Drug treatment of allergic conjunctivitis. A review of the evidence.

REVIEW ARTICLE

Drugs 43 (2): 154-176, 1992 0012-6667/92/0002-0154/$11.50/0 © Adis International Limited. All rights reserved. DRUll06

Drug Treatment of Allergic Conjunctivitis A Review of the Evidence

Giorgio Ciprandi, Sandra Buscaglia, Piera M. Cerqueti and Giorgio W. Canonica Allergy and Clinical Immunology Service, Department of Internal Medicine, DI.M.I., University of Genoa, and C1inica Oculistica, University of Genoa, Genoa, Italy

Contents 155 155 155 156 156 157 157 157

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158 158 159

159

159 160 160 160 161 161

161 168 168 169

170 170 171

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Summary I. Overview of Allergic Conjunctivitis 1.1 Pathophysiological Aspects 1.1.1 Adhesion Molecules 1.2 Clinical Features 1.3 Diagnosis 1.3.1 Clinical Presentation 1.3.2 Ophthalmological Examination 1.3.3 In Vivo and In Vitro Methods of IgE Research 1.3.4 Ocular Cytology: Conjunctival Scraping 1.3.5 Specific Conjunctival Provocation Test (CPT): A Diagnostic Procedure 1.3.6 CPT and Treatment Efficacy 2. Principles of Therapy 2.1 Prophylactic Drugs 2.1.1 Sodium Cromoglycate 2.1.2 Nedocromil 2.1.3 Other Cell-Stabilisers 2.2 Symptomatic Approach 2.2.1 Decongestant Drugs 2.2.2 Antihistamines 2.2.3 Newer Antihistamines 2.2.4 Perspectives in the Employment of Antihistamines 2.2.5 Anti-Inflammatory Drugs 3. Strategy of Therapy 3.1 Seasonal Allergic Conjunctivitis 3.2 Perennial Allergic Conjunctivitis 4. Specific Immunotherapy 5. Conclusions

Drug Treatment of Ocular Allergy

Summary

1. Overview

155

Allergic conjunctivitis, unlike several other ocular diseases, is seldom followed by permanent visual impairment; nevertheless, it is important because of both its frequency and its severity. Two major forms, seasonal and perennial, are considered in this review. To recognise the hallmarks of allergic conjunctivitis, clinicians have need ofa thorough knowledge of its pathophysiological aspects and clinical features, enabling them to choose the best and most suitable therapy among the alternatives. The aims of treatment vary according to the symptoms, severity and characteristics of the allergic reactions; in general, treatment is based mainly on environmental control, pharmacotherapy and (sometimes) specific immunotherapy. Topical vasoconstrictors, decongestant compounds, standard antihistamines or combinations of these drugs have been used for a number of years to treat the acute and/or persistent symptomatology, and in order to prevent the side effects of a prolonged treatment with topical glucocorticosteroids. Nevertheless, the latter represent the most powerful anti-inflammatory drugs, and are particularly recommended in short term treatment (5 to 7 days) in severe acute symptomatology. Orally administered.'classic' antihistamines, i.e. histamine HI-receptor antagonists, are effective and very convenient in either short or long term treatment, largely because the new compounds also act on the inflammatory process secondary to the allergic events. Recently, other topical compounds such as sodium cromoglycate (cromolyn sodium), nedocromil and nonsteroidal anti-inflammatory drugs (NSAIDs) [i.e. piroxicam, aspirin] have become available. Sodium cromoglycate and nedocromil act as prophylactic compounds, able to prevent the allergic reaction; NSAIDs represent a valid and effective alternative to glucocorticosteroids in several situations.

0/ Allergic Conjunctivitis

1.1 Pathophysiological Aspects The eye is a common target of inflammation in both local and systemic hypersensitivity reactions. The vast majority of ocular allergies affect the conjunctiva, which is largely exposed to the environment and, for this reason, is the site of interaction between allergens and immunocompetent cells (Friedlaender 1988, 1991). The importance of allergic conjunctivitis is due more to its frequency than to its severity: I-year studies show that between 5 and 22% of people suffer from this disease, with an incidence which varies according to the area studied (Weeke 1987). It is well known that IgE antibodies mediate reaginic hypersensitivity reactions in vitro and in vivo, and participate in the induction of allergic manifestations. Immediate hypersensitivity reactions are triggered when allergen molecules crosslink to the frequent antigen binding (Fab) components of adjacent IgE molecules on the mast cells or basophil surface; subsequent events stimulate a series of membranous and cytoplasmic changes, culminating in the release of preformed mediators from se-

cretory granules and the generation and release of newly formed products able to recruit and activate secondary inflammatory cells (Allansmith 1982). Preformed mediators include histamine (which has Hl- and H2-receptor-mediated effects on smooth muscle, endothelium and nerve endings), serotonin (with its specific bronchoactive and vasoactive effects) and chemotactic factors (Capron 1989) [i.e. eosinophils chemotactic factor of anaphylaxis (ECF-A), neutrophils chemotactic factor of anaphylaxis (NCF-A) and inflammatory factor of anaphylaxis (IF-A)] relate~ to the late-phase reaction, and kinins. Newly formed products include the arachidonic acid-derived mediators [i.e. prostaglandins, leukotrienes and platelet activating factor (Braquet et al. 1987)]. High concentrations of chemical mediators can drive neutrophils into the perivascular space and lead to the first stage of activation; the second stage of inflammatory cell activation can lead to a late reaction, which develops hours after the allergen exposure and is characterised by a rekindling of the inflammatory process. Several studies have been performed on the development and importance of late phase reactions (LPRs) of inflammatory cell activation, showing the fundamental role played

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by basophils (Bonini et al. 1988a,b; Gleich 1982; Lemanske & Kalmer 1988). Several studies have been performed after a challenge test on ocular LPRs, all leading to the general statement that this reaction is dose dependent. Low doses of allergen produce an immediate hypersensitivity reaction characterised by conjunctival hyperaemia, lacrimation and itching. Mild rhinitis is also associated. Neutrophils and eosinophils are commonly found in conjunctival scrapings. The reaction gradually decreases and disappears I hour after the challenge. High doses of allergen produce an intense, immediate reaction followed by a conspicuous neutrophil infiltrate. Clinical signs and symptoms decrease, but do not disappear, over the next 24 to 48 hours. The cellular response is characterised by monocytes (Bonini et al. 1989a,b). Clinical appearance and histological events are very closely related.

1.1.1 Adhesion Molecules Current research on the pathophysiology of allergic diseases is undoubtedly focused on the relationship between the immediate and late reactions and how both events may be related to the initial signal presented to the tissues by the offending allergen. However, a further aspect should be considered: the possible involvement of adhesion molecules in the pathogenesis of allergic diseases. The adhesive cell-to-cell and cell-to-extracellular matrix interaction is a crucial step in the development of the immune response (Springer 1990). Previous data showed the relevant contribution of intercellular adhesion molecule-I (ICAM-1) in eosinophil migration and airway responsiveness specifically induced by allergens, envisaging also a possible new therapeutic approach: antagonism to ICAM-l [mAb (monoclonal antibody) to ICAM-1] may reduce airWay inflammation, hyper-responsiveness and asthma symptoms (Wegner et al. 1990). Further studies have also demonstrated the role of ICAM-1 as a viral receptor (i.e. in rhinovirus infections), which may explain the relationship between inflammation and viral infections. Therefore, soluble ICAM-I has been investigated

in the treatment of rhinovirus infection (Marlin et al. 1990). The presence of adhesion molecules on epithelial cells lines (bronchus, gut and conjunctiva) was also investigated in our laboratory; our results showed the presence of LFA-1 on immunocompetent cells (CD1Ia), and CD54 on epithelial cells (ICAM-I) [Ciprandi et aI., unpublished data]. This expression was modified throughout different stimuli, i.e. PMA (phorbol/myristate/acetate), and could be modulated by drugs such as cetirizine and deflazacort (Parodi et al. 1991). These data would suggest new insights about the pharmacological activity of anti-inflammatory drugs. With a more detailed understanding of the pathophysiological mechanisms, there is a real chance that more selective and potent pharmacological agents may be designed to block and/or prevent the allergic immune response and, therefore, provide the best control of allergic manifestations. 1.2 Clinical Features Although several types of allergic conjunctivitis exist, this article focuses on 2 major groups: the seasonal form (pollen-related) and the perennial form, related to house dust and animal dander (Secchi et al. 1990). Allergic conjunctivitis can occur at any age, although the perennial form usually occurs during early infancy, while the seasonal form appears around the age of 20 to 40 years; there is no difference in sex distribution (Montgomery 1988). In both forms under consideration the symptoms usually consist of low grade ocular and periocular itching, lacrimation, photophobia, burning, swelling of eyelids, sensation of a foreign body and watery discharge. The conjunctiva shows mild or moderate oedema and hyperaemia; chemosis and increased mucoid secretions are less frequent complaints (table I). Rhinitis is often associated with conjunctivitis, whereas asthma, urticaria and angioedema are rare. Perennial allergic conjunctivitis presents signs and symptoms throughout the year; the seasonal form is characterised by its appearance in the pollen season. Signs and symptoms


Table I. Signs and symptoms in allergic conjunctivitis

Signs

Symptoms

Conjunctival hyperaemia Puffy lids Ciliary flush Peripheral corneal vascularisation Diffuse infiltration Oedema Micro!esions of cornea Papillae Phlyctena Plaques Scars Ulcer

Burning Itching Lacrimation Foreign body sensation Soreness Grittiness WaterY discharge Photophobia Chemosis Associated rhinitis

usually undergo exacerbations and remissions depending on the weather (i.e. symptoms get worse when the weather is warm and dry), the pollen season, the patient's activities and contact with irritants (Friedlaender 1988). In its chronic form, allergic conjunctivitis may present as a chronic ocular irritation with variable conjunctival inflammation; conjunctival hyperaemia and a papillary and follicular response on the inner eyelid may occasionally be observed. From a long term perspective, allergic conjunctivitis is rarely a blinding disease, although patients usually complain of the 'wearying and annoying symptomatology. 1.3 Diagnosis The evaluation of patients with allergic conjunctivitis requires 2 different approaches: first, the allergist's perspective includes any history of illness, and the research of cutaneous and seric-specific 19E; second, the ophthalmologist's approach includes an accurate ophthalmological investigation. Accurate diagnoses are determined also by histological and immunological studies (table II). 1.3.1 Clinical Presentation The physician should note the beginning and development of allergic conjunctivitis; it is necessary to record the frequency of symptoms (i.e. daily

157

or episodic, seasonal or perennial), their duration in terms of weeks, months or years, their severity and variability according to precipitating or aggravating factors (i.e. allergens, irritants and atmospheric conditions), and concomitant factors (i.e. infections or local disorders). A complete history . details the patient's response to drugs (including dose, dur~on and beneficial/adverse effects), and to environmental changes; the history should also include information on possible allergic symptoms in family members, age and type of house, length of pollen season and animal, irritant and occupational exposure. Physical examination of the patient involves not only the eyes but also other contiguous tissues (i.e. the nose), with attention to the patient's general status. 1.3.2 Ophthalmological Examination The key to ophthalmological investigation is the slit lamp examination; it permits evaluation of the conjunctival blood vessels and the cornea. Chemosis, severe oedema and periorbital oedema or ecchimoses can sometimes be revealed. Corneal micro lesions or papillae, phlyctens, plaques; scars or ulcers are not usually present; nevertheless, they must be investigated and excluded. Table II. Diagnostic procedures in allergic conjunctivitis

First step: allergologlcal examination History of illness Physical examination Skin prick test Seric specific IgE Second step: ophthalmological examination External ocular examination Slit lamp examination Third step: conjunctival examination Ocular cytology conjunctival scraping Conjunctival provocation test (aspecific, specific) external ocular examination slit lamp examination conjunctival scraping mediator level (e.g. histamine, prostaglandins)

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1.3.3 In Vivo and In Vitro Methods of 19E Research It has been a common procedure to establish a diagnosis by the re-exposure of the patient or a sample of serum to the suspected substance. The most common in vivo method is known as the skin prick test. It correlates with the clinical history and is simple, rapidly performed highly sensitive and low in cost. In vitro methods include a variety of analytical techniques adapted as immunometric assays (radioimmunoassay or enzymatic assay) to evaluate specific IgE. 1.3.4 Ocular Cytology: Conjunctival Scraping The routine work-up can also include an analysis of ocular cytology by conjunctival scraping. In fact, the latter provides a good clue to the cause and characteristics of an inflammatory response and to differentiate other forms of conjunctivitis. The method is simple and can be performed at the onset or during the acute phase of the disease, especially when any other factor, such as drugs or any other inflammatory processes, can interfere with the allergic reaction. The procedure involves placing a drop of topical anaesthetic in the lower conjunctival sac; after 10 to 20 seconds the upper lid is gently scraped several times with a spatula and the material is spread on a microscope slide, which is dried, fixed and finally stained with May-Grunwald Giemsa or other common morphological stains. The slide is examined for the presence of epithelial cells, eosinophils, neutrophils and other inflammatory cells (Abelson et al. 1983). The absence of eosinophils and/or inflammatory cells should not rule out a diagnosis of allergy. 1.3.5 Specific Conjunctival Provocation Test (CPT): A Diagnostic Procedure The conjunctival provocation test (CPT) is commonly used in the diagnosis of allergic conjunctivitis because of its high specificity, simplicity and low cost. 10 to 20 seconds after a drop oftopical anaesthetic is placed in the lower conjunctival sac, small quantities of serial dilutions of the allergenic extract are introduced and the patient is

Drug:} 43 (2) 1992

A

B

Fig. 1. Conjunctival scrapings: (A) epithelial cells in basal conditions; (8) epithelial cells and granulocytes 30 min after allergen-specific conjunctival provocation test (CPT) in I atopic patient; (C) epithelial cells, lymphocytes and monocytes 6h after allergen-specific CPT in I atopic patient.

observed for lacrimation, conjunctival hyperaemia, sneezing and other symptoms. Scraping can be performed 15 to 30 minutes after introduction of the allergen; the material is spread on a slide, fixed, stained and examined for the presence of epithelial and inflammatory cells (fig. I). Clinical observation and scraping can be per-


formed 6 to 8 and 24 hours later to determine the presence of a late phase reaction (Bonini et al. I 988a,b). Clinical reactions and cellular infiltrate are usually very closely related. CPT provides a useful tool to study symptomless patients (outside the pollen season, for instance) and a unique chance to define the most correct and precise diagnosis in multi-sensitised allergic patients. 1.3.6 CPT and Treatment Efficacy Several trials have already used CPT with allergens as a fruitful in vivo model for evaluating the clinical efficacy and cytological effects of different compounds commonly employed in the treatment of allergic conjunctivitis (Ciprandi et al. 1990a,b; Rimas et al. 1990; Schoeneich & Pecoud 1990; Zuber & Pecoud 1988). In double-blind, placebo-controlled studies, patients underwent clinical and cytological evaluations of the conjunctiva before and after specific CPT, prior to and following I to 2 weeks of treatment with levocabastine (Zuber & Pecoud· 1988), sodium cromoglycate (cromolyn sodium) [Rimas et ai. 1990], cetirizine (Schoeneich & Pecoud 1990), terfenadine (Ciprandi et ai. 1990a,b) and loratadine (Ciprandi et aI., unpublished data). The results of CPT were reproducible and very interesting, showing a relevant decrease in clinical and cytological events following I to 2 weeks of treatment, after CPT in patients receiving the active compound. The drugs studied conclusively showed protective effects against specific CPT and allergic conjunctivitis. In conclusion, CPT is a simple and reliable method both to define the correct diagnosis and to evaluate drugs intended for allergic conjunctivitis treatment.

. 2. Principles 0/ Therapy The goals of treatment vary according to the characteristics and severity of allergic conjunctivitis. There are 3 possible avenues of approach: environmental control, pharmacotherapy and, occasionally, specific immunotherapy.

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Avoidance of allergen-triggering factors should be the firSt line of defence in the management of allergic conjunctivitis. In addition, irritant or nonspecific factors that may trigger symptoms should also be avoided. Specific immunotherapy is indicated in the management of patients with perennial or seasonal rhinoconjunctivitis that is not adequately controlled by environmental control and pharmacotherapy (Lichtenstein & Fauci 1988). From a general viewpoint there are 2 major groups of treatment to be considered: prophylactic agents (cell stabilisers) and symptomatic drugs (decongestants, antihistamines and anti-inflammatory drugs). Two routes of drug administration are especially suitable for allergic conjunctivitis; these are topical and systemic. 2.1 Prophylactic Drugs Compounds able to stabilise mast Cell membranes are considered here. Their mechanism of action is to prevent not only the release ofhistamine and other mediators but also many of the signs and symptoms associated with allergic conjunctivitis. All the drug effects are strictly dose dependent (Ciprandi et ai. 1991). These drugs have minimal ocular side effects and several studies have already demonstrated their therapeutic value (Settipane et al. 1979): it is important to emphasise that with prophylactic agents, treatment should obviously start before symptoms appear. Prophylactic agents are ,sometimes combined with other drugs, i.e. decongestants or antihistamines (table III). Table III. Cell stabilisers in the prophylaxis of aHerglc conjunctivitis Compound

Formulation

Dosage in adults

Sodium cromoglycate

Eyedrops 2 or 4% solution

Nedocromil

Eyedrops 2% solution

1-2 drops in each eye 4 to 6 times daily 1-2 drops in each eye 2 to 3 times daily

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2.1.1 Sodium Cromoglycate Sodium cromoglycate was developed from khellin, isolated from the seeds of Amni visnaga. As a cell stabiliser its effects are due to changes in calcium ion permeability or inhibition of intracellular cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (Altounyan 1979; Andersson & Berstrand 1981; Lavin et al. 1976; Mazurek et al. 1980; Theoharides et al. 1980). It is not effective except to prevent the allergic reaction (Bernstein et al. 1978); it has no direct vasoconstrictor, bronchodilator, antihistamine or anti-inflammatory activity (Cox 1967; Sorkin & Ward 1986). Sodium cromoglycate is effective only by topical administration due to its lipid insolubility (Bernstein et al. 1978). The mean time taken for solution of sodium cromoglycate eye drops to produce clinical effects in patients has ranged between 2 and 5 days (Nizami 1981). Uncontrolled and controlled studies demonstrated ocular sodium cromoglycate to be very effective in relieving subjective signs and symptoms and in decreasing the need for supplementary oral antihistamines and, more importantly, the need for ocular corticosteroids (table IV). The combined application of sodium cromoglycate and corticosteroids may be very effective in chronic allergic conjunctivitis (Greenbaum et al. 1977; Portellinha et al. 1978; Welsh et al. 1979). Sodium cromoglycate is also commercially combined with antihistamines (e.g. chlorpheniramine eye drops 0.2% solution) or vasoactive compounds (e.g. tetrizoline 5% solution). No systemic or severe adverse reactions have been reported with ocular sodium cromoglycate (Chin 1978), even after long term treatment. Transient local burning and stinging have been attributed to a preservative (EI Hennawi 1980; Inerfield et al. 1984). 2.1.2 Nedocromil Nedocromil is the disodium salt of pyranoquinoline dicarboxylic acid; it stabilises mast cell membrane, preventing histamine release (Gonzalez & Brogden 1987), and is more potent than sodium cromoglycate (Moqbel et al. 1988). It inhibits

Table IV. Clinical trials of ocular sodium cromoglycate Reference

No. of patients

Study Dosage (drops Efficacya design per eye)/ (weeks) solution

Bec et al. (1982) Ciprandi et al. (1990b)

143c

DB (4) 1 qid/2%

59 (31)

30b

DB (4) 1 qid/2% CR 1 qid/0.5 mg/ml L PR (3) 1 x 6/2%

60 (60)8

DB (4) 1 tid/4%

89 (16)

DB (4) 2 qid/2%

85 (43)

DB (4) 1 tid/4%

60 (30)

Dawson (1979) Hechanova (1984) Lindsay-Miller (1979) Ruggieri & Scorcia (1987)

18b 23 20d 20 20b 23 31 M

77 (39)

Percentage of patients with fair or good relief of symptoms; figures in parentheses refer to placebo controls or comparator drug. b Hay fever conjunctivitis. c Hay fever conjunctivitis (n = 69) or chronic allergic conjunctivitis (n = 74). d ChroniC allergic conjunctivitis. e Levocabastine results. Abbreviations: PR = parallel randomised; DB = double-blind; qid = 4 times daily; tid = 3 times daily; CR = sodium cromoglycate; L = levocabastine. a

the activation of different inflammatory cells, i.e. neutrophils, eosinophils, macrophages, mast cells and platelets; there is evidence, both in vitro and in vivo, that it also affects the recruitment of secondary inflammatory cells into the site of inflammation (Corrado et al. 1987; Younghaiyud & Lee 1986). It has a dual action on mediators, i.e. inhibition of secretion and antagonism of action (Dahlen et al. 1989). Although several studies have already been performed on nedocromil and asthma [showing it to be effective in preventing the immediate and late response after antigen challenge (Younghaiyud & Lee 1986)], few trials have been performed on this drug in allergic conjunctivitis (table V) [Bonnet et al. 1985; floyd et al. 1988; Kalpaxis & Austin 1987; Van Bijsterveld et al. 1986]. 2.1.3 Other Cell-Stabilisers Few data are available on other experimental


161

2.2.1 Decongestant Drugs Astringent and vasoconstrictor agents are available for use as decongestants (Lanier et al. 1983). They are useful for short term treatment before initiation of topical anti-inflammatory drugs to improve the delivery of those compounds, to prevent exacerbation of symptoms and signs, and (combined with antihistamines) for a faster resolution of symptoms.

Vasoconstrictor Drugs Sympathomimetic amines stimulate both a- and jj-receptors. They cause marked vasoconstriction and decrease the oedema and conjunctival hyperaemia, but they have no effect on the conjunctival response to antigen. None of the types of vasoconstrictor in general use for treating allergic conjunctivitis causes systemic sympathomimetic effects, but prolonged use can cause rebound of congestion resulting in conjunctivitis medicamentosa. Naphthazoline hydrochloride 0.1 % solution, tetrahydrazoline hydrochloride 0.05% solution or ephedrine 0.1 % solution are commonly employed. They are usually available combined with a topical astringent and/or antihistamine (Abelson et al. 1980). Patients may instil one drop of these drugs as needed without medical supervision, but they should be instructed not to use topical sympathomimetics for more than 3 to 5 days, consecutively.

Astringent Drugs Astringent drugs consist of a solution of zinc sulphate or silver nitrate, administered as I drop in each eye 3 times daily for 3 to 5 days. They are locally acting and precipitate proteins; they have so little penetrative ability that only the cell surface is affected, increasing cell membrane resistance (Goodman et al. 1990).

2.2.2 Antihistamines This review considers only the 'classic' antihistamines, that is, the histamine HI-receptor antagonists (table VI). The mechanism of action of these drugs is based primarily on their ability to compete with histamine for binding to HI-receptors on blood vessels

cell-stabilisers, e.g. N-acetylaspartylglutamic acid (NAAGA) and 19E-pentapeptide (HEPP). Although clinical double-blind trials have shown these compounds to be very effective in the treatment of allergic conjunctivitis compared with sodium cromoglycate and nedocromil (table V) additional data are needed to establish their validity as topical formulations for use in allergic conjunctivitis. 2.2 Symptomatic Approach

Table V. Clinical trials of cell stabilisers in allergic conjunctivitis

Reference

Drug

Bonnet et al. (1985) Floyd et al. (1988) Hirsch et al. (1988) Kalpaxis & Austin (1987) Leino et al. (1990) Stockwell & Easty (1988) Van Bijsterveld et al. (1986)

NAAGA HEPP Nedocromil HEPP Nedocromil Nedocromil

No. of patients

Study design (period)

858

DBb (2 weeks)

1268 •C 648

DBb (2 weeks) DBb (2 weeks)

NAAGA

Patients with hay fever conjunctivitis. Placebo-controlled. Nedocromil n = 64, placebo n = 62. Abbreviations: NAAGA = N-acetylaspartylglutamic acid; HEPP bid = twice daily; N = nedocromil; P = placebo.

Dosage (drops per eye)/solution 1 or 2 qid/6% 1 or 2 qid/0.5% 1 bid/2% 1 or 2 qid/0.5% 1 bid/2% 1 bid/2%

Efficacy

N>P

N>P N>P

1 or 2 qid/6%

a b c

IgE-pentapeptide; DB

double-blind; qid

=4

times daily;

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Table VI. Antihistamines used in allergic conjunctivitis

Drug

Formulation

Dosage in adults (mg)

Astemizole

10mg tab Syrup 2 mg/ml 10mg tab Syrup 0.5 mg/drop 1mg tab Syrup 0.02% soln Drops 0.5 mg/ml

10 ad

Cetirizine Ketotifen Levocabastine Loratadine Oxatomide Terfenadlne

10mg tab Syrup 0.1% 30mg tab Syrup 2.5% 60, 120mg tab Syrup 0.6% soln

1 bid 1 drop each eye qid 100d 1 mg/kg bw 60 bid 1200d

= solution; od = once = twice daily; qid = 4 times daily; bw = badyweight.

Abbreviations: tab = tablet; soln

bid

100d

daily;

and smooth muscle. In addition, certain antihistamines may also inhibit mediator release (e.g. ketotifen, terfenadine, cetirizine, etc.) and they possess an anticholinergic effect that may be useful in the management of chronic rhinoconjunctivitis (Pearlman 1973; Trzecrakowski et al. 1988). Antihistamines are classified into 3 generations. The first includes drugs not well tolerated because of sedation and central nervous system {CNS} depression; the second and third generations may be distinguished primarily by the kinetics of their binding to and dissociation from H I-receptors, and by their lack of detectable CNS and anticholinergic side effects {Norman 1985}. Antihistamines provide improved therapeutic results when administered routinely or prophylactically as histamine HI-receptor sites can be blocked before histamine is released. Clinical experience has suggested that prolonged antihistamine use may lead to decreased responsiveness, tolerance or subsensitivity. In these cases, substitution with an antihistamine of another class may be helpful; thus, individualisation of patient therapy is an essential part of treatment. Several second- and third-generation drugs are covered here; all are available as topical and/or systemic formulations.

Ketotifen Ketotifen is a second-generation histamine H 1receptor antagonist, a derivative of the tricyclic compound benzocycloheptathiophene; it is an orally active prophylactic agent which also has antihistaminie and anti anaphylactic properties. It produces a moderate to marked improvement of symptoms in the majority of patients with asthma and allergic disorders, including seasonal and perennial conjunctivitis {Leclercq-Foucart et al. 1986; Rackham et al. 1989}. Ketotifen interferes with several components of the inflammatory reaction, including recruitment and activation of effector cells and release of mediators {Grant et al. 1990}; in particular, it affects platelet-activating factor (Chung et al. 1988) and the eosinophil response (Craps & Ney 1984). A further effect is the inhibition of the immune response by ketotifen compared with other antihistamines {Canonica & Ciprandi 1989; Canonica et al. 1989}. Although there is a large body of data available on the clinical use of ketotifen in asthma, in both children and adults, few studies have been performed on its use in ocular allergy {table VII}; nevertheless, all available data show effective relief of ocular and nasal symptoms in perennial and seasonal conjunctivitis, the improvement being most pronounced in children with seasonal symptoms {Businco et al. 1984; Leclercq-Foucart et al. 1986}. Ketotifen is usually well tolerated; common adverse effects, i.e. sedation, dizziness, dry mouth and nausea, occur in about 10 to 20% of patients but decline after 1 to 2 weeks of continued use (Prowse I 980); weight gain seldom occurs (Maclay & Crowder 1982). The recommended dosage is ketotifen 1mg twice daily or 2mg once daily as a single slow release tablet in adults and children over 3 years old. Children aged 6 months to 3 years should be given a dosage of 0.5mg twice daily, in tablet or syrup form. Astemizole Astemizole is a long acting histamine HI-receptor antagonist of the third generation, with no chemical relationship to known drugs. It shows high


potency as an antihistaminic and antiallergic compound, assessed in studies in vitro and in vivo. In vivo it has low antiserotoninergic activity and no anticholinergic activity (Richards et al. 1984a). There is an absence of significant CNS side effects with the usual dose (Seppala & Savolainen 1982); moreover, astemizole did not potentiate the central effects of either alcohol or diazepam (Mygind et al. 1984). It promotes increased appetite and weight gain in long term treatment (Laduron et al. 1982; 1984). Its efficacy in the treatment of seasonal and perennial rhinoconjunctivitis has been demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other antihistamines (Heykants 1984) [table VII]. Astemizole has a very long serum half-life (> 7 days); the onset of action is relatively slow and inhibitory effects last for an extended amount of time (> 4 hours). Administration of the drug with food significantly decreases its bioavailability. The recommended adult dosage is 10 mg/day taken on an empty stomach; for children the suspension formulation [lml (2mg}/lOkg bodyweight daily] is preferred. Oxatomide Oxatomide is an orally active histamine HIreceptor antagonist which is chemically related to cinnarizine. In vitro and in vivo trials have assessed its dual action activity, i.e. antihistaminic activity and inhibition of mast cell degranulation (Awouters et al. 1980); it also presents some antiserotonin, anticholinergic and antileukotriene activity (A wouters et al. 1980; Truneh et al. 1982). Peak plasma concentration occurs within 4 hours of an oral dose of oxatomide 60mg; its serum halflife is approximately 14 hours (Richards et al. 1984b). In placebo-controlled studies in allergic rhinoconjunctivitis, both seasonal and perennial, oxatomide improved symptoms and decreasedsupplemental antihistamine use. It has been demonstrated to be at least as effective as other H I-receptor antagonists, i.e. chlorpheniramine, diphenhydramine or the combination cinnarizine plus phenylpropanolamine (table VII). Oxatomide ap-

163

pears to be a potentially useful alternative in the treatment of allergic rhinoconjunctivitis in patients who have not responded to previously administered antihistamines (De Cree et al. 1980; Moller & Bjorksten 1980) [table VII]. The recommended dosage in adults is oxatomide 30mg twice daily after breakfast and after the evening meal. Oral drops, 0.5 mg/kg bodyweight, are recommended in children. Oxatomide has usually been well tolerated, but mild sedation, drowsiness, dry mouth and weight gain occasionally occur (Richards et al. 1984b; Verhaegen & De Cree 1980). Terfenadine Terfenadine is a highly selective histamine HIreceptor antagonist ofthe third generation, with no significant affinity for H2-receptors, a- and (j-adrenergic receptors, and has poor or absent anticholinergic, antiserotoninergic and a- or (j-adrenergic activity (Sorkin & Heel 1985; Wiech & Martin 1982). It has significant antihistaminic and antiallergic activity, and is also an effective inhibitor of mediator release from mast cells, basophils and eosinophils (McTavish et al. 1990; Nabe et al. 1989). Its efficacy has been clearly demonstrated (Kjellman & Andersson 1986; Pecoud et al 1988; Rafferty & Holgate 1987; Shall et al. 1988; Simons et al. 1988), wit~ the drug proving to be superior to placebo and comparable with other histamine H I-receptor antagonists including loratadine, cetirizine and chlorpheniramine in double-blind studies in the treatment of rhinoconjunctivitis (table VII), asthma and allergic dermatological diseases. Although sedation is the most frequently reported adverse effect, its incidence is similar to that which occurs after placebo administration, and comparable with instances reported with the other new nonsedating antihistamines (i.e. loratadine, cetirizine) [Campoli-Richards et al. 1990]. Dry mouth, nose or throat seldom occur (Brandon & Weiner 1980; Brion et al. 1988). The recommended dosage in adults is terfenadine 60mg twice daily or 120mg once daily. Children aged between 3 and 5 should receive 15mg twice daily as an oral suspension; in

Drugs 43 (2) 1992

164

Table VII. Double-blind clinical trials of drugs used in the treatment of allergic conjunctivitis

Reference

No. of patients

Study period (weeks)

Astemizole (A) Perennial rhinoconjunctivitis Boland (1988)

27

4

Brobyn et al. (1982)

56

4

Seasonal rhinoconjunctivitis Callier et al. (1981)

86

2 6

69

2 6 8

Malmberg et al. (1983)

30 32 28 97 60 31

Wilson & Hillas (1983)

32

2 6

130 127 130 79 78 78 79 79 78 78 16

8

28

2

Ketotifen (K) Perennial rhinoconjunctivitis Okuda (1984)

221

4

Saito et al. (1988)

173

4

Seasonal rhinoconjunctivitis Leclercq-Foucart et al. (1986)

100

4

Howarth & Holgate (1984)

Juniper et al. (1988)

Cetirizine (C) Davies et al. (1989)b

Fox et al. (1989)b

Kaiser et al. (1989)b

Panayotopoulos & Panayotopoulou (1990)b Schmeisser et al. (1989)C

7 3

4

6

Drug/dosage (mg)

Result8

A/10 od T/60 bid A/10 od P

85 81 65 16

A/10 od A/10/wk P A/50 qd A/25/wk P A/10 od T/60 bid P A/10 od T/60 bid A/10 od P A/30 qd A/20 qd P

50-68

Overall efficacy

30-32 66-75 30-32 67 63 13

T=A>P

A>T 62 34 A 75 vs P 31 A 69 vs P 18

C=T

C/10 mane C/10 nocte T/60 bid C/5 od T/60 bid P C/5 mane C/10 nocte Ch/8 bid P C/10 od P C/10 od T/60 bid P

C>P

C5 = C10 = Ch > P

C>P C=T>P

K/0.51 bid CI/1.4 bid K/1 bid T/60 bid

55-73 35 80 85

K/1 bid A/10 qd

42 81-87


165

Table VII. Contd

Reference

No. of patients

Okuda (1986)

221

4

35

17

107

12

Ciprandi et al. (1990b)b

30

4

Pipkorn et al. (1985)b

40

4

228

23 24 23 91 88

Warner & Goldsworthy (1982)d Wheatley (1984)


Drug/dosage (mg)

Result8

K/l bid P K/l bid CI/l bid K/1 bid Chl12 tfld

81 38 60 35

Overall efficacy

K;;' Ch

Levocabastine (L)

Loratadine (Lo) Perennial rhinoconjunctivitis Bruttmann et al. (1988b)

Seasonal rhinoconjunctivitis Bruttmann et al. (1988b)

Gutkowski et al. (1988)

L/1 ou qid Cr/l ou qid L 1 ou qid P

L=C

4

Lo/l0 od T/60 bid P

Lo=T>P

2

Lo/40 od T/60 bid P Lo/40 od T/60 bid P Lo/40 od Cr/l bid Lo/l0 od A/l0 od P

Lo=T>P

2

83 Irander et al. (1990)

107

2

22 22 21

2

Cerqueti et al. (1987)

7

2

Ciprandi et al. (1991)

8 10

2

Oei et al. (1987)

L>P

Lo=T>P

Lo=Cr>P Lo>A>P

NSAIDs

10 10

Sacca et al. (1988)

10 7 7 7

2

Pi 5% soln/l ou tid P H 1% soln/1 dr tid ASA 1% soln/1 dr tid Pi 5% soln/1 dr tid P ASA 1% soln/1 dr qid ASA 0.5% soln/1 dr qid P

57 30 82 71 63 27 69 61 32

(continued)

166

Drugs 43 (2) 1992

Table VII. Contd

Reference

Outomide (0) Juniper et al. (1981)

No. of patients


41

4

207

31d

26

31d

Vannieuwenhuys et al. (1982)

56

40d

Wood (1982)

63

12

68 73 74 75 67

4

79 78 78 68 35 88 91

4

Moller & Bjorksteln (1980)

Terfenlldlne (T) Perennial rhinoconjunctivitis Bruttmann et al. (1988a)

Saito et al. (1988)

4

Drug/dosage (mg)

Result"

Overall efficacy

o =Ch

Ch/l0.20 qd 0/60-120 qd 0/1-2/kg/d P Ch/l0 od Ph/25 od 0/1-2/kg/d 0/30-60 bid P 0/30 tid P

O>P O=Ch+Ph

O> P O>P

T/60 bid Lo/l0 od P T/60 bid K/l bid

57

C/5 od T/60 bid P T/30-60 bid P T/60 bid Lo/40 od P T/60 bid A/l0 od P T/60 bid P T/60 bid Ch/4 tid P

69 70 18 85 60 65 67 16

63 26 85 81

Seasonal rhlnoconjunctlvltls Fox et al. (1989)

Gutkowski et al. (1988) Guill et al. (l986)d

2

83 Howarth & Holgate (1984)

Kagan et al. (1980) Kemp et al. (1965)

a b c d

32 30 28 55 55 113 119 119

8

Percentage of patients receiving fair or good relief from symptoms. Patients with hay fever conjunctivitis. Patients with chronic allergic conjunctivitis. Children enrolled in study.

63 67 13 76 44 60 60 30

Abbreviations: ASA = aspirin (galenic formulation); C = cetirizine; Ch = chlorpheniramine; CI = clemastine; Cr = sodium cromoglycate (cromolyn sodium); H = hydrocortisone; P = placebo; Ph - phenylpropanolamine; Pi = piroxicam; od = once daily; bid = twice daily; tid '" 3 times day; qld = 4 times daily; qd = every day; mane = in the morning; nocte = in the evening; ou = drop (in each eye); d = day; wk = week.


those 6 to 12 years old 30 to 60mg twice daily according to bodyweight is recommended (Kemp et al. 1985; Robinson et al. 1989). Loratadine Loratadine is a potent, long-acting histamine HIreceptor antagonist structurally related to azatadine (Clissold et al. 1989). It has high selectivity for peripheral HI-receptors and very low affinity for HI-receptors in the CNS in vivo and in vitro (Friedman 1987; Roth et al. 1987). The drug displays poor activity on acetylcholine and aI-adrenergic receptors (Barnett et al. 1984). In vitro and in vivo studies have assessed its antihistaminic and antiallergic activity; the effectiveness and duration of action were dose related, and response was greater with loratadine than with placebo (Bousquet et al. 1988). Loratadine also suppressed histamine release from rat mast cells (Kreutner et al. 1987). Loratadine is rapidly absorbed after a single oral dose, with the peak plasma concentration occurring after I hour; its serum half-life is 8 to 19 hours (Clissold et al. 1989). The therapeutic efficacy of loratadine has been investigated in allergic seasonal and perennial rhinoconjunctivitis. Short term clinical trials showed loratadine to be as effective as other histamine HI-receptor antagonists such as terfenadine and clemastine, with loratadine possessing a more rapid onset of action (table VII). In addition, loratadine 5mg combined with pseudoephedrine 120mg twice daily in seasonal rhinoconjunctivitis is significantly effective (Bruttmann et al. 1988a,b; Dockorn et al. 1987; Skassa-Brociekerae et al. 1987). Loratadine is extremely well tolerated and it appears to cause a lower incidence of sedation than other old antihistamines, e.g. azatadine or clemastine (Dockorn et al. 1987). The recommended adult dosage is loratadine tOmg once daily. Although no paediatric dosage recommendations are available, children aged 6 to 12 should receive 5 to 10mg once daily, or loratadine 5mg plus pseudoephedrine 120mg once daily.

167

Cetirizine Cetirizine is a piperazine derivative and carboxylated metabolite of hydroxyzine. It possesses a high and selective affinity for histamine HIreceptors and low affinity for calcium channel, aadrenergic, dopamine, serotonin and muscarinic receptors (Campoli-Richards et al. 1990; Snyder & Snowman 1987). Its antihistaminic activity has been assessed in animal and human studies; this effect was protracted for prolonged periods of administration with no development of tolerance (Maniatakou et al. 1990). The antiallergic activity of cetirizine includes a minor effect on mast cells and on the release of mediators of immediate hypersensitivity (Naclerio et al. 1989), and an inhibitory effect on eosinophil chemotaxis (Fadel et al. 1987; Leprevost et al. 1988) and on the responses of neutrophils and platelets (De Vos et al. 1989; Michel et al. 1988; Van Epps et al. 1987). Cetirizine is rapidly absorbed, reaching peak plasma concentration after I hour; its serum halflife is between 7 and to hours (Campoli-Richards et al. 1990). Food may slightly reduce the rate of absorption (Wood et al. 1987). Several randomised, double-blind clinical trials have established the efficacy of cetirizine in the treatment of allergic rhinoconjunctivitis (table VII); it provides a similar symptomatic control to other common antihistamines, e.g. terfenadine and chlorpheniramine. The incidence of sedation is generally similar between cetirizine and terfenadine, and not significantly different from that reported with placebo (Gengo & Gabos 1987; Seidel et al. 1987). The recommended dosage in adults and children over 12 years old is 10mg once daily for rapid onset and prolonged duration of action. Recently, drops have become available (0.5 mg! drop), thus providing a possible treatment for children under 12. Levocabastine Levocabastine is a pure and highly selective histamine HI-receptor antagonist of the second generation, available as topical eyedrops for the treatment of allergic conjunctivitis (International

168

New Drug Brochure 1984). In animal studies it has been demonstrated to be 65 times more potent than astemizole. The peak plasma concentration is reached within I to 2 hours after oral administration; its serum half-life is between 35 and 40 hours (Dechant & Goa 1991). A few clinical trials have evaluated the efficacy of cetirizine as a topical formulation (0.5 mgjml ' eye drops). Other trials evaluated the effects of this drug administered topically in a specific CPT, showing an increase of the conjunctival tolerance to the allergen (Pecoud et al. 1987; Rimas et al. 1990; Zuber & Pecoud 1988). Levocabastine would seem to be a good effective alternative to other topical antihistamine treatments in allergic conjunctivitis (Ciprandi et al. 1990b; Pipkorn et al. 1985) [table VII]. Mild redness of the eyes was reported in these studies in few patients. The recommended dosage is I drop in each eye 4 times daily. Combined Use of Histamine HI- and H2-Receptor Antagonists While the place of histamine HI-receptor antagonists in allergic diseases is clearly defined, the role of histamine H2-blockers is still controversial. Nevertheless, there are increasing data on the beneficial effects of histamine H)- and H2-antagonist combinations in a broad variety of allergic and pseudoallergic conditions [i.e. chronic urticaria (Monroe et al. 1981); anaphylactoid reactions to colloid volume substitutes, opioid analgesics and radiographic contrast media; asthma (Nathan et al. 1981); rhinitis (Secher et al. 1982); seasonal rhinitis (Carpenter et al. 1983); and rhinoconjunctivitis] as oral or sometimes topical formulations (Ring & Behrendt 1990). It should be borne in mind that the marked inhibitory activity of an HI-H2-antagonist combination on the histamine or allergenic reaction has not been clearly demonstrated to date (Ring & Behrendt 1990). It is not clear if the therapeutic benefit is due to the cumulative pharmacological effects of the 2 antagonists or only to the increased bioavailability of the HI-antagonist (Ring & Behrendt 1990). Moreover, in animal studies and the

Drugs 43 (2) 1992

few clinical trials, the combined use of H I-H2-antagonists may have exerted a cell-stabilising effect. The major drawback is the relatively pronounced side effects (Douglas 1984). Further studies will be of interest to define the real efficacy of this combined therapy in allergic diseases. 2.2.3 Newer Antihistamines The pharmaceutical industry is engaged in the synthesis and development of new histamine HIreceptor antagonists which it is hoped will provide additional therapeutic advances. The high specificity of these compounds allows their use in clinical practice of larger doses, while avoiding the common CNS side effects. Some drugs have been shown to prevent mast cell and basophil release at low concentrations and to have a modulatory effect on eosinophils, neutrophils and platelets, which play a role in allergic inflammatory processes. Ring and Behrendt (1990) have reported on this newest generation of HI-receptor antagonists (azelastine, acrivastine, mizolastine and picumast). Some clinical reports are already available for the first 2 named (Brogden & McTavish 1991; McTavish & Sorkin 1989), while other, unpublished reports suggest that mizolastine has a very good efficacy (Ciprandi & Canonica, personal observation). 2.2.4 Perspectives in the Employment of Antihistamines Several of these recently developed histamine HI-receptor antagonists present a convenient combination of pharmacokinetic characteristics and pharmacological properties: very low level of metabolism, regular and highly selective affinity for the histamine for H I-receptors, rapid onset and prolonged duration of action, little or no effect on the CNS, powerful anti histaminic and antiallergic activity, and significant effects on the cellular and mediator components of the inflammatory response related to the allergic reaction. Several clinical trials in vitro and in vivo have already investigated the inflammatory aspect of allergic diseases. In vitro models evaluate the inhibitor effect of HI-receptor antagonists on mediator


release and on neutrophil, eosinophil and basophil chemotaxis, leading to deep modification of the allergic inflammatory cell component (De Weck 1990). In vivo models include the challenge test performed through aspecific (i.e. albumin) or specific (allergen) stimulus, applied to the eye (Bonini et al. 1988a,b; Ciprandi et al. I 990a,b; Schoeneich & Pecoud 1990; Zuber & Pecoud 1988), nose (Bousquet et al. 1988) and bronchus (Metzger et al. 1987). For example, in our recent experience (doubleblind placebo-controlled trials) both terfenadine and loratadine showed a protective and prophylactic effect on conjunctival inflammatory events, both mediator- and cell-recruitment-related, induced by specific CPT in atopic patients out of the pollen season (unpublished observations). Cetirizine also displayed a protective action in atopic patients after allergen challenge (Schoeneich & Pecoud 1990). Since all the new developed compounds are similar in pharmacokinetic and pharmacological properties, a very broad range of uses for histamine H I-receptor antagonists appears to be available in the treatment of the different allergic diseases.

2.2.5 Anti-Inflammatory Drugs Anti-inflammatory drugs include a heterogeneous group o(compounds, chemically unrelated and characterised by different pharmacokinetic and pharmacological properties. The rationale of their use is related to their powerful action on the inflammatory a~d immune responses which always occur during the allergic reaction; the development of the allergic disease is strictly related to these responses. Basically, 2 major groups can be distinguished: glucocorticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). They are generally available for treating allergic conjunctivitis as oral or topical formulations; the latter represented an effective alternative and it permits avoidance of the systemic side effects due to oral administration, especially in long term treatment.

169

Glucocorticosteroids Glucocorticosteroids show a clear beneficial effect in the treatment of several forms of conjunctivitis, including allergic conjunctivitis; their mechanism of action is connected with the inhibition of phospholipase A2 which is responsible for the generation of several new-formed mediators (i.e. leukotrienes, prostaglandins, and platelet-activating factor) [Si~el 1985]. These drugs have the capacity to prevenior suppress the development of the immunological and inflammatory response (Polansky & Weinreb 1984). They inhibit both the early phenomena of the inflammatory process (i.e. oedema, fibrin deposition, capillary dilatation, migration of leucocytes and phagocytosis activities) and the later events (i.e. capillary proliferation and deposition of collagen). In addition, they suppress the immune response, apparently by inhibiting the recruitment of leucocytes, their proliferation and differentiation, cytokine release and phagocytic activity. Only the late phase of the allergic reaction is affected by glucocorticosteroids, while no action has been demonstrated on the early phase ,of the allergic mechanism (Naclerio et al. 1989). The use of glucocorticosteroids in ocular allergy should normally be restricted to a topical formulation, in severe cases, for short term treatment (i.e. 5 to 7 days), because oftheir well known local side effects (i.e. cataract, increase of ocular tone, etc.). Data on the specific uses of topical glucocorticosteroids in allergic conjunctivitis are not available; common ophthalmological glucocorticosteroid preparations are listed in table VIII. Ophthalmological preparations include dexamethasone phosphate solution, betamethasone and prednisone (frequently associated with intraocular hypertension). Hydrocortisone, medrysone and desonide are pharmacologically less effective than betamethasone, but show less evidence of side effects (Frankland & Walker 1981). Glucocorticosteroids are usually combined with other agents such as vasoconstrictors (antazoline, phenilephrine).

170

Drugs 43 (2) 1992

Table VIII. Common topical glucocorticosteroids available in allergic conjunctivitis Compound

Formulation

Betamethasone phosphate Clobethasone Dexamethasone

Eye drops 0.1%

Dexamethasone phosphate Hydrocortisone Medrysone Prednisone acetate Abbreviation: soln

Ophthalmic suspension 0.1% Eye drops 0.1 or 0.2% soln Ophthalmic ointment 0.2% soln Eye drops 0.15% soln Eye drops 0.3% soln Ophthalmic ointment 0.1% soln Eye drops 0.5% soln Ophthalmic ointment 0.5% soln Eye drops 0.5% soln Ophthalmic ointment 0.5% soln

= solution.

Nonsteroidal Anti-Inflammatory Drugs NSAIDs represent an effective alternative to corticosteroids, since they have a powerful anti-inflammatory activity with no significant side effects when administered topically (Settipane 1983). NSAIDs inhibit prostaglandin synthesis, blocking the cyclo-oxygenase pathway; they also inhibit neutrophil chemotaxis and the subsequent products released from these cells, i.e. Oi-, H202 and OH-, which have a proinflammatory activity (Abelson et a1. 1983; Abramson & Weissman 1989; Vane 1987). These agents have already been employed with success in several forms of conjunctivitis, such as vernal conjunctivitis (Abelson et a1. 1983). Nevertheless, few reports have appeared of clinical trials on topical aspirin (Abelson et a1. 1983; Sacca et a1. 1988) and topical piroxicam (Cerqueti et a1. 1987) in the treatment of perennial and seasonal conjunctivitis; the available data show a good efficacy in the relief of signs and symptoms (table VII). No side effects were reported in these studies. Aspirin is avaihlble as a galenic formulation (I % solution); the recommended dosage is 1 drop in each eye 4 times daily while symptoms are acute. Piroxicam is available as an eye drop solution, with a recommended dosage of 1 drop in each eye 3 times daily (Ciprandi et aI., unpublished data). Oral antihistamines combined with oral cyclo-

oxygenase-inhibiting drugs have also been reported to be effective in the treatment of hay fever (Brooks & Karl 1988).

3. Strategy of Therapy Several therapeutic strategies in the treatment of allergic conjunctivitis can be evaluated from all the foregoing information. The choice will be governed by the clinical appearance, the diagnostic investigation and the experience of the physician. On the basis of the signs and symptoms, the therapeutic effort should' be turned towards preventing and/ or blocking the allergic reaction. The seasonal and perennial forms of allergic conjunctivitis require different approaches, but similar therapeutic behaviour in the maintenance. 3.1 Seasonal Allergic Conjunctivitis The prophylactic approach should be initiated before, and maintained throughout, the pollen season. Topical sodium cromoglycate and nedocromil are commonly employed. The severity of any acute episode determines the acute phase approach. Mild symptoms require vasoconstrictor agents, sodium cromoglycate and histamine H I-receptor antagonists, administered for the duration of the exposure to allergens; severe symptoms require topical glucocorticosteroids, 3 or 4 times daily for 5 to 7 days, as the first step. An alternative approach is 'pulse' therapy, consisting of hourly applications of topical glucocorticosteroids for 3 days, combined with decongestant agents, antihistamines and sodium cromoglycate; one 3-day application of 'pulse' therapy usually shows remarkable efficacy. It is also convenient to administer oral histamine HI-receptor antagonists (e.g. cetirizine or terfenadine) which can affect not only the allergic reaction, but also the inflammatory cell component. When the pollen season is very prolonged (e.g. in the Mediterranean area for Parietaria pollen), the maintenance therapy will last for a long period (Ciprandi et a1. 1990a,b); therefore, nonsteroidal drugs are suitable and their use as an alternative avoids the well known side effects of glucocorti-


costeroids. Sodium cromoglycate is useful in mild cases; sodium cromoglycate plus antihistamines or vasoconstrictor agents, topical NSAIDs and oral histamine HI-receptor antagonists are useful in severe cases. Recently, we successfully evaluated the clinical efficacy of different therapeutic protocols employing NSAIDs (aspirin and piroxicam) in the treatment of seasonal allergic conjunctivitis (Ciprandi et aI. , unpublished data). 3.2 Perennial Allergic Conjunctivitis Environmental control should be the first line of defence against the perennial form of alIergic conjunctivitis; the goal should be the complete removal of house dust and animal dander. It appears that the removal of alI textile objects (e.g. carpets, padded furniture, mattresses and stuffed animals) and regular vacuuming are not effective if dustmites are still present. Effective sanitation should include the extermination of the mites using acaricidal cleaning agents such as solidified benzylbenzoate compounds (Kniest et al. 1989). Environmental control should be combined with prophylactic strategy: topical sodium cromoglycate or nedocromil are the drugs of choice. The acute phase approach is more or less similar to polIinosis conjunctivitis, considering the onset and severity of the disease. Glucocorticosteroids should be employed in severe cases for 5 to 7 days, followed by histamine HI-receptor antagonists administered either topicalIy or by mouth. NSAIDs can represent an effective and valid alternative to glucocorticosteroids. For milder forms, topical decongestants and topical or oral histamine H I-receptor antagonists are useful. When ocular symptomatology is severe and combined with severe rhinitis and/or asthma, immunotherapy represents a further appropriate choice. In mild cases, the choice for maintenance should be topical sodium cromoglycate or nedocromil plus one of the newer oral antihistamines (i.e. antiallergic compounds: cetirizine, terfenadine, loratadine). The newly developed histamine HI-receptor

171

antagonist compounds are recommended in prolonged treatment for their efficacy, safety and lack of tachyphylaxis or tolerance.

4. Specific Immunotherapy Specific immunotherapy (SIT) should be considered when alIergy sensitivity has a major relevance in the symptoms and severity of alIergic disease. Pollinosis and mite-induced alIergy are specific indications, especially when symptoms are prolonged and only partialIy controlIed by drug treatment. The aim should be to increase the patient's clinical tolerance to an alIergen by regular administration (as subcutaneous injections, inhalant or oral solution) of increasing doses of the alIergen. An effective treatment should last at least 3 to 5 years. SIT is primarily useful in children and young adults. Its clinical efficacy in rhinoconjunctivitis and asthma has been demonstrated in a number of welI controlIed studies (Van Metre & Adkinson 1988). In addition, it is the only alIergen-oriented treatment and has been recently shown to be effective OIl eosinophils (Rak et al. 1990), T lymphocyte subsets (Kay et al. 1991) and the early and late phases of IgE-mediated reactions (MalIing 1988; Van Bever & Stevens 1990).

5. Conclusions The appropriate therapeutic management of allergic conjunctivitis should be selected for each individual according to a precise diagnosis. The physician should be accurate in recording the history of the illness and consider the potential factors that can be associated with allergic conjunctivitis [overlapping bacterial infections, refraction troubles (myopia), convergence deficiency (strabismus), modification of the lacrimatory film or poor compliance by the atopic patient]. There is considerable and growing interest in the available antialIergic and anti-inflammatory compounds, and in the development of more powerful and selective agents that can be successfulIy and safely employed in ocular alIergy. The judicious use

172

of individualised appropriate pharmacotherapy will contribute to improved patient care in the treatment of this common disorder.

Acknowledgements This work was supported by grant No. 5710 from P.F. CNR FATMA SP2 to Dr G.W. Canonica, and by the Associazione Ricerca Malattie Allergiche e Immunologiche (ARMIA). The authors would like to thank the following for their kind collaboration: Bruschettini (Genoa), Fisons Italchimici (Rome), Formenti (Milan), Gruppo Lepetit (Milan), Janssen (Rome), Laboratori UCB (Turin) and Schering-Plough (Milan). Finally, thanks go to Dr Rina Miriello for her skilful secretarial assistance.

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Correspondence and reprints: Dr Giorgio W. Canonico. Allergy and Clinical Immunology Service, DIMI, Department of Internal Medicine, Vie Benedetto XV 6, 16132 Genoa, Italy.

New trends in the treatment of allergic conjunctivitis.

Oxymetazoline in the treatment of allergic and non-infectious conjunctivitis.

A human model of allergic conjunctivitis.

Allergic conjunctivitis: a survey of new antihistamines.

Treatment of allergic conjunctivitis with bepotastine besilate ophthalmic solution 1.5%.

Combination treatment for allergic conjunctivitis - Plant derived histidine decarboxylase inhibitor and H1 antihistaminic drug.

Allergic conjunctivitis: a cross-sectional study.

Emerging drugs for allergic conjunctivitis.

Loteprednol etabonate in the treatment of allergic conjunctivitis: a meta-analysis.

Conjunctivitis: a systematic review of diagnosis and treatment.

Evaluation of allergic conjunctivitis by thermography.

Oral immunotherapy for allergic conjunctivitis.

Allergic conjunctivitis in Jos-Nigeria.

Allergic conjunctivitis due to diazepam.

Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine.

Efficacy and safety of nedocromil sodium ophthalmic solution in the treatment of seasonal allergic conjunctivitis.

Update and clinical utility of alcaftadine ophthalmic solution 0.25% in the treatment of allergic conjunctivitis.

Neonatal conjunctivitis - a review.

Advances in pharmacotherapy for allergic conjunctivitis.

DSCG eye drops in allergic rhino-conjunctivitis.

Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis.

Optic nerve injury in a patient with chronic allergic conjunctivitis.

Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis.

Ocular itch associated with allergic conjunctivitis: latest evidence and clinical management.