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Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
ISSN: 1871-5230
Current Medicinal Chemistry
- Anti-Infective and Anti Allergy Agents
Volume 4, Number 5, October 2005
Contents
Antihistamines
Guest Editor: Esen Özkaya
Editorial Pp.449
Development of New H1 Antihistamines: The Importance
of Pharmacokinetics in the Evaluation of Safe and Therapeutically
Effective Agents Pp.451
Rhys Whomsley and Margherita Strolin Benedetti
[Abstract]
Action Mechanism of Antihistamines and the New Antihistamines
Pp.465
Neslihan Sendur and Meltem Uslu
[Abstract]
The Role of Antihistamines in the Management of Allergic
Rhinitis Pp.477
Murat Ünal and Günter Hafiz
[Abstract]
Use of Antihistamines in Ocular Therapy Pp.481
Acun Gezer
[Abstract]
Antihistamine Use in Dermatologic Disorders Pp.485
Emel Fetil
[Abstract]
New Oral Antihistamines in Pediatrics and Safety of
Antihistamines in Children Pp.495
Ülker Ones and Zeynep Tamay
[Abstract]
Adverse Systemic Reactions of Antihistamines: Highlights
in Sedating Effects, Cardiotoxicity and Drug Interactions
Pp.507
Tülin Ergun and Sadiye Kus
[Abstract]
Adverse Effects of Antihistamines on Skin Tests and
Antihistamines in Pregnancy Pp.517
Isil Kilinc and Sibel Alper
[Abstract]
Adverse Cutaneous Reactions of Systemic Antihistamines
Pp.521
Esen Özkaya
[Abstract]
General Articles
Implication for Thiazolidinediones (TZDs) as Novel
Potential Anti-Inflammatory Drugs Pp.531
H. Xu, D. Finas, F. Köster, G. Griesinger, M. Friedrich,
K. Diedrich and D. Hornung
[Abstract]
Inhibition of DNA Polymerase λ Suppresses 12
O- Tetradecanoylphorbol-13-Acetate-Induced Inflammation
Pp.543
Yoshiyuki Mizushina, Hiromi Yoshida and Kengo Sakaguchi
[Abstract]
Abstracts
[Back to top]
Editorial
Antihistamines are among the most commonly prescribed drugs
in the world. They are widely used in the treatment of conditions
such as urticaria and angioedema, seasonal and perennial rhinoconjunctivitis,
and pruritic diseases occurring in children and adults.
The first generation antihistamines are still widely available
and in use today since their first introduction more than
50 years ago. As these drugs have considerable sedative effects
that can interfere with the quality of life of patients, the
second generation antihistamines were introduced as nonsedating
alternatives. However, some of them have shown rare but lethal
cardiotoxic side effects. The third generation antihistamines
are metabolites of the earlier drugs with favourable pharmacokinetic
properties, and few adverse events.
This special issue of the journal deals with advances in
the development of the new antihistamines, mechanism of action
of the old and new antihistamines, their use in different
allergic and nonallergic conditions, principals of antihistamine
use in children and pregnancy, the systemic and cutaneous
adverse reactions of antihistamines as well as their adverse
effects on skin tests.
Antihistamines seem to be the mainstay of therapy of many
allergic conditions in the future, too. The considerable evolution
of new antihistamines is promising, and the improvement in
their clinical benefit / risk ratio will improve the quality
of life of patients.
Esen Özkaya, MD
Professor of Dermatology
Istanbul University, Istanbul Medical Faculty
Department of Dermatology
34093 Istanbul
Turkey
[Back to top]
Development of New H1 Antihistamines: The Importance
of Pharmacokinetics in the Evaluation of Safe and Therapeutically
Effective Agents
Rhys Whomsley and Margherita Strolin Benedetti
H1 antihistamines are widely used in the treatment
of allergic disorders. The CNS depressant and antimuscarinic
effects of the first generation compounds limited their use
in allergic disorders, and the second generation compounds
were developed to reduce or eliminate these effects. However,
the use of the first second generation H1 antihistamines,
terfenadine and astemizole, under certain circumstances, was
associated with adverse cardiac effects, which were occasionally
fatal and they were withdrawn from the market. This review
examines the pharmacokinetics of the second generation antihistamines
and the impact of the pharmacokinetic properties on their
efficacy and safety, particularly with regard to their effects
on the central nervous and cardiovascular systems and their
potential for interactions with concomitantly administered
drugs and dietary components.
[Back to top]
Action Mechanism of Antihistamines and the New Antihistamines
Neslihan Sendur and Meltem Uslu
Antihistamines have an important role in dermatology. In order
to understand how antihistamines work, effects of histamine
should be examined first. Histamine was first defined in 1920s
and was shown to take part in the pathogenesis of diseases
such as urticaria, anaphylaxis, asthma, and allergic rhinitis.
The main goal in the treatment of urticaria and other diseases
related to histamine is to keep this powerful mediator’s
effects under control. So many anti-histamines have been presented
to the market since 1942 and still, new compounds are being
developed. For years, an-tihistamines have been categorized
as first, second and third generation. In this text, a review
of the action mechanism of antihistamines and the new antihistamines
will be presented.
[Back to top]
The Role of Antihistamines in the Management of Allergic
Rhinitis
Murat Ünal and Günter Hafiz
Allergic rhinitis is a common disease worldwide and antihistamines
remain the mainstay of pharmacotherapy for allergic rhinitis.
Histamine is one of main mediators involved in the disease
pathophysiology. The primary mechanism of antihistamine action
is believed to be competitive antagonism of histamine receptors,
specifically the H1-receptors. These receptors
are present on nerve endings, smooth muscles, and glandular
cells. However, H1- antagonism may not be their
sole mechanism of action. Antihistamines have been used in
two forms; oral and topical, in the management of allergic
rhinitis. The use of the first-generation oral antihistamines
(chlorpheniramine, diphenhydramine, promethazine, tripolidine,
clemastine, and tripelennamine) is considerably limited by
their sedative and anticholinergic effects. The second-generation
antihistamines (acrivastine, astemizole, azelastine, cetirizine,
ebastine, fexofenadine, loratadine, mizolastine, and terfenadine)
are effective in reducing nasal symptoms, and have no sedative
effects. However, terfenadine, astemizole and recently, loratadine,
have been found to cause prolongation of the QT interval on
electrocardiogram, and can increase the risk for development
of potentially lethal ventricular tachyarrhythmias, or torsades
de pointes. The next-generation antihistamines (fexofenadine,
desloratadine, tecastemizole, and levocetirizine) are typi-cally
the structurally modified, active metabolites or isomers of
second-generation antihistamines. These agents retain the
non-sedating properties of second-generation antihistamines
while eliminating or limiting the cardiac risks. Topical antihistamines
(azelastine and levocabastine), delivered by nasal spray,
avoid or minimize systemic adverse effects. They have a rapid
onset of action (less than 15 min) at low drug dosage, but
their action is limited to the treated organ.
[Back to top]
Use of Antihistamines in Ocular Therapy
Acun Gezer
Approximately 20% of the general population have allergic
symptoms of various forms. One third of these people have
also ocular symptoms. Some forms of ocular allergy can cause
severe symptoms and result in significant ocular morbidity.
Allergic ocular disease consists of allergic conjunctivitis
(including seasonal hay fever and perennial allergic rhinocon-junctivitis
and acute anaphylaxis), giant papillary conjunctivitis (including
vernalis, atopic keratoconjunctivitis and con-tact lens induced
conjunctivitis), contact dermatokeratoconjunctivitis and microbioallergic
disease.
Histamine is the most prominent mediator in allergic ocular
disease and causes increased vasopermeability, vasodila-tion,
and bronchoconstriction, mediated through histamine receptors.
Both H1 and H2 receptors have been identified
on the ocular surface.
Oral H1-receptor blockers can be given to relieve
symptoms in the allergic ocular disease, but side effects
such as seda-tion and systemic anticholinergic reactions are
possible. Newer oral antihistamines such as astemizole and
terfenadine supposedly have lesser side effects. Topical H1-receptor
blocking antihistamine drugs are now available. Levocabastine
is an agent with proven efficacy. There are no topical H2-receptor
antagonists presently available for ocular use, but such agents
have theoretic potential, especially in combination with an
H1-receptor blocker
[Back to top]
Antihistamine Use in Dermatologic Disorders
Emel Fetil
Antihistamines can be used in various disorders of dermatology.
They are the mainstay of pharmacological therapy used in the
management of urticaria and angioedema. They are also important
in the management of atopic dermatitis, mastocytosis, eosinophilic
disorders, contact dermatitis and flushing. Pruritus associated
with other conditions such as lichen planus, pityriasis rosea,
lichen simplex chronicus, dermatomyositis, amyloidosis, nummular
dermatitis, exfoliative dermatitis, prurigo gravidarum, herpes
gestationis, pruritic urticarial papules and plaques of pregnancy,
ery-thema annulare centrifugum and erythema gyratum repens
may also be relieved by antihistamines. Sedative antihista-mines
may help patients to reduce pruritus in scabies, prurigo nodularis,
pruritus ani, lichen sclerosus and Grover dis-ease. In bedbug,
spider, human flea, bee, wasp, hornet or mosquito bites and
in autosensitization dermatitis besides topical antipruritic
agents, systemic antihistamines can be used against pruritus.
Also, antihistamines may relieve pruri-tus in infestations,
sponge dermatitis or cercarial dermatitis and can be used
in varicella infection. Antihistamines are often helpful for
relieving pruritus in exanthematous reactions to medications.
Pruritus secondary to underlying medical disorders or of an
idiopathic nature may also be relieved by these antihistamines,
although controlled trials do not exist.
[Back to top]
New Oral Antihistamines in Pediatrics and Safety of
Antihistamines in Children
Ülker Ones and Zeynep Tamay
H1 antihistamines are first line drugs in the treatment
of allergic rhinitis and chronic idiopathic urticaria and
widely used in children as well as in adults. Although first-generation
antihistamines are effective in relieving allergic symptoms,
they are not preferred because of their sedative side effects.
The earliest “second generation” antihistamines,
terfenadine and astemizole, non-sedating alternatives to the
first generation counterparts are not commonly used due to
their potential arythmogenic effects. The newer second-generation
antihistamines such as loratadine, fexofenadine, mizolastine,
ebastine, cetirizine, levocetirizine and desloratadine have
been shown to be efficacious and well tolerated with additional
anti-inflammatory effects and lacking cardiotoxic potential
activity in adults. The early treatment of atopic children
study, the long term clinical trial with cetirizine of infants
with atopic dermatitis demonstrated that ceti-rizine delayed
the onset of asthma in patients sensitized to grass pollen
or house dust mite; and also reduced the dura-tion and the
amount of topical steroids used in the treatment of atopic
dermatitis. In the Preventia I study, which was de-signed
to evaluate the efficacy of loratadine in reducing the number
of respiratory infections in young children at risk of recurrent
infections, loratadine was not found to be significantly different
from placebo. Both drugs were found to have a similar safety
profile to that of placebo confirming their long-term use
in infants and children. Pediatric formulation of desloratadine,
which has favorable effect on nasal congestion, is marketed
worldwide now. The effectiveness of new an-tihistamines in
the treatment of urticaria in pediatric age group is based
on extrapolation of adult studies performed in this area.
Further studies with new antihistamines are needed for their
evidence-based use in children with urticaria and atopic dermatitis.
[Back to top]
Adverse Systemic Reactions of Antihistamines: Highlights
in Sedating Effects, Cardiotoxicity and Drug Interactions
Tülin Ergun and Sadiye Kus
Antihistamines are already among the most frequently used
pharmaceutical compounds and with the predictable increase
of the prevalence of atopic disease, even more patients are
expected to use them in future. Though the common belief on
their safety has existed since some decades, they, including
the over the counter ones, might potentially bear serious
side effects. Thus , the following article focuses on the
adverse effects of antihistamines by summarizing the current
data mainly on central nervous system and cardiovascular side
effects. Meanwhile, less common side effects, and important
issues like their use in pregnancy and lactation are also
included. Updated information is provided on drug interactions
and overdose situations along with their management. As a
finalstep, pitfalls in choosing suitable antihistamine/s in
special circumstances to avoid adverse effects are also covered.
[Back to top]
Adverse Effects of Antihistamines on Skin Tests and
Antihistamines in Pregnancy
Isil Kilinc and Sibel Alper
Allergy skin tests are the best and most reliable method
of diagnosing allergies. Medications may influence the interpretation
of skin testing. Antihistamines interfere with prick and intradermal
skin tests, while they do not suppress patch tests. Some other
medications also have influence on allergy skin tests. It’s
important to know the suppression mechanism and the duration
of the inhibitory effect of these drugs on the skin test to
get correct interpretation, which would be a valuable guide
in allergen identification and avoidance in treatment of allergies.
Allergic diseases are common and bothering medical problems
in pregnant patients. It’s generally recommended to
avoid all medications during pregnancy, if possible. But sometimes
antihistamines are needed to be used in the treat-ment of
allergic diseases regarding the benefit/risk ratio. In such
cases, antihistamines should be carefully chosen. Con-sidering
the animal and human data available, chlorpheniramine seems
to be the antihistamine to choose with the least risk.
[Back to top]
Adverse Cutaneous Reactions of Systemic Antihistamines
Esen Özkaya
Cutaneous adverse reactions to systemic antihistamines are
rare but an important finding. The reaction may vary from
an eczematous eruption as the most frequent type, to rare
but severe reactions such as urticaria / angioedema, erythema
multiforme / Stevens-Johnson syndrome or Lyell syndrome. This
is a review of the reported types of cutaneous adverse reactions
due to systemically administered old and new antihistamines.
[Back to top]
Implication for Thiazolidinediones (TZDs) as Novel
Potential Anti-Inflammatory Drugs
H. Xu, D. Finas, F. Köster, G. Griesinger, M. Friedrich,
K. Diedrich and D. Hornung
PPAR-γ
(peroxisome proliferator activated receptor gamma) mediates
ligand-dependent transcriptional activation and repression.
PPAR-γ
was shown to be directly activated by naturally occurring
fatty acids and several synthetic compounds such as thiazolidinediones
(TZDs), agonists of PPAR-γ.
TZDs are used in the first place as orally active antidiabetic
agents in the treatment of type 2 diabetes. Lately, it has
been implicated that TZDs might also serve as regulators of
inflammatory diseases. TZDs inhibit the production of monocyte
inflammatory cytokines such as RANTES, TNF-α,
IL-6 and IL-1β
in vitro and reduce plasma concentrations of TNF-α,
sICAM-1, MCP-1, CRP and PAI-1 in vivo. TZDs can also
stimulate the secretion of IL-6, IL-8 and CSF-1 in a cultured
human endometrial cell line (EM42), which suggested a role
of PPAR-γ
in the pathogenesis of endometriosis.
Although TZDs are not currently in clinical use as anti-inflammatory
drugs, more recent observations were done to show that TZDs
act as anti-inflammatory substances in several diseases. TZDs
have anti-inflammatory, antiatherogenic and anti-oxidative
stress effects reducing the incidence and severity of atherosclerosis
and can reduce blood pressure. TZDs may be of therapeutic
benefits in patients with Alzheimer’s disease (AD) based
on convergent findings that insulin also plays a role in aspects
of CNS function.
It has been confirmed that TZDs can prevent progressive cavitation
by limiting inflammation subsequent secondary damage after
CNS trauma in vivo and in vitro. TZDs can
also prevent experimental autoimmune encephalomyelitis. The
beneficial effects of TZDs in some autoimmune or atopic diseases,
such as multiple sclerosis (MS), psoriasis, atopic dermatitis
and asthma, and a common chronic liver disease, nonalcoholic
steatohepatitis (NASH) have been shown in several clinical
trials.
There are some recent data demonstrating that TZDs may have
anti-inflammatory properties in animal models and in cellular
systems of other diseases such as inflammatory bowel disease,
arthritis, glomerulonephritis, sepsis, chronic ob-structive
pulmonary disease (COPD) and endometriosis.
All of the above mentioned results reveal a novel potential
anti-inflammatory pathway of TZDs in these diseases.
[Back to top]
Inhibition of DNA Polymerase λ Suppresses
12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammation
Yoshiyuki Mizushina, Hiromi Yoshida and Kengo Sakaguchi
We found that compounds, which can selectively inhibit the
activity of mammalian DNA polymerase λ
(pol λ)
in vitro, show an anti-12-O-tetradecanoylphorbol-13-acetate
(TPA)-induced inflammatory effect in mice. Originally, we
screened selective inhibitors for each of the mammalian DNA
polymerases, and found two novel pol λ-inhibitors,
phenolic compounds termed petasiphenol and curcumin (diferuloylmethane).
Curcumin is known as an anti-chronic inflammatory agent and
structurally quite similar to petasiphenol. The IC50
values of petasiphenol and curcumin for pol λ
were 7.8 μM
and 7.0 μM,
respectively, and neither compound influenced any other mammalian
DNA polymerases. Expectedly, petasiphenol also showed an anti-TPA-induced
inflammatory effect. A relationship between the pol λ-inhibition
and the anti-inflammatory activity is suggested. Therefore,
we investigated whether other anti-inflammatory compounds
such as terpeno benzoic acids, triterpene acids and epolactaene
derivatives could be pol λ-inhibitors.
Although all the compounds influenced not only several different
DNA polymerase species but DNA topoisomerase II, they all
most efficiently inhibited the pol λ-activity.
These results unexpectedly suggest that there is a physiological
relationship between pol λ
inhibition and anti-TPA-induced inflammation. This finding
may provide insight into the molecular mechanism of TPA-induced
inflammation, or neoplastic promotion.
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