|
RESULTS
In three groups，drug-applied eyes exhibited lower evans blue extravasation ［（6.50±2.34）μg／ml．g for CKF，（6.76±2.32）μg／ml．g KF and （11.22±3.24）μg／ml．g DM］than those of the relevant vehicle-applied eyes［（14.94±4.49）μg／ml．g，（10.46±5.15）μg／ml．g and （13.74±3．87）μg／ml．g，respectively］．The statistical differences between drug-and vehicle-treated eyes were significant in CKF （P＝0.0007） and KF （P＝0.043） groups．（See Tab．1）
Tab．1 Evans blue（EB）extravasation in ocular tissues
| Drugs |
EB extravasation in eyes （μg／ml．g） |
 ±s |
P value |
| 1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
| CKF |
4.38 |
4.68 |
7.20 |
5.15 |
6.27 |
7.08 |
11.90 |
7.31 |
4.58 |
6.50±2.34 |
|
| Veh |
23.97 |
7.32 |
14.26 |
11.95 |
16.83 |
15.98 |
16.89 |
14.29 |
13.02 |
14.94±4.49 |
0.0007 |
| KF |
4.46 |
4.75 |
4.56 |
4.95 |
10.44 |
7.96 |
6.33 |
7.54 |
9.88 |
6.76±2.32 |
|
| Veh |
5.50 |
3.65 |
9.09 |
19.06 |
15.27 |
6.81 |
7.74 |
12.35 |
14.72 |
10.46±5.15 |
0.043 |
| DM |
8.21 |
6.16 |
13.45 |
9.62 |
12.53 |
10.48 |
17.43 |
12.24 |
10.82 |
11.22±3.24 |
|
| Veh |
6.28 |
17.57 |
15.73 |
11.20 |
19.38 |
14.90 |
11.63 |
14.34 |
12.67 |
13.74±3.87 |
0.16 |
CKF：Compound ketotifen eye drops；KF：0.1％ Ketotifen eye drops；DM：0.0005％ Dexamethasone eye drops；Veh：Vehicle
EB leakage significantly decreased by 53.98％±15.57％ in CKF treated-eyes，when compared with either KF（27.91％±28.36％，P＝0.028）or DM（11.90％±34.16％，P＝0.004） treated eyes．The differences were statistically significant．（See Tab．2）
Tab．2 Inhibition rates of the drugs on evans blue leakage in eyes（％）
| |
Inhibition of EB extravasation in eyes |
±s |
| 1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
| CKF |
81.37 |
36.06 |
49.51 |
56.90 |
62.74 |
55.69 |
29.54 |
48.84 |
64.82 |
53.98±15.57 |
| KF |
18.91 |
－30.14 |
49.83 |
74.03 |
31.63 |
16.89 |
18.22 |
38.95 |
32.88 |
27.91±28.36 |
| DM |
－30.73 |
64.94 |
14.49 |
14.15 |
35.34 |
29.62 |
－49.87 |
14.64 |
14.52 |
11.90±34.16 |
CKF had a significantly high inhibition rate，when compared with either KF （P＝0.028）or DM（P＝0.004）．
DISCUSSION
Allergic conjunctivitis is a response resulting from a reaction of allergen with IgE antibodies on mast cells in the conjunctival stroma．This reaction triggers a cascade of events resulting in the degranulation of mast cells，and releasing chemical mediators（e．g．，histamine，prostaglandins and leukotrienes） into the conjunctival stroma and tears．These mediators cause vasodilation and increasing in vascular permeability，which induce ocular itching，burning，conjunctival injection，chemosis and limbal hyperemia．［4，5］
Corticosteroids，histamine H1-receptor antagonists，mast cell stabilizers and non-steroidal anti-inflammatory drugs，which exert antiallergenic effects by different pharmacological mechanism，have been used to treat anaphylactic ocular disorders［4，5］．
Ketotifen is the second generation histamine H1-receptor antagonist and also possesses stabilizing mast cell activity，which prevents the mast cell degranulation and chemical mediators release in the conjunctiva，and reduces the ocular symptoms and signs［1，6］．Hagihara［7］ has clinically evaluated oral ketotifen for the treatment of 22 cases with efficacy rate of 80％．No serious drug side effect was found in his study．Mikuni［8］ determined quantitatively the therapeutic effect of 0.08％ ketotifen eye drops in 10 volunteers suffering from seasonal cedar pollinosis provocated during a quiescent stage．The efficacy rate of the preparation was found to be 80％．
It is well-known that corticosteroids have a pronounced antianaphylactic action．The application of topical corticosteroids is now an indispensable modality in the treatment of severe ocular allergic conditions．Unfortunately，topical ocular corticosteroids may cause serious adverse effects，such as glaucoma，cataract formation，diminished epithelial wound healing，and the risk of ocular infection，which make long-term corticosteroid use invadisable．However，there was evidence that an administration of micro-dexamethasone could not only offer its desired pharmacological activity，but also minimize the adverse effects［9］．
In order to avoid the corticosteroid side effects and retain the antiallergenic effect，we conducted micro-dexamethasone and prepared topical ophthalmic formulation with 0.1％ ketotifen and 0.0005％ dexamethasone in this study．The micro-dexamethasone-applied eyes revealed lower EB extravasation than that of the control eyes，although no statistically significant difference was revealed between the two treated groups．The combination of 0.1％ ketotifen and 0.0005％ dexamethasone were a synergic effect on ocular anaphylaxis，inhibiting remarkably ocular evans blue extravasation in the model of acute allergic conjunctivitis with an inhibitory ratio of 53.98％，which was considerably higher than that of each drug used alone（27.91％ and 11.90％ for 0.1％ ketotifen and 0.0005％ dexamethasone，respectively）．The differences were statistically significant．The results of this study suggested the potential of compound ketotifen eye drops in the treatment of allergic conjunctivitis．
REFERENCES
1，Grant SM，Goa KL，Fitton A，et al．Ketotifen．A review of its pharmacodynamic and pharmacokinetic properties，and therapeutic use in asthma and allergic disorders．Drugs，1990，40（3）∶412
2，Calonge MC，Pastor JC，Herreras JM，et al．Pharmacologic modulation of vascular permeability in ocular allergy in the rat．Invest Ophthalmol Vis Sci，1990，31（1）∶176
3，Trocme SD，Trocme MC，Bloch KJ，et al．Topically induced ocular anaphylaxis in rats immunized with egg albumin．Ophthalmic Res，1986，18（1）∶68
4，Jaanus SD，Hegeman SL，Swanson MW．Antiallergy drugs and decongestants．In：Bartlett JD，Jaanus SD，eds．Clinical Ocular Pharmacology．3rd ed．Boston：Butterworth-Heinemann，1995．337-53
5，Abelson MB，Sloan JE，Mooshian M．Basis of ocular allergy and mechanisms for successful management．Ophthalmoic Practice，1993，11（6）∶278
6，Heyman SN，Karmeli F，Brezis M，et al．The effect of ketotifen on nitric oxide synthase activity．Br J Pharmacol，1997，120（8）∶1545
7，Hagihara M，Sakashita M，Inoue A．Clinical evaluation of ketotifen （zaditen） of the treatment of allergic conjunctival disorders．Folia Ophthalmol Jpn，1988，39∶392
8，Mikuni L，Sato K，Togawa K，et al．A quantitative tear fluids determination of therapeutic efficacy for allergic conjunctivitis．Tokai J Exp Clin Med，1984，9（1）∶35
9，Chen ZJ．Practical Ocular Pharmacology．Beijing：Scientific %26 Technological Press of China，1993．212-34
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