Antiallergic Agents 1

Antiallergic Agents
Norbert Höfgen, Arzneimittelwerk Dresden GmbH, Radebeul, Federal Republic of Germany
Sonja Beckh, Medizinische Klinik 3, Pneumologie, Klinikum Nürnberg Nord, Nürnberg, Federal Republic of
Germany
Istvan Szelenyi, Arzneimittelwerk Dresden GmbH, Radebeul, Federal Republic of Germany
Pal L. Bölcskei, Semmelweis Medical University, Budapest, Hungary

1. Introduction . . . . . . . . . . . . . . . 2 4.4. Allergen Vaccines for

2. Antihistamines . . . . . . . . . . . . . . 3 Immunotherapy . . . . . . . . . . . . . 24
2.1. First Generation Antihistamines . . 3 4.5. Storage . . . . . . . . . . . . . . . . . . . 24
2.1.1. Ethylenediamines . . . . . . . . . . . . . 4 4.6. Uses . . . . . . . . . . . . . . . . . . . . . 24
2.1.2. Ethanolamine Derivatives . . . . . . . . 6 4.6.1. Diagnostic Use . . . . . . . . . . . . . . 25
2.1.3. Alkylamines . . . . . . . . . . . . . . . . 7 4.6.2. Therapeutic Use—Immunotherapy . . 25
2.1.4. Piperazines . . . . . . . . . . . . . . . . . 9 4.6.3. Legal Aspects, Quality Requirements,
2.1.5. Piperidines . . . . . . . . . . . . . . . . . 11 and Safety . . . . . . . . . . . . . . . . . 26
2.1.6. Phenothiazines . . . . . . . . . . . . . . 11 5. Anti-IgE-Omalizumab . . . . . . . . . 26
2.1.7. Other Tricyclic Systems . . . . . . . . . 13 5.1. IgE and its Role for the Allergic
2.2. Second-Generation Antihistamines 15 Response . . . . . . . . . . . . . . . . . . 27
2.2.1. Ethanolamines . . . . . . . . . . . . . . . 15 5.2. IgE-Mediated Allergic Diseases . . . 27
2.2.2. Alkylamines . . . . . . . . . . . . . . . . 15 5.3. Properties of Omalizumab . . . . . . 28
2.2.3. Piperazines . . . . . . . . . . . . . . . . . 15 5.3.1. Chemistry and Production of
2.2.4. Piperidines . . . . . . . . . . . . . . . . . 16 Omalizumab . . . . . . . . . . . . . . . . 28
2.2.5. Phthalazinones . . . . . . . . . . . . . . 18 5.3.2. Pharmacology and Effect of
2.2.6. Others . . . . . . . . . . . . . . . . . . . . 18 Omalizumab . . . . . . . . . . . . . . . . 30
2.2.7. Combinations of Antihistamines and 5.3.3. Pharmacokinetics . . . . . . . . . . . . . 30
Sympathomimetic Agents . . . . . . . 18 5.4. Indication for the Teatment with
2.3. Inhibitors of Histamine Synthesis . 19 Omalizumab, Guidelines for Use . . 30
3. Mast Cell Stabilizing Agents . . . . . 19 5.5. Application, Dosage, Costs . . . . . . 31
4. Allergen Preparations for 5.6. Side Effects . . . . . . . . . . . . . . . . 31
Desensitization . . . . . . . . . . . . . . 20 5.7. Legal Aspects, Safety . . . . . . . . . . 32
4.1. Properties of Allergens . . . . . . . . 20 5.8. Possible Applications in the Future 32
4.2. Raw Materials . . . . . . . . . . . . . . 22 6. Acknowledgement . . . . . . . . . . . 32
4.3. Allergen Standardization . . . . . . . 22 7. References . . . . . . . . . . . . . . . . . 32

Abstract responses involving release of preformed me-

Allergic reactions cause a number of acute
and chronic diseases. The antigen or aller-
gen causing the allergic reaction is usually a
protein, a polysaccharide, or a low molecular
mass compound (hapten) bound to an endoge-
nous protein. Antigens induce the synthesis of
antibodies, which are serum proteins, referred
to as immunoglobulins (Igs). Antigen cross-
linking of the IgE molecules leads to cellular
diators, e.g., histamine. Antihistamines or his-
tamine H1 receptor antagonists are used in the
treatment of allergic diseases. In contrast to the
first-generation or classical antihistamines the
second-generation antihistamines do not have
the side effects sedation, fatigue, and drowsi-
ness. Mast cells are the predominant storage site
for histamine in most tissues. Cromolyn sodium
or disodium cromoglycate (DSCG) probably

c 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a02 419.pub2
2 Antiallergic Agents
acts on certain types of chloride channels ex-
pressed in mast cells and sensory nerves.
Allergen immunotherapy is a well estab-
lished and accepted treatment of allergic dis-
eases. Immunogenic tolerance is achieved by
applying gradually increasing quantities of an
allergen vaccine to the sensitized patient. Al-
lergen preparations derive from reference stan-
dards containing defined amounts of relevant al-
lergens. For efficient and well-tolerated therapy
extracts are physically or chemically modified or
conjugated. Recombinant DNA technology of-
fers a new standard of qualitiy by selecting the
disease causing major allergens.
The development of an anti-IgE antibody
(omalizumab, XolairTM ) offers a unique and
novel treatment not only for therapeutic but also
for preventive applications in IgE-mediated dis-
eases. Omalizumab is a DNA-derived mono-
clonal humanized antibody which is well toler-
ated by the immune system. Omalizumab binds
in form of complexes to free IgE in the serum
and interacts with any kind of IgE, but not with
other immunoglobulines. Omalizumab leads to
a downregulation of IgE receptors on mast cells
and tissue cells in target organs. The substance
showed immunomodulatory effects on dendritic
cells and reduced significantly the number of
eosinophils. Effects of treatment on allergic
rhinitis and asthma have been evaluated in sev-
eral studies.
1. Introduction
Allergic diseases are worldwide on the increase.
Studies in several countries show that about
15 – 20 % of all adults suffer from one of the
many different allergic disorders. Allergic reac-
tions cause a number of acute and chronic dis-
eases, such as conjunctivitis, rhinitis, dermatitis,
gastroenteritis, asthma, and anaphylactic shock.
Allergic responses are immediate reactions to
specific foreign substances to which individu-
als have developed hypersensitivity. Sensitizing
antigens come from a variety of environmen-
tal sources: they can be airborne (e.g., pollens,
molds, animals dander and urine, house dust
mites), taken up orally (e.g., foods, drugs) or
be injected (insect bites, drugs). The antigen
or allergen is usually a protein, a polysaccha-
ride or a low molecular mass compound (hap-
ten) bound to an endogenous protein to form an
antigenic complex. Antigens induce the synthe-
sis of antibodies. In sensitized individuals, the
subsequent exposure to the antigen results in the
initiation of a series of cellular reactions that
lead to the symptoms observed in allergy. An-
tibodies are serum proteins, referred to as im-
munoglobulins (Ig) such as IgG, IgM, IgA, and
IgE. Allergic responses have been divided into
four general categories [6]. Type I, or anaphy-
lactic reactions are mediated by IgE antibod-
ies (reagin). The main targets of this type of
reaction are the skin (urticaria, atopic dermati-
tis), the gastrointestinal tract (food allergies),
the eyes (conjunctivitis), the respiratory tract
(rhinitis, asthma) and the vascular system (ana-
phylactic shock). Type II or cytolytic reactions
are mediated by IgG and IgM (mainly blood
transfusion- and drug-induced hemolytic reac-
tions). Type III or Arthus phenomenon is medi-
ated by IgG (e.g., serum sickness); the type IV
or delayed-hypersensitivity reactions are medi-
ated by macrophages and T lymphocytes (e.g.,
contact dermatitis).
Allergy, in a strict sense, is an IgE-mediated
inflammation. As a part of an allergic response
to an antigen, reaginic antibodies (IgE) are gen-
erated and bound to the surface of mast cells and
basophils via high affinity Fc receptors (FcεRI)
that are specific for IgE [7]. Antigen cross-
linking of the IgE-molecules leads to cellular
responses involving release of preformed me-
diators (e.g., histamine), lipid mediator forma-
tion and release, and cytokin generation. Mast
cells with their mediators can be regarded as cen-
tral to the initiation and mediation of the early
phase of allergic inflammation and may also be
responsible for the initiation of chronic allergic
inflammation. Recent investigations have shown
that many other cells with their mediators, first
of all, eosinophils and lymphocytes are also in-
volved in the maintenance and progress of al-
lergic inflammation. Histamine, lipid mediators,
bradykinin, enzymes, and cytokins are among
the many important chemical mediators charac-
terized so far.
This article discusses drugs for the treatment
of allergic disorders already available on the
market or undergoing advanced clinical trials.
 Antiallergic Agents 3

2. Antihistamines ceptor antagonists [11]. Following the introduc-

tion of the nonsedating antihistamines, sedating
Histamine [51-45-6], a potent effector agent in histamine H1 receptor antagonists have been re-
allergic diseases, was first synthesized in 1907 placed almost completely by the new antihis-
by Windaus and Vogt [8] without being aware tamines. Members of the first generation of anti-
of its pharmacological activities. Dale and Laid- histamines have nowadays only a relatively lim-
law [9] suggested in 1910 that histamine might ited therapeutic value. They are often given as
be responsible for anaphylaxis, and that its phar- multi-ingredient preparations for the treatment
macological activity resembled that of many tis- of cough and common cold. In some cases, an
sue extracts. In 1927 Best and coworkers [10] attempt has been made to find new indications
were able to show that histamine was present in for the first-generation antihistamines.
fresh samples of liver and lung. This was fol-
lowed by demonstration of its presence in a va-
riety of other tissues, hence the name histamine 2.1. First Generation Antihistamines
after the Greek word for tissues, histos. Every
mammalian tissue that contains histamine is ca- Research on antihistamines was initiated in 1933
pable of synthesizing it from histidine by ac- by Fourneau and Bovet [12], who observed that
tion of l-histidine decarboxylase. Mast cells are 2-(N-piperidinomethyl)-1,4-benzodioxane pro-
the predominant storage site for histamine in tected animals from histamine-induced bron-
most tissues, in the blood, histamine is stored choconstriction.
in the basophil granulocytes. These cells syn-
thesize histamine and store it in their secretory
granules. Once released, histamine is metabo-
lized via two major pathways: (1) methylation
of the ring nitrogen in position 1, catalyzed by
histamine-N-methyl-transferase; and (2) oxida- The first recorded evidence of a histamine
tive deamination by diamine oxidase. antagonist originates from Bovet and Staub
Three types of histamine receptors exist: H1 , [13] from the Pasteur Institute who noticed that
H2 , and H3 . Symptoms of allergy and ana- a compound designated F 929, (5-isopropyl-2-
phylaxis are mainly mediated via stimulation methyl-phenoxyethyl)-diethylamine, attenuated
of histamine H1 receptors. Other effects, no- some of the actions of histamine.
tably gastric acid secretion and increase in car-
diac rate, are the result of H2 receptor activa-
tion. Some responses, such as the hypotension
that results from vasodilatation, are mediated by
both H1 and H2 receptors. H3 receptors are pre-
synaptic receptors on histaminergic nerve ter-
minals. Antihistamines or histamine H1 recep- This compound protected guinea pigs against
tor antagonists are used in the treatment of al- lethal doses of histamine, and lessened the symp-
lergic diseases. Antihistamines can be divided toms of anaphylactic shock. Isosteric replace-
into two groups: the so-called classical or sedat- ment of the ether oxygen by an amino group led
ing and the modern, nonsedating antihistamines. to F 1571.
All first-generation or classical antihistamines
show the major side effects sedation, fatigue,
and drowsiness to a varying extent. This can
be put down to the fact that they interact with
the H1 receptors in the brain. Other side effects
that apparently are caused by the antimuscarinic
action of some of the first-generation antihis-
tamines include dryness of the mouth, diplopia, This first ethylenediamine derivative was syn-
and dysuria. All these effects are not observed thesized by Fourneau and its pharmacological
with the modern, the second-generation H1 re- actions were described by Staub [14] in 1937,
4 Antiallergic Agents

who concluded that an ethylenediamine moiety [2508-72-7], mp 237 – 241 ◦ C; sulfate [24359-
is probably the basic structure of antihistamines. 81-7].
In fact, most H1 antagonists have a tertiary ami-
no group linked by a two or three atom chain
to two aromatic substituents and conform to the
general formula:

Antazoline is used for local application to the

where Ar is aryl and X is nitrogen or a –C–
O– ether linkage to the β-aminoethyl side chain
[15, 16]. Sometimes the two aromatic rings are
bridged, as in the tricyclic derivatives, or the
ethylamine group may be part of a ring struc-
ture. Other variations also are possible [17].
2.1.1. Ethylenediamines
In 1942, phenbenzamine was introduced as the
first clinically useful antihistamine [18].
eye in allergic conjunctivitis.
Preparation: [20].
Trade name: Antistin (CibaVision); often
combined with vasoconstrictor agents such as
tetryzoline.
Chlorpyramine [59-32-5], N-[(4-chloro-
phenyl)methyl]-N  ,N  -dimethyl-N-2-pyridinyl-
1,2-ethanediamine, C16 H20 ClN3 , M r 289.8.
Hydrochloride [6170-42-9], mp 172 – 174 ◦ C.

Preparation: [21].
Trade names: Synopen (Geigy), Chloropy-
ribenzamine (Polfa); several multi-ingredient
preparations.
Synthesis of Ethylenediamines. Three dif- Chlorothen [148-65-2], N-[(5-chloro-2-
ferent methods of synthesizing ethylenedi- thienyl)methyl]-N  ,N  -dimethyl-N-2-pyridi-
amines are widely used [19]: nyl-1,2-ethanediamine, C14 H18 ClN3 S, M r
295.8. Citrate [148-64-1], hydrochloride [135-
1) Reaction of tertiary chloroethylamines with
35-3].
secondary amines in the presence of a base,
e.g., NaH, NaNH2 , NaOC2 H5 , or KOH.
2) Alkylation of secondary amines, such as N-
(2-dimethylaminoethyl)aniline with benzyl
chlorides in the presence of a strong base.
3) Reaction of reactive heterocyclic halogen
compounds, such as 2-bromopyridine with
secondary amines, such as N-(2-dimethyl-
aminoethyl)-aniline, also in the presence of
a strong base. Chlorothen is synthesized by condensation of 5-
chloro-2-thienylchloride and N,N-dimethyl-N  -
Antazoline [91-75-8], 4,5-dihydro-N-phen- (2-pyridinyl)ethylenediamine in the presence of
yl-N-(phenylmethyl)-1H-imidazole-2-methan- sodium or potassium amide [22].
amine, C17 H19 N3 , M r 165.3. Hydrochloride Trade name: Tagathen (Lederle).

Histapyrrodine [493-80-1], N-phenyl-
N-(phenylmethyl)-1-pyrrolidineethanamine,
C19 H24 N2 , M r 280.4. Hydrochloride, mp 196 –
197 ◦ C.
Preparation: [23].
Trade names: Domistan (Servier), Luvistin
(Boehringer Ingelheim), Calcistin (Galenus).
Mepyramine [91-84-9], N-[(4-methoxy-
phenyl)methyl]-N  ,N  -dimethyl-N-2-pyridinyl-
1,2-ethanediamine, C17 H23 N3 O, M r 285.4. Hy-
drochloride [6036-95-9], mp 143 ◦ C; maleate
[59-33-6].
Preparation: [24].
Trade names: Neo-Antergan (Rhône-
Poulenc; Merck USA), Neo-Bridal (Bayer),
Pyramal (Roxane). Several multi-ingredient
preparations.
Methapyrilen [91-80-5], N,N-dimethyl-N  -
2-pyridinyl-N  -(2-thienylmethyl)-1,2-ethanedi-
amine, C14 H19 N3 S, M r 261.4. Hydrochloride
[135-23-9], mp 162 ◦ C; fumarate [33032-12-1].
Methapyrilene is synthesized by heating a
2-thienyl halide with an alkali metal salt
of N,N-dimethyl-N  -(2-pyridinyl)-1,2-ethane-
diamine [25].
Antiallergic Agents 5
Trade names: Thenylene (Abbott), Semikon
(Beecham), Thionylan (Lilly).
Phenbenzamine [961-71-7], N,N-di-
methyl-N  -phenyl-N  -(phenylmethyl)-1,2-
ethanediamine, C17 H22 N2 , M r 254.4. (Struc-
tural formula above.) Monohydrochloride
[2045-52-5], mp 210 – 211 ◦ C; dihydrochloride
[64335-73-5]; citrate [5956-46-7].
Preparation: [26].
Trade names: Antergan (Rhône-Poulenc),
Bridal (Bayer), Several multi-ingredient prepa-
rations.
Thenyldiamine [91-79-2] is the 3-thenyl
isomer of methapyrilen. Hydrochloride [958-
93-0]
Preparation: [27].
Trade names: Thenfadil (Sterling-Wintrop).
Thonzylamine [91-85-0], N-[(4-meth-
oxyphenyl)methyl]-N  ,N  -dimethyl-N-2-
pyrimidinyl-1,2-ethanediamine, C16 H22 N4 O,
M r 287.3. Hydrochloride [63-56-9], mp 173 –
176 ◦ C.
Thonzylamine is synthesized by treating
the sodium salt of 2-(4-methoxybenzyl)ami-
nopyrimidine with N,N-dimethyl-2-chloro-
ethylamine [28].
Trade names: Tonamil (Ecobi).
Tripelenamine [91-81-6], N,N-dimethyl-
N -(phenylmethyl)-N  -2-pyridinyl-1,2-ethane-
diamine, C16 H21 N3 , M r 255.3. Hydrochloride
[154-69-8], mp 192 – 193 ◦ C. Citrate [6138-56-
3], mp 106 – 110 ◦ C.
Preparation: [24, 29].
Trade names: Pyribenzamine
(Ciba – Geigy), Azaron (Chefaro).
6 Antiallergic Agents

2.1.2. Ethanolamine Derivatives

Derivatives of aminoalkyl ethers were preferen-

tially synthesized in the 1940s and 1950s in the
United States. The most frequently used repre-
sentative of this series is diphenhydramine that
has been introduced into therapy in 1946.
In general, the histamine antagonistic po-
tency of these basic ethers is lower than that Preparation: [32].
of the ethylenediamines. Beside their antihis- Trade names: Allergefon (Lafon), Clistin
taminic activity, they have antimuscarinic and (McNeil), Ciberon (Taisho), Polistin T-Caps
pronounced central sedative effects and are (Trommsdorff). Several multi-ingredient prepa-
thus suited as sleeping aids. Because of their rations.
antiemetic properties they are used for preven- Clemastine [15686-51-8], meclastine, 2-
tion and treatment of motion sickness, emesis. [2-[1(4-chlorophenyl)-1-phenylethoxy]ethyl]-
Furthermore, these ethanolamine derivatives are 1-methylpyrrolidine, C21 H26 ClNO, M r 343.9.
commonly included in preparations used for the Hydrochloride, mp 152 – 155 ◦ C; fumarate
treatment of cold and cough. [14976-57-9].
Synthesis of Ethanolamines. In all known
synthetic methods a benzhydryl unit is used as
starting material [30]. Two synthetic routes are
normally followed:
1) The sodium salt of a benzhydrol, prepared
with NaH, NaNH2 , or NaOC2 H5 , is treated
with an aminoethyl halide, e.g., dimethylami-
noethyl chloride.
2) Sometimes a benzhydryl halide is condensed Preparation: [33].
with an aminoethanol in the presence of potas- Trade names: Tavegil (Sandoz – Novartis),
sium carbonate. Telgin-G (Takeda). Some multi-ingredient
preparations such as Dexa Tavegil.
Bromdiphenhydramine [118-23-0], bro-
mazine, 2-[(4-bromophenyl)phenylmethoxy]- Diphenhydramine [58-73-1], 2-(di-
N,N-dimethylethanamine, C17 H20 BrNO, M r phenylmethoxy)-N,N-dimethylethanamine,
334.3. Hydrochloride [1808-12-4], mp 144 – C17 H21 NO, M r 255.3. Hydrochloride [147-24-
145 ◦ C. 0], mp 166 – 170 ◦ C.

Preparation: [30]. To counteract the sedat-

Preparation: [31].
Trade names: Ambodryl (Parke – Davis),
multi-ingredient preparations such as Ambenyl.
Carbinoxamine [486-16-8], 2-[(4-chloro-
phenyl)-2-pyridinylmethoxy]-N,N-dimethyl-
ethanamine, C16 H19 ClN2 O, M r 290.8. Hy-
drochloride, mp 162 – 164 ◦ C; maleate [3505-
38-2].
ing effects, diphenhydramine is combined with
8-chlorotheophylline (Dimenhydrinate).
Trade names: Benadryl (Parke – Davis), Be-
nadryl N (Warner – Lambert), Fenylhist (Mal-
lard). Several multi-ingredient preparations.

Doxylamine [469-21-6], N,N-dimethyl-2-
[1-phenyl-1-(2-pyridinyl)ethoxy]ethanamine,
C17 H22 N2 O, M r 270.4. Succinate [562-10-7],
mp 100 – 104 ◦ C.
Doxylamine is synthesized from phenyl-2-
pyridinylmethyl carbinol and dimethylamino-
ethyl chloride in the presence of NaNH2 in xy-
lene [34]. It exhibits pronounced sedative ef-
fects. Therefore, doxylamine is mainly used as
a sedative, a sleeping aid.
Trade names: Mereprine (Merrell), Hoggar
N (Stada), Unisom (Pfizer).
Ebramine [3565-72-8], 2-[(4-bromophen-
yl)-1-phenylethoxy]-N,N-dimethylethanamine,
C18 H22 BrNO. Hydrochloride [13977-28-1], mp
150 – 152 ◦ C.
Preparation: [35].
Trade names: Bromadryl (Spofa).
Mephenhydramine [3572-74-5], 2-(1,1-
diphenylethoxy)-N,N-dimethylethanamine,
C18 H23 NO, M r 269.4. Hydrochloride, mp
168 ◦ C.
Compared with diphenhydramine the antihis-
taminic activity of mephenhydramin has been
enhanced by the introduction of an additional
methyl group.
Antiallergic Agents 7
Preparation: [36].
Trade names: Alphadryl (Spofa). Several
multi-ingredient preparations.
Phenyltoloxamine [92-12-6], N,N-di-
methyl-2-[2-(phenylmethyl)phenoxy]ethan-
amine, C17 H21 NO, M r 255.4. Citrate [1176-
08-5], mp 138 – 140 ◦ C.
Preparation: [37].
Trade names: Phenyltoloxamine is avail-
able only in multi-ingredient preparations, e.g.,
Codipront (Mack Illertissen).
Trimethobenzamide [138-56-7], N-[[4-[2-
(dimethylamino)ethoxy]phenyl]methyl]-3,4,5-
trimethoxybenzamide, C21 H28 N2 O5 , M r 388.5.
Hydrochloride [554-92-7].
Preparation: [38].
Trade names: Anaus (Molteni), Tigan (Smith
Kline Beecham).
2.1.3. Alkylamines
At the end of the 1940s, it was observed that ap-
propriately substituted aminopropanes exhibit
antihistaminic activities [39, 40]. Substituted
aminopropanes have been introduced into ther-
apy as antihistamines in the early 1950s. One
of the remarkable features of these alkylamine
derivatives is their strong and long-lasting an-
tihistaminic activity. They are only moderately
sedating and show some antimuscarinic proper-
ties. Among the stereoisomers, the dextrorotary
form (d-form) is the eutomer (i.e., enantiomer
with the higher bilological activity) [41].
8 Antiallergic Agents
Brompheniramine [86-22-6],
3-(4-bromophenyl)-3-(2-pyridinyl)-N,N-dime-
thylpropanamine, C16 H19 BrN2 , M r 319.2.
Maleate [980-71-2], mp 132 – 134 ◦ C.
Preparation [42]:
where X = Br (bromopheniramine), Cl
(chloropheniramine) or H (pheniramine).
Similarly to other pheniramine derivatives,
brompheniramine can also be administered par-
enterally.
Trade names: Ilvin (Merck), Dimegan
(Dexo). Several multi-ingredient preparations.
Chlorpheniramine [132-22-9], 3-
(4-chlorophenyl)-3-(2-pyridinyl)-N,N-di-
methylpropanamine, C16 H19 ClN2 , M r 274.8.
Maleate [113-92-8], mp 130 – 135 ◦ C. Synthe-
sis [42], formula see page 8. The racemate can
be separated into the enantiomers; the d-form,
dexchlorpheniramine, is active [43].
Trade names: Teldrin (SKF), d-form: Po-
laronil (Schering), Polaramin (Schering),
Phenamin (Nycomed). Several multi-ingredient
preparations, e.g., Codicaps (Thiemann).
Dimetindene [5636-83-9], N,N-dimethyl-
3[1-(2-pyridinyl)ethyl]-1H-indene-2-ethan-
amine, C20 H24 N2 , M r 292.4. Maleate [3614-
69-5], mp 159 – 161 ◦ C.
Preparation: Benzylmalonic acid is esteri-
fied with dihydropyran and reacted with sodium
hydride and 2-dimethylaminoethyl chloride in
toluene to give ditetrahydropyranyl-2-benzyl-2-
(2-dimethylaminoethyl)malonate, which is cy-
clized with the help of polyphosphoric acid
to 2-(2-dimethylaminoethyl)-indan-1-one. This
compound reacts with 2-ethylpyridine and phen-
yllithium to give the carbinol, which is dehy-
drated by heating to dimetindene [44].
Trade names: Fenistil (Zyma), Forhistal
(Ciba). Several multi-ingredient preparations.
Pheniramine [86-21-5], N,N-dimethyl-γ-
phenyl-2-pyridinepropanamine, C16 H20 N2 , M r
240.3. Maleate [132-20-7], mp 107 ◦ C. (For-
mula and preparation see page 8).
Trade name: Avil (Hoechst). Several multi-
ingredient preparations.
Tolpropamine [5632-44-0], 3-phenyl-3-
(4-methylphenyl)-N,N-dimethylpropanamine,
C18 H23 N, M r 253.4. Hydrochloride [3339-11-
5].
Preparation: [41].
Trade name: Pragman Gelee (Milanfarma).
Triprolidine [486-12-4], (E)-2-[1-(4-meth-
ylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]pyri-
dine, C19 H22 N2 , M r 278.4. Hydrochloride [550-
70-9], mp 116 – 118 ◦ C; hydrochloride mono-
hydrate [6138-79-0]. Synthesis [45]:

Trade names: Pro-Actidil (Wellcome), Ve-
nen (Tanabe). Several multi-ingredient prepara-
tions, e.g., Actifed (Warner – Lambert).
2.1.4. Piperazines
Buclizine [82-95-1], 1-[(4-chlorophenyl)-
phenylmethyl]-4-[4-(1,1-dimethylethyl)phen-
yl]methyl]piperazine, C28 H33 ClN2 , M r 433.0.
Dihydrochloride [29-74-8].
Preparation: [46]. Buclizine is mainly used
in the prevention of motion sickness and in com-
bination with analgesics for treatment of mi-
graine.
Trade names: Buclifen (Pfizer), Posdel
(UCB). Several multi-ingredient preparations,
e.g., Migralave N (Tremmler Pharma).
Chlorcyclizine [82-93-9], 1-[(4-chloro-
phenyl)phenylmethyl]-4-methylpiperazine,
Antiallergic Agents 9
C18 H21 ClN2 , M r 300.8. Hydrochloride [1620-
21-9], mp 216 ◦ C.
Preparation: [47].
Trade names: Di-Paralene (Abbott), His-
tantin (Wellcome).
Cinnarizine [298-57-7], 1-(diphenyl-
methyl)-4-(3-phenyl-2-propenyl)piperazine,
C26 H28 N2 , M r 368.5.
Preparation: Cinnarinzine is prepared by
alkylation of 1-diphenylmethyl piperazine with
3-phenyl-2-propenyl chloride [48]. In addition
to its antihistaminic activity, cinnarizine pos-
sesses Ca2+ channel blocking activity. Its va-
sodilator effect probably results from blocking
the Ca2+ channels in the vascular smooth mus-
cle cells. Therefore, cinnarizine is used in pe-
ripheral and central vascular diseases. Labyrinth
disorders (e.g. vertigo, Ménière syndrome) are
also often treated with cinnarizine.
Trade names: Stutgeron (Janssen), Aplactan
(Eisai), Mitronal (Searle).
Clocinizine [298-55-5], 1-[(4-chlorophe-
nyl)phenylmethyl]-4-(3-phenyl-2-propenyl)pi-
perazine, C26 H27 ClN2 , M r 403.0.
10 Antiallergic Agents

ethoxy]ethanol, C21 H27 ClN2 O2 , M r 410.0.

Preparation: [49]. Dihydrochloride [2192-20-3], mp 193 ◦ C.
Trade names: Clocinizine is used only in
multi-ingredient preparations, e.g., Denoral
(Rorer).
Cyclizine [82-92-8], 1-diphenylmethyl-4-
methylpiperazine, C18 H22 N2 , M r 266.4, mp
105 – 107 ◦ C. Hydrochloride [303-25-3].

Preparation: [51]. Hydroxyzine has antihis-

Preparation: Cyclizine is prepared by reac-
tion of benzhydryl chloride and N-methyl piper-
azine [50]. It can be used not only in the treat-
ment of allergic diseases, but also in the man-
agement of postoperative, irradiation or drug-
induced vomiting. Cyclizine dependence has
been suggested to occur when it is used in com-
bination with analgesics in long-term therapy.
For this reason, several countries have removed
cyclicine from analgesic combination prepara-
tions.
Trade names: Marziné (Burroughs Well-
come). Some multi-ingredient preparations,
e.g., Cyclimorph.
Flunarizine [52468-60-7], (E)-1-
[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-
propenyl)-piperazine, C26 H26 F2 N2 , M r 404.5.
Dihydrochloride [30484-77-6].
taminic, antimuscarinic, and central nervous
properties. Hydroxizine is used not only in the
treatment of allergic diseases, but also as an
anxyolitic.
Trade names: Atarax (Pfizer), Orgatrax
(Organon).
Meclozine [569-65-3], mezlizine, 1-[(4-
chlorophenyl)phenylmethyl]-4-[3-methylphe-
nyl)methyl]piperazine, C25 H27 ClN2 , M r 391.0.
Dihydrochloride monohydrate [31884-77-2].
Preparation: The synthesis of meclozine is
very similar to that of cyclizine.
Trade names: Postafen (UCB), Bonine
(Pfizer), Veritab (Vista).
Niaprazine [27367-90-4], N-[3-[4-(4-
fluorophenyl)-1-piperazinyl]-1-methylpropyl]-
3-pyridinecarboxamide, C20 H25 FN4 O, M r
356.4.

Flunarizine is the difluorinated derivative of cin-

narizine. Thus, its preparation and therapeutic
use are identical to those of cinnarizine.
Trade names: Sibelium (Janssen), Fluxarten
(Beecham). Preparation: [52].
Trade names: Nopron (Carrion).
Hydroxyzine [68-88-2], 2-[2-[4-[4-
(chlorophenyl)phenylmethyl]-1-piperazinyl]- Oxatomide [60607-34-3], 1-[3-[4-(diphen-
ylmethyl) -1-piperazinyl] propyl]-1,3-dihydro-
 Antiallergic Agents 11

2H-benzimidazol-2-one, C27 H30 N4 O, Mr Pipoxizine [55837-21-3], 2-[2-[2-[4-(Di-

426.2. phenylmethylene)piperidinyl]ethoxy]ethoxy]eth-
anol, C24 H31 NO3 , M r 381.3. Hydrochloride,
mp 144 – 145 ◦ C. Synthesis [56]:

Preparation: Oxatomide is synthesized

by alkylation of 1-diphenylmethylpipera-
zine with 1-(3-chloropropyl)-1,3-dihydro-2H-
benzimidazol-2-one in the presence of Na2 CO3
[53]. In addition to its histamine H1 receptor an-
tagonistic effect, oxatomide may have mast-cell
stabilizing activities [54].
Trade names: Tinset (Janssen), Celtect (Ky-
owa).

2.1.5. Piperidines
Bamipine [4945-47-5], 1-methyl-N-
phenyl-N-(phenylmethyl)-4-piperidinamine,
C19 H24 N2 , M r 280.4. Dihydrochloride [61732-
85-2]. Trade names: Respacal (UCB).

Thenalidine [86-12-4], 1-methyl-N-phen-

yl-N-(2-thienylmethyl)-4-piperidinamine.
C17 H22 N2 S, M r 286.5. Tartrate, mp 170 –
172 ◦ C.

Preparation: [55].
Trade names: Soventol (Knoll).
Diphenylpyraline [147-20-6], 4-(diphenyl-
methoxy)-1-methylpiperidine, C19 H23 NO, M r
281.4. Hydrochloride [132-18-3].
Preparation: Thenalidine is synthesized by
alkylation of 1-methyl-4-phenylaminopiperi-
dine with 2-chloromethyl thiophene [57].
Trade names: Sandosten (Sandoz).

2.1.6. Phenothiazines
Alimemazone [84-96-8], 10-[3-(dimeth-
Preparation: [160]. ylamino)-2-methylpropyl]phenothiazine,
Trade names: Arbid N (Bayer), Lergobine C18 H22 N2 S, M r 298.5. Tartrate [4330-99-8].
(3M). Some multi-ingredient preparations.
12 Antiallergic Agents

Hydroxyethylpromethazine [7647-63-
4], (2-hydroxyethyl)dimethyl-(1-methyl-2-
phenothiazi-10-ylethyl)ammonium chloride,
C19 H25 ClN2 OS, Mr 364.9.

Preparation: [58].
Trade names: Theralene (Rhône – Poulenc),
Temaril (Allergan).
Dimethothiazine [7456-24-8], 10-[2-(di-
methylamino)-propyl]-N,N-dimethyl-10H-
phenothiazine-2-sulfonamide, C19 H25 N3 O2 S2 ,
M r 391.6. Methanesulfonate [7455-39-2].
Preparation: [60].
Trade names: Aprobit (Kabi).
Isothipendyl [482-15-5], 10-(2-dimethyl-
amino-2-methylethyl)-10H-pyrido[3,2-b][1,4]-
benzothiazine, C16 H19 N3 S, Mr 285.4. Hy-
drochloride [1225-60-1] mp 222 – 223 ◦ C.
Preparation [61]:

Preparation: [59].
Trade names: Banistyl (M & B), Migristene
(Specia).
Dimelazine [15302-12-2], 10-[(1,3-di-
methyl-3-pyrrolidinyl)methyl]-10H-pheno-
thiazine, C19 H22 N2 S, M r 310.1.

Trade names: Centrophene (Biosedra),

Tacaryl (Westwood).
Dioxopromethazone [13754-56-8], 10-[2-
(dimethylamino)propyl]-10H-phenothiazine-
5,5-dioxide, C17 H20 N2 O2 S, M r 316.2.
Isothipendyl is more active than promethazine
and less sedating [62].
Trade names: Theruhistin (Ayerst).
Mequitazine [29216-28-2], 10-(1-azabicy-
clo[2.2.2]oct-3-ylmethyl)-10H-phenothiazine,
C20 H22 N2 S, M r 322.5.

Trade names: Prothanon (LAW).


Preparation: [63]. Mequitazine has mild cen-
tral sedating effects.
Trade names: Metaplexan (Rhône – Poulenc
– Rorer), Butix (Fabre).
Methdilazine [1982-37-2], 10-[(1-methyl-
3-pyrrolidinyl)methyl]-10H-phenothiazine,
C18 H20 N2 S, M r 296.4. Hydrochloride [1229-
35-2], mp 187 – 189 ◦ C.
Preparation: [64].
Trade names: Dilosyn (British Drug
Houses), Tacaryl (Westwood).
Oxomemazine [3689-50-7], 10-(3-dimeth-
ylamino-2-methylpropyl)phenothiazine-5,5-
dioxide, C18 H22 N2 O2 S, M r 330.5. Hydrochlo-
ride [4784-40-1].
Preparation: [65].
Trade names: Doxergan (Rhône – Poulenc).
Promethazine [60-87-7], 10-(2-dimethyl-
amino-propyl)phenothiazine, C17 H20 N2 S, M r
284.4. Hydrochloride [58-33-3] mp 244 –
246 ◦ C.
Preparation: [66]. Promethazine is synthe-
sized from 10-phenothiazine-2-propyl chloride
Antiallergic Agents 13
and dimethylamine in the presence of Cu. In ad-
dition to its antihistaminic activity, it has marked
central sedative properties.
Trade names: Atosil (Bayer), Phenergan
(Rhône – Poulenc, Wyeth), Hiberna (Yoshit-
omi). Several multi-ingredient preparations.
Propiomazine [362-29-8], 1-[2-(dimeth-
ylamino)propyl]-10H-phenothiazin-2-yl]-1-
propanone, C20 H24 N2 OS, M r 340.5. Hy-
drochloride [1240-15-9].
Preparation: [67].
Trade names: Propavan (Kabi), Indorm
(Wyeth).
Thiazinamium [2338-21-8], trimethyl-(1-
methyl-2-phenothiazin-10-ylethyl)ammonium
methyl sulfate, C19 H26 N2 O4 S2 , M r 410.6.
Preparation: Thiazinamium is prepared by
reacting promethazine with dimethyl sulfate
[68].
Trade names: Padisal (Bayer), Multergan
(Specia).
2.1.7. Other Tricyclic Systems
Azatadine [3964-81-6], 6,11-dihydro-11-
(1-methyl-4-piperidylidene)-5H-benzo[5,6]cy-
clohepta[1,2-b]pyridine, C20 H22 N2 , M r 290.4,
mp 124 – 126 ◦ C. Dimaleate [3978-86-7]. Syn-
thesis [69]:
14 Antiallergic Agents
Trade names: Idulian (Unilabo), Zadine
(Schering).
Clobenzepam [1159-93-9], 7-chloro-
10-(2-dimethylaminoethyl)-5,10-dihydro-
11H-dibenzo[b,e][1,4]diazepin-11-one,
C17 H18 ClN3 O, M r 315.8, Hydrochloride
[2726-03-6], mp 225 – 233 ◦ C.
Preparation: [70].
Trade names: Tarpan (Wander).
Cyproheptadine [129-03-3], 4-(5H-
dibenzo[a,d]cyclohepten-5-ylidene)-1-methyl-
piperidine, C21 H21 N, M r 287.4. Hydrochloride
[969-33-5], mp 252 – 254 ◦ C. In addition to its
antiallergic action cyproheptadine also exhibits
an appetite-stimulating effect. For this reason, it
is often used for promotion of weight gain.
Preparation [71]:
Trade names: Nuran (Frosst), Periactin
(MSD), Peritol (EGYT). Some multi-ingredient
preparations.
Ketotifen [34580-13-7], 4,9-dihydro-4-(1-
methyl-4-piperidylidene)-10H-benzo[4,5]cy-
clohepta[1,2-b]thiophene-10(9H)-one,
C19 H19 NOS, M r 309.2. Hydrogen fumarate
[34580-14-8], mp 192 ◦ C.

Preparation: [71].
Trade names: Zaditen (Sandoz – Novartis).
Some multi-ingredient preparations.
Mebhydroline [524-81-2], 2,3,4,5-
tetrahydro-2-methyl-5-(phenylmethyl)-1H-
pyrido[4,3-p]indole, C19 H20 N2 , M r 276.4. 1,5-
Naphthalendisulfonate [6153-33-9].
Preparation: [72].
Trade names: Omeril (Bayer).
Phenindamine [82-88-2], 2,3,4,9-tetrahy-
dro-2-methyl-9-phenyl-1H-indeno[2,1-c]pyri-
dine, C19 H19 N, M r 261.4. Hydrogen tartrate
[569-59-5], mp 165 – 167 ◦ C.
Preparation: [73].
Trade names: Pernovin (Chinoin), Thephorin
(Sinclair).
Pimethixene [314-03-4], 1-methyl-4-(9H-
thioxanthen-9-ylidene)piperidine, C19 H19 NS,
M r 293.4, mp 120 – 121 ◦ C. Synthesis [74]:
Trade names: Muricalm (Sandoz – Novar-
tis).
Antiallergic Agents 15
2.2. Second-Generation Antihistamines
Antihistamines of the second generation are gen-
erally free of sedation. However, this effect is
dose-dependent. At higher doses and, conse-
quently, at higher plasma levels of the drugs,
mild sedative effects can be observed.
2.2.1. Ethanolamines
Setastine [64294-95-7], 1-[2[1-(4-chloro-
phenyl)-1-phenylethoxy]ethyl]hexahydro-1H-
azepine, C22 H28 ClNO, M r 357.9. Hydrochlo-
ride [59767-13-4].
Preparation: [75].
Trade names: Loderix (EGIS).
2.2.2. Alkylamines
Acrivastine [87848-99-5], (E,E)-3-[6-[1-(4-
methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]-
-2-pyridinyl]propenoic acid, C22 H24 N2 O2 , M r
348.4.
Preparation: [76].
Trade names: Semprex (Glaxo – Wellcome).
2.2.3. Piperazines
Cetirizine [83881-51-0], 2-[4-[1-(4-chlorophe-
nyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic
acid, C21 H25 ClN2 O3 , M r 388.5. Dihydro-
chloride [83881-52-1].
16 Antiallergic Agents

Preparation: [77]. Cetirizine is a metabolite

of hydroxizine with a long plasma half-life.
Trade names: Zyrtec (UCB), Reactine
(Pfizer).

2.2.4. Piperidines
Astemizole [68844-77-9], 1-(4-fluorophen-
yl)-methyl-N-[1-[2-(4-methoxyphenyl)ethyl]-
4-piperidinyl]-1H-benzimidazol-2-amine,
C28 H31 FN4 O, M r 458.3, mp 149 ◦ C. Synthesis
[78]:
Astemizole is a strong histamine H1-receptor
antagonist with an extremely long elimination
half-life. Prolongation of QTc interval and car-
diac arrhythmias can be associated with its use
[79].
Trade names: Histmanol (Janssen), Cilergil
(Cilag), Almizol (Nobel).
Betotastine Besilate [190786-44-8], (+)-
(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)-
methoxy]piperidin-1-yl]butanoic acid mono-
benzenesulfonate, C21 H25 ClN2 O3 · C6 H6 O3 S,
M r 547.1.

Preparation: [80]. Under development by

Tanabe Seiyaku and Ube.
Ebastine [90729-43-4], 1-[4-(1,1-dimeth-
ylethyl)phenyl]-4-[4-(diphenylmethoxy)-1-pi-
peridinyl]-1-butanone, C32 H39 NO2 , M r 469.0.

Preparation: [81].
Trade names: Ebastel (Almirall).
Fexofenadine [153439-40-8], 2-methyl-
2-[4-[1-hydroxy-4-[4-(1,1-diphenylhydroxy-
methyl)-1-piperidinyl]butyl]phenyl]propionic
acid, C32 H39 NO4 , M r 501.2.
Fexofenadine is a metabolite of terfenadine (see
page 17) and is free of cardiovascular side effects
[82].
Trade names: Allegra (Hoechst Marion
Roussel).
Levocabastine [79516-68-0], 1-[4-cyano-4-
(4-fluorophenyl)cyclohexyl]-3-methyl-4-phen-
yl-4-piperidinic acid, C26 H26 FN2 O2 , M r 417.2.
Hydrochloride [79547-78-7].
Trade names: Livocab (Janssen), Levocon
(Johnson & Johnson).
Mizolastine [108612-45-9], 1-(4-fluoro-
benzyl)-2-[4-[N-(3,4-dihydro-4-oxopyrimidin-
2-yl)-N-methylamino]piperidin-1-yl]benzimid-
azole, C24 H25 FN6 O, M r 432.5.
Antiallergic Agents 17
Preparation: [83]. Mizolastine is a potent
nonsedating H1 -receptor antagonist providing
satisfactory symptom relief in allergic rhinitis
and urticaria [84].
Trade names: Mizollen (Synthelabo).
Noberastine [110588-56-2], 3-[(5-
methyl-2-furanyl)methyl]-N-4-piperidinyl-3H-
imidazo[4,5-b]pyridin-2-amine, C17 H21 N5 O,
M r 311.1.
Under development by Cilag (phase III). Dur-
ing clinical trials noberastine did not produce
any sedative effects.
Terfenadine [50679-08-8], 4-(1,1-di-
methylethyl)-1-[1-hydroxy-4-[4-(1,1-diphenyl-
hydroxymethyl)-1-piperidinyl]butyl]benzene,
C32 H41 NO2 , M r 471.2.
Due to its arrhythmogenic activity, terfenadine
has been replaced by its metabolite, fexofena-
dine (see page 17) [85].
18 Antiallergic Agents
Trade name: Teldane (Hoechst Marion Rous-
sel).
2.2.5. Phthalazinones
Azelastine [58581-89-8], 4-[(4-chloro-
phenyl)methyl]-2-(hexahydro-1-methyl-
1H-azepin-4-yl)-1(2H)-phthalazinone,
C22 H24 ClN3 O, M r 381.7. Hydrochloride
[37932-96-0], mp 225 – 229 ◦ C. Synthesis [86]:
Azelastine has potent, long-lasting histamine
H1 -receptor blocking activity and several other
interesting anti-inflammatory properties related
to its antiallergic efficacy [86].
Trade names: Allergodil, Rhinolast (ASTA
Medica).
2.2.6. Others
Emedastine [87233-61-2], 1-(2-ethoxyethyl)-
-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-
yl]-1H-benzimidazole, C17 H26 N4 O, M r 302.2.
Trade names: Daren (Kanebo), Remicut
(Kowa).
Epinastine [80012-43-7], 9,13b-dihy-
dro-1H-dibenzo[c,f ]imidazo[1,5-a]azepin-3-
amine, C16 H15 N3 , M r 249.1.
Preparation: [87].
Trade name: Alesion (Boehringer Ingel-
heim).
Loratadine [79794-75-5], 8-chloro-6,11-
dihydro-11-(1-ethoxycarboxy-4-piperidin-
ylidene)-5H-benzo[5,6]cyclohepta[1,2-b]-pyri-
dine, C22 H23 ClN2 O2 , M r 382.5.
Loratadine is a selective antihistamine for the
relief of symptoms of allergic rhinoconjunctivi-
tis and chronic urticaria [88]. In 1997, loratadine
has been shown to produced cardiac arrhythmias
probably via blocking cardiac K+ channels [89].
However, the concentrations at which this block-
ade occurred were much higher that the observed
therapeutic plasma levels [90].
Trade name: Claritin (Schering – Plough),
Lisino (Essex Pharma).
2.2.7. Combinations of Antihistamines and
Sympathomimetic Agents
Antihistamines are often combined with sympa-
thomimetic agents. For oral administration, in-
directly acting sympathomimetics (e.g., pseudo-
ephedrine) are preferred. Combinations for top-
ical applications contain α-adrenergic agonists

(e.g., oxymetazoline). Recently it has been
demonstrated that pseudoephedrine might in-
crease the stroke risk. As regards combinations
for topical applications, it should be kept in mind
that long-term application of α-adrenergic com-
pounds may cause serious undesired effects (re-
bound effect, nasal congestion).
2.3. Inhibitors of Histamine Synthesis
Tritoqualine [14504-73-5], 7-amino-4,5,6-
triethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-
methyl-1,3-dioxolo[4,5-g]-isoquinolin-5-yl)-
-1(3H)isobenzofuranone, C26 H32 N2 O8 , M r
500.5.
Preparation: [91].
Trade names: Inhibostamin (Zyma), Livalfa
(Mitsubishi).
3. Mast Cell Stabilizing Agents
The prototype drug, disodium cromoglycate re-
sulted from research on khellin, a chromone 2-
carboxylic acid derived from the Middle East-
ern herb Ammi visnaga [92]. Cromolyn sodium
or disodium cromoglycate (DSCG) was synthe-
sized in 1965 and introduced as a prophylac-
tic, nonbronchodilating anti-inflammatory drug
into the therapy of allergic disorders. Although
DSCG was initially thought to be merely a
mast cell stabilizer, subsequent pharmacologi-
cal studies showed that it has multiple effects.
Probably, it acts on certain types of chloride
channels expressed in mast cells and sensory
nerves [93]. Penner et al. [94] described the ex-
istence of a small conductance chloride chan-
nel in rat peritoneal mast cells. Activation of
this channel causes an influx of chloride ions
and results in hyperpolarization of the mem-
brane which then drives a calcium influx, lead-
ing to degranulation. Disodium cromoglycate
Antiallergic Agents 19
blocks these intermediate conductance channels
which are activated after immunological stimu-
lation [95]. Since cromones are practically not
absorbed in the gastrointestinal tract, they must
be administered by inhalation. All attempts to
develop orally active cromones have been un-
successful until now.
Amlexanox [68302-57-8], 2-amino-7-(1-
methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-
b]pyridine-3-carboxylic acid, C16 H14 N2 O4 , M r
298.2.
Amlexanox acts in two ways. Besides its mem-
brane-stabilizing property amlexanox also in-
hibits leucotriene-mediated effects [101].
Preparation: [100].
Trade name: Solfa (Takeda).
Disodium cromoglycate [15826-37-6],
DSCG, cromolyn sodium, 5,5 -[(2-hydroxy-
1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-
benzopyran-2-carboxylic acid]disodium salt,
C23 H14 Na2 O11 , M r 512.3.
Preparation: [96].
Trade names: Intal, Adrane ( Fisons).
Lodoxamide [53882-12-5], 2,2 -[(2-chloro-
5-cyano-1,3-phenylene)diimino]bis[2-oxoace-
tic acid], C11 H6 ClN3 O6 , M r 311.6.
Trometamol (2-amino-2-(hydroxymethyl)-1,3-
propanediol) salt [63610-09-3]. Lodoxamide is
an antiallergic drug acting as a mast-cell stabi-
20 Antiallergic Agents
lizer, which is effective in the treatment of aller-
gic conjunctivitis [99].
Trade names: Alomide (Alcon), Lomide
(Pharmacia & Upjohn).
Nedocromil [69049-73-6], 9-ethyl-6,9-di-
hydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-
g]quinoline-2,8-dicarboxylic acid, C19 H17 NO7 ,
M r 371.1. Disodium salt [69049-74-7].
Nedocromil sodium acts mainly by inhibiting
the release of inflammatory mediators. It has a
stabilizing action on mast cells similar to that
of DSCG. Nedocromil is capable of inhibiting
chloride ion flux in mast cells, epithelial cells,
and neurons. This feature may explain why it can
prevent responses such as mast cell degranula-
tion and neuronal activation [97]. Nedocromil is
given by inhalation in the prophylactic control
of asthma and rhinitis [98].
Trade name: Tilade (Rhône – Poulenc –
Rorer).
4. Allergen Preparations for
Desensitization
The aim of allergen immunotherapy (hyposen-
sitization, desensitization) is to achieve allergen
tolerance in the atopic patient by administer-
ing gradually increasing quantities of an aller-
gen vaccine. This treatment was first used by
Noon [102] and Freeman [103] in 1911 for al-
lergic rhinitis on an empirical basis. Since then,
immunotherapy has become a widely accepted
method of treatment in IgE-mediated allergic
diseases, caused by various seasonal or peren-
nial inhalant allergens.
Since the 1970s venom immunotherapy is the
standard of care for hymenoptera sting-induced
systemic allergic reactions [104]. Venom im-
muntherapy results in significantly lower risk
of systemic reactions even 10 to 20 years after
therapy is stopped [105, 106]. Knowledge has
been gained about the mechanism of action of
immunotherapy. Like vaccines allergen extracts
act as immune modifiers, so it seems justified to
call them allergen vaccines. The important role
of TH 1 and TH 2 lymphocytes has been explored
as well as the cytokine regulation of the immune
response [107]. Immunotherapy is the only treat-
ment that may affect the natural course of aller-
gic diseases, especially the chronification of in-
flammation of the respiratory tract [108 – 111].
Successful immunotherapy is dependent on the
quality of allergen vaccines. The vaccines have
to be standardized and manufactured properly
with batch-to-batch consistency.
The ideal allergen vaccines permit a maxi-
mum efficacy while minimizing the incidence
of adverse reactions. The pharmaceutical indus-
try is constantly developing and investigating
safer and at the same time equally or more ef-
fective forms of therapies. The molecular aller-
gen characterization by recombinant DNA tech-
nology leads to novel forms of diagnostics and
immunotherapy based on recombinant allergens
[112 – 114]. Recombinant allergens identify ex-
actly those IgE-binding molecules responsible
for the allergic reaction.
4.1. Properties of Allergens
Allergenic components are most often of a
proteinaceous nature. Their molecular weight
ranges between 5 and 70 kD. Pollens of
grasses, trees, and weeds are the main source
of disease-causing allergens, followed by dust
mites, molds, pets, and food. The allergic reac-
tion to insect stings represents a special form,
because it will not elicit any chronic inflamma-
tory organic disease, but usually lead to a local
or even systemic life-threatening anaphylactic
shock. Some molecules bind as haptens to hu-
man proteins and lead only as a protein complex
to allergic reactions.
Those allergenic parts to which most patients
respond with formation of antibodies are called
major allergens, those less often answered by an
immunologic response minor allergens. A spe-
cial and important kind of allergens are the so-
called profilines. They are highly cross-reactive
proteins with a similar amino acid structure
found in related or nonbotanical related plants,
food, or even in human cells. Patients who are
sensitized to profilines are allergic to a broad
 Antiallergic Agents 21
Table 1. Physicochemical properties of a choice of purified allergens (Comprehensive list under [117])

Species Common name Allergen Comment Aa length

Aero Allergen Plants

Ambrosia artemisifolia Short ragweed Amb a 6 Lipid transfer protein 118
Artemisia vulgaris Mugwort Art v 1 Major allergen precursor 132
Betula pendula European white birch Bet v 1 Isoform at 8 160
Betula pendula European white birch Bet v 2 Profilin 133
Corylus avellana European hazelnut Cor a 2 Profilin 131
Cryptomeria japonica Japanese cedar Cry j 1 Pectate lyase 374
Lollium perenne Perennial ryegrass Lol p 5.0102 Ribonuclease 308
Olea europea Olive tree Ole e 2 Profilin 3 134
Parietaria judaica Weed Par j 3 Profilin 2 131
Phleum pratense Common timothy Phl p 13 Polygalactorunase 394
Zea mays Corn Zea m 1 Beta-expansin 1 a 269
Aero Allergen Animal
Canis familiaris Dog Can f 2 Lipocalin 180
Equus caballus Horse Equ c 3 Preproalbumin 607
Felis catus Cat Fel d 1 Beta chain 20
Rattus norvegicus Rat Rat n 1 Alpha-2u-globulin 179
Aero Allergen Mite
Acarus siro Mite Aca s 13 Lipid binding protein 64
Dermatophagoides farinae House dust mite Der f 1 Cysteine proteinase 321
Dermatophagoides pteronyssinus House dust mite Der p 3 Trypsin-like protein 261
Dermatophagoides pteronyssinus House dust mite Der p 4 Alpha-Amylase 496
Lepidoglyphus destructor Storage mite Lep d 10 Tropomyosin 284
Tyrophagus putrescentiae Dust mite Tyr p 2 Group 2 allergen 141
Aero Allergen Fungi
Alternaria alternata Fungus Alt a 1 Major allergen 1 157
Aspergillus fumigatus Fungus Asp f 2 Metalloprotease 310
Apergillus niger Fungus Asp n 14 Xylosidase 804
Davidiella tassiana Fungus Cla h 4 60S acidic ribosomal protein P2 111
Aero Allergen Insect
Blattella germanica German cockroach Bla g 2 Aspartic protease-like 352
Periplaneta americana American cockroach Per a 7.0102 Tropomyosin 284
Food Allergen Plant
Apium graveolens Celery Api g 1 PRB Bet v 1 family 154
Arachis hypogaea Peanut Ara h 4 Glycinin 530
Corylus avellana European hazelnut Cor a 1.0403 Cor a 1 (Bet v 1 homologue) 161
Daucus carota Carrot Dau c 4 Profilin 134
Glycine max Soybean Gly m 3 Profilin1 131
Malus x domestica Apple Mal d 1 PR-10 (Bet v 1 homologue) 159
Persea americana Avocado Pers a 1 Endochitinase 326
Prunus avium Cherry Pru av 3 Lipid transfer protein 117
Solanum tuberosum Potato Sola t 4 Serine protease inhibitor 7 221
Vitis sp. Grape Vit v 1 Nonspecific lipid-transfer protein P4 37
Venom Salivary Allergens
Apis cerana Indian honeybee Api c 1 Phospholipase A 2 134
Polistes annularis Paper wasp Pol a 2 Hyaluronidase 367
Solenopsis invicta Red fire ant Sol i 4 Venom allergen IV 117
Vespula maculifrons Wasp Ves m 1 Phospholipase A1 300
Contact Allergens
Hevea brasiliensis Para rubber tree Hev b 8 Profilin, chain A 131
Hevea brasiliensis Para rubber tree Hev b 6 Prohevein 204

spectrum of allergens. The fragments of aller-
gens which bind to the T helper cells or B cells
are called epitopes. Molecules of major antigens
may possess 2–5 major epitopes, the total num-
ber of epitopes per allergen molecule may be
much higher. Each epitope includes 8–15 amino
acid residues. The allergen molecules have no
physical or chemical features which distinguish
them from any other proteinic antigens except
that they are relatively small, and in some indi-
viduals give rise to initiation and maintenance of
IgE production. Several hundred major allergen
22 Antiallergic Agents
molecules have been isolated and characterized
up to now, and they have been shown to possess
different biological properties, such as enzymes
or to be involved in transport, reproduction or
secretion [115, 116]. A comprehensive list of al-
lergens whose amino acid sequences are known
at present can be found in [117]. The nomencla-
ture follows the recommendation of the WHO.
The name of an allergen is formed out of the
first three letters of the latin word, followed by
the first letter of the accompanying adjective and
then numbered. Some of the most common al-
lergens are listed in Table 1.
4.2. Raw Materials
Raw materials for allergen immunotherapy are
the biologic materials containing the allergenic
components. The allergen raw material should
be selected from relevant sources. Instructions
for harvesting, storage, extraction, and purifi-
cation have been described by the International
Union of Immunologic Societies (IUIS) [118],
in the Nordic Guidelines [119] and by the Euro-
pean Union [120] in order to achieve good batch-
to-batch consistency of allergenic potency. Man-
ufacturing of allergen extracts should be based
on The Code of Good Manufacturing Practice
(GMP) [121]. Figure 1 shows the production
process of allergenic products.
4.3. Allergen Standardization
A prerequisite for standardization of allergen
preparations extracted from well-defined source
materials is that the content of major and minor
allergens and the relation between these aller-
gens is constant from batch to batch [122]. The
most common vaccines used in clinical allergy
practice are now available as standardized prod-
ucts. However, for some vaccines standardiza-
tion is neither feasible nor economically possi-
ble. Several reference standards of widespread
allergens containing defined amounts of relevant
allergens are maintained under stable conditions
[104]. These standards have been produced as
part of the WHO/IUIS allergen standardization
program for a number of vaccines [123]. Based
on the precision of methods used for estima-
tion of relative potency, the FDA and the Nordic
Council on Medicine require a maximum vari-
ation in activity between batches of the same
allergen from 50 to 200 % of the labeled value
[104].
Methods of Standardization. The former
classification in protein nitrogen units or
weight/volume estimates is no longer used. Stan-
dardized products have been tested for potency
both in vivo and in vitro using methods for de-
tection of IgE antibodies to allergens. Using the
technique of skin testing, allergen vaccines can
be defined in biological units. The size of the al-
lergen induced wheal is compared to a histamine
reference solution (1 mg/mL). The allergen so-
lution which produces a medium wheal in sensi-
tized persons receives one HEP/mL (histamine
equivalence prick) [119]. For representative re-
sults, however, this method depends on the avail-
ability of allergic and, moreover, comparable
patients. The inhibition of the binding capacity
of IgE antibodies is determined with methods
derived from radioallergosorbent test (RAST)-
inhibition. Those tests for measurement of al-
lergenic potency are required by the European
Pharmacopoeia [115]. International reference
extracts are withheld by the WHO. Manufactur-
ers rely on definite values for quality controls.
One international reference value is defined as
100 000 international units (IU). Standardized
extracts show improved consistency to nonstan-
dardized ones. This holds true both for extracts
produced by different manufacturers and differ-
ent batches produced by the same manufacturer
[124]. The biologic effects of standardized ex-
tracts have been tested and thus the range of
major allergen levels is much narrower than
in nonstandardized products. However, some
variation occurs with in vivo and in vitro tests,
and it may be difficult to compare total aller-
genic potency of vaccines produced by different
manufacturers. The composition of the vaccine
can be determined by methods such as enzyme-
linked immunosorbent assay (ELISA) tech-
niques, sodium dodecyl sulfate – polyacrylam-
ide gel (SDS – PAGE) electrophoresis, isoelec-
tric focusing, IgE immunoblotting and crossed
immunoelectrophoresis/crossed radioimmuno-
electrophoresis (CIE/CRIE) [125].
Current Analysis Techniques. DNA and
protein analysis offers excellent opportunities
for standardization. The selection of the relevant
 Antiallergic Agents 23

Figure 1. Production process of allergenic products according to [122]

CIE = crossed immunoelectrophoresis; CRIE = crossed radioimmunoelectrophoresis; RAST = radioallergosorbent test

disease-causing major allergens is best achieved
by recombinant DNA technology [126]. The
most important allergens such as pollens, mites,
animal dander and insects have been cloned, se-
quenced and expressed. They show comparable
IgE antibody binding to their natural counter-
parts and excellent reactivity in skin and in in
vitro testing [127, 128]. With DNA and protein
analysis allergen vaccines are characterized in
terms of content of major allergen (nanograms
or micrograms), and the consistency of each lot
can be accurately monitored. Other techniques
include high-performance liquid chromatogra-
phy, capillary electrophoresis, and mass spec-
trometry [124].
Units. A critical problem in determining total
allergenic potency, whether based on biologic or
on in vitro assays, is the use of varying units over
the years. Only two systems have been supported
by authorities, i.e., the Nordic Biological Unit
(BU/mL, former HEP) and the U.S. Bioequiv-
alent Allergy Unit (BAU/mL). Both measuring
methods are based on the skin sensitivity of sam-
ple patients clinically sensitive to the allergens in
question. The unit BU/mL is similar and repro-
ducible in different regions of Europe. 1 BU of
common inhalant allergen has been shown to be
equal to 1 ng (± a factor of 2) of the most impor-
tant major allergens [129]. In practice manufac-
turers use different terms for concentrations: TE
24 Antiallergic Agents
(therapeutical unit–concentration in three steps
from 50 to 5000 TE/mL) is common besides SQ-
E (standardized qualitiy units–concentration in
four steps from 100 to 100 000 SQ-E/mL), AUeq
(allergy units equivalent–concentration 20 000
AUeq/mL), and SU (standardized units–concen-
tration in three steps from 300 to 2000 SU/mL).
All extracts with common allergens are stan-
dardized according the content of the major al-
lergen. Yet there are no obligatory prescriptions
for the total major allergen dose. Concentrations
differ between manufacturers and therefore a
switch among products should be avoided.
4.4. Allergen Vaccines for
Immunotherapy
Allergen vaccines are manufactured in different
preparations. Formerly, aqueous allergen vac-
cines were most commonly employed for an-
tiallergic immunotherapy, mainly for venom and
inhalant allergies. Depot and modified vaccines
have been developed in an attempt to make im-
munotherapy more effective and reduce side ef-
fects. The principle of preparing modified vac-
cines is to reduce or remove allergenicity, e.g.,
the capacity to induce IgE-mediated reaction. At
the same time the immunogenicity, which is the
capacity to modulate the immune system and
maintain clinical efficacy should be preserved
or increased.
Modification. For safer and more efficient
therapy, extracts are prepared as depot vac-
cines in different varieties. Physical modi-
fication means the adsorption of allergens
on aluminum, calcium phosphate, or tyro-
sine, or trapping of allergens in liposomes.
Allergenic reactivity concerning adverse re-
actions can be reduced by chemical modi-
fication of allergens to the so-called aller-
goids, such as formaldehyde-, glutaraldehyde-
and alginate-modified vaccines. Combinations
of physically and chemically modified vac-
cines include tyrosine-adsorbed glutaraldehyde-
modified vaccines and aluminum hydroxide
adsorbed- formaldehyde-modified vaccines. A
new technique is the conjugation of aller-
gen to immunostimulatory bacterial molecules.
Monophosphoryl-Lipid A (MPL r ) has been in-
troduced as such a novel adjuvant since 2001.
The preparation derived from the lipopolysac-
charide of Salmonella Minnesota R595 and has
Th1-inducing effects [130, 131]. This effect is
long-lasting and thus the number of vaccine in-
jections can be significantly reduced.
Allergen mixtures present several problems.
Excessive dilution by multiple allergens may
result in suboptimal doses of individual aller-
gens. Further, the potency of individual aller-
gens may deteriorate more rapidly when diluted
or mixed with other allergen vaccines. Some al-
lergens possess enzymatic activity which can al-
ter the composition of other allergens [104]. Al-
lergen vaccines should be distributed as either
vaccines from a single source material or mix-
tures of related cross-reacting allergen vaccines.
For any mixture of allergen vaccine stability data
and data on clinical efficacy should be available
[104].
4.5. Storage
Allergen vaccines are protein solutions that are
labile at elevated temperatures. Therefore, ster-
ilization can only be achieved by filtration. So-
lutions may be destroyed by microbial and en-
zymatic degradation, so they routinely contain
preservatives and should be stored in a refrig-
erator between 2 and 8 ◦ C. The most common
preservative is phenol in concentrations of 0.2–
0.5 %.
Concentrated aqueous extracts in 50 % glyc-
erin that are only to be used for skin prick testing
remain stable for about three years if stored at
4 ◦ C. Diluted extracts lose their potency more
rapidly [132]. To avoid loss of potency by ad-
sorption of active components on the surfaces of
containers and syringes, Tween 20 (an ethoxy-
lated sorbitan ester) and human serum albumin
have been employed. Vials should be labeled
in accordance with the requirements of regula-
tory authorities. Labeling includes a designation
of relevant units (see Units) obtained by an ap-
proved method.
4.6. Uses
Allergenic extracts are used for diagnosis and as
vaccines for treatment.

4.6.1. Diagnostic Use
Skin testing with concentrated solutions of al-
lergens is used to detect the individual sensitiv-
ities of an allergic patient. The most common
techniques are the prick test and the intracuta-
neous test. The prick test is performed by punc-
turing the skin with a sterile lancet through a
small drop of the allergenic extract. The intracu-
taneous (i.c.) test consists of injecting a minute
amount (ca. 0.02 mL) of an allergen extract into
the superficial layers of the skin. This method
is more sensitive than the prick test, and the
concentration of the test solution must be 10
– 100 fold lower than that for prick testing. In
cases of sensitivity both tests will result in the
development of a wheal and erythema reaction
within 15–20 min. To confirm clinical relevance
of an allergen in selected cases the nasal and/or
bronchial provocation test is performed. A small
amount of adequately diluted allergenic extract
is instilled into the nose or inhaled as nebulized
aerosol. A positive reaction is indicated by typ-
ical allergic symptoms and can be quantified by
special measurement procedures.
4.6.2. Therapeutic Use—Immunotherapy
Immunotherapy has been accepted as an ef-
ficient treatment for allergic rhinitis and hay
fever since the early 20th century. Besides al-
lergen avoidance immunotherapy is the only
chance that may modify the natural course of
the disease, e.g., the development from rhinitis
to asthma. Nevertheless, different points of view
exist concerning immunotherapy and asthma.
According to the consensus report on diagno-
sis and management of asthma of the National
Institutes of Health immunotherapy for asthma
is only rarely used in the United Kingdom or
even not recommended following the British
Thoracic Society guidelines [133, 134]. Im-
munotherapy treatment of allergic diseases in-
cluding asthma is widely accepted in the USA
and in European countries except Scandinavia.
Immunotherapy is absolutely indicated for
patients who had severe IgE-mediated anaphy-
lactic reactions to bee and wasp stings [135].
Hymenoptera venom is the only allergen for
which an efficacious maintenance dose has been
securely established (e.g., 100 µg of purified
Antiallergic Agents 25
venom, corresponding to about two bee stings
or five to ten wasp stings) [136]. Immuniza-
tion with venoms regularly results in essentially
complete protection [105, 106, 137].
Mechanism of Immunotherapy. In former
years the efficacy of immunotherapy was mea-
sured by decrease of IgE or increase in IgG an-
tibodies. In the mid-1990s it has been suggested
that immunomodulation plays a major role in
immunotherapy. Immunotherapy alters the bal-
ance of cytokines released from T helper lym-
phocytes in the respiratory tract, with a shift
from the TH 2 cells—that release interleukin-4
(IL-4) and interleukin-5 (IL-5) in association
with allergic inflammation—to TH 1 cells that re-
lease γ-interferon, which inhibit TH 2 cells [136,
138]. Successful immunotherapy might then be
associated with a shift in IL-4/γ-interferon pro-
duction either as a consequence of down reg-
ulation TH 2 cells responses or increased TH 1
cells responses. IL-10 has been found to play
an important role. Subsequent to immunother-
apy allergen-specific IL-10 will increase even
in the respiratory mucosa. IL-10 mediates the
immunotolerogenic effects by inducing the B
cells to produce IgG4, by inhibition of IgE-
dependent mast-cell activation and inhibition of
eosinophil cytokine production and suppression
of IL-5 [139]. Different mechanisms may be
valid in venom immunotherapy in nonatopic per-
sons and in immunotherapy with inhalant aller-
gens in atopic patients. Until now no measurable
parameters of patient characteristics or symptom
severity have been found that can predict or cor-
relate with a successful outcome [132].
Administration. Immunotherapy is started
with very small amounts of allergen vaccine in-
jected into the arm every two weeks. The al-
lergen concentration is slowly increased until
the maximum tolerated dose is reached. The in-
tervals of injection may then be prolonged to
about four weeks. A maintenance dose of ap-
proximately 5 to 20 µg of major allergen (rag-
weed, grass, mite, cat) is associated with signif-
icant improvement in patient symptom scores
[124]. In venom immunotherapy the usually
recommended maintenance dose is 100 µg of
venom protein. In pollen immunotherapy a re-
duced dose should be given during season to
avoid serious reactions. Local reactions occur
very often at the injection site, early reactions
26 Antiallergic Agents
within 20–30 min, some later than 30 min. Sys-
temic reactions with generalized symptoms are
the worse the earlier they occur. To minimize the
risk of immunotherapy each patient should stay
under supervision for at least 30 min after injec-
tion and every immunotherapy-practicing doc-
tor has to be trained in the treatment of allergic
shock and resuscitation [140].
New ways of immunotherapy, for instance
oral, sublingual or local application of allergen
vaccine have been tested . The sublingual way
seems to be the most promising for allergic rhini-
tis and asthma. Efficacy and safety have been
proven for children and adults in many trials.
Compared to the subcutaneous route a much
higher amount of allergen is necessary [139,
141]. A disadvantage might be that there is less
control by the treating physician because pa-
tients take the needed dose at home. Moreover
there are no experiences about long-time effi-
cacy comparable to the decades of subcutaneous
application.
Contraindications for immunotherapy in-
clude malignant and in immunodeficiency dis-
eases, treatment with β-blockers, poor com-
pliance, severe asthma, and significant cardio-
vascular diseases. During pregnancy treatment
should not be started but may be continued.
4.6.3. Legal Aspects, Quality Requirements,
and Safety
Only standardized extracts should be used for di-
agnosis and treatment. Potency should be quoted
in allergy units or in micrograms of a major con-
stituent whenever possible [137]. In the USA the
registration of allergenic products is controlled
by the FDA Center for Biologics Evaluation and
Review (CBER), where a new Division of Aller-
genic Products and Parasitology (DAPP) deals
with development, controlling, use, and safety
of allergenic products [142]. Since 1998 in the
EU allergenic extracts are registered by the Paul-
Ehrlich-Institut (PEI–Bundesamt für Sera und
Impfstoffe) which is also a WHO-Collaboration
Center. The PEI is responsible for the exami-
nation and registration of allergenic extracts for
diagnosis and therapy. Allergen products should
be manufactured under conditions which com-
ply with GMP.
Guidelines for immunotherapy with inhalant
allergens and venoms have been published in
the past ten years by the WHO, the European
Academy of Allergy and Clinical Immunology
(EAACI), the International Consensus Report
on Asthma, the Global Strategy for Asthma
Management and Prevention, the International
Consensus Report on Rhinitis, the British So-
ciety for Allergy and Clinical Immunology
(BSACI), the American Academy of Allergy,
Asthma and Immunology (AAAAI), the Amer-
ican College of Allergy, Asthma and Immunol-
ogy (ACAAI) , the International Union of Im-
munological Societies (IUIS) and the Deutsche
Gesellschaft für Allergologie und Immunologie
(DGAI) [104, 121, 124, 134, 135, 140, 143].
In immunotherapy the incidence of severe re-
actions is low. The mortality rate during im-
munotherapy is about one death per 2 × 106 in-
jections [136]. A study carried out in the Mayo
Clinic over a ten year period with 79 953 injec-
tions showed 0.137 % systemic reactions in an
average time of 35 min after injection. The sys-
temic reactions were equally frequent during the
rising and maintenance phases [144]. Bernstein
et al. reported in 2004 similar rates of fatal re-
actions to diagnostic or therapeutic procedures
as published in previous surveys [145]. The PEI
analyzed severe reactions to diagnostic and ther-
apeutic allergen extracts in Germany in the time
period from 1991 to 2000. The authors conclude
that the benefits of allergy diagnosis and im-
munotherapy outweigh the risk of adverse re-
actions [146]. Diagnosis and therapy of allergic
diseases should only be practiced by specially
trained physicians. Extreme caution is necessary
in treating any asthmatic individual [121, 143].
5. Anti-IgE-Omalizumab
The knowledge about mechanisms of the aller-
gic reaction has opened new strategies for treat-
ment of allergic diseases. A novel therapeutic
principle in treating IgE-mediated allergic dis-
eases forms the introducing of anti-IgE antibod-
ies. The substance (former name rhuMAb-E25,
new nomenclature omalizumab) is a recombi-
nant humanized monoclonal antibody (see →
Monoclonal Antibodies). The trade name is Xo-
lair (Novartis).

5.1. IgE and its Role for the Allergic
Response
The IgE was first identified in the 1960s. In the
normal individual there are usually low levels
of circulating IgE. The IgE is part of the phys-
iologic mucosal defence in parasitic infections.
In allergic patients TH-2 lymphocytes release
cytokines under the influence of allergens which
induce B cells to produce allergen-specific IgE.
The priming of B cells is located mainly in the
lymphatic tissue of the gastrointestinal and res-
piratory tract. The IgE molecule (Fig. 2) is built
out of two identical heavy (H) and two light
(L) chains, which are separated in variable (V)
and constant (C) parts. All four chains form a
Y-like molecule, whose upper part consists of
two double and variable H and L chains. This
part binds the specific antigen and is called Fab2
(fragment antigen binding).The opposite site –
called Fc (fragment crystallisable)–is formed
out of two H chains and attaches to the cell-
bound receptors. There are high- (FcεRI) and
low-affinity (FcεRII) receptors on mast cells,
basophils, other blood cells, and tissue cells in
target organs. High-affinity receptors allow a
sensitization of the individual even with low
amounts of allergen. This effect lasts more
longer than the normal two to three days half-life
of the free circulating IgE. The FcεR receptor
consists of an IgE-binding a chain, one β chain
Figure 2. Structure of the IgE molecule (V=variable,
C=constant, H=heavy, L=light). With courtesy of S. Ew-
ert, Novartis.
Antiallergic Agents 27
and two γ chains (Fig. 3). In an allergic individ-
ual the first contact with an allergen leads to a
specific sensitization and an IgE formation. In
further contacts with the disease-causing aller-
gen the allergen proteins bind to the receptor–
IgE complex in form of a cross-linking. By
this reaction basophils degranulate immediately
and release preformed substances such as his-
tamine and TNF-α. On mast cells and tissue cells
the bridging reaction starts to synthesize other
substances such as leukotrienes, cytokines and
prostaglandins, which are the main mediators of
the late allergic response [4, 5].
Figure 3. The IgE receptor on basophiles. Modified accord-
ing to [5].
5.2. IgE-Mediated Allergic Diseases
In sensitized individuals allergens cause inter-
mittent or chronic diseases of the skin, eyes, air-
ways, gastrointestinal tract and sometimes other
organs. Allergic rhinitis and asthma are the most
common allergen-induced diseases, mainly due
to inhalant and less often to food allergens. It
is estimated that 2–15 % of the European pop-
ulation suffer from asthma, in some countries
allergy may affect over 50 % of children [147].
The release of IgE and other mediators of the
allergic reaction cause a constant and chronic
inflammation, which in the case of asthma will
lead to often hospitalization, destruction of lung
parenchyma and loss of quality of life. In Great
Britain every second patient suffers from severe
asthma symptoms. More than two millions of
patients have a bad controlled asthma despite
of comprehensive therapy [148]. Another im-
portant entity of allergic diseases are the ana-
phylactic IgE-mediated disorders. The individ-
28 Antiallergic Agents
Figure 4. Molecular structure of monoclonal antibody. Genes encoding the Ig L and H chains are shown on top and on the
right side, respectively. With courtesy of B. Gysin, Novartis.
ual has been sensitized by an insect sting with-
out having any following chronic disease. But
the next venom sting may lead to an immediate
life threatening anaphylactic reaction. A similar
reaction may occur in patients who have been
sensitized to some kind of drugs for instance
penicillin.
5.3. Properties of Omalizumab
In the year 1992 a recombinant monoclonal anti-
IgE antibody was cloned for the first time. A
decade passed till the substance was ready for
the commercial use in human beings. Omal-
izumab is a recombinant DNA-derived human-
ized monoclonal antibody (see → Monoclonal
Antibodies) that selectively binds to human
IgE. Omalizumab does not bind to other im-
munoglobulins such as IgG or IgA.
5.3.1. Chemistry and Production of
Omalizumab
The first step in the generation of anti-IgE an-
tibodies has been immunizing mouse with hu-
man IgE. The DNA of selected murine anti-
IgE producing B cells and the DNA of hu-
man immunoglobulin IgG producing B cells
are matched together and form a recombinant
DNA. The selected hybridoma cell line produces
the specific monoclonal antibody which subse-
quently was cloned into an industrial producer
cell line. This cell line produces an anti-IgE
antibody which is only 5 % of murine and 95 %
of human origine (Fig. 4). The humanizing of
the anti-IgE antibody achieves tolerance of the
human immune system. The manufacturing pro-
cess takes place in large bioreactors (Fig. 5). The
final stage of the cultivation procedure needs
fourteen days (Fig. 6). Purification is performed
by several downstream processing steps (Tab. 2).
Important factors of the produced antibody so-
lution such as identity, content, purity, stability,
biological activity and sterility are checked with
Figure 5. Pilot-scale Bioreactors at Novartis. With courtesy
of B. Gysin, Novartis.
 Antiallergic Agents 29

Figure 6. Cultivation of monoclonal antibodies. The process from master cell bank to large-scale bioreactor is shown. With
courtesy of B. Gysin, Novartis.

Table 2. Downstream processing of monoclonal antibodies. With Table 3. Analytical methods for biopharmaceuticals. With courtesy
courtesy of B. Gysin, Nova. of B. Gysin, Novartis.

MAB XY Reasons for STEP Identity

Spin filter or centrifugation Cell-product separation, • MALDI-TOF mass

and/or expanded-bed cation separation of product from cell spectrometry
exchange debris and low-molecular-weight • Amino acid sequencing
compounds • Isoelectric focussing (IEF &
Virus inactivation Inactivation (low pH) and cIEF),
removal (filtration) • Western blotting
Protein A IgG selection
Content
Anion exchange Removal of DNA
Cation exchange Removal of variants and • Amino acid analysis
contaminating protein A • Size-exclusion
Ultrafiltration Concentration chromatography (SEC)
Filling freezing Storage • Affinity chromatography
• UV Spectroscopy

By- and degradation products

• HPLC (size exclusion, ion
exchange, hydrophobic
interaction, reversed phase)
• CE
• SDS PAGE

Process related impurities

• ELISA for protein A
• Host cell protein assay

Aggregates
• SEC, LLS

Thermodynamic stability Differential scanning calorimetry

(DSC)
Secondary structure Fourier transform infrared
(FTIR), circular dichroism (CD),
second derivative UV absorbance
spectroscopy
Figure 7. The analytical characterization by cation-
Adventitious agents Endotoxins, viruses, DNA,
exchange HPLC reveals the molecular heterogeneity of
mycoplasms
monoclonal antibodies. With courtesy of B. Gysin, Novar- Biological activity ELISA, cell assays, Biacore
tis. Sterility MLT etc
30 Antiallergic Agents
different analytical methods (Tab. 3). Changes of
the molecular heterogeneity that may occur over
time are analyzed with cation-exchange HPLC
(Fig. 7) The produced anti-IgE antibody is not
specific for a definite allergen-induced IgE. It
binds to any IgE in human blood and on cells.
5.3.2. Pharmacology and Effect of
Omalizumab
There are four effects of omalizumab [149,
149 – 152]:
1) Omalizumab binds to the Cε3 domain of the
IgE molecule which aggregates with the high-
affinity receptor on mast cells and basophils.
Thus the binding of the IgE molecule to the
cell receptors is blocked and the release of
mediators inhibited. Omalizumab does not in-
teract with already bound IgE on FcεR recep-
tors, therefore no degranulation or forming of
mediators will be induced.
2) Omalizumab binds to the free IgE and forms
molecular complexes. The relation of the free
IgE to the concentration of omalizumab de-
terminates the forming of trimers or hexamers
(Fig. 8). The molecular complexes will have
a molecular weight from 490 to 1000 kD. The
application of omalizumab immediately leads
to a reduction of the free IgE, but the values
of total IgE, which include the measuring of
the complexes will rise. The complexes have
no pathogenic meaning. The most important
step for suppressing the allergic reaction is the
decrease of the free IgE.
3) Under the treatment with omalizumab the
number of receptors on basophils and mast
cells decreases significantly. Thus the capac-
ity of IgE binding is reduced. This effect will
last for several months.
4) Omalizumab plays also an important role in
immunomodulation. The number of receptors
on other cells involved in the allergic reaction
such as tissue and dendritic cells decreases
as well. This effect will have a long-lasting
suppression of the induction and stimulation
of the TH 2 response. Recent work showed
significant reduction of nasal and bronchial
eosinophils, bronchial mast cells, T cells, and
B cells [149].
Though the free IgE decreases immediately
after application of omalizumab the clinical ef-
fect will only occur after several weeks. In all
treated allergic individuals a release of symp-
toms will be achieved within 16 weeks. The ef-
ficacy of omalizumab is only warranted under
application of the dose, symptoms of allergic
disease will relapse after end of therapy.
5.3.3. Pharmacokinetics
The humanizing of the murine antibody assures
immunogenic tolerance by the human immune
system. The average absolute bioavailability of
omalizumab after subcutaneous administration
is 62 %. In a clinical study of adults with al-
lergic rhinitis omalizumab was slowly absorbed
after subcutaneous administration of 0.15 mg/kg
and resulted in peak serum concentrations of 2
mg/L after 14 days. The substance is cleared
slowly from circulation, with a mean ±S.D. ap-
parent clearance of 2.4±1.1 mL/L/kg/d, result-
ing in a terminal elimination half-life of one to
four weeks [150]. Omalizumab has an IgG struc-
ture and is delayed eliminated by the reticuloen-
dothelial system of liver endothel cells. The half-
life of omalizumab will be 19 to 22 days on av-
erage. After withdrawal of omalizumab the for-
mer IgE level will be reached within 12 months
[149]. There is no rebound effect. The IgE –
omalizumab complexes are not pathogenic, they
do not accumulate in the kidney and they do not
bind complement.
5.4. Indication for the Teatment with
Omalizumab, Guidelines for Use
Immunoglobulin E plays a key role in allergic
diseases. Omalizumab offers the opportunities
to stop the cascade of the allergic reaction in a
very early stage. Omalizumab inhibits the early
and late reaction of inflammation. There might
be a wide range of indications but till now mainly
the treatment of patients with allergic asthma and
rhinitis [149, 152] has been evaluated in stud-
ies. In spite of full therapy there remain world-
wide about 26 % (Europe) to 42 % (UK) of pa-
tients with insufficient or bad controlled asthma.
Those instable patients are at an increased risk
of hospitalization, visits in emergency rooms
or asthma death. In several studies including

patients with medium or severe asthma omal-
izumab reduced significantly exacerbations and
hospitalization, the dose of additional inhalant
glucocorticosteroids could be decreased [153,
154]. Omalizumab was found to be an effec-
tive add-on therapy for difficult-to-treat asthma
patients, who have an important unmet medi-
cal need despite best available therapy. Quality
of life ameliorated significantly [155]. The ef-
ficacy of omalizumab was the better the severe
the degree of asthma [149, 153, 154].
The recommendation of the EMEA [156] for
the registration of omalizumab follows the indi-
cations approved till present:
→ Omalizumab is indicated as add-on therapy
in adult and adolescent patients (12 years of
age and above) with severe persistent allergic
asthma who have a positive skin test or in vitro
reactivity to a perennial aeroallergen and who
have reduced lung function (FEV1 < 80 %) as
well as frequent daytime symptoms or night-
time awakenings and who have had multiple
documented severe asthma exacerbations de-
spite daily high-dose inhaled corticosteroids,
plus a long-acting inhaled beta-2 agonist.
→ Omalizumab treatment should only be con-
sidered for patients with convincing IgE-
mediated asthma
→ It is proposed that omalizumab is initiated by
physicians experienced in the diagnosis and
treatment of severe persistent asthma
5.5. Application, Dosage, Costs
The concentration of the free IgE has to fall
under 20.8 IU/mL (50 ng/mL) before expect-
ing any clinical effect. Omalizumab has to be
given in a relation of 15 to 20:1 to the ab-
solute number of IgE molecules. Before start-
ing treatment the needed omalizumab concen-
tration is measured out of the total IgE concen-
tration and the body weight. The dosage has to
Figure 8. Omalizumab-IgE complexes. With courtesy of Novartis.
Antiallergic Agents 31
be determined individually for each patient, at
least 0.016 mg/kg/IgE [IU/mL] every four weeks
[150]. The maximum dosage is 750 mg every
four weeks. The dosage is limited to a max-
imum of 700 kU/mL IgE and to a maximum
body weight of 130 kg, because in these cases
the calculated amount of the substance can no
more be injected. The substance is supplied as
a lyophilized sterile powder in a single-use, 5-
mL vial designed to deliver 150 mg (1.2 mL) of
drug after reconstitution. The lyophilized prod-
uct takes about 15 – 20 min to dissolve while
shaking the vial. The prepared solution should
be used within eight hours when stored in the vial
at 2 – 8 ◦ C or within four hours when stored at
room temperature. Reconstituted omalizumab is
for single use only, it contains no preservatives.
The recommended dosage per injection ranges
between 150 mg and 375 mg omalizumab ev-
ery two to four weeks according the necessary
amount of the substance. The substance has to
be given subcutaneously. More than one injec-
tion site should be used if the dosage exceeds
150 mg [150]. Total IgE levels remain elevated
approximately for up to one year after ending
of treatment. Dosage determination during ther-
apy has always to be based on the initial IgE
level. Significant changes in body weight must
be taken into account. Omalizumab costs about
540 dollars (460 ¤) per vial, for a one-year ther-
apy a sum of about 6000 to 10 000 dollars will
be estimated. Yet evaluating this sum one has to
consider that 5 to 10 % percent of patients with
the most severe form of asthma contribute some
50 % of the total costs associated with asthma
[157].
5.6. Side Effects
Placebo controlled studies have shown a very
good tolerability of omalizumab. In a study with
children occurred mainly urticaria (1.3 %), itch-
ing, rash, and pain on the site of the injection
32 Antiallergic Agents
(each 0.4 %) [158]. In several controlled stud-
ies with adults there were no differences in ad-
verse events between the omalizumab and con-
trol groups [149]. Till present in clinical studies
three not severe anaphylactic reactions (< 0,1 %
of treated patients) were observed. Symptoms
were urticaria, throat, or tongue edema [150].
There are no special substance related severe
side effects. The IgE–omalizumab complexes
are small, no serum sickness or immune com-
plex nephropathy will be induced. A small per-
centage (< 0,1 %) of patients may develop anti-
bodies to omalizumab.
5.7. Legal Aspects, Safety
Omalizumab is currently approved for
moderate-to-severe persistent allergic asthma
in the USA, Canada, and Brazil, for moderate
persistent allergic asthma in Australia, and for
severe persistent allergic asthma in New Zealand
[149]. Till the end of 2005 omalizumab will be
registered in Germany. The official use of the
substance is restricted for definite criteria fol-
lowing the guidelines (Section 5.4). Detailed
conditions for the use of this product will be
described in the Summary of Product Charac-
teristics (SPC) which will be published in the
European Public Assessment Report (EPAR)
and will be available in all official European
languages after the marketing authorization
has been granted by the European Commission
[156]. The Global Initiative for Asthma (GINA)
recommends treatment with omalizumab in her
recent guidelines [148]. Because of the limited
data regarding the safety and effectiveness in
children, the official use of omalizumab is rec-
ommended for patients 12 years of age or older.
Safety and efficacy have not been established
for patients with a body weight or a serum IgE
outside the recommended range. During preg-
nancy omalizumab should only be applied when
clearly needed. In breast-feeding women cau-
tion is recommended, because in animal studies
omalizumab was excreted in the milk [150].
5.8. Possible Applications in the Future
Omalizumab is an innovative and unique form
of treatment, because it offers preventive therapy
of IgE-mediated disorders. Future aspects for in-
dication with omalizumab could be seasonal al-
lergic airways disease, atopic eczema with high
IgE values, venom allergy, food allergy, and
desensitization in high-reactive patients. In a
study of patients with peanut allergy the treat-
ment with anti-IgE (TNX-901, similar to omal-
izumab) gave a protection against small amounts
of unintended ingestions of peanuts [159]. The
therapy will not be given widespread because
of the relatively high costs, but further expe-
riences will be gathered within the next years.
Omalizumab will surely offer new interesting
perspectives of antiallergic therapy.
6. Acknowledgement
Thanks to Drs. S. Ewert and B. Gysin from No-
vartis for giving scientific advice.
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