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`EXHIBIT A
`
`EXHIBIT A
`
`

`
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`MAY 1951
`
`THE USES AND ABUSES OF
`
`ANTIHISTAMINE DRUGS*
`
`WILLIAM BOWEN SHERMAN
`
`Assistant Clinical Professor of Medicine, Columbia University, College of Physicians and Surgeons.
`Attending Physician, Roosevelt Hospital. Assistant Attending Physician, The Presbyterian Hospital.
`
`B
`
`9 “ARLY last year a drug manufacturer estimated that one
`hundred million dollars worth of antihistaminic drugs
`would be sold during i95o!1 Whether or not this pre-
`diction proves accurate, it emphasizes the fact that these
`n a drugs are being used in tremendous quantities. Since they
`were first introduced in America only five years ago, first physicians
`and then the public have been offered such a confusing mass of adver-
`tising that a careful appraisal of their therapeutic value is warranted at
`this time.
`
`Since the discovery of anaphylaxis and the recognition of its relation-
`ship to human allergy, many investigators have studied non—specific
`methods of preventing or controlling anaphylactic shock. In 1932, Hill
`and Martin? reviewed the results obtained by 165 such methods which
`were more or less effective in experimental animals; not one of these
`was applicable to the practical treatment of allergic disease in man.
`Many other methods have since been proposed; of these the most
`successful are based on the concept of histamine as an intermediary
`between the antigen-antibody reaction and the manifestations of allergy
`and anaphylaxis. This theory, proposed by Dale and Laidlawa in 1910,
`is supported by many researchers showing that histamine is released in
`anaphylactic shock and in allergies of the immediate urticaria] type and
`gives rise to many of their chief manifestations. In certain aspects of
`anaphylaxis, such as the loss of coagulability of the blood in dogs, and
`in the delayed types of human allergy, such as tuberculin sensitization
`and contact dermatitis, histamine appears to play no part.
`VVithin these limits, therapy directed at controlling the action of
`histamine offered the promise of a single form of treatment effective in
`" Read at The New York Academy of Medicine, November 3, 1950 in the 25th Series of Friday
`Afternoon Lectures.
`
`APOTEX_AZFL 0061929
`
`

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`310
`
`THE BULLETIN
`
`many allergic diseases, without the need of determining the specific
`causative allergen. The earlier efforts in this direction, employing the
`enzyme histaminase, injections of histamine in attempts to induce toler-
`ance, and histamine azo—protein (Hapamine) to produce antibodies to
`histamine, met with no significant success and have been abandoned.
`In 1937, Staub and Bovet“ reported investigations in experimental
`animals of the anti-anaphylactic and antihistaminic properties of a series
`of phenolic ethers synthesized by Fourneau. These properties were
`found to be shown to asignificant degree by thymoxyethyl-diethylamine,
`designated as 929F, which may be considered the first synthetic anti-
`histaminic but was too toxic for clinical use. The ethanolamine portion
`of its structure is utilized in the modern drugs Benadryl and Decapryn.
`Subsequently Staub5 studied the antihistaminic properties of other
` pm1nm and showed that 151113, an ethylene diamine
`derivative, was more potent than 92oF, but still too toxic for clinical
`use. In 1942 Halpern‘ described a related compound, Antergan, which I
`was 10 times as potent in animals and sufficiently safe for clinical use.
`This antihistaminic drug showed definite therapeutic effects in allergic
`rhinitis and urticaria, but was soon replaced by Neoantergan, another
`ethylenediamine compound which proved less toxic and more potent.
`During the past war, while these studies were being made in France,
`American investigations led to the development of Benadryl, an ethanol-
`amine derivative, and Pyribenzamine, an ethylenediamine compound
`related to Neoantergan. Both of these compounds had definite thera-
`peutic efiects in certain allergic diseases but were sufliciently toxic to
`stimulate further search for more potent and less toxic agents. During
`the past five years dozens of such compounds have been produced and
`screened by the drug industry and seventeen have been marketed, each
`with its own claims of potency and freedom from toxicity. The average
`physician is justifiably bewildered by this choice of essentially similar
`medications and may be comforted by the statement of the Council on
`Pharmacy that “the number of preparations on the market has served
`to provide confusion.”
`The confusion is further increased by the application of both generic
`and proprietary names to each drug, and in many instances by the fact
`that the same drug is offered by two or more manufacturers under
`different proprietary names. For example, chlorcyclizine is marketed by
`Burroughs Wellcome as Perazil and by Abbott as Di-Paralene. In general,
`
`APOTEX_AZFL 0061930
`
`

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`Anfibistmdne Drugs
`
`3 1 r
`
`the proprietary names are the most familiar and will be used in this
`discussion.
`
`With the licensing of antihistaminic drugs for sale without prescrip-
`tion, many of the familiar drugs are being offered in reduced dosage
`under a variety of newly coined names. For example, pyranisamine
`25 mg., familiar to physicians as Neoantergan, is offered to the public
`under thirty-two different names such as Kriptin, Anatamine, Macy’s
`Antihistamine, Superhist, etc.
`Chemistry: Chemically the twenty antihistaminic drugs more or
`less familiar to physicians, represent variations on a relatively few basic
`structures. The most commonly used structure is the ethylenediamine
`base (Fig. 1). In Pyrrolazote the nitrogen written at the left is included
`in a phenothiazine radical and that at the right is a pyrrolidine ring. In
`Antistine the 2nd carbon of the central chain is linked to 2 nitrogen
`atoms as part of an imidazoline ring, while in chlorcyclizine the 2
`nitrogens form part of a piperazine ring rather than a simple chain.
`
`R,
`
`R2
`
`H H
`N-C‘ C'N
`
`CH3
`
`H H
`
`CH3
`
`Fig. 1: Ethylene diamine structure. Antergan, Neoanter-
`gan, Pyribenzamine, Histadyl
`(Thenylene), chlorothen
`(Tagathen), Diatrin, Neohetramine and Thenfadil are
`represented by this formula with variations in the radi-
`cals R1 and R2.
`
`H H H
`
`CH3
`
`C—C-C.-N
`
`H H
`
`CH3
`
`Fig. 2: Aminopropane structure.
`
`(Trimeton)
`
`If the nitrogen at the left.is replaced by carbon, the ethylenediamine
`structure is converted to aminopropane, but the antihistaminic activity
`is preserved, as in Trimeton and Chlor-Trimeton (Fig. 2).
`
`APOTEX_AZFL 0061931
`
`

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`312
`
`THE BULLETIN
`
`If an oxygen atom or ether linkage is introduced at the same point,
`the ethanolamine series of antihistaminics,
`typified by Benadryl and
`Decapryn, is produced (Fig. 3).
`The one chemically unique antihistaminic, Thephorin, has a complex
`ring structure based on pyridindene but is believed to break down in
`metabolism to a structure of the ethyldimethylamine type (Fig. 4).
`
`H
`
`H H
`
`CH3
`
`C“O"C"C"N
`
`H H
`
`CH3
`
`Fig. 3: Ethanolamine structure.
`
`(Benadryl)
`
`CH
`
`Assumed point
`of breakdown
`Fig. 4: Thephorin.
`
`All of these are qualitatively similar in their pharmacologic actions,
`although differing quantitatively in antihistamine potency and toxicity.
`Pharmacology: Pharmacologically, an antihistaminic drug has been
`defined by Bovet‘ as “a counterpoison having no specific activity of its
`own on the normal animal, its properties becoming apparent only when
`it can manifest a detoxifying power against the action of histamine.”
`While the drugs marketed as antihistaminics represent
`the nearest
`approaches to this ideal found in screening hundreds of compounds,
`and all show definite antagonism to the actions of histamine, none can
`be said to be actually free of activity upon the normal animal.
`The antagonism to histamine may be readily demonstrated by in-
`hibition of the effects of histamine in causing contraction of smooth
`
`APOTEX_AZFL 0061932
`
`

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`Amibistamine Drugs
`
`3 I 3
`
`muscle, capillary dilatation and wheal formation in the skin, hypotension
`and lachrymation. On the other hand, the stimulation of gastric secretion
`by histamine is not appreciably affected. The exact nature of the hista-
`mine antagonism has not been established but has been assumed to result
`from blocking the access of histamine to cell receptors.
`Presumably through inhibiting the action of histamine as an inter-
`mediary, the antihistaminic drugs inhibit anaphylactic shock in guinea
`pigs, rabbits and dogs; also inhibit the Dale reaction in the isolated
`smooth muscle of the sensitized guinea pig. In adequate concentrations,
`these drugs inhibit the specific wheal reaction in the skin of allergic
`humans.
`
`The other pharrnacologic effects, considered as side effects, vary some-
`what among the various drugs. Most of the group show a minor degree
`of atropine—like effect
`in antagonizing the actions of acetylcholine.
`The dry mouth of which some patients complain while taking the anti-
`histaminics may be attributed to this action.
`Practically all
`the antihistaminic drugs act as local anesthetics.
`Benadryl, Pyribenzamine and Neoantergan are said to be two or three
`times as active as procaine in this effect. Some authors have recommended
`the practical use of these drugs for this purpose and it is probable that
`their antipruritic effect as local applications may be due to action as
`anesthetics rather than antihistaminics. The relation of local anesthetic
`
`and antihistaminic effects is also of interest since procaine and its deriva-
`tive diethylaminoethanol have been shown to inhibit allergic urticarial
`reactions. Local anesthetics may be expected to decrease the effects of
`histamine in the skin by blocking the axone reflexes which take part in
`the spread of the flare produced. The careful studies of Code” and his
`associates indicate that the inhibition of the histamine reaction in human
`
`skin by Benadryl, Pyribenzamine and Neoantergan is not dependent
`upon local anesthesia. These three drugs showed greater antihistaminic
`effects than concentrations of procaine equally effective as anesthetics,
`and their antihistaminic effect persisted after the local anesthetic effect
`wore off, while that of procaine did not. Furthermore, when many
`different antihistaminics were tested,
`it was found that
`those most
`effective as local anesthetics were often least active against histamine.
`The actions of the antihistaminics on the central nervous system are
`among the most important side effects. In experimental animals, the
`nervous effect is usually excitement, but with ordinary doses in man,
`
`APOTEX_AZFL 0061933
`
`

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`314
`
`THE BULLETIN
`
`sedation or depression is the usual effect. With the clinical use of the
`various drugs this may be apparent in I0 to 60 per cent of the patients,
`the incidence being highest with Benadryl and Decapryn.
`Occasional individuals are excited rather than sedated by these drugs
`and in the case of Thephorin, excitement is the predominant nervous
`effect. With excessive doses of practically any of the drugs excitement
`and confusion of psychotic degree may result.
`Choice of Drugr: The different antihistaminic drugs show consider-
`able variations in eflicacy and toxicity, but no one of them has a suffi—
`ciently greater ratio of potency to toxicity to be called the best. There
`are dozens of statistical reports of therapeutic and toxic effects of the
`various drugs but attempts to compare them are fraught with error
`because of variations in dosage used by various authors and differences
`in evaluation of results. An exact order of eflicacy or toxicity cannot
`be established, but general classifications are helpful as a guide to physi-
`cians who can scarcely be expected to be familiar with all of the seven-
`teen drugs that are available. In this grouping, I have borrowed freely
`from that given by Feinberg, Malkiel and Feinberg in their recent book
`“The Antihistamines.”‘° Among the most potent drugs are Benadryl,
`Pyribenzamine, Neoantergan, Histadyl
`(Thenylene), Chlorathen and
`Decapryn. Of these Benadryl and Decapryn are the most sedative. A
`second group of drugs which are somewhat less potent but also less
`toxic includes Chlor-Trimeton and chlorcylizine (Perazil or Di-Para-
`lene) which also have the advantage of longer duration of action. A
`third group of drugs less effective but valuable because of low toxicity
`includes Neohetramine, Antistine and Thephorin.
`Such a classification does not accurately predict the reaction on
`each individual patient, but serves as a guide in selecting a drug for
`a particular purpose and in choosing a substitute if the one first tried
`proves ineffective or too toxic. For example, in mild hay fever one does
`well to choose a drug of relatively low toxicity, such as Perazil or
`Chlor-Trimeton, while for a patient confined to bed with intolerably
`itching urticaria, one of the most potent and most sedative drugs such
`as Benadryl or Decapryn is suitable. If a patient with rhinitis finds
`Pyribenzamine effective but too sedative, Neohetramine would be a
`more logical substitute than Benadryl, which is even more depressing.
`Dosage Forms: All of the common antihistaminics are readily ab-
`sorbed from the gastro-intestinal tract and are most commonly given
`
`APOTEX_AZFL 0061934
`
`

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`Ann’/oz'sta1m'ne Drugs
`
`3 1 5
`
`by mouth. They are marketed in pills or capsules containing one average
`adult dose which may be 4 to 100 mg. with different drugs. Details of
`dosage are different for each drug but in general the maximum dose
`is twice the average dose, repeated three to four times a day. Most of
`the drugs are also offered in liquid preparations for administration of
`fractional doses to children. The dosage of preparations offered for sale
`without a prescription is in general half the average dose offered to
`physicians.
`The average duration of effect is about four hours, but the action of
`chlorcyclizine and Chlor—Trimeton is reported to last 8-12 hours.
`In addition to the oral preparations, Benadryl and Histadyl are
`available in sterile solutions for intramuscular and intravenous use. These
`
`routes give prompter and often more powerful effects than oral admin-
`lStI'atl0n.
`
`For local application to itching eruptions most of the common anti-
`histaminics are offered in ointments, creams and lotions. A few are
`offered in drops for ophthalmic or nasal use.
`Uses: The primary purpose of the development of the antihistaminic
`drugs was the symptomatic relief of those allergic diseases in the patho-
`genesis of which histamine was known or believed to play a part, such
`as allergic rhinitis, asthma, urticaria, atopic dermatitis and serum sickness.
`Subsequently they have been tried empirically in many other diseases
`not known to be related to histamine. Such eflicacy as they show is
`always in temporary symptomatic relief; in no disease are they curative.
`Even in those allergic disorders for which they have proved most useful,
`their efl-icacy is often surpassed by that of cortisone and ACTH.
`For evaluation of their eflicacy in various diseases, a host of statistics
`are available. When one attempts to consolidate various reports, however,
`it is apparent that the simple figures do not show the entire picture. In a
`single disease entity, mild and early cases many prove amenable to treat-
`ment while advanced cases are not. Some authors have used an “average
`dose” two or three times daily while others have prescribed two or
`three times as much four times a day. In evaluating results some have
`reported any significant degree of relief as a favorable result, while
`others have restricted this term to cases essentially free of symptoms.
`Therefore, we can best speak in general terms and use actual percentages
`of relief sparingly.
`The most extensive clinical evaluation has been in allergic rhinitis.
`
`APOTEX_AZFL 0061935
`
`

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`316
`
`THE BULLETIN
`
`Here the results obtained vary greatly with the severity and chronicity
`of the disease. In the acute stage of allergic rhinitis, either seasonal or
`non—seasonal, with sneezing, rhinorrhea and itching of the eyes and
`throat, satisfactory temporary relief may be obtained in 60-80 per cent
`of cases by use of the antihistaminics. On the other hand,
`the nasal
`obstruction due to engorgement of the mucosa, which is a prominent
`feature of long—standing rhinitis, is less susceptible to their action. Ad-
`vanced rhinitis with polypoid changes in the membrane is only slightly
`affected. These differences are reflected in the statistics which usually
`show 60-75 per cent relief of seasonal hay fever and roughly 50 per
`cent for non—seasonal rhinitis.
`
`In the case of hay fever, it means that patients with mild intermittent
`symptoms during the pollen season or with a short season caused by
`one of the tree pollens, may expect considerable relief from these drugs.
`while those who suffer continuously for 4-8 weeks during the grass
`or ragweed season will usually obtain only partial alleviation of symp-
`toms. Since no other type of drugs except
`the recently introduced
`cortisone and ACTH offers as much symptomatic relief, the choice of
`treatment lies between the use of antihistaminics and the more elaborate
`
`and time-consuming method of prophylactic injections of pollen ex-
`tract, started six or more weeks before the onset of the pollen season.
`Statistically the injection treatment is shown to be more effective but
`symptomatic treatment with antihistaminics has obvious advantages of
`simplicity and convenience. When the patient is first seen during the
`hay fever season, there is no opportunity for prophylactic injections
`and the antihistaminics should be used. The results obtained that season
`
`offer a basis for decision as to the choice of treatment in the following
`year. However,
`if pollen asthma occurs during the hay fever season,
`injection treatment is definitely indicated, since its occurrence is not
`appreciably prevented by the antihistaminics and it tends to become
`progressively more severe from year to year if other measures are not
`taken. On the other hand, a suitable course of pollen injections may be
`expected to relieve pollen asthma in 80 per cent of the cases.
`This comparison of the effects of pollen injections and antihista-
`minics on hay fever does not mean that a choice must be made between
`them;
`the best results are obtained by combining both methods of
`treatment.
`
`In non—seasonal allergic rhinitis it has been indicated that the anti-
`
`APOTEX_AZFL 0061936
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`

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`Am1'bz'stmm’12:e Drugs
`
`3 1 7
`
`histaminics are more effective for relief of acute symptoms than for
`persistent nasal congestion. Therefore,
`these drugs are most useful as
`a temporary measure and long—standing cases should be‘ studied for
`determination of the causative factors. When the symptoms are due to
`sensitization to dust, animal danders or other inhalant allergens, much
`greater relief may be expected from allergic treatment than from con-
`tinuous use of symptomatic drugs.
`In bronchial asthma, the antihistaminics are considerably less effec-
`tive than in allergic rhinitis. Many studies report 20-40 per cent of all
`asthmatics benefited by these drugs, but the patients relieved are almost
`invariably those with mild asthma usually more easily controlled by
`other oral medications such as ephedrine and aminophylline. In severe
`chronic asthma, when treatment is a real problem, the antihistaminics
`are generally useless. Certain proprietary combinations of antihistaminics
`with aminophyllin or ephedrine are moderately effective for the relief
`of mild asthma; but on the whole the antihistaminics offer no notable
`advance in the symptomatic relief of asthma.
`Among the allergic dermatoses, urticaria is the most responsive to
`antihistaminic drugs. Most statistics indicate that 70-90 per cent of pa-
`tients with acute urticaria are benefited by these medications. In some
`cases the “average dose” of the drug selected is effective, but often
`this must be doubled and repeated three or four times a day. In severe
`urticaria, intramuscular injections may be more effective than oral use.
`Relief of itching is often obtained although wheals may persist.
`Chronic urticaria is somewhat less responsive than acute but the anti-
`histaminics are still among the most valuable drugs for symptomatic
`relief. Continuous control may require large doses repeated three or
`four times daily. As in other chronic diseases, the effect of these drugs
`is only symptomatic and patients with urticaria persisting or recurring
`over a period of weeks should be carefully studied to determine the
`causative factors.
`
`Angioedema or giant urticaria is less susceptible to these drugs but
`it is also relatively resistant to most other forms of treatment, so a trial
`of their eflicacy is warranted. In acute attacks, large doses of antihista-
`minics by mouth or injected parenterally may be used concurrently
`with injections of epinephrine in oil. For prevention of recurrent attacks
`continuous use of one of the antihistaminics may be advised, but as in
`chronic urticaria, a diligent search for etiologic factors should be made.
`
`APOTEX_AZFL 0061937
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`

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`318
`
`THE BULLETIN
`
`The antihistaminics are of definite value in treatment of serum sick-
`
`ness and similar reactions to penicillin. Relatively large doses are re-
`quired and intramuscular administration may be more effective. The
`effects are chiefly in the relief of itching and urticaria; arthralgia and
`fever are not appreciably affected. In very severe cases, the antihista-
`minics may prove ineffectual and ACTH or cortisone should be used.
`In severe anaphylactic reactions resulting from the injection of
`heterologous antisera or other biologic products, the effect of the anti-
`histaminics is too slow to be the main therapeutic effort. Epinephrine
`is more rapid and eflicacious, but its action may be supplemented by
`parenteral injections of Benadryl or Histadyl.
`The antihistaminic drugs have been widely used in atopic dermatitis,
`but estimates of favorable results have been reported by various authors
`as o to 75 per cent. This discrepancy is due to the fact that more than
`half of the patients treated have some relief of itching but there is no
`immediate change in the appearance of the skin lesions such as is pro-
`duced by cortisone and ACTH. However, since itching is one of the
`most troublesome symptoms of atopic dermatitis and a considerable
`part of the objective change in the skin results from scratching and
`secondary infection, control of the itching constitutes an important
`part of treatment. For this purpose, the antihistaminics are among the
`most effective systemic medications. When the itching is severe, the
`drugs having a pronounced sedative effect such as Benadryl and De-
`capryn are most effective. In addition to oral preparations, many of
`the drugs are supplied in ointments, creams and lotions for local appli-
`cations. Such preparations are reasonably effective in the control of
`itching, either through local anesthetic or antihistaminic actions.
`Contact dermatitis,
`in contrast to atopic dermatitis,
`is a delayed
`form of allergic reaction in the pathogenesis of which histamine has not
`been shown to play a part. However, empirical trial of the antihista-
`minics, both as oral medications and topical applications, has been found
`to afford some relief of itching but not to alter the appearance or
`direction of the lesions. Indeed the antipruritic effect of these drugs
`is by no means limited to the allergic dermatoses. Itching due to such
`varied causes as chicken pox, jaundice and Hodgkin’s disease may be
`alleviated to some degree by the local or general use of antihistaminics.
`Here again, these drugs may be exerting an anesthetic action on the
`nerve endings and one need not assume that histamine is being an-
`
`APOTEX_AZFL 0061938
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`

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`Anti/aistaimine Drugs
`
`3 I 9
`
`tagonized. In pruritus ani and vulvae, moderate relief comparable to
`that afforded by local anesthetics of the procaine group may be attained.
`Trials of antihistaminic drugs in cases of gastrointestinal allergy
`have given some favorable results but experience in this field is limited.
`In evaluating the results one must remember that many of these drugs
`have sedative and anti—cholinergic as well as specific antihistaminic
`effects.
`
`In the type of headaches classed as histamine cephalalgia, the re-
`sults are on the whole disappointing. Satisfactory control is rarely ob-
`tained with the antihistaminics. Such failures cast some doubt on the
`
`diagnosis but it may be recalled that not all known effects of histamine,
`such as that on the gastric secretion, are prevented by these drugs. Also
`in migraine attributed to food allergy,
`the results are generally dis-
`appointing.
`As in contact dermatitis, the antihistaminic drugs have been applied
`empirically or illogically to other forms of hypersensitivity in which
`histamine has not been shown to play a part. For example, these drugs
`have been administered to patients with pulmonary tuberculosis in an
`attempt to eliminate the factor of tuberculin sensitization from the
`pathogenesis of the disease. The clinical results of such therapy are not
`convincing and most careful studies have shown that the readily ob-
`served manifestation of the sensitization. namely the cutaneous reaction
`to the tuberculin test,
`is not inhibited by the antihistaminics.
`The results obtained in allergic reactions to drugs are variable as
`are the mechanisms of these reactions. In general, urticarial reactions in
`which histamine is presumably a factor, are benefited while other mani-
`festations of drug sensitization such as drug fever, dermatitis medica-
`mentosa and leukopenia, are not. Histamine-like reactions to injections
`of Diodrast are not prevented by prophylactic use of antihistaminics.
`Bronchospastic reactions to curare, believed to result from release of
`histamine, are benefited.“
`In view of the similarity of symptoms of the common cold and
`allergic rhinitis, it is not surprising that the effects of antihistaminics on
`virus rhinitis were soon tested. In 194.5 Tr0escher—Elam, Ancona and
`Kerr” reported the presence of a histamine-like substance in the nasal
`secretions of patients with common colds. This study has not been con-
`firmed, but in 1949 Fox and Liv/ingston,‘3 without conclusive evidence,
`expressed the opinion that allergy to the cold virus played a prominent
`
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`320
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`THE BULLETIN
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`part in the pathogenesis of the cold.
`Actual use of Benadryl in the treatment of the common cold with
`apparently brilliant results was reported by Brewster in 1947 in the
`U.S. Navy Medical Bulletin.“ This and four subsequent reports by the
`same author stressed the point that the use of Benadryl during the first
`few hours after the onset of a cold brought about recovery within
`twenty-four hours in a large proportion of colds. Murray“ and also
`Gordon” published similar reports and a more carefully controlled
`study by Arminio and Sweet” indicated that the antihistaminics were
`effective in the prevention and cure of colds. These reports were ana-
`lyzed by the Council on Pharmacy“ and criticized on the grounds of
`the diagnostic criteria, failure to exclude allergic rhinitis adequately,
`lack of suitable control groups in most cases, and the methods of com-
`piling
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`with a potent strain of cold virus would offer the best basis for a con-
`trolled trial.
`
`Such an experimental inoculation study was undertaken by Feller
`and associates” while other groups started carefully controlled obser-
`vations on natural colds in large groups of individuals. Before the re-
`sults were obtained, the matter became one of public controversy as
`well as scientific inquiry. The claims of Brewster were presented to
`the public in a sensational and uncritical article in the Reader’s Digest”
`as the long-awaited preventative and cure of the common cold. At
`about the same time, the Federal Food and Drug Administration per-
`mitted the sale of certain antihistaminics without prescriptions and the
`manufacturers were quick to exploit their use for common colds in
`spectacular advertising, much of which claimed or implied the approval
`of not only the Reader’s Digest but also the Navy Medical Department
`and the Food and Drug Administration. In March of 1950 the Federal
`Trade Commission entered complaints against five of the largest manu-
`facturers of antihistaminic drugs for over—the—counter sales, charging
`misrepresentation of the efficacy of these compounds in the prevention
`and cure of the common cold. With millions of dollars of sales at stake
`and the public having been promised an effective cure of the common
`cold, the controversy aroused great interest in the press but was settled
`within a few months with the manufacturers agreeing to advertise that
`the antihistaminics relieve the symptoms of colds rather than being effec-
`tive cures.
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`i Antihistmnine Drugs
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`3 2 1
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`During the past six months many reports of carefully controlled
`studies have shown that the antihistaminics have little or no value in
`
`preventing or curing the common cold. Experimental inoculations of
`volunteers with cold virus by Feller and associates” showed that these
`drugs had no effect in prevention of colds. Shaw and VVightman?1 at
`Cornell, Cowan and Diehl” at the University of Minnesota, Hoagland”
`at West Point and a group of workers in the Navy“ all presented care-
`ful reports of the treatment of large series of patients with colds with
`comparable groups receiving antihistaminic drugs and placebos as con-
`trols. In every case the results in the antihistamine—treated and control
`groups were essentially the same. It was a striking find that in every
`instance the patients given inert placebos reported considerable bene-
`fits. Cowan and Diehl reported that one student who returned to the
`universigz after graduation specifically to obtain some more of the
`medication was found to belong to the control group.
`The consensus of medical evidence supports the opinion that the
`antihistaminic drugs are not effective in the prevention or cure of the
`common cold. The person who takes a pill after the first sneeze or
`sniflle cannot be sure that he is suffering from a cold infection rather
`than the effects of a chill, draft or minor allergy and so is not helpful
`as a part of a scientific experiment. Some of the early symptoms of a
`cold such as sneezing and rhinorrhea are in many cases relieved partially
`or completely by the antihistaminics, as they are by atropine, but the
`progress of the infection is not stopped. Patients with chronic allerg