Efficacy and Safety of Nedocromil Sodium Ophthalmic Solution in the Treatment of Seasonal Allergic Conjunctivitis Malcolm Blumenthal, M.D., Thomas Casale, M.D., Robert Dockhorn, M.D., Irene Jarmoszuk, M.D., Harold Kaiser, M.D., Robert Smith, M.D., and Howard J. Zeitz, M.D. To assess the efficacy and safety of twicedaily administration of nedocromil sodium 2% ophthalmic solution, we performed a multicenter study involving 140 patients with seasonal allergic conjunctivitis. Subjects had a history of seasonal allergic conjunctivitis and positive results of a skin test to ragweed. The trial coincided with the peak ragweed pollen season at five treatment centers. Pa tients treated with nedocromil sodium had improvements in symptoms with statistically significant reductions recorded for eye itching (P < .04), conjunctival injection (P :£ .001), and overall disease severity (P < .001) as compared to the placebo-treated group. Adverse events were minor and transient. We concluded that nedocromil sodium 2% ophthalmic solution administered twice daily is effective in reliev ing major symptoms associated with seasonal allergic conjunctivitis. SEASONAL ALLERGIC conjunctivitis is usually a conjunctival IgE-mediated hypersensitivity re action to the following airborne allergens: mold spores and pollens of trees, grasses, and weeds. 1 Although the pathophysiologic condi tions associated with seasonal allergic conjunc-
Accepted for publication Nov. 11, 1991. From the Department of Medicine, University of Min nesota, Minneapolis, Minnesota (Drs. Blumenthal and Kaiser); Department of Internal Medicine, University of Iowa Hospitals, Iowa City, Iowa (Drs. Casale and Smith); Department of Medicine, University of Kansas School of Medicine, Prairie Village, Kansas (Dr. Dockhorn); and Clinical Research Unit (Dr. Jarmoszuk) and Max Samter Institute of Allergy and Clinical Immunology (Dr. Zeitz), Grant Hospital of Chicago, Chicago, Illinois. This study was supported by a grant from Fisons Pharmaceuticals. Reprint requests to Malcolm Blumenthal, M.D., U . M . H . C , Box 434, 420 Delaware St. S.E., Minneapolis, MN 55455.
56
tivitis are not completely understood, evidence strongly suggests that it is a type I hypersensi tivity response mediated by IgE antibodies bound to the membrane of mast cells in the conjunctival substantia propria. 23 The binding of antigen to IgE antibodies causes the release of proinflammatory mediators (for example, histamine, leukotrienes, and others). These me diators cause itching, glandular secretion, local conjunctival vasodilation, and increased vascu lar permeability, which in turn, cause the tear ing and eyelid edema characteristic of ocular allergy. Definitive treatment options have been scarce. Although avoidance of known allergens remains an essential approach to minimizing the discomforts of ocular allergic disease, it is difficult for patients to avoid exposure to sea sonal pollens and spores without a marked impairment of the quality of life. The ability of immunotherapy to ameliorate the ocular signs and symptoms of seasonal allergy is not clearly established. Saline, vasoconstrictor, and antihistamine eyedrops are commonly prescribed for the treatment of patients with seasonal allergic conjunctivitis. Vasoconstrictors are not recommended for extended use. The use of topical corticosteroids, although clinically effi cacious, is not usually appropriate in the treat ment of seasonal allergic conjunctivitis because of the associated risk of cataract, glaucoma, and other unwanted side effects. Cromolyn sodium, a carboxychromone deriv ative with mast-cell membrane-stabilizing properties, has been effective in the treatment of several diseases with immunologic compo nents, including seasonal allergic conjunctivi tis. 45 However, the dosage frequency has usual ly been four to six times daily. This clinical observation suggests that addressing the mast cell directly, for both prophylaxis and treat ment, might have a marked therapeutic effect."a
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Nedocromil Sodium and Allergic Conjunctivitis
Nedocromil sodium is the first topically ap plied agent of a new class of drugs, the pyranoquinolines. It is chemically distinct from other agents currently used to treat seasonal allergic conjunctivitis including antihistamines, decongestants, anticholinergics, and cromolyn sodi um. In vitro 68 and animal 9 1 0 studies have shown that nedocromil sodium inhibits several of the processes that are likely to be important in the pathogenesis of seasonal allergic conjunctivi tis. 9 Specifically, nedocromil sodium inhibits human eosinophil activation," mast-cell medi ator release, 712 and antigen-induced inflamma tion. 13 Nedocromil sodium's inhibitory effects on these biologic processes are likely to con tribute to the efficacy of this drug in the treat ment of seasonal allergic conjunctivitis. Clini cal studies have demonstrated the clinical efficacy and safety of nedocromil sodium espe cially in the treatment of patients with asth ma.1417 The goal of our study was to evaluate the safety and efficacy of nedocromil sodium 2% ophthalmic solution administered twice daily in the treatment of seasonal allergic conjuncti vitis.
Methods Study population—One hundred fifty-five pa tients between the ages of 12 and 62 years were screened at five centers, and 140 were entered into the study (Table 1). Sixty-nine patients were assigned to the nedocromil sodium treat ment group and 71 patients were assigned to the placebo treatment group. Of the 140 pa tients who entered the study, 132 completed the study (63 in the nedocromil sodium treat ment group and 69 in the placebo treatment group). All subjects had a history of seasonal allergic conjunctivitis requiring continuous treatment during the two previous pollen seasons and had a skin-test reaction of at least 2+ to ragweed. Patients with documented seasonal sensitivity to ragweed pollen were treated with a stable regimen of immunotherapy for at least three months before and during the study. Patients were excluded from the study if they met any of the following criteria: childbearing age and not using contraception, absent or minimal symp toms during the previous ragweed pollen sea son, no requirement for medication to control seasonal allergic conjunctivitis, evidence of pe rennial allergic conjunctivitis rather than sea
57
sonal allergic conjunctivitis, and clinical signs and symptoms suggesting ocular disease other than seasonal allergic conjunctivitis. The protocol and informed-consent forms were approved by the institutional review boards in each participating medical center. Written consent was obtained from all partici pants. Study sites—The study was conducted for eight weeks. The start of the double-masked portion was timed to coincide with the predict ed peak of the ragweed pollen season in each of the regions where the study centers were locat ed (approximately middle August). Two of the five sites participating in this multicenter study were located in Minneapolis, Minnesota. The other three were located in Prairie Village, Kansas; Iowa City, Iowa; and Chicago, Illinois. Study design—The study was designed as a multicenter, double-masked, group-compara tive, placebo-controlled trial of eight weeks' duration in which patients were randomly as signed to treatment. Patients were screened for entry into the program before the baseline period. At the screening visit, a complete medi cal history was obtained, and blood and urine samples were taken for urinalysis and routine hematologic and biochemical tests. The base line period was initiated with the first clinic visit, during which the status of the patient's conjunctivitis was assessed and a slit-lamp ex amination was performed. Patients also were given daily-symptom diary cards and instruc tions on how to record their symptoms. After a one-week baseline period, patients were ran domly assigned to either the nedocromil sodi um treatment group or to the placebo treatment group. In both groups, the treatment dose was one drop (0.04 ml) of solution per eye twice daily (8:00 A.M. and 6:00 P.M.). The composition of the active drug was as follows: nedocromil sodium 2%, benzalkonium chloride 0.01%, edetate disodium 0.05%, sodium chloride 0.55%, and sufficient purified water to consti tute 100%. The composition of the placebo was the same as that of the active drug, excluding the nedocromil sodium and including a nonirritating yellow coloring agent (riboflavin 0.0005%) to make the placebo visually indistin guishable from the active drug. The clinical status of the patients and the diary cards were reviewed at the end of the baseline period and at clinic visits after one, three, five, and eight weeks.
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TABLE 1 DEMOGRAPHIC CHARACTERISTICS OF PATIENTS WITH SEASONAL ALLERGIC CONJUNCTIVITIS NEDOCROMIL SODIUM-TREATED
PLACEBO-TREATED
PATIENTS
PATIENTS
(N = 69)
(N = 71)
NO. (%)
NO. (%)
35 (51) 34 (49)
41 (58) 30 (42)
32.4 years (12-62 years)
32.2 years (14-58 years)
17.7 (3-56)
19.3 (3-45)
5(7)
2(3)
Males Females Mean age (range) Mean No. of years of conjunctivitis history (range) Immunotherapy-treated patients
Concomitant treatment—Other than the nedocromil sodium, no medications were per mitted for treatment of ocular allergy. Orally and topically administered ocular corticosteroid preparations were not permitted for two weeks before the start of the study. Any treat ment that required the use of corticosteroids during the trial was considered a failure. Rhini tis medications (nasally administered cromolyn sodium, orally administered antihistamines, orally administered decongestants, a combina tion of these products, and topically applied vasoconstrictors) were not permitted during the study. Orally administered theophylline and inhalation of cromolyn sodium for the treat ment of asthma were not permitted during the study period. Inhaled and orally administered B-adrenergic agents and inhaled corticoste roids were permitted for asthma management as necessary, and the dosage of these drugs was recorded on a daily basis. Artificial tears (Lyteers, Sola/Barns-Hind, Sunnyvale, California) and nasally adminis tered corticosteroid medication (Nasalide, Syntex Laboratories, Palo Alto, California) were permitted during the study. Measured amounts of each were provided, and consumption was monitored by weighing the medicine container at each patient visit. Symptom diary cards and clinical evaluation— The primary outcome measure was the symp tom summary score, defined as the sum of scores for itchy eyes and overall eye condition. Overall eye condition included patient evalua tions of burning, tearing, redness, swelling, as
well as grittiness and photophobia. Patients rated eye itching, and overall eye condition on the basis of the following scale: 0 = none, symptoms absent; 1 = mild, symptoms barely noticeable; 2 = moderate, symptoms caused some discomfort; 3 = moderately severe, symp toms caused much discomfort without interfer ing with daily routine; and 4 = severe, symp toms present for most of the day and caused enough discomfort to interfere with daily rou tine. Patients also recorded the use of the study drug, use of concomitant medications, and the number of hours spent in air-conditioned rooms. At each study visit, the examining physician evaluated the clinical status of each patient on a five-point scale (0 = none to 4 = severe) for conjunctival edema, conjunctival injection, tearing, and overall severity of conjunctivitis. Additionally, at the first and last visit, each patient underwent a thorough ophthalmic ex amination that was performed by an ophthal mologist and included obtainment of an ocular history, a visual acuity test, determination of intraocular pressure, physical examination of the eye and the ocular adnexa, and slit-lamp examination. Pollen counts—Daily ragweed pollen counts were recorded at each study site using a Rotorod sampler set (Tad Brown Associates, Los Altos Hills, California) to sample one minute every ten minutes. Rods were changed every 24 hours to obtain daily counts. To ensure uniform reporting from all sites, the exposed rods were mailed to a central laboratory where the pollen counts were performed.
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Data analysis—Because the study was con ducted at several sites that were separated geo graphically and had variations in weed blooms and pollen production, it was necessary to account for regional differences in ragweed pollen counts in the data collection and analy sis. Daily ragweed pollen counts were used only as an indicator of the three-week period of maximal possible ragweed pollen challenge. To permit accurate pooling of data across the five medical centers participating in this study, a difference score was computed for each pa tient. The difference score was defined as the difference in diary card scores and clinical eval uation scores between the peak pollen season and the baseline period. Data for different visits thus could be pooled for different clinics, de pending on the time of the peak pollen season in each region. The composition of the two treatment groups was assessed for comparability before the trial, and the responses were evaluated during the trial both within and across clinics. The statisti cal significance of dichotomous variables was measured by Fisher's exact test and the MantelHaenszel test.18 Quantitative or semiquantitative data were evaluated by two-sample (-tests and two-way analysis of variance. A P value of .05 (two-tailed test) was considered the upper limit of statistical significance. The justification for pooling data from five centers was analyzed by testing for significant clinic by treatment interactions by means of a two-way analysis of covariance. None of the tests for clinic by treatment interactions ap proached statistical significance; thus, pooling data across the five clinics was statistically justi fied. Adverse experiences—All adverse experienc es, whether or not ascribed to the drug, were documented.
Results Patients—The demographic characteristics of the 140 patients were analyzed (Table 1). No statistically significant differences were ob served between the treatment groups with re gard to age, gender, conjunctivitis history, or history of immunotherapy. Compliance with the study treatment was good. Of the 140 patients who entered the study, eight patients withdrew from the study
59
after starting test medication. Reasons for with drawal included the following: protocol viola tion (one placebo-treated patient), other illness (four nedocromil sodium-treated patients), noncompliance (one nedocromil sodiumtreated patient), treatment failure (one place bo-treated patient), and loss to follow-up (one nedocromil sodium-treated patient). Local pollen counts at participating study sites—The ragweed pollen season began before or during the baseline period at each study site. The peak pollen season coincided with the first three weeks of the double-masked treatment segment of the study for all participating medi cal centers (Fig. 1). The pollen count was high est in Prairie Village, Kansas; and was decreasingly lower in Iowa City, Iowa; Minneapolis, Minnesota; and Chicago, Illinois, respectively. Daily diary card scores—During the baseline period, all patients experienced symptoms of ocular allergy that coincided with increasing pollen counts. As compared to the symptom status of placebo-treated control patients, pa tients treated with nedocromil sodium during the peak pollen period had improvements in ocular symptoms usually associated with sea sonal allergic conjunctivitis. This was evi denced by lower symptom scores after the initi ation of treatment despite increasing pollen counts. During the three-week peak pollen pe riod, patients treated with nedocromil sodium had lower symptom scores for itchy eyes, over all eye condition, and hence, the symptom summary score (Fig. 2). Mean individual symp tom score during the peak pollen period had a statistically significant difference for eye itching ( P ^ . 0 4 ) between the placebo- and nedocromil-treated groups. Clinical assessments—As determined by phy sicians, no statistically significant differences in tearing, conjunctival injection, edema, and overall severity of conjunctivitis at the end of the baseline period were found between pa tients subsequently assigned to either the nedocromil or placebo treatments. During the peak pollen season, patients using nedocromil sodium had statistically significant reductions in conjunctival injection (P s .001) and overall disease severity (P < .001) when compared with those of the placebo-treated group (Fig. 3). Clinical assessment of symptom scores for tear ing and conjunctival edema was lower in nedocromil-treated patients, although these
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Iowa City
Chicago
Run In
Bate line
1
Run in
Minneapolis
Base 1 line
Prairie Village
Fig. 1 (Blumenthal and associates). Ragweed pollen counts. Pollen concentration was measured at each of the four cities where the treatment centers were located. In all four cities, the ragweed pollen season began before or during the baseline period, and peak pollen season coincided with the first three weeks of the trial. Pollen count was highest in Prairie Village, Kansas.
differences failed to reach statistical signifi cance. Clinician and patient opinions—In evaluating the effectiveness of nedocromil sodium for al lergic conjunctivitis control, clinicians rated the severity of conjunctivitis as one of the following: (1) fully controlled, (2) mostly con trolled, (3) fairly controlled, (4) poorly con trolled, or (5) not controlled. Of the 69 patients treated with nedocromil sodium, 38 (55%) had conjunctivitis symptoms that were at least mostly controlled. In contrast, only 23 of the 71 placebo-treated patients (32%) had similar symptom control, a difference that was statisti cally significant (P ^ .004). Likewise, 36 of the 69 patients (52%) reported that the nedocromil
sodium treatment mostly controlled conjuncti vitis symptoms as opposed to only 26 of the 71 (37%) placebo-treated patients (P < .03) re porting mostly controlled symptoms. Concomitant medications—In all clinics, artifi cial tear use was low at baseline and during the peak pollen period. No statistically significant differences were found between treatment groups across clinics. Use of artificial tears was comparable at baseline between treatment groups (nedocromil sodium mean, 1.31 drops per day; placebo mean, 1.27 drops per day; P £ .78). During the peak pollen period, the use of artificial tears was lower in the nedocromil sodium-treated group than it was in the place bo-treated group; but the difference failed to
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I Nedocromil Sodium
C h a n g e
Placebo
0.4 -i
0.2
f
r o m B a -0.2s e I i -0.4 n e
Symptoms
Itchy Eyes
Overall Eye Condition
Symptom Summary Score
r e a c h statistical significance ( n e d o c r o m i l s o d i u m m e a n , 0.45; p l a c e b o m e a n , 0.65; P < .52). No statistically significant g r o u p differences w e r e r e p o r t e d in the u s e of topically a d m i n i s tered N a s a l i d e for r h i n i t i s d u r i n g the p e a k pollen period. Adverse experiences—Fifty-eight of the 71 p a t i e n t s in the p l a c e b o - t r e a t e d g r o u p (82%) a n d 59 of the 69 p a t i e n t s in t h e n e d o c r o m i l s o d i u m t r e a t e d g r o u p (86%) r e p o r t e d at least o n e a d verse e x p e r i e n c e d u r i n g t h e trial. T r a n s i e n t b u r n i n g eyes ( e x p e r i e n c e d b y eight [12%] of the nedocromil sodium-treated patients and by five [7%] of the p l a c e b o - t r e a t e d p a t i e n t s ) , s t i n g ing eyes ( e x p e r i e n c e d by seven [10%] of the n e d o c r o m i l s o d i u m - t r e a t e d p a t i e n t s a n d by
I Nedocromil
Discussion The clinical trial was c o n d u c t e d d u r i n g a p e r i o d of m a x i m a l r a g w e e d p o l l e n c o u n t s . The r e s u l t s d e m o n s t r a t e d the efficacy of the twicedaily a d m i n i s t r a t i o n of n e d o c r o m i l s o d i u m 2 % o p h t h a l m i c s o l u t i o n in the t r e a t m e n t of s e a s o n -
Placebo
I m P r o v e m e n t
f r o m
Tearing
Conjunctival Injection
Fig. 2 (Blumenthal and associates). Daily diary score changes. During the peak pollen period, patients treated with nedocromil sodium demonstrat ed a statistically significant difference in eye itching (compared to the place bo-treated group, P < .04,) with im provements in overall eye condition and summary score. Values are ex pressed as the difference in symptom scores between the peak pollen period and baseline testing. Negative num bers, therefore, indicate an improve ment in seasonal allergic conjunc tivitis symptom score. In contrast, during the peak pollen season, patients treated with placebo had increases in seasonal allergic conjunctivitis symptoms.
t w o [3%] of the p l a c e b o - t r e a t e d p a t i e n t s ) , a n d u n p l e a s a n t taste ( e x p e r i e n c e d b y n i n e [13%] of the n e d o c r o m i l s o d i u m - t r e a t e d p a t i e n t s a n d by n o n e [0%] of the p l a c e b o - t r e a t e d p a t i e n t s ) w e r e the most c o m m o n a d v e r s e effects associated w i t h t r e a t m e n t (Table 2).
C h a n 9 e
B a s e I i n e
61
Conjunctival Edema
Overall Severity
Fig. 3 (Blumenthal and associates). Clinicians' assessments of conjuncti vitis. Physicians rated seasonal aller gic conjunctivitis on a five-point scale (0 = absent, and 4 = severe). Numbers represent changes from baseline mea sures. Patients treated with nedo cromil sodium had significant im provements in both conjunctival injection (P < .001) and overall severi ty (P < .001) when compared to pa tients treated with placebo.
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TABLE 2 FREQUENCY OF ADVERSE CONDITIONS CONSIDERED RELATED TO NEDOCROMIL SODIUM COMPARED WITH THE FREQUENCY OF THE SAME CONDITIONS IN PLACEBO-TREATED PATIENTS NEDOCROMIL SODIUM-TREATED
PLACEBO-TREATED
PATIENTS (N = 69)
PATIENTS (N = 71)
ADVERSE CONDITION
NO. (%)
NO. (%)
Eye burning Eye stinging Taste perversion Abnormal vision Eye itching Conjunctivitis Eye redness Eye irritation Photophobia
8(12) 7(10) 9(13) 1(1) 0(0)
5(7) 2(3) 0(0) 2(3) 2(3) 0(0) 0(0)
al allergic conjunctivitis. The data supported previous studies of the efficacy of nedocromil sodium for the treatment of allergic conjuncti vitis.19,20 All treatment differences favored nedocromil sodium, with statistically signifi cant differences noted for ocular pruritus and for the clinicians' assessments of conjunctival injection and overall severity of conjunctivitis. Opinions of treatment effectiveness expressed by both the clinician and the patient were strongly in favor of nedocromil sodium. Al though the mean diary symptom summary score and overall eye condition did not reach statistical significance, trends for these symp toms also indicated a favorable response to nedocromil sodium. The lack of statistical significance observed in several of the variables may have been caused by the treatment's initiation after the start of the pollen season when the patients were al ready experiencing symptoms. Optimal control of seasonal allergic conjunctivitis may be af forded by initiating treatment before the pollen season. Concomitant use of Lyteers also was lower in the placebo-treated group during the peak pollen period than during the baseline period, implying a marked placebo effect per haps caused by the regular flushing of the eye with the eyedrop solution. This was further confirmed by the mean symptom scores that were between 1 and 2 (on the basis of a fivepoint scale, 0 through 4) even during peak pollen exposure. Another factor that might have accounted for the lack of statistical significance was the fixed dosing regimen. Initial dosing four times daily
1(1) 1(1) 0(0) 0(0)
1(1) 1(1)
may further improve the symptom control 21 in these patients. After symptoms improve, treat ment may be reduced to a twice-daily regi men.17 Nedocromil sodium has a potentially impor tant role in the treatment of seasonal allergic conjunctivitis. Although alternative methods are available for treatment, including saline irrigation, topically administered vasoconstric tors, topically administered antihistamines, and topically administered corticosteroids, these agents have either limited clinical efficacy or have caused unwanted side effects. The use of the mast-cell stabilizer, cromolyn sodium (4% aqueous solution) has been an effective treatment for seasonal allergic conjunctivitis when administered four times daily. Nedo cromil sodium, with its broad range of antiinflammatory activity, has been shown in vitro to be more potent than cromolyn sodium in inhibiting eosinophil activation and mast-cell mediator release, both of which are considered important in the pathogenesis of seasonal aller gic conjunctivitis. 81112 The results of this study showed that nedocromil is clinically effective in relieving the major symptoms of seasonal aller gic conjunctivitis when administered four times daily. When prompted, many patients in both the nedocromil sodium-treated and placebotreated groups reported adverse experiences, but the specific complaints were usually minor. The high degree of satisfaction with the nedocromil sodium treatment and the high de gree of adherence to the trial protocol demon strated that the rate of unusual adverse experi-
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ences with the test medication did not have great clinical significance. The potential use of a drug such as nedocromil sodium, with mini mal side effects and good therapeutic efficacy at twice-daily dosing, should be a beneficial addi tion to the clinician's armamentarium in treat ing patients with seasonal allergic conjunctivi tis.
References 1. Allansmith, M. R., Greiner, J. V., and Ross, R. N.: Ocular allergy. In Samter, M. (ed.): Immunological Disease, ed. 4. Boston, Little, Brown, and Company, 1987, pp. 1917-1943. 2. Irani, A. M., Butrus, S. I., Tabbara, K. F., and Schwartz, L. B.: Human conjunctival mast cell. Dis tribution of MCT and MVTC in vernal conjunctivitis and giant papillary conjunctivitis. J. Allergy Clin. Immunol. 86:34, 1990. 3. Allansmith, M. R., and Ross, R. N.: Ocular aller gy and mast cell stabilizers. Surv. Ophthalmol. 30:229, 1986. 4. Friday, G. A., Biglan, A. W., Hiles, D. A., Murphey, S. M., Miller, D. L., Rothbach, C , and Rand, S.: Treatment of ragweed allergic conjunctivitis with cromolyn sodium 4% ophthalmic solution. Am. J. Ophthalmol. 95:169, 1983. 5. Greenbaum, J., Cockcroft, D., Hargreave, F. E., and Dolovich, J.: Sodium cromoglycate in ragweedallergic conjunctivitis. ]. Allergy Clin. Immunol. 59:437, 1977. 6. Bruijnzeel, P. L. B., Warringa, R. A. J., Kok, M. L., Hamelink, M. L., and Kruekniet, J.: Inhibitory effects of nedocromil sodium on the in vitro induced migration and leukotriene formation of human granulocytes. Drugs 37(suppl. 1):9, 1989. 7. Busse, W. W., Randlev, B., Arbabian, M., and Ruoho, A.: Effect of nedocromil sodium on the Badrenergic response of human polymorphonuclear leukocytes. Drugs 37(suppl. 1):26, 1989. 8. Enerback, L., and Bergstrom, S.: Effect of nedocromil sodium on the compound exocytosis of mast cells. Drugs 37(suppl. 1):44, 1989. 9. Abraham, W. M.: In vitro effects of nedocromil sodium in human and animal models. Drugs 37(suppl. 1):78, 1989. 10. Church, M. K., Hutson, P. A., and Holgate, S. T.: Effects of nedocromil sodium on early and late
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phase responses to allergen challenge in the guineapig. Drugs 37(suppl. 1):101, 1989. 11. Moqbel, R., Cromwell, O., and Kay, A. B.: The effect of nedocromil sodium on human eosinophil activation. Drugs 37(suppl. 1):19, 1989. 12. Pearce, F. L., Al-Laith, L., Bosman, J., Brostoff, J., Cunniffe, T. M., Flint, K. C , Hudspith, B. N., Jaffar, Z. H., Johnson, N. M., Kassessinoff, T. A., Lau, H. Y. A., Lee, P. Y., Leung, K. B. P., Liu, W. L., and Tainsh, K. R.: Effects of sodium cromoglycate and nedocromil sodium on histamine secretion from mast cells from various locations. Drugs 37(suppl. 1):37, 1989. 13. Dahlen, S. E., Bjorck, T., Kumlin, M., Suabom, A., Raud, J., Palmertz, U., Franzen, L., Gonneberg, R., and Hedquist, P.: Dual inhibitory action of nedocromil sodium on antigen-induced inflamma tion. Drugs 37(suppl. 1):63, 1989. 14. Lai, S., Malhotra, S., Gribben, D., and Hodder, D.: Nedocromil sodium. A new drug for the manage ment of bronchial asthma. Thorax 39:809, 1984. 15. Eady, R. P.: The pharmacology of nedocromil sodium. Eur. J. Respir. Dis. 69(suppl. 44):112, 1986. 16. Neale, M. G., Brown, K„ Foulds, R. A., Lai, S., Morris, D. A., and Thomas, D.: The pharmacokinetics of nedocromil sodium, a new drug for the treat ment of reversible obstructive airways disease, in human volunteers and patients with reversible ob structive airways disease. Br. ]. Clin. Pharmacol. 24:493, 1987. 17. Fairfax, A. J., and Albeson, M.: A double-blind group comparative trial of nedocromil sodium and placebo in the management of bronchial asthma. J. Int. Med. Res. 16:216, 1988. 18. Mantel, N.: Chi-square tests with one degree of freedom. Extensions of the Mantel-Haenszel pro cedure. J. Am. Stat. Assoc. 58:690, 1963. 19. Stockwell, A., and Easty, D.: Double-blind group comparative trial of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis. Invest. Ophthalmol. Vis. Sci. 29:229, 1988. 20. Leino, M., Carlson, D., Jaanio, E., Koivunen, T., Lavikkala, H., Riihela, A., and Takalo, E.: Doubleblind group comparative study of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis. Ann. Allergy 64:398, 1990. 21. Bianco, S., DelBono, N., Grassi, V., and Orefice, U.: Effectiveness of nedocromil sodium versus placebo as additions to routine asthma maintenance therapy. A multicenter, double blind, group compar ative trial. Respiration 56:204, 1989.
Accepted for publication Nov. 11, 1991. From the Department of Medicine, University of Min nesota, Minneapolis, Minnesota (Drs. Blumenthal and Kaiser); Department of Internal Medicine, University of Iowa Hospitals, Iowa City, Iowa (Drs. Casale and Smith); Department of Medicine, University of Kansas School of Medicine, Prairie Village, Kansas (Dr. Dockhorn); and Clinical Research Unit (Dr. Jarmoszuk) and Max Samter Institute of Allergy and Clinical Immunology (Dr. Zeitz), Grant Hospital of Chicago, Chicago, Illinois. This study was supported by a grant from Fisons Pharmaceuticals. Reprint requests to Malcolm Blumenthal, M.D., U . M . H . C , Box 434, 420 Delaware St. S.E., Minneapolis, MN 55455.
56
tivitis are not completely understood, evidence strongly suggests that it is a type I hypersensi tivity response mediated by IgE antibodies bound to the membrane of mast cells in the conjunctival substantia propria. 23 The binding of antigen to IgE antibodies causes the release of proinflammatory mediators (for example, histamine, leukotrienes, and others). These me diators cause itching, glandular secretion, local conjunctival vasodilation, and increased vascu lar permeability, which in turn, cause the tear ing and eyelid edema characteristic of ocular allergy. Definitive treatment options have been scarce. Although avoidance of known allergens remains an essential approach to minimizing the discomforts of ocular allergic disease, it is difficult for patients to avoid exposure to sea sonal pollens and spores without a marked impairment of the quality of life. The ability of immunotherapy to ameliorate the ocular signs and symptoms of seasonal allergy is not clearly established. Saline, vasoconstrictor, and antihistamine eyedrops are commonly prescribed for the treatment of patients with seasonal allergic conjunctivitis. Vasoconstrictors are not recommended for extended use. The use of topical corticosteroids, although clinically effi cacious, is not usually appropriate in the treat ment of seasonal allergic conjunctivitis because of the associated risk of cataract, glaucoma, and other unwanted side effects. Cromolyn sodium, a carboxychromone deriv ative with mast-cell membrane-stabilizing properties, has been effective in the treatment of several diseases with immunologic compo nents, including seasonal allergic conjunctivi tis. 45 However, the dosage frequency has usual ly been four to six times daily. This clinical observation suggests that addressing the mast cell directly, for both prophylaxis and treat ment, might have a marked therapeutic effect."a
© A M E R I C A N JOURNAL OF OPHTHALMOLOGY 113:56-63, JANUARY,
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Nedocromil Sodium and Allergic Conjunctivitis
Nedocromil sodium is the first topically ap plied agent of a new class of drugs, the pyranoquinolines. It is chemically distinct from other agents currently used to treat seasonal allergic conjunctivitis including antihistamines, decongestants, anticholinergics, and cromolyn sodi um. In vitro 68 and animal 9 1 0 studies have shown that nedocromil sodium inhibits several of the processes that are likely to be important in the pathogenesis of seasonal allergic conjunctivi tis. 9 Specifically, nedocromil sodium inhibits human eosinophil activation," mast-cell medi ator release, 712 and antigen-induced inflamma tion. 13 Nedocromil sodium's inhibitory effects on these biologic processes are likely to con tribute to the efficacy of this drug in the treat ment of seasonal allergic conjunctivitis. Clini cal studies have demonstrated the clinical efficacy and safety of nedocromil sodium espe cially in the treatment of patients with asth ma.1417 The goal of our study was to evaluate the safety and efficacy of nedocromil sodium 2% ophthalmic solution administered twice daily in the treatment of seasonal allergic conjuncti vitis.
Methods Study population—One hundred fifty-five pa tients between the ages of 12 and 62 years were screened at five centers, and 140 were entered into the study (Table 1). Sixty-nine patients were assigned to the nedocromil sodium treat ment group and 71 patients were assigned to the placebo treatment group. Of the 140 pa tients who entered the study, 132 completed the study (63 in the nedocromil sodium treat ment group and 69 in the placebo treatment group). All subjects had a history of seasonal allergic conjunctivitis requiring continuous treatment during the two previous pollen seasons and had a skin-test reaction of at least 2+ to ragweed. Patients with documented seasonal sensitivity to ragweed pollen were treated with a stable regimen of immunotherapy for at least three months before and during the study. Patients were excluded from the study if they met any of the following criteria: childbearing age and not using contraception, absent or minimal symp toms during the previous ragweed pollen sea son, no requirement for medication to control seasonal allergic conjunctivitis, evidence of pe rennial allergic conjunctivitis rather than sea
57
sonal allergic conjunctivitis, and clinical signs and symptoms suggesting ocular disease other than seasonal allergic conjunctivitis. The protocol and informed-consent forms were approved by the institutional review boards in each participating medical center. Written consent was obtained from all partici pants. Study sites—The study was conducted for eight weeks. The start of the double-masked portion was timed to coincide with the predict ed peak of the ragweed pollen season in each of the regions where the study centers were locat ed (approximately middle August). Two of the five sites participating in this multicenter study were located in Minneapolis, Minnesota. The other three were located in Prairie Village, Kansas; Iowa City, Iowa; and Chicago, Illinois. Study design—The study was designed as a multicenter, double-masked, group-compara tive, placebo-controlled trial of eight weeks' duration in which patients were randomly as signed to treatment. Patients were screened for entry into the program before the baseline period. At the screening visit, a complete medi cal history was obtained, and blood and urine samples were taken for urinalysis and routine hematologic and biochemical tests. The base line period was initiated with the first clinic visit, during which the status of the patient's conjunctivitis was assessed and a slit-lamp ex amination was performed. Patients also were given daily-symptom diary cards and instruc tions on how to record their symptoms. After a one-week baseline period, patients were ran domly assigned to either the nedocromil sodi um treatment group or to the placebo treatment group. In both groups, the treatment dose was one drop (0.04 ml) of solution per eye twice daily (8:00 A.M. and 6:00 P.M.). The composition of the active drug was as follows: nedocromil sodium 2%, benzalkonium chloride 0.01%, edetate disodium 0.05%, sodium chloride 0.55%, and sufficient purified water to consti tute 100%. The composition of the placebo was the same as that of the active drug, excluding the nedocromil sodium and including a nonirritating yellow coloring agent (riboflavin 0.0005%) to make the placebo visually indistin guishable from the active drug. The clinical status of the patients and the diary cards were reviewed at the end of the baseline period and at clinic visits after one, three, five, and eight weeks.
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TABLE 1 DEMOGRAPHIC CHARACTERISTICS OF PATIENTS WITH SEASONAL ALLERGIC CONJUNCTIVITIS NEDOCROMIL SODIUM-TREATED
PLACEBO-TREATED
PATIENTS
PATIENTS
(N = 69)
(N = 71)
NO. (%)
NO. (%)
35 (51) 34 (49)
41 (58) 30 (42)
32.4 years (12-62 years)
32.2 years (14-58 years)
17.7 (3-56)
19.3 (3-45)
5(7)
2(3)
Males Females Mean age (range) Mean No. of years of conjunctivitis history (range) Immunotherapy-treated patients
Concomitant treatment—Other than the nedocromil sodium, no medications were per mitted for treatment of ocular allergy. Orally and topically administered ocular corticosteroid preparations were not permitted for two weeks before the start of the study. Any treat ment that required the use of corticosteroids during the trial was considered a failure. Rhini tis medications (nasally administered cromolyn sodium, orally administered antihistamines, orally administered decongestants, a combina tion of these products, and topically applied vasoconstrictors) were not permitted during the study. Orally administered theophylline and inhalation of cromolyn sodium for the treat ment of asthma were not permitted during the study period. Inhaled and orally administered B-adrenergic agents and inhaled corticoste roids were permitted for asthma management as necessary, and the dosage of these drugs was recorded on a daily basis. Artificial tears (Lyteers, Sola/Barns-Hind, Sunnyvale, California) and nasally adminis tered corticosteroid medication (Nasalide, Syntex Laboratories, Palo Alto, California) were permitted during the study. Measured amounts of each were provided, and consumption was monitored by weighing the medicine container at each patient visit. Symptom diary cards and clinical evaluation— The primary outcome measure was the symp tom summary score, defined as the sum of scores for itchy eyes and overall eye condition. Overall eye condition included patient evalua tions of burning, tearing, redness, swelling, as
well as grittiness and photophobia. Patients rated eye itching, and overall eye condition on the basis of the following scale: 0 = none, symptoms absent; 1 = mild, symptoms barely noticeable; 2 = moderate, symptoms caused some discomfort; 3 = moderately severe, symp toms caused much discomfort without interfer ing with daily routine; and 4 = severe, symp toms present for most of the day and caused enough discomfort to interfere with daily rou tine. Patients also recorded the use of the study drug, use of concomitant medications, and the number of hours spent in air-conditioned rooms. At each study visit, the examining physician evaluated the clinical status of each patient on a five-point scale (0 = none to 4 = severe) for conjunctival edema, conjunctival injection, tearing, and overall severity of conjunctivitis. Additionally, at the first and last visit, each patient underwent a thorough ophthalmic ex amination that was performed by an ophthal mologist and included obtainment of an ocular history, a visual acuity test, determination of intraocular pressure, physical examination of the eye and the ocular adnexa, and slit-lamp examination. Pollen counts—Daily ragweed pollen counts were recorded at each study site using a Rotorod sampler set (Tad Brown Associates, Los Altos Hills, California) to sample one minute every ten minutes. Rods were changed every 24 hours to obtain daily counts. To ensure uniform reporting from all sites, the exposed rods were mailed to a central laboratory where the pollen counts were performed.
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Data analysis—Because the study was con ducted at several sites that were separated geo graphically and had variations in weed blooms and pollen production, it was necessary to account for regional differences in ragweed pollen counts in the data collection and analy sis. Daily ragweed pollen counts were used only as an indicator of the three-week period of maximal possible ragweed pollen challenge. To permit accurate pooling of data across the five medical centers participating in this study, a difference score was computed for each pa tient. The difference score was defined as the difference in diary card scores and clinical eval uation scores between the peak pollen season and the baseline period. Data for different visits thus could be pooled for different clinics, de pending on the time of the peak pollen season in each region. The composition of the two treatment groups was assessed for comparability before the trial, and the responses were evaluated during the trial both within and across clinics. The statisti cal significance of dichotomous variables was measured by Fisher's exact test and the MantelHaenszel test.18 Quantitative or semiquantitative data were evaluated by two-sample (-tests and two-way analysis of variance. A P value of .05 (two-tailed test) was considered the upper limit of statistical significance. The justification for pooling data from five centers was analyzed by testing for significant clinic by treatment interactions by means of a two-way analysis of covariance. None of the tests for clinic by treatment interactions ap proached statistical significance; thus, pooling data across the five clinics was statistically justi fied. Adverse experiences—All adverse experienc es, whether or not ascribed to the drug, were documented.
Results Patients—The demographic characteristics of the 140 patients were analyzed (Table 1). No statistically significant differences were ob served between the treatment groups with re gard to age, gender, conjunctivitis history, or history of immunotherapy. Compliance with the study treatment was good. Of the 140 patients who entered the study, eight patients withdrew from the study
59
after starting test medication. Reasons for with drawal included the following: protocol viola tion (one placebo-treated patient), other illness (four nedocromil sodium-treated patients), noncompliance (one nedocromil sodiumtreated patient), treatment failure (one place bo-treated patient), and loss to follow-up (one nedocromil sodium-treated patient). Local pollen counts at participating study sites—The ragweed pollen season began before or during the baseline period at each study site. The peak pollen season coincided with the first three weeks of the double-masked treatment segment of the study for all participating medi cal centers (Fig. 1). The pollen count was high est in Prairie Village, Kansas; and was decreasingly lower in Iowa City, Iowa; Minneapolis, Minnesota; and Chicago, Illinois, respectively. Daily diary card scores—During the baseline period, all patients experienced symptoms of ocular allergy that coincided with increasing pollen counts. As compared to the symptom status of placebo-treated control patients, pa tients treated with nedocromil sodium during the peak pollen period had improvements in ocular symptoms usually associated with sea sonal allergic conjunctivitis. This was evi denced by lower symptom scores after the initi ation of treatment despite increasing pollen counts. During the three-week peak pollen pe riod, patients treated with nedocromil sodium had lower symptom scores for itchy eyes, over all eye condition, and hence, the symptom summary score (Fig. 2). Mean individual symp tom score during the peak pollen period had a statistically significant difference for eye itching ( P ^ . 0 4 ) between the placebo- and nedocromil-treated groups. Clinical assessments—As determined by phy sicians, no statistically significant differences in tearing, conjunctival injection, edema, and overall severity of conjunctivitis at the end of the baseline period were found between pa tients subsequently assigned to either the nedocromil or placebo treatments. During the peak pollen season, patients using nedocromil sodium had statistically significant reductions in conjunctival injection (P s .001) and overall disease severity (P < .001) when compared with those of the placebo-treated group (Fig. 3). Clinical assessment of symptom scores for tear ing and conjunctival edema was lower in nedocromil-treated patients, although these
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Iowa City
Chicago
Run In
Bate line
1
Run in
Minneapolis
Base 1 line
Prairie Village
Fig. 1 (Blumenthal and associates). Ragweed pollen counts. Pollen concentration was measured at each of the four cities where the treatment centers were located. In all four cities, the ragweed pollen season began before or during the baseline period, and peak pollen season coincided with the first three weeks of the trial. Pollen count was highest in Prairie Village, Kansas.
differences failed to reach statistical signifi cance. Clinician and patient opinions—In evaluating the effectiveness of nedocromil sodium for al lergic conjunctivitis control, clinicians rated the severity of conjunctivitis as one of the following: (1) fully controlled, (2) mostly con trolled, (3) fairly controlled, (4) poorly con trolled, or (5) not controlled. Of the 69 patients treated with nedocromil sodium, 38 (55%) had conjunctivitis symptoms that were at least mostly controlled. In contrast, only 23 of the 71 placebo-treated patients (32%) had similar symptom control, a difference that was statisti cally significant (P ^ .004). Likewise, 36 of the 69 patients (52%) reported that the nedocromil
sodium treatment mostly controlled conjuncti vitis symptoms as opposed to only 26 of the 71 (37%) placebo-treated patients (P < .03) re porting mostly controlled symptoms. Concomitant medications—In all clinics, artifi cial tear use was low at baseline and during the peak pollen period. No statistically significant differences were found between treatment groups across clinics. Use of artificial tears was comparable at baseline between treatment groups (nedocromil sodium mean, 1.31 drops per day; placebo mean, 1.27 drops per day; P £ .78). During the peak pollen period, the use of artificial tears was lower in the nedocromil sodium-treated group than it was in the place bo-treated group; but the difference failed to
Nedocromil Sodium and Allergic Conjunctivitis
Vol. 113, No. 1
I Nedocromil Sodium
C h a n g e
Placebo
0.4 -i
0.2
f
r o m B a -0.2s e I i -0.4 n e
Symptoms
Itchy Eyes
Overall Eye Condition
Symptom Summary Score
r e a c h statistical significance ( n e d o c r o m i l s o d i u m m e a n , 0.45; p l a c e b o m e a n , 0.65; P < .52). No statistically significant g r o u p differences w e r e r e p o r t e d in the u s e of topically a d m i n i s tered N a s a l i d e for r h i n i t i s d u r i n g the p e a k pollen period. Adverse experiences—Fifty-eight of the 71 p a t i e n t s in the p l a c e b o - t r e a t e d g r o u p (82%) a n d 59 of the 69 p a t i e n t s in t h e n e d o c r o m i l s o d i u m t r e a t e d g r o u p (86%) r e p o r t e d at least o n e a d verse e x p e r i e n c e d u r i n g t h e trial. T r a n s i e n t b u r n i n g eyes ( e x p e r i e n c e d b y eight [12%] of the nedocromil sodium-treated patients and by five [7%] of the p l a c e b o - t r e a t e d p a t i e n t s ) , s t i n g ing eyes ( e x p e r i e n c e d by seven [10%] of the n e d o c r o m i l s o d i u m - t r e a t e d p a t i e n t s a n d by
I Nedocromil
Discussion The clinical trial was c o n d u c t e d d u r i n g a p e r i o d of m a x i m a l r a g w e e d p o l l e n c o u n t s . The r e s u l t s d e m o n s t r a t e d the efficacy of the twicedaily a d m i n i s t r a t i o n of n e d o c r o m i l s o d i u m 2 % o p h t h a l m i c s o l u t i o n in the t r e a t m e n t of s e a s o n -
Placebo
I m P r o v e m e n t
f r o m
Tearing
Conjunctival Injection
Fig. 2 (Blumenthal and associates). Daily diary score changes. During the peak pollen period, patients treated with nedocromil sodium demonstrat ed a statistically significant difference in eye itching (compared to the place bo-treated group, P < .04,) with im provements in overall eye condition and summary score. Values are ex pressed as the difference in symptom scores between the peak pollen period and baseline testing. Negative num bers, therefore, indicate an improve ment in seasonal allergic conjunc tivitis symptom score. In contrast, during the peak pollen season, patients treated with placebo had increases in seasonal allergic conjunctivitis symptoms.
t w o [3%] of the p l a c e b o - t r e a t e d p a t i e n t s ) , a n d u n p l e a s a n t taste ( e x p e r i e n c e d b y n i n e [13%] of the n e d o c r o m i l s o d i u m - t r e a t e d p a t i e n t s a n d by n o n e [0%] of the p l a c e b o - t r e a t e d p a t i e n t s ) w e r e the most c o m m o n a d v e r s e effects associated w i t h t r e a t m e n t (Table 2).
C h a n 9 e
B a s e I i n e
61
Conjunctival Edema
Overall Severity
Fig. 3 (Blumenthal and associates). Clinicians' assessments of conjuncti vitis. Physicians rated seasonal aller gic conjunctivitis on a five-point scale (0 = absent, and 4 = severe). Numbers represent changes from baseline mea sures. Patients treated with nedo cromil sodium had significant im provements in both conjunctival injection (P < .001) and overall severi ty (P < .001) when compared to pa tients treated with placebo.
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TABLE 2 FREQUENCY OF ADVERSE CONDITIONS CONSIDERED RELATED TO NEDOCROMIL SODIUM COMPARED WITH THE FREQUENCY OF THE SAME CONDITIONS IN PLACEBO-TREATED PATIENTS NEDOCROMIL SODIUM-TREATED
PLACEBO-TREATED
PATIENTS (N = 69)
PATIENTS (N = 71)
ADVERSE CONDITION
NO. (%)
NO. (%)
Eye burning Eye stinging Taste perversion Abnormal vision Eye itching Conjunctivitis Eye redness Eye irritation Photophobia
8(12) 7(10) 9(13) 1(1) 0(0)
5(7) 2(3) 0(0) 2(3) 2(3) 0(0) 0(0)
al allergic conjunctivitis. The data supported previous studies of the efficacy of nedocromil sodium for the treatment of allergic conjuncti vitis.19,20 All treatment differences favored nedocromil sodium, with statistically signifi cant differences noted for ocular pruritus and for the clinicians' assessments of conjunctival injection and overall severity of conjunctivitis. Opinions of treatment effectiveness expressed by both the clinician and the patient were strongly in favor of nedocromil sodium. Al though the mean diary symptom summary score and overall eye condition did not reach statistical significance, trends for these symp toms also indicated a favorable response to nedocromil sodium. The lack of statistical significance observed in several of the variables may have been caused by the treatment's initiation after the start of the pollen season when the patients were al ready experiencing symptoms. Optimal control of seasonal allergic conjunctivitis may be af forded by initiating treatment before the pollen season. Concomitant use of Lyteers also was lower in the placebo-treated group during the peak pollen period than during the baseline period, implying a marked placebo effect per haps caused by the regular flushing of the eye with the eyedrop solution. This was further confirmed by the mean symptom scores that were between 1 and 2 (on the basis of a fivepoint scale, 0 through 4) even during peak pollen exposure. Another factor that might have accounted for the lack of statistical significance was the fixed dosing regimen. Initial dosing four times daily
1(1) 1(1) 0(0) 0(0)
1(1) 1(1)
may further improve the symptom control 21 in these patients. After symptoms improve, treat ment may be reduced to a twice-daily regi men.17 Nedocromil sodium has a potentially impor tant role in the treatment of seasonal allergic conjunctivitis. Although alternative methods are available for treatment, including saline irrigation, topically administered vasoconstric tors, topically administered antihistamines, and topically administered corticosteroids, these agents have either limited clinical efficacy or have caused unwanted side effects. The use of the mast-cell stabilizer, cromolyn sodium (4% aqueous solution) has been an effective treatment for seasonal allergic conjunctivitis when administered four times daily. Nedo cromil sodium, with its broad range of antiinflammatory activity, has been shown in vitro to be more potent than cromolyn sodium in inhibiting eosinophil activation and mast-cell mediator release, both of which are considered important in the pathogenesis of seasonal aller gic conjunctivitis. 81112 The results of this study showed that nedocromil is clinically effective in relieving the major symptoms of seasonal aller gic conjunctivitis when administered four times daily. When prompted, many patients in both the nedocromil sodium-treated and placebotreated groups reported adverse experiences, but the specific complaints were usually minor. The high degree of satisfaction with the nedocromil sodium treatment and the high de gree of adherence to the trial protocol demon strated that the rate of unusual adverse experi-
Nedocromil Sodium and Allergic Conjunctivitis
Vol. 113, No. 1
ences with the test medication did not have great clinical significance. The potential use of a drug such as nedocromil sodium, with mini mal side effects and good therapeutic efficacy at twice-daily dosing, should be a beneficial addi tion to the clinician's armamentarium in treat ing patients with seasonal allergic conjunctivi tis.
References 1. Allansmith, M. R., Greiner, J. V., and Ross, R. N.: Ocular allergy. In Samter, M. (ed.): Immunological Disease, ed. 4. Boston, Little, Brown, and Company, 1987, pp. 1917-1943. 2. Irani, A. M., Butrus, S. I., Tabbara, K. F., and Schwartz, L. B.: Human conjunctival mast cell. Dis tribution of MCT and MVTC in vernal conjunctivitis and giant papillary conjunctivitis. J. Allergy Clin. Immunol. 86:34, 1990. 3. Allansmith, M. R., and Ross, R. N.: Ocular aller gy and mast cell stabilizers. Surv. Ophthalmol. 30:229, 1986. 4. Friday, G. A., Biglan, A. W., Hiles, D. A., Murphey, S. M., Miller, D. L., Rothbach, C , and Rand, S.: Treatment of ragweed allergic conjunctivitis with cromolyn sodium 4% ophthalmic solution. Am. J. Ophthalmol. 95:169, 1983. 5. Greenbaum, J., Cockcroft, D., Hargreave, F. E., and Dolovich, J.: Sodium cromoglycate in ragweedallergic conjunctivitis. ]. Allergy Clin. Immunol. 59:437, 1977. 6. Bruijnzeel, P. L. B., Warringa, R. A. J., Kok, M. L., Hamelink, M. L., and Kruekniet, J.: Inhibitory effects of nedocromil sodium on the in vitro induced migration and leukotriene formation of human granulocytes. Drugs 37(suppl. 1):9, 1989. 7. Busse, W. W., Randlev, B., Arbabian, M., and Ruoho, A.: Effect of nedocromil sodium on the Badrenergic response of human polymorphonuclear leukocytes. Drugs 37(suppl. 1):26, 1989. 8. Enerback, L., and Bergstrom, S.: Effect of nedocromil sodium on the compound exocytosis of mast cells. Drugs 37(suppl. 1):44, 1989. 9. Abraham, W. M.: In vitro effects of nedocromil sodium in human and animal models. Drugs 37(suppl. 1):78, 1989. 10. Church, M. K., Hutson, P. A., and Holgate, S. T.: Effects of nedocromil sodium on early and late
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phase responses to allergen challenge in the guineapig. Drugs 37(suppl. 1):101, 1989. 11. Moqbel, R., Cromwell, O., and Kay, A. B.: The effect of nedocromil sodium on human eosinophil activation. Drugs 37(suppl. 1):19, 1989. 12. Pearce, F. L., Al-Laith, L., Bosman, J., Brostoff, J., Cunniffe, T. M., Flint, K. C , Hudspith, B. N., Jaffar, Z. H., Johnson, N. M., Kassessinoff, T. A., Lau, H. Y. A., Lee, P. Y., Leung, K. B. P., Liu, W. L., and Tainsh, K. R.: Effects of sodium cromoglycate and nedocromil sodium on histamine secretion from mast cells from various locations. Drugs 37(suppl. 1):37, 1989. 13. Dahlen, S. E., Bjorck, T., Kumlin, M., Suabom, A., Raud, J., Palmertz, U., Franzen, L., Gonneberg, R., and Hedquist, P.: Dual inhibitory action of nedocromil sodium on antigen-induced inflamma tion. Drugs 37(suppl. 1):63, 1989. 14. Lai, S., Malhotra, S., Gribben, D., and Hodder, D.: Nedocromil sodium. A new drug for the manage ment of bronchial asthma. Thorax 39:809, 1984. 15. Eady, R. P.: The pharmacology of nedocromil sodium. Eur. J. Respir. Dis. 69(suppl. 44):112, 1986. 16. Neale, M. G., Brown, K„ Foulds, R. A., Lai, S., Morris, D. A., and Thomas, D.: The pharmacokinetics of nedocromil sodium, a new drug for the treat ment of reversible obstructive airways disease, in human volunteers and patients with reversible ob structive airways disease. Br. ]. Clin. Pharmacol. 24:493, 1987. 17. Fairfax, A. J., and Albeson, M.: A double-blind group comparative trial of nedocromil sodium and placebo in the management of bronchial asthma. J. Int. Med. Res. 16:216, 1988. 18. Mantel, N.: Chi-square tests with one degree of freedom. Extensions of the Mantel-Haenszel pro cedure. J. Am. Stat. Assoc. 58:690, 1963. 19. Stockwell, A., and Easty, D.: Double-blind group comparative trial of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis. Invest. Ophthalmol. Vis. Sci. 29:229, 1988. 20. Leino, M., Carlson, D., Jaanio, E., Koivunen, T., Lavikkala, H., Riihela, A., and Takalo, E.: Doubleblind group comparative study of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis. Ann. Allergy 64:398, 1990. 21. Bianco, S., DelBono, N., Grassi, V., and Orefice, U.: Effectiveness of nedocromil sodium versus placebo as additions to routine asthma maintenance therapy. A multicenter, double blind, group compar ative trial. Respiration 56:204, 1989.
