The effect of Nucleinat on bronchial hyperresponsiveness, the parameters of the phagocytic activity and phagocytic index of neutrophils their oxygendependent metabolism and the blood content of nitric oxide metabolites in 98 school age children with bronchial asthma has been studied by means of a double-blind placebocontrolled method. Two clinical groups were formed with the help of the table of accidental numbers. The first clinical group included 47 children who took Nucleinat in a dose of 0,25 g per diem during 21 days in a complex of
base-line theraphy. The second clinical group was formed of 51 children who took placebo according to the same regimen. It has been shown that thanks to the use of Nucleinat
a reduction of bronchial hypersensitivity and optimization of disease control have been achieved, which was indirectly evidenced by an increased risk of detecting moderate
bronchial responsiveness to histamine (OR = 3,6; 95% CІ: 1,3-9,3) and a decrease of the phagocytic activity of neutrophils (OR=1,9 with 95% CI (0,9-4,4)).Кафедра педіатрії та дитячих інфекційних хворо

Bezrukov, L.O.

Koloskova, O.K.

Marusyk, U.I.

The effect of Nucleinat on bronchial hyper-responsiveness, the parameters of the phagocytic activity and phagocytic index of neutrophils their oxygen-dependent metabolism and the blood content of nitric oxide metabolites in 98 school age children with bronchial asthma lias been studied by means of a double-blind placebo-controlled method. Two clinical groups were formed with the help of the table of accidental numbers. The first clinical group included 47 children who took Nucleinat in a dose of 0,25 g per diem during 21 days in a complex of base-line therapy. The second clinical group was formedof 51 children who took placebo according lo the same regimen. It has been shown that thanks to the use of Nucleinat a reduction of bronchial hypersensitivity and optimization of disease control have been achieved, which was indirectly evidenced by an increased risk of detecting moderate bronchial responsiveness to histamine (OR = 3.6; 95% CI: 1,3-9,3) and a decrease of the phagocytic activity of neutrophils (OR=l,9 with 95% CI (0,9-4,4))

Bezrukov, Leonid Oleksiuovich

Koloskova, Olena Kostantunivna

Marusyk, Uliana Ivanivna

Цифровий Репозиторій - Інтелектуальні Фонди Буковинського державного медичного університету

What is the role of nucleinat in a complex of control therapy of bronchial asthma in school-age children? Double-blind placebo controlled method

 7 Буковинський медичний вісник        Том 14, № 4 (56), 2010  © L.O.Bezrukov, O.K.Koloskova, U.I.Marusyk, 2010 Abstract. The effect of Nucleinat on bronchial hyper-responsiveness, the parameters of the phagocytic activity and phagocytic index of neutrophils their oxygen-dependent metabolism and the blood content of nitric oxide metabolites in 98 school age children with bronchial asthma has been studied by means of a double-blind placebo-controlled method. Two clinical groups were formed with the help of the table of accidental numbers. The first clini-cal group included 47 children who took Nucleinat in a dose of 0,25 g per diem during 21 days in a complex of base-line theraphy. The second clinical group was formed of 51 children who took placebo according to the same regimen. It has been shown that thanks to the use of Nu-cleinat a reduction of bronchial hypersensitivity and optimi-zation of disease control have been achieved, which was indirectly evidenced by an increased risk of detecting mod-erate bronchial responsiveness to histamine (OR = 3,6; 95% CІ: 1,3-9,3) and a decrease of the phagocytic activity of neutrophils (OR=1,9 with 95% CI (0,9-4,4)). Key words: children, bronchial asthma, bronchial hyperresponsiveness, immunity, Nucleinat. УДК 616.248-059.3-085 L.O.Bezrukov, O.K.Koloskova, U.I.Marusyk  WHAT IS THE ROLE OF NUCLEINAT IN A COMPLEX OF CONTROL  THERAPY OF BRONCHIAL ASTHMA IN SCHOOL-AGE CHILDREN?  DOUBLE-BLIIND PLACEBO CONTROLLED METHOD Department of Pediatrics and Children Infectious Diseases (Head of the Department, Prof. O. K.Koloskova)  Bukovinian State Medical University, Chernivtsi Introduction. Changes of the immune response underlie bronchial asthma (BA). They are the causes of the organism’s sensibilization, the development of bronchial allergic (immunologic) inflammation [5] and hyperresponsiveness [7]. Thanks to these inflam-matory changes it is very important to use anti-inflammatory drugs for children with bronchial asthma [11]. But, when we use basic therapy this child’s pathology, sometimes, it is impossible to at-tain full control of the diseases [6]. The insufficient effectiveness of the inhalation of glucocorticosteroid (iGCS) [3] substantiates the use of new medications (for example Nucleinat) which can improve BA.  Since Nucleinat possesses immunomodulating and antiinflammatory effects [9], it may be suggested that its use in combined basic therapy in children with bronchial asthma would be accompanied with the positive dynamics of bronchial hyperresponsive-ness, the phagocytic activity and the phagocytic in-dex of neutrophils, oxygen-dependent metabolism of neutrophilic granulocytes and the blood content of oxygen. The object of the study: To estimate the role of Nucleinat in the complex of control therapy of chil-dren’s BA and its effects on bronchial hypersensitiv-ity, the parameters of the phagocytic activity and the phagocytic index of neutrophils, oxygen-dependent metabolism of neutrophilic granulocytes and the blood content of nitric oxide (NO). Material and Methods: Altogether, 98 school-age children with bronchial asthma during the period of remission were subjected to a complex examina-tion. The examinations were performed by means of a double blind, randomized, placebo controlled method. Using the table of random numbers, all the patients were divided into two clinical groups. The first (I) group consisted of 47 patients, who were administered Nucleinat in a dose of 0.25 g/day for 21 days as an addition to combined basic therapy. The second (II) group consisted of 51 patients, who, in-stead of Nucleinat were administered placebo. The groups did not differ significantly by age, the dura-tion of the disease, the levels of bronchial asthma control or the type of anti-inflammatory therapy. The first clinical group consisted of 32 boys (68,0 %) and 15 girls (31,9 %). The second clinical group consisted of 31 boys (60,8%, Pφ>0,05) and 20 girls (39,2%, Pφ>0,05).  The average child’s age was 11,7±0,5 years in the basic groups and 12,3±0,4 years (P>0,05) in the control group.  According to the classifications of BA, which is in the GINA-2006, there were 5 children (10,6±4,5)% with controlled asthma in the first group and 9 patients (17,6±5,3)% in the second one (P>0,05), 24 children (51,1±7,1)% with partly controlled asthma of group I and 32 (62,7±6,8)% sick children of group II (P>0,05). Uncontrolled bronchial asthma was observed in 18 children (38,3±7,1)% in the first group and in 10 pa-tients (19,6±5,5)% in the second one (P<0,05). In addition to the generally accepted clinical examinations, the determination of respiratory tract hyperresponsiveness was performed with the use of a portable calibrating spirograph MicroLab (Micro Medical). Bronchial hypersensitivity was estimated by the findings of an inducing dose of histamine, which resulted in a 20% reduction of FEV1 (PC20H), and a cumulative dose (PD20Н) with the use of a histamine serial dilution [12]. Bronchial reactivity was determined by means of the bronchial lability index (BLI). A response of the respiratory tracts to a dosed physical exercise (5-min running with a submaximal heart rate) as the bronchospasm index (BSI) and following the inhalation of a beta2-agonist (salbutamol) as the bronchodilation index (BDI) [1]. At the same time, a blood immunological examination of the IInd-IIId levels was performed. In addition to an evaluation of the phagocytic activity (PA, percent) and the phagocytic index (PI, arbitrary units) of blood neutrophils, oxygen-dependent me-Буковинський медичний вісник        Том 14, № 4 (56), 2010 8  tabolism of neutrophilic granulocytes by the parame-ters of both spontaneous and stimulated NBT-test, expressed in the form of a relative content (percent) of pharmasan-positive blood neutrophils (V.V. Kli-mov et al., 1988) was carried out. A determination of blood nitric oxide was also performed (N.L. Yem-chenko et al., 1994).  Besides, the risk of the realisation of an event in the first group of children to the patients from the control group (OR with its CI) was calculated. Results and Discussion. Following the therapy carried out in both groups, a reduction in bronchial hypersensitivity was revealed in the form of an ele-vated inducing and cumulative doses of histamine. However, significant elevations in PC20Н and PD20H were only noted in the patients of the first group, while a trend towards elevations of these parameters was noted in the second group patients (Tabl. 1). The results obtained can be explained by a reduc-tion of the inflammatory component of bronchial hy-persensitivity as a result of the therapy instituted [8]. The risk of a reduction of bronchial hypersensi-tivity in the patients of the first clinical group was higher relative to the children, receiving placebo (OR=3,6; 95 % CІ: 1,3-9,3). Following the therapy, spirographic tests with a dosed physical exercise and with the inhalation of a beta2-agonist showed a trend towards elevations of the bronchial lability index in the patients of both groups (Tabl. 2). Therefore, a clear trend towards a rise in bron-chial sensitivity to beta2-agonist inhalation, but with unchanged bronchospasm as the respiratory tract response to physical exercise was noted in the chil-dren receiving Nucleinat. The trend towards en-hanced sensitivity of the respiratory tracts to a bron-chodilatator, but with the same bronchospasm fol-lowing a dosed physical exercise in the Nucleinat recipients could be explained by a reduction of the inflammatory component, but with the preserved hereditary component of bronchial reactivity [4]. At the same time, following the therapy in the patients of both clinical groups changes in the oxida-tion-reduction processes in the blood neutrophilic granulocytes were noted and which were confirmed by the NBT-test findings in both spontaneous and stimulated versions. Thus, significant reductions in the oxygen-dependent bactericidal action of neutro-phils were revealed in the children, who received Nu-cleinat, but only those based on the parameters of the spontaneous NBT-test in the second group patients. An estimation of the relative content of blood neutro-phils stimulated with pyrogenal showed a trend to-wards their reductions in the patients of both clinical groups. An estimation of the functional activity pa-rameters of the phagocytic immunity link showed that Nucleinat in the complex of the basic therapy of chil-dren’s BA didn’t change substantially the phagocytic index and phagocytic activity (Tabl. 3). Significant reductions in the percentage of pharmasan-positive neutrophils in patients of the first clinical group indicate a plausible reduction of the body’s chronic inflammatory process [12].  It is necessary to note, that the probability of a decrease of the phagocytic activity in the patients of the 1st-clinical group relative to the children, receiv-ing placebo was increased (OR=1,9 with 95 % CI (0,9-4,4)). Following the therapy performed, a significant elevation of the blood nitric oxide content was noted in the first clinical group patients who received Nu-cleinat (Tabl. 4). The significant elevated blood nitric oxide con-tent in the first clinical group patients, who received Table 1 Parameters of respiratory tract hypersensitivity in patients of both clinical groups Group  Therapy PC20H (mg/ml) PD20H (mg) І group (n=47) ІІ group (n=51) І group (n=47) ІІ group (n=51) Prior to the therapy 1,3±0,2 1,7±0,3 0,29±0,05 0,37±0,06 Following the therapy 2,8±0,5 2,2±0,4 0,6±0,1 0,48±0,1 Р Р<0,05 Р>0,05 Р<0,05 Р>0,05 Table 2 Parameters of the respiratory tract hyperreactivity in patients  of both clinical groups Group Therapy Bronchial lability index,% Bronchodilation index, % Bronchospasm index, % І group (n=32) ІІ group (n=33) І group (n=32) ІІ group (n=33) І group (n=32) ІІ group (n=33) Prior to the  therapy 23,4±2,3 22,4±2,2 9,9±1,4 11,3±1,6 12,4±1,8 11,1±1,2 Following the therapy 24,6±2,5 24,8±3,3 11,7±1,6 10,8±1,2 13,04±1,6 14,0±2,7 Р P>0,05 P>0,05 P>0,05 P>0,05 P>0,05 P>0,05  9 Буковинський медичний вісник        Том 14, № 4 (56), 2010  Table 3 Functional activity parameters of blood neutrophils in patients  of both clinical groups Group NBT-test (%) FA (%) PI (a.u.) Spontaneous Stimulated Prior to therapy Follo- wing ther-apy Prior to therapy Follo- wing therapy Prior to therapy Follo- wing therapy Prior to therapy Follo- wing ther-apy І group (n=47) 36,2±2,5 28,0±2,0* 51,3±2,6 45,8±2,6 80,1±1,7 78,3±2,3 9,1±0,6 7,8±2,3 ІІ group (n=51) 31,4±1,8 32,1±2,1 46,4±2,4 43,3±2,2 80,9±1,3 83,9±1,3 9,1±0,6 9,9±0,5 Note. *P<0,05 Table 4 Blood nitric oxide content in the patients of both clinical groups Group of patients Therapy NO, mcmol/L І group (n=32) ІІ group (n=33) Prior to the therapy 19,6±0,7 20,1±1,5 Following the therapy 25,9±2,9 18,6±0,4 Р P<0,05 P>0,05 Nucleinat, could be explained by a plausible reduc-tion in the manifestations of chronic hypoxia, which is inherent to this disease [6].  Therefore, the use of Nucleinat in combined therapy for bronchial asthma ensures a significant reduction of the inflammatory process in children, manifested by lowered bronchial hyperresponsive-ness, lowered oxygen-dependent bactericidal activity of neutrophils and reduced signs of chronic hypoxia (an elevated blood content of nitric oxide). Conclusions 1. The use of Nucleinat in combined therapy for bronchial asthma in children ensures a significant re-duction in bronchial hyperresponsiveness. The risk of a reduction of bronchial hypersensitivity in the first clini-cal group of patients was higher relative to the chil-dren, receiving placebo (OR = 3,6; 95% CІ: 1,3-9,3). 2. Following the use of Nucleinat, a clear trend was noted towards an elevated bronchodilation after beta2-agonist inhalation. 3. The use of Nucleinat in combined therapy for bronchial asthma was accompanied with significant reductions in the parameters of oxygen-dependent bactericidal action of blood neutrophilic granulo-cytes. The probability of a decrease of the phago-cytic activity in the Ist clinical group patients relative to the children receiving placebo, was increased (OR=1,9 with 95% CI (0,9-4,4)). 4. Following the use of Nucleinat, a clear trend was noted towards an elevated level of the blood nitric oxide. Perspectives of future investigations in this direction are to estimate the effect of Nucleinat in the complex of control therapy of children’s BA on the rate of the clinical signs. Literature 1. Сидельников В.М. Практическая аллерголо-гия детского возраста / Сидельников В.М., Безруков Л.А., Мигаль В.Г. – К.: Здоров’я, 1985. – 160 с. 2. Effect of an inducible nitric oxide synthase in-hibitor on differential flow-exhaled nitric oxide in asthmatic patient and healthy volunteers / C. Brindicci, K. Ito, P.J. Barnes [et al.] // Chest. – 2007. – № 132. – P. 581-588. 3. Global Strategy for Asthma Management and Prevention. – National Institutes of Health Na-tional Heart and Lung and Blood Institute: Re-sived, 2009. – 112 p. 4. Increased airway closure is a determinant of air-way hyperresponsiveness / D.G. Chapman, N. Berend, G.G. King [et al.] // Eur. Respir. J. – 2008. – № 32. – P. 1563-1569. 5. Innate immune activation in neutrophilic asthma / E.H. Walters, R. Wood-Baker, D.E.C. Reid [et al.] // Thorax. – 2008. – № 63. – P. 88-89. 6. Henderson A. What have we learned from pro-spective cohort studies of asthma in children? / A. Henderson // Chronic Respiratory Disease. – 2008. – № 5 (4). – P. 225-231. 7. Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomized controlled trial / M.Nuijsink, W.C.J. Hop, P.J. Sterk [et al.] // Eur. Respir. J. – 2007. –№ 30. – P. 457-466. 8. Lundblad Airway hyperresponsiveness in allergi-cally inflamed mice / K.A. Lennart, J. Thompson-Figueroa, B.A. Gilman [et al.] // Am. J. Respir. Crit. Care Med. – 2007. – Vol. 175. – P. 768-774. 9. Tkachuk Z. Compound, compozisionand method for treatment of inflammatory and inflammatory-Буковинський медичний вісник        Том 14, № 4 (56), 2010 10  © L.O.Bezrukov, O.K.Koloskova, U.I.Marusyk, 2010 related disorders / Z. Tkachuk // United States Patent № US 6,737,271. May 18, 2004. 10. Townshend J. Diagnosis of asthma in children / J. Townshend, S. Hails, M. Mckean // BMJ. – 2007. – № 335. – P. 198-202. 11. Townshend J. Management of asthma in children / J. Townshend, S. Hails, M.Mckean // BMJ. – 2007. – № 335. – P. 253-257. 12. Innate immune activation in neutrophilic asthma / Walters E.H., Wood-Baker R., Reid D.E. [et al.] // Thorax. – 2008. – № 63. – P. 88-89. КАКАЯ РОЛЬ НУКЛЕИНАТА В КОМПЛЕКСЕ КОНТРОЛИРУЮЩЕЙ ТЕРАПИИ  БРОНХИАЛЬНОЙ АСТМЫ У ШКОЛЬНИКОВ? ДВАЖДЫ СЛЕПОЕ ПЛАЦЕБО–  КОНТРОЛИРОВАННОЕ ИССЛЕДОВАНИЕ Л.О.Безруков, О.К.Колоскова, У.И.Марусик Резюме. Дважды слепым плацебо– контролированным методом проведено исследование влияния Нуклеината на гипервосприимчивость дыхательных путей, показатели фагоцитарной активности и фагоцитарного числа нейт-рофилов, их кислородозависимого метаболизма и концентрации метаболитов оксида азота в крови в комплексном лечении бронхиальной астмы у 98 школьников. С помощью таблицы случайных чисел было сформировано две клинические группы. В первую клиническую группу вошли 47 больных, которые в комплексе базисной терапии принимали Нуклеинат в дозе 0,25 г в сутки в течение 21 дня. Вторую группу сформировали 51 школьник, которые получали плацебо. Показано, что благодаря использованию Нуклеината достигнуто снижение гипервосприимчиво-сти дыхательных путей, а также оптимизации контроля этого заболевания, на что косвенно указывал прирост риска выявления умеренной восприимчивости бронхов к гистамину (СШ=3,6; 95 % ДИ: 1,3-9,3) и снижение фагоцитар-ной активности нейтрофилов (СШ=1,9 з 95 % ДИ (0,9-4,4)). Ключевые слова: дети, бронхиальная астма, гипервосприимчивость бронхов, иммунитет, Нуклеинат. ЯКА РОЛЬ НУКЛЕЇНАТУ В КОМПЛЕКСІ КОНТРОЛЬОВАНОЇ ТЕРАПІЇ  БРОНХІАЛЬНОЇ АСТМИ У ШКОЛЯРІВ? ДВІЧІ СЛІПИЙ  ПЛАЦЕБО-КОНТРОЛЬОВАНИЙ МЕТОД Л.О.Безруков, О.К.Колоскова, У.І.Марусик Резюме. Двічі сліпим плацебо –  контрольованим методом досліджено вплив Нуклеїнату на гіперсприйнятли-вість дихальних шляхів, показники фагоцитарної активності та фагоцитарного числа нейтрофілів, їх кисне-залежного метаболізму та концентрації метаболітів монооксиду нітрогену в крові в комплексному лікуванні брон-хіальної астми в 98 школярів. За допомогою таблиці випадкових чисел сформовані дві клінічні групи. До першої групи увійшли 47 осіб, які в комплексі базисної терапії приймали Нуклеїнат у дозі 0,25 г на добу протягом 21 дня. Другу групу сформували з 51 дитини, що отримували плацебо за тією ж схемою. Показано, що завдяки використан-ню Нуклеїнату досягнуте зниження гіперсприйнятливості дихальних шляхів, та оптимізацію контролю захворю-вання, на що опосередковано вказувало зростання ризику виявлення помірної сприйнятливості бронхів до гістаміну (СШ=3,6; 95 % ДІ: 1,3-9,3) та зниження фагоцитарної активності нейтрофілів (СШ=1,9 з 95 % ДІ (0,9-4,4)). Ключові слова: діти, бронхіальна астма, гіперсприйнятливість бронхів, імунітет, Нуклеїнат. Буковинський державний медичний університет (Чернівці) Рецензент – проф. Т.В.Сорокман                                          Buk. Med. Herald. – 2010. – Vol. 14, № 4 (56). – P. 7-10 Надійшла до редакції 21.10.2010 року  

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What is the role of nucleinat in a complex of control therapy of bronchial asthma in school-age children? Double-blind placebo controlled method

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Цифровий Репозиторій - Інтелектуальні Фонди Буковинського державного медичного університету

Цифровий Репозиторій - Інтелектуальні Фонди Буковинського державного медичного університету