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Local nasal therapy with pyribenzamine in seasonal and nonseasonal hay fever
LOCAL EMANUEL
NASAL
THERAPY WITH PYRIBENZAMINE AND NONSEASONAL HAY FEVER*
SCHWARTZ,
M.D., AND HARRY LEIBOWITZ,
IN SEASONAL +$
M.D.,
N. Y.
BROOKLYN,
A NTIHISTAMINIC cell receptors,
drugs are believed to attach themselves to the histamine thus blocking the attachment of released histamine. These drugs have the ability to alter the wheals produced locally on the human skin by histamine and ragweed solutions. Most of them also have anesthetic properties. In addition, all exhibit strong local anesthetic action several times that of procaine. Code, Keating, and Leavittl showed the order of anesthetic potency of several antihistaminic drugs was the exact reverse of that noted for the flare reducing activity and concluded that the effect of the drugs on the size of the flare is not directly dependent upon their anesthetic action. Even in the absence of anesthesia, which in some eases lasted one hour, the drugs continued to show considerable flare reducing activity. On the other hand, the flare reducing activity of procaine after its anesthetic effects had gone was slight or absent. Yonkman, Roth, Smith, Hansen, and Craver,2 have detected the local anesthetic properties of pyribenzamine by the following experiments : 1. Fine crystals of Pyribenzamine placed between the lips (and held in place by the tip of the tongue) produced within three or four minutes marked local anesthesia which lasted fifteen to thirty minutes. Similar anesthesia occurred after the elixir of Pyribenzamine was held in the mouth two to three minutes. 2. The instillation of Pyribenzamine or Antistine into one eye of nine albino rabbits produced a loss of the blink reflex within a few minutes and lasted twenty to thirty minutes. The loss of the blink reflex induced by stroking the cornea served as a criterion for the loss of sensation. 3. Withdrawal of a frog’s foot from a solution of 0.5 per cent hydrochloric acid before and after treatment with a 2 per cent solution of Pyribenzamine served as a criterion for the development of local anesthesia. Anesthesia developed within five to ten minutes and lasted as long as sixty minutes. Yonkman and his co-workers further proved that anesthesia of the afferent neural components of the exposed sciatic nerve of a cranially pithed frog preceded that of contiguous efferent fibers. They first showed that faradization of the nerve below the area medicated with 2 per cent Pyribenzamine produced a loss of the “cross reflex ” stimulation of the contralateral leg with the maintenance of the ipsilateral motor control. Faradization above the medicated area induced contralateral activity (cross reflex) but no ipsilateral response. Hospital.
*From
the
Division
of Allergy
TRead before the Fifth Annual N. J., Dec. 6-8, 1948. SPyribenzamine solution was Products, Inc., Summit, N. J.
City,
of the Meeting furnished
Department of
The
through 269
of
Medmine,
American the
The
Academy courtesy
of
Long
Island
of Allergy, Ciba
College Atlantic
Pharmaceutical
270
THE
JOURNAL
OF ALLERGY
They also produced anesthesia of the conjunctivae in man with 0.5 to 1.0 per cent solutions of Pyribenzamine and Antistine. Mosely3 has employed Pyribenzamine satisfactorily to anesthetize the oral and pharyngeal mucosa prior to gastroscopy. However, all this evidence of the anesthetic action does not detract from the concept that the action of Pyribenzamine is primarily antihistaminic. It was, therefore, of interest to study the effect of an isotonic buffered solution of Pyribenzamine hydrochloride applied locally on the nasal mucosa in seasonal and nonseasonal hay fever patients. At the beginning of the evaluation of the local application of Pyribenzamine, a 1 per cent solution was used in drop form. The first t,wo patients ran an almost similar course. Both were male patients, aged 47 and 54 years, and both had vasomotor rhinitis of five and seven years duration, respectively. Various forms of therapy, such as elimination of substances giving positive skin reactions, dust desensitization, catarrhal vaccine therapy, and the local nasal application of Privine, Neosynephrine cocaine, Adrenalin, and ephedrine solutions had been given without benefit. No relief was obtained from the following antihi&aminic drugs given orally : Pyribenzamine, Antistine, Benadryl, Neo-Antergan, Neo-hetramine, Thephorin, and Histadyl. In March, 1948, a 1 per cent solution of Pyribenzamine was used as nose drops and in both cases there was almost immediate relief of nasal obstruction and the watery nasal discharge. In the beginning, the medication was applied every three to four hours and relief was obtained almost immediately and lasted from one-half to four hours. After one week the applications were decreased to twice daily, and after eight months of medication, these patients obtained relief of all nasal symptoms by the instillation of Pyribenzamine drops once daily in the morning on arising. There was no burning sensation of the nose or throat and no general side effects. However, in subsequent st,udies in a large series of patients, it was soon found that a 1 per cent solut,ion of Pyribenzamine applied locally to the nasal mucous membrane in the average patient was too strong and produced burning of the nose and throat. The present report deals with the local nasal therapy with a 0.5 per cent isotonic buffered solution of Pyribenzamine hydrochloride in a group of 100 patients having either seasonal or nonseasonal hay fever. For continuous symptoms, three to four drops were instilled in each nostril four times daily, and for intermittent symptoms, only as required. The hay fever patients were sensitive to ragweed pollen and also had received either preseasonal, coseasonal, or perennial hyposensitization. The nonseasonal cases had had no concomitant treatment at the time this study was being made. None of the patients received oral antihistaminic therapy at this time. Of sixty patients with seasonal hay fever, fifty-two or 86.7 per cent experienced symptomatic relief. Of this number, forty-eight had satisfactory relief and four had only slight relief. Eight or 13.3 per cent had no relief. Of forty patients with nonseasonal hay fever, twenty-seven or 67.5 per cent were relieved. Of this number, twenty-four had satisfactory relief and three had slight relief.
SCHWARTZ
AND
LEIBOWITZ
:
PYRIBENZAMINE
IN
HAY
FEVER
271
Thirteen patients or 32.5 per cent had no relief. The overall picture for both types was 79.0 per cent obtained relief and 21.0 per cent obtained no relief; Of 100 patients, seventy-nine were relieved and twenty-one were not. Thirty-eight patients or 38 per cent complained of a, burning sensation of the nose or throat, or both. Three discontinued the use of Pyribenzamine nose drops because of marked burning of the nose and throat. In one patient it initiated a severe cough which was soon followed by an asthmatic attack. In another patient, when the drop method was changed to a nasal spray, the burning sensation was completely eliminated. In another case the nasal obstruction was increased. The burning sensation lasted in the average patient from one to three minutes and then suddenly completely disappeared. In most of the patients, when the drop method was changed to a nasal spray, the burning sensation was decreased or was eliminated. Usually, relief was almost immediate and lasted from one-half hour to four hours. The symptoms of watery nasal discharge, sneezing, and itching of the nose responded more readily than the nasal obstruction. None of the patients experienced any systemic toxic reactions. DISCUSSION
The efficiency of local nasal therapy with isotonic buffered solution of Pyribenzamine hydrochloride may possibly depend upon two factors : (1) local anesthesia and (2) antihistaminic activity. The anesthetic properties of Pyribenzamine probably play a minor role but cannot be discounted. We feel that the benefits derived from the local application are due principally to the antihistaminic activity. Local nasal therapy may in some cases be preferred to the oral administration because of the lack of side effects and greater relief obtained because of the ability to concentrate the medication at the point where the histamine attaches itself to the receptor cells in the shock organ, thus blocking the attachment of released histamine. A relatively high incidence of unpleasant local burning of the nose and throat is a major difficulty when 0.5 per cent Pyribenzamine solution is used as nose drops. However, the use of a DeVilbiss atomizer, either No. 114 or No. 251, will produce a more even surface distribution of the medication and eliminate the burning sensation in the majority of patients. One patient who had complained of severe burning with the nose drops had no burning at all and received symptomatic relief when Pyribenzamine was used in the form of a spray. However, it should be emphasized that the local application of 0.5 per cent Pyribenzamine to the nasal mucosa is solely palliative medication. Nasal symptoms recur after withdrawal of the drug. Local therapy is not a substitute for the determination of the etiological factors, the elimination of the offending allergens and hyposensitization. If symptomatic relief is obtained with the local application of 0.5 per cent Pyribenzamine, it is to be preferred to the oral administration of the antihistaminic drug because of the absence of systemic side effects. In some patients the oral administration is recommended and in others a combination of oral and local nasal therapy is advisable. For
272
THE
JOURNAL
OF
ALLERGY
local therapy, one may also use a combination of antihkaminic and vasoconstrictor drugs. These drugs are valuable symptomat,ic drugs either locally, orally, or in combination until specific therapeutic measures are helpful. SUMMARY
In consideration of the results reported here and in view of the absence of systemic side effects, 0.5 per cent isotonic buffered solution of Pyribenzamine hydrochloride appears to be a valuable antihistaminic drug for local nasal application in seasonal and nonseasonal hay fever. REFERENCES
1. Code,
C. F., Keating, J. U., and Leavitt, M. I).: Conference on Antihistamine in Allergy, The New York Academy of Sciences, Oct. 3, 1947. 2. Yonkman, F. F., Roth, F., Smith, J., Hansen, N., and Craver, R. N.: Local Properties of Antistine Hydrochloride (2.phenyl-benzyl-aminomethyl-imidazoline) and Pyribenzamine (N, N-dimethyl-N-benzyl-N’(a-pyridyl) -ethylenediamine hydrochloride, in press. 3. Mosely, V.: Am. J. Digest. Dis. 15: 410, 1948.
Agents Anesthetic mono-
NASAL
THERAPY WITH PYRIBENZAMINE AND NONSEASONAL HAY FEVER*
SCHWARTZ,
M.D., AND HARRY LEIBOWITZ,
IN SEASONAL +$
M.D.,
N. Y.
BROOKLYN,
A NTIHISTAMINIC cell receptors,
drugs are believed to attach themselves to the histamine thus blocking the attachment of released histamine. These drugs have the ability to alter the wheals produced locally on the human skin by histamine and ragweed solutions. Most of them also have anesthetic properties. In addition, all exhibit strong local anesthetic action several times that of procaine. Code, Keating, and Leavittl showed the order of anesthetic potency of several antihistaminic drugs was the exact reverse of that noted for the flare reducing activity and concluded that the effect of the drugs on the size of the flare is not directly dependent upon their anesthetic action. Even in the absence of anesthesia, which in some eases lasted one hour, the drugs continued to show considerable flare reducing activity. On the other hand, the flare reducing activity of procaine after its anesthetic effects had gone was slight or absent. Yonkman, Roth, Smith, Hansen, and Craver,2 have detected the local anesthetic properties of pyribenzamine by the following experiments : 1. Fine crystals of Pyribenzamine placed between the lips (and held in place by the tip of the tongue) produced within three or four minutes marked local anesthesia which lasted fifteen to thirty minutes. Similar anesthesia occurred after the elixir of Pyribenzamine was held in the mouth two to three minutes. 2. The instillation of Pyribenzamine or Antistine into one eye of nine albino rabbits produced a loss of the blink reflex within a few minutes and lasted twenty to thirty minutes. The loss of the blink reflex induced by stroking the cornea served as a criterion for the loss of sensation. 3. Withdrawal of a frog’s foot from a solution of 0.5 per cent hydrochloric acid before and after treatment with a 2 per cent solution of Pyribenzamine served as a criterion for the development of local anesthesia. Anesthesia developed within five to ten minutes and lasted as long as sixty minutes. Yonkman and his co-workers further proved that anesthesia of the afferent neural components of the exposed sciatic nerve of a cranially pithed frog preceded that of contiguous efferent fibers. They first showed that faradization of the nerve below the area medicated with 2 per cent Pyribenzamine produced a loss of the “cross reflex ” stimulation of the contralateral leg with the maintenance of the ipsilateral motor control. Faradization above the medicated area induced contralateral activity (cross reflex) but no ipsilateral response. Hospital.
*From
the
Division
of Allergy
TRead before the Fifth Annual N. J., Dec. 6-8, 1948. SPyribenzamine solution was Products, Inc., Summit, N. J.
City,
of the Meeting furnished
Department of
The
through 269
of
Medmine,
American the
The
Academy courtesy
of
Long
Island
of Allergy, Ciba
College Atlantic
Pharmaceutical
270
THE
JOURNAL
OF ALLERGY
They also produced anesthesia of the conjunctivae in man with 0.5 to 1.0 per cent solutions of Pyribenzamine and Antistine. Mosely3 has employed Pyribenzamine satisfactorily to anesthetize the oral and pharyngeal mucosa prior to gastroscopy. However, all this evidence of the anesthetic action does not detract from the concept that the action of Pyribenzamine is primarily antihistaminic. It was, therefore, of interest to study the effect of an isotonic buffered solution of Pyribenzamine hydrochloride applied locally on the nasal mucosa in seasonal and nonseasonal hay fever patients. At the beginning of the evaluation of the local application of Pyribenzamine, a 1 per cent solution was used in drop form. The first t,wo patients ran an almost similar course. Both were male patients, aged 47 and 54 years, and both had vasomotor rhinitis of five and seven years duration, respectively. Various forms of therapy, such as elimination of substances giving positive skin reactions, dust desensitization, catarrhal vaccine therapy, and the local nasal application of Privine, Neosynephrine cocaine, Adrenalin, and ephedrine solutions had been given without benefit. No relief was obtained from the following antihi&aminic drugs given orally : Pyribenzamine, Antistine, Benadryl, Neo-Antergan, Neo-hetramine, Thephorin, and Histadyl. In March, 1948, a 1 per cent solution of Pyribenzamine was used as nose drops and in both cases there was almost immediate relief of nasal obstruction and the watery nasal discharge. In the beginning, the medication was applied every three to four hours and relief was obtained almost immediately and lasted from one-half to four hours. After one week the applications were decreased to twice daily, and after eight months of medication, these patients obtained relief of all nasal symptoms by the instillation of Pyribenzamine drops once daily in the morning on arising. There was no burning sensation of the nose or throat and no general side effects. However, in subsequent st,udies in a large series of patients, it was soon found that a 1 per cent solut,ion of Pyribenzamine applied locally to the nasal mucous membrane in the average patient was too strong and produced burning of the nose and throat. The present report deals with the local nasal therapy with a 0.5 per cent isotonic buffered solution of Pyribenzamine hydrochloride in a group of 100 patients having either seasonal or nonseasonal hay fever. For continuous symptoms, three to four drops were instilled in each nostril four times daily, and for intermittent symptoms, only as required. The hay fever patients were sensitive to ragweed pollen and also had received either preseasonal, coseasonal, or perennial hyposensitization. The nonseasonal cases had had no concomitant treatment at the time this study was being made. None of the patients received oral antihistaminic therapy at this time. Of sixty patients with seasonal hay fever, fifty-two or 86.7 per cent experienced symptomatic relief. Of this number, forty-eight had satisfactory relief and four had only slight relief. Eight or 13.3 per cent had no relief. Of forty patients with nonseasonal hay fever, twenty-seven or 67.5 per cent were relieved. Of this number, twenty-four had satisfactory relief and three had slight relief.
SCHWARTZ
AND
LEIBOWITZ
:
PYRIBENZAMINE
IN
HAY
FEVER
271
Thirteen patients or 32.5 per cent had no relief. The overall picture for both types was 79.0 per cent obtained relief and 21.0 per cent obtained no relief; Of 100 patients, seventy-nine were relieved and twenty-one were not. Thirty-eight patients or 38 per cent complained of a, burning sensation of the nose or throat, or both. Three discontinued the use of Pyribenzamine nose drops because of marked burning of the nose and throat. In one patient it initiated a severe cough which was soon followed by an asthmatic attack. In another patient, when the drop method was changed to a nasal spray, the burning sensation was completely eliminated. In another case the nasal obstruction was increased. The burning sensation lasted in the average patient from one to three minutes and then suddenly completely disappeared. In most of the patients, when the drop method was changed to a nasal spray, the burning sensation was decreased or was eliminated. Usually, relief was almost immediate and lasted from one-half hour to four hours. The symptoms of watery nasal discharge, sneezing, and itching of the nose responded more readily than the nasal obstruction. None of the patients experienced any systemic toxic reactions. DISCUSSION
The efficiency of local nasal therapy with isotonic buffered solution of Pyribenzamine hydrochloride may possibly depend upon two factors : (1) local anesthesia and (2) antihistaminic activity. The anesthetic properties of Pyribenzamine probably play a minor role but cannot be discounted. We feel that the benefits derived from the local application are due principally to the antihistaminic activity. Local nasal therapy may in some cases be preferred to the oral administration because of the lack of side effects and greater relief obtained because of the ability to concentrate the medication at the point where the histamine attaches itself to the receptor cells in the shock organ, thus blocking the attachment of released histamine. A relatively high incidence of unpleasant local burning of the nose and throat is a major difficulty when 0.5 per cent Pyribenzamine solution is used as nose drops. However, the use of a DeVilbiss atomizer, either No. 114 or No. 251, will produce a more even surface distribution of the medication and eliminate the burning sensation in the majority of patients. One patient who had complained of severe burning with the nose drops had no burning at all and received symptomatic relief when Pyribenzamine was used in the form of a spray. However, it should be emphasized that the local application of 0.5 per cent Pyribenzamine to the nasal mucosa is solely palliative medication. Nasal symptoms recur after withdrawal of the drug. Local therapy is not a substitute for the determination of the etiological factors, the elimination of the offending allergens and hyposensitization. If symptomatic relief is obtained with the local application of 0.5 per cent Pyribenzamine, it is to be preferred to the oral administration of the antihistaminic drug because of the absence of systemic side effects. In some patients the oral administration is recommended and in others a combination of oral and local nasal therapy is advisable. For
272
THE
JOURNAL
OF
ALLERGY
local therapy, one may also use a combination of antihkaminic and vasoconstrictor drugs. These drugs are valuable symptomat,ic drugs either locally, orally, or in combination until specific therapeutic measures are helpful. SUMMARY
In consideration of the results reported here and in view of the absence of systemic side effects, 0.5 per cent isotonic buffered solution of Pyribenzamine hydrochloride appears to be a valuable antihistaminic drug for local nasal application in seasonal and nonseasonal hay fever. REFERENCES
1. Code,
C. F., Keating, J. U., and Leavitt, M. I).: Conference on Antihistamine in Allergy, The New York Academy of Sciences, Oct. 3, 1947. 2. Yonkman, F. F., Roth, F., Smith, J., Hansen, N., and Craver, R. N.: Local Properties of Antistine Hydrochloride (2.phenyl-benzyl-aminomethyl-imidazoline) and Pyribenzamine (N, N-dimethyl-N-benzyl-N’(a-pyridyl) -ethylenediamine hydrochloride, in press. 3. Mosely, V.: Am. J. Digest. Dis. 15: 410, 1948.
Agents Anesthetic mono-