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Histamine Antagonists in the Treatment of Allergic Disease in Children
HISTAMINE ANTAGONISTS IN THE TREATMENT OF" ALLERGIC DISEASE IN CHILDREN GEORGE
B.
LOGAN
WITHIN the past two years, several so-called histamine antagonists have been shown to be useful drugs. It is the purpose of this paper to consider the usefulness and shortcomings of two of these chemical compounds (benadryl and pyribenzamine) in the treatment of allergic diseases in children in the light of our recent experience. In recent articles by Code and Feinberg the background for the use of the drugs in the treatment of allergic conditions is reviewed. It may be said here, however, that there is good experimental evidence that release of histamine or a similar substance (H substance) plays an important role in the production of the symptoms of anaphylactic shock. There is some evidence, also, that the release of histamine ( or H substance) is equally important in human allergic disease. It is recognized, however, that histamine is not responsible for all of the allergic reaction. In the experimental laboratory the currently available histamine antagonists, at best, prevent only about 90 per cent of the symptoms of histamine shock. The histamine antagonists in some way block the allergic or histamine reaction, and contribute to its disappearance when it is already established. It may be seen, therefore, that even theoretically it cannot be expected that complete relief of symptoms of allergic disease will follow the use of the drugs which are at present obtainable. However, a drug which will give 50 to 75 per cent relief from allergic symptoms usually is felt by the patients to be a useful drug. Our clinical results to date in the treatment of children with allergic diseases have been sufficiently encouraging to justify the employment of these or similar drugs. Active research continues in this field, and it is anticipated that new "antihistamine" compounds will be introduced. As the antihistamine powers are enhanced and the untoward reactions are decreased, the newer compounds will displace the old. It is well to emphasize, however, that the use of these drugs in the control or prevention of the allergic reaction is not a substitute for thorough investigation of the allergy in question. They are drugs which bring only symptomatic relief to some, but not all, patients treated for allergic disease. They in no way immunize the child. Beneficial results which follow the administration of benadryl or pyribenzamine suggest that the disease treated may have an allergic basis or a similar mechanism of action. If no beneficial result ensues, 948
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
949
it cannot, however, be concluded that the disease being treated does not have an allergic basis. Our experience has been limited to observation of the effect in children of the two histamine antagonists: benadryl (beta-dimethylaminoethyl benzhydryl·ether hydrochloride) and pyribenzamine (N'pyridyl-N'-benzyl-N-dimethyl-ethylene diamine hydrochloride). Halpern, Bovet and others in France have reported their clinical and experimental experience with two other compounds: antergan (N'phenyl-N'benzyl-N-dimethyl-ethylene diamine) and neo-antergan (N-p-methaxy benzyl-N-dimethyl-amino ethyl a amino pyridine). Another drug, as yet unnamed, has been reported by Halpern to exert approximately sixteen times the antihistaminic effect of neo-antergan. These drugs are not yet commercially available in the United States. Reports 8 concerning antistine (2-[N-phenyl N-benzyl-amino ethyl] imidazolin) have appeared in the Swiss literature. It, likewise, is not as yet available for clinical use in the United States. DOSAGE AND ADMINISTRATION
The principles of adequate dosage and suitable means of administration are very important in pediatric therapeutics. Too large a dose of a drug must be avoided, and yet enough must be administered to obtain a therapeutic effect. Often, those only slightly familiar with the use of these drugs have shown a tendency to administer too small a dose for children. Our early experience with benadryl suggested that approximately 2 mg. per pound of body weight constituted an adequate total twenty-four hour dose. This amount is generally divided into three or four doses. However, children less than five or six years old often require more than this. We have administered up to 6 mg. per pound of body weight in a twenty-four !lour period, but not for more than one day. Older children may not need the entire suggested amount. It is necessary, at times, to administer benadryl and pyribenzamine at more frequent intervals. Often, we have found that a dose of pyribenzamine smaller than that of benadryl suffices. Both drugs may benefit a child, though sometimes one and sometimes the other is effective. Sometimes neither drug is of value. When two boys, nine and twelve years old, who had vasomotor rhinitis were being treated, 50 mg. given three times daily was without effect, but the same amount given five times daily, produced a favorable effect. EFFECTS IN GENERAL
Favorable Effects.-The favorable effect is prompt if an adequate dose has been administered. Rarely does one have to wait longer than an hour to observe it. In some instances, especially when the drugs have been ingested when the stomach was empty, effects have been
950
GEORGE B. LOGAN
noted within ten to fifteen minutes. The duration of the beneficial effect has varied from ninety minutes to nearly twenty-four hours. Untoward Effects.-Various observers have noted untoward reactions to the use of benadryl and pyribenzamine in 25 to 80 per cent of cases. Our experience with children has been that the reactions occur in 25 to 30 per cent of cases, and that they are sufficiently undesirable to cause discontinuance of use of the drug in about 10 to 15 per cent of cases. One author 3 recently has suggested that since some of the untoward reactions, particularly drowsiness, occur so frequently, they should be considered to be a part of the action of the drugs. His contention that the favorable effect of the histamine antagonists is not dependent on the antihistamine action, but on a sedative action, remains to be proved~ We have encountered the following reactions: drowsiness, vomiting, diarrhea, nausea, headache, tachycardia and hematuria. Except for drowsiness and vomiting, only single instances of these effects have been noted. Other undesirable reactions noted by other workers are: dizziness, dry mouth, feeling of nervousness, insomnia, epigastric distress, dermatitis, difficulty in co-ordination and dilatation of the pupils and also asthma, urticaria, collapse, muscular aching and acute melancholia. Leukopenia has not been reported to follow the use of benadryl or pyribenzamine, but it has followed the use of antergan. It would seem desirable to carry out periodic erythrocyte and leukocyte counts among children who are receiving these drugs for a prolonged period; such counts probably should be made at least every six to eight weeks. Drowsiness is not an undesirable reaction when these drugs .are administered at night. In some patients, the concomitant administration of caffeine and sodium benzoate or benzedrine in small doses has been reported to have overcome this side effect. One observer5 has reported the successful use of 25 mg. of pyridoxine or 50 mg. of niacinamide daily for the saIne purpose. Recently, we admitted a two year old boy to our hospital service because of the sudden onset twelve hours before of irrational behavior. He had hallucinations and attempted to pick things out of the air. After several hours of this sort of behavior, he went to sleep and seemed entirely normal on awakening some time later. Results of a complete neurologic examination were normal. The boy told his parents that he had ingested a capsule from the medicine cabinet. The capsule contained 50 mg. of benadryl. A somewhat similar instance recently was reported by Weil. The question of habit formation or addiction has been raised' by some physicians. We have had no such experience with children.. However, I do not think that these drugs are designed for an indefinite period of administration. Some physicians have noted that the sudden
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
951
stopping of administration of one of the antihistamine drugs to a .patient in the midst of a pollen season seems to precipitate a severe attack of the type of allergic disease from which the patient suffers. SPECIFIC CONDITIONS
Asthma.-There is considerable difference of opinion regarding the value of the histamine antagonists in the treatment of asthma. We feel that for children these antagonists are useful additions to therapy. It is generally agreed, however, that patients suffering from chronic asthma, especially if emphysematous changes are present, are rarely if ever benefited from the use of these drugs. A few patients suffering from what appears to b·e uncomplicated asthma seemingly are helped by the use of benadryl or pyribenzamine. Among children, we have often found that the concomitant use of one of these drugs with a saturated solution of sodium or potassium iodide is more effective than the use of either drug alone. Administration of this combination should be started at the first sign of an impending attack, since such a procedure utilizes the liquefying action of the iodides on bronchial secretions and the bronchodilating and antihistamine actions of benadryl or pyribenzamine. Children in whom wheezing develops whenever they contract a respiratory infection often are greatly relieved by the use of one of the antihistamine agents throughout the course of the infection. If these drugs do not give prompt relief, there is no contraindication to the institution of treatment with epinephrine, ephedrine or aminophylline; in fact, they can be used in conjunction with these latter drugs if it seems advisable. There are very few statistics in the literature regarding the use of the histamine antagonists in the treatment of children suffering from asthma or any other allergic disease. In one group of twenty-four children 7 who had both single and multiple asthmatic episodes, sixteen obtained good relief from the use of benadryl. The ages of the children varied from nine months to thirteen years. Another observer5 reported that six children were benefited among nine treated. Hay Fever.-Many children suffering from hay fever receive considerable symptomatic benefit from the use of benadryl or pyribenzamine. Among patients whose symptoms are severe or are complicated by much asthma, the use of these two drugs is not a substitute for a program of hyposensitization with the pollen antigen responsible for the hay fever. Benadryl and pyribenzamine are especially useful in relief of those youngsters who appear in the office for treatment for tne first time during the pollen season. They are also useful to complement a program of hyposensitization which is giving the patient inadequate relief. Pollen seasons vary in severity from year to year. Pollen counts also vary greatly from day to day. For this reason, the dose of histamine
952
GEORGE B. LOGAN
antagonists must be varied from day to day. It is important that both the patient, or parents, and physician understand this need for adjustment of the dose to the varying needs of the patient from day to day. In thirty-six cases reported in the literature,5, 7 thirty-two patients obtained good relief of symptoms. Vasomotor Rhinitis.-Patients suffering from vasomotor rhinitis frequently benefit from the use of these (antihistamine) drugs. Vasomotor rhinitis is a chronic, usually perennial, and frequently a longstanding disease. Dependence entirely on symptomatic treatment month after month with benadryl or pyribenzamine may be associated with some degree of hazard and, as noted previously herein, the patient should be seen at intervals of two months and erythrocyte and leukocyte counts should be made to ascertain the toxic effects, if any, arising from these drugs. Benadryl and pyribenzamine have their greatest field of usefulness in this disease during the period of allergic investigation and cleanup. An additional instance in which these drugs apparently are effective -was noted among a few children who perennially had plugged and running noses and who needed to undergo removal of their tonsils and adenoids, but whose congested nasal condition constantly seemed to contraindicate the procedures. Within a few days after they started to take benadryl, the nasal discharge and congestion abated, and one week to two weeks later the tonsils and adenoids were removed without incident. In each case, administration of the drug was stopped postoperatively. Its use during the first few weeks after surgery was unnecessary. At the time of this report, one of our young patients has been taking benadryl for seventeen months. She has cerebral palsy as well as vasomotor rhinitis. Both benadryl and pyribenzamine are equally effective in controlling her nasal symptoms. The patient prefers benadryl, however, because it also controls drooling. This is probably an instance in which the dry-mouth action of benadryl is a beneficial one. This action might be useful in the control of drooling in other children, even those who do not have an underlying allergic disease. Thorough allergic study and environmental cleanups are preferable to the long-continued use of the antihistamine drugs in vasomot01' rhinitis. Urticaria.-Those who have used the antihistamine drugs in the treatment of urticaria agree that it produces excellent therapeutic results. Prompt administration of one of these drugs usually is followed by prompt relief of symptoms. However, some of our patients who secured immediate symptomatic relief had to continue to take repeated doses every three hours for ten to twenty-one days before the urticaria cleared. More often, however, one dose is, or two doses are, sufficient to produce lasting subjective and objective relief of acute
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
953
urticaria. It should not be concluded that either benadryl or pyribenzamine has failed unless an adequate dose has been administered. Eczema.-The results of the use of these antihistamine drugs in the treatment of eczema have been disappointing. Our experience so far has shown that some of the patients experience relief of itching, but that the cutaneous lesion itself seems rarely to be abated. SUMMARY There are available at present two drugs, benadryl and pyribenzamine, which have an antihistamine action as evidenced by laboratory data. Administration of these drugs to patients has caused unpleasant side effects such as drowsiness, dryness of the mouth, vomiting and other effects in almost 30 per cent of cases. Use of the drugs has had to be discontinued because of these reactions in 10 to 15 per cent of cases. These drugs provide symptomatic relief only, and their use does not replace a thorough allergic investigation and the carrying out of all known precautions to avoid offending allergens. The drugs have been found useful in the treatment of children suffering from asthma, hay fever, vasomotor rhinitis, urticaria and to a much less extent, eczema. REFERENCES 1. Bovet, D.: Quoted by Feinberg, S. M. 2. Code, C. F.: The mechanism of anaphylactic and allergic reactions; an evaluation of the role of histamine in their production. Ann. Allergy. 2:457-471 (Nov.-Dec.) 1944. 8. Editorial: Benadryl-further comment. Ann. Allergy. 4:466-467 (Nov.-Dec.) 1946. • 4. Feinberg, S. M.: Histamine and antihistaminic agents; their experimental and therapeutic status. ].A.M.A. 182:702-718 (Nov. 28) 1946. 5. Goldstein, Hyman: The treatment of allergic patients with Benadryl; a report of seventy-nine cases. J. Pediat. 80:41-44 (Jan.) 1947. 6. Halpern, B. N.: Quoted by Feinberg, S. M. 7. Logan, G. B.: The use of benadryl in the treatment of certain allergic diseases of childhood. Ann. Allergy. 5:105-112; 192 (Mar.-Apr.) 1947. 8. Schindler, 0.: Klinische Untersuchungen mit der Antihistaminsubstanz Antistin Ciba. Schweiz. med. Wchnschr. 76:800-805 (Apr. 6) 1946. 9. Weil, H. R.: Unusual side effect from Benadryl. J.A.M.A. 188:898 (Feb. 8) 1947.
B.
LOGAN
WITHIN the past two years, several so-called histamine antagonists have been shown to be useful drugs. It is the purpose of this paper to consider the usefulness and shortcomings of two of these chemical compounds (benadryl and pyribenzamine) in the treatment of allergic diseases in children in the light of our recent experience. In recent articles by Code and Feinberg the background for the use of the drugs in the treatment of allergic conditions is reviewed. It may be said here, however, that there is good experimental evidence that release of histamine or a similar substance (H substance) plays an important role in the production of the symptoms of anaphylactic shock. There is some evidence, also, that the release of histamine ( or H substance) is equally important in human allergic disease. It is recognized, however, that histamine is not responsible for all of the allergic reaction. In the experimental laboratory the currently available histamine antagonists, at best, prevent only about 90 per cent of the symptoms of histamine shock. The histamine antagonists in some way block the allergic or histamine reaction, and contribute to its disappearance when it is already established. It may be seen, therefore, that even theoretically it cannot be expected that complete relief of symptoms of allergic disease will follow the use of the drugs which are at present obtainable. However, a drug which will give 50 to 75 per cent relief from allergic symptoms usually is felt by the patients to be a useful drug. Our clinical results to date in the treatment of children with allergic diseases have been sufficiently encouraging to justify the employment of these or similar drugs. Active research continues in this field, and it is anticipated that new "antihistamine" compounds will be introduced. As the antihistamine powers are enhanced and the untoward reactions are decreased, the newer compounds will displace the old. It is well to emphasize, however, that the use of these drugs in the control or prevention of the allergic reaction is not a substitute for thorough investigation of the allergy in question. They are drugs which bring only symptomatic relief to some, but not all, patients treated for allergic disease. They in no way immunize the child. Beneficial results which follow the administration of benadryl or pyribenzamine suggest that the disease treated may have an allergic basis or a similar mechanism of action. If no beneficial result ensues, 948
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
949
it cannot, however, be concluded that the disease being treated does not have an allergic basis. Our experience has been limited to observation of the effect in children of the two histamine antagonists: benadryl (beta-dimethylaminoethyl benzhydryl·ether hydrochloride) and pyribenzamine (N'pyridyl-N'-benzyl-N-dimethyl-ethylene diamine hydrochloride). Halpern, Bovet and others in France have reported their clinical and experimental experience with two other compounds: antergan (N'phenyl-N'benzyl-N-dimethyl-ethylene diamine) and neo-antergan (N-p-methaxy benzyl-N-dimethyl-amino ethyl a amino pyridine). Another drug, as yet unnamed, has been reported by Halpern to exert approximately sixteen times the antihistaminic effect of neo-antergan. These drugs are not yet commercially available in the United States. Reports 8 concerning antistine (2-[N-phenyl N-benzyl-amino ethyl] imidazolin) have appeared in the Swiss literature. It, likewise, is not as yet available for clinical use in the United States. DOSAGE AND ADMINISTRATION
The principles of adequate dosage and suitable means of administration are very important in pediatric therapeutics. Too large a dose of a drug must be avoided, and yet enough must be administered to obtain a therapeutic effect. Often, those only slightly familiar with the use of these drugs have shown a tendency to administer too small a dose for children. Our early experience with benadryl suggested that approximately 2 mg. per pound of body weight constituted an adequate total twenty-four hour dose. This amount is generally divided into three or four doses. However, children less than five or six years old often require more than this. We have administered up to 6 mg. per pound of body weight in a twenty-four !lour period, but not for more than one day. Older children may not need the entire suggested amount. It is necessary, at times, to administer benadryl and pyribenzamine at more frequent intervals. Often, we have found that a dose of pyribenzamine smaller than that of benadryl suffices. Both drugs may benefit a child, though sometimes one and sometimes the other is effective. Sometimes neither drug is of value. When two boys, nine and twelve years old, who had vasomotor rhinitis were being treated, 50 mg. given three times daily was without effect, but the same amount given five times daily, produced a favorable effect. EFFECTS IN GENERAL
Favorable Effects.-The favorable effect is prompt if an adequate dose has been administered. Rarely does one have to wait longer than an hour to observe it. In some instances, especially when the drugs have been ingested when the stomach was empty, effects have been
950
GEORGE B. LOGAN
noted within ten to fifteen minutes. The duration of the beneficial effect has varied from ninety minutes to nearly twenty-four hours. Untoward Effects.-Various observers have noted untoward reactions to the use of benadryl and pyribenzamine in 25 to 80 per cent of cases. Our experience with children has been that the reactions occur in 25 to 30 per cent of cases, and that they are sufficiently undesirable to cause discontinuance of use of the drug in about 10 to 15 per cent of cases. One author 3 recently has suggested that since some of the untoward reactions, particularly drowsiness, occur so frequently, they should be considered to be a part of the action of the drugs. His contention that the favorable effect of the histamine antagonists is not dependent on the antihistamine action, but on a sedative action, remains to be proved~ We have encountered the following reactions: drowsiness, vomiting, diarrhea, nausea, headache, tachycardia and hematuria. Except for drowsiness and vomiting, only single instances of these effects have been noted. Other undesirable reactions noted by other workers are: dizziness, dry mouth, feeling of nervousness, insomnia, epigastric distress, dermatitis, difficulty in co-ordination and dilatation of the pupils and also asthma, urticaria, collapse, muscular aching and acute melancholia. Leukopenia has not been reported to follow the use of benadryl or pyribenzamine, but it has followed the use of antergan. It would seem desirable to carry out periodic erythrocyte and leukocyte counts among children who are receiving these drugs for a prolonged period; such counts probably should be made at least every six to eight weeks. Drowsiness is not an undesirable reaction when these drugs .are administered at night. In some patients, the concomitant administration of caffeine and sodium benzoate or benzedrine in small doses has been reported to have overcome this side effect. One observer5 has reported the successful use of 25 mg. of pyridoxine or 50 mg. of niacinamide daily for the saIne purpose. Recently, we admitted a two year old boy to our hospital service because of the sudden onset twelve hours before of irrational behavior. He had hallucinations and attempted to pick things out of the air. After several hours of this sort of behavior, he went to sleep and seemed entirely normal on awakening some time later. Results of a complete neurologic examination were normal. The boy told his parents that he had ingested a capsule from the medicine cabinet. The capsule contained 50 mg. of benadryl. A somewhat similar instance recently was reported by Weil. The question of habit formation or addiction has been raised' by some physicians. We have had no such experience with children.. However, I do not think that these drugs are designed for an indefinite period of administration. Some physicians have noted that the sudden
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
951
stopping of administration of one of the antihistamine drugs to a .patient in the midst of a pollen season seems to precipitate a severe attack of the type of allergic disease from which the patient suffers. SPECIFIC CONDITIONS
Asthma.-There is considerable difference of opinion regarding the value of the histamine antagonists in the treatment of asthma. We feel that for children these antagonists are useful additions to therapy. It is generally agreed, however, that patients suffering from chronic asthma, especially if emphysematous changes are present, are rarely if ever benefited from the use of these drugs. A few patients suffering from what appears to b·e uncomplicated asthma seemingly are helped by the use of benadryl or pyribenzamine. Among children, we have often found that the concomitant use of one of these drugs with a saturated solution of sodium or potassium iodide is more effective than the use of either drug alone. Administration of this combination should be started at the first sign of an impending attack, since such a procedure utilizes the liquefying action of the iodides on bronchial secretions and the bronchodilating and antihistamine actions of benadryl or pyribenzamine. Children in whom wheezing develops whenever they contract a respiratory infection often are greatly relieved by the use of one of the antihistamine agents throughout the course of the infection. If these drugs do not give prompt relief, there is no contraindication to the institution of treatment with epinephrine, ephedrine or aminophylline; in fact, they can be used in conjunction with these latter drugs if it seems advisable. There are very few statistics in the literature regarding the use of the histamine antagonists in the treatment of children suffering from asthma or any other allergic disease. In one group of twenty-four children 7 who had both single and multiple asthmatic episodes, sixteen obtained good relief from the use of benadryl. The ages of the children varied from nine months to thirteen years. Another observer5 reported that six children were benefited among nine treated. Hay Fever.-Many children suffering from hay fever receive considerable symptomatic benefit from the use of benadryl or pyribenzamine. Among patients whose symptoms are severe or are complicated by much asthma, the use of these two drugs is not a substitute for a program of hyposensitization with the pollen antigen responsible for the hay fever. Benadryl and pyribenzamine are especially useful in relief of those youngsters who appear in the office for treatment for tne first time during the pollen season. They are also useful to complement a program of hyposensitization which is giving the patient inadequate relief. Pollen seasons vary in severity from year to year. Pollen counts also vary greatly from day to day. For this reason, the dose of histamine
952
GEORGE B. LOGAN
antagonists must be varied from day to day. It is important that both the patient, or parents, and physician understand this need for adjustment of the dose to the varying needs of the patient from day to day. In thirty-six cases reported in the literature,5, 7 thirty-two patients obtained good relief of symptoms. Vasomotor Rhinitis.-Patients suffering from vasomotor rhinitis frequently benefit from the use of these (antihistamine) drugs. Vasomotor rhinitis is a chronic, usually perennial, and frequently a longstanding disease. Dependence entirely on symptomatic treatment month after month with benadryl or pyribenzamine may be associated with some degree of hazard and, as noted previously herein, the patient should be seen at intervals of two months and erythrocyte and leukocyte counts should be made to ascertain the toxic effects, if any, arising from these drugs. Benadryl and pyribenzamine have their greatest field of usefulness in this disease during the period of allergic investigation and cleanup. An additional instance in which these drugs apparently are effective -was noted among a few children who perennially had plugged and running noses and who needed to undergo removal of their tonsils and adenoids, but whose congested nasal condition constantly seemed to contraindicate the procedures. Within a few days after they started to take benadryl, the nasal discharge and congestion abated, and one week to two weeks later the tonsils and adenoids were removed without incident. In each case, administration of the drug was stopped postoperatively. Its use during the first few weeks after surgery was unnecessary. At the time of this report, one of our young patients has been taking benadryl for seventeen months. She has cerebral palsy as well as vasomotor rhinitis. Both benadryl and pyribenzamine are equally effective in controlling her nasal symptoms. The patient prefers benadryl, however, because it also controls drooling. This is probably an instance in which the dry-mouth action of benadryl is a beneficial one. This action might be useful in the control of drooling in other children, even those who do not have an underlying allergic disease. Thorough allergic study and environmental cleanups are preferable to the long-continued use of the antihistamine drugs in vasomot01' rhinitis. Urticaria.-Those who have used the antihistamine drugs in the treatment of urticaria agree that it produces excellent therapeutic results. Prompt administration of one of these drugs usually is followed by prompt relief of symptoms. However, some of our patients who secured immediate symptomatic relief had to continue to take repeated doses every three hours for ten to twenty-one days before the urticaria cleared. More often, however, one dose is, or two doses are, sufficient to produce lasting subjective and objective relief of acute
HISTAMINE ANTAGONISTS IN ALLERGIC DISEASE
953
urticaria. It should not be concluded that either benadryl or pyribenzamine has failed unless an adequate dose has been administered. Eczema.-The results of the use of these antihistamine drugs in the treatment of eczema have been disappointing. Our experience so far has shown that some of the patients experience relief of itching, but that the cutaneous lesion itself seems rarely to be abated. SUMMARY There are available at present two drugs, benadryl and pyribenzamine, which have an antihistamine action as evidenced by laboratory data. Administration of these drugs to patients has caused unpleasant side effects such as drowsiness, dryness of the mouth, vomiting and other effects in almost 30 per cent of cases. Use of the drugs has had to be discontinued because of these reactions in 10 to 15 per cent of cases. These drugs provide symptomatic relief only, and their use does not replace a thorough allergic investigation and the carrying out of all known precautions to avoid offending allergens. The drugs have been found useful in the treatment of children suffering from asthma, hay fever, vasomotor rhinitis, urticaria and to a much less extent, eczema. REFERENCES 1. Bovet, D.: Quoted by Feinberg, S. M. 2. Code, C. F.: The mechanism of anaphylactic and allergic reactions; an evaluation of the role of histamine in their production. Ann. Allergy. 2:457-471 (Nov.-Dec.) 1944. 8. Editorial: Benadryl-further comment. Ann. Allergy. 4:466-467 (Nov.-Dec.) 1946. • 4. Feinberg, S. M.: Histamine and antihistaminic agents; their experimental and therapeutic status. ].A.M.A. 182:702-718 (Nov. 28) 1946. 5. Goldstein, Hyman: The treatment of allergic patients with Benadryl; a report of seventy-nine cases. J. Pediat. 80:41-44 (Jan.) 1947. 6. Halpern, B. N.: Quoted by Feinberg, S. M. 7. Logan, G. B.: The use of benadryl in the treatment of certain allergic diseases of childhood. Ann. Allergy. 5:105-112; 192 (Mar.-Apr.) 1947. 8. Schindler, 0.: Klinische Untersuchungen mit der Antihistaminsubstanz Antistin Ciba. Schweiz. med. Wchnschr. 76:800-805 (Apr. 6) 1946. 9. Weil, H. R.: Unusual side effect from Benadryl. J.A.M.A. 188:898 (Feb. 8) 1947.