A controlled, double-blind comparison of napha;:.oline hydrochloride 0.05%, all1a;:.oline phosphate 0.5%, a combination of both components and a placebo was performed on 5/ ragweed sensitive pati~nts presenting al­lergic conjunctivitis. Evaluation of response at various times after instilla­tion of medication for lacrimation, conjunctival inflammation, pruritis, photophobia and pain showed napha;:.oline hydrochloride, anta;:.oline phosphate and the combination product superior to placebo. The combina­tion product was statistically significantly superior for conjunctival inflam­mation and photophobia. The need for post-challenge treatment with epinephrine hydrochloride was significantly less in those eyes treated with the combination product, demonstrating prophylactic efficacy.

ANTAZOLINE PHOSPHATE AND NAPHAZOLINE HYDROCHLORIDE,

SINGLY AND IN COMBINATION FOR THE TREATMENT OF ALLERGIC

CONJUNCTIVITIS-A CONTROLLED, DOUBLE-BLIND CLINICAL TRIAL

JEROME MILLER. M.D .• AND EDWARD H. WOLF. Ph.D.

Introduction

THE USE OF sympathomimetic vasoconstrictors and antihistamines to relieve conjunctival congestion as­sociated with allergic conditions is widespread and well accepted. The combination* tested combines the de­congestant activity of a sym­pathomimetic. naphazoline

*Vasocon-A. SMP Division Cooper Laboratories (p. R.) San German. Puerto Rico 00753. contains 0.05% naphazoline hydrochloride and 0.5% antazoline phosphate.

Doctor Miller is Chief. Department of Allergy. J. F. Kennedy Memorial Hospital. Philadelphia. Penn­sylvania.

Doctor Wolf is Associate Professor of Statistics. Baruch College of the City of New York. New York. New York.

VOLUME 35. AUGUST. 11)75

hydrochloride, with the antihistaminic, antazoline phosphate. Naphazoline hydrochloride has been found to be devoid of the customary rebound phenomenon seen with other com­pounds of its type. 1.3 When used in combination with antazoline phosphate the synergistic effect of the combination permits a reduction in naphazoline hydrochloride dosage and reduces the possibility of developing an acute attack of glaucoma in suscep­tible individuals.

Antazoline phosphate is less irritat­ing than other antihistamines4 and has been successfully used as topical therapy for allergic ophthalmological conditions. 5·1o The concomitant ad­ministration of separate preparations of antazoline phosphate and

81

ANTAZOLINE PHOSPHATE -MILLER & WOLF

naphazoline hydrochloride has also been shown to have significant ef­ficacy in various subjective clinical trials.5.11·16 In addition, it was recently shown that antazoline phosphate may lower intraocular pressure,17.18 sup­porting the rationale for this combina­tion.

Materials and Method Fifty-one patients (36 females and

15 males) 12 to 67 years of age, with a clinical diagnosis of allergic con­junctivitis, were studied. In addition to possessing signs and symptoms of al­lergic conjunctivitis all patients had a history of ragweed pollen sensitivity. Excluded from the study were patients with narrow angle glaucoma or known hypersensitivity or idiosyncracy to either of the component compounds of the combination or related drugs, pa­tients who had received cor­ticosteroids within 30 days prior to the study or those who had received either salicylates or antihistamines (topical or systemic) within three days. Patients were assigned a study number in se­quence according to a previously ran­domized assignment to one of four treatment groups. All patients received a placebo in one eye and either naphazoline hydrochloride, antazoline phosphate, the combination or blinded placebo in the other eye.

All medications were supplied in identically appearing containers with blinded labels. The placebo consisted of the sterile, buffered vehicle used in the combination product. Naphazoline hydrochloride was employed in 0.05% strength and antazoline phosphate in 0.5% strength, both being the same concentration employed in the com­bination product.

Five parameters were scored. These were as follows: Signs

Lacrimation - Tearing or watering of the eye.

81

Conjunctivitis - Redness of the eye. SVlIlptOIllS

. Pruritis - Itching, grainy feeling of the eye.

Photophobia - Discomfort of the eye due to light exposure.

Pain - Burning discomfort of the eye.

These signs and symptoms were rat­ed on the baseline and follow-up ob­servations as follows:

Absent 0 - Not present. Mild 1 - Present but not too annoy­

ing or bothersome. Moderate 2 - Frequent and quite

annoying. Severe 3 -Interferes with patient's

functions. Following the baseline evaluation

two drops of placebo were ad­ministered into one eye of the patient and two drops of study medication in­to the other eye. A second evaluation of each of the five parameters was made five to fifteen minutes af­terwards.

Each patient was then placed in a supine position and one drop of ragweed pollen (5000 protein nitrogen units/cc.) was instilled into the central pordon of the cornea of both eyes via a tuberculin syringe without needle. The same bottle of ragweed pollen ex­tract was used for all patients. Fifteen minutes later the five parameters were again evaluated as a measure of the prophylactic efficacy of the study medication against the allergen challenge. The investigator had the op­tion of administering epinephrine ophthalmic solution (l: 1000) to either or both eyes if he deemed it advisable.

All patients were required to return from 24 to 72 hours later for a follow­up examination and evaluation of study parameters. Adverse reactions were recorded and evaluated on a four-point severity scale as follows: o = None, I = Mild, 2 = Mod­erate, 3 = Severe.

ANNALS OF ALLERGY

ANTAZOLINE PHOSPHATE -MILLER & WOLF

Statistical evaluations included the difference 'in initial response to the study medication and the known placebo as well as the between-group differences in response. In addition the prophylactic efficacy of the study medications following the ragweed challenge was analyzed and the need for subsequent administration of epinephrine was determined.

Results All 51 patients completed the pre­

scribed study period. The tabulation of the results is presented in Tables I-V. Fifteen minutes after administration of medication the responses to napha­zoline hydrochloride and to the com-

bination product were superior to placebo for all five parameters. The administration of antazoline phosphate demonstrated a response superior to that of placebo for lacrimation, con­junctival inflammation and pruritis but slightly inferior to placebo for relief of pain and photophobia. Naphazoline hydrochloride was more effective than antazoline phosphate for all para­meters except pruritis. The combina­tion product provided greater relief of pruritis and photophobia, whereas lacrimation and pain responded better to naphazoline hydrochloride. The superiority of the combination product was most marked with respect to pruritis and photophobia and equal to

TABLE I. EFFECT OF NAPHAZOLINE HYDROCHLORIDE 0.05% AND ANTAZOLINE PHOSPHATE 0.5% IN COMBINATION ON OCULAR SIGNS AND SYMPTOMS OF ALLERGIC CONJUNCTI­VITIS.

Sign or Symptom

Lacrimation Conj u nctivitis

Pruritis Photophobia

Pain

Mean Control Score 1.35 1.85 2.28 1.07 1.00

Percent Change From Control

15 Min. Post-Drug

-32 -46 -69 -93 -50

15 Min. Post­Challenge

-21 -50 -69 -87 -57

24-72 Hrs. Post­Challenge

-26 -35 -37 -74 -65

TABLE II. EFFECT OF NAPHAZOLINE HYDROCHLORIDE 0.05% ON OCULAR SIGNS AND SYMPTOMS OF ALLERGIC CONJUNCTI­VITIS

Sign or Symptom Lacrimation

Conjunctivitis Pruritis

Photophobia Pain

Mean Control Score 1.62 1.54 1.70 0.54 0.46

Percent Change From Control

15 Min. Post-Drug

-43 -50 -41 -72 -67

15 Min. Post­Challenge

+ 9 +20 -24 -30 +50

24-72 Hrs. Post­Challenge

- 38 - 50 - 63 - 72 -100

TABLE III. EFFECT OF ANTAZOLINE PHOSPHATE 0.5% ON OCULAR SIGNS AND SYMPTOMS OF ALLERGIC CONJUNCTIVITIS

Percent Change From Control

Sign or Symptom Lacrimation

Conjunctivitis Pruritis

Photophobia Pain

VOLUME 35. AUGUST. 1'175

Mean Control Score 1.36 1.27 2.00 0.73 0.64

15 Min. Post-Drug

-26 -35 -41 -25 +14

15 Min. Post­Challenge

+ 7 + 7 -41 -51 - 0

24-72 Hrs. Post­Challenge

-67 -35 -55 -51 -58

83

ANTAZOLINE PHOSPHATE - MILLER & WOLF

naphazoline hydrochloride in relief of conjunctival inflammation. Antazoline phosphate also demonstrated relief of lacrimation, pruritis and conjunctival inflammation.

At the post-challenge evaluation for prophylactic efficacy (i.e ., following installation of ragweed extract 15 minutes post-drug) all three active medications were superior to placebo for all parameters, except for napha­zoline hydrochloride with respect to relief of pain . Antazoline phosphate appeared more effective than naphazoline hydrochloride for all parameters evaluated. The combina­tion product was significantly more ef­fective than either of its components administered singly for all parameters.

At the follow-up examination it was apparent that pharmacological activity was still evident in those eyes which were treated with active medication . Antazoline phosphate was most active in suppressing lacrimation while naphazoline hydrochloride wa s superior for conjunctival inflamma­'tion, pruritis' and pain. The combina­tion product was superior for

photophobia and was active in relief of lacrimation, conjunctival inflamma­tion, pruritis and pain .

Following ragweed challenge epinephrine hydrochloride administra­tion in both eyes was judged advisable for seven patients in the placebo/ placebo group, seven patients in the placebo/ naphazoline hydrochloride group, three patients in the place­bo/antazoline phosphate group and three patients in the placebo/combina­tion product group. Five cases re­quired epinephrine in one eye only and in all instances this was the placebo­treated eye . Overall , 50% of the placebo treated eyes required the ad­ministration of epinephrine hydrochloride, compared to only 21 % of the eyes to which the combination product had been applied. Ep'inephrine hydrochloride administration was re­quired in 54% of the eyes treated with naphazoline hydrochloride and 27% of the eyes treated with antazoline phosphate. Of the three active study medications, only the combination product achieved a statistically signifi­cant reduction in frequency of

TABLE IV. EFFECT OF PLACEBO ON SIGNS & SYMPTOMS OF ALLERGIC CONJUNCTIVITIS - IN DRUG-TREATED CONTRA­LATERAL EYE_

84

Sign or Symptom Lacrimation

Conj unctivitis Pruritis

Photophobia Pain

Mean Control Score 1.42 1.58 1.89 0 .71 0.76

Percent Change From Control

15 Min , Post-Drug

-24 -22 -32 -34 -32

15 Min. Post­Challenge

+23 +35 -11 -11 +25

24-72 Hrs. Post­Challenge

-35 -32 -36 -45 -55

TABLE V. EFFECT OF PLACEBO IN PLACEBO/PLACEBO TREATED EYES ON SIGNS & SYMPTOMS OF ALLERGIC CON­JUNCTIVITIS.

Sign or Symptom Lacrimation

Conjunctivitis Pruritis

Photophobia Pain

Mean Control Score 1.15 1.35 1.81 0 .85 0 .73

Percent Change From Control

15 Min. Post-Drug

-17 -17 -25 -32 -26

15 Min. Post­Challenge

+57 +57 +20 +36 +37

24-72 Hrs. Post­Challenge

- 3 -20 -19 -14 -63

ANNALS O F ALLERGY

ANTAZOLINE PHOSPHATE -MILLER & WOLF

epinephrine hydrochloride administra­tion.

Statistical analysis by means of the Wilcoxon signed rank tests was used to compare the response to active medication versus placebo among those patients receiving both (i.e ., ex­cluding the placeb~/placebo group). The response to the combination pro­duct was statistically significant at the post-challenge evaluations for con­junctival inflammation (p <0.01) and photophobia (p < 0.05). The response to naphazoline hydrochloride alone was significant (p <0.05) at the post­treatment evaluation for conjunctival inflammation and for pruritis at the post-challenge evaluation. Comparison of the three active-medication groups by the Mann-Whitney U tests showed the combination product provided significantly greater relief from con­junctival inflammation following ragweed challenge than either compo­nent administered alone. No adverse reactions were observed or reported by any patient during the course of this study .

Discussion The possibility of a bilateral

response in patients who received ac­tive medication in one eye and placebo in the other may explain the dif­ferences in response observed between the placeb~/medicated treat­ment groups versus the placebo/ placebo treatment groups. The data in Tables IV and V suggest that the pa­tients who received placebo in both eyes had more severe symptom ratings than those receiving placebo in one eye only. All parameters showed this tendency .

The statistically significant superiority of the combination product was demonstrated for two of the five parameters studied. Favorable statistical trends emerged from the analyses of the other three para­meters . The results of this clinical

VOLUME .15. AUGUST. 1'175

study substantiate the contention that the combination product offers a significant superiority over either of the components administered singly. thus supporting the rationale of the combination. Recent experiments in rabbits have also confirmed that the topical administration of 0.5% an­tazoline phosphate, 0.05% naphazoline hydrochloride and the combination product markedly reduce experimen­tally induced conjunctival inflamma­tion. 19

In addition these studies de­monstrated a statistically significant prophylactic effect when analyzing those eyes which were subsequently judged in need of epinephrine follow­ing antigen challenge.

References l. Babel J: Action of 2-(i-naphthylmethyl) im­

idazoline hydrochloride on the eye. Schweiz Med Wochschr 71: 561. 1941.

2. Burki E von: Die therapeuticshe verwen­dung des privin s (Ciba) in der ophthalmologie. Ophthalmologica. 1942. p . 254.

3. Hurwitz P and Thompson JM: Uses of naphazoline (Privine®) in ophthalmology. Arch Ophthal 43: 712. 1950.

4. Havener WH: OClIlClr Plll/rIl/Clcolog.\". 2nd Ed. Antihistaminic Agents. p. 151. St. Louis. Mo.; The C V Mosby Company. 1970.

5. Bourquin JB: A new synthetic antihistamine substance and its use in ophthalmology. Schweiz Med Wochschr 76: 296. 1946.

6. Hurwitz P: Local antihistaminic agents in ophthalmology. Illinois Med J 98: 113. 1950.

7. Peiffer H von: Behandlung allergischer erkrankungen des auges mit einem neuen antihi stamin-praparat (Antistin). Klin Mbl Augenheilk 116: 293 . 1950.

8. Stocker FW: Use of antihistaminic drug (especially antazoline. imidazole derivative and his tadyl methapyrilene). Southern Med J 43: 242. 1950.

9. D'Ermo F: Indication for the use of syn­thetic a ntihistaminics in ophthalmology. Minerva Med 48: 2382, 1957.

10. D'Ermo F: Further observations on the use of synthetic antihistaminics in the therapy of allergic eye disorders. Boll Oculist 39: 73. 1960.

II. Grossmann EE and Lori ng MJ: Local use

ANT AZOLINE PHOSPHATE - MILLER & WOLF

of antistine in nodular episcleritis. Am J Ophthal 32: 1122. 1949.

12. Daily RK and Daily L Jr: Use of privine­antis tine drops in ophthalmology. Am J Ophthal32: 441.1949.

13. N erne t h L: Ant i his tam i n e sin ophthalmology. Brit J Ophthal 33: 665 . 1949. •

14. Panepinto V and Locpascio G: L 'antistin­privina in terapia oculare. Gior Ital Of tal 3: 391. 1950.

15. Knupffer N von: Behandlungserfolge mit privin und antistin-privin bei allergischer konjunktivitis. Klin Monatsbl Angenh 116: 304, 1950.

16. Theodore FH: The treatment of ocular al­lergy. Am J Ophthal 45: 435. 1958.

17. Langham ME. Kitazawa Y and Hart RW: Adrenergic responses in the human eye. J Pharm Exp Therap 179: 47. 1971.

18. Noah VB . Brown JL and Geeraets J: The effect of I-norepinephrine on the facility of outflow in normal and buphthalmic rabbits. Acta Ophthal49: 338. 1971.

19. Salem H, Dunn BJ and Loux JJ: Con­junctival temperature: a measure of ocular decongestant and anti-inflammatory lKtivi­ty. Ann Ophth. In Press.

Rl'(I/W\"{S for r('prilll.l· should he addrl'SH'd 10: Dr. Jerollle Mill..,. 191 Pr('sidl'lIlia/ Bh·d. Bait/ CYllltTd, Pl'III/s.l"il"flllia /9004

ACHIEVING WISDOM The e~sence of wisdom is emancipation, as far as possible. from the tyranny of

the hal' and the 110 .... We cannot help the egoism of our senses. Sight and sound and touch are bound with our own bodies and cannot be made impersonal. Our emotions start similarly from ourselves. An infant feels hunger or discomfort. and is unaffected except by his own physical condition. Gradually with the years his horizon widens and as his thoughts and feelings become less personal and less concerned with his own physical states. he achieves growing wisdom.

"In some degree wisdom can be taught .. . This teaching should have a larger intellec­tual element than has been customary. It is true that the kind of specialized knowledge which is required for various kinds of skill has very little to do with wisdom. But it should be supplemented in education by wider survr:ys calculated to put it in its place in the Illtal of human activities ."

Bertrand Russell

ANNALS OF ALL.ERGY