Molecular mechanisms and pharmacogenetic determinants of II–III generation antihistamines efficacy in allergic bronchial asthma: personalized therapy prospects

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Abstract

Introduction. Allergic bronchial asthma (BA) is accompanied by activation of histamine H1/H4 receptors and variable response to antihistamines.

The aim of this review is to analyze the molecular mechanisms of action of second- and third-generation antihistamine drugs, their pharmacokinetic features and pharmacogenetic aspects of application in bronchial asthma, as well as prospects for developing new drugs with improved characteristics.

Methods. Narrative review of the literature (PubMed/Scopus, 2019–2024), including data from cryo-EM structures of the H4 receptor, single-cell RNA-seq profiles of bronchial epithelium and clinical pharmacogenetic studies of the CYP family (41 sources).

Results. Key signaling pathways (FcεRI–MAPK/NF-κB, IL-13/STAT6) indirectly targeted by H1 blockers have been identified. Increased HRH4 expression in IL-13^high Th2 clusters has been shown to correlate with asthma severity. Modern cryo-EM models of H4R have allowed us to refine the architecture of binding sites and optimize the design of promising ligands. CYP2D6 and ABCB1 polymorphisms account for up to 30–50% of interindividual variability in plasma concentrations of loratadine/desloratadine and bilastine according to clinical cohort data.

Conclusion. Integration of omics data and pharmacogenetic testing opens the way to targeted and personalized asthma therapy with antihistamines.

About the authors

Elena A. Borodulina

Federal State Budgetary Educational Institution of Higher Education “Samara State Medical University” of the Ministry of Healthcare of the Russian Federation

Author for correspondence.
Email: borodulinbe@yandex.ru
ORCID iD: 0000-0002-3063-1538

Doctor of Medical Sciences, Professor, Head of the Department of Phthisiology and Pulmonology

Russian Federation, Chapaevskaya, 99, Samara, 443099

Elena V. Yakovleva

Federal State Budgetary Educational Institution of Higher Education “Samara State Medical University” of the Ministry of Healthcare of the Russian Federation

Email: elena130894@mail.ru
ORCID iD: 0000-0003-1858-5206

Candidate of Medical Sciences, Assistant of the Department of Phthisiology and Pulmonology

Russian Federation, Chapaevskaya, 99, Samara, 443099

Boris E. Borodulin

Federal State Budgetary Educational Institution of Higher Education “Samara State Medical University” of the Ministry of Healthcare of the Russian Federation

Email: borodulinbe@yandex.ru
ORCID iD: 0000-0002-8847-9831

Doctor of Medical Sciences, Professor; Professor of the Department of Phthisiology and Pulmonology

Russian Federation, Chapaevskaya, 99, Samara, 443099

Elena P. Gladunova

Federal State Budgetary Educational Institution of Higher Education “Samara State Medical University” of the Ministry of Healthcare of the Russian Federation

Email: e.p.gladunova@samsmu.ru
ORCID iD: 0000-0002-8137-7197

Doctor of Pharmaceutical Sciences, Professor; Professor of the Department of Pharmacy Management and Economics

Russian Federation, Chapaevskaya, 99, Samara, 443099

Sevara D. Marchenko

Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)

Email: marchenko_s_d@staff.sechenov.ru
ORCID iD: 0000-0002-0177-6826

Candidate of Pharmaceutical Sciences, Associate Professor of the Department of Organization and Management in the Field of Drug Circulation, Institute of Professional Education

Russian Federation, Trubetskaya str., 8, build. 2, Moscow, 119048

Olga V. Krylova

Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)

Email: krylova_o_v@staff.sechenov.ru
ORCID iD: 0000-0002-0552-639X

Candidate of Pharmaceutical Sciences, Associate Professor of the Department of Pharmacy, A.P. Nelyubin Institute of Pharmacy

Russian Federation, Trubetskaya str., 8, build. 2, Moscow, 119048

Elza R. Mamontova

Federal State Autonomous Educational Institution of Higher Education “Russian National Research Medical University named after N.I. Pirogov” of the Ministry of Health of the Russian Federation

Email: elza.mamontova@mail.ru
ORCID iD: 0000-0001-8199-2053

Candidate of Pedagogical Sciences, Associate Professor of the Department of Pharmacy, Institute of Pharmacy and Medical Chemistry

Russian Federation, Ostrovityanova str., 1, Moscow, 117997

Anastasia R. Rekalo

Federal State Autonomous Educational Institution of Higher Education “Russian National Research Medical University named after N.I. Pirogov” of the Ministry of Health of the Russian Federation

Email: rekalonastya@gmail.com
ORCID iD: 0009-0008-7211-4134

5th year student

Russian Federation, Ostrovityanova str., 1, Moscow, 117997

Zarina R. Minnullina

Federal State Autonomous Educational Institution of Higher Education “Russian National Research Medical University named after N.I. Pirogov” of the Ministry of Health of the Russian Federation

Email: zarinam93@mail.ru
ORCID iD: 0009-0006-7867-4461

6th year student

Russian Federation, Ostrovityanova str., 1, Moscow, 117997

Bella R. Bagirova

Federal State Budgetary Educational Institution of Higher Education “North Caucasian State Academy”

Email: gm2112@mail.ru
ORCID iD: 0009-0008-0627-5167

6th year student, Medical Institute

Russian Federation, Stavropolskaya St., 36, Cherkessk, Karachay-Cherkess Republic, 369001

Alana A. Salpagarova

Federal State Budgetary Educational Institution of Higher Education “North Caucasian State Academy”

Email: alanasalpagarova3@gmail.ru
ORCID iD: 0009-0000-8946-612X

6th year student, Medical Institute

Russian Federation, Stavropolskaya St., 36, Cherkessk, Karachay-Cherkess Republic, 369001

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Supplementary files

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2. Fig. 1. scRNA-seq Map of HRH4 Expression in Airway Cells

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3. Fig. 2. Key signaling cascades modulated by second- and third-generation antihistamines are presented

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