EFFECTIVENESS AND TOLERANCE OF ENISAMIUM IODIDE NASAL SPRAY: PRE-CLINICAL STUDY AND CLINICAL TRIAL RESULTS
DOI:
https://doi.org/10.11603/mcch.2410-681X.2020.v.i1.11059Keywords:
experimental rhinosinusitis, Enisamium Iodide (nasal spray), portability, safetyAbstract
Introduction. There are differences in acute rhinosinusitis (ARS) treatment approaches depending on the leading clinical symptoms, in particular, nasal obstruction and facial pain. Farmak JSC (Ukraine) has developed a new nasal spray with Enisamium Iodide (EI) aqueous solution – original dosage form of a well-known pharmaceutical substance.
The aim of the study – to substantiate the effectiveness of EI (nasal spray) in the treatment of certain pathology and tolerance/safety of its use.
Researsch Methods. EI (nasal spray) 10 mg/mL was the study subject. BNO-101 under the trade name Sinupret® was used as a reference drug in the experimental part of the study. Experimental rhinosinusitis (ERS) was induced in 24 rabbits (4 groups, 6 rabbits in each group) on the first experimental day. Since 15th day, the animals received the drugs for 10 days: 0.9 % saline at 0.1 ml intranasally in the intact control and control pathology group, EI (nasal spray) at 0.1 ml intranasally in the 3rd group and BNO-101 at 25 mg/mL intragastrally in the 4th group. Treatment results were evaluated on the 25th day (laboratory observation, peripheral blood analysis results). The clinical part of the work has been conducted as a single-centre, randomized, double-blinded, placebo-controlled clinical trial with dose escalation – study of local tolerance and safety (Phase I) of different doses of the new drug EI (nasal spray) 10 mg/mL with healthy volunteers.
Results and Discussion. The results indicate that EI (nasal spray) is able to positively influence on ERS significantly due to local action. Statistical data analysis of local tolerance indicates that EI is not inferior to placebo in indicators of “local tolerance” and “safety”, and all differences are statistically insignificant.
Conclusions. The preclinical study results indicate that Enisamium iodide under the laboratory observations and hematological analyzes has a positive effect on ERS, and in activity is not inferior to BNO-101 as comparison drug. Statistical data analysis of clinical trial indicates good tolerance/safety of Enisamium Iodide (nasal spray) 10 mg/mL.
References
Kwah, J.H., & Peters, A.T. (2019). Nasal polyps and rhinosinusitis. Allergy Asthma Proc., 40 (6), 380-384. Retrieved from: http://doi: 10.2500/aap. 2019.40.4252
De Boer, D.L., & Kwon, E. (2019). Acute sinusitis. StatPearls. Treasure Island (FL): StatPearls Publishing.
Fokkens, W.J., Lund, V.J., Hopkins, C., Hellings, P.W., Kern, R., Reitsma, S. …, & Zwetsloot, C.P. (2020). European position paper on rhinosinusitis and nasal polyps 2020. Rhinology, 58 (29), 1-481.
(2016). Ministerstvo okhorony zdorovia Ukrainy. Unifikovanyi klinichnyi protokol pervynnoi, vtorynnoi (spetsializovanoi) ta tretynnoi (vysokospetsializovanoi) medychnoi dopomohy: hostryi rynosynusyt. Nakaz Ministerstva okhorony zdorovia Ukrainy [Ministry of Health of Ukraine. Unified clinical protocol for primary, secondary (specialized) and tertiary (highly specialized) care: acute rhinosinusitis. Order of the Ministry of Health of Ukraine]. No. 85, 17-24 [in Ukrainian].
Zhulai, T.S., Zupanets, I.A., & Shebeko, S.K. (2017). Doslidzhennia dozozalezhnosti antyeksudatyvnoi dii novoho nazalnoho spreiu z protyzapalnymy vlastyvostiamy [Investigation of dose dependence of anti-exudative action of a new nasal spray with anti-inflammatory properties]. Klinichna farmatsiya – Clinical Pharmacy, 21 (4), 11-17. Retrieved from: http://doi.org/10.24959/cphj.17.1446 [in Ukrainian].
Zhulai, T.S. (2018). Preclinical study of a new nasal spray with anti-inflammatory properties: the effect on the leukotriene-induced inflammation. Klinichna farmatsiia – Clinical Pharmacy, 22 (4), 27-33. Retrieved from: http://doi.org/10.24959/cphj.18.1473 [in Ukrainian].
Zhulai, T., Shebeko, S., & Goy, A. (2018). Perspectives for use of the new nasal spray with anti-inflammatory action in treatment of acute rhinosinusitis. Rhinology, 56 (27), 585. Retrieved from: https://www.rhinologyjournal.com
Poriadok provedennia klinichnykh vyprobuvan likarskykh zasobiv ta ekspertyzy materialiv klinichnykh vyprobuvan i typove polozhennia pro komisii z pytan etyky (zatverdzheno Nakazom Ministerstva okhorony zdorovia Ukrainy vid 23.09.2009 h. № 690 zi zminamy [Procedure for conducting clinical trials of medicinal products and examination of clinical trial materials and Model Regulations on Ethics Committees (approved by Order of the Ministry of Health of Ukraine dated 23.09.2009 № 690 as amended)]. Retrieved from: http://zakon1.rada.gov.ua/laws/show/z1010-09.
(2009). Nastanova ST-N MOZU 42-7.0:2008 “Likarski zasoby. Nalezhna klinichna praktyka” [Guideline of the Ministry of Health of Ukraine 42-7.0: 2008 “Medicines. Good clinical practice”]. Кyiv [in Ukrainian].
Dobrova, V.Ie., Zupanets, I.A., Shalamai, A.S., & Starchenko, M.H. (2010). Pat. 54725 Ukrainy na korysnu model, MPK (2009) A 61 V 5/00. Sposib vyznachennia perenosymosti likarskykh zasobiv pry provedenni pershoi fazy klinichnykh doslidzhen ta doslidzhenni bioekvivalentnosti [Pat. 54725 Ukraine for utility model, IPC (2009) А 61 В 5/00. The method of determining the tolerability of drugs during the first phase of clinical trials and bioequivalence studies]. zaiavnyk ta patentovlasnyk Natsionalnyi farmatsevtychnyi universytet. – №u 2010 04542; zaiavl. 19.04.10; opubl. 25.11.10, Biul. № 22 [in Ukrainian].
ICH E6: Good Clinical Practice: Consolidated guideline. CPMP/ICH/135/95.
Chow, S.C., Shao, J., & Wang, H. (2003). Sample size calculations in clinical research. London: Taylor& Francis.
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. L 121, 1.5.2001
Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with Investigational Medicinal Products. EMEA/CHMP/SWP/28367/07.
Sibille, M., Patat, A., Caplain, H., & Donazzolo, Y. (2010). A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry- into-man studies. British Journal of Clinical Pharmacology, 70, 5, 736-748.
(2005). Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. FDA/CDER.
Ministerstvo okhorony zdorovia Ukrainy, Nakaz № 509 vid 12 travnia, 2017. Pro derzhavnu reiestratsiiu (perereiestratsiiu) likarskykh zasobiv (medychnykh imunobiolohichnykh preparativ) ta vnesennia zmin do reiestratsiinykh materialiv [Ministry of Health of Ukraine, Order No. 509 of May 12, 2017. On state registration (re-registration) of medicinal products (medical immunobiological preparations) and amendments to registration materials]. Retrieved from: http://search.ligazakon.ua/l_doc2.nsf/link1/MOZ27507.html [in Ukrainian].
Parliament, European & Council, European. (2010). DIRECTIVE 2010/63/EU on the protection of animals used for scientific purposes. EU Official Journal. L276.
Guidance for industry. (2005). Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. FDA, 1-30.
Turner, P.V., Pekow, C., Vasbinder, M.A., & Brabb, T. (2001). Administration of substances to laboratory animals: Equipment considerations, vehicle selection, and solute preparation. Journal of the American Association for Laboratory Animal Science, 50 (5), 614-627.
Flecknell, P.A. (2015). Laboratory Animal Anesthesia, 4th ed. Oxford: Academic Press, 1-350. Retrieved from: http://dx.doi.org/10.1016/C2013-0-13494-0
Pereza, A.C, Buzattob G.P, de Picole Dantasb, I., & Vicente, J. (2014). Review of experimental models: sinusitis in rabbits. Braz. J. Otorhinolaryngol., 80 (5), 435-440. Retrieved from: http://dx.doi.org/10.1016/j.bjorl.2014.07.011
Costa, H.O., Ruschi e Luchi, G.E., Augusto, A.G., Castro, M., & Coelho de Souza, F. (2007). Comparative study of several sinusitis experimental modelling techniques in rabbits. Rev. Bras. Otorrinolaringol., 73 (5), 627-631. Retrieved from: http://dx.doi.org/10.1590/S0034-72992007000500007
Cohen-Kerem, R., Marshak, T., Uri, N., Gruber, M., Huberfeld O., Paz D., ... Ronen, O. (2019). Is nasal endoscopy of diagnostic value in chronic rhinosinusitis without nasal polyps? Ear, Nose Throat J., 1-5. Retrieved from: http://doi.org/10.1177/0145561319864578
Wuister, A.M., Goto, N.A., Oostveen, E.J., de Jong, W.U., van der Valk, E.S., Kaper, N.M., ..., & van der Heijden, G.J.M.G. (2014). Nasal endoscopy is recommended for diagnosing adults with chronic rhinosinusitis. Otolaryngol Head Neck Surg., 150 (3), 359-364. Retrieved from: https://doi.org/10.1177/ 0194599813514510
Colley, P., Mace, J.C., Schaberg, M.R., Smith, T.L., & Tabaee, A. (2015). Impact of educational intervention on the interrater agreement of nasal endoscopy interpretation. Laryngoscope, 125 (10), 2259-2265. Retrieved from: https://doi.org/10.1002/lary.25240
Dolgov, V.V., & Menshikov, V.V. (Ed.) (2012). Klinicheskaya laboratornaya diagnostika: naczionalnoe rukovodstvo [Clinical laboratory diagnostics: national leadership]. Moscow: GEOTAR-Media [in Russian].
Karpishhenko, A.I. (Ed.) (2002). Meditsinskie laboratornye tekhnologii: Spravochnik [Medical laboratory technology: Reference]. Saint-Petersburg: Intermedika [in Russian].
Kamyshnikov, V.S. (Ed.). (2011). Metody klinicheskikh laboratornykh issledovanii [Methods of clinical laboratory research]. 4-e izd. Moscow: MEDpress-inform [in Russian].
OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring No 20. (2019). Guidance Document for Receiving Authorities on the Review of the GLP Status of NonClinical Safety Studies. ENV/JM/MONO, 25.
Chow, S.C., Shao, J., & Wang, H. (2003). Sample size calculations in clinical research. London: Taylor& Francis.
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal of the European Communities, L 121, 1.5.2001
Guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with Investigational Medicinal Products. EMEA/CHMP/SWP/28367/07.
Islam, M.A., & Al-Shiha, A. (2018). Foundations of Biostatistics. Springer Nature Singapore Ltd.
Quirk, T.J., Quirk, M.H., & Horton, H.F. (2016). Excel 2016 for Biological and Life Sciences Statistics: A Guide to Solving Practical Problems. Springer International Publishing Switzerland.
Dobrova, V.Ye., Zupanecz, I.A., Morozov, A.M., Nikolayeva, V.V., Bezugla, N.P., & Starchenko, M.G. (2012). Naukove obhruntuvannia metodolohii statistychnoi oczinky perenosymosti likarskykh zasobiv pry provedenni klinichnykh vyprobuvan: metod. rek. [On the science of methodology of statistical estimation of tolerability of drug problems during clinical trials: guidelines]. Kharkiv: FOP Petrov V. V. [in Ukrainian].
