Rengalin, a Novel Drug for Treatment of Cough in Children. Intermediate Data on Multicentre, Comparative Randomized Clinical Trial

Rengalin liquid formulation on the basis of antibodies to bradlkinin histamine and morphine was specially designed for the treatment of cough in children. The three-component combination in therapeutically active against both dry and wet cough due to effect on diverse pathogenetic aspects of the cough reflex. The aim of the multicenter, comparative, randomized clinical trial was to estimate the efficacy and safety of rengalin in the treatment of cough in patients with acute respiratory infection (ARI) of the upper respiratory tract. Methods. One hundred forty six patients at the age of 3 to 17 years (the average age of 8.2+3.6 years) from 14 medical centres of Russia were observed. The patients sufferedfrom dry/nonproductive, frequent, sore cough preventing from day-time activity and/or night sleep (>4 by the Cough Severity Scale). The cough duration ranged from 12 hours to 3 days. For 3 days the patients of group 1 (n=71) and group 2 (n=75) were treated with rengalin and sinekod (butamirate) respectively. For the following 4 days the patients (in case of viscid expectoration were treated with ambroxole in the age doses. The results of the Per Protokol Analysis (n=67 rengalin group and n=73 sinekod group) with an account of the Non-Infectiority Design are presented. Results. In 3 days the number of the group 1 patients with significant improvement/recovery by the day and night estimates amounted to 90% and 88% respectively (vs. 81% and 88% in the group 2 patients, no night opisodes of cough after 3-days rengalin use being recorded in 52% of the patients vs. 34% in the sinekod group patients (p=0.0003). On the 7^th day of the treatment with rengalin the number of the children with significant improvement of or recovery from day-time cought amounted to 99%and that of the patients with significant improvement of or recovery from night-time cough amounted to 93%, in 90% of them no night-time cough being recorded (p=0.0008). As for the patients of the reference group, the respective values were 93% and 90%, no night-time cough being recorded in 81% of the patients. The time required for development of productive/moist cough during the 3-day treatment course in the patients of both the group was the same (2.9+0.3 days in the patients of group 1 and 2.9+0.4 days in the group 2 patients. Moreover, in 34% of the rengalin dry cough became residual (as rare episode of tussiculation with scantly exudation). After 3-day course of the rengalin therapy, 66% of the patients was treated with ambroxole (versus 95% in sinecod group (p<0.0001) based on comparative analysis and χ²=17.7, p>0.0001 by the results of the frequency analysis). The total duration of cough in the patients of groups 1 and 2 was 6.5±0.8 and 6.7±0.7 days respectively (the comparability truth, p=0.0001). The severity of the day-time cough by the area under the curve estimates for 7 days of the treatment in the rengalin group patients was equel to 14.3+5.6 numbers - days and that of the patients of the sinekod® group was equal to 15.9±6.1 numbers - days. The severity of the night-time cough was equal to 4.2+2.7 number - days respectively. In 2 patients (3%) treated with sinekod® signs of ARI generalization was observed after the 3-day treatment (p>0.0001). The research physicians-investigators (CGI-EL Scale) the combination of the anti- and protussive activities in one drug to be efficient and absolutely safe for the chilgren. The therapeutic efficacy in the patients of the rengalin group was higher in 3 days (2.1±0.5 numbers) and even in 7 days (2.7±0.5 numbers). The results value in the patients of the sinekod® group being 1.8±0.4 and 2.5±0.6 numbers (one-way ANOVA for repeated estimates ANOVA: Visit - F_1/138=146, p<0.0001, TREATMENT - F_1/138=9.0, p=0.003). The factor of the side effects in the patients of the rengalin group was zero (no side effects due to the treatment were recorded in the patients), whereas in the patients treated with sinekod® for 3 days the respective value was 0.1+0.3 (true superiority of rengalin by the ANOVA data. TREATMENT - F_1/138=4.7, p=0.03). The efficacy factor of the rengalin was also in its favour (ANOVA: Visit - F_1/138=182, p<0.0001, TREATMENT - F_1/138=7.3, p=0.008). In the patients treated with rengalin there were defected no deviations in the biochemical and general clinical analyses of blood and urine, no adverse reactions characteristic of antitussive drugs of the action. 100-percent adherence to the therapy was stated. Conclusion. He antitussive effect of rengalin in the treatment of frequent dry day-time and night-time cough was observed earlier and proved to be comparable with that of butamirate (sinekod®). Rengalin prevented significant exudation and viscid expectoration in many patients, promoted rapid residual in the patients with dry cough and the patients recovery. The use of rengalin for 3 days significantly lowered the percentage of the patients requiring treatment with mucolytics at the subsequent stages of ARI.

rengalin, cough, children, antitussive action

1. Геппе H.A., Волков И.К. Актуальные вопросы детской пульмоно логии в России Вестник Российской академии медицинских наук. 2008; (10): 32-4.

2. Footitt J., Johnston S. L. HYPERLINK «http://www.ncbi.nlm.nih.gov/ pubmed/19480062» Cough and viruses in airways disease: mechanisms. Pulm Pharmacol Ther. 2009; 22(2): 108-13.

3. Tecu C., Mihai M.E., Alexandrescu V.I. et al. Single and multipathogen viral infections in hospitalized children with acute respiratory infections. Roum Arch Microbiol Immunol. 2013; 72 (4): 242-9.

4. Canning B. J. Anatomy and Neirophysiology of the Cough Reflex. ACCP evidence-based clinical practice guidelines.Chest, 2006; 129 (1): 33-47.

5. Геппе Н.А., Снегоцкая М.Н. Диагностический поиск и принципы лечения кашля у детей. Consilium medicum, Педиатрия, 2012; (1): 52-55.

6. Геппе Н.А., Снегоцкая М.Н., Пенкина М.В. Алгоритм лечения кашля у детей. Фарматека, 2014; (1):71-75.

7. Чучалин А. Б., Абросимов В. Н. Кашель. Издание второе, переработанное и дополненное. - М.: «Эхо», 2012: 128 с.

8. Bolser D.C. Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines. Chest, 2006; 129 (1): 238-249.

9. Irwin R. S., Baumann M. H., Bolser D. C. et al. Diagnosis and management of cough. Executive Summary: ACCP evidence-based clinical practice guidelines. Chest, 2006; 129: 1S-23S.

10. Dicpinigaitis P. V., Colice G. L., Goolsby M. J. et al. Acute cough: a diagnostic and therapeutic challenge. Cough, 2009; 5: 11.

11. Smith S. M., Schroeder K., Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. The Cochrane Library, 2010, Issue 9. The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd. http://www.thecochranelibrary.com

12. Charpin J., Weibel M. A. Comparative evaluation of the antitussive activity of butamirate citrate linctus versus clobutinol syrup. Respiration. 1990; 57 (4): 275-9.

13. Kovaleva V. L., Zak M. S., Sergeeva S. А., Epstein O. I. Antitussive activity of antibodies in ultralow doses. XIV World Congress of Pharmacology «The New Century of Pharmacology», San Francisco, California, July 7-12, 2002. Abstract Volume. Pharmacologist, 2002; 44 (2), suppl. 1: 227-28.

14. Сергеева C. A., Ковалева В. Л., Зак М. С., Эпштейн О. И. Исследование противокашлевой активности сверхмалых доз антител к брадикинину у морских свинок. IX Российский национальный конгресс «Человек и лекарство», материалы. Москва, 2002: 694-94.

15. Ковалева В. Л., Зак М. С., Эпштейн О. И., Сергеева C. A. Изучение влияния свермалых доз антител к гистамину на контрактуру гладких мышц изолированной трахеи морской свинки. X Российский национальный конгресс «Человек и лекарство», материалы. Москва, 2003: 721-21.

16. Ковалева В. Л., Зак М. С., Эпштейн О. И., Сергеева C. A. Исследование влияния сверхмалых доз антител к брадикинину на кашлевой рефлекс у интактных и иммунизированных морских свинок. X Российский национальный конгресс «Человек и лекарство», материалы. Москва, 2003: 721-21.

17. Эпштейн О. И., Ковалева В. Л., Зак М.С., Дугина Ю. Л. Сверхмалые дозы антител к медиаторам воспаления: противокашлевые свой ства антител к брадикинину, гистамину и серотонину. Бюлл. эксперим. биол., 2003. Прил. 1: 61-64.

18. Эпштейн О. И., Штарк М. Б., Дыгай А. М. и др. Фармакология сверхмалых доз антител к эндогенным регуляторам функций. М.: Издательство РАМН, 2005; 226.

19. Эпштейн О.И. Феномен релиз-активности и гипотеза «пространственного» гомеостаза. Успехи физиологических наук, 2013, 44 (3): 54-76.

20. ICH Harmonised Tripartite Guideline. Clinical Investigation of Medicinal Products in the Pediatric Population (E11). Current Step 4 version, July 2000; 12 p.

21. Hsu J. Y., Stone R. A., Logan-Sinclair R. B. et al. Coughing frequency in patients with persistent cough: assessment using a 24 hour ambulatory recorder. Eur. Respire. J. 1994; 7: 1246-53.

22. Morice A. H., Fontana G. A., Belvisi M. G. et al. ERS guidelines on the assessment of cough. ERS Task Force. Eur. Respir. J., 2007; 29: 1256-76.