Documenta Ophthalmologica 82: 353-360, 1992. 1992 Kluwer Academic Publishers. Printed in the Netherlands.
9
New trends in the treatment of allergic conjunctivitis W. PARYS, S. BLOCKHUYS & M. JANSSENS Janssen Research Foundation, Beerse, Belgium Accepted 22 November 1992
Key words: Allergy, Conjunctivitis, Cromoglycate, Histamine, Levocabastine, Terfenadine Abstract. Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H~ antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistaminic compound available, being 15 000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action, In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.
Introduction The development of new and effective treatments for allergic conjunctivitis must depend on a clear understanding of the underlying causes of the condition. For some time this has been the subject of controversy. Symptoms of allergic conjunctivitis have long been regarded as the result of an IgE-mediated release of histamine from mast cells and basophils [1]. However studies of histamine levels in the tears of conjunctival patients showed no elevation over those in normal subjects [2]. This anomaly was only resolved with the discovery of a histaminase enzyme in tears produced after conjunctival allergen challenge. Inactivation of this enzyme showed that histamine levels were indeed increased and thus re-established the central role of histamine in creating conjunctival symptoms [3]. Some evidence suggests that the itching which is characteristic of conjunctivitis is the result of activation of the histamine H 1 receptor in the eyelid, whilst redness and hyperaemia result from an H2-mediated effect [4, 5].
354
Several different approaches have been taken to the treatment of allergic conjunctivitis. They range from the use of corticosteroids in the extreme case, to inhibit a wide range of IgE-mediated responses, to the topical use of sodium cromoglycate, a compound believed to stabilize the mast cell membrane and hence to prevent histamine release in the conjunctiva. Although the action of this compound has been linked to a reduction in calcium transport across the cell membrane, its precise mode of action is still not fully understood [6]. A logical approach to the treatment of allergic conjunctivitis obviously involves the direct use of antihistamines. However, systemic antihistamines, even those free from sedative action, are capable of achieving only relatively C o m p o u n d 4 8 / 8 0 s h o c k in rats 1 2 3
pyrilamine diphenhydramine cNorpheniramine
4 5 6 7
terfenadine eetirizine ketotifen azatadine
8 9 10
cyproheptadine Ioratadine astemizole
11
levocabastine
100 1 50.0-
20.010.05.00-
2.001.00-
o.~o.
0.20-
o~o 0,05"
I
0.020.01 0.005-
0,002. ~
Time in hours
Fig. 1. Time course of the oral antihistaminic activity of levocabastine and 13 reference compounds, as measured by protection against compound 48/80-induced lethality in rats (Janssen Pharmaceutica, unpublished data).
355 low levels of antihistaminic activity within the conjunctival sac. More logical would be the use of a topical antihistamine designed to inhibit histamine activity directly within the conjunctiva. Even by this route, however, clinical efficacy can only be achieved with a compound of adequate antihistamine potency. Levocabastine is a recently introduced histamine H 1 receptor antagonist. It has a highly specific action, being virtually devoid of antiserotonergic, anticholinergic or antidopaminergic activity [7]. It has a remarkably high antihistaminic potency. Indeed, it is the most potent H 1 receptor antagonist available, being 15 000 times more potent than chlorpheniramine (Fig. 1) in preventing mortality in the rat induced by compound 48/80 [8]. The efficacy of ophthalmic levocabastine has been shown in challenge tests involving histamine, compound 48/80, or allergen [14]. In such provocation tests, the efficacy of levocabastine has been compared to that of sodium cromoglycate. For example, in a study by Abelson and colleagues (unpublished observations) one eye was pre-treated for two weeks with cromoglycate, the other with placebo. Ten minutes before ocular challenge, the cromoglycate treated eye received a final dose of that drug. The placebo treated eye received a single dose of levocabastine. Signs and symptoms of allergic conjunctivitis recorded three, five and 10 minutes after challenge showed that a single application of levocabastine had been more effective than a two week prophylaxis with cromoglycate in reducing the incidence of challenge induced itching, redness, eyelid swelling, chemosis and tearing. Levocabastine has been shown to be safe and well tolerated. Ophthalmological studies have revealed no clinically significant abnormalities when levocabastine eye drops have been used up to four times daily for up to eight weeks (Janssens and Blockhuys, submitted [15]. This current paper briefly describes some data from therapeutic trials including over 1700 patients with allergic conjuntivitis who have received levocabastine for periods of 2-16 weeks.
Clinical trial results
Clinical trial data are available comparing the use of levocabastine eye drops (1 drop given from one to four times daily, or 2 drops twice daily) against placebo, cromoglycate and antazoline/naphazoline eye drops, and also against oral terfenadine. Many of these individual trial results have been tabulated by Dechant & Goa [9] in an authoritative review of the subject.
A. Comparison with placebo Global evaluation, both by the patient and the investigator, show levocabastine to be consistently superior to placebo in alleviating signs and symptoms of allergic conjunctivitis. For example, in one investigation Pipkorn and
356 co-workers [10] found significant differences in the mean ratings of treatments judged to be 'excellent' or 'good' when assessed both by the patients (77% versus 57%) and the investigators (67% versus 50%), both differences being significant ( p < 0 . 0 5 ) . Janssens and co-workers in a review of available data recorded a difference in global symptom evaluation (excellent or good) of 71% with levocabastine compared to 55% with placebo (p < 0.001; Fig. 2) [71. An opportunity was also taken to assess the speed of action of levocabastine eye drops in one such placebo comparison trial (Walker et al., unpublished observations). Within 15 minutes of instillation of levocabastine eye drops, no less than 94% of patients said that they had experienced symptom relief (Fig. 2).
B. Comparison with cromoglycate Janssens & Vanden Bussche [7] list 12 individual studies comparing levocabastine with cromoglycate, involving over 700 patients. Dechant & Goa [9] reviewing a similar database conclude that, for the treatment of allergic conjunctivitis, levocabastine showed a 'superior clinical efficacy' in both prophylaxis and treatment of this disorder, under conditions of both high and low pollen count. Overall, treatments assessed by the patients as
[] complete reliet
I
[] considerable relief partial relief no reliel
!
[ i
J
Fig. 2. Percentage of patients showing complete, considerable or partial relief of symptoms 15 minutes after instillation of levocabastine eye drops (data from Walker J et al., unpublished observations, quoted by Janssens M, Vanden Bussche G, reference 7, Fig. 6).
357 80%
80
76% /t/.,r~
I
//////. //////
60
55%
-////// //////
40 o~ $
I/////. //////
Y////~ "//////
~- 20 I
I Levocabastine (n=201)
Placebo
Levocabastine Crcrnogtycate
(n=149)
(n=221)
(n=213)
Fig. 3. Global evaluation of response rate (percentage of 'good' or 'excellent' results) at the end of treatment in placebo-controlledand cromoglycate-controlledstudies (data from Vanden Bussche G, Heykants J, SchuermansV, quoted by Janssens M, Vanden Bussche G, reference 7, Fig. 7). good or excellent show a response rate of 80% for levocabastine versus 76% for cromoglycate (Fig. 3) [7]. Some studies show a distinct shift in favour of levocabastine (e.g. 89% for levocabastine versus 67% for cromoglycate in one recently published study) [11]. In general, however, the two drugs appear to show similar efficacy, although the twice daily administration of levocabastine compares with a recommended four times daily administration for cromoglycate.
C. Comparison with antazoline/naphazoline Bende & Pipkorn [12] showed a somewhat better control of ocular symptoms with levocabastine than with antazoline/naphazoline in a group of 69 patients. Ocular irritation was reported by 36% of the patients on levocabastine.
D. Comparison with terfenadine Parys & Janssens [13] reported on international trials comparing levocabastine eye drops and nasal spray with oral terfenadine in 351 patients with seasonal allergic rhinoconjunctivitis. Topical levocabastine was at least as effective as oral terfenadine: global evaluation of eye symptoms showed good to excellent results in 80% of levocabastine patients vs. 73% of terfenadine patients (Fig. 4).
E. Long-term studies Studies conducted with levocabastine for up to 16 weeks [7] have shown no tachyphylaxis or reduction in efficacy with increasing time.
358 80
80% 73% 61%
60
I I
40
I 20
I eye symptoms [ ] Levocabastine
nose symptoms [ ] Terfenadine
Fig. 4. Global evaluation by patient of the efficacy of topical levocabastine and oral terfenadin~
for eye (and nose) symptoms of allergic rhinoconjunctivitis (data from Parys W, Janssens M, reference 13).
Safety profile.
Ophthalmological observations made at varying times up to eight weeks of continuous levocabastine treatment have been reviewed by Janssens [14]. No relevant changes were observed in t h e ocular or periocular tissues. A number of studies have shown that levocabastine (0.05% eye drops) was well tolerated and that the incidence of side-effects was similar to that observed with either cromoglycate (20 mg/ml) or placebo (Table 1) [9] and considerably lower than that observed with antazoline/ naphazoline [11]. Eye irritation immediately following instillation is the
Table I. Incidence of adverse effects reported during administration of levocabastine 0.05% (0.5 mg/ml) eye drops (L), placebo (P) and sodium cromoglycate 20 mg/ml eye drops (C)
Adverse reaction
Eye irritation Headache Other eye symptoms" Tiredness Somnolence Dry mouth Coughing Epistaxis
Incidence (% of patients) L (n = 599)
P (n = 215)
C (n
16,4 3.5 2.3 2 2 1 1 1
15.8 4.2 1.9 1.4 5.1 4.2 1.4 0.5
15.6 6.5 1.2 1.9 0 1.9 0.3 0.9
321)
aOther eye symptoms= eye pain, eyelid oedema, conjunctival congestion, photophobia, abnormal lacrimation (from Dechant KL, Goa KL, reference 9, Table 5).
359 c o m m o n e s t a d v e r s e effect. T h e t y p e a n d f r e q u e n c y of a d v e r s e r e a c t i o n s a p p e a r to b e u n r e l a t e d to the n u m b e r o f daily a p p l i c a t i o n s o f the e y e d r o p s . H a e m a t o l o g i c a l a n d b i o c h e m i c a l results r e p o r t e d in o v e r 600 s u b j e c t s t r e a t e d with l e v o c a b a s t i n e show no c o n s i s t e n t c h a n g e s o f clinical significance.
Discussion L e v o c a b a s t i n e has r a p i d o n s e t o f a c t i o n in allergic c o n j u n c t i v i t i s a n d a d u r a t i o n o f a c t i o n t h a t allows for twice daily dosing. It is effective in relieving all c o n j u n c t i v a l s y m p t o m s , e v e n h y p e r a e m i a which was t h o u g h t to be an H 2 - m e d i a t e d effect. It is at least as effective in this r e g a r d as t o p i c a l s o d i u m c r o m o g l y c a t e o r oral a n t i h i s t a m i n e s . It is well t o l e r a t e d with m i n i m a l a d v e r s e effects which a r e no m o r e f r e q u e n t t h a n t h o s e f o u n d w i t h placebo. L e v o c a b a s t i n e is thus an efficacious, fast-acting a n d w e l l - t o l e r a t e d d r u g in t h e m a n a g e m e n t of allergic conjunctivitis.
References 1. Enerbfick L, Pipkorn U, Granerus G. Intraepithelial migration of nasal mucosal mast cells in hayfever, lnt Arch Allergy Appl Immunol 1986; 80: 44-51. 2. Abelson MB, Baird RS, Atlansmith MR. Tear histamine levels in vernal conjunctivitis and other ocular inflammations. Ophthalmology 1980; 87: 812-14. 3. Berdy G J, Levene RB, Bateman ST et al. Identification of histaminase activity in human tears after conjunctival allergen challenge. Invest Ophthalmol Vis Sci 1990; 31 (Suppl): 65. 4. Weston JH, Udell IJ, Abelson MB. Ht receptors in the human ocular surface. Invest Ophthalmol Vis Sci 1981; 20 (Suppl): 32. 5. Abelson MB, Udell IJ. H 2 receptors in the human ocular surface. Arch Ophthalmol 1981; 99: 302-4. 6. Foreman JC, Garland LG. Cromoglycate and anti-allergic drugs: A possible mechanism of action. Br Med J 1976; 1: 820-1. 7. Janssens MML, Vanden Bussche G. Levocabastine: An effective topical treatment for allergic rhinoconjunctivits, Clin Exp Allergy 1991; 21 (Suppl 2): 29-36. 8. Abelson MB, George MA, Smith LM. Evaluation of 0.05% levocabastine versus 4% cromolyn sodium in the allergic challenge model, Ophthalmology (submitted for publication, 1992). 9. Dechant KL, Goa KL. Levocabastine: A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis. Drugs 1991; 4l: 202-24. 10. Pipkorn U, Bende M, Hedner J, Hedner T. A double-blind evaluation of topical levocabastine, a new specific H~ antagonist in patients with allergic conjunctivitis, Allergy 1985; 40: 491-6. l l. Azevedo M, Castel-Branco MG, Ferraz Oliveira J, et al. Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy 1991; 21: 689-694.
360 12. Bende M, Pipkorn U. Topical levocabastine, a selective H1 antagonist, in seasonal allergic rhinoconjunctivitis. Allergy 1987; 42: 512-15. 13. Parys W, Janssens M. The efficacy and tolerability of topical levocabastine and oral terfenadine in seasonal allergic rhinoconjunctivitis: An international study. Presented at the 15th European Congress of Allergology and Clinical Immunology, Paris 1982 (Abstract). 14. Janssens M. Efficacy of levocabastine in conjunctival provocation studies. Doc Ophthalmol 1992; 82: 341-51. 15. Janssens M, Blockhuys S. Tolerability of levocabastine eye drops. Doc Ophthalrnol 1993; submitted.
Address for correspondence: W. Parys, Janssen Research Foundation, Turnhoutseweg 30, 2340 Beerse, Belgium. Phone: 014 60 38 30; Fax: 014 60 28 41.
9
New trends in the treatment of allergic conjunctivitis W. PARYS, S. BLOCKHUYS & M. JANSSENS Janssen Research Foundation, Beerse, Belgium Accepted 22 November 1992
Key words: Allergy, Conjunctivitis, Cromoglycate, Histamine, Levocabastine, Terfenadine Abstract. Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H~ antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistaminic compound available, being 15 000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action, In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.
Introduction The development of new and effective treatments for allergic conjunctivitis must depend on a clear understanding of the underlying causes of the condition. For some time this has been the subject of controversy. Symptoms of allergic conjunctivitis have long been regarded as the result of an IgE-mediated release of histamine from mast cells and basophils [1]. However studies of histamine levels in the tears of conjunctival patients showed no elevation over those in normal subjects [2]. This anomaly was only resolved with the discovery of a histaminase enzyme in tears produced after conjunctival allergen challenge. Inactivation of this enzyme showed that histamine levels were indeed increased and thus re-established the central role of histamine in creating conjunctival symptoms [3]. Some evidence suggests that the itching which is characteristic of conjunctivitis is the result of activation of the histamine H 1 receptor in the eyelid, whilst redness and hyperaemia result from an H2-mediated effect [4, 5].
354
Several different approaches have been taken to the treatment of allergic conjunctivitis. They range from the use of corticosteroids in the extreme case, to inhibit a wide range of IgE-mediated responses, to the topical use of sodium cromoglycate, a compound believed to stabilize the mast cell membrane and hence to prevent histamine release in the conjunctiva. Although the action of this compound has been linked to a reduction in calcium transport across the cell membrane, its precise mode of action is still not fully understood [6]. A logical approach to the treatment of allergic conjunctivitis obviously involves the direct use of antihistamines. However, systemic antihistamines, even those free from sedative action, are capable of achieving only relatively C o m p o u n d 4 8 / 8 0 s h o c k in rats 1 2 3
pyrilamine diphenhydramine cNorpheniramine
4 5 6 7
terfenadine eetirizine ketotifen azatadine
8 9 10
cyproheptadine Ioratadine astemizole
11
levocabastine
100 1 50.0-
20.010.05.00-
2.001.00-
o.~o.
0.20-
o~o 0,05"
I
0.020.01 0.005-
0,002. ~
Time in hours
Fig. 1. Time course of the oral antihistaminic activity of levocabastine and 13 reference compounds, as measured by protection against compound 48/80-induced lethality in rats (Janssen Pharmaceutica, unpublished data).
355 low levels of antihistaminic activity within the conjunctival sac. More logical would be the use of a topical antihistamine designed to inhibit histamine activity directly within the conjunctiva. Even by this route, however, clinical efficacy can only be achieved with a compound of adequate antihistamine potency. Levocabastine is a recently introduced histamine H 1 receptor antagonist. It has a highly specific action, being virtually devoid of antiserotonergic, anticholinergic or antidopaminergic activity [7]. It has a remarkably high antihistaminic potency. Indeed, it is the most potent H 1 receptor antagonist available, being 15 000 times more potent than chlorpheniramine (Fig. 1) in preventing mortality in the rat induced by compound 48/80 [8]. The efficacy of ophthalmic levocabastine has been shown in challenge tests involving histamine, compound 48/80, or allergen [14]. In such provocation tests, the efficacy of levocabastine has been compared to that of sodium cromoglycate. For example, in a study by Abelson and colleagues (unpublished observations) one eye was pre-treated for two weeks with cromoglycate, the other with placebo. Ten minutes before ocular challenge, the cromoglycate treated eye received a final dose of that drug. The placebo treated eye received a single dose of levocabastine. Signs and symptoms of allergic conjunctivitis recorded three, five and 10 minutes after challenge showed that a single application of levocabastine had been more effective than a two week prophylaxis with cromoglycate in reducing the incidence of challenge induced itching, redness, eyelid swelling, chemosis and tearing. Levocabastine has been shown to be safe and well tolerated. Ophthalmological studies have revealed no clinically significant abnormalities when levocabastine eye drops have been used up to four times daily for up to eight weeks (Janssens and Blockhuys, submitted [15]. This current paper briefly describes some data from therapeutic trials including over 1700 patients with allergic conjuntivitis who have received levocabastine for periods of 2-16 weeks.
Clinical trial results
Clinical trial data are available comparing the use of levocabastine eye drops (1 drop given from one to four times daily, or 2 drops twice daily) against placebo, cromoglycate and antazoline/naphazoline eye drops, and also against oral terfenadine. Many of these individual trial results have been tabulated by Dechant & Goa [9] in an authoritative review of the subject.
A. Comparison with placebo Global evaluation, both by the patient and the investigator, show levocabastine to be consistently superior to placebo in alleviating signs and symptoms of allergic conjunctivitis. For example, in one investigation Pipkorn and
356 co-workers [10] found significant differences in the mean ratings of treatments judged to be 'excellent' or 'good' when assessed both by the patients (77% versus 57%) and the investigators (67% versus 50%), both differences being significant ( p < 0 . 0 5 ) . Janssens and co-workers in a review of available data recorded a difference in global symptom evaluation (excellent or good) of 71% with levocabastine compared to 55% with placebo (p < 0.001; Fig. 2) [71. An opportunity was also taken to assess the speed of action of levocabastine eye drops in one such placebo comparison trial (Walker et al., unpublished observations). Within 15 minutes of instillation of levocabastine eye drops, no less than 94% of patients said that they had experienced symptom relief (Fig. 2).
B. Comparison with cromoglycate Janssens & Vanden Bussche [7] list 12 individual studies comparing levocabastine with cromoglycate, involving over 700 patients. Dechant & Goa [9] reviewing a similar database conclude that, for the treatment of allergic conjunctivitis, levocabastine showed a 'superior clinical efficacy' in both prophylaxis and treatment of this disorder, under conditions of both high and low pollen count. Overall, treatments assessed by the patients as
[] complete reliet
I
[] considerable relief partial relief no reliel
!
[ i
J
Fig. 2. Percentage of patients showing complete, considerable or partial relief of symptoms 15 minutes after instillation of levocabastine eye drops (data from Walker J et al., unpublished observations, quoted by Janssens M, Vanden Bussche G, reference 7, Fig. 6).
357 80%
80
76% /t/.,r~
I
//////. //////
60
55%
-////// //////
40 o~ $
I/////. //////
Y////~ "//////
~- 20 I
I Levocabastine (n=201)
Placebo
Levocabastine Crcrnogtycate
(n=149)
(n=221)
(n=213)
Fig. 3. Global evaluation of response rate (percentage of 'good' or 'excellent' results) at the end of treatment in placebo-controlledand cromoglycate-controlledstudies (data from Vanden Bussche G, Heykants J, SchuermansV, quoted by Janssens M, Vanden Bussche G, reference 7, Fig. 7). good or excellent show a response rate of 80% for levocabastine versus 76% for cromoglycate (Fig. 3) [7]. Some studies show a distinct shift in favour of levocabastine (e.g. 89% for levocabastine versus 67% for cromoglycate in one recently published study) [11]. In general, however, the two drugs appear to show similar efficacy, although the twice daily administration of levocabastine compares with a recommended four times daily administration for cromoglycate.
C. Comparison with antazoline/naphazoline Bende & Pipkorn [12] showed a somewhat better control of ocular symptoms with levocabastine than with antazoline/naphazoline in a group of 69 patients. Ocular irritation was reported by 36% of the patients on levocabastine.
D. Comparison with terfenadine Parys & Janssens [13] reported on international trials comparing levocabastine eye drops and nasal spray with oral terfenadine in 351 patients with seasonal allergic rhinoconjunctivitis. Topical levocabastine was at least as effective as oral terfenadine: global evaluation of eye symptoms showed good to excellent results in 80% of levocabastine patients vs. 73% of terfenadine patients (Fig. 4).
E. Long-term studies Studies conducted with levocabastine for up to 16 weeks [7] have shown no tachyphylaxis or reduction in efficacy with increasing time.
358 80
80% 73% 61%
60
I I
40
I 20
I eye symptoms [ ] Levocabastine
nose symptoms [ ] Terfenadine
Fig. 4. Global evaluation by patient of the efficacy of topical levocabastine and oral terfenadin~
for eye (and nose) symptoms of allergic rhinoconjunctivitis (data from Parys W, Janssens M, reference 13).
Safety profile.
Ophthalmological observations made at varying times up to eight weeks of continuous levocabastine treatment have been reviewed by Janssens [14]. No relevant changes were observed in t h e ocular or periocular tissues. A number of studies have shown that levocabastine (0.05% eye drops) was well tolerated and that the incidence of side-effects was similar to that observed with either cromoglycate (20 mg/ml) or placebo (Table 1) [9] and considerably lower than that observed with antazoline/ naphazoline [11]. Eye irritation immediately following instillation is the
Table I. Incidence of adverse effects reported during administration of levocabastine 0.05% (0.5 mg/ml) eye drops (L), placebo (P) and sodium cromoglycate 20 mg/ml eye drops (C)
Adverse reaction
Eye irritation Headache Other eye symptoms" Tiredness Somnolence Dry mouth Coughing Epistaxis
Incidence (% of patients) L (n = 599)
P (n = 215)
C (n
16,4 3.5 2.3 2 2 1 1 1
15.8 4.2 1.9 1.4 5.1 4.2 1.4 0.5
15.6 6.5 1.2 1.9 0 1.9 0.3 0.9
321)
aOther eye symptoms= eye pain, eyelid oedema, conjunctival congestion, photophobia, abnormal lacrimation (from Dechant KL, Goa KL, reference 9, Table 5).
359 c o m m o n e s t a d v e r s e effect. T h e t y p e a n d f r e q u e n c y of a d v e r s e r e a c t i o n s a p p e a r to b e u n r e l a t e d to the n u m b e r o f daily a p p l i c a t i o n s o f the e y e d r o p s . H a e m a t o l o g i c a l a n d b i o c h e m i c a l results r e p o r t e d in o v e r 600 s u b j e c t s t r e a t e d with l e v o c a b a s t i n e show no c o n s i s t e n t c h a n g e s o f clinical significance.
Discussion L e v o c a b a s t i n e has r a p i d o n s e t o f a c t i o n in allergic c o n j u n c t i v i t i s a n d a d u r a t i o n o f a c t i o n t h a t allows for twice daily dosing. It is effective in relieving all c o n j u n c t i v a l s y m p t o m s , e v e n h y p e r a e m i a which was t h o u g h t to be an H 2 - m e d i a t e d effect. It is at least as effective in this r e g a r d as t o p i c a l s o d i u m c r o m o g l y c a t e o r oral a n t i h i s t a m i n e s . It is well t o l e r a t e d with m i n i m a l a d v e r s e effects which a r e no m o r e f r e q u e n t t h a n t h o s e f o u n d w i t h placebo. L e v o c a b a s t i n e is thus an efficacious, fast-acting a n d w e l l - t o l e r a t e d d r u g in t h e m a n a g e m e n t of allergic conjunctivitis.
References 1. Enerbfick L, Pipkorn U, Granerus G. Intraepithelial migration of nasal mucosal mast cells in hayfever, lnt Arch Allergy Appl Immunol 1986; 80: 44-51. 2. Abelson MB, Baird RS, Atlansmith MR. Tear histamine levels in vernal conjunctivitis and other ocular inflammations. Ophthalmology 1980; 87: 812-14. 3. Berdy G J, Levene RB, Bateman ST et al. Identification of histaminase activity in human tears after conjunctival allergen challenge. Invest Ophthalmol Vis Sci 1990; 31 (Suppl): 65. 4. Weston JH, Udell IJ, Abelson MB. Ht receptors in the human ocular surface. Invest Ophthalmol Vis Sci 1981; 20 (Suppl): 32. 5. Abelson MB, Udell IJ. H 2 receptors in the human ocular surface. Arch Ophthalmol 1981; 99: 302-4. 6. Foreman JC, Garland LG. Cromoglycate and anti-allergic drugs: A possible mechanism of action. Br Med J 1976; 1: 820-1. 7. Janssens MML, Vanden Bussche G. Levocabastine: An effective topical treatment for allergic rhinoconjunctivits, Clin Exp Allergy 1991; 21 (Suppl 2): 29-36. 8. Abelson MB, George MA, Smith LM. Evaluation of 0.05% levocabastine versus 4% cromolyn sodium in the allergic challenge model, Ophthalmology (submitted for publication, 1992). 9. Dechant KL, Goa KL. Levocabastine: A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis. Drugs 1991; 4l: 202-24. 10. Pipkorn U, Bende M, Hedner J, Hedner T. A double-blind evaluation of topical levocabastine, a new specific H~ antagonist in patients with allergic conjunctivitis, Allergy 1985; 40: 491-6. l l. Azevedo M, Castel-Branco MG, Ferraz Oliveira J, et al. Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis. Clin Exp Allergy 1991; 21: 689-694.
360 12. Bende M, Pipkorn U. Topical levocabastine, a selective H1 antagonist, in seasonal allergic rhinoconjunctivitis. Allergy 1987; 42: 512-15. 13. Parys W, Janssens M. The efficacy and tolerability of topical levocabastine and oral terfenadine in seasonal allergic rhinoconjunctivitis: An international study. Presented at the 15th European Congress of Allergology and Clinical Immunology, Paris 1982 (Abstract). 14. Janssens M. Efficacy of levocabastine in conjunctival provocation studies. Doc Ophthalmol 1992; 82: 341-51. 15. Janssens M, Blockhuys S. Tolerability of levocabastine eye drops. Doc Ophthalrnol 1993; submitted.
Address for correspondence: W. Parys, Janssen Research Foundation, Turnhoutseweg 30, 2340 Beerse, Belgium. Phone: 014 60 38 30; Fax: 014 60 28 41.
