epinastine on cell membranes19. This may also suggest the reason epinastine received an indication for ocular itching only, rather than for all signs and symptoms of allergic conjunctivitis, as had been originally requested.
A careful review of the evidence provided by preclinical studies has been confirmed in clinical trials, and is summarized in Table 1. Comparative clinical studies against cromolyn\, nedocromil, levocabastine, ketorolac, epinastine, ketotifen, azelastine and loteprednol concluded that olopatadine had superior efficacy and greater tolerability.
Table 1. Olopatadine: relationship of pre-clinical to clinical data
Population subsets
A portion of overlap exists between the contact lens wearing population, which is estimated to be at 36 million in the United States33, and ocular allergy sufferers, who comprise approximately 20% of the general population36.
In a CAC model evaluation of comfort and efficacy in contact lens wearers37, olopatadine was revealed to be significantly more efficacious in managing the signs and symptoms of allergy (n = 20, p
Multiple sites of allergic sensitivity are known to be more the rule than the exception in the clinical manifestations of allergy, providing a challenge for its treatment by the health care professional. Systemic anti-histamines may be a treatment option prescribed by clinicians or self-selected by patients in an attempt to control ocular allergies. However, clinical studies have shown that a topical anti-allergy therapy often provides superior alleviation of ocular allergy as compared to systemic agents. In two original reports, the oral antihistamine, loratadine 10mg was compared to topical olopatadine using the CAC model (n = 14; n = 29)40,41. Results showed that the itch associated with ocular allergy was controlled by olopatadine and not systemic loratadine (p
Further study of olopatadine combined it with other types of treatment, evaluating the combined efficacy of fluticasone propionate nasal spray and olopatadine eye drops (i.e. an entirely local regimen) as compared to fluticasone and the oral anti- histamine fexofenadine, a regimen with a systemic component (n = 80)44. In this study, the primary efficacy variables were ocular itching and hyperemia, as well as nasal symptoms (itching of the nose and palate, rhinorrhea, and sneezing). Results indicated that olopatadine treated eyes had less ocular itching and hyperemia (p
The effects of ophthalmic olopatadine drops on rhinitis spurred subsequent studies to better define the effects of this drug in the commonly observed allergic combination of conjunctivitis and rhinitis. Olopatadine dosed ocularly was shown to attenuate nasal symptoms in 131 rhinoconjunctivitis patients in a seasonal environmental study (rhinorrhea: p
A recent study with an environmental, crossover design enrolled rhinitis patients being treated on a steady regimen for their rhinitis with a systemic antihistamine and/or a nasal spray47. These patients were then separated into two groups. For the first 2 weeks of study, Group A (n = 97) received 2 weeks of olopatadine therapy added to their systemic or nasal regimen; Group B (n = 103) did not receive additional ophthalmic therapy. Cross-over took place after 2 weeks, with Group A ceasing olopatadine use, and Group B commencing twice-daily administration of olopatadine for two weeks. All patients were administered two quality of life questionnaires (Allergic Conjunctivitis Quality of Life Questionnaire; Rhinitis Quality of Life Questionnaire) at baseline, at the 2-week cross- over, and at 4 weeks when the study concluded. Results indicated that significant improvements in quality of life were evident when an eye drop was added to patients’ existing rhinitis regimens (p
Finally, a highly favorable comfort and tolerability profile of an ophthalmic eye drop formulation might be regarded as a relatively important attribute for effective usage and compliance particularly in the pediatric population. Pediatric data was retrospectively extracted from two studies (n = 30; n = 22) assessing olopatadine treatment, as well as 2% cromolyn sodium and 0.05% levocabastine. The mean ages of pediatric patients were 7.2 years (male) and 8.5 (female) in the olopatadine versus cromolyn study, and 8.3 (male) and 8.8 (female) in the comparison to levocabastine. The results of these two studies revealed that all three treatments were well tolerated, however olopatadine exhibited superior efficacy in relief of itching and hyperemia as compared to cromolyn and levocabastine (p
Discussion
Many of the anti-histamine/mast cell stabilizer agents currently available, with the exception of olopatadine, cause significant degranulation of human mast cells due to their high non-specific surface activity (Figure 1)19. This effect leads to a release of histamine from ruptured human mast cells and corneal epithelial cell membranes. Notably, these degranulation effects occur at commercially available concentrations of ketotifen, azelastine and epinastine. The degranulationinducing nature of these compounds may contribute to high ocular surface irritability and/or lesser patient acceptance and lesser efficacy.
Based upon the body of research summarized here, it appears that the pharmacology of olopatadine is unique, even compared to other ophthalmic antiallergic agents in its category, including epinastine, azelastine, and ketotifen19. While the pharmacological effects of many of the currently available topical ocular anti- allergic products block histamine receptors, peer-reviewed literature to date demonstrates a nonspecific degranulation effect on human conjunctival mast cells for epinastine, azelastine, and ketotifen at marketed concentrations. This is in contrast to the mast cell stabilization effects of olopatadine at marketed concentrations and across all other concentrations (i.e. lesser and greater) tested19. Therefore, careful review of the data suggests that this point of preclinical differentiation contributes to the observed clinical effects of olopatadine and its ability to offer the complete range of relief across all signs and symptoms (including itching, chemosis, hyperemia, tearing, and eyelid swelling). These pre-clinical data may also suggest a component of the molecule’s behavior that explains the consistent results generated by the myriad clinical studies supporting the clinical efficacy of olopatadine.
Conclusions
Analysis of the peer-reviewed literature indicatesthat olopatadine is a potent, selective, and longacting anti-allergic molecule. The combined antihistaminic and mast cell stabilizing properties across varying concentrations are unique to olopatadine and differentiate this molecule from all comparators in control of all the signs and symptoms associated with allergic conjunctivitis.
Acknowledgments
Declaration of interest: The publication of this review article has been supported by Alcon Laboratories, Inc., Fort Worth, TX (the manufacturers of olopatadine).
* Patanol is a registered trade name of Alcon Laboratories Inc, Fort Worth, TX, USA
References
1. Dale HH, Laidlaw PP. The physiologic action of beta- imidazolethyamine. J Physiology 1910;41:318
2. Staub AM, Bovet D. Action de la thymoxyethyl-diethylamine (929F) et des ethers phenoliques sur le choc anaphylactique du cobaye. CR Soc Biol 1937;125:818
3. Abelson MB, Katelaris C, Slugg AP, et al. Ocular Immunology in Allergie Diseases of the Eye. Abelson M, editor. Philadelphia: WB Saunders Co. 2000, pp. 20-7
4. Yanni JM, Stephens DJ, Miller ST, et al. The in vitro and in vivo ocular pharmacology of olopatadine (AL-4943A), an effective anti-allergic/antihistaminic agent. J Ocul Pharmacol Ther 1996; 12:389-400
5. Sharif NA, Xu SX, Miller ST, et al. Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL- 4943A), a novel drug for treating ocular allergic diseases. J Pharmacol Exp Ther 1996;278:1252-61
6. Nonaka H, Ishii A, Kase H. Effect of KW-4679, a novel antiallergic agent, on histamine Hl receptor. Jpn J Pharmacol 1993;61(suppl):87P
7. Ishii H, Kitamura S, Ohmoti K. Inhibitory effect of KW-4679 on allergic models in rats. Jpn J Pharmacol 1991;55(suppl): 375P
8. Yanni JM, Miller ST, Gamache DA, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol 1997;79:541-5
9. Sharif NA, Xu SX, Yanni JM. Olopatadine (AL-4943A): Ligand binding and functional studies on a novel, long acting Hlselective histamine antagonist and anti-allergic agent for use in allergie conjunctivitis. J Ocul Pharmacol Ther 1996; 12: 401-7
10. Nonaka H, Otaki S, Ohshima E, et al. Unique binding pocket for KW-4679 in the histamine Hl receptor. Eur J Pharmacol 1998)345:111-7
11. Katz HR, Stevens RL, Austen KF. Heterogeneity of mammalian mast cells differentiated in vivo and in vitro. J Allergy CHn Immunol 1985)76:250-9
12. Irani AMA, Schwartz LB. Mast cell heterogeneity. Clin Exp Allergy 1989)19:143-55
13. Hingorani M, Calder V, Buckley RJ, et al. The role of conjunctival epithelial cells in chronic ocular allergic disease. Exp Eye Res 1998)67:491-500
14. Sharif NA, Xu SX, Magnino PE, et al. Human conjunctival epithelial cells express histamine-1 receptors coupled to phosphoinositide turnover and intracellular calcium mobilization: Role in ocular allergic diseases. Exp Eye Res 1996)63:169-78
15. Yanni JM, Sharif NA, Gamache DA, et al. A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs. Acta Ophthalmol Scand 1999)77:33-7
16. Yanni JM, Weimer LK, Sharif NA, et al. Inhibition of histamineinduced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol 1999)117:643-7
17. Cook EB, Stahl JL, Barney NP, et al. Olopatadine inhibits antiimmunoglobulin E-stimulated conjunctival mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells. Ann Allergy Asthma Immunol 2001)87:424-9
18. Cook EB, Stahl JL, Barney NP, et al. Olopatadine inhibits TNF- a release from human conjunctival mast cells. Ann Allergy Asthma Immunol 2000)84:504-8
19. Brockman HL, Momsen MM, Knudtson JR, et al. Interactions of olopatadine and selected antihistamines with model and natural membranes. Ocular Immunol Inflamm 2003)2:247-68
20. Abelson MB, Chambers WA, Smith LM. Conjunctival Allergen Challenge: A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990)108:84-8
21. Abelson MB, Spitalny L. Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am J Ophthalmol 1998)125:797-804
22. Leonardi AA, Abelson MB. Double-masked, randomized, placebo- controlled controlled clinical study of the mast cell stabilizing effect of treatment with olopatadine in the conjunctival allergen challenge model in humans. Clin Ther 2003)25: 2539-52
23. Abelson MB, Pratt S, Mussoline JF, et al. One-visit, randomized, placebo-controlled, conjunctival allergen challenge study of scanning and imaging technology for objective quantification of eyelid swelling in the allergic reaction with contralateral use of olopatadine and artificial tears. Clin Ther 2003)25:2070-84
24. Deschenes J, Discepola M, Abelson MB. Comparative evaluation of olopatadine ophthalmic solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using the provocative antigen challenge model. Acta Ophthalmol Scand Suppl 1999)228:47-52
25. Butrus S, Greiner JV, Discepola M, et al. Comparison of the clinical efficacy and comfort of olopatadine hydrochloride 0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model. Clin Ther 2000)22:1462-72
26. Berdy GJ, Spangler DL, Bensch G, et al. A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther 2000)22:826-33
27. Katelaris CH, Ciprandi G, Missotten L, et al. International Olopatadine Study Group. A comparison of the efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and cromolyn sodium 2% ophthalmic solution in seasonal allergic conjunctivitis. CHn Ther 2002)24:1561-75
28. Spangler DL, Bensch G, Berdy GJ. Evaluation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochloride 0.5% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther 2001 ;23: 1272-80
29. Berdy GJ, Stoppel JO, Epstein AB. Comparison of the clinical efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension in the conjunctival allergen challenge model. Clin Ther 2002;24:918-29
30. Lanier BQ, Finegold I, D’Arienzo P, et al. Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival challenge model. Curr Med Res Opinion 2004;20:1227-33
31. Abelson MB, Spangler D, Giovanoni A, et al. Chemosis is an important diagnostic tool for evaluating new ophthalmic antiallergic agents using the conjunctival allergen challenge model. American College of Allergy, Asthma and Immunology meeting: Nov 7-12, 1997; San Diego, CA [abstract]
32. Aguilar AJ. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Acta Ophthalmol Scand Suppl 2000)230:52-5
33. Artal MN, Luna JD, Discepola M. A forced choice comfort study of olopatadine hydrochloride 0.1% versus ketotifen fumarate 0.05%. Acta Opthalmol Scand Suppl 2000; 78:64-5
34. Leonardl A, Zafirakis P. Efficacy and comfort of olopatadine versus ketotifen ophthalmic solutions: a double-masked environmental study of patient preference. Curr Med Res Opinion 2004;20:1167-73
35. Bausch & Lomb. Annual report to vision care professionals. Available from http://www.optistock.com/trends_contact_ lenses_2001_dec.pdf [Accessed 14 Dec 2001] pp. 8-11
36. Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr Allergy 1987;21:1-20
37. Brodsky M, Berger WE, Butrus S, et al. Evaluation of comfort using olopatadine hydrochloride 0.1% ophthalmic solution in the treatment of allergic conjunctivitis in contact lens wearers compared to placebo using the conjunctival allergen-challenge model. Eye Contact Lens 2003;29:113-6
38. Brodsky M. Allergic conjunctivitis and contact lenses: experience with olopatadine hydrochloride 0.1% therapy. Acta Ophthalmol Scand Suppl 2000;230:56-9
39. Dassanayake NL, Carey TC, Owen GR. A laboratory model to determine the uptake and release of olopatadine by soft contact lenses. Acta Ophthalmol Scand 2000;78:16-7
40. Abelson MB, Lanier RQ. The added benefit of local patanol therapy when combined with systemic Claritin for the inhibition of ocular itching in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl 1999;228:53-6
41. Abelson MB, Welch DL. An evaluation of onset and duration of action of Patanol (olopatadine hydrochloride ophthalmic solution 0.1%) compared to Claritin (loratadine lOmg) tablets in acute allergic conjunctivitis in the conjunctival allergen challenge model. Acta Ophthalmol Scand Suppl 2000; 230:60-3
42. Ousler GW, Wilcox KA, Gupta G, et al. An evaluation of the ocular drying effects of 2 systemic antihistamines: loratadine and cetirizine hydrochloride. Ann All Asth Immunol 2004;93: 460-464
43. Welch D, Ousler GW, Nally LA, et al. Ocular drying associated with oral antihistamines (loratadine) in the normal population – an evaluation of exaggerated dose effect. Adv Exp Med Biol 2002;506:1051-55
44. Lanier RQ, Abelson MB, Berger WE, et al. Comparison of the efficacy of combined fluticasone propionate and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by conjunctival allergen challenge. Clin Ther 2002;24:1161-74
45. Spangler DL, Abelson MB, Ober A, et al. Randomized, doublemasked comparison of olopatadine ophthalmic solution, mometasone furoate monohydrate nasal spray, and fexofenadine hydrochloride tablets using the conjunctival and nasal allergen challenge models. Clin Ther 2003;25:2245-67
46. Abelson MB, Turner D. A randomized, double-blind\, parallelgroup comparison of olopatadine 0.1% ophthalmic solution versus placebo for controlling the signs and symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Clin Ther 2003;25:931-47
47. Berger WE, Beck M, Kimura S, et al. Effects of adjuvant therapy with 0.1% olopatadine hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using systemic or nasal therapy. Ann All Asth Immunol 2005;95 [in press]
48. Ciprandi G, Turner D, Gross RD. Double-masked, randomized, parallel-group study comparing olopatadine 0.1% ophthalmic solution with cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in children with seasonal allergic conjunctivitis. Curr Ther Res 2004;65:186-99
49. Bertin D, Fedrigo A, Cano-Parra J. Efficacy and safety of olopatadine (Patanol) eye drops 0.1% compared to levocabastine 0.05% in seasonal allergic conjunctivitis. European Association for Vision and Eye Research meeting, In: Ophthal Res 2001,’33 (suppl 1) [abstract]
50. Cook EB, Stahl JL, Sedgwick JB, et al. The promotion of eosinophil degranulation and adhesion to conjunctival epithelial cells by IgE-activated conjunctival mast cells. Ann Allergy Asthma Immunol 2004;92:65-72
51. Fukuishi N, Matsuhisa M, Shimono T, et al. Inhibitory effect of olopatadine on antigen-induced eosinophil infiltration and the LFA-I and Mac-1 expression in eosinophils. Jpn J Pharmacol 2002;88:46
CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3068_5, Accepted for publication: 28 June 2005
Published Online: 03 August 2005
doi: 10.1185/030079905X56547
Lanny J. Rosenwasser(a), Terrence O’Brien(b) and Jonathan Weyne(c)
a Marjorie and Stephen Raphael Chair in Asthma Research, and Professor of Allergy and Immunology, National Jewish Medical and Research Center, Denver, CO, USA
b Professor of Ophthalmology, External Diseases and Cornea, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
c Clinical Assistant Professor, NYU Department of Ophthalmology, School of Medicine, New York, NY, USA
Address for correspondence: Jonathan S. Weyne, MD, 178 East 71st Street, New York, NY 10021, USA. Tel.: +1-212-650-0400; Fax: +1-212- 288-4223; email: [email protected]
Copyright Librapharm Sep 2005
Comments