Adenomyosis is characterized by polymorphism of clinical manifestations and is the cause of chronic pelvic pain associated with endometriosis in 53–80% of cases. Heavy dysmenorrhea in adenomyosis is a key factor that reduces the quality of life and, moreover chronic pain reduces stress resistance and launches the rehabilitation cytokines cascade, which causes exacerbation of endometriosis. Formation of painful syndrome with adenomyosis may be due to: changes in neurohumoral regulation, stimulation of nerves and blood vessels growth and myometrium inflammatory remodeling against the background of circulatory disorders and vascular sclerosis. These processes lead to violation of neuroimmune relationships that determine the increase in the number and sensitivity of nociceptors against the background of the chronic immuno-inflammatory process in endometrials and myometry.Experimental studies have shown that the supraspinal role of the nitric oxide (NO) is to indirect mechanical nociceptive reflexes. The dose-dependent L-arginine role in the pain syndrome formation also was shown; it was found that small doses of L-arginine lead to the activation of nNO-synthase and analgesic effect. Large doses are activated by cotorphine synthase to form a dipeptide of cortorphine (L-tyrosine-L-arginine), which induces the met-enkephalin release and analgesic effect. Individual studies have demonstrated a decrease in the symptoms of urinary pain syndrome during L-arginine treatment, which made it possible to include it into the European Association of Urologists recommendations on the chronic pelvic pain treatment in 2017.Clinical comparative study (2013) of the NO donator (L-arginine) effectiveness in the treatment of endometriosis-associated intermenstrual pelvic pain and dysmenorrhea showed a high efficiency of a 3-month course of combination therapy (dienogest 2 mg + Tivortin 4.2 g). Supplement of basic therapy by NO donator (L-аrginine) has shown a faster reaching the clinical effect on reducing endometriosis-associated symptoms and sustainable maintenance of the result achieved. The multifaceted pharmacological effects of L-arginine directly affect a number of essential factors for the adenomyosis development and progression, which allows using this drug in clinical practice.
Standartnaya terapiya bronhial'noj astmy (BA) vklyuchaet naznachenie β2-agonistov. Izmenenie funkcional'noj aktivnosti β2-adrenoreceptora associirovano s polimorfizmom gena ADRB2 i svyazano s nizkim terapevticheskim otvetom na β2-agonisty. Vyyavlenie nositelej klinicheski znachimyh variantov gena pomozhet izbezhat' neeffektivnogo lecheniya i posluzhit osnovaniem dlya naznacheniya al'ternativnoj terapii. Cel'yu issledovaniya bylo ocenit' klinicheskuyu znachimost' associirovannyh s terapevticheskim otvetom na β2-agonisty polimorfnyh variantov gena ADRB2 (Arg16Gly i Gln27Glu) dlya gruppy pacientov s BA. Provedeno klinicheskoe i geneticheskoe obsledovanie nebol'shoj gruppy vzroslyh nekuryashchih pacientov (n = 21) s BA srednej stepeni tyazhesti (III–IV stupen' po GINA), v tom chisle pacientov novogo teratipa, dlya kotoryh harakterny plohoj otvet na β2-adrenergicheskie sredstva, no znachimyj otvet na M-holinergicheskie sredstva. V pervuyu gruppu byli opredeleny pacienty s podtverzhdennoj effektivnost'yu primeneniya sal'butamola, kotorye v to zhe vremya imeli horoshij otvet na ipratropiya bromid. Vo vtoruyu gruppu voshli pacienty s nizkoj effektivnost'yu terapii sal'butamolom i polozhitel'nym testom s ipratropiya bromidom. Analiz raspredeleniya polimorfnyh variantov Arg16Gly i Gln27Glu pokazal otsutstvie dostovernoj svyazi allelej i genotipov s effektivnost'yu primeneniya β2-agonistov (0,52 — dlya varianta rs1042713, p = 1,0; i 1,0 — dlya varianta rs1042714, r = 0,74 sootvetstvenno). Pri etom pacienty s otsutstviem otveta na sal'butamol imeli genotip libo Arg16Gly, libo Gly16Gly. Neobhodimy dal'nejshie issledovaniya s bol'shim chislom pacientov i rasshireniem perechnya testiruemyh polimorfnyh variantov.
Standard asthma therapy includes prescription of β2-agonists. Changes in the functional activity of β2-adrenergic receptor are associated with ADRB2 genepolymorphism and related to the low therapeutic response to β2-agonists. Identification of carriers of the clinically significant gene variants will help to avoidineffective treatment and prescribe an alternative therapy. This study aimed to assess clinical significance of the ADRB2 gene polymorphisms (Arg16Gly andGln27Glu) associated with the therapeutic response to β2-agonists in the group of asthma patients. We subjected a small group of adult nonsmoking patients(n = 21) with moderate asthma (III–IV stage of GINA) to clinical and genetic examination. The group included patients with the new theratype, those that poorlyrespond to β2-adrenergic drugs but significantly to M-cholinergic agonists. The first group included patients responding well to both salbutamol and ipratropiumbromide. The second group was comprised of the patients for whom salbutamol was not effective but who tested positive for response to ipratropium bromide. Theanalysis of distribution of polymorphic variants of Arg16Gly and Gln27Glu revealed no significant relationship between alleles and genotypes and the efficacy of β2-agonists(0.52 for the rs1042713 variant, p = 1.0; 1.0 for the rs1042714 variant, p = 0.74, respectively). The genotype of patients that did not respond to salbutamol waseither Arg16Gly or Gly16Gly. Further studies are needed that would involve a larger number of patients and an expanded list of the tested polymorphic variants.
Актуальность. Основанием для проведения данного исследования послужило наличие группы пациентов с бронхиальной астмой (БА), которые предпочитают для купирования приступов удушья использовать короткодействующие антихолинергические препараты (КДХП). Цель. Изучение возможной низкой эффективности длительно действующих Р2агонистов (ДДБА) у пациентов с БА, не имеющих достаточного ответа на КДБА, а также вероятности уменьшения бронхиальной обструкции с помощью длительно действующих антихолинергических препаратов (ДДХП) у этих пациентов. Материалы и методы. В исследовании приняли участие 12 взрослых некурящих пациентов с БА средней степени тяжести (IIIIV ступень по GINA), получавшие в качестве базисной терапии ИГКС в средних или высоких дозах в сочетании с ДДБА, при этом характеризовались отсутствием или неполным контролем над симптомами БА. В первую (n7) группу были определены пациенты с клинически и инструментально подтвержденной эффективностью сальбутамола, которые в то же время имели хороший ответ на ипратропия бромид (КДБАКДХП). Во вторую группу (n5) вошли пациенты с низким ответом на сальбутамол и положительным тестом с ипратропия бромидом (КДБАКДХП). Пациентам проводили серию исследований функции внешнего дыхания (ФВД) до и через 5, 10, 15, 30, 60, 120 и 240 мин после ингаляции бронхолитического средства (салметерола 50 мкг, формотерола 12 мкг и тиотропия бромида 18 мкг). Результаты. Было показано, что пациенты с БА и фенотипом КДБАКДХП имеют низкий ответ на ДДБА: максимальный прирост ОФВгпосле ингаляции сальметерола составил 7,641,67 и 156,0116,03 мл, а после формотерола 9,435,84, 166,71103,14 мл (в сравнении с группой КДБАКДХП, где ответ на сальметерол составил 20,812,42 и 551,4393,94 мл, а на формотерол 30,216,75 и 718,57140,78 мл), и хороший ответ на ДДХП (13,735,78 и 250,0361,61). Заключение. Результаты исследования дают основание к выделению отдельного фенотипа БА с низкой обратимостью бронхиальной обструкции в ответ на КДБА и достаточной обратимостью в ответ на КДХП (КДБАКДХП). Этой группе пациентов в качестве базисной терапии следует рассматривать сочетание ИГКСДДБА и ДДХП (тиотропия бромида).Background. The aim of this study was to analyse the group of patients with asthma, who prefer to use shortacting anticholinergics (SAMA) for relief of asthma attacks. At the same time, these patients are prescribed inhaled glucocorticosteroids (ICS) in combination with longacting P2agonists (LABA) as a basic therapy according to the standards. Tha aim. To study the cause of low efficacy of LABA in patients with asthma who do not have a sufficient response to SABA, as well as the probability of reducing of bronchial obstruction with LAMA. Materials and methods. 12 nonsmoking adults with moderate to severe asthma (IIIIV stage of GINA), receiving medium or high doses of ICS in combination with LABA as a basic therapy without adequate control over asthma symptoms were included in the study. First group of patients showed the efficacy of salbutamol (FEV1reversibility was more than 12 and more than 200 ml after 400 g of salbutamol) and ipratropium bromide (SABASAMA). Second group included patients with low response to salbutamol and positive test (FEVtreversibility) with ipratropium bromide (SABASAMA). Spirometry was performed at baseline point and in 5, 10, 15, 30, 60, 120 and 240 min after inhalation of bronchodilator (salmeterol 50 g, formoterol 12 g and tiotropium bromide 18 g in the different days). Results. It was shown that SABASAMA phenotype asthma patients demonstrated low response to LABA: FEV1increased up to 7.641.67, 156.016.0 ml after salmeterol inhalation and up to 9.45.8, 166.7103.1 ml after formoterol inhalation (compared with a group of SABASAMA, where the response to salmeterol was 20.812.42, 551.4393.94 ml and the response to formoterol was 30.216.75, 718.57140.78 ml, p0.05), and a good response to LAMA (13.75.8 and 250.061.6). Conclusion. The results of the study allowed to define asthma phenotype with low bronchial obstruction reversibility to SABA and sufficient reversibility to SAMA (SABASAMA). This group of asthma patients need the basic treatment with the combination of ICS and LABA and LAMA (tiotropium bromide).
Статья представляет собой реферативно-аналитический обзор исследований, посвященных изучению полиморфизмов генов 2-адренорецептора (ADRB2) и их ассоциаций со степенью тяжести бронхиальной астмы (БА) и ответа на стандартную фармакотерапию. Результаты анализа продемонстрировали высокую неоднородность полученных данных, что усугубляется различным целями, задачами и дизайном этих исследований. Учитывая то, что полиморфизм гена ADRB2 влияет на экспрессию данного рецептора, можно было бы предположить, что такие пациенты с БА будут демонстрировать низкий ответ на короткодействующие 2-агонисты (КДБА) и длительно действующие 2-агонисты (ДДБА), а в качестве бронхолитической терапии для них предпочтительны коротко- и длительно действующие холинергические средства. По изученным нами публикациям невозможно сделать однозначного вывода о связи полиморфизмов генов ADRB2 и ответа на КДБА и ДДБА. Данные, демонстрирующие распространенность гомозиготных аллелей и изучаемых ассоциаций среди представителей различных популяций, противоречивы. Достижение контроля над симптомами является основной целью терапии БА, в то же время, несмотря на наличие современных эффективных фармакологических средств, для ограниченного контингента среди пациентов с БА это не представляется возможным. Данные аспекты обусловливают необходимость изучения молекулярно-генетических механизмов патогенеза БА с целью улучшения диагностики и индивидуального подхода к выбору фармакотерапии для пациентов с плохим контролем БА.This article represents an abstract and analytical review of studies devoted to the polymorphisms of 2-adrenergic receptor gene (ADRB2) and their associations with the degree of severity of bronchial asthma (BA) and response to standard pharmacotherapy. The results of the analysis showed a high heterogeneity of the data obtained, which is aggravated by different goals, objectives and study design. If the polymorphism of ADRB2 gene affects the expression of this receptor, it is possible that these asthma patients will show a low response to SABA / LABA short- and long-acting anticholinergics will be preferred as bronchodilators. It is impossible to make a unique conclusion about the association between the polymorphisms of ADRB2 gene and the SABA / LABA responsiveness according to the results of analyzed publications. Data of the prevalence of homozygous alleles and studied associations among different populations are contradictory. Achievement of the asthma symptoms control is the main goal of asthma therapy. At the same time its impossible for a limited number of asthma patients in spite of the provision of current effective pharmacological resources. These aspects necessitate the research of the molecular-genetic mechanisms of pathogenesis in order to improve diagnostics and individual approach to the pharmacotherapy choice for patients with poor asthma control.
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