REVIEWS

Antihistaminic, Anti-Inflammatory, and Antiallergic

Properties of the Nonsedating Second-Generation
Antihistamine Desloratadine: A Review of the Evidence
G. Walter Canonica, MD,1 and Michael Blaiss, MD2

Abstract: The allergy cascade presents widespread inflammatory INTRODUCTION

and proinflammatory activation, robust cytokine and chemokine
signaling, and heterogeneous immune and endothelial responses
H istamine, one of the most intensively studied molecules
in medicine,1 is a key mediator in allergic rhinitis (AR)
and urticaria. Interacting with a unique group of membrane-
that lead ultimately to the manifestations of allergic reaction.
bound receptors widely distributed across immune cell sub-
Histamine, a small peptide with inherent vasoactive properties, is
types, histamine participates in intricate bidirectional messag-
released from granules contained within mast cells, basophils,
ing between cytokines and inflammatory cells or their
lymphocytes, and other reservoirs and interacts with histamine
precursors, facilitates migration of cells to inflammatory sites,
receptors to regulate numerous cellular functions involved in
stimulates lymphocyte activity, modulates aspects of eosino-
allergic inflammation and immune modulation. Of the known
phil, neutrophil and mast cell behavior (Fig. 1),1– 4 and is
histamine receptors, the H1-receptor is most clearly associated
directly implicated in the generation of cardinal allergic
with potentiation of proinflammatory immune cell activity and
symptoms such as rhinorrhea; sneezing; congestion; nasal,
enhanced effector function and is the prime focus of suppressive
ocular, and dermal pruritus; hives; and flushing.5
therapy. Second-generation oral H1-antihistamines, such as ceti- The H1-histamine receptor is most clearly associated with
rizine, desloratadine, fexofenadine, levocetirizine, and lorata- modulation of proinflammatory immune cell activity,6,7 and its
dine, are mainstays of allergy treatment, acting as highly specific, interaction with histamine is the prime focus of suppressive
long-acting H1-receptor agonists at its unique receptor. The therapy for AR and urticaria with second-generation H1-antihis-
ongoing identification of immune effector cells and mediators tamines such as cetirizine, desloratadine, ebastine, fexofenadine,
involved in the allergic cascade indicates that further research is levocetirizine, loratadine, and rupatadine.
necessary to define the role of antihistamines such as deslorata- As a class, these antihistamines are consistently effec-
dine in anti-inflammatory therapy. tive for symptom relief in histamine-mediated diseases.
Key Words: allergic rhinitis, antihistamine, anti-inflammatory, When used at recommended doses, second-generation anti-
desloratadine, second-generation antihistamines, urticaria histamines are essentially devoid of undesirable central ner-
vous system (CNS) effects such as somnolence, and are much
(WAO Journal 2011; 4:47–53) less likely to cause other undesirable anticholinergic side
effects characteristic of first-generation antihistamines.8 Cur-
rent management guidelines recommend second-generation
antihistamines for first-line therapy for AR and urticaria.9,10
Differences exist in the pharmacology of individual
From the 1Allergy and Respiratory Diseases Clinic, DIMI, University of
second-generation antihistamines (Table 1)8,11–13 and, possi-
Genoa, Genoa, Italy; 2Division of Clinical Immunology and Allergy, bly, in their individual ability to suppress proinflammatory
University of Tennessee Health Science Center, Memphis, TN. mediators associated with an unfolding allergic response.14
Prof Canonica reports having received research grants as well as lecture fees, Some anti-inflammatory effects of antihistamines seem to
from A.Menarini, AlkAbello, AllergyTheapeutics, Almirall, Anallergo,
AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmith-
require initial interaction with the histamine receptor while
Kline, Lallemand, Lofarma, Merck, Merck Sharp & Dome, Novartis, others are receptor-independent.15 Further study is needed to
Pfizer, Phadia, Sanofi-Aventis, Schering-Plough, a Division of Merck & determine whether these differences in anti-inflammatory
Co., Stallergenes, UCB Pharma, and Uriach Pharma.; Dr Blaiss reports pharmacology translate into clinically meaningful effects.8
that he is a member of the Speaker’s Bureaus of AstraZeneca, Sanofi-
Aventis, UCB, Merck, GSK, Alcon, Teva, Sepracor, Nycomed, and acts
Desloratadine, the active metabolite of loratadine, is a
as consultant for AstraZeneca, Sanofi-Aventis, UCB, Merck, Alcon, second-generation oral antihistamine with proven efficacy in
Teva, ISTA, Sepracor, Proctor & Gamble. randomized, controlled clinical trials, and a safety and toler-
Correspondence to: G. Walter Canonica, MD, Allergy and Respiratory ability profile similar to placebo.16 –27 In the European Union,
Diseases Clinic, DIMI, University of Genoa, Pad. Maragliano, L.go R.
Benzi 10, 16132 Genoa, Italy.
desloratadine is indicated for the treatment of intermittent and
Telephone: ⫹39-10-353-8933. Fax: ⫹39-10-353-8904. E-mail: [email protected]. persistent AR and urticaria in adults and children aged ⱖ1
Copyright © 2011 by World Allergy Organization year.28 Desloratadine is approved in the United States for the

WAO Journal ● February 2011 47

Canonica and Blaiss WAO Journal • February 2011

FIGURE 1. The allergic cascade.

Mast cell mediators, including
cytokines, cause degranulation
and contribute to the bidirec-
tional messaging with other in-
flammatory cells or their precur-
sors, lymphocyte activity, and
migration of immune cells to in-
flammatory sites. CNS, central
nervous system; ECP, eosinophil
cationic protein; ICAM, intracellu-
lar adhesion molecule; Ig, immu-
noglobulin, IL, interleukin; LT,
leukotriene; MBP, mannose-bind-
ing protein; MHC II, major histo-
compatability complex; PGs,
prostaglandins. Reprinted with
permission from Baena-Cagnani
et al.4

TABLE 1. Pharmacology of Select Second-Generation Antihistamines(8,11–13)

Receptor-Binding
Affinity, Ki, Onset of Duration of Protein
Compound nmol/L (SEM) tmax, h (SD) Action, h Action, h t1/2, h (SD) Vd, L/kg (SD) Binding, %
3
Cetirizine 47.2 (10) 1.0 (0.5) 0.7 24 6.5–10 0.56 93
Desloratadine 0.87 (0.1) 3 3 3
24 27 ⬎100 95
Ebastine/carebastine 51.7 (6.8) 2.6 (5.7) 1–3 3
24 10.3 (19.3) 90–14 ⬎95
Fexofenadine 175 (68) 2.6 1–2 24 14.4 5.8 (0.7) 60–70
Levocetirizine 2.0 (0.1) 0.8 (0.5) 0.5 ⬎24 7 (1.5) 0.33 96
Loratadine 138 (23) 1.2 (0.3) 3–4 24 7.8 (4.2) 119 98
Mizolastine 22 (6) 1.5 1 24 12.9 1.4 98
Rupatadine 1.6 0.75 2 24 5.9 143 ⬎95

treatment of seasonal AR in adults and children aged ⱖ2 histamine receptor undergoing activation determines the type
years and perennial AR and chronic idiopathic urticaria (CIU) of effector response that is elicited.6,8 Most cells involved in
in adults and children aged ⱖ6 months.29 In vitro studies, inflammatory reactions express H1, H2, and H4 subtypes,6
studies in animal models, and in vivo investigations demon- with the H1-receptor playing a major role in potentiation of
strate that desloratadine, similar to antihistamines such as proinflammatory immune cell activity and effector responses
levocetirizine (the active enantiomer of cetirizine) and others, fundamental to an allergic reaction; the H2-receptor, in con-
inhibits a range of inflammatory mediators in addition to trast, appears to suppress inflammatory and effector func-
exerting potent H1-receptor antagonism.12 The present review tions, while data regarding the role of the H4-receptor in
will report recently available information expanding the an- immune response are limited.1,3
tihistaminic, anti-inflammatory, and antiallergic profile of The H1-receptor is a transmembrane protein belonging
desloratadine. to the G-protein coupled receptor family. Signal transduction
from the extracellular to the intracellular environment occurs
THE H1-HISTAMINE RECEPTOR as the GCPR becomes activated after binding of a specific
Four specialized, widely distributed receptors (desig- ligand or agonist. A subunit of the G-protein subsequently
nated H1, H2, H3, H4) mediate the effects of histamine.1 The dissociates and affects intracellular messaging including
local concentration of histamine and predominant type of downstream signaling accomplished through various interme-

48 © 2011 World Allergy Organization

WAO Journal • February 2011 Properties of the Second-Generation Antihistamine Desloratadine

diaries such as cyclic AMP, cyclic GMP, calcium, and nu-

clear factor kappa B (NF-␬B), a ubiquitous transcription
factor thought to play an important role in immune-cell
chemotaxis, proinflammatory cytokine production, expres-
sion of cell adhesion molecules, and other allergic and in-
flammatory conditions.1,8,12,30 –32
The classic model of receptor activation requires bind-
ing by a specific ligand, or agonist. Advances in understand-
ing of histamine receptor behavior have established that
histamine receptors can exhibit inherent, spontaneous activity
(“constitutive activity”) that is independent of receptor occu-
pancy by an agonist. A spontaneously activated histamine
receptor interacts with its intracellular effector system
through its typical intermediary, and elicits a downstream
event even in the absence of histamine binding.15 The concept
of constitutive activity has led to a reclassification of drugs
acting at the H1-receptor. Antihistamines that combine with
the inactive form of the receptor can be considered “inverse
agonists,” stabilizing receptor behavior in the inactive state
and reducing the population of receptors exhibiting constitu-
tive activity.15,33,34 For example, the H1-receptor promotes
NF-␬B in both a constitutive and agonist-dependent manner
and all clinically available H1-antihistamines inhibit consti-
tutive H1-receptor-mediated NF-␬B production; an inverse
H2-agonist or an H3-antagonist have no effect15,35 (Fig. 2).
Ligands having no effect on basal levels of receptor consti-
tutive activity but that interfere with binding of agonists are
considered “neutral antagonists” under this scheme. Impor-
tantly, because antihistamines can theoretically behave as
inverse agonists or neutral antagonists, they are more prop-
erly described as H1-antihistamines rather than H1-receptor
antagonists.15

Desloratadine: Antihistaminic, FIGURE 2. H1-receptors may be activated by an antagonist,

such as histamine (A) or exhibit spontaneous basal, or con-
Anti-Inflammatory, and Antiallergic Effects stitutive, activity in the absence of ligand binding (B). Anti-
Affinity for the H1-receptor histamines repress both histamine-induced and constitutive
Desloratadine binds avidly and noncompetitively to a activity, eventually restoring the receptor to an inactive state
(C). AH, antihistamine; H, histamine.
recombinant human H1-receptor, displaying 52, 57, 194, and
153 times more potency for the interaction than cetirizine,
ebastine, fexofenadine, and loratadine, respectively (Table 1); Effects on Immune Cells: Eosinophil Activation,
measured change in histamine-induced intracellular cal- Migration, and Survival
cium was the effector end point used in the assay.36 Once Eosinophils, key effector cells in the allergic response,
desloratadine is bound, disassociation from the receptor is are recruited from the circulation to sites of inflammatory
slow; only 37% of desloratadine is unbound at 6 hours, activity where they participate in immune reactions and
suggesting pseudo-irreversibility and supporting an ex- secrete an array of preformed cytotoxic cationic proteins
tended duration of action.36 (major basic protein, cationic protein, peroxidase, neurotoxin
As a second-generation antihistamine, desloratadine protein). Eosinophils also produce cytokines, chemokines,
demonstrated inverse agonism, reducing downstream mes- leukotrienes, and neuromodulators.38 Desloratadine may ex-
saging by spontaneously active receptors. In one study, deslo- ert effects on eosinophil chemoattractants, precursors, activa-
ratadine effectively inhibited downstream signaling of a con- tion, and survival.
stitutively active human H1-receptor associated with NF-␬B Desloratadine reduces the expression of NF-␬B, a
formation, reducing basal NF-␬B activity to a greater extent known inducer of RANTES (regulated upon activation, nor-
than did equivalent concentrations of cetirizine, fexofenadine, mal T-cell expressed and secreted), a principal chemoattrac-
loratadine, or pyrilamine.37 In addition, desloratadine was tant for eosinophils, monocytes, and t-lymphocytes. RAN-
more potent than comparators in blocking the rise of NF-␬B TES promotes eosinophil activation and the release of
after activation of the receptor by exposure to histamine.37 histamine from basophils.37,39 Desloratadine inhibited the

© 2011 World Allergy Organization 49

Canonica and Blaiss WAO Journal • February 2011

release of RANTES by nasal polyp epithelial cell lines in

response to tumor necrosis factor (TNF),40 eosinophil cat-
ionic protein, and activated mast cells; this inhibition was
also reflected in diminished production of tryptase and leu-
kotriene C4.32,41 In an investigation enrolling atopic individ-
uals with persistent asthma randomized to multiweek treat-
ment with desloratadine or an oral steroid, both medications
significantly reduced the expression of mRNA specific for
chemokines involved in T-cell signaling and eosinophil or
basophil activation, including RANTES, macrophage inflam-
matory protein (MIP)-1 ␣, and MIP-1 ␤.39,42
The number of eosinophil/basophil progenitors (Eo/B)
in the peripheral circulation typically falls in atopic individ-
uals as these cells migrate to sites of inflammation through
chemoattraction, vascular adhesion, and extravasation.43 In a
randomized, placebo-controlled study of 45 subjects with
symptomatic, seasonal AR treated with desloratadine (20 mg
daily) or placebo, those receiving desloratadine demonstrated
a significantly greater increase in peripheral blood Eo/B
progenitors during the first 2 weeks of treatment compared
with subjects given placebo. Further, a statistically significant
decrease in nasal lavage eotaxin was found in the deslorata-
dine group compared with placebo, which may support the
concept that desloratadine blocks the migration of these cells FIGURE 3. Inhibition of cytokine release from human mast
from circulation to sites of inflammation within nasal tissue.43 In cells with cetirizine, desloratadine, and dexamethasone. *P ⬍
a study assessing eosinophil survival at the site of upper airway 0.05.14 Experiments were conducted by preincubating hu-
inflammation, the survival of peripheral blood eosinophils incu- man leukemic mast cells with the H1-blockers cetirizine and
bated with human epithelial cell conditioned media from nasal desloratadine and the H-2 blocker dexamethasone for 1
hour, followed by a 24-hour coincubation with phorbol my-
mucosa or nasal polyp tissue was reduced in a dose-dependent ristate acetate (25 ng/mL) and the calcium ionophore A
manner after preincubation with desloratadine.44 23187 (2.5 ⫻ 10⫺7 M). Data are expressed as means of at
least 4 experiments. GM-CSF, granulocyte-macrophage
Effects on Immune Cells: Mast Cells colony-stimulating factor; IL, interleukin; TNF-␣, tumor ne-
and Basophils crosis factor-␣.
Antihistamines relieve symptoms of AR and urticaria
primarily by competing with histamine at the H1-receptor;
emerging evidence indicates that antihistamines may also mine release by mast cells after stimulation with each of the
inhibit mast cell degranulation and subsequent histamine 3 test substances (42.6, 53.7, and 39.9% inhibition; P ⬍ 0.01
release.45,46 vs. 100% stimulation for each test substance in the absence of
Human mast and basophilic cells exposed to deslorata- desloratadine).48
dine show reduced production of cytokines central to inflam- IL-4 is a B-lymphocyte growth factor and a major
matory responses.14,46 – 48 In one report, desloratadine reduced mediator of the allergic response, implicated in antigen pre-
phorbol 12-myristate 13-acetate secretagogue-stimulated sentation and cytokine production.49 Human basophils are a
mast cell release of interleukin (IL)-3, IL-6, TNF-␣, and major source of IL-4 produced in experimental immune cell
granulocyte-macrophage colony-stimulating factor (GM- cultures.50 In one investigation, basophil-enriched suspen-
CSF) by 32.1, 32.6, 64.5, and 27.8%, respectively; reductions sions were incubated with various concentrations of deslor-
displayed dose-dependency, optimal effects were obtained at atadine for 15 minutes before stimulation with anti-IgE anti-
concentrations easily achieved in clinical settings and were in body, calcium ionophore, IL-3, or phorbol ester. Notably,
some instances comparable with suppression obtained with desloratadine was nearly 6 to 7 times more potent in prevent-
dexamethasone and always significantly better than cetirizine ing the secretion of IL-4 and IL-13 induced by anti-IgE than
(P ⬍ 0.05)14 (Fig. 3). it was at inhibiting the release of histamine and leukotriene
Desloratadine demonstrated dose-dependent inhibition C4. After desloratadine pretreatment, IL-4 mRNA was inhib-
of CD107a (a marker of mast cell degranulation) expression ited by as much as 80%.50 These results are consistent with an
on human mast cells after stimulation with anti-IgE, calcium earlier evaluation of the inhibitory effects of desloratadine
ionophore, or substance P. At the highest desloratadine con- and steroids (budesonide and dexamethasone) on mast cell
centration (10⫺4 M), the inhibitory effect for anti-IgE, sub- release of IL-4, IL-6, IL-8, GM-CSF, and TNF-␣ after secre-
stance P, and calcium ionophore (50.7, 48.0, and 26.7% tagogue stimulation. Desloratadine demonstrated less cyto-
inhibition; P ⬍ 0.05 vs. 100% stimulation for each test kine inhibition compared with a glucocorticoid, but statisti-
substance in the absence of desloratadine). Desloratadine at cally significant (P ⬍ 0.01) inhibition of IL-4 was noted at all
the highest concentration also significantly inhibited hista- desloratadine concentrations (10⫺6 to 10⫺10 M) and time

50 © 2011 World Allergy Organization

WAO Journal • February 2011 Properties of the Second-Generation Antihistamine Desloratadine

points (6, 12, and 24 hours). Inhibition of TNF-␣ was statis- separated by 14-day washout periods. After cold provocation,
tically significant (P ⬍ 0.05) at concentrations of 10⫺6 M (all urticarial reactions were assessed with digital 3-dimensional
time points) and 10⫺8 M (6 and 12 hours), whereas inhibition imaging and thermography; critical temperature and critical
of IL-6 and GM-CSF was statistically significant (P ⬍ 0.05) stimulation time thresholds were measured. High-dose deslo-
at one concentration (10⫺6 M and 10⫺8 M, respectively) and ratadine significantly improved objective signs of ACU and
at a single time point (6 hours).51 significantly reduced ACU lesion severity versus deslorata-
dine 5 mg without any adverse safety or tolerability con-
Effects on Immune Cell Adhesion cerns.17 These results strongly suggest that the antihistaminic
Desloratadine has effects on the adhesion of activated and anti-inflammatory effects of desloratadine increase in a
immune cells to endothelial and epithelial tissues. Deslorata- clinically relevant fashion with dose escalation, and support
dine inhibits the in vitro histamine-induced expression of current guidelines recommending desloratadine dosage esca-
P-selectin (implicated in the adhesion and migration of neu- lation for treatment of ACU.17
trophils and eosinophils) and leads to decreased production of
IL-6, IL-8, and IL-8 mRNA.52 Nasal epithelial cells incubated
with desloratadine for 24 hours demonstrate significantly DISCUSSION
reduced expression of intercellular adhesion molecule H1-receptors are expressed on many cell types, includ-
(ICAM)-1 (implicated in nasal epithelial cell activation) after ing mast cells, basophils, dendritic cells, endothelial cells,
histamine exposure.53 and smooth muscle cells.2,6 Their stimulation by histamine
produces the cardinal symptoms of an allergic response. The
Effects on Inflammatory Mediators presence of histamine up-regulates the population of hista-
In the first study to evaluate the potential anti-inflam- mine receptors, and it is likely that up-regulation is a contin-
matory activities of desloratadine on human epidermal cells, uous process while histamine is present. Receptor up-regula-
keratinocyte cultures from normal skin were activated by tion is blocked experimentally by the presence of
interferon (IFN)-␥ in the absence or presence of desloratadine antihistamines.7 Further, H1-receptors can demonstrate spon-
and evaluated for the release of RANTES, CXCL8, CCL17/ taneous, constitutive signaling even in the absence of hista-
TARC, and CXCL10. Desloratadine dose-dependently inhib- mine stimulation. H1-receptor antagonists effectively miti-
ited the constitutive and induced release of RANTES, gate allergy symptoms and reduce both constitutive and
CXCL8, and CXCL10. In addition, supernatant from kera- histamine-stimulated receptor signaling.
tinocytes was evaluated at 48 hours for its capacity to attract Desloratadine, a second-generation H1-receptor antag-
immune cell types. Desloratadine dose-dependently reduced onist, has proven clinical efficacy across a range of hista-
the migration of T-helper (TH)1 and TH2 cells toward IFN- mine-mediated conditions and a safety and tolerability profile
␥–stimulated keratinocytes and inhibited the release of con- similar to placebo.16 –27 It has the longest half-life of any of
stitutive and IFN-␥–induced chemoattractants for human neu- the second-generation antihistamines8 and binds to the H1-
trophils and eosinophils. RANTES-associated eosinophil receptor with the highest affinity, disassociates slowly, dis-
trafficking demonstrating the most significant reduction. In plays noncompetitive antagonism and inverse agonism, and
this study, concentrations of desloratadine (1–100 ␮M) re- effectively modulates histamine-mediated allergic phenom-
quired for inhibition of cytokines were higher than those ena associated with AR and urticaria. Desloratadine is nonse-
considered achievable in plasma at a typical dose of 10 dating in adults and free of muscarinic side effects.8,55–57
mg/d.54 It should be noted that other second-generation antihis-
tamines exhibit antiallergic, antihistaminic, and anti-inflam-
In Vivo Investigation matory effects similar to desloratadine’s. In a series of pilot
Cold urticaria: Dose-dependency of studies in subjects with persistent allergic rhinitis (PER),
anti-inflammatory and antihistaminic effects Ciprandi et al investigated the effects of several of the newer
While in vitro findings strongly suggest that deslorata- second-generation antihistamines at indicated doses on nasal
dine possesses an anti-inflammatory capability directed congestion, nasal airflow, and allergic inflammation. Rupata-
against important cytokines, the clinical relevance of these dine significantly improved nasal congestion (P ⫽ 0.0015)
findings using standard dosing remains unclear. Many of the and increased nasal airflow (P ⫽ 0.0025) in 20 subjects with
reported anti-inflammatory effects of desloratadine are seen PER.58 Ebastine treatment in 20 patients with PER also
with higher than standard doses in experimental set- significantly improved nasal congestion (P ⫽ 0.0025) and
tings.44,48,49,54 In contrast, an open, uncontrolled in vivo nasal airflow (P ⫽ 0.0001).59 Desloratadine and levocetiriz-
investigation of standard-dose desloratadine given to subjects ine improved nasal airflow in a 30 patients with PER (P ⫽ ns
with seasonal AR and concomitant asthma failed to document and P ⬍ 0.001, respectively).60 Levocetirizine also signifi-
a significant reduction in any examined mediator (IL-4, IL-8, cantly improved nasal airflow (P ⬍ 0.001) in a study of 40
IL-10, tumor growth factor-␤) after 4 weeks of treatment.49 In patients with PER.61
a prospective, randomized, double-blind, crossover trial, 30 Some limitations of this review should also be men-
subjects with acquired cold urticaria (ACU), a disease in tioned. The volume of distribution (Vd) of desloratadine of
which clinical features are because of release of mast cell ⬎100 L/kg is much greater than that of other second-gener-
mediators in response to cold, received placebo, desloratadine ation antihistamines, which may counterbalance its higher
5 mg, or desloratadine 20 mg every day, each for 7 days, receptor affinity. Vd is the apparent volume in which a

© 2011 World Allergy Organization 51

Canonica and Blaiss WAO Journal • February 2011

determined dose of the drug distributes itself in the body at itself through activation of receptor gene transcription. J Pharmacol Sci.
equilbrium. However, receptor occupancy is due to several 2007;103:374 –382.
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