CC BY
15PHARMACEUTICAL SCIENCES
MYRAMISTIN AS AN ANTISEPTIC AND DISINFECTANT
Pavliuk B.,
I. Horbachevsky Ternopil National Medical University
Ternopil, Ukraine Chubka M.,
I. Horbachevsky Ternopil National Medical University
Ternopil, Ukraine Hroshovyi T.,
I. Horbachevsky Ternopil National Medical University
Ternopil, Ukraine Debrivskyj V.
I. Horbachevsky Ternopil National Medical University
Ternopil, Ukraine
DOI: 10.5281/zenodo.7618404
ABSTRACT
Nowadays, the rapid growth of resistance of pathogens of nosocomial infections to disinfectants and antiseptics forces the list of drugs in this group to be increasingly expanded.
The aim is to summarize the data of literary sources regarding the peculiarities of the use of myramistin as an active pharmaceutical ingredient (API) in the medical field, in particular, in the pharmaceutical industry, with the aim of developing and expanding the range of disinfectant medicinal products in various forms of release.
Myramistin is an API for local use with a wide spectrum of antibacterial action, and is widely used in surgery, traumatology, obstetrics, dermatovenerology, combustiology, otorhinolaryngology and stomatology. Microbiological action is aimed at suppressing and destroying populations of gram-positive, gram-negative, aerobic and anaerobic microorganisms, including those resistant to antibiotics, in the centers of the infectious agent of the skin, mucous membranes, and serous cavities. The mechanism of myramistin's antimicrobial action is justified by its belonging to quaternary ammonium compounds characterized by the specificity of its antimicrobial action.
Supplementing the assortment of medicines, expanding possible indications for the use of myramistin in clinical areas based on its already known properties are promising goals of medicine and pharmacy as a whole.
Keywords: antiseptic; myramistin; disinfectant; microbiological action.
Introduction. ammonium compounds, a surface-active substance that
Myramistin - benzyldimethyl[3-[(1-oxo- exhibits antiseptic properties. MF:- C26H47N2O+ tetradecyl)amino]propyl]ammonium chloride, mono- MW: 403.7g/mol [1, 2]. hydrate (Fig. 1) is a cationic derivative of quaternary
Figure 1. Chemical formula of Myramistin
According to its physical properties, it is a colorless, transparent liquid that foams when shaken.
The substance myramistin was first synthesized in the 1980s as a substance that exhibits antiseptic properties, which could be used in the space industry, in fact, it was obtained for the purpose of possible use by astronauts on orbital stations. The main requirements that the obtained substance had to meet were the ability to affect bacteria and fungi even at high temperatures without harming people. By the mid-1980s, the drug had passed preclinical tests and was ready for clinical trials. A change in approaches to the treatment of some diseases caused by microorganisms in 1982 led to the possibility of using myramistin for local therapy of pathological conditions of the lor-organs [3, 4], for the treatment of herpes of various types, as well as in com-bustiology, obstetrics and gynecology. For the first time, the drug with myramistin was officially registered in 1991 under the name "Infacept", which was later replaced by the modern version - "Myramistin". The concentration of the solution for local use is from 0.01% [2]. And therefore, in common cases of resistance to antimicrobial, antiseptic and disinfectant agents that are used incorrectly or have lost their activity against some microorganisms, as well as taking into account the need to expand the range of this group of agents, especially
On the pharmaceutical market of Ukraine, Myra-mistin exists in many medicinal forms, namely, in the form of a solution, spray, drops, suppositories and ointment for local use (Fig. 3). The availability of various dosage forms with myramistin accordingly expands the
said that myramistin is promising disinfectant, because it is positioned as a low-toxic antiseptic [4-6].
Materials and methods. The work uses methods of information search, analysis of statistical data and information from scientific and professional literature regarding myramistin. In particular, the grouping of thematic publications was done using PubMed, Elsevier and Google scholar on request "myramistin", which made it possible to cover the information space of the Internet in the most complete way. Data from more than 57 sources were analyzed and summarized, of which 26 sources of modern foreign and domestic literature on the expediency of using myramistin in medicine, pharmacy and cosmetology were used in this review. Data from the State Register of Medicinal Products of Ukraine and the Compendium directory were also used as information sources [7].
Results and discutions: Myramistin is an API for local use with a wide spectrum of antibacterial action [6] and is used in health care facilities to prevent and control the phenomena of infection, putrefaction, and the development of sepsis. Myramistin is used in various fields of medicine, in particular, in surgery, traumatology, obstetrics, dermatovenerology, combustiology, otorhinolaryngology and stomatology (Fig. 2). Due to its wide range of applications, it is a popular antiseptic
list of areas of application in the medical field. Also, the variety of medicinal forms makes it possible to increase the probability of selecting the optimal medicinal form for the treatment of a specific disease.
taking into account the Covid-19 epidemic, it can be and disinfectant.
Fields of application in medicine
Proctology. 2%
Pediatrics 14%
Family medicine 6%
Dentistry 10%
Otorhinolaryngol ogy 16%
. Surgery 9%
Traumatology
6%
Obstetrics 8%
Venereology 8%
Dermatology 11%
Combustiology 10%
Figure 2. Application of myramistin in various fields of medicine
Figure 3. List of dosage forms with myramistin on the pharmaceutical market of Ukraine
Medicinal products containing myramistin in the indicated dosage forms are presented in different ATC groups.
D08A Antiseptics and Disinfectants/D08AJ Quaternary Ammonium Compounds
• Myramistin-Darnitsa® solution for external use 0.1 mg/ml bottle of 50 ml with a urethral nozzle, PrJSC "Pharmaceutical firm " Darnitsa";
• Veromistin-Darnitsa® solution for external use 0.1 mg/ml, 100/200/400 ml, PrJSC "Pharmaceutical firm " Darnitsa";
• Myramidez® skin alcohol solution 0.1%, 100 ml, "Ternofarm" LLC;
• Celista® solution for the oral cavity 0. 1 mg/ml bottle 100 ml with a measuring cup, PrJSC "Pharmaceutical firm " Darnitsa";
• Celista® spray for the oral cavity 0.1 mg/ml bottle 50 ml atomizer nozzle, PrJSC "Pharmaceutical firm " Darnitsa";
• Europol® solution for external use 0.1 mg/ml bottle 20/50 ml, "Slavia 2000" LLC".
Otologicals. S02AA Antiinfectives
Myramidez® ear drops, alcohol solution 0.1% bottle with dropper 5 ml, "Ternofarm" LLC.
S03D Other Ophthalmological And Otological Preparations
• Okomistyn® eye/ear/nose drops, solution 0.01% 5 ml in a bottle with a dropper, "Farmak" JSC;
• Oftaklin® eye drops, solution 0.1 mg/ml bottle 5 ml, PrJSC "Pharmaceutical firm "Darnitsa";
S03D Other Ophthalmological and Otological Preparations/R01A Decongestants And Other Nasal Preparations For Topical Use
• Oftamirin® eye/ear/nasal drops 0.1 mg/ml bottle 5 ml, PrJSC "Pharmaceutical firm "Darnitsa".
AG01A Antiinfectives and Antiseptics, Excl. Combinations with Corticosteroids / A07E Intestinal Antiinflammatory Agents
• Tamistol® suppositories N5 0.015 g, PrJSC "Lekhim-Kharkiv".
The percentage ratio of monocomponent medicinal products based on myramistin of different groups of the ATC classification is shown in Figure 4.
Distribution of ATC groups of monocomponent drugs in Ukraine
G01A antiinfectives
S03D, R01A Decongestants and other nasal preparations for topical use 9%
S03D Other ophthalmological and otological preparations 18%
S02AA Antiinfectives 9%
and antiseptics,
excl. combinations with corticosteroids / A07E...
D08AJ Quaternary ammonium compounds 55%
Figure 4. Assortment of monocomponent medicinal products based on Myramistin by ATC code
Also, the myramistin substance is included in many combined medicinal products from different groups of the ATC classification:
- D07BB03 triamcinolone and antiseptics
• Trimistin-Darnitsa® ointment 14 g in a tube. It contains triamcinolone acetonide micronized - a synthetic substance from the group of glucocorticoid hormones that gives the drug anti-inflammatory, anti-allergic and anti-exudative effects and Myramistin, PrJSC "Pharmaceutical firm "Darnitsa".
- D03AX Other cicatrizants
• Methyluracil & myramistin® ointment 30 g in a tube, PrJSC "Pharmaceutical firm "Darnitsa". Methyluracil is a derivative of uracil that has anabolic and anti-catabolic properties. It affects regeneration by speeding it up and, accordingly, wound healing, positive effect on immunity, and anti-inflammatory effect.
• Panthestin-Darnitsa® gel 15 g in tubes, PrJSC "Pharmaceutical firm "Darnitsa". Contains Dexpanthenol - a derivative of pantothenic acid, provitamin B s, which has a regenerating, anti-inflammatory, dermato-protective effect characteristic of pantothenic acid and contains Myramistin itself.
- R01AB Sympathomimetics, combinations excl. corticosteroids / R01AB06 xylometazoline
• Rynomistin® nasal drops, 0.1%/0.01%, 10 ml each in a dropper bottle, "Farmak" JSC. In addition to Myramistin, the composition contains xylometazoline -an imidazole derivative, which is a sympathomimetic substance with an alpha-adrenergic effect. It has a pronounced vasoconstrictive effect, reduces swelling of the mucous membranes of the nose.
The percentage ratio of combined medicinal products of different groups of the ATC classification con-
taining myramistin is shown in Figure 5. Distribution of ATC groups of combined drugs in Ukraine
R01AB Sympathomimeti cs, combinations
excl. corticosteroids /
R01AB06 Xylometazolin.
D07BB03 triamcinolone and antiseptics 25%
D03AX Other cicatrizants 50%
Figure 5. Assortment of combined medicinal products based on Myramistin by ATC code.
Usually, monocomponent medicinal products based on myramistin contain a minimum amount of auxiliary components, in particular, purified water, water for injections and sodium chloride. These excipients are indifferent substances that expand the range of use and safety of medicines of this composition. Combinations, in turn, require a more careful appointment, since each active substance adds its own list of possible interactions, side effects and determines certain storage requirements.
Myramistin as an API exhibits a high antimicrobial effect against gram-positive and gram-negative mi-
Gram-positive bacteria
Staphylococcus spp.
Streptococcus spp.
Streptococcus pneumoniae etc.
Myramistin also Ascomycetes (Ascomycota) Yeast (Saccharomycetaceae) Dimorphic (yeast-like) Dermatophytes
Sexually transmitted pathogens
Chlamydia spp., Treponema spp, Trichomonas vaginalis, Neisseria gonorrhoeae
The mechanism of myramistin's antimicrobial action is explained by its relationship to quaternary ammonium compounds, which have a significant specificity of antimicrobial action [13, 14]. These compounds have their own code according to the ATC classification - group D08AJ (antiseptic and disinfectants), which have a pronounced pharmacological effect and demonstrate their effective use. Myramistin is also known for its high permeability and ability to affect resistant forms of microorganisms, because derivatives of quaternary ammonium compounds have a multi-purpose nature and are quite studied. Such characteristics and properties allowed them to occupy their place between antiseptic and disinfectant solutions [13, 14], and myramistin in particular is positioned as a fairly safe antiseptic component of medicinal products in various dosage forms.
After analyzing the results of clinical studies of such drugs as "Veromistin", "Myramistin" and "Celista" (PrJSC "Pharmaceutical firm "Darnitsa"), which are monopreparations of Myramistin, only individual sensitivity is noted among the contraindications to use. This is explained by the fact that this API does not penetrate through the skin and mucous membranes and does not cause allergic reactions. It is also indicated
croorganisms [8]. It is due to this activity that the antiseptic solution can provide a reliable level of protection. As you know, antiseptics are a group of drugs known for their wide use in medical practice, because local antiseptics have a unique ability to control the spread of infections and potential human infection [911]. Exactly this characteristic of myramistin makes it possible to ensure the reliability of disinfectant and antiseptic action during medical use.
According to the instructions for medical use and the results of clinical and microbiological studies, myramistin is active against such bacterial pathogens [12]:
Gram-negative bacteria
Pseudomonas aeruginosa Escherichia coli Klebsiella spp. etc.
that the phenomena of overdose with these drugs were not observed, which potentially indicates the safety of myramistin as an API in the composition of these drugs.
In addition to the above-mentioned ways of using the myramistin substance, a special way of using it -inhalation is also possible. Inhalation treatment consists in the introduction of the drug to the site of the pathological process, which potentially accelerates its effect when using smaller doses of the drug, and with such slow administration, it is possible to prevent some systemic unwanted effects that could occur during treatment. This method is characterized by an effect on mucociliary clearance (the mechanism of self-cleaning of the airways of the respiratory system), the anti-inflammatory and trophic effect of myramistin was also observed during clinical trials [15]. Thus, it is possible to create and clinically use an inhalation form of the drug based on myramistin for the treatment of patients with respiratory diseases of the upper and lower respiratory tract.
Myramistin is positioned not only as a bactericidal agent, but also as an agent that affects biofilms of microorganisms. Such films are a structured grouping of microorganisms that have a protective function, pro-
ias an antifungal effect on representatives of the following genera: Genera Aspergillus and Penicillium Rhodotorula rubra, Torulopsis gabrata etc. Candida albicans, Candida tropicalis, Candida krusei etc. Families Arthrodermataceae: Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Trichophyton verrucosum, Trichophyton schoenleini, Trichophyton violacent, Microsporum gypseum, Microsporum canis, Epidermophyton Kaufinan-Wolf, etc.
The unique property of impact on pathogens:
Herpes viruses
Herpes simplex viruses — herpesviruses 1 and 2 types; Chicken pox - type 3; Epstein-Barr virus — type 4; Cytomegalovirus — type 5; type 6 — causes false rubella; 7 and 8 types, etc
Human immunodeficiency viruses (HIV)
Genus of lentiviruses (retroviruses) that cause acquired immunodeficiency syndrome (AIDS)
mote reproduction and are generally one of the most reliable ways to survive in the environment. Myramistin slows the formation and growth of biofilms in S. py-ogenes, S. aureus, E. coli, L. acidophilus, and L. planta-rum [16]. Taking group A streptococcus (Streptococcus pyogenes) as an example, which is the causative agent of streptococcal pharyngitis, scarlet fever, otitis, sepsis, dysentery and other serious diseases, is a very resistant microorganism to the action of environmental factors [17]. Since biofilms are a grouping of even resistant microorganisms to the influence of extreme conditions, such as the effect of UV radiation, high temperatures, high pressure, antibiotics, high salinity and insufficient nutrients, changes in the pH value [18], the use of myra-mistin becomes even more promising.
It has been experimentally confirmed that myra-mistin exhibits a high cytotoxic effect at higher concentrations (>8x10-4 %) and thus has a positive effect on the healing rate of chronic wounds (bedsores, trophic ulcers, ulcers in diabetic foot syndrome) [19, 20]. In such cases, myramistin can be used as the first stage of treatment of the affected area of the wound before applying the gel or ointment.
The use of suppositories with myramistin for the treatment of nonspecific vaginitis in the II trimester of pregnancy on the eve of the installation of a cervical pessary provided a pronounced clinical effect without further recurrence of the disease [21].
As a result of conducting numerous laboratory and clinical studies, as well as over many years of wide use in real urological practice, myramistin has proven itself as a highly effective antimicrobial drug with a wide spectrum of action and the absence of resistance in most sexually transmitted pathogens. Thanks to additional immunomodulatory and anti-inflammatory properties, myramistin allows to significantly improve the results of treatment of patients with chronic and indolent forms of urogenital infections. Currently, myramistin is a good alternative among drugs for individual prevention of sexually transmitted infections [22, 23].
Since the coronavirus disease has become one of the world's pandemics, today the question of expanding the range of medicines for the treatment and prevention of morbidity in the case of COVID-19 is still relevant and needs to be studied. Scientists have determined that myramistin probably has its in vitro effect against SARS-CoV-2 [24]. The possibility of using quaternary ammonium compounds as nasal antiseptics to prevent SARS-CoV-2 infection is also being investigated. The main mechanism of this action is an increase in endo-cytic and lysosomal pH and the destruction of the viral capsid (the outer protein shell of the virus, which performs a protective function) [25]. According to the Ministry of Health of Ukraine, alcohol-containing antiseptics (ethyl alcohol 60-70-80%, isopropanol 45%, n-propanol 30%), solutions and gels based on them, as well as solutions of chlorhexidine 1%, hydrogen peroxide 0.5 % and sodium hypochlorite 0.1% [11]. In order to expand the list of antiseptic agents used for surface treatment, it is possible to alternately add myramistin, as one of the new and promising means of controlling the spread of infections.
Studying the online portal Tabletki.ua [26], which is an official partner of the Ministry of Health of Ukraine and allows to analyze the availability of drugs in pharmacies and their prices, it is possible to characterize medicinal products with myramistin as drugs with a high level of prevalence and a relatively low price, which in general, it is one of the biggest advantages of this API. Available to the public are such dosage forms with myramistin as a solution, spray, suppositories, drops and ointments, which can be purchased at any pharmacy.
Conclusions: Thus, the results of a brief review of the literature confirm the promising use of myramistin as an antiseptic agent in medicine and pharmacy. Currently, myramistin is most widely used in otorhinolar-yngology, surgery, dermatology and dentistry. Therefore, supplementing the assortment of medicines, expanding the possible indications for the use of myramistin in clinical areas based on its already known properties are promising goals of medicine and pharmacy in general. Also, the pharmaceutical development of new dosage forms such as medical/hemostatic sponges with myramistin can be a valuable addition to the already registered pharmaceutical products on the pharmaceutical market of Ukraine.
References
1. Chernysheva MG, Shnitko AV, Skrabkova HS, Badun GA. Peculiarities of alkylamidopropyl-dimethylbenzylammonium (Myramistin) in the relationship to lysozyme in comparison with quaternary ammonium surfactants: Coadsorption at the interfaces, enzymatic activity and molecular docking. Colloids and Surfaces A: Physicochemical and Engineering Aspects [Internet]. 2021 Nov [cited 2023 Jan 17];629:127503.
2. PubChem [Internet]. Myramistin ion; [cited 2023 January 17]. Available from: https://pub-chem.ncbi.nlm.nih.gov/compound/Myramistin-ion
3. Osmanov A, Farooq Z, Richardson MD, Denning DW. The antiseptic Myramistin: a review of its comparative in vitro and clinical activity. FEMS Microbiology Reviews [Internet]. 2020 May 9;44(4):399-417.
4. Osmanov A, Wise A, Denning DW. In vitro and in vivo efficacy of Myramistin against drug-resistant fungi. J Med Microbiol. 2019 Jul;68(7):1047-1052. Osmanov A, Wise A, Denning DW. In vitro and in vivo efficacy of Myramistin against drug-resistant fungi. Journal of Medical Microbiology [Internet]. 2019 Jul 1;68(7):1047-52.
5. Mishen'kin N. V. Sovremennyye tendentsii i vozmozhnosti pri khirurgicheskom lechenii khronich-eskogo gnoynogo srednego otita // Vestn. otori-nolaringologii. 1999;5:30-31.
6. Zavaliy M. A., Balabantsev A. G., Krivoshein YU. S. Metod konservativnogo lecheniya bol'nykh si-nusitami s ispol'zovaniyem novogo immunomoduliru-yushchego antiseptika miramistina: Inform. listok, № 89-97. - Simferopol': TSNTEN, 1997:4 s.
7. Compendium [Internet]. Active ingredient MYRAMISTINUM*| Dovidnyk likars'kykh preparativ Kompendium; [cited 2023 January 17]. Available
from: https://compen-
dium.com.ua/uk/akt/77/151/myramistinum/. [in
Ukrainian]
8. Osmanov A, Wise A, Denning DW. In vitro and in vivo efficacy of Myramistin against drug-resistant fungi. J Med Microbiol. 2019 Jul;68(7):1047-1052.
9. Nazarchuk OA, Chereshniuk IL, Nazarchuk HH. The research of antimicrobial efficacy of antiseptics decamethoxin, Myramistin and their effect on nuclear DNA fragmentation and epithelial cell cycle. Wiad Lek. 2019;72(3):374-380.
10. McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999 Jan;12(1):147-79. doi: 10.1128/CMR.12.1.147. Erratum in: Clin Microbiol Rev 2001 Jan;14(1):227.
11. Jackson MM. Topical antiseptics in healthcare. Clin Lab Sci. 2005 Summer;18(3):160-9.
12. Normative and directive documents of the Ministry of Health of Ukraine. Available from: https://mozdocs.kiev.ua/likiview.php?id=12147 [in Ukrainian]
13. Quaternary ammonium compounds. IUPAC Compendium of Chemical Terminology. Research Tri-agle Park, NC. URL: https://doi.org/10.1351/goldbook.q05003 (date of access: 25.07.2022).
14. Wessels S, Ingmer H. Modes of action of three disinfectant active substances: a review. Regul Toxicol Pharmacol. 2013 Dec;67(3):456-67.
15. Gerba C. P. Quaternary Ammonium Biocides: Efficacy in Application. Applied and Environmental Microbiology. 2014;Vol. 81, no. 2:464-469.
16. Maris P. Modes of action of disinfectants. Revue Scientifique et Technique de l'OIE. 1995; Vol. 14, no. 1:47-55.
17. Khan MA, Lian NA, Vakhova EL, Mikitchenko LI, Radetskaia LI. [Inhalation of Myramistin in the children presenting with acute respiratory diseases]. Vopr Kurortol Fizioter Lech Fiz Kult. 2015 May-Jun;92(3):35-39.
18. Danilova TA, Danilina GA, Adzhieva AA, Minko AG, Nikolaeva TN, Zhukhovitskii VG, Pronin AV. Effects of Myramistin and Phosprenil on Microbial Biofilms. Bull Exp Biol Med. 2017 Aug;163(4):439-442. doi: 10.1007/s10517-017-3823-x. Epub 2017 Aug 29.
19. Kramer A., Schwebke I., Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infectious Diseases. 2006;Vol. 6, no. 1.
20. Yin W, Wang Y, Liu L, He J. Biofilms: The Microbial "Protective Clothing" in Extreme Environments. Int J Mol Sci. 2019 Jul 12;20(14):3423. doi: 10.3390/ijms20143423.
21. Fromm-Dornieden C, Rembe JD, Schäfer N, Böhm J, Stuermer EK. Cetylpyridinium chloride and Myramistin as antiseptic substances in chronic wound management - prospects and limitations. J Med Microbiol. 2015 Apr;64(Pt 4):407-414.
22. Klinichna efektyvnist' vahinal'nykh supozytoriyiv, shcho mistyat' miramistyn, u korys-tuvachiv akushers'koho pesariyu pry nespetsyfichnomu vahiniti. Kon'kov D. H., Starovyer A. V., Bulavenko O. V., Voznyuk A. V. Health of woman. 2017;7(123):52-58. [in Ukrainian]
23. Mikhail Korinchuk. Vozmozhnosti prime-neniya miramistina v urologii. Zdorovya Ukraini, medichna gazeta. s 17. Available from https://health-ua.com/article/6156-vozmozhnosti-primeneniya-Myramistina-v-urologii
24. Martinez-Guerrero L, Zhang X, Zorn KM, Ek-ins S, Wright SH. Cationic Compounds with SARS-CoV-2 Antiviral Activity and Their Interaction with Organic Cation Transporter/Multidrug and Toxin Extruder Secretory Transporters. J Pharmacol Exp Ther. 2021 0ct;379(1):96-107.
25. Cegolon L, Javanbakht M, Mastrangelo G. Nasal disinfection for the prevention and control of COVID-19: A scoping review on potential chemo-pre-ventive agents. Int J Hyg Environ Health. 2020 Sep;230:113605.
26. Online portal Tabletki.ua. Available from: https://tabletki.ua/uk/
