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Оториноларингология
Zebo Raximberdievna Djabbarova
Assistant of the Department of Normal Physiology
Samarkand State Medical Institute
yokubjon1994@mail.ru
COMBINATION THERAPY FOR ALLERGIC RHINITIS: SEARCH FOR THE OPTIMAL
SOLUTION
For citation:
Zebo Raximberdievna DJABBAROVA COMBINATION THERAPY FOR
ALLERGIC RHINITIS: SEARCH FOR THE OPTIMAL SOLUTION
.
Journal of Biomedicine and
Practice. 2021, vol. 6, issue 1, pp.110-117
http://dx.doi.org/10.26739/2181-9300-2021-1-16
ANNOTATION
Allergic rhinitis is a disease that is based on IgE-mediated inflammation of the nasal mucosa (caused
by allergens), characterized by at least two of the following symptoms daily: nasal congestion, nasal
discharge (rhinorrhea), sneezing, itching in the nasal cavity. Allergic rhinitis is often combined with
other allergic diseases, such as bronchial asthma, allergic conjunctivitis, atopic dermatitis, and
certainly is a global medical and social problem. Although allergic rhinitis is a serious, life-
threatening disease, nevertheless, its medical and social significance is due to its high prevalence
among children, adolescents and adults, especially in combination with acute and chronic sinusitis,
otitis media and bronchial asthma.
Key words:
allergic rhinitis, bronchial asthma, antihistamines, oral antihistamines, long-term and
intensive treatment, diagnosis of allergic rhinitis.
Зебо Раксимбердиевна Джаббарова
Ассистент кафедры нормальной физиологии
Самаркандский Государственный Медицинский Институт
yokubjon1994@mail.ru
КОМБИНИРОВАННАЯ ТЕРАПИЯ АЛЛЕРГИЧЕСКОГО РИНИТА: ПОИСК
ОПТИМАЛЬНОГО РЕШЕНИЯ
АННОТАЦИЯ
Аллергический ринит - это заболевание, в основе которого лежит IgE-опосредованное
воспаление слизистой оболочки носа (вызываемое аллергенами), которое ежедневно
характеризуется как минимум двумя из следующих симптомов: заложенность носа, выделения
из носа (ринорея), чихание, зуд в полости носа. . Аллергический ринит часто сочетается с
другими аллергическими заболеваниями, такими как бронхиальная астма, аллергический
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конъюнктивит, атопический дерматит, и, безусловно, представляет собой глобальную
медицинскую и социальную проблему. Хотя аллергический ринит - серьезное, опасное для
жизни заболевание, тем не менее его медицинское и социальное значение связано с его
высокой распространенностью среди детей, подростков и взрослых, особенно в сочетании с
острым и хроническим синуситом, средним отитом, бронхиальной астмой.
Ключевые слова:
аллергический ринит, бронхиальная астма, антигистаминные препараты,
пероральные антигистаминные препараты, длительное и интенсивное лечение, диагностика
аллергического ринита.
Zebo Raximberdievna Djabbarova
Normal fiziologiya kafedrasi assistenti
Samarqand davlat tibbiyot instituti
yokubjon1994@mail.ru
ALLERGIK RINIT UCHUN KOMBINASION DAVOLASH: OPTIMAL DAVOLASH
YO'LLARINI IZLASH
ANNOTATSIYA
Allergik rinit - bu burun shilliq qavatining IgE vositachiligidagi yallig'lanishiga (alergenlardan kelib
chiqqan holda) asoslangan kasallik bo'lib, har kuni quyidagi belgilarning kamida ikkitasi bilan
tavsiflanadi: burun tiqilishi, burun oqishi (rinoreya), aksirish, burun bo'shlig'ida qichishish. Allergik
rinit ko'pincha boshqa allergik kasalliklar, masalan, bronxial astma, allergik konyunktivit, atopik
dermatit bilan birlashtiriladi va bu global tibbiy va ijtimoiy muammo hisoblanadi. Allergik rinit
jiddiy, hayot uchun xavfli kasallik bo'lsada, uning tibbiy va ijtimoiy ahamiyati bolalar, o'spirinlar va
kattalar orasida, ayniqsa, o'tkir va surunkali sinusit, otitis media, bronxial astma bilan birgalikda
tarqalishining yuqori darajasi bilan bog'liq.
Kalit so'zlar:
allergik rinit, bronxial astma, antigistaminlar, og'iz antigistaminlari, uzoq muddatli va
intensiv davolash, allergik rinit diagnostikasi.
Introduction.
The prevalence of allergic rhinitis is from 10 to 40% of the population, and
every year the number of patients suffering from this disease is increasing. According to
epidemiological studies, in different regions of Russia 13.9–35% of the population suffer from
allergic rhinitis, in England - 16%, in Denmark - 19%, in Germany - 17%. An increase in the
prevalence of allergic rhinitis is associated with factors such as changes in lifestyle and diet [1, 2].
The minimal persistence of allergic inflammation of the nasal mucosa leads to more frequent viral
and colds, which, in turn, contributes to an increase in the number of patients requiring long-term and
intensive treatment, including in a hospital setting [1, 2].
Material and Methods:
Allergic rhinitis undoubtedly reduces the quality of life of patients
and motivates them to seek help from doctors of all specialties. All specialists should be aware that
for the correct diagnosis of allergic rhinitis and the appointment of adequate therapy, it is necessary
to conduct an allergic examination to identify a causal allergen. The cause of allergic rhinitis in the
overwhelming majority of cases are household, epidermal, pollen allergens, spores of lower fungi,
insect particles that enter the div by inhalation. Unfortunately, we have to state a significant
underdiagnosis of allergic rhinitis in modern society, patients are treated symptomatically for a long
time, without a correct diagnosis, only 18% of patients are referred to a specialist within the first year
from the onset of the disease [3].
On the recommendation of WHO experts, patients with persistent allergic rhinitis should be
screened for the presence of bronchial asthma. The main objectives in the treatment of allergic rhinitis
are: achieving and maintaining control of the disease, eliminating symptoms, reducing the risk of
complications and improving the quality of life of patients. Treatment of allergic rhinitis implies an
integrated approach, while it is necessary to take into account the course, the severity of symptoms,
individual social and psychological characteristics of the patient, concomitant pathology.
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Allergic rhinitis is a common allergic condition. There are a variety of pharmacologic
treatments, including antihistamines, oral decongestants, and intranasal corticosteroids. Leukotrienes
cause significant nasal obstruction. Leukotriene receptor antagonists decrease symptoms and improve
quality of life in patients with seasonal allergic rhinitis. Similar to antihistamines, antileukotrienes
appear to be less efficacious than nasal corticosteroids.
Combination therapy of histamine and leukotriene antagonists produces symptomatic
improvement as well as improved quality of life. Areas of study for combination antimediator therapy
include expanding the initial findings with regard to nasal steroids, investigation of patient preference
and compliance, use in perennial allergic rhinitis, and treatment of "one airway," i.e., treatment of
concurrent allergic rhinitis and asthma.
Since their introduction in the 1940s, antihistamines (AHs) have been the most utilized class
of medications for the treatment of AR. First-generation AHs are associated with adverse central
nervous system (CNS) and anticholinergic side effects. On the market in the 1980s, newer generation
AHs have improved safety and efficacy. Compared to antihistamines, intranasal corticosteroids
(INCS) have significantly greater efficacy but longer onset of action. Intranasal AH and INCS
combinations offer a single medication option that offers broader disease coverage and faster
symptom control. However, cost and twice-per-day dosing remain a major limitation. Allergen
immunotherapy (AIT) is the only disease-modifying option and can be provided through
subcutaneous (SCIT) or sublingual (SLIT) routes. While SCIT has been the definitive management
option for many years, SLIT tablets (SLIT-T) have also been proven to be safe and efficacious.
Antihistamines
For more than 72 years, antihistamines have been used for allergic rhinitis. The pathogenetic
rationale for their use is the participation of histamine in allergic inflammation as the main mediator
with a wide spectrum of biological activity. There are two groups of antihistamines - first and second
generation. First generation antihistamines include: hydroxyzine, diphenhydramine, hifenadine,
clemastine, mebhydroline, promethazine, chloropyramine.
Allergic rhinitis (AR) is an IgE-mediated inflammatory disease of the nasal mucosa, triggered
by exposure to airborne allergens. It is estimated to afflict almost 25% of Canadians and has a
significant impact on sleep, work, and school performance. AR is often associated with atopic
dermatitis, food allergy, and asthma; this allergic disease progression known as the atopic march [2].
Symptoms primarily include rhinorrhea, nasal blockage, and sneezing, though ocular symptoms can
also occur. In Canada, AR tends to be classified as either seasonal (SAR) or perennial (PAR) [3].
Standard of care for AR includes a treatment plan that considers patient preferences, the
severity of the disease, and most essentially involves a shared decision-making process between
patient and provider. Diagnosing AR and finding a care plan should consist of in-depth patient history,
physical exam, and skin test to confirm allergies . The patient’s history should include evaluating
nasal and ocular symptoms such as rhinorrhea, nasal itching, sneezing, allergic conjunctivitis, and
nasal congestion . The timing of the onset of symptoms is essential in determining which allergens
are suspect. A comprehensive review of concomitant medications such as nonsteroidal anti-
inflammatory drugs, angiotensin converting enzyme (ACE) inhibitors, beta-blockers, and intranasal
decongestants helps diagnose or rule out other causes of rhinitis . Concomitant atopic diseases such
as asthma must be assessed as up to 40% of patients with allergic rhinitis, also have asthma .
Oral antihistamines
For decades, AHs have been the most utilized class of medications for the treatment of AR.
AHs are inverse agonists; that is, they target H1 receptors (H1 antihistamines) at binding sites that
are different from those of histamine [10]. There are two generations of oral antihistamines (first-,
and newer-generation AHs), with newer-generation AHs being an improvement of their predecessor.
First-generation AHs, such as diphenhydramine are associated with adverse central nervous system
(CNS) side effects, including sedation and mental impairment, as well as anticholinergic side effects
such as dry mouth, dry eyes, urinary retention, and constipation. Newer generation H1-antihistamines
are safer than first-generation agents and should be the first-line antihistamines for the treatment of
allergic rhinitis. However, for reasons that are discussed elsewhere, both patients and practitioners
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continue to select first-generation AHs. This section aims to review the recognized risks of first-
generation AH and to explore recent advances in newer generation AHs.
Adverse effects of first-generation AHs
The adverse effects associated with first-generation AHs have been reported since their
introduction in the 1940s. Currently, it is well-known that these drugs have poor receptor selectivity
and can bind non-selectively to several receptors in the div, including antimuscarinic-, anti-
serotonin-, and anti-α-adrenergic receptors as well as cardiac potassium channels.
First-generation AHs can also cross the blood–brain barrier (BBB) and bind H1-receptors on
neurons throughout the CNS and, therefore, may cause drowsiness, sedation, somnolence, and fatigue
leading to impairment of cognitive function, memory, and psychomotor performances. The strong
sedative qualities of older, first-generation AHs are why they are used as sleep aids. Paradoxically,
the same dose is utilized to promote sleep as is used to relieve rhinitis symptoms.
Long-term, randomized, controlled studies of the safety of first-generation antihistamines are
limited. However, many studies outline the association of these drugs with transportation-related
injuries and fatalities. A recent review of toxicology tested profiles from 6677 fatally injured civil
aviation pilots in the US from 1990 to 2012. In this study diphenhydramine was the most common
drug found on autopsy capable of causing impairment (7.3%) [17]. As a result, first-generation AHs
are now banned for use by commercial and military pilots before or during flights.Cardiac toxicity
was previously an under-recognized risk of first-generation AHs. Diphenhydramine and hydroxyzine
interfere with cardiac potassium channels involved in action potential repolarization. As a
consequence, these drugs may cause dose-related prolongation and a form of polymorphic ventricular
dysrhythmia called ‘torsade de pointes’.
The studies published to date demonstrate that leukotriene receptor antagonists are sometimes
more effective than placebo, are no more effective than nonsedating antihistamines, and are less
effective than intranasal corticosteroids in the treatment of allergic rhinitis. The combination of a
leukotriene receptor antagonist and an antihistamine has not been proven to be more effective than
either agent alone. This review reveals several inconsistencies that require resolution. First, whereas
leukotriene receptor antagonists are predicted on the basis of their mechanism of action to improve
nasal congestion significantly, clinical studies reveal leukotriene receptor antagonists to be no better
than antihistamines at improving congestion. Second, leukotriene receptor antagonists would not be
expected on the basis of their putative mechanism of action or nasal challenge data to improve
significantly sneezing, nasal itching, or drainage. However, some studies show improvement in these
symptoms during treatment with leukotriene receptor antagonists. Considered in aggregate, the data
available to date do not clearly support a unique role of leukotriene receptor antagonists in the
treatment of allergic rhinitis whether or not it is accompanied by asthma. They are characterized by
low selectivity for H1 receptors and a short duration of action (within 4-12 hours). These properties
are due to competitive and rapidly reversible binding to receptors and force the use of first-generation
antihistamines in higher doses of 3-4 r. / Day to achieve a clinical effect. Second-generation
antihistamines include acrivastine, loratadine, cetirizine, ebastine, rupatadine, bilastine - highly
selective drugs with a duration of 18-24 hours. Also, second-generation drugs include active
metabolites of known molecules: desloratadine, a metabolite of loratadine and rupatadine,
levocetirizine, active isomerzine. cetirizine and fexofenadine are a metabolite of terfenadine.
The advantage of active metabolites is not only high selectivity, but also the absence of
sedative and cardiotoxic effects. Second-generation antihistamines bind noncompetitively to H1-
receptors, forming a ligand-receptor complex, which slowly dissociates, which causes a long half-life
of the drug, allowing it to be used 1 r. / Day. One of the effective and safe antihistamines of the second
generation is levocetirizine. Levocetirizine is a highly selective and potent antihistamines, is rapidly
absorbed in the intestine, reaching a maximum plasma concentration in 0.5-1.0 hours after
administration. Unlike most antihistamines of the first and second generation, levocetirizine shows
systemic oral bioavailability of more than 77%, which indicates that the drug almost completely
enters the systemic circulation. Levocetirizine is not metabolized in the liver and does not interact
with cytochrome P450, therefore it has no competitive drug interactions. This makes it possible to
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combine it with antibiotics, antifungal and other drugs and use it in patients with liver pathology. The
ability to bind and the duration of communication with the H1-receptor in levocetirizine is 2 times
higher than the affinity of cetirizine and approximately 30 times higher than the affinity of
dextrocetirizine [4].
In the human div, levocetirizine does not undergo inversion, i.e., dextrocetirizine is not
formed, which indicates the stability of the substance. Levocetirizine is 600 times more selective for
H1 receptors than for other receptors and ion channels that are structurally similar, such as H2-, H3-
, β- and β-adrenergic receptors, 5-HT1A and 5-HT2, dopamine D2, adenosine A1 and muscarinic
receptors. Due to this, the drug has practically no anticholinergic and antiserotonin activity [5]. The
listed parameters indicate the optimal pharmacokinetic profile of levocetirizine and determine its high
clinical efficacy and high level of safety.
There have been many clinical studies proving the clinical efficacy and safety of
antihistamines, where a pronounced positive effect on the severity of AR and the quality of life of
patients was noted. The XPERT (Xyzal PErsistent Rhinitis Trial) study found that levocetirizine is
highly effective and reduces the cost of long-term treatment. Also, when AR was combined with BA,
the number of asthma attacks in the group of patients receiving levocetirizine significantly decreased
[6].
Leukotriene receptor antagonist
: For the treatment of AR, montelukast, a representative of
the group of leukotriene receptor antagonists, can also be used, a highly effective drug that
significantly improves inflammation indicators. Montelukast is rapidly and almost completely
absorbed after oral administration. Regular food intake does not affect bioavailability and maximum
plasma concentration. In adults, when taken on an empty stomach, montelukast is in the form of film-
coated tablets at a dosage of 10 mg, the maximum concentration in the blood is reached after 3 hours.
The oral bioavailability of the drug is 64%. Montelukast is actively metabolized in the liver.
It is assumed that cytochrome P450 CYP isoenzymes (3A4 and 2C9) are involved in the metabolism
of montelukast, while montelukast does not inhibit cytochrome P450 CYP isoenzymes in therapeutic
concentrations: 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6 [7]. in diseases of both the upper and lower
respiratory tract, it may be especially useful for patients suffering from AR in combination with BA.
According to a retrospective study by Borderias et al., Montelukast was added to patients with asthma
in combination with AR in addition to the previously prescribed basic therapy. According to the
results of this work, the high efficiency of this therapeutic strategy has been confirmed in the form of
better control over the clinical manifestations of both BA and AR [8].
Despite the significant progress in understanding the pathogenesis of the disease, one cannot
but take into account such an important component of the treatment process as adherence to treatment.
(compliance), that is, the correct fulfillment by the patient of all the doctor's recommendations on
drug treatment, non-drug procedures, lifestyle changes, etc. Previously, it was believed that each
patient actively fulfills the doctor's prescriptions, which in most cases was true. However, the situation
gradually changed, and, according to a number of authors, cases of non-compliance with the
recommendations received by patients have become more frequent [9].
Results and discussion:
According to WHO estimates, about half of all patients do not follow
the recommendations of medical professionals, which complicates treatment. The reasons for not
following the recommendations are different: partial or complete refusal of treatment, irregular
medication due to the upcoming side effects [9]. It is possible to significantly improve compliance if
we take into account the individual characteristics of the patient, optimize the intake of the drug,
reduce the frequency while maintaining efficiency and use fixed combinations.
Intranasal antihistamines
One concern regarding oral antihistamines (OAHs) is the possibility that OAHs cannot reach
high enough concentrations in the nasal mucosa following oral administration to inhibit histamine-
stimulated cytokine release and other mediators of early- and late-phase allergic reactions. Intranasal
antihistamines (INAHs) ensure drug delivery to the nasal mucosa, enhancing local anti-allergic and
anti-inflammatory effects while minimizing systemic exposure to therapy. The 2016 ARIA guidelines
recommend using intranasal antihistamines (e.g., olopatadine, and levocabastine) in intermittent but
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not persistent AR .While azelastine (AZE) is the most well-studied INAH, it is not available in
Canada. However, levocabastine hydrochloride nasal spray (LEVO), another INAH, is available in
Canada (see Table 1 for clinical usage information) and has shown to be equivalent to AZE in terms
of efficacy and safety. In a recent multicenter, randomized, double-blind, parallel-group trial, 244
patients with moderate-to-severe allergic rhinitis were randomized to receive either AZE (0.1%) or
LEVO for 14 consecutive days. Statistically significant changes from baseline in TNSS were seen in
both treatment groups. No significant differences were seen between the two groups in terms of
evaluation of therapeutic effect, total effective rate, and onset of action, except for a higher symptom
relief rate in the LEVO group than the AZE group within 30 min of administering the first dose.
Adverse reactions were mild to moderate, with an incidence of 0.9% for LEVO and 2.5% for AZE.
In short, while intranasal antihistamines are safe and effective, only one is available in Canada and is
often hard to obtain currently.
Intranasal corticosteroids
ARIA guidelines recommend INCS as the best option for both mild and moderate to severe
AR in both children and adults . INCS inhibit the early and late-phase allergic in AR by preventing
the recruitment of immune cells, and the release of inflammatory mediators from cells involved in
the pathophysiology of AR . Many INCS have been approved since the introduction of
beclomethasone in the late 1970s . All of the INCS currently available are efficient in controlling
symptoms of AR, such as nasal congestion and itching, rhinorrhea, and sneezing .To differentiate
products involves factors such as cost, ease of dosing, and sensory issues, such as aroma and taste,
which can affect patient preference . As will be described in more detail below, the significant
disadvantages of INCS are patient adherence and the length of time they take to reach maximal effect.
Safety of intranasal corticosteroids
INCS are less likely to display the systemic effects of oral steroids such as growth suppression,
and ocular effects, due to reduced exposure and lower bioavailability. However, INCS are associated
with mild to moderate local adverse effects. These include, epistaxis, nasal drying, burning, and
stinging sensations. The literature examining the risk of development of glaucoma and/or cataracts
from the use of INCS is also complex and controversial. While it is clear that inhaled and oral
corticosteroid use is associated with high long-term risks of cataract development.the potential risk
of cataracts with the use of nasal corticosteroids is more complex. Recently, a systematic review
assessed whether the use of INCS is associated with increased intraocular pressure (IOP) above
20 mm Hg, glaucoma, or formation of posterior subcapsular cataracts in adult patients with rhinitis
.A total of 484 studies were identified with 10 randomized controlled trials meeting the inclusion
criteria. Meta-analysis of 2226 patients revealed that the use of INCS is not associated with a
significant risk of elevating IOP or developing a posterior subcapsular cataract in patients with
allergic rhinitis. The absolute increased incidence of elevated IOP in patients using INCS compared
to placebo was 0.8% (95% CI 0 to 1.6%). There were zero cases of glaucoma in both placebo and
INCS groups at 12 months. Future studies should formally evaluate for glaucoma rather than use IOP
measures as a surrogate.
Efficacy of intranasal corticosteroids
Compared to placebo and antihistamines, INCS have significantly greater efficacy .This is
further demonstrated in a systematic review comparing the efficacy of INCSs and OAHs that
analyzed 5 controlled trials with a total of 990 patients. INCS were superior to OAHs in improving
total nasal symptoms score and in relieving nasal obstruction, rhinorrhea, nasal itching, sneezing, and
quality of life mean difference. However, there was no difference in relief of ocular symptoms
.Similarly, Carr et al., compared the efficacy of AZE and fluticasone propionate (FP) in SAR via a
post hoc analysis of data from a previously published direct-comparison study.
Intranasal antihistamine and intranasal corticosteroid combination
It is evident that no single medication class is without limitations (Table 1). The 2016 update
of the ARIA guidelines does suggest (with low to moderate certainty) that combination treatment
with an OAH or INAH and an INCS may be appropriate for patients with SAR. Indeed, the concurrent
use of an INCS and INAH has provided benefits over monotherapy in patients with moderate-severe
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SAR. The efficacy and safety of AZE/FP have been assessed in several controlled clinical studies.
One 14-day SAR study compared AZE/FP with formulation- and device-matched AZE and FP. The
AZE/FP combination provided greater overall nasal symptom relief than either FP, AZE, or placebo.
More AZE/FP-treated patients achieved a 50% reduction in their overall nasal symptom burden. They
did so many days earlier than those treated with FP or AZE.
The combination had an onset of action of 30 min, and the clinical benefit was observed during
the first day of assessment and sustained over the entire course of treatment. AZE/FP was also
compared to commercially available FP (Flonase generic) and AZE (Astelin
®
), respectively. The
treatment difference was more considerable. When nasal and ocular symptoms were combined,
AZE/FP was more than twice as effective as either FP or AZE. Likewise, patients reached a 50%
reduction in their overall nasal symptom burden one week faster than those treated with FP or AZE.
The long-term safety of AZE/FP has been evaluated in subjects with PAR or vasomotor rhinitis. There
were no safety findings that would preclude the long-term use of AZE/FP in the treatment of allergic
rhinitis .In patients who do not respond to INCS, a combination INAH/INCS should be considered,
assuming cost is not prohibitive to the patient. Entropy or entopic end type is a new phenomenon
discovered in allergology and immunology several years ago [6]. As our investigations showed,
almost all parameters were the same as in healthy persons, and there are no systemic allergy signs.
Nowadays, clinicians such as ENT specialists and lung physicians are involved in a discussion related
to the diagnosis, treatment, and the relationship between local allergy and conventional or systemic
allergy. Currently, the term "local rhinitis" is widely used, whereas there are only two references to
"local asthma" [9, 10]. However, a positive response in "non-allergic" severe asthma was described
[11, 12] that demonstrated the presence of atopic IgE-dependent inflammation in such patients.
Atopic conditions are characterized by heterogeneity and may accompany the covert or
clinical food sensitization, which enables down regulating the course of any atopic disease. The
identification of atopic end types will promote and drive innovative developments in both allergen-
specific immunotherapy and anti-inflammatory approaches, including severe asthma.
Conclusion
AR remains an urgent problem due to its high prevalence, negative impact on the quality of
life and frequent combination with other allergic diseases, including BA. Modern diagnostics and
treatment of AR are an important area in the practice of doctors of many specialties: therapists,
allergists, otorhinolaryngologists. Identification of allergic factors will allow diagnosing AR and
choosing adequate prophylaxis and therapy, which will significantly improve the prognosis of the
disease as a whole. The results of clinical studies have shown the high efficacy of levocetirizine and
montelukast in the treatment of patients with AR, which makes it possible to include these drugs in
therapy regimens. The possibility of using combined drugs with a single dosage regimen helps to
achieve high adherence to treatment, increase doctor-patient cooperation. Thus, Montlesir is a
promising drug that significantly expands the possibilities of choosing a doctor and patient in AR
therapy.
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Brenner J.S. et al. Asthma and obesity in adolescents: is there an association? // Asthma. – 2001
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