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Histamine and Antihistamines / Histamin i antihistamini


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In recent years, there has been a steady increase in the prevalence of allergic diseases. Allergic immune response represents a complex network of cellular events involving numerous immune cells and mediators. It represents the interaction of innate and acquired immune response. The key role in the immune cascade is taken by histamine, a natural component of the body, which in the allergic inflammatory response is releasesd by the mast cells and basophils. The aim of this study was to highlight the role of histamine in allergic immunological events, their effect on Th1 and Th2 subpopulation of lymphocytes and the production of the corresponding cytokines, as well as the role of histamine blockers in the treatment of these conditions. Histamine achieves its effect by binding to the four types of its receptors, which are widely distributed in the body. Histamine blockers block a numerous effects of histamine by binding to these receptors. As a highly selective second-generation antihistamine, cetirizine not only achieves its effects by binding to H1 receptors, but also attenuates numerous events during the inflammatory process. Knowledge of the effects of histamine blockers, including cetirizine, may lead to the selection of proper therapy for the treatment of allegic diseases.
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Review article
Histamine and Antihistamines
Nikola Stojković
, Snežana Cekić
, Milica Ristov
, Marko Ristić
Davor Đuk
, Maša Binić
, Dragan Virijević
University of Niš, Faculty of Medicine, PhD student, Serbia
Institute of Physiology, University of Niš, Faculty of Medicine , Serbia
Doctor of Medicine
UDC: 615.218
In recent years, there has been a steady increase in the prevalence of allergic diseases. Allergic
immune response represents a complex network of cellular events involving numerous immune
cells and mediators. It represents the interaction of innate and acquired immune response. The key
role in the immune cascade is taken by histamine, a natural component of the body, which in the
allergic inflammatory response is releasesd by the mast cells and basophils. The aim of this study
was to highlight the role of histamine in allergic immunological events, their effect on Th1 and Th2
subpopulation of lymphocytes and the production of the corresponding cytokines, as well as the
role of histamine blockers in the treatment of these conditions.
Histamine achieves its effect by binding to the four types of its receptors, which are widely
distributed in the body. Histamine blockers block a numerous effects of histamine by binding to
these receptors. As a highly selective second-generation antihistamine, cetirizine not only achieves
its effects by binding to H1 receptors, but also attenuates numerous events during the inflammatory
process. Knowledge of the effects of histamine blockers, including cetirizine, may lead to the
selection of proper therapy for the treatment of allegic diseases.
Key words: histamine, immune response, histamine blockers, cetirizine
Corresponding author:
Nikola Stojković
phone: +381643455599
DOI: 10.1515/afmnai-2015-0001
Scientific Journal of the Faculty of Medicine in Niš 2015;32(1):7-22
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Review article
Over the last 30 years, the prevalence of allergic
diseases (asthma, allergic rhinitis, atopic dermatitis
etc.) has been rapidly growing. The goal of treatment
of these conditions represents a blocking effect of
histamine release from basophils and mast cells and is
considered to be the key cause of all the symptoms
associated with allergic inflammatory response.
Antihistamines are drugs that are widely used in
dealing with this type of disease. The aim of this
paper was to provide the insight into the mechanism
of allergic immune responses and highlight the
possibility of using histamine blockers, including
cetirizine, a second generation antihistamine, in
solving many problems in allergy caused by intracellular
communication and numerous mediators.
An immune cascade of allergic conditions is
the interactions between numerous cell types and
inflammatory mediators (1). Allergic inflammatory
response has three distinct phases: sensitization,
early-phase responses and late-phase responses. The
sensitization phase begins with the production of
allergen-specific IgE-antibodies that bind to the
surfaces of mast cells, basophils and antigen
presentation cells (APC), causing degranulation and
subsequent mediator release. Just before that occurs a
differentiation and clonal expansion of allergen-
specific CD4+Th2 cells, with the capability of
producing IL-4 and IL-13, which are the key events in
induction of IgE. Engagement of IgE on effector cells
leads to sensitization of patients to specific allergen
(2). At the early stage of the reaction from the mast
cells and basophils are released many inflammatory
mediators such as tryptase, eosinophil chemotactic
factor in addition to histamine as well as newly
synthesized molecules (PGD2, LCT4, bradykinin). The
process of secretion of these mediators is crucial
characteristic of the early stages of the response.
About half of all patients who exhibit an early-phase
allergic response experience a late phase
inflammatory reaction approximately 4-24 hours
following allergen exposure. Late phase response is
manifested by activation of endothelial cells and
secretion of many inflammatory cytokines (TNF-α,
granulocyte-macrophage colony-stimulating factor,
IL-3, IL-4, IL-5, IL-6, IL-8, IL-13) with strong inflows of
inflammatory granulocytes (eosinophils, basophils,
neutrophils and lymphocytes), except for eosinophils
which have a particular role because they secrete
several substances that promote the chronic late-
phase inflammatory reaction. During the late phase of
allergic inflammatory response, which is
characterized by inflammation and tissue injury, there
is a return of symptoms in the early stage.
Allergic diseases represent complex innate and
adaptive immune responses to environmental
antigens leading to inflammatory reactions with a T
helper-2 type cell and allergen-specific IgE
predominance (3,4). Allergy is essentially an
inflammatory disease. Our knowledge of the cells and
mediators that are involved in the allergic
inflammation has increased immensely during the
last decade. This knowledge provides the basis of a
more rational way for the development of therapeutic
principles and prevention of allergic symptoms. The
allergic inflammation involves a large number of cells.
However, three types of cells seem to be of particular
importance. These are the eosinophil granulocyte, the
mast cell and the T-lymphocyte of the Th2-type. The
cytokines and other molecules and the cells present in
the microenvironment are the main factors which
determine differentiation of naive T cells into distinct
subsets such as Th1, Th2, Th9, Th17 and Th22 type
memory and effector cells (5). In conditions of allergic
diseases, effector Th2 cells produce not only
traditional Th2 cytokines such as IL-4, IL-5, IL-9 and
IL-13 (6,7), but also novel cytokines such as IL-25, IL-
31 and IL-33 which have proinflammatory functions
(8-14). These cytokines induce eosinophilia, mucus
production, producing of allergen-specific IgE and the
recruitment of inflammatory cells to inflamed tissues.
Th2 cells are the leader of the process. The main
effector cells are the eosinophils and mast cells.
Predominance of Th2 cells might be caused by an
increased tendency to activate induced cell death of
high IFN-gama producing Th1 cells as it is commonly
observed in patients with atopic disorders (15). Th1
cells induce apoptosis of keratinocytes in atopic
dermatitis and epithelial cells and/or smooth muscle
cells in asthma in the effector phase of these allergic
diseases (16-20). As the major consequences of the
activation of mast cells, the release of histamine and
other mediators occur, which leads to acute allergic
reaction. Activation of eosinophils lead to the
extracellular release of a number of potent cytotoxic
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Nikola Stojkovet al.
proteins. These proteins play a very important role in
the development of subacute and chronic symptoms
of allergy. Macrophages, epithelial cells, neutrophil
granulocytes and endothelial cells also play an
important role in allergic diseases. Antigen-induced
immunological cascade is presented in Figure 1.
Treatment of allergic diseases still has stereotyped
character and consists of international and national
This treatment shows varying degrees of
success and there are many reasons for this
variability. One of the very important reasons for this
may be the fact that we are not seeing the mechanisms
that underlie the individuality of the patient. It is clear
that there are large differences in terms of
inflammatory cells and mediators that are crucial for
allergic diseases.
Figure 1: The allergic cascade. Mast cell mediators, including cytokines, cause degranulation and contribute to
the bidirectional messaging with other inflamatory cells or their precursors, leading to lymphocyte activity,
and migration of immune cells to inflamatory sites (21) (source: Canonica GW, Blaiss M. Antihistaminic, anti-
inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a
review of the evidence. World Allergy Organ J 2011;4(2):47-53.)
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Review article
Histamine (2-4 imodazol-ethylamine) was first
identified as a mediator of biological functions in the
early 20
century. It was identified in 1911, owing to
vasoactive properties by Barger and Dale, and drugs
that work on the principle of binding to histamine
receptor have been clinically used for more than 60
years. It is one of the most extensively studied
molecules in medicine, of which synthesis,
metabolism, receptors, signal transduction,
physiological and pathological effects there is a large
number of collected evidence. It has a wide range of
both physiological and pathological effects, whereby
the width of the spectrum has continuously been
increasing by new research. Histamine is a low-
molecular-weight amine, a natural body constituent,
synthesized from L-histidine by histidine
decarboxylase, an enzyme that is expressed in many
tyipes of cells throughout the body, including the
central nervous system neurons, gastric-mucosa
parietal cells, Mast cells, basophils, lymphocytes, and
enterophromaphiles cells. Histamine plays an
important role in human health, exerting its diverse
biological effects through four types of receptors. It
plays a key role in the hematopoiesis, proliferation of
cells, differentiation of cells, regeneration and
wound healing, embryonic development. Histamine
is produced in neurons of the central nervous system
which have cell bodies located exclusively in the
tuberomamillary nucleus of the posterior
hypothalamus. Their axons perform transmission of
histamine to the frontal and temporal cortexes of the
brain. In the phylogenetically old part of
neurotransmitter systems, histamine has a role in the
regulation of basic body function through the H1-
receptor such as the cycle of sleeping and waking,
appetite, cognition and memory, energy and
endocrine homeostasis. Histamine also has
anticonvulsant activity (22, 23).
The roles of histamine in inflammation, gastric
acid secretion and as a neurotransmitter are the best
described roles in the human body. Mast cells and
basophils release histamine during inflammation.
Smooth muscle cells and endothelial cells are the
target places of action of histamine. This leads to
vasodilatation and increase in vascular permeability.
In the skin, histamine results in the triple response,
which is an immediate local reddening due to
vasodilatation, a wheal due to increased vascular
permeability and a flare due to indirect
vasodilatation via the stimulation of axonal reflex.
Histamine has an essential role in the gastrointestinal
system for gastric acid secretion. Gastrin and vagal
stimulation induce enterochromaffine cells to release
histamine. Then histamine can act on the
H+K+ATPases, which results finally in the secretion
of H
+, a key element for synthesis of HCl in the
Level of histamine is increased in
bronchoalveolar lavage fluid in patients with allergic
asthma and this increase negatively correlates with
airway function (24-29). An increase in histamine
levels has
been noted in the skin and plasma of
patients with atopic dermatitis (30,31) and in chronic
urticaria (32, 33). Histamine levels are also increased
in multiple sclerosis (34) and in psoriatic skin (35).
Both plasma and synovial fluid of patients with
rheumatoid arthritis and plasma of patients with
psoriatic arthritis have increased histamine levels
(36, 37). It is know that the diverse biological effects
of histamine are mediated through different types of
histamine receptor in treatment. Histamine can have
varying and sometimes counteracting effects on a
particular cell depending on the concentration used,
and which histamine receptors are activated.
Receptor levels may change during different stages
of cell development or under pathophysiological
conditions and could vary among species
There are four major types of histamine
receptors: H1, H2, H3 and H4 receptors which differ
in their expression, signal transduction and function
(38-45). Exspression of H1 and H2 receptors are
widely expressed in contrast to H2 and H4 receptors.
H1, H2 and H4 receptors are expressed on the surface
of many cells involved in inflammatory reactions,
with the H1-receptor playing a major role in
potentiation of proinflammatory immune cell activity
and effector responses fundamental to an allergic
reaction. The H1 receptors have been associated with
many actions in relation to allergic inflammation,
such as rhinorrhea, smooth muscle contraction and
many forms of itching (pruritus). This is mediated by
the transduction of extracellular signals through G
protein and intracellular second messengers (inositol
triphosphate, diacylglycerol, phospholipase D and A2,
and increases in intracellular calcium concentration).
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Nikola Stojkovet al.
Making of H1 receptors is encoded by genes,
localized on chromosome 3. The H2-receptor, in
contrast, appears to suppress inflammatory and
effector functions, while data regarding the role of the
H4-receptor in immune response is limited. Evidence
of the existence of a third histamine receptor groups
(H3) was based on the activity of histamine, which
could not be blocked by antagonists of H1 or H2-
receptor antagonist (46). The histamine H3 receptor
has been identified in the central and peripheral
nervous systems as pre-synaptic receptors controlling
the release of histamine and other neurotransmitters.
The local concentratcion of histamine and
predominant type of histamine receptor undergoing
activation determines the type of effector response
that is elicited.
All four types of histamine receptor are
heptahelical transmembrane molecules that transduce
extracellular signals by way of G proteins to
intracellular second-messenger systems. The classic
model of receptor activation requires binding by a
specific ligand, or agonist and binding of inverse
agonist (antagonist in the older literature) leads to the
inactivation, blockade of these receptors. Aspartic acid
located in the third transmembrane domain of the
human receptor is crucial for the affinity of histamine
and histamine antagonists; this amino acid is a
hallmark of G-protein-coupled receptors. All types of
receptor have constitutive activity, which is defined as
the ability to trigger events even in the absence of
ligand binding. It can be said that there is a balance
between active and inactive states of the receptor. H1-
receptor polymorphisms have been described,
although it is not yet clear how they influence the
clinical response to H1-antihistamines (47). Target
disruption of the genes encoding the H1 receptor, is
applied in mice which results in CNS function
disorders, such as memory, learning, locomotion and
aggressive behavior. H1 receptor deficiency also leads
to numerous immunological abnormalities such as
weakening of antigenic-specific response of T and B
cells (48,49).
The presence of histamine leads to
upregulation of H1 receptors. It was experimentally
proven that antagonists cause blockade of upregulation.
The concept of constitutive activity has led to a
reclassification of drugs acting at the H1- receptor. For
example, the H1-receptor promotes NF-kB in both a
constitutive and agonist-dependent manner and all
clinically available H1-antihistamines inhibit
constitutive H1-receptor-mediated NF-kB production
(50, 51).
Histamine can also be linked to one type of
intracellular histamine receptor (Hic), which was
described several years ago in the microsomes and
nucleus. These types of receptors are comprised of the
cytochrome P450 and cytochrome c (52). This type of
receptor cannot yet be discussed with absolute
certainty, because it is not yet clear which type of
reactions are induced by histamine binding to this
Localization of histamine receptors as well
as the mechanism of their activation are presented in
Table 1.
Table 1. Histamine receptors, the localization of their expression and mechanism of action (53) (source: Akdis
CA, Simons FER. Histamine receptors are hot in immunopharmacology. Eur J Pharmacol 2006; 533:69-76.)
H1 receptors
Nerve cells, airway and vascular smooth muscles, hepatocytes,
chondrocytes, endothelial cells, epithelial cells, neutrophils,
eosinophils, monocytes, dendritic cells (DC), T and B cells
, cGMP, phospholipase
D, phospholipase A2, NF-kB
H2 receptors
Nerve cells, airway and vascular smooth muscle, hepatocytes,
chondrocytes, endothelial cells, epithelial cells, neutrophils,
eosinophils, monocytes, dendritic cells, T and B cells
Adenylatecyclase, cAMP, c-
Fos, c-Jun, PKC, p70S6K
H3 receptors
Histaminergic neurons, eosinophils, DC, monocytes, low
expression in peripheral tissues
H4 receptors
High expression on bone marrow and peripheral hematopoetic
cells, eosinophils, neutrophils, DC, T cells, basophils, mast
cells; low expression in nerve cells, hepatocytes and peripheral
, inhibition of cAMP Gi/os
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Review article
Histamine plays a key role in allergic
inflammation, which is a complex network of cellular
events that involve many cells and mediators.
Histamine is released from the mast cells and
basophils together with tryptase and other preformed
mediators such as prostaglandins, leukotrienes, after
the cross-linking of surface IgE by allergen or through
mechanisms that are independent of IgE. After
allergen challenge in sensitized persons, the local
concentration of histamine is much higher compared
to leukotrienes and other mediators. The
concentration of histamine can then be measured in
micrograms, whereas the concentration of leukotrienes,
and other mediators may be measured in picograms.
Most of the changes in allergic disease occur as
a consequence of binding histamine to H1 receptor
(38-40, 54). Hypotension, tachycardia, flushing and
headache occur through both the H1 and H2 receptors
(55), whereas irritation of the skin in the form of
itching and nasal congestion can be caused by the
activation of H1 and H3 receptors (56, 57). The role of
histamine can be discussed also as a stimulatory
signal for the production of cytokines and the
expression of cell adhesion molecules in the late-
phase of allergic reaction (55, 56, 58, 59).
Histamine may have proinflammatory or
antiinflammatory effects, depending on the
predominance of the type of histamine receptor.
Through the H1-receptor, histamine has
proinflammatory effect, which activation can be
greatly involved in several aspects of antigen-specific
immune response, including maturation of dendritic
cells and the modulation of the balance of Th1 cells
and Th2 cells. Histamine may induce an increase in
the proliferation of Th1 cells and in the production of
interferon γ, which may result in blocking humoral
immune responses by means of this mechanism.
Histamine has the capacity to influence the activity of
basophils, eosinophils and fibrobalsts.
The binding of histamine to histamine H1
receptor leads to many effects that are associated with
symptoms of anaphylaxis and other allergic diseases
(60), however, increasing evidence suggests that this
process also affects a number of immune
/inflammatory and effector functions (38,59).
Under the influence of histamine occurs
secretion of proinflammatory cytokines such as IL-
IL-1β, IL-6 as well as chemokines such as regulated
activation (RANTES) or IL-8. This process takes place
in several types of cells and tissues and leads to the
progression of allergic-inflammatory responses.
Histamine H1 receptor and histamine H2
receptor are found on the surface of endothelial cells.
Histamine through H1 receptor leads to increased
expression of adhesion molecules such as vascular
cellular adhesion molecule (VCAM-1), intracellular
adhesion molecule (ICAM-1) and P-selectin.
Histamine regulates granulocyte accumulation
in tissues in distinct ways. Allergen-induced
accumulation of eosinophils in the skin, nose and
airways is inhibited by histamine H1 receptor
antagonists. The effect of histamine on eosinophil
migration may differ according to the concentration.
Whereas high concentrations inhibit eosinophil
chemotaxis via histamine H1 receptor, low
concentrations enhance eosinophil chemotaxis via
histamine H1 receptor. One study has shown that
histamine H4 receptor is the histamine receptor
responsible for the selective recruitment of eosinophils.
Histamine possesses all the properties of a classical
leukocyte chemoattractant, including: alteration in cell
shape, mobilization of intracellular calcium and up-
regulation of adhesion molecule expression.
More than 45 types of antihistamines are
widely used around the world, thus representing the
largest group of medicines used in the treatment of
allergic conditions.
Traditionally, this group of drugs is classified
in six chemical groups: ethanolamines, ethylenediamines,
alkylamines, piperazines, piperidines and
phenothiazines. If antihistamines are classified
according to function, then we distinguish two
generations of antihistamines: first and second
generation antihistamines, which are distinguished
by the fact that first generation antihistamines
penetrate the blood-brain barrier and have a sedative
effect, while the second generation antihistamines do
not possess these qualities. They are very different in
terms of chemical structure, pharmacology and toxic
potential. Representative of the first and second
generation of antihistamines are given in Figure 2.
Consequently, knowledge of their pharmacokinetic
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Nikola Stojkovet al.
and pharmacodynamics characteristics is important for
the correct usage of such drugs, particularly in
patients belonging to extreme age groups, pregnant
women, or subjects with concomitant diseases.
Figure 2: Drugs of the first and second generation of antihistamines (61) (source: Simons FER, Simons KJ.
The pharmacology and use of H1-receptor antagonist drugs. N Engl J Med 1994; 330: 1663-1670)
After oral application, most antihistamines
show a good degree of absorption. The effective
concentration of antihistamines is achieved three
hours after application, which confirms the above
thesis. These molecules have the characteristic of
liposolubility, which enables them to pass through
cell membranes with extreme ease. Concomitant
administration with food can change the plasma
concentrations of these drugs, which can be
explained by the presence of P glycoprotein across
cell membranes and the organic anion transporter
polypeptides. These proteins function as active
transport systems for other molecules, showing
affinity for them. Antihistamine shows a good
degree of binding to plasma proteins (78% to 99%).
The group of enzymes belonging to the P450
cytohrome system performs metabolization and
detoxification of most antihistamines. Only acrivastine,
levocetirizine, desloratadine and fexofenadine (62)
avoid this metabolic passage through the liver to an
important degree, which makes them more predictable
in terms of their desirable and undesirable effects.
Fexofenadine is eliminated in stool, while cetirizine and
levocetirizine are eliminated in urine. Fexofenadine is
eliminated without metabolic changes while cetirizine
and levocetirizine are eliminated in unaltered form.
Other antihistamines undergo the transformation in
the liver, thereby resulting in metabolites which may
be active or inactive. Their concentrations in plasma
depend on the activity of the P450 enzyme system.
Metabolism of antihistamines and drug interaction are
given in Table 2.
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Review article
Table 2:Antihistamines, their metabolism and interaction with other drugs (63) (modified from del Cuvillo A,
Mullol J, Bartra J, Davila I et al. Comparative pharmacology of the H1 antihistamines.
J Investig Allergol Clin Immunol 2006; 16(1):3-12.)
Generation of
Drug Liver metabolization Drug interactions
Yes (P glycoprotein)
Antagonists of H1 receptors are used in
treatment of allergic rhinoconjuctivitis and relieve
sneezing nasal and ocular itching, rhinorrhea,
conjujctival erythema and early phase of
inflammatory response, but they are less effective in
the treatment of late phase of inflammatory response
Pretreatment with H1 antagonists may
provide some protection against bronchospasm
induced by histamine, exercise, hyperventilation of
cold and dry air, hypertonic or hypotonic saline,
distilled water, adenosine 5 monophosphate, or
allergen. The amount of protection varies with the
dose of H1 antagonists and stimulus used (65-68).
In patients with chronic urticaria, H1
antagonists relieve pruritus and reduce the number,
size and duration of urticarial lesions (69-75).
In patients with anaphylactic or anaphylactoid
reactions, the initial drug of choice is epinephrine;
however, H1 antagonists are useful in the ancillary
treatment of priuritus, urticarial and angioedema.
For anaphylaxis, H2 antagonists are used concurrently
with H1 antagonists to reduce the effects of
histamine on the peripheral vasculature and the
myocardium (76,77).
Cetirizine is a highly selective, long-acting,
peripheral H1 antagonist of the second generation,
carboxylated metabolite of hydroxyzine, which
represents a combination of the two enantiomers
levocetirizine (R enantiomer) and dextrocetirizine
(S enantiomer). It has very low affinity for the
number of types of receptors such as α1-adrenergic,
dopaminergic (D2 receptors), muscarinic and
serotonergic receptors. Cetirizine also shows a low
degree of affinity for calcium channels. Owing to
some of its properties in the allergic response to
antigenic stimulus, cetirizine shows antiallergic, anti-
inflammatory and antihistamine effect. It exists as a
zwitterion (has a separate positive and negative
charged groups). The absorption of cetirizine is good
after the oral administration of this drug. After oral
application of cetirizine in a dosage of 10 to 20 mg,
the maximum plasma concentration (Cmax) is
attained for 1h and it is 257μg/L to 580μg/L. There is
no difference in action of this medication if it is
administered in the form of tablet or in the form of
syrup. Ninety percent of the drug binds to plasma
albumin. Cetirizine is widely distributed throughout
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Nikola Stojkovet al.
the body, although it does not pass the blood-brain
barrier easily. 70% of the cetirizine is eliminated via
urine, and about 10% through the digestive tract in
the feces. This H1 antagonist has a low degree of
interaction with other drugs, since it avoids the
metabolic pathway through the liver.
The consensus of the British Society for
Allergology and Clinical Immunology confirmed the
anti-allergic and anti-inflammatory properties of
cetirizine in vitro and in vivo. Antihistamine agents
such as cetirizine do not act only through H1
receptors, but may attenuate many events during the
inflammatory process. Cetirizine shows some
modulation effects on the inflammatory response. It
leads to reduction of the migration of eosinophils
that is induced by inflammatory mediators in atopic
and nonatopic individuals (78-87). In addition to the
classic role in antagonizing the H1 receptor,
cetirizine induces reduction of the expression of
adhesion molecules associated with the migration of
eosinophils and eosinophil cells in in vitro studies
(88-90) and in atopic patients (91-94), so that the
recipients and the effect of cetirizine consists of the
inhibition of eosinophil infiltration into tissues. It has
a lipophilic and ionizing properties enabling it to act
directly on the cell membrane leading to its
stabilization. Cetirizine inhibits binding of NF-kB,
inhibits the expression of adhesion molecules
(ICAM-1) on immune cells and endothelial cells. It
also inhibits migration of inhibitory factor (MIF) (95)
as well as the production of IL-8, and leukotriene B4
production of two very potent chemoattractans.
Cetirizine leads to the release of PGE2, suppressors
of expression of antigen and presentation of MHC
class II on monocytes and reducing macrophages
(96), reducing the chemotaxis of monocytes and T
lymphocytes (97). Cetirizine reduces the number of
tryptase-positive mast cells at sites of inflammation
(98). An increasing number of data points to the
importance of fibroblasts in many organs. In
particular, it highlights the role of fibroblasts in the
respiratory system, where they play an important
role in allergic and inflammatory diseases of the
respiratory system, not only in the formation of
fibrosis, because they have the ability to respond to
Th2 cytokines. Cetirizine may have a very significant
antifibrotic effect for its ability to reduce the level of
profibrotic cytokine, transforming growth factor beta
(TGF-β), tumor necrosis factor (TNF-α) and IL-6 (99).
It has been shown that the fibroblasts of the airways
have functional receptors for IL-4 and IL-13.
Numerous studies have shown that cetirizine results
in a reduction of the expression of CD54 induced by
Knowledge of the mechanisms underlying the
allergic reaction, records a constant growth and tells
us about the complex network of cells and
mediators, which are at the core of allergic
inflammatory response. Through its receptors,
histamine as an important chemical messenger plays
an important role in the physiological response,
including neurotransmission, allergic inflammation
and immunomodulation. Drugs that have the
histamine receptors as target for their activity can be
considered as a very good choice for the treatment of
allergic conditions. Pharmacodynamic and
pharmacokinetic differences between the first and
second generation of antihistaminics should be well
known, because it can help when choosing the right
drug. Cetirizine is a potent second-generation
antihistamine which shows remarkable
immunoregulatory properties. It influences the
interaction of mediator cells with all systems. It
affects the interaction of eosinophils, mast cells and
fibroblasts and thus may participate in the
regulation of the internal environment
1. Pearlman DS. Pathophysiology of the
inflammatory response. J Allergy ClinImmunol
1999 ;104(4 Pt 1):132-7.
Wang M, Takeda K, Shiraishi Y et al. Peanut
induced intestinal allergy is mediated through a
mast cell-IgE- FcepsilonRI-IL-13 pathway. J Allergy
ClinImmunol 2010; 126(2):306-16, 316 e1-12.
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Review article
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Review article
Histamin i antihistamini
Nikola Stojković
, Snežana Cekić
, Milica Ristov
, Marko Ristić
, Davor Đukić
, Maša Binić
Univerzitet u Nišu, Medicinski fakultet, Student postdiplomskih studija, Srbija
Institut za patofiziologiju, Univerzitet u Nišu, Medicinski fakultet, Srbija
Doktor medicine
Poslednjih godina beleži se kontinuirani rast prevalencije alergijskih oboljenja. Alergijski imunski
odgovor predstavlja jednu kompleksnu mrežu ćelijskih događaja u kojoj učestvuju mnogobrojne imunske
ćelije i medijatori. On predstavlja interakciju urođenog i stečenog imunskog odgovora. Ključnu ulogu u
imunološkoj kaskadi zauzima histamin, prirodni sastojak tela, koga u alergijskom inflamatornom odgovoru
oslobađaju mastociti i bazofili. Cilj ovog rada bio je naglasiti ulogu histamina u alergijskim imunološkim
događajima, njegov efekat na Th1 i Th2 subpopulaciju limfocita i produkciju odgovarajućih citokina, kao i
ulogu blokatora histamina u tretmanu ovih stanja. Histamin ostvaruje svoj efekat vezivanjem za četiri tipa
svojih receptora koji su široko distribuirani u organizmu. Blokatori histamina blokiraju mnogobrojne efekte
histamina vezivanjem za ove receptore. Cetirizin, visoko selektivni antihistaminik druge generacije, ne
ostvaruje svoje efekte samo vezivanjem za H1 receptore već dovodi do atenuisanja mnogobrojnih zbivanja
tokom inflamacijskog procesa. Dobro poznavanje efekata histaminskih blokatora, među njima i cetirizina,
može dovesti do pravog odabira terapije u tretmanu alergijskih oboljenja.
Ključne reči: histamin, imunski odgovor, blokatori histamina, cetirizin
Scientific Journal of the Faculty of Medicine in Niš 2015;32(1):7-22
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... Meanwhile, the H4 receptor responsible for immune system reaction by regulating cytokine release and mediating the chemotaxis of neutrophils and mast cells. Among the receptors, the receptor that plays a pivotal role in an allergic reaction is the H1 receptor [29]. H1 antagonists, which are also known as an antihistamine, stabilize the H1 receptor by maintaining the receptor state in an inactive form [30]. ...
... It will inhibit the release of allergic mediators from mast cells and basophil in addition to inhibiting the chemotaxis of eosinophils and the expression of cell adhesion molecules. There are two types of antihistamine, which are first-and second-generation antihistamine [29]. The first-generation antihistamine penetrates the blood-brain barrier which causes sedative effect while second-generation antihistamine does not. ...
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Phyllanthus amarus Schum. & Thonn. (Phyllanthaceae) is a medicinal plant that is commonly used to treat diseases such as asthma, diabetes, and anemia. This study aimed to examine the antiallergic activity of P. amarus extract and its compounds. The antiallergic activity was determined by measuring the concentration of allergy markers release from rat basophilic leukemia (RBL-2H3) cells with ketotifen fumarate as the positive control. As a result, P. amarus did not stabilize mast cell degranulation but exhibited antihistamine activity. The antihistamine activity was evaluated by conducting a competition radioligand binding assay on the histamine 1 receptor (H1R). Four compounds were identified from the high performance liquid chromatography (HPLC) analysis which were phyllanthin (1), hypophyllanthin (2), niranthin (3), and corilagin (4). To gain insights into the binding interactions of the most active compound hypophyllanthin (2), molecular docking was conducted and found that hypophyllanthin (2) exhibited favorable binding in the H1R binding site. In conclusion, P. amarus and hypophyllanthin (2) could potentially exhibit antiallergic activity by preventing the activation of the H1 receptor.
... Allergic conjunctivitis is marked as pathological alterations which characterized by eosinophilic recruitment which being activated by releasing harmful mediators as major basic protein, exotoxins and peroxidase, besides, secretion of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6 or IL-8 as well as chemokines which have adverse effects on the tissues. 52 The conjunctiva has high incidence of exposure to multiple allergens and it is a highly sensitive, where, it contains sebaceous glands and apocrine secreting glands that produce the highly essential secretions for eye integrity and vitality. Since allergic inflammatory response in the conjunctiva is detrimental and its severity can be estimated by the number of eosinophilic infiltrates and other detrimental leukocytes in the inflammatory response as plasma cells, macrophages and histiocytes, in addition to pathological alterations in the conjunctival mucosa and associated glandular tissue. ...
Full-text available
Background: Mizolastine (MZL) is a dual-action nonsedating topical antihistamine anti-inflammatory agent that is used to relieve allergic conditions, such as rhinitis and conjunctivitis. Solid lipid nanoparticles (SLNs) are advanced delivery system in ophthalmology, with the merits of increasing the corneal drug absorption and hence improved bioavailability with the objective of ocular drug targeting. Methods: First, MZL was formulated as MZL-SLNs by hot homogenization/ultrasonication adopting a 32 full factorial design. Solid-state characterization, in vitro release, and stability studies have been performed. Then, the optimized MZL-SLNs formula has been incorporated into ocular hydrogels using 1.5% w/v Na alginate and 5% w/v polyvinylpyrrolidone K90. The gels were evaluated via in vitro release as well as in vivo studies by applying allergic conjunctivitis congestion in a rabbit-eye model. Results: The optimized formula (F4) was characterized by the highest entrapment efficiency (86.5±1.47%), the smallest mean particle size (202.3±13.59 nm), and reasonable zeta potential (-22.03±3.65 mV). Solid-state characterization of the encapsulation of MZL in SLNs was undertaken. In vitro results showed a sustained release profile from MZL-SLNs up to 30 hours with a non-Fickian Higuchi kinetic model. Stability studies confirmed immutability of freeze-dried MZL-SLNs (F4) upon storage for 6 months. Finally, hydrogel formulations containing MZL-SLNs, proved ocular congestion disappearance with completely repaired conjunctiva after 24 hours. Moreover, pretreatment with MZL-SLNs-loaded hydrogel imparted markedly decreased TNF-α and VEGF-expression levels in rabbits conjunctivae compared with post-treatment with the same formula. Conclusion: MZL-SLNs could be considered a promising stable sustained-release nanoparticulate system for preparing ocular hydrogel as effective antiallergy ocular delivery systems.
Background The Current study describes the construction of three carbon paste electrodes for the quantitative measurement of the third-generation antihistamines fexofenadine (FEX), Desloratadine (DES), and Levocetirizine (LEV). The different assembly steps of the sensor are described. The proposed potentiometric method Presents a green, fast, simple, and sensitive procedure for the determination of these drugs in their pure and pharmaceutical forms. Results The quantitative determination of the antihistamines drugs was achieved using the constructed carbon paste electrodes. The presented analytical method obeyed linearity in the concentration range (5 × 10⁻⁶-1 × 10⁻²) M for FEX and DES, (1 × 10⁻⁵ – 1 × 10⁻²) M for LEV. The values of the Nernstian slopes (-57.40, -29.01, -56.01) mV/ decade indicate the closeness of these values from the ideal Nernstian slope value. The limits of quantification (LOQ) were (2.17 × 10⁻⁸- 6.31 × 10⁻⁸- 3.3 × 10⁻⁸) M respectively. In addition, the electrodes exhibited good selectivity, repeatability (RSD<2%), stability, and fast response time. The method was validated and employed for the determination of the studied drugs in pharmaceutical dosage forms, the average recovery values were (99.13-99.53-99.90) % for FEX, DES, and LEV respectively. Conclusion Our study included the construction of the first carbon paste electrodes for potentiometric determination of some of the third-generation antihistamines. The findings have shown that carbon paste electrodes excel over the traditional ion -selective electrodes and present an accurate, precise, green, robust, and cost-effective analytical method.
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Snake venoms are sources of molecules with proven and potential therapeutic applications. However, most activities assayed in venoms (or their components) are of hemorrhagic, hypotensive, edematogenic, neurotoxic or myotoxic natures. Thus, other relevant activities might remain unknown. Using functional genomics coupled to the connectivity map (C-map) approach, we undertook a wide range indirect search for biological activities within the venom of the South American pit viper Bothrops jararaca. For that effect, venom was incubated with human breast adenocarcinoma cell line (MCF7) followed by RNA extraction and gene expression analysis. A list of 90 differentially expressed genes was submitted to biosimilar drug discovery based on pattern recognition. Among the 100 highest-ranked positively correlated drugs, only the antihypertensive, antimicrobial (both antibiotic and antiparasitic), and antitumor classes had been previously reported for B. jararaca venom. The majority of drug classes identified were related to (1) antimicrobial activity; (2) treatment of neuropsychiatric illnesses (Parkinson’s disease, schizophrenia, depression, and epilepsy); (3) treatment of cardiovascular diseases, and (4) anti-inflammatory action. The C-map results also indicated that B. jararaca venom may have components that target G-protein-coupled receptors (muscarinic, serotonergic, histaminergic, dopaminergic, GABA, and adrenergic) and ion channels. Although validation experiments are still necessary, the C-map correlation to drugs with activities previously linked to snake venoms supports the efficacy of this strategy as a broad-spectrum approach for biological activity screening, and rekindles the snake venom-based search for new therapeutic agents.
A method of continuous in vivo subcutaneous perfusion using Tyrode solution which permits direct analysis of pharmacological agents released in inflamed human skin is described. An examination was carried out using bioassay with three isolated organ preparations and spectrofluorometry. In dermographic skin of patients with urticaria pigmentosa the perfusate was consistently found to contain histamine. Additionally, smooth muscle-contracting activity against the rat uterus was detected but this was shown not to be due to bradykinin, histamine, serotonin, or acetylcholine. In urticaria factitia histamine was regularly recovered from the perfusate; bradykinin was detected in perfusates from only two of eight subjects studied. Similar experiments carried out in a group of control subjects revealed evidence of low concentrations of kinins in a minority of subjects but no other pharmacological activity was found.
Background: In the present work, we studied the effect of cetirizine on the cytokine-stimulated immune response of human umbilical vein endothelial cells (HUVECs). Methods: Our research was directed to analyze the effect of preincubation of HUVECs with cetirizine (1 μg/ml) on (1) the TNFα-, IL-4- and IFNγ-induced surface expression of ICAM-1 and VCAM-1, (2) the secretion of IL-6 and IL-8, (3) the recruitment of NFκB and AP-1 and (4) the adhesion of histiocytic monocytes (U937) to activated endothelial monolayers. Results and Conclusion: Cetirizine exerts a stimulus-dependent pattern of regulatory action on various parameters of endothelial cell activation. In detail, cetirizine significantly reduces the expression of ICAM-1 and VCAM-1 paralleled by a reduced monocytic adhesion in particular to TNFα-activated HUVECs. With regard to the cytokine release, dual effects are obtained by cetirizine: IL-6 and IL-8 secretion is suppressed by cetirizine in TNFα and IL-4-activated cells, whereas the IFNγ-induced suppression of IL-8 is nearly abrogated. In this context, the TNFα-induced signal transduction with regard to NFκB and AP-1 was also suppressed by cetirizine.
ICAM-1, a transmembrane glycoprotein promoting adhesion in immunologic and inflammatory reactions, was found to be increased on nasal epithelial cells of patients with allergic rhinitis. Loratadinae, an H1-Mocker, was found to reduce in vitro the expression of ICAM-1 on nasal epithelial cells. A double-blind, parallel-group study was carried out during the pollen season to compare the effect of two H1-blockers, cetiraizine (10 mg OD) and loratadine (10 mg OD), on the release of soluble ICAM-1 in nasal secretions. A group of untreated patients was used as a control group. sICAM-1 was measured by enzyme immunoassay before and after 2 weeks of treatment. Symptoms were significantly decreased in the actively treated groups. sICAM-1 levels were unchanged in the control group but were significantly reduced in the two treated groups (P