Clinical and Experimental Allergy, 1999, Volume 29, Supplement 3, pages 1–11

Histamine and the antiallergic antihistamines: a history of

their discoveries
M. B. EMANUEL
Research Associate, Department of Medicine, University of Southampton, Southampton, UK

Summary
The paper provides a historical overview of the discovery of both histamine and the H1
antihistamines. The context of these discoveries is provided in relation to the development
of medicinal chemistry during the 19th century. Background is provided on the history of
discovery of mechanisms of anaphylaxis and allergy and the immunology of hypersensi-
tivity at the end of the 19th and early 20th century. The discovery of histamine and the
antihistamines is then discussed in relation to the development of pharmacological receptor
theory culminating in the discovery of the first antihistamines in the 1930s and their
widespread clinical introduction in the 1940s.
Keywords: history, pharmacological receptor theory, antihistamines, allergy

Introduction produced instead the first synthetic dye, aniline purple. The
synthetic dyestuff and pharmaceutical industries were to
1997 was the 90th anniversary of the identification of the
remain closely interwoven for the next 100 years and more.
amine now known as histamine and the 60th anniversary of
The new dyes were used in microscopy and photography,
the first clear demonstration that a synthetic antihistamine
and companies making these synthetic dyes, especially in
could protect an animal from induced anaphylaxis. This
Germany, began to embark on the production of drugs,
paper will review the scientific environment surrounding
firstly by purification from natural sources and later by
these two major discoveries and explore the road on which
synthesis. Quinine itself remained elusive and was not
histamine and the antihistamines travelled from 1907 to
synthesized until 1944. As the 19th century progressed the
1937 and beyond, to the introduction of the first clinically
empirical discoveries of the volatile anaesthetics, bromides
useful antihistamines in the early 1940s.
for epilepsy and amyl nitrate and nitroglycerine for angina
pectoris raised fundamental questions about how drugs
The birth of medicinal chemistry worked. But not enough was known about the basis of
physiology to answer these questions. Nevertheless, the
In the early part of the 19th century it was shown that
pharmaceutical chemical industry continued to develop
carbon-based compounds found in living organisms could
rapidly. Compounds that bore some resemblance to part of
be made synthetically without the intervention of a magic
the quinine molecule were found to be synthesizable from
‘life force’. The breakthrough was the synthesis of urea
products of coal tar distillation and some of these were shown
from ammonium sulphate and potassium cyanate in 1828 by
to be antipyretics which relieved headache, minor pains and
Woehler [1]. Quinine had been isolated from cinchona bark
reduced fever. These included phenazone (known as anti-
in 1820 and was in great medical demand for the treatment
pyrine), acetanilide and phenacitin and were the forerunners of
of malaria. However, supplies were only available from
paracetomol. Aspirin was synthesized in 1853 although its
mountainous parts of South America. Clearly there would
medicinal properties were not recognized until 1899.
be great benefit if the new science of organic chemistry
By 1881 the Cambridge physiologist T.H. Huxley stated
could make quinine in a laboratory. The English chemist
[2] ‘There can surely be no ground for doubting that, sooner
William Henry Perkin attempted to synthesize quinine by
or later, the pharmacologist will supply the physician with
the oxidation of allyltoluidine – his attempt failed but he
the means of affecting, in any desired sense, the functions of
Correspondence: Dr M. B. Emanuel, Harrowdown House, Tucks Lane, any physiological element of the body. It will, in short,
Longworth, Abingdon, Oxon OX13 5ET, UK. become possible to introduce into the economy a molecular
q 1999 Blackwell Science Ltd 1
2 M. B. Emanuel
mechanism which, like a very cunningly contrived torpedo,
shall find its way to some particular group of living elements
and cause an explosion among them, leaving the rest
untouched. The search for the explanation of diseased states
in modified cell life; the discovery of the important part played
by parasitic organisms in the aetiology of disease; the elucida-
tion of the action of medicaments by the methods and the data
of experimental physiology – appear to me to be the greatest
steps which have ever been made towards the establishment of
medicine on a scientific basis’.
The story of the discovery of the chemistry and physiol-
ogy of histamine and the chemistry and pharmacology of the
H1 antihistamines was one of the first great realizations of
Huxley’s vision.
Anaphylaxis and allergy
Anaphylaxis
Richet and Portier’s description of anaphylaxis in 1902 [3]
and the concept of altered reactivity, termed allergy,
described shortly afterwards by Von Pirquet [4] provided
a new focus to others interested in the mechanisms of what
is now known as allergic disease.
Fig. 1. Charles Richet (courtesy of the University of Winsconsin
Library).
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Charles Richet’s description of anaphylaxis published in
1902 provided the biological foundation for the understand-
ing of immunological reactions within which histamine was
to play a central role. Richet’s work demonstrated that the
first dose of a protein injected into an animal was followed
by a condition of markedly increased susceptibility to that
specific protein after a suitable incubation period. The time
lapse required before anaphylaxis appeared was variable
depending on the experimental design. For example, fol-
lowing injection of horse serum into the guinea-pig no
reaction was seen if the time interval was less than 6 days
and the reaction was maximal after 14 days. In 1898, Richet,
Professor of Physiology in Paris (Figure 1), became inter-
ested in a toxin produced by the Portuguese man-of-war
(Physalia), a jellyfish that produces a severe contact urti-
caria. He continued these investigations with extracts of the
tentacles of the sea-anemone, which on a single injection
were harmless but if administered to the same animal for a
second time after a lapse of a few days, caused toxic, often
fatal, reactions. He called this phenomenon anaphylaxis to
express its antithesis to prophylaxis or protective effects.
Despite his novel terminology Richet’s experimental phe-
nomenon had been described on a number of occasions
during the 19th century. In 1839 Magendie described the
sudden death of dogs that had been repeatedly injected with
egg albumin [5] and in 1894 Flexner, whilst injecting dog
serum into rabbits, recorded typical instances of experimen-
tal anaphylaxis [6]. Nevertheless, the earlier descriptions of
Fig. 2. Maurice Arthus (courtesy of the National Library of
Medicine).

anaphylactic reactions had not been assimilated into the
mainstream of scientific thought.
Shortly after Richet presented his work, Theobald Smith
in the USA [7], Arthus in France [8] and Otto in Germany
[9] reported similar observations. Their findings confirmed
the outcome described by Richet. However, Richet believed
that anaphylaxis could only be produced by poisons
whereas these later experiments showed that intrinsically
harmless proteins could induce anaphylaxis with repeated
exposure.
In 1903 Arthus (Figure 2) found that repeated subcuta-
neous injection of horse serum in rabbits at intervals of
several days eventually gave rise to local inflammatory
reactions, a phenomenon still known as the Arthus reaction
[8]. Clearly horse serum was not intrinsically a poison. In
1904 Theobald Smith communicated to Ehrlich that guinea-
pigs previously injected with horse serum for the purpose of
standardizing diphtheria antitoxin could die suddenly after a
subsequent inoculation of the serum [7]. The reaction
seemed not to be dependent upon any poisonous character
of the injected substance. Therefore, the anaphylactic reac-
tion must depend primarily on some change within the
animal organism which was so profound that small amounts
of ordinarily harmless material could cause a disastrous
adverse effect on the animal.
Allergy
In 1905, the Austrians, Von Pirquet (Figure 3) and Schick
[4] noted that in many instances patients given antitoxin
Fig. 3. Clemens von Pirquet (courtesy of the National Library of
Medicine).
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History of antiallergic antihistamines 3
recovered from their infectious disease but developed high
fever, joint pains and swelling, enlarged glands and a
widespread itchy rash, 6–12 days after the first injection
of antitoxin. If these symptoms came on after a second
injection of antitoxin they did so much more rapidly and
patients occasionally died immediately following the
second injection. They named this syndrome serum sick-
ness. Because of the marked resemblance between serum
sickness in patients and the anaphylactic reactions occurring
in laboratory animals following an injection of the serum of
another species, von Pirquet and Schick considered serum
sickness to be an anaphylactic reaction in man. They
thought that the first injection in some way changed the
reaction of the body so that it became hypersensitive to
the second injection of the same material. This was very
different to Richet’s belief that there was a reduction of the
body’s defence mechanism against a poison. To describe
this state of specific altered reactivity they invented the
word ‘allergy’ derived from the Greek ‘allos’ meaning other
and ‘ergos’ meaning work.
Von Pirquet demonstrated the presence of antibodies in
the human blood-stream in serum sickness but was unable to
prove any constant relationship between them and the
course of the disease. This led him to conclude that other,
unexplained factors, not operative in anaphylaxis were
involved in serum sickness. While Von Pirquet included
all types of altered state of immune reactivity within his
word ‘allergy’ this term subsequently became restricted in
its use to acute anaphylaxis or clinical hyperreactivity states.
The first definite suggestion that a chronic clinical con-
dition of human hypersensitivity, hay fever, was related to
anaphylaxis in animals was made by Wolff-Eisner in 1906
[10]. The same author a year later suggested that urticaria
was also anaphylactic in nature. Charles Blackley in 1873
had shown in a series of brilliant experiments that hay fever
was caused by exposure to atmospheric pollens in suscep-
tible individuals [11]. Wolff-Eisner now saw a relationship
between Blackley’s work and that of Richet. Pollen must be
the antigen in hay fever. The symptoms only appeared after
a period of sensitization to the particular pollen. He pro-
posed that the years of contact with pollen before the
individual experienced symptoms were equivalent to the
first injection of antigen in the model of animal anaphylaxis.
When sensitivity reached a critical threshold the next pollen
season precipitated the symptoms as though it were the
second (or shocking) dose of injectable antigen.
Physiological investigation of anaphylaxis
Schultz [12,13] and Dale [14], experimenting on isolated,
exsanguinated organs from sensitized animals, discovered
that the in vitro addition of foreign protein, now termed
allergen, produced a sustained smooth muscle contraction,
4 M. B. Emanuel
suggestive of a cellular-tissue reaction occurring on allergen
exposure. In further experiments, Dale demonstrated that
intravenously administered histamine produced bronchocon-
striction in guinea-pigs and a shock-like syndrome in anaes-
thetized rabbits. Based on these findings, Dale postulated that
histamine played a major role in the pathogenesis of anaphy-
laxis [15]. The subsequent demonstration of allergen-induced
release of histamine in vitro from sensitized guinea-pig lung
[16] and in vivo in dogs [17] and guinea-pigs [18] in quantities
sufficient to account for symptoms, supported this hypothesis.
The identification that antihistamines (newly developed at
that time) afforded guinea-pigs significant protection from
allergen-induced anaphylaxis [19] gave further support to
these theories.
Cellular investigation of anaphylaxis
Subsequent parallel investigations focused attention on
the tissue mast cell as a source of the mediators of anaphyl-
axis. The mast cell was first described in 1863 by
von Recklinghausen [20] and named and characterized in
1879 by Paul Ehrlich (Figure 4) when investigating the
histochemical staining characteristics of basic aniline dyes
[21]. Ehrlich identified the presence of a connective tissue
Fig. 4. Paul Ehrlich (courtesy of the National Library of Medicine).
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cell whose granules altered the colour of the dye (meta-
chromasia). As these cells were more numerous in connec-
tive tissue whose nutrition was enhanced, he named them
‘Mastzellen’ (well-nourished cells). There was considerable
scientific interest in this cell and subsequent investigations
showed that the anticoagulant heparin was responsible for
its metachromatic staining property [22]. However, the link
between the mast cell and anaphylaxis was not made until
1941 when Jacques and Walters [23] proved that the anti-
coagulation in dogs undergoing anaphylactic reactions, as
previously reported by Arthus in 1909 [24] and Biedl and
Kraus in 1910 [25], was due to the release of heparin.
Subsequent investigations linked these findings and those
of Dale by correlating the histamine, heparin and mast-
cell content of tissues [26]. Direct evidence of mast cell
degranulation accompanying allergen-induced anaphylaxis
in guinea-pigs soon followed [27].
Immunology of hypersensitivity
In parallel with these physiological and cellular investiga-
tions an immunological story was unfolding to reveal the
nature of the factor responsible for sensitization following
exposure to foreign protein. This arose from the case report
by Ramiriz in 1919 who observed that a non-allergic
recipient, following transfusion with blood from a horse-
sensitive donor, developed wheeze when exposed to horses
[28]. This suggested a transferable circulating agent was
responsible for the sensitization causing bronchoconstric-
tion and by inference anaphylaxis. This was called ‘reagin’
by Praüstnitz and Kustner in their classical experiment [29].
Praüstnitz passively sensitized sites on his own forearm to
fish allergen by means of intradermal injection of serum
from his fish-allergic patient, Kustner. In this way Praüstnitz
demonstrated that the substance or substances responsible
for this transfer could be localized in the skin, where
challenge with fish-allergen produced a classical weal and
flare response. This observation was followed by similar
demonstrations of the transfer of hypersensitivity to other
allergens, such as horse serum and grass pollen. It was not,
however, until 45 years later that the Ishizakas identified
immunoglobulin E (IgE) [30,31] in the serum of ragweed-
sensitive subjects, as the carrier of reaginic antibody. Injec-
tion into normal skin of a purified ragweed IgE preparation
resulted in sensitization of the skin site for the Praustnitz–
Kustner reaction, while removal of the IgE antibody was
accompanied by loss of this sensitizing activity. Raised
levels of this immunoglobulin were identified in the sera
of hay fever sufferers [32].
The discovery of histamine
The concept that small molecules with potent biological
activities are involved in the pathogenesis of acute allergic

reactions dates back to the discovery of beta-iminazolyethyl-
amine now known as histamine (Figure 5). Histamine was
the first of a series of biogenic amines released in the
inflammatory process to be characterized [33]. Histamine
was first prepared synthetically by decarboxylation of the
amino-acid histidine. Yields of histamine were increased by
Ackermann and Kutscher in 1910 [34] who used bacterial
putrefaction of pancreatic tissue to achieve the decarboxyl-
ation of histidine. The compound became available to Sir
Henry Dale and his co-workers at Wellcome shortly after-
wards where they isolated it from the mould ergot. Dale
initially termed the compound beta-1 and there is no doubt
that his work on beta-1 ranks among the great achievements
of medical science. The story of beta-1, later known as
histamine, forms a major part of Dale’s Adventures in
Physiology with Excursions into Autopharmacology pub-
lished in 1953 and consisting of a selection of 30 of his
major scientific publications [35].
The physiology of histamine
T.H. Huxley’s successor at Cambridge, Sir Michael Foster
went on to develop one of the outstanding schools of
physiology at a time that coincided with the early career
of Sir Henry Dale who had qualified in medicine from
Cambridge and London [36]. In 1904, at the age of 29, Dale
was appointed to a research post at Sir Henry Wellcome’s
physiological research laboratory where he worked with the
research chemist George Barger, a friend from his time in
Cambridge. In 1906 he became director of the physiology
laboratory. Wellcome had commercial reasons for working
on medicines derived from the parasitic mould ergot, which
grows on rye. Ergot has a long medical history particularly
as the causative agent of epidemics of St Anthony’s fire,
now known to be poisoning as a result of consumption of
ergot-infected rye bread. Symptoms of St Anthony’s fire
could include miscarriage and the ability of ergot to induce
Fig. 5. Structure of histamine.
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History of antiallergic antihistamines 5
miscarriage had been turned to medical use to accelerate
childbirth and to reduce postpartum bleeding. Sir Henry
Wellcome included a liquid extract of ergot among the
medicines he sold and he believed that with such a potent
medicine standardization of potency would give him an
important commercial advantage. Therefore, both Barger
and Dale worked on ergot and in 1907 a new alkaloid,
ergotoxine, was isolated. The work on ergot continued; the
mould deteriorated in storage and a number of its decom-
position products were isolated and identified. One of
these compounds was shown to be histamine, another was
acetylcholine. Although there is little pharmacological
significance in the isolation of histamine from ergot the
availability of the compound now led directly to one of the
most remarkable series of experiments in the history of
physiology as Dale set out to explore the biological action of
the histamine at his disposal.
Barger and Dale [37] showed that histamine caused
constriction of isolated guinea-pig ileum and subsequently,
in a series of crucial experiments, Dale and Laidlaw [38]
found that histamine induced a shock-like syndrome when
injected into mammals. Histamine caused bronchiolar con-
striction, constricted cardiac and pulmonary arteries and
stimulated cardiac contraction.
The identification of histamine in normal tissues came in
1927 when Best et al. [39] demonstrated its presence,
especially in the lungs. Dale [15] stated: ‘We may picture
the anaphylactic shock therefore as a result of cellular injury
due to the intracellular reaction of the antigen with an
aggravating antibody. Whether this is general or localized
in a particular organ, histamine will be released and its
effects will be prominent in the resulting reaction imposing
a general resemblance to the syndrome produced by hista-
mine itself, on the symptoms seen in each species. The cell
injury, however, is not limited to the degree required to
produce a release of histamine and involves other and more
direct results. Such a conception is in accordance with all
the facts as yet available, and it has the advantage of
rendering intelligible, not only the striking resemblance
between symptoms of the anaphylactic reaction and those
produced by injecting histamine, but also the various and
equally significant points of difference between the two
syndromes’.
The first important experiments designed to demonstrate
an actual release of histamine in association with the
anaphylactic reaction were those of Watanabe [40] showing
differences in the histamine content of guinea-pig lung
before and after shock. Dragstedt and Mead [17] showed
that the striking increase in the histamine content of the
blood and lymph of dogs after anaphylaxis was sufficient to
explain the shock and Code in 1937 [18] noted that the
amounts of histamine liberated in shocked guinea-pigs were
sufficient to produce anaphylactic symptoms.
6 M. B. Emanuel
The development of the receptor theory
John Langley and Paul Ehrlich
The fact that one substance might counteract the physiological
effects of another had been recognized for centuries in the
concept of antidotes to poisons. In 1874, Langley (Figure 6)
(who was one of Dale’s teachers at Cambridge) working with
Michael Foster at the School of Physiology showed that
atropine and pilocarpine are mutually antagonistic in their
actions on the secretion of saliva by the submaxillary gland
[41]. He stated: ‘we may, I think, without much rashness,
assume there is a substance or substances in the nerve endings
or gland cells with which both atropin and pilocarpin are
capable of forming compounds. On this assumption then the
atropin or pilocarpin compounds are formed according to
some law of which their relative mass and chemical affinity
for the substances are factors’.
Here we have the basis on which the receptor theory
would be built. The development of this theory was to
depend once again on the relationships between dyes
and physiology. In the same year, 1878, Paul Ehrlich in
his work on histological staining had argued that the process
of staining was not merely physical adhesion but involved
a specific chemical reaction [42]. Ehrlich went on to
adopt Pfluger’s view that protoplasm can be envisaged as
a giant molecule consisting of a chemical nucleus of special
Fig. 6. John Newport Langley (courtesy of the National Library of
Medicine).
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 1–11
structure (which is responsible for the particular functions of
the specialized cell) with attached chemical side chains. In
1897 he published his first account of the side-chain theory
of immunity [43] (Figure 7). The side chain is normally
involved in ordinary physiological processes, such as nutri-
tion, but when a toxin molecule becomes attached to the side
chain, poisoning of the cell results as normal function breaks
down. Ehrlich compared the interaction between the toxin
and side chain to that between a lock and key analogous to
the lock and key theory of enzyme action proposed earlier by
Emil Fischer. In 1900 Ehrlich introduced the term receptor to
refer to the ‘receptive side chains’ of the cell [44].
At the time Ehrlich did not believe that drugs worked in
the same way as these toxins. The common view was that
drugs induced their effects through physical properties such
as surface tension, osmotic pressure and so on, rather than
by true chemical combination. Ehrlich supported this view,
his position being based on the ease with which solvents
could wash out alkaloids, aromatic amines, antipyretics or
aniline dyes from animal cells.
However, new work from Langley at Cambridge was to
change this belief. In the first years of the new century
Langley was working on antagonism between nicotine and
curare on striated muscle. He showed [45,46] that after
cutting the nerves to the muscle, nicotine still produced
contraction which curare continued to antagonize. To
explain this antagonism he returned to the work he had
done 25 years earlier on the antagonism between atropine
and pilocarpine. The two drugs must act on the same
protoplasmic substance or substances in the muscle and
presumably this involves a combination of the alkaloid with
protoplasm. In the presence of both nicotine and curare,
which muscle-alkaloid compound is formed depends on the
amount of each alkaloid present and their relative chemical
affinities for the muscle substance.
‘I conclude then that in all cells two constituents at least
must be distinguished: 1) substances concerned with carrying
out the chief functions of the cells and 2) receptive substances
especially liable to change nicotine, curare, atropine, pilo-
carpine, strychnine, and most other alkaloidsproduce their
effects by combining with the receptive substance.’
Langley commented on the similarities between this
model and Ehrlich’s side-chain theory of immunity and in
1908 wrote [47]: ‘My theory of the action is in general on
the lines of Ehrlich’s theory of immunitythe contractile
molecule of the muscle has a number of receptive (or
side-chain) radicles and that dilute nicotine combines with
one of these causing tonic contraction and with another
causing fibrillar twitching. Curari prevents dilute nicotine
from causing contraction in the denervated as well as in the
normal muscle’.
Ehrlich now used Langley’s ideas in his own work on
drug therapy. In 1907 he stated that some drugs are bound to
 History of antiallergic antihistamines 7

X it affects a variety of tissues and produces different types

of actions in different tissues and;
X it acts rapidly and its action is quickly and completely

reversible, so that a large number of experiments can be

done on a single preparation.
He examined the action of the drug on two different muscle
types and in both cases showed a simple mathematical
relationship between the concentration of the drug and the
action produced. The simplest explanation for this relationship
was ‘to suppose that a reversible monomolecular reaction
occurs between the drug and some receptor in the cells’. He
also observed that there was no direct relationship between the
amount of drug entering the cell and the amount of action
produced and suggested that such a reaction might take place
if the receptor was on the surface of the cell and not inside it.
Clark developed his receptor theory in detail in his classic
book on the mode of action of drugs [50] using current
knowledge in physico-chemical theory, contemporary the-
ories of catalysis and recent advances in biochemistry and cell
biology. Although there was not yet complete acceptance that
the receptor theory of drug action was proven there was
enough agreement to make the search for a specific receptor
antagonist to block the effects of histamine a worthwhile goal
for medicinal chemistry allied to 1930s pharmacology.
Fig. 7. Paul Ehrlich’s side chain theory of antibody formation.
Note the use of geometric shapes to indicate different specificities.

protoplasm in a manner similar to the binding of toxins [48].

A given drug or poison would only attack a cell (or a
unicellullar organism such as the trypanosomes he was
working on) if the cell possessed the chemoreceptors cap-
able of combining with it. However, the chemoreceptors are
normally involved with processes such as nutrition or
metabolism and hence are present in all cells. So, Ehrlich
explained, any chemical drug is likely to have an affinity for
the cells of the host as well as for the parasite. In order to
have a beneficial effect the ‘parasitotropic’ force must be
greater than the ‘organotropic’ force. So although focused
mainly on infectious disease we have here the basis of both
receptor theory and drug specificity.

Alfred Clark
Alfred Joseph Clark (Figure 8) was another product of the
Cambridge school of physiology. His time there from 1903
to 1907 coincided with the period of Langley’s work on nico-
tine and curare. The receptor theories of Ehrlich and Langley
had had little impact in their lifetimes (Ehrlich had died in
1915 and Langley in 1925). Clark published his first paper
on the activity of acetylcholine in 1926 [49] in which he
stated it was particularly well suited to the study of the laws
governing the reactions between drugs and cells because:
X it produces a graded response over a wide range of

concentrations; Fig. 8. Alfred Joseph Clark (courtesy of Dr David H. Clark).

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8 M. B. Emanuel
Fig. 9. 5-methyl phenoxyethyl diethylamine (929 F).
The antihistamines
The evidence assigning histamine an active role in allergy
and anaphylaxis prompted scientists to attempt methods of
reducing histamine manifestations.
The systematic search for compounds having the specific
property of counteracting the physiological effects of histamine
began in the Pasteur Institute in the 1930s [51]. The parent
compound of the first antihistamines was thymoxyethyldi-
ethylamine first synthesized as early as 1911 [52]. In 1933
Fourneau and Bovet [53] reported that certain phenolic ethers
had the property of inhibiting or counteracting the action of
histamine; the most effective of these was 2-isopropyl-5-
methyl phenoxyethyl diethylamine (929 F). This is the
parent compound of the ethanolamine series (Figure 9).
Staub and Bovet [19] demonstrated that 929 F could
protect guinea-pigs from histamine-induced anaphylaxis but
its toxicity precluded its clinical use. Because of this
toxicity Staub [54] went on to investigate a series of Four-
neau compounds of the general phenoxyethylamine type.
She showed that substitution in the benzene ring played a
critical role (Figures 10 and 11).
Staub had produced and tested highly active potent anti-
histamines of which the new compound (1571 F) was out-
standing but the toxicity of these compounds precluded their
use in man. Antihistaminic research continued separately in
France and North America during the war years of the early
1940s. In France, Rhone Poulenc patented RP 2339 in May
1941. This compound antergan (N1N dimethyl-N1-benzyl-N-
phenyl-ethylenediamine), described by Halpern in 1942 [55]
was the first antihistamine used clinically in man. Many
new antihistamines followed in rapid succession including
Fig. 10. Ethylenediamine group.
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 1–11
Fig. 11. 1571 F.
diphenhydramine in 1945, and RP 3277 (Phenergan) in
1948. Huttrer’s review of 1950 lists 20 clinically available
antihistamines (Figure 12).
In 1946 Loew et al. [56] described the ethanolamine
derivative diphenhydramine (Benadryl) (Figure 13).
In 1966 Ash and Schild [57] proposed the name H1 for
receptors blocked by known antihistamines. Actions of
histamine (such as stimulation of isolated gastric secretion,
inhibition of rat uterine contraction and stimulation of
isolated atria) not blocked by these drugs are mediated
through a second group of receptors now known as H2
receptors. In 1972 Black et al. [58] confirmed the existence
of H2 receptors by synthesizing a group of drugs that
specifically blocked them.
Antihistamines (H1 antagonists) are classified tradition-
ally into groups according to their chemical structure
(Figures 14 and 15).
Clinical use of antihistamines
Antihistamines became widely used in the mid- to late-
1940s. They quickly became established in the treatment of
various allergic disorders, particularly rhinitis, conjunctivi-
tis and urticaria [59]. A quarter of a century later their status
was described in the 13th edition of the Merck manual [60]
as follows: ‘Antihistamines are useful for treating the
symptoms of allergic reactions, including seasonal hay-
fever, allergic rhinitis and conjunctivitis. They are mildly
effective in perennial vasomotor rhinitis. Acute and chronic
urticaria and certain allergic dermatoses respond well and
Fig. 12. Antergan 2339rp.
 History of antiallergic antihistamines 9

Fig. 13. Diphenhydramine.

pruritis may be alleviated. They are also useful for treating

minor transfusion incompatibility reactions and systemic
reactions to IV X-ray contrast media’.
Side-effects occurred commonly with all of these anti-
histamines. Those seen most often were sedation and dry
mouth (atropine-like). The occurrence of side-effects
limited their efficacy by constraining the degree of H1
blockade that could be achieved clinically.
The search for H1 antagonism without sedation became a
goal within the pharmaceutical industry but this was not
achieved until four decades later in the 1980s when the non-
sedative antihistamines astemizole and terfenadine were
introduced.

Fig. 15. Structure of representative H1 antagonists.

Conclusion
The discovery of histamine, its physiological role and the
reversal of its pharmacological effects by pharmaceutical
synthetic compounds takes us on a tour through the origins
of modern physiology and medicinal chemistry operating
within a framework of the rising understanding of pharma-
cology at the end of the 19th and the early part of the 20th
century. The story is populated by some of the greatest
scientists of the era including five Nobel Laureates; Wind-
aus, Ehrlich, Richet, Bovet and Dale. In parallel to this
scientific story the development of the modern pharma-
ceutical industry can also be seen. Scientific theory,
Fig. 14. Histamine and antagonists.
q 1999 Blackwell Science Ltd, Clinical and Experimental Allergy, 29, Supplement 3, 1–11
experimentation and technology in a wide number of
disciplines came together to bring about a major advance
in the clinical treatment of human disease. Success was
based on the various achievements of each discipline and
each was dependent on the others. The discovery of
histamine and the antihistamines and their subsequent
development still provides a model framework for
therapeutic research today.
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