ArticlePDF AvailableLiterature Review

Role of histamine and platelet-activating factor in allergic rhinitis


Abstract and Figures

This review is focused on the effects of histamine and platelet-activating factor (PAF) in allergic rhinitis and the plausible implications for therapy. Rhinitis is defined as a heterogeneous disorder resulting from an IgE-mediated reaction associated with nasal inflammation of variable intensity. Two phases of response are triggered by an IgE/allergen cross-linking event: the first is the release of preformed mediators such as histamine or interleukins from mast cells and basophils; the second begins when cells start producing lipid-derived mediators. One of these mediators is PAF. Apart from leukotrienes, PAF is perhaps the most potent inflammatory mediator in allergic rhinitis for inducing vascular leakage, a response that may contribute to the appearance of rhinorrhea and nasal congestion.
Content may be subject to copyright.
Correspondence to V. Alfaro (Tel.: +34 934 021 526;
Fax: +34 934 110 358; e-mail:
Role of histamine and platelet-activating
factor in allergic rhinitis
V. Alfaro
Department of Physiology, University of Barcelona
Avda. Diagonal 645, 08028 Barcelona, Spain
(Received on )
V. ALFARO. Role of histamine and platelet-activating factor in allergic rhinitis
(minireview). J. Physiol. Biochem., 60 (2), 101-112, 2004.
This review is focused on the effects of histamine and platelet-activating factor
(PAF) in allergic rhinitis and the plausible implications for therapy. Rhinitis is
defined as a heterogeneous disorder resulting from an IgE-mediated reaction associ-
ated with nasal inflammation of variable intensity. Two phases of response are trig-
gered by an IgE/allergen cross-linking event: the first is the release of preformed
mediators such as histamine or interleukins from mast cells and basophils; the second
begins when cells start producing lipid-derived mediators. One of these mediators is
PAF. Apart from leukotrienes, PAF is perhaps the most potent inflammatory medi-
ator in allergic rhinitis for inducing vascular leakage, a response that may contribute
to the appearance of rhinorrhea and nasal congestion.
Key words: Histamine, PAF, Rhinitis.
J. Physiol. Biochem., 60 (2), 101-112, 2004
Rhinitis is a heterogeneous disorder
characterized by one or more of the fol-
lowing nasal symptoms: sneezing, itching,
rhinorrhea, and/or nasal congestion. It is
often accompanied by symptoms involv-
ing the eyes, ears, and throat, including
postnasal drainage (77). Many causes have
been described that induce rhinitis, but
about 50% of all cases are caused by aller-
gy. Allergic rhinitis results from an IgE-
mediated reaction associated with nasal
inflammation of variable intensity (11).
Potential allergens include pollens, molds,
animal dander, and dust mites.
The immune response to allergens
involves the release of inflammatory
mediators and the activation and recruit-
ment of inflammatory cells to the nasal
mucosa (77). Nasal biopsies conducted in
individuals with active disease revealed an
accumulation of mast cells, eosinophils,
and basophils within the airway epitheli-
um, together with eosinophil accumula-
tion within the deeper lamina propria (13,
14, 26). The accumulated cells have been
activated, and the mediators they release
generate the symptoms of the disease
through stimulation of specific receptors
on the sensory nerves and blood vessels
within the nasal mucosa (Fig. 1) (36, 37).
Allergic rhinitis has a relevant impact
on society because of its high prevalence
(> 10% of whole population), its associa-
tion with an impaired quality of life, and
the presence of comorbidities such as
asthma, sinusitis, and otitis media (12, 29,
80). The management of allergic rhinitis
has several objectives, one of which is to
reduce the symptoms caused by allergen
The allergens: perennial and seasonal
allergic rhinitis
The hallmark of allergic rhinitis is the
temporal relationship of symptoms with
the exposure to an allergen. Allergens can
be classified as perennial or seasonal.
Perennial allergens include indoor mold
spores, dust mites, animal dander, and
specific chemicals (cleaning agents or cer-
tain powders). If a patient has allergic
rhinitis symptoms lasting for more than 2
hours per day for more than 9 months,
this would be classified as a perennial
allergic rhinitis, most likely caused by
something in their home or workplace.
Perennial rhinitis is a complex disease that
includes many different categories; the
most common are allergic rhinitis, the
NARES syndrome and vasomotor rhinitis
(11). The major symptom of perennial
allergic rhinitis is nasal obstruction.
Sneezing and rhinorrhea are often present,
but they are less troublesome than in sea-
sonal allergic rhinitis. Unlike perennial
allergic rhinitis, patients with seasonal
allergic rhinitis often present with con-
junctivitis and sometimes asthma. The
symptoms of seasonal allergic rhinitis
appear during a defined season in which
aeroallergens are abundant in the outdoor
air. The pollen from tree, grass, and weed,
together with outdoor mold spores, are
common seasonal allergens. Major symp-
toms include sneezing, rhinorrhea and
nasal blockage, which may not be con-
stant. Additionally, the symptoms of
allergic rhinitis may also be perennial with
seasonal exacerbations, depending on the
spectrum of allergen sensitivities (77).
Epidemiological studies have shown a
prevalence of 10% for seasonal allergic
rhinitis and of 10-20% for perennial aller-
gic rhinitis (52). Based on the concept that
allergic rhinitis is a complex syndrome
involving both the upper and lower air-
ways, as well as on confounding issues
related to the classification of allergic
rhinitis as seasonal, perennial, and occupa-
tional, the ARIA (Allergic Rhinitis and its
Impact on Asthma) panel has proposed
revised classifications for allergic rhinitis
J. Physiol. Biochem., 60 (2), 2004
Tissue cell
recruitment and
Structural cell
Mast cells
Epithelial cells
Mast cells
Lymphocytes T
Lymphocytes B
Disease expression
Cell type involved
Fig. 1. Schematic representation of cellular involvement and sequence underlying allergic rhinitis
(adapted from (6)).
Phases of the allergic response
An allergic reaction can be best thought
of as a cascading set of inflammatory reac-
tions, started by the immune system in
response to environmental antigens (37,
64). Once an allergen is inhaled, it is
processed by the immune cells and stimu-
lates a B-cell mediated IgE response. IgE
is one of 5 types of immunoglobulins pro-
duced by B-cells: IgA, IgD, IgM and IgG
are the others. Each type of antibody can
bind to antigens or allergens, but differ in
the type of responses produced once they
are bound to the antigen. The typical
allergic response is mediated by IgE anti-
bodies when they bind to the allergen
with one end, and to the IgE receptor of
the inflammatory cells with the other end.
This cross-linking on the surface of the
inflammatory cell (e.g., mast cell) triggers
a multi-step process leading to activation
and degranulation of mast cells (typically
located at mucosal surfaces and around
blood vessels) and the release of histamine
and other inflammatory mediators (65).
Once the cascade starts, a whole array of
secondary responses is triggered.
Two phases of responses are triggered
by an IgE/allergen cross-linking event.
The first is the release, in seconds, of pre-
formed mediators such as histamine or
interleukins from mast cells and baso-
phils. These chemical mediators are found
in preformed vesicles and are released by a
calcium-dependent process induced by
the cross-linking of two or more IgE
receptors. Once these products are
released, they are responsible for allergic
(inflammatory) processes like vasodila-
tion, increased vascular permeability, and
increased chemotaxis of other inflamma-
tory cells. The chemotactic factors
released are responsible for recruiting
eosinophils (the major effector inflamma-
tory cells), neutrophils and basophils into
the inflammatory site on the nasal
mucosa. The second phase of the response
begins, in minutes, when cells start pro-
ducing lipid-derived mediators. These
mediators are derived from the conversion
of phospholipids into arachidonic acid via
phospholipase A (PLA
), followed by the
subsequent conversion of arachidonic acid
into leukotrienes and prostaglandins (the
so-called eicosanoids). However, another
relevant mediator is the platelet-activating
factor (PAF). Recent studies have shown
that the epithelial/endothelial cells of the
target organs are actively involved in the
recruitment and activation of inflammato-
ry cascades in allergic diseases (50). These
endothelial cells promote the expression
of vascular cell adhesion molecules and E-
selectin, which increase the adhesion of
circulating leukocytes to the endothelial
cells. Chemoattractant cytokines such as
IL-5 promote their infiltration into the
mucosa (60).
The immediate response to the antigen,
which is known as the early-phase allergic
reaction, occurs in more than 90% of
patients with a history of allergic rhinitis
and positive skin tests (38). This early-
phase includes the products of degranula-
tion (preformed mediators such as hista-
mine), and de novo inflammatory media-
tors (e.g., prostaglandin D
or LTE
). The
late-phase reaction occurs in up to 50% of
patients with allergic rhinitis (38), begins
at two to five hours after allergen chal-
lenge and peaks at six to eight hours after
exposure (77). During the late-phase reac-
tion, an exaggerated non-specific nasal
hyperreactivity occurs simultaneously
with the heightened response to the initial
allergenic stimulus. Therefore, preventing
or suppressing both the early-phase and
late-phase allergen-induced inflammatory
J. Physiol. Biochem., 60 (2), 2004
reactions is crucial for the successful treat-
ment of allergic rhinitis (62).
The role of histamine in allergic rhinitis
Histamine is a biogenic amine synthe-
sized and stored mainly in mast cells and
basophils that was first identified in 1910
thanks to its potent vasoactive properties
and plays a relevant role in the patho-
physiology of allergic diseases (89). Aller-
gen challenge significantly increases the
levels of histamine in nasal secretions of
patients with allergic rhinitis, therefore
suggesting that this mediator is involved
in the pathophysiology of allergic rhinitis
(60, 83). In fact, nasal challenge with hist-
amine induces nasal blockage, sneezing
and rhinorrhea (23). The effects of hista-
mine in allergic disease are derived from
its interaction with the H
subclass of his-
tamine G protein-coupled receptors (31).
The interaction of histamine with its H
receptor mediates several pathophysiolog-
ical effects, including nasal blockage,
sneezing, itching and discharge in rhinitis
The classical effects of histamine at the
organ level are well documented, but there
is increasing evidence suggesting that
histamine also has direct or indirect
effects on the activity of different inflam-
matory/effector/immunologic cell types
involved in the pathogenesis of allergic
disease (5, 72). Several studies have shown
that histamine receptors are expressed on
the cell surface of basophils, mast cells,
neutrophils, lymphocytes, macrophages,
epithelial cells and endothelial cells, and
therefore is likely to modulate the func-
tion of these cells (5). This finding has led
to the speculation by some investigators
that the antiinflammatory effects reported
for newer second-generation antihista-
mines might derive from their interaction
with the H
receptor, rather than with
other non-histamine receptors (66). Due
to their basic structure and their cationic
amphiphilic nature, antihistamines might
also induce non-specific antiinflammato-
ry/antiallergic effects resulting from ionic
association with cell membranes, de-
creased Ca
binding, and inhibition of
membrane-associated enzymes (5). Nev-
ertheless, the antiinflammatory effects of
antihistamines have been found in vitro at
high concentrations and their clinical rele-
vance remains controversial (19).
Antihistamines in the treatment
of allergic rhinitis
Drug therapy for allergic rhinitis is
directed to control symptoms. Antihista-
mines, decongestants, mast cell stabilizers
and corticosteroids are currently used to
provide symptomatic relief of allergic
rhinitis. For many years, antihistamines
were the first-line pharmacological
approach to the management of allergic
rhinitis (71). Acute-phase allergic
responses are mediated primarily by hist-
amine, and the therapeutic effect of anti-
histamines is based on the blockade of H
histamine receptors located in the nasal
vasculature and nerve endings. Overall
advantages shown by antihistamine treat-
ment are oral administration, effectiveness
in relieving ocular symptoms, good com-
pliance with the new formulations that
require only one or two administrations
per day, and reduction of sedative and
anticholinergic side effects with the sec-
ond- and third-generation drugs (63).
Nevertheless, most antihistamines are
ineffective in relieving nasal obstruction
and some of them (e.g., astemizole and
terfenadine) were the source of a persis-
J. Physiol. Biochem., 60 (2), 2004
tent concern for their cardiovascular safe-
ty who led to their market withdrawal.
The relative advantages of antihista-
mines were initially based on their ability
to competitively inhibit the H
binding of histamine (50). However, at the
appropriate doses many antihistamines
inhibited histamine release from mast cells
and perhaps mast-cell activation itself
(21). In fact, the antiallergic properties of
antihistamines generally refer to their
ability to inhibit mast-cell and basophil
activity (e.g., degranulation), including the
release of preformed mediators such as
histamine, tryptase, leukotrienes, and oth-
ers (7).
More recently, it has been reported that
some antihistamines can also regulate the
expression and/or release of cytokines
(44), chemokines (1), adhesion molecules
(20) and/or inflammatory mediators (33).
Some second-generation antihistamines
inhibit the influx of eosinophils to the site
of allergen challenge in sensitized individ-
uals (93), alter adhesion molecule expres-
sion on epithelium (55) and eosinophils
(20), decrease in vitro cytokine-enhanced
eosinophil survival (73), and alter
eosinophil activation/granule release (24).
Moreover, some antihistamines alter the
production of certain cytokines both in
vitro and in vivo. These include inflamma-
tory cytokines (e.g., TNF-α, IL-1β, and
IL-6) (86) and immunoregulatory
2 cytokines (e.g., IL-4 and IL-13)
(30) in both basophils and T cells (57).
Second-generation antihistamines are
active in the down-regulation of inflam-
matory mediators such as superoxides,
prostaglandins, PAF and others (85).
The platelet-activating factor
Phospholipids are major components
of cell membranes. They are also known
to be sources of arachidonic acid, which is
metabolized into bioactive eicosanoids
(leukotrienes and prostaglandins), and of
the platelet-activating factor (PAF, Fig. 2).
PAF (1-O-alkyl-2-acetyl-sn-glycero-3-
phosphocholine) is a phospholipid that
exerts bioactive effects via a specific cog-
nate receptor. The term PAF derived from
it being first described in 1972 as the sub-
stance responsible for the aggregation of
platelets that is released from IgE-sensi-
tized rabbit basophils after antigen chal-
lenge (8). The chemical structure of PAF
was later determined in 1979 (9, 22) (Fig.
3). In contrast to unsaturated fatty acid-
derived major autacoid species (e.g.,
prostaglandins and leukotrienes), PAF is
unusual in its intact gylcerophospholipid
As PAF was the first bioactive phos-
pholipid whose structure had been char-
acterized, this research area was rapidly
developed (17, 32, 70). Besides platelet
activation and hypotensive effects, a wide
variety of PAF bioactions have been eluci-
dated, such as facilitation of hemostasis
and contribution to events associated with
reproduction (49, 92). Nevertheless, PAF
acts as a pathologic mediator in bronchial
asthma and other allergic responses, vas-
cular damage including ischemia-reperfu-
sion injury, several forms of shock (espe-
cially endotoxin shock), acute respiratory
distress syndrome, and inflammatory
bowel disease (18, 32, 34, 70, 92). PAF is
so potent that it can always induce signif-
icant biological responses at nanomolar
concentrations both in vitro and in vivo.
Thus, PAF activates platelets, neutrophils,
monocytes, macrophages, and vascular
smooth muscle cells at concentrations as
low as 10
to 10
mol/L (32, 69, 78, 84).
PAF is not preformed in storage gran-
ules but produced from phospholipids
mobilized from cell membranes by phos-
J. Physiol. Biochem., 60 (2), 2004
pholipase A
by many stimulated cell
types (e.g., basophils, neutrophils, mono-
cytes, macrophages or endothelial cells).
PAF produced by monocytes and poly-
morphonuclear leukocytes is secreted (45,
48, 76), whereas PAF synthesized by vas-
cular endothelial cells activated by various
physiologic agonists (e.g., thrombin,
bradykinin, histamine, hydrogen perox-
ide, and leukotrienes C
and D
) is not
released. In these cells, PAF is expressed
on the cell surface with the polar head
translocated to the outer surface, and
serves as a signal for neutrophils to bind
to the endothelium (68, 91). Leukocyte
adhesion to the endothelium is the first
step in the physiological inflammatory
response and PAF has a homeostatic func-
tion. However, inappropriate or excessive
expression of this adhesion signal and the
subsequent recruitment and activation of
a large number of leukocytes might result
in further vascular damage caused by the
secretion of proteases and oxygen radicals
in these cells (91).
Considerable advances have been made
in understanding the biosynthetic and
catabolic pathways of PAF metabolism
J. Physiol. Biochem., 60 (2), 2004
COX 1 (constitutive)
Cytosolic phospholipase A
Increased vascular permeability
Platelet aggregation
COX 2 (inducible)
Membrane phospholipids
Arachidonic acid
Increased vascular
Edema potentiation
Platelet - activating factor (PAF)
Fig. 2. Relationship of the platelet-activating factor (PAF) with other metabolites derived from membrane
phospholipids (eicosanoids: leukotrienes and prostaglandins).
Platelet Activating Factor (PAF)
Fig. 3. Molecular structure of the platelet-activating
factor (PAF).
J. Physiol. Biochem., 60 (2), 2004
CDP choline
lysoalkyl GPE
alkylalcyl GPC
lyso PAF
Choline phosphotransferase
Fig. 4. Synthesis od PAF. A) Platelet-activating factor (PAF) de novo pathway: starting with alkyl acetylglyc-
erol; B) re-modeling pathway: inflammation, cell stimulation and injury activate phospholipase A
which converts the membrane lipid alkylacyl GPC (glycero-3-phosphocholine) into arachidonic acid and
lyso-PAF; in the next step, this PAF precursor is converted into active PAF by acetylation.
(35, 79). The synthesis of PAF can occur
through one of two described synthetic
pathways (Fig. 4) (3, 10) and it is tightly
regulated (25, 51, 87, 88). PAF is degraded
by PAF acetylhydrolase, which catalyzes
the hydrolysis of the esterified acetate at
the sn-2 position (82). Three PAF acetyl-
hydrolases have been described: two
intracellular enzymes (tissue types I and
II) and one secreted enzyme (plasma type)
(6). Potential mechanisms that might
explain PAF-induced pathologies could
be the inappropriate activation of PAF
synthesis in PAF-producing cells or the
reduction of PAF acetylhydrolase activity
(90). In both cases, the accumulation of
PAF may provoke a pathological re-
Evidence supporting a role for PAF in
pathological processes includes the obser-
vation that several PAF receptor antago-
nists attenuate specific disorders in which
PAF is suspected to act as a mediator (22,
30, 57, 85). The development of PAF
antagonists has contributed both to the
identification of specific PAF receptors
and to the clinical application of PAF.
PAF evokes various intracellular events
though the PAF receptor, a member of the
family of G protein-coupled receptors
that has been linked to inositol phospho-
lipid turnover, changes in intracellular cal-
cium, activation of protein kinase C and
tyrosine kinases, and synthesis of
eicosanoids (75). The human PAF recep-
tor is encoded by a single gene located on
chromosome 1 (75). Two promoters regu-
late the synthesis of two forms of receptor
mRNA, each of which is expressed in dif-
ferent tissues and cells (68, 91).
The platelet-activating factor (PAF)
in allergic rhinitis
Of all the inflammatory mediators
involved in allergic rhinitis, PAF is per-
haps the most potent for inducing vascu-
lar leakage, a response that may contribute
to the appearance of rhinorrhea and nasal
congestion (21, 63). PAF has potent pro-
inflammatory properties and has been
implicated in bronchial asthma (60), but
its role in allergic rhinitis is less well estab-
Several studies have been performed
with a few PAF receptor antagonists in
animal models of the disease. In guinea
pigs, CV-3988 blocked vascular perme-
ability and increased nasal airway resis-
tance induced by topical application of
PAF, whereas SM-10661 attenuated anti-
gen-induced increase in late-phase nasal
airway resistance (35, 45). Another PAF
antagonist, ABT-491, both inhibited anti-
gen-induced leakage and decreased airway
resistance in rats and guinea pigs (11).
In the clinical setting, instillation of
PAF into the nose induces many of the
symptoms of rhinitis, such as increases in
nasal airway resistance, rhinorrhea, nasal
neutrophil influx, and nasal hyper-
responsiveness to subsequent allergen
challenge (4, 47, 53). Both PAF and its
metabolite (lyso-PAF) have been detected
in the nasal fluids and plasma of patients
with rhinitis (46, 54, 74).
Therefore, a number of experiments
conducted in animal models, and some-
times in humans, have shown that PAF is
involved in many pathophysiological con-
ditions, including allergic rhinitis. This
hypothesis is based on PAF-induced
pathological responses, prevention of the
pathological condition by PAF-r antago-
nists or the presence of PAF-related com-
pounds in the areas affected by the pathol-
ogy. To date, however, few PAF antago-
nists have reached clinical use, whereas
most compounds still in development are
being studied mostly in biological testing
or preclinical phase for the anti-
allergic/antiasthmatic indication. Other
indications often studied include treat-
ment of septic shock, hypertension or
antiplatelet therapy.
In conclusion, PAF and histamine
complement each other in vivo: histamine
is a mediator of early allergic response
released from preformed reservoirs in
mast cells, whereas PAF can be regarded
as a late-response mediator and is mainly
synthesized de novo . Both histamine and
PAF promote the release of each other in
some tissues and cells. Therefore, block-
ing both PAF and histamine might show
greater clinical efficacy than blocking just
one of them. P
IWINSKI et al. (67) reported
that the replacement of the ethoxycar-
J. Physiol. Biochem., 60 (2), 2004
bonyl group of loratadine, a widely used
antihistamine, by an acetyl group gave
the resulting compound (SCH-37370) a
dual character, maintaining its antihista-
mine activity and conferring an additional
PAF antagonist activity. A further step
was to increase the potency of compounds
derived from SCH-37370. Two series of
benzocycloheptapyridines (3-pyridy-
lalkyl derivatives and nicotinoyl deriva-
tives) were synthesized and analyzed for
PAF antagonist and H
activities. The analysis of different pyri-
dine substitutes led to the discovery of
rupatadine fumarate as a potent dual
antagonist (16). Further clinical studies
have confirmed the usefulness of rupata-
dine as treatment of allergic rhinitis (42).
Epinastine is another antiallergic agent
that has not only antihistaminic properties
but also provides antileukotriene, anti-
PAF and antibradykinin activities, which
are associated with its antiallergic actions
V. ALFARO. Papel de la histamina y del
factor activador de plaquetas en la rinitis alér-
gica (minirrevisión). J. Physiol. Biochem., 60
(2), 101-112, 2004.
Esta revisión se centra en los efectos de la
histamina y del factor de activación plaquetaria
(PAF) en la rinitis alérgica y sus posibles impli-
caciones en terapia. La rinitis alérgica es un
desorden heterogéneo que resulta de una reac-
ción mediada por IgE asociada con inflamación
nasal de intensidad variable. La reacción cruza-
da IgE/alergeno da lugar a una respuesta que
incluye dos fases: la primera implica la libera-
ción de mediadores formados previamente
tales como la histamina o las interleuquinas por
parte de mastocitos y basófilos; la segunda fase
empieza cuando las células empiezan a produ-
cir mediadores inflamatorios derivados de lípi-
dos. Uno de estos mediadores es el PAF. Apar-
te de los leucotrienos, el PAF es quizás el más
potente mediador inflamatorio en la rinitis
alérgica para inducir infiltración vascular, una
respuesta que puede contribuir a la aparición
de rinorrea y congestión nasal.
Palabras clave: Histamina, PAF, Rinitis.
1. Albanesi, C., Pastore, S., Fanales-Belasio, E. and
Girolomoni, G. (1998): Clin. Exp. Allergy, 28,
2. Albert, D. H., Malo, P. E., Tapang, P., Shaugh-
nessy, T. K., Morgan, D. W., Wegner, C. D.,
Curtin, M. L., Sheppard, G. S., Xu, L., Davidsen,
S. K., Summers, J. B. and Carter, G. W. (1998): J.
Pharmacol. Exp. Ther., 284, 83-88.
3. Alonso, F., Gil, M. G., Sanchez-Crespo, M. and
Mato, J. M. (1982): J. Biol. Chem., 257, 3376-
4. Andersson, M. and Pipkorn, U. (1988): Eur. J.
Clin. Pharmacol., 35, 231-235.
5. Bachert, C. (2002): Allergy, 57, 287-296.
6. Bae, K., Longobardi, L., Karasawa, K., Malone,
B., Inoue, T., Aoki, J., Arai, H., Inoue, K. and
Lee, T. (2000): J. Biol. Chem., 275, 26704-26709.
7. Baroody, F. M. and Naclerio, R. M. (2000):
Allergy, 55 (64), 17-27.
8. Benveniste, J., Henson, P. M. and Cochrane, C.
G. (1972): J. Exp. Med., 136, 1356-1377.
9. Benveniste, J., Tence, M., Varenne, P., Bidault, J.,
Boullet, C. and Polonsky, J. (1979): C. R. Seances
Acad. Sci. D., 289, 1037-1040.
10. Blank, M. L., Lee, Y. J., Cress, E. A. and Snyder,
F. (1988): J. Biol. Chem., 263, 5656-5661.
11. Bousquet, J. (1998): Clin. Exp. Allergy, 28(6), 49-
12. Bousquet, J., Van Cauwenberge, P., Khaltaev,
N., Aria Workshop Group and World Health
Organization (2001): 108, 147-334.
13. Bradding, P., Feather, I. H., Wilson, S., Bardin,
P. G., Heusser, C. H., Holgate, S. T. and
Howarth, P. H. (1993): J. Immunol., 151, 3853-
14. Bradding, P., Feather, I. H., Wilson, S., Holgate,
S. T. and Howarth, P. H. (1995): Am. J. Respir.
Crit. Care Med., 151, 1900-1906.
15. Braquet, P., Touqui, L., Shen, T. Y. and Var-
gaftig, B. B. (1987): Pharmacol. Rev., 39, 97-145.
16. Carceller, E., Merlos, M., Giral, M., Balsa, D.,
Almansa, C., Bartroli, J., Garcia-Rafanell, J. and
Forn, J. (1994): J. Med. Chem., 37, 2697-2703.
17. Chao, W. and Olson, M. S. (1993): Biochem. J.,
292 (3), 617-629.
18. Christie, P. E. and Henderson, W. R., Jr. (2002):
Clin. Allergy Immunol., 16, 233-254.
J. Physiol. Biochem., 60 (2), 2004
19. Church, M. K. (1999): Clin. Exp. Allergy, 29 (3),
20. Ciprandi, G., Passalacqua, G. and Canonica, G.
W. (1999): Clin. Exp. Allergy, 29 (3), 49-53.
21. Cuss, F. M. (1999): Clin. Exp. Allergy, 29 (3), 54-
22. Demopoulos, C. A., Pinckard, R. N. and Hana-
han, D. J. (1979): J. Biol. Chem., 254, 9355-9358.
23. Doyle, W. J., Boehm, S. and Skoner, D. P. (1990):
J. Allergy Clin. Immunol., 86, 924-935.
24. Eda, R., Sugiyama, H., Hopp, R. J., Bewtra, A.
K. and Townley, R. G. (1993): Ann. Allergy, 71,
25. Elstad, M. R., McIntyre, T. M., Prescott, S. M.
and Zimmerman, G. A. (1991): Am. J. Respir.
Cell. Mol. Biol., 4, 148-155.
26. Enerback, L., Pipkorn, U. and Olofsson, A.
(1986): Int. Arch. Allergy Appl. Immunol., 81,
27. Evans, T. W., Rogers, D. F., Aursudkij, B.,
Chung, K. F. and Barnes, P. J. (1988): Am. Rev.
Respir. Dis., 138, 395-399.
28. Evans, T. W., Rogers, D. F., Aursudkij, B.,
Chung, K. F. and Barnes, P. J. (1989): Clin. Sci.
(Lond), 76, 479-485.
29. Fineman, S. M. (2002): Ann. Allergy Asthma
Immunol., 88, 2-7.
30. Gibbs, B. F., Vollrath, I. B., Albrecht, C., Amon,
U., and Wolff, H. H. (1998): Naunyn Schmiede-
bergs Arch. Pharmacol., 357, 573-578.
31. Haaksma, E. E., Leurs, R. and Timmerman, H.
(1990): Pharmacol. Ther., 47, 73-104.
32. Hanahan, D. J. (1986): Annu. Rev. Biochem., 55,
33. Hayashi, S. and Hashimoto, S. (1999): Clin. Exp.
Allergy, 29, 1593-1596.
34. Healy, D. P. (2002): Ann. Pharmacother., 36,
35. Honda, Z., Ishii, S. and Shimizu, T. (2002): J.
Biochem. (Tokyo), 131, 773-779.
36. Howarth, P. H. (1997): Allergy, 52, 12-18.
37. Howarth, P. H., Salagean, M. and Dokic, D.
(2000): Allergy, 55, 7-16.
38. Iliopoulos, O., Proud, D., Adkinson, N. F., Jr.,
Norman, P. S., Kagey-Sobotka, A., Lichtenstein,
L. M. and Naclerio, R. M. (1990): J. Allergy Clin.
Immunol., 86, 851-861.
39. Imaizumi, T. A., Stafforini, D. M., Yamada, Y.,
McIntyre, T. M., Prescott, S. M. and Zimmer-
man, G. A. (1995): J. Intern. Med., 238, 5-20.
40. Imrie, C. W. and McKay, C. J. (1999): Baillieres
Best. Pract. Res. Clin. Gastroenterol., 13, 357-
41. Ioculano, M., Squadrito, F., Altavilla, D., Canale,
P., Campo, G. M., Bussolino, F., Sardella, A.,
Urna, G. and Caputi, A. P. (1994): J. Cardiovasc.
Pharmacol., 23, 7-12.
42. Izquierdo, I., Merlos, M. and Garcia-Rafanell, J.
(2003): Drugs Today (Barc.), 39, 451-468.
43. Koltai, M., Hosford, D., Guinot, P., Esanu, A.
and Braquet, P. (1991): Drugs, 42, 9-29.
44. Konno, S., Asano, K., Okamoto, K. and Adachi,
M. (1994): Eur. J. Pharmacol., 264, 265-268.
45. Krump, E. and Borgeat, P. (1999): Adv. Exp.
Med. Biol., 447, 107-115.
46. Labrakis-Lazanas, K., Lazanas, M., Koussissis,
S., Tournis, S. and Demopoulos, C. A. (1988):
Haematologica, 73, 379-382.
47. Leggieri, E., Tedeschi, A., Lorini, M., Bianco, A.
and Miadonna, A. (1991): Allergy, 46, 466-471.
48. Leirisalo-Repo, M. (1994): Pharmacol. Toxicol.,
75 (2), 1-3.
49. Levine, A. S., Kort, H. I., Toledo, A. A. and
Roudebush, W. E. (2002): J. Androl., 23, 471-
50. Marshall, G. D., Jr. (2000): J. Allergy Clin.
Immunol., 106, 303-309.
51. McIntyre, T. M., Reinhold, S. L., Prescott, S. M.
and Zimmerman, G. A. (1987): J. Biol. Chem.,
262, 15370-15376.
52. Meltzer, E. O. (1997): J. Allergy Clin. Immunol.,
99, 805-828.
53. Miadonna, A., Milazzo, N., Lorini, M., Sala, A.
and Tedeschi, A. (1996): J. Allergy Clin.
Immunol., 97, 947-954.
54. Miadonna, A., Tedeschi, A., Arnoux, B., Sala, A.,
Zanussi, C. and Benveniste, J. (1989): Am. Rev.
Respir. Dis., 140, 142-147.
55. Mincarini, M., Cagnoni, F., Canonica, G. W.,
Cordone, G., Sismondini, A., Semino, C., Pietra,
G. and Melioli, G. (2000): Allergy, 55, 226-231.
56. Misawa, M. and Iwamura, S. (1990): Jpn. J. Phar-
macol., 54, 217-226.
57. Munakata, Y., Umezawa, Y., Iwata, S., Dong, R.
P., Yoshida, S., Ishii, T. and Morimoto, C.
(1999): Clin. Exp. Allergy, 29, 1281-1286.
58. Mutoh, H., Bito, H., Minami, M., Nakamura,
M., Honda, Z., Izumi, T., Nakata, R., Kurachi,
Y., Terano, A. and Shimizu, T. (1993): FEBS
Lett., 322, 129-134.
59. Mutoh, H., Fukuda, T., Kitamaoto, T.,
Masushige, S., Sasaki, H., Shimizu, T. and Kato,
S. (1996): Proc. Natl. Acad. Sci. USA, 93, 774-779.
60. Naclerio, R. M., Proud, D., Togias, A. G.,
Adkinson, N. F., Jr., Meyers, D. A., Kagey-
Sobotka, A., Plaut, M., Norman, P. S. and Licht-
enstein, L. M. (1985): N. Engl. J. Med., 313, 65-
61. Narita, S. and Asakura, K. (1993): Auris. Nasus.
Larynx., 20, 175-183.
62. Nathan, R. A. (1996): Ann. Allergy Asthma
Immunol., 77, 255-259.
63. Oppenheimer, J. J. and Casale, T. B. (2002):
Expert Opin. Investig. Drugs, 11, 807-817.
J. Physiol. Biochem., 60 (2), 2004
64. Park, Y. J. and Baraniuk, J. N. (2002): Clin.
Allergy Immunol., 16, 275-293.
65. Pawankar, R., Yamagishi, S. and Yagi, T. (2000):
Am. J. Rhinol., 14, 309-317.
66. Petersen, L. J., Church, M. K., Rihoux, J. P. and
Skov, P. S. (1999): Allergy, 54, 607-611.
67. Piwinski, J. J., Wong, J. K., Green, M. J., Gangu-
ly, A. K., Billah, M. M., West, R. E., Jr. and
Kreutner, W. (1991): J. Med. Chem., 34, 457-461.
68. Prescott, S. M., McIntyre, T. M. and Zimmer-
man, G. A. (1990): Thromb. Haemost., 64, 99-
69. Prescott, S. M., Zimmerman, G. A. and McIn-
tyre, T. M. (1990): J. Biol. Chem., 265, 17381-
70. Prescott, S. M., Zimmerman, G. A., Stafforini, D.
M. and McIntyre, T. M. (2000): Annu. Rev.
Biochem., 69, 419-445.
71. Rachelefsky, G. S. (1998): J. Allergy Clin.
Immunol., 101, 367-369.
72. Schneider, E., Rolli-Derkinderen, M., Arock, M.
and Dy, M. (2002): Trends Immunol., 23, 255-
73. Sedgwick, J. B. and Busse, W. W. (1997): Ann.
Allergy Asthma Immunol., 78, 581-585.
74. Shirasaki, H. and Asakura, K. (1990): Nippon
Jibiinkoka Gakkai Kaiho, 93, 420-427.
75. Shukla, S. D. (1992): Faseb J., 6, 2296-2301.
76. Sisson, J. H., Prescott, S. M., McIntyre, T. M.
and Zimmerman, G. A. (1987): J. Immunol., 138,
77. Skoner, D. P. (2001): J. Allergy. Clin. Immunol.,
108, 2-8.
78. Snyder, F. (1990): Am. J. Physiol., 259, 697-708.
79. Snyder, F. (1995): Biochem. J., 305 (3), 689-705.
80. Storms, W.W. (2002): Ann. Allergy Asthma
Immunol., 88, 30-35.
81. Tasaka, K. (2000): Drugs Today (Barc), 36, 735-
82. Tjoelker, L. W., Eberhardt, C., Wilder, C.,
Dietsch, G., Trong, H. L., Cousens, L. S., Zim-
merman, G. A., McIntyre, T. M., Stafforini, D.
M., Prescott, S. M. and Gray, P. W. (1996): Adv.
Exp. Med. Biol., 416, 107-111.
83. Togias, A., Naclerio, R. M., Proud, D., Baum-
garten, C., Peters, S., Creticos, P. S., Warner, J.,
Kagey-Sobotka, A., Adkinson, N. F., Jr., Nor-
man, P. S., et al. (1985): Am. J. Med., 79, 26-33.
84. Venable, M. E., Zimmerman, G. A., McIntyre, T.
M. and Prescott, S. M. (1993): J. Lipid. Res., 34,
85. Walsh, G. M., Annunziato, L., Frossard, N.,
Knol, K., Levander, S., Nicolas, J. M.,
Taglialatela, M., Tharp, M. D., Tillement, J. P.
and Timmerman, H. (2001): Drugs, 61, 207-236.
86. Weimer, L. K., Gamache, D. A. and Yanni, J. M.
(1998): Int. Arch. Allergy Immunol., 115, 288-293.
87. Whatley, R. E., Fennell, D. F., Kurrus, J. A.,
Zimmerman, G. A., McIntyre, T. M. and
Prescott, S. M. (1990): J. Biol. Chem., 265, 15550-
88. Whatley, R. E., Nelson, P., Zimmerman, G. A.,
Stevens, D. L., Parker, C. J., McIntyre, T. M. and
Prescott, S. M. (1989): J. Biol. Chem., 264, 6325-
89. White, M. V. (1990): J. Allergy Clin. Immunol.,
86, 599-605.
90. Yamada, Y. and Yokota, M. (1998): Jpn. Circ. J.,
62, 328-335.
91. Zimmerman, G. A., McIntyre, T. M., Prescott, S.
M. and Otsuka, K. (1990): J. Lipid. Mediat., 2,
92. Zimmerman, G. A., McIntyre, T. M., Prescott, S.
M. and Stafforini, D. M. (2002): Crit. Care Med.,
30, 294-301.
93. Zweiman, B., Atkins, P. C., Moskovitz, A., von
Allmen, C., Ciliberti, M. and Grossman, S.
(1997): J. Allergy Clin. Immunol., 100, 341-347.
J. Physiol. Biochem., 60 (2), 2004
... The role of PAF in allergic rhinitis (AR) has also been suggested. PAF is considered the strongest inducer of vascular permeability, and therefore plays a key role in rhinorrhoea and nasal congestion [21,22]. Similar to asthma, increased levels of both PAF and its precursor lyso-PAF have been found in nasal lavages and plasma samples in AR patients [23]. ...
... However, other cell types such as basophils [69], and mediators such as cysteinyl leukotrienes, serotonin, TNF-α and PAF are also thought to play a part in urticaria [12,66,68]. PAF effects on urticaria seem to be related to the increase of vascular permeability, particularly in skin capillaries, enhancing the effect of other mediators and the development of wheals [12,21,70]. A recent study published in 2019 by Ullambayar et al. [71] has shown that patients with spontaneous CU have higher levels of PAF and lower levels of PAF-AH, the enzyme degrading PAF, in comparison to a group of healthy individuals. ...
... In vivo effects Reproduces rhinitis symptoms (PAF concentration 10 to 500 nmol) [20,22,25,39] Increases vascular permeability (associated with rhinorrhea and nasal congestion) [21] Nasal hyperreactivity [20,22,24] Priming phenomenon [25] In vitro findings PAF receptor is expressed in multiple cell types (mast cells, eosinophils, platelets, endothelial cells, basophils, neutrophils, epithelial cells, etc.) [9] Potent chemoattractant (eosinophils and neutrophils) [12,13] ...
Full-text available
Platelet-activating factor (PAF) is a lipid mediator involved in several allergic reactions. It is released from multiple cells of the immune system, such as eosinophils, neutrophils, and mast cells, and also exerts its effect on most of them upon specific binding to its receptor, becoming a pleiotropic mediator. PAF is considered a potential relevant mediator in allergic rhinitis, with a key role in nasal congestion and rhinorrhoea due to its effect on vascular permeability. Interestingly, despite its potential relevance as a therapeutic target, no specific PAF inhibitors have been studied in humans. However, rupatadine, a second-generation antihistamine with dual antihistamine and anti-PAF effects has shown promising results by both blocking nasal symptoms and inhibiting mast cell activation induced by PAF, in comparison to antihistamine receptor drugs. In conclusion, the inhibition of PAF may be an interesting approach in the treatment of allergic rhinitis as part of a global strategy directed at blocking as many relevant inflammatory mediators as possible.
... PAF is a potent lipid inflammatory mediator released by several cell types [8], whose role was first reported in literature by a French immunologist, Jacques Benveniste, as a mediator of anaphylaxis [9]. In AR, PAF has been recognized to have an important role in inducing vascular permeability associated with rhinorrhoea and nasal congestion, consequently nasal hyperreactivity is then encouraged [10][11][12]. Furthermore, PAF serves as a powerful chemoattractant for eosinophils and neutrophils to the site of allergic inflammation. ...
Full-text available
Background Platelet-activating factor (PAF) has been suggested to be a potent inflammatory mediator in Allergic rhinitis (AR) pathogenesis. Vitamin E, an essential nutrient that comprises tocopherol and tocotrienol, is known as a potential therapeutic agent for airway allergic inflammation. This study aimed to investigate the beneficial effects of intranasal Tocotrienol-rich fraction (TRF) on PAF-induced AR in a rat model. Methods Sprague Dawley rats were randomly assigned into 3 groups: Control, PAF-induced AR and PAF-induced AR with TRF treatment. To induce AR, 50 μl of 16 μg/ml PAF was nasally instilled into each nostril. From day 1 to 7 after AR induction, 10 μl of 16 μg/μl TRF was delivered intranasally to the TRF treatment group. Complete upper skulls were collected for histopathological evaluation on day 8. Results The average severity scores of AR were significantly higher in the PAF-induced AR rats compared to both control and PAF-induced AR with TRF treatment. The histologic examination of the nasal structures showed moderate degree of inflammation and polymorphonuclear cells infiltration in the lamina propria, mucosa damage and vascular congestion in the PAF-induced AR rats. TRF was able to ameliorate the AR symptoms by restoring the nasal structures back to normal. H&E staining demonstrated a statistically significant benefit upon TRF treatment, where minimal degree of inflammation, and a reduction in the infiltration of polymorphonuclear cells, mucosa damage and vascular congestion were observed. Conclusion TRF exhibited symptomatic relief action in AR potentially due to its antioxidant, anti-inflammatory and anti-allergic properties.
... In this model, the early phase is related to the production of histamine, leukotrienes, platelet-activating factors, and possibly cyclooxygenase products. The anti-inflammatory activity of the thin layer chromatography-separated portion of the supernatant of W. somnifera might be due to the presence of rich phenolic acids and flavonoids [75]. In vitro data on withanolides demonstrate inhibitory effects on the cyclooxygenase enzyme and confirm the scientific support for the use of W. somnifera leaf in the treatment of inflammation, according to Ichikawa et al. ...
... A wide range of inflammatory cells is involved in this IgEmediated response, being histamine one of the major contributors to hallmark AR symptoms. The plateletactivating factor (PAF) was later discovered as a mediator of nasal congestion and rhinorrhea symptoms of AR since it promotes an increase in vascular permeability and bronchoconstriction [14]. ...
Full-text available
Background: The clinical efficacy of rupatadine in terms of responders has not been previously explored in perennial allergic rhinitis (PAR). Methods: This pooled analysis included data from 6 randomised, double-blind, placebo-controlled trials conducted in PAR patients treated with rupatadine 10 mg or 20 mg, or placebo. Participants were aged ≥ 18 years, with diagnosis of PAR and a Total 4 Nasal Symptom Score (T4NSS) ≥ 5. We evaluated the T4NSS and Total 5 Symptom Score (T5SS) for 28 days of treatment, the responder proportion (50% and 75% response), and the time to response. Results: Efficacy data from 1486 patients were analysed: 585 received placebo, 682 rupatadine 10 mg, and 219 rupatadine 20 mg. Compared with placebo, rupatadine promoted greater symptom improvements and higher responder proportions (50% and 75% response) for T4NSS and T5SS over 28 days. Symptom improvements and responder proportions were higher in the rupatadine 20 mg group vs the 10 mg group. The time to response was shorter in the rupatadine 20 mg group vs the 10 mg group for T4NSS (16 and 9 days for the 50% and 75% responses, respectively) and for T5SS (13 and 8 days for the 50% and 75% responses, respectively). Conclusions: Rupatadine was efficacious in reducing allergic rhinitis symptoms, showing high responder proportions. The faster and stronger effect of rupatadine 20 mg may suggest its use in patients with severe PAR or not responding to the standard dose.
... Histamine is mainly responsible for itching and sneezing symptoms [8]. Platelet-activating factor (PAF) is a key mediator of nasal congestion and rhinorrhoea responses through its involvement in vasodilatation and vascular permeability functions [9,10]. ...
Full-text available
Background: Different clinical trials showed the superior efficacy of rupatadine compared to placebo at improving seasonal allergic rhinitis (SAR) symptoms, but no study has assessed if the response promoted is clinically meaningful. Methods: This study is a pooled analysis of data of seven randomized, double-blind, placebo-controlled SAR studies comparing responder proportions upon treatment with rupatadine (10 or 20 mg) or placebo. We evaluated the following symptom scores at baseline (Visit 1) and over 14 days of treatment: Total 4 Nasal Symptom Score (T4NSS), Total 2 Ocular Symptom Score (T2OSS) and Total 6 Symptom Score (T6SS). The proportion of responders (50% and 75% response) and the time to response were compared between groups on days 7 (Visit 2) and 14 (Visit 3). Responder rates were compared between groups on days 7 and 14 for the complete/near-to-complete response for T4NSS (TN4SS score ≤ 2 and each symptom score ≤ 1) and T6SS (T6SS score ≤ 3 and each symptom score ≤ 1). Results: Data from 1470 patients were analyzed: 332 treated with placebo, 662 with rupatadine 10 mg and 476 with rupatadine 20 mg. The reduction in T4NSS, T2OSS and T6SS over 14 days of treatment relative to baseline was statistically higher in rupatadine groups vs the placebo group, with greater improvements in the 20 mg group. A statistically higher proportion of patients reached the 50% and 75% response for T4NSS, T2OSS and T6SS in rupatadine groups compared to the placebo group across the visits. Among rupatadine-treated patients, those receiving 20 mg compared favourably for both cut-off responses. The time to achieve a proportion of responders was shorter in the rupatadine 20 mg group than in the rupatadine 10 mg and placebo groups for all the symptom scores. The number of patients who achieved a complete/near-to-complete response for both symptom scores was higher in rupatadine groups than in the placebo group, with higher proportions in the 20 mg group. Conclusions: This responder analysis confirms the superior efficacy of rupatadine vs placebo to treat SAR. Rupatadine promoted higher proportions of responders according to stringent response criteria and in a dose-dependent manner, with faster and higher response rates in the 20 mg group.
... This drug has a lutidinyl component, which has been shown in vitro and in vivo to prevent PAF from binding to its receptor [9]. Histamine and PAF are major inflammatory mediators in AR [10]. In a study by Shirasaki et al., expression of PAF receptor was evident in the nasal mucosa of patients with refractory nasal obstruction, insinuating the association between PAF and nasal airway resistance [11]. ...
Full-text available
Objective: Long-term safety and efficacy of 10- and 20-mg rupatadine in Japanese patients with perennial allergic rhinitis (PAR) were investigated in a 52-week open-label study (JapicCTI-152952, Methods: The rupatadine dose was fixed to 10 mg once daily for the first 2 weeks. Thereafter, the study investigator was allowed to increase the dosage to 20 mg if the response was insufficient. Safety was evaluated on the basis of treatment-emergent adverse events, laboratory findings, and vital sign measurements. The primary efficacy endpoint was changed from baseline to Week 2 in the total 4 nasal symptom score. Secondary efficacy endpoints included changes over time in ocular symptoms, patient and physician clinical overall impression, and patient quality of life. Results: Seventy-two immunoglobulin E positive patients (mean age, 32.1 years), consisting of 58 adults (age, ≥ 18 years) and 14 adolescents (12 to 17 years), were enrolled. Ninety-four treatment-emergent adverse events were reported in 48 patients (66.7%), including 9 adverse drug reactions in 9 patients (12.5%). The most frequently reported adverse drug reaction was somnolence (9.7%). The primary and secondary efficacy endpoints demonstrated a statistically significant clinical benefit with rupatadine. The rupatadine dose was increased from 10 to 20 mg in 36 patients (50.0%), which resulted in better symptom management. Conclusions: Rupatadine 10- and 20-mg once-daily doses were well tolerated in long-term use. Updosing to 20 mg is a reasonable option in PAR patients whose symptoms cannot be controlled effectively by the 10-mg dose.
... Because PAF is involved in the occurrence of nasal congestion, rhinorrhea, and other allergic conditions, inhibition of the PAF signaling pathway can be a promising modality for treating allergic symptoms. 9,10 The pharmacokinetic and pharmacodynamic profile of rupatadine indicates that this drug is a fast-acting, once daily therapy. Following oral ingestion in humans, rupatadine is readily absorbed and reaches the peak plasma concentration with a median time to peak concentration (t max ) of 0.67e1.00 ...
Full-text available
Background Rupatadine is a novel non-sedating second-generation H1-antihistamine with antiplatelet-activating factor activity, first marketed in Spain in 2003. It is used for treating allergic rhinitis in more than 80 countries. This study investigated its efficacy and safety in Japanese patients with seasonal allergic rhinitis (SAR). Methods This was a randomized, placebo-controlled, double-blind study conducted at 4 medical institutions in Japan (JapicCTI-152785). Adolescent and adult SAR outpatients aged 12–64 years entered a 1-week placebo run-in period. After eligibility was confirmed, patients orally received placebo, rupatadine 10 mg, or 20 mg once daily for 2 weeks. The primary endpoint was a change from baseline to second week of treatment in total 4 nasal symptom score (T4NSS). Results Nine hundred patients were randomly assigned to placebo, rupatadine 10 mg, or rupatadine 20 mg (302, 298, and 300 patients, respectively). The least squares mean difference in the primary endpoint between rupatadine and placebo was −1.085 for 10 mg, and −1.415 for 20 mg (analysis of covariance, both P < 0.001). The rates of adverse events were 6.6%, 14.1%, and 15.0% for placebo, rupatadine 10 mg, and rupatadine 20 mg, respectively. Somnolence was most frequently reported: 7.0% for rupatadine 10 mg and 7.3% for rupatadine 20 mg. No serious adverse drug reactions were observed, and no adverse events resulted in premature discontinuation. Conclusions Rupatadine 10 and 20 mg were significantly superior to placebo in improving nasal and ocular symptoms of SAR, and were well tolerated.
... Anaphylaxis is defined as a severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by a dose of stimulus that is well tolerated by healthy persons [197,198]. Recently, PAF and PAF-AH have been reported as clinically valuable biomarkers of anaphylaxis [197], since PAF produced and released by mast cells, basophils, neutrophils, eosinophils, fibroblasts, platelets, endothelial cells, and even cardiac muscle cells plays an important role in anaphylaxis and several other allergic reactions, from allergic rhinitis to asthmatic complications [67,[197][198][199][200][201][202][203]. Eosinophils, mast cells, and basophils are implicated in allergies, and they have the capacity to influence each other's functions through a crosstalk, where other mediators such as PAF are also implicated [199][200][201]204]. ...
Full-text available
Since the Seven Countries Study, dietary cholesterol and the levels of serum cholesterol in relation to the development of chronic diseases have been somewhat demonised. However, the principles of the Mediterranean diet and relevant data linked to the examples of people living in the five blue zones demonstrate that the key to longevity and the prevention of chronic disease development is not the reduction of dietary or serum cholesterol but the control of systemic inflammation. In this review, we present all the relevant data that supports the view that it is inflammation induced by several factors, such as platelet-activating factor (PAF), that leads to the onset of cardiovascular diseases (CVD) rather than serum cholesterol. The key to reducing the incidence of CVD is to control the activities of PAF and other inflammatory mediators via diet, exercise, and healthy lifestyle choices. The relevant studies and data supporting these views are discussed in this review.
... For example, patients with diabetes may have increased concentrations of PAF, a potent pro-inflammatory factor implicated in the pathogenesis of DN (17). Under certain stimuli, various cell types may secrete PAF, including platelets, endothelial cells and MCs (18). The primary source of PAF, however, is the kidney, in which 20-25% of PAF is secreted by MCs (19). ...
Full-text available
Platelet-activating factor (PAF) promotes glomerular extracellular matrix (ECM) deposition, primarily through activation of the protein kinase C (PKC) pathway. The present study was designed to investigate whether atorvastatin, which mediates a protective effect against glomerular ECM deposition and diabetic neuropathy, may interfere with the PKC‑transforming growth factor‑β1 (TGF‑β1) pathway in a model of human mesangial cells (HMCs) exposed to a high glucose (HG) and lysophosphatidylcholine (LPC) environment. HMCs were divided into three treatment groups: Control, high glucose and lysophosphatidylcholine (HG+LPC), and HG+LPC+atorvastatin. Cells were cultured for 24 h. The levels of the ECM‑associated molecules collagen IV (Col IV) and fibronectin (Fn) in the supernatant were detected using an ELISA kit. PKC‑β1, TGF‑β1 and PAF‑receptor gene expression was detected by reverse transcription‑quantitative polymerase chain reaction. PKC‑β1 and TGF‑β1 protein expression was detected by western blotting, and the subcellular localization of PKC‑β1 was assessed using immunofluorescence. The results indicated that atorvastatin may reduce the secretion of ECM components (Fn and Col IV) in HMCs in a HG and LPC environment, by inhibiting the increase in PAF secretion and the activation of the PKC‑TGF‑β1 signaling pathway.
In dem Kapitel »Antiallergische und antientzündliche Pharmakotherapie« werden die pharmakologischen Therapieoptionen zur Behandlung von den wichtigsten allergischen Erkrankungen dargestellt. Neben klassischen Medikamenten, die vorwiegend zur symptomorientierten Behandlung verwendet werden, werden neue Pharmaka, die eine zielgerichtetere Behandlung erlauben sollen, vorgestellt. Es werden die unterschiedlichen Wirkmechanismen der Medikamente sowie deren wichtigsten unerwünschten Wirkungen besprochen. Des Weiteren werden die gängigen Therapien von akuten Notfallsituationen wie des Status asthmaticus und des anaphylaktischen Schocks dargestellt.
Full-text available
Platelet-activating factor (PAF)-dependent transacetylase (TA) is an enzyme that transfers an acetyl group from PAF to acceptor lipids such as lysophospholipids and sphingosine. This enzyme is distributed in membrane and cytosol of the cells. We previously revealed that TA purified from rat kidney membrane showed an amino acid sequence similarity to that of bovine PAF-acetylhydrolase (AH) (II). In the present study, we purified TA from the rat kidney cytosol and analyzed its amino acid sequence. The amino acid sequence of the cytosolic TA is similar to that of bovine PAF-AH (II) and membrane TA. To clarify the relationship between TA and PAF-AH (II), we isolated cDNA of rat PAF-AH (II). The predicted amino acid sequence of rat PAF-AH (II) from isolated cDNA included all the sequences found in TAs purified from the membrane and cytosolic TAs. In addition, monoclonal antibody to recombinant PAF-AH (II) cross-reacted with both cytosolic and membrane TAs. Consistent with sequence identity, recombinant PAF-AH (II) showed TA activity, whereas recombinant PAF-AH Ib, which is a different subtype of intracellular PAF-AHs, did not possess TA activity. Analysis of a series of site-directed mutant PAF-AH (II) proteins showed that TA activity was decreased, whereas PAF-AH activity was not affected in C120S and G2A mutant proteins. Thus, Cys¹²⁰ and Gly² are implicated in the catalysis of TA reaction in this enzyme. Furthermore, the transfer of acetate from PAF to endogenous acceptor lipids was significantly increased in a time-dependent manner in CHO-K1 cells transfected with PAF-AH (II) gene. These results demonstrate that PAF-AH (II) can function, as a TA in intact cells, and PAF-AH (II) and TA are the same enzyme.
Full-text available
Endothelial cells (EC) synthesize platelet-activating factor (PAF) when stimulated with agonists that bind to cell-surface receptors. We examined events that link receptor binding to synthesis of PAF by EC. Bovine EC stimulated with agonists that interact with specific cell-surface receptors accumulated PAF only in the presence of extracellular calcium. Hormonal stimulation of EC resulted in Ca²⁺ entry characteristic of that seen with receptor-operated calcium channels; Indo-1 measurements demonstrated that this inward flux of Ca²⁺ caused prolonged elevated levels of intracellular Ca²⁺. EC were exposed to melittin or theta toxin from Clostridium perfringens (pore-forming peptides that increase the permeability of the plasma membrane for small molecules) resulting in an inward flux of Ca²⁺ and accumulation of PAF. Ca²⁺ appears to be regulatory for PAF production at the level of phospholipase A2-mediated production of the PAF precursor 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine, as Ca²⁺ was required for the stimulated hydrolysis of 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine. PAF accumulation in EC is also regulated by protein kinase C. Pretreatment of EC with phorbol esters that activate protein kinase C or with dioctanoylglycerol, followed by stimulation, resulted in a 2-fold increase in stimulated PAF production. The regulatory effect of protein kinase C also appears to be at a phospholipase A2-mediated hydrolysis of 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine.
Platelet-activating factor (PAF) is a pro-inflammatory lipid mediator possessing a unique 1-O-alkyl glycerophospholipid (GPC) backbone (I-O-alkyl-2-acetyl-sn-glycero-3-phosphocholin). Cloned PAF receptor, which belongs to the G protein-coupled receptor superfamily, transduces pleiotropic functions including cell motility, smooth muscle contraction, and synthesis and release of mediators and cytokines via multiple heterotrimeric G proteins. Pharmacological studies have suggested that PAF functions in a variety of settings including allergy, inflammation, neural functions, reproduction, and atherosclerosis. Establishment of PAFR mice confirmed that the PAF receptor is responsible for pro-inflammatory responses, but that its roles in other settings remain to be clarified.
Allergic rhinitis is an inflammatory disorder of the nasal mucosa typified by the symptoms of nasal itch, sneeze, anterior nasal secretions, and nasal blockage. These symptoms arise from the interaction between mediators and neural, vascular, and glandular structures within the nose. Nasal itch, sneezes, and rhinorrhoea are predominantly neural in origin, while nasal obstruction is predominantly vascular. Nasal biopsy studies show accumulation of eosinophils within the lamina propria and epithelium and an increase in tissue and cell surface basophils in both seasonal and perennial allergic rhinitis. These cells are in an activated state. Within the epithelium, increased numbers of mast cells, T cells and Langerhans' cells, which induce T-cell activation, are found. The accumulation of these cells can be linked to chemokine and cytokine generation by the epithelial cells themselves. Thus, the tissue cell recruitment is orchestrated by activated mast cells, T cells, and epithelial cells, with the recruited tissue eosinophils also contributing to their persistence at this site through autocrine mechanisms. Mast cells generate an array of mediators including histamine, tryptase, leukotrienes, and prostaglandins. Histamine is also generated by basophils. Eosinophils and basophils contribute to the leukotriene synthesis within the tissue. Histamine nasal insufflation induces nasal itch, sneeze, and rhinorrhoea as well as nasal blockage, thereby reproducing all the symptoms of allergic rhinitis. These effects are primarily mediated by H1-receptors, and H1-receptor antagonists are a prominent treatment. Antagonism of histamine at these receptors reduces symptoms by about 40-50%, with the greatest effect on the neurally mediated responses. Thus, histamine is a major mediator of allergic rhinitis, but not the sole contributor. Nasal insufflation with leukotrienes, prostaglandins, or kinins is associated with the development of nasal blockage. These mediators act primarily on the nasal vasculature and, in this respect, leukotrienes are potent mediators. Leukotrienes also induce plasma protein exudation, which contributes to the anterior nasal secretions. Studies with combination products have suggested that modifying the effects of both leukotrienes and histamine has complementary effects in relieving nasal symptoms, indicating that both these mediators are relevant to disease expression.
In previous studies we found that guinea pigs demonstrate an increase in airway reactivity and eosinophil numbers 4 days after a respiratory infection with parainfluenza-3 (PI3) virus. Clinical data support the possible involvement of eosinophils in virus-induced airway hyperresponsiveness. Eotaxin, a newly discovered chemokine, could be involved in eosinophil migration to the airways. In this study, eosinophil numbers were counted in blood and bronchoalveolar lavage (BAL) fluid and related with eotaxin concentrations in BAL fluid 1, 2, 3, and 4 days after intratracheal PI3 virus administration. On day 1, blood eosinophils increased by more than 200% (P < 0.01). The number of eosinophils were only slightly enhanced from day 2 to day 4 (40%–70%). BAL fluid eosinophils were not increased on day 1 but were significantly elevated on day 2 (180%) and remained high on days 3–4 (>300%, P < 0.05). This increase in lung eosinophils correlated well with eotaxin levels measured in BAL fluid. There was no significant increase in eotaxin on day 1 following PI3 infection; however, on days 2–4 eotaxin levels in BAL fluid were significantly elevated (four–sixfold increase) when compared with medium inoculated controls. Eotaxin appears to play an important role in eosinophil accumulation in guinea pig lung following PI3 infection.
There is renewed interest in the role of respiratory virus infections in the pathogenesis of asthma and in the development of exacerbations in pre-existing disease. This is due to the availability of new molecular and experimental tools. Circumstantial evidence points towards a potentially causative role as well as to possibly protective effects of certain respiratory viruses in the cause of allergic asthma during early childhood. In addition, it now has become clear that exacerbations of asthma, in children as well as adults, are mostly associated with respiratory virus infections, with a predominant role of the common cold virus: rhinovirus. Careful human in vitro and in vivo experiments have shown that rhinovirus can potentially stimulate bronchial epithelial cells to produce pro-inflammatory chemokines and cytokines, may activate cholinergic- or noncholinergic nerves, increase epithelial-derived nitric oxide synthesis, upregulate local ICAM-1 expression, and can lead to nonspecific T-cell responses and/or virus-specific T-cell proliferation. Experimental rhinovirus infections in patients with asthma demonstrate features of exacerbation, such as lower airway symptoms, variable airways obstruction, and bronchial hyperresponsiveness, the latter being associated with eosinophil counts and eosinophilic cationic protein levels in induced sputum. This suggests that multiple cellular pathways can be involved in rhinovirus-induced asthma exacerbations. It is still unknown whether these mechanisms are a distinguishing characteristic of asthma. Because of the limited effects of inhaled steroids during asthma exacerbations, new therapeutic interventions need to be developed based on the increasing pathophysiological knowledge about the role of viruses in asthma.
Rupatadine is a new agent for the management of diseases with allergic inflammatory conditions, such as seasonal and perennial rhinitis. The pharmacological profile of rupatadine offers particular benefits in terms of a strong antagonist activity towards both histamine H 1 receptors and platelet-activating factor (PAF) receptors. Rupatadine has a rapid onset of action, and its long-lasting effect (> 24 h) permits once-daily dosing. Rupatadine should not be used in combination with the cytochrome P450 inhibitors, such as erythromycin or ketoconazole, due to an increase in AUC and C m a x for rupatadine, although no clinically relevant adverse events have been reported. In addition, rupatadine, at the recommended dose of 10 mg, has been shown to be free of sedative effects and not to cause significant changes in the corrected QT interval in special populations, including the elderly, nor when coadministered with erythromycin or ketoconazole. Preclinical data have also shown that rupatadine and its main active metabolites did not interfere with cloned human HERG channel and did not affect in vitro isolated dog Purkinje fibers at concentrations at least 2000 times greater than those obtained with therapeutic doses in humans. Rupatadine is clinically effective in relieving symptoms in patients with seasonal and perennial allergic rhinitis. Newly published data on its efficacy and safety suggest that this compound may improve the nasal and non-nasal symptoms in comparison to other currently available second generation H 1 receptor antihistamines.
The influence of anti-allergic drugs on lymphocyte function was investigated by examining the blastic activity and cytokine production of human peripheral blood leukocytes in response to concanavalin A stimulation in vitro. Addition of ketotifen, disodium cromoglycate and oxatomide did not influence peripheral blood leukocyte blastic activity even when high concentrations (10.0 μg/ml) of these drugs were added to cell cultures. However, azelastine and terfenadine caused inhibition of peripheral blood leukocyte activation. Interleukin-2, interleukin-3, interleukin-4 and interleukin-5 production from peripheral blood leukocytes was strongly suppressed when the cells were cultured in the presence of these agents. This suppression was observed even when lower concentrations (1.0 and 0.5 μg/ml) of these agents were added to the cultures.
Cetirizine is a H1 histamine antagonist which possesses anti-inflammatory properties through inhibition of leucocyte recruitment and activation, and reduction of ICAM-1 expression on mucosal epithelial cells. No studies have addressed the potential anti-inflammatory activities of cetirizine on skin keratinocytes. Cetirizine and hydrocortisone were compared in their capacity to counteract human keratinocytes activation by IFNgamma. In particular, expression of immuno-modulatory membrane molecules and chemokine release have been examined. Keratinocyte cultures established from normal skin of healthy donors were activated by IFNgamma (100-500 U/mL) in the absence or presence of cetirizine (10(-3)-10(3) microM) or hydrocortisone (10(-3)-10(2) microM), and tested for expression of ICAM-1, HLA-DR, MHC class I and CD40 as well as for release of RANTES, IL-8, macrophage chemotactic protein-1 (MCP-1) and granulocyte macrophage-colony stimulating factor (GM-CSF). Cetirizine at high concentrations (10(2)-10(3) microM) markedly inhibited IFNgamma-induced expression of membrane ICAM-1, HLA-DR and up-regulation of MHC class I, but had no effect on CD40 expression. In contrast, hydrocortisone (10(2) microM) enhanced IFNgamma-induced membrane ICAM-1, reduced expression of HLA-DR and did not alter expression of MHC class I and CD40. Consistently, high doses of cetirizine decreased, whereas hydrocortisone increased, soluble ICAM-1 levels in the supernatants of IFNgamma-treated keratinocytes. The inhibiting and stimulating effects of cetirizine and hydrocortisone, respectively, on ICAM-1 expression were confirmed at the mRNA level by Northern blot analysis. Finally, cetirizine, but not hydrocortisone, inhibited the release of MCP-1 and RANTES from IFNgamma-stimulated keratinocytes. In contrast, hydrocortisone, but not cetirizine, reduced GM-CSF and IL-8 release. The results indicate that cetirizine has the capacity to block the IFNgamma-induced activation of keratinocytes, and thus can exert important regulatory effects on TH1 cell-mediated immune responses in the skin. The high doses required for evidencing these activities suggest the potential benefits of a topical use of cetirizine.