Download Antazoline phosphate and naphazoline hydrochloride

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 antihistamines 4 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 eye.
Redness of the
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 annoying 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 prescribed 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.
Percent Change From Control
Mean
Control
15 Min.
15 Min. Post- 24-72 Hrs. PostSign or Symptom
Score
Post-Drug
Challenge
Challenge
Lacrimation
1.35
-32
-21
-26
Conj u nctivitis
1.85
-46
-50
-35
Pruritis
2.28
-69
-69
-37
Photophobia
1.07
-93
-87
-74
Pain
1.00
-50
-57
-65
TABLE II. EFFECT OF NAPHAZOLINE HYDROCHLORIDE 0.05%
ON OCULAR SIGNS AND SYMPTOMS OF ALLERGIC CONJUNCTIVITIS
Percent Change From Control
Mean
Control
15 Min.
15 Min. Post- 24-72 Hrs. PostSign or Symptom
Score
Post-Drug
Challenge
Challenge
Lacrimation
1.62
-43
+ 9
- 38
Conjunctivitis
1.54
-50
+20
- 50
Pruritis
-41
1.70
-24
- 63
Photophobia
0.54
-72
- 72
-30
Pain
0.46
-67
-100
+50
TABLE III. EFFECT OF ANTAZOLINE PHOSPHATE 0.5% ON
OCULAR SIGNS AND SYMPTOMS OF ALLERGIC CONJUNCTIVITIS
Percent Change From Control
Mean
Control
15 Min.
15 Min. Post- 24-72 Hrs. PostSign or Symptom
Score
Post-Drug
Challenge
Challenge
Lacrimation
1.36
-26
+ 7
-67
Conjunctivitis
1.27
-35
+ 7
-35
Pruritis
-41
2.00
-41
-55
Photophobia
0.73
-25
-51
-51
Pain
+14
0.64
- 0
-58
VOLUME 35. AUGUST. 1'175
83
ANTAZOLINE PHOSPHATE 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 napha zoline 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
MILLER & WOLF
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 admini stration 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_
Percent Change From Control
Mean
15 Min , 15 Min. Post- 24-72 Hrs. PostControl
Sign or Symptom
Score
Post-Drug
Challenge
Challenge
Lacrimation
+23
1.42
-24
-35
+35
Conj unctivitis
1.58
-22
-32
Pruritis
-11
1.89
-36
-32
Photophobia
0 .71
-11
-34
-45
+25
-55
Pain
0.76
-32
TABLE V. EFFECT OF PLACEBO IN PLACEBO/PLACEBO
TREATED EYES ON SIGNS & SYMPTOMS OF ALLERGIC CONJUNCTIVITIS.
Percent Change From Control
Mean
Control
15 Min .
15 Min. Post- 24-72 Hrs. PostPost-Drug
Sign or Symptom
Score
Challenge
Challenge
-17
Lacrimation
1.15
+57
- 3
Conjunctivitis
1.35
-20
+57
-17
Pruritis
1.81
+20
-25
-19
Photophobia
+36
0 .85
-32
-14
Pain
0 .73
+37
-26
-63
84
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
respon se 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
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ANT AZOLINE PHOSPHATE - MILLER & WOLF
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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