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COMPARATIVE STUDY OF EXTEMPORANEOUS MOUTHWASHES FOR MUCOSITIS: WORLD SITUATION AND PERSPECTIVES FOR UKRAINE
Lysianska Hanna, Department of Technology of medications, Zaporizhzhia State Medical University, Ukraine, ORCID ID: https://orcid.org/0000-0002-7685-4040
Al Zedan Fadi, Department of Technology of medications, Zaporizhzhia State Medical University, Ukraine, ORCID ID: https://orcid.org/0000-0001-9596-2779
DOI: https://doi.org/10.31435/rsglobal_ws/30122021/7725
ABSTRACT
Oral mucositis is one of the most common toxicities observed during radiotherapy and chemotherapy for patients with cancer. It is painful and significantly affect nutrition process and mouth care. Painful mucositis impairs the ability to eat and drink fluids and impacts quality of life. Mixed medication mouthwash is commonly used to prevent or treat oral mucositis in world's medical practice. It is typically compounded by a pharmacy and most often contains anticholinergic agents (diphenhydramine), an anesthetic (lidocaine) and an antacid or mucosal coating agent (magnesium or aluminum hydroxide, kaolin, or sucralfate). The mixture may also contain an antibiotic or an antifungal medication (nystatin) and a corticosteroid. In comparison, assortment of compounded topical medications consisted of mostly dosage forms for applications with benzocaine (anestezine) oily solutions, antiseptics (chlorhexidine), antibiotic or an antifungal medication (nystatin), natural additions (infusion of medical herbs) and vitamins. So, this article presents an analysis of literature data and the assortment of the compounded mouthwashes in Ukraine and in the world. Perspectives for development of new formulas are proposed for Ukrainian pharmacies.
Citation: Lysianska Hanna, Al Zedan Fadi. (2021) Comparative Study of Extemporaneous Mouthwashes for Mucositis: World Situation and Perspectives for Ukraine. World Science. 11(72). doi: 10.31435/rsglobal_ws/30122021/7725
Copyright: © 2021 Lysianska Hanna, Al Zedan Fadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Introduction. Modern treatment of oncologic diseases includes chemotherapy with radiology. Extensive use of newer radiotherapy and chemoradiotherapy techniques resulted in improved local control and survival. This approach has increased the risk of complications especially mucositis. At present, oral mucositis is considered to be the most serious non-hematological complication of cancer treatment It occurs in up to 40% of patients receiving conventional therapy and as high as 80% of patients receiving high-dose chemotherapy [5, 8, 19].
Oral mucositis is inflammatory or ulcerative lesions of the oral cavity. It is very painful for patients and can compromise nutritional intake. Also increasing risk for local and systemic infection can be causative.
As it is known high dose chemotherapy and localized high dose radiation therapy are the main factors for developing oral mucositis. Such therapy targets the rapidly dividing cancer cells, however, it also affects normal healthy cells that rapidly turnover, for example, the oral mucosa. Speaking, chewing, and swallowing during the food intake may stimulate some damaging of the mouth. And it is sufficient to breakdown the mucosa and formation of painful ulcerations [6, 12, 14, 16].
ARTICLE INFO
Received: 13 October 2021 Accepted: 02 December 2021 Published: 30 December 2021
KEYWORDS
oral mucositis, topical treatment, mouthwashes, compounded.
So, oral mucositis is characterized by damage to the epithelium of the oral mucosa. A reduction of the saliva barrier, disruption of epithelial cells, thinning of the epithelium, ulceration and altered sense of taste also occur [13, 14, 18]. It is reported that sometimes only partial recovery of taste occurs. Pain and the inability to chew, swallow, talk may lead to dehydration, malnutrition. The lack of saliva can cause tooth caries, loss of fillings, mouth ulcers, and pain. These complications make it more difficult to eat. Infection of the sores or ulcerations by a virus, bacterium, or fungus may occur [17]. Moreover, patients affected by a high-grade mucositis have to reduce chemotherapy regimen.
So, mucositis is not an infectious process and cannot be prevented with medications. Management of oral mucositis include nutritional support, pain control, oral decontamination, palliation of dry mouth, management of oral bleeding and therapeutic interventions for oral mucositis [2, 4, 8].
Materials and methods. For presented study the search, analysis, generalization and systematization of compounded topical medications for prevention and therapy of mucositis were carried out. On-line data and some publications were used for the research. It was studied and systematized results from State Register of Medicines of Ukraine, Compendium on-line (A01A Stomatological preparations), Pharmacist's Letter (Internet resource), special sites, literature data and assortment of pharmacies for estimation for Ukrainian compounding practice [3, 5, 9, 11-13, 17].
It must be admitted that the primary symptom of oral mucositis is pain. This pain greatly affects nutritional intake, mouth care and quality of life. Thus, management of mucositis pain is a primary aim of mucositis management strategy. Pharmacists use saline mouth rinses, ice chips and topical mouthrinses containing an anesthetic such as lidocaine. Such agents may provide short-term relief.
So, therapy of mucositis includes such compounded medications as medicinal multipurpose mouthwashes. Prepared by compounding pharmacists, these mouthwashes commonly come in a multitude of formulations.
Results. There are numerous "magic" mouthwash preparations. Most formulations are used every 6-8 hours with instructions to hold in the mouth for 1-2 minutes then spit out or swallow. The mostly used components for topical preparations are presented in the table 1.
Table 1. Composition of compounded topical preparations for mucositis in Ukraine and in the world
Foreign pharmacy Ukrainian pharmacy
Diphenhydramine hydrochloride Dexamethasone
Chlorpheniramine Hydrocortisone
Lidocaine hydrochloride Prednisolone
Dyclonine hydrochloride Benzocaine
Coating agent (Hydroxpropyl cellular gel, Polyvinylpyrrolidone/sodium hyaluronate gel) Procaine (Novocain)
Magnesium hydroxide, aluminium hydroxide (Maalox) Tannin
Sucralfate* Borax
Dexamethasone* Sulfadimezine
Hydrocortisone* Tetracycline hydrochloride
Prednisone Norsulfazol
Tetracycline hydrochloride Rifampicin
Misoprostol* Doxycyclin
Chlorhexidine Chlorpheniramine
Benzydamine hydrochloride Nystatin
Clotrimazole Vitamin B2
Nystatin* Tocopherol
Tocopherol Vitamin A
Vitamin A Methyluracil
Aloe plant Hydrogenous peroxide
Allopurinol Propolis
Pentoxifylline Sea buckthorn oil
Ketamine Medical plants (decoctions, infusions)
Morphine Nitrofuran (furacilin)
* Ingredient has not been shown to be effective in treating oral mucositis or has not been adequately studied
Analysis of Ukrainian extemporaneous drugs revealed mostly used oily solutions, suspensions for applications and spreading. Among active components benzocaine, antibiotics, antifungals, vitamins are prescribed the most frequently. Besides, compounded medications may include glucocorticoid, antiseptics and agent for trophic improving in tissues.
In comparison, foreign pharmacy presented different formulas. It has been admitted that combination of ingredients may vary, but the most common products often include antihistamines (diphenhydramine, chlorpheniramine) for creating an anesthetic or pain relieving effect; corticosteroids (hydrocortisone, dexamethasone, clobetasol) for reducing inflammation and aids in healing; antibiotics (tetracycline) to stop bacterial infections; anti-inflammatory agents to reduce inflammation; topical anesthetics (tetracaine, lidocaine) to reduce pain and irritation; liquid antacid to help the medication coat the tissues of the mouth. Other common ingredients include misoprostol (anti-inflammatory and protective activity); sucralfate (a protective coating for the healing process); ketamine or morphine for pain relief. Chan A. and Ignoffo R. (2005) determined the top five medical agents used to compound the magic mouthwash: diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin and corticosteroids [3].
Some ingredients of the mouthwashes have negative or discordant data about their efficacy. The Aloe plant contains multiple pharmacologically active compounds which have healing and antiinflammatory effects. Puataweepong, et al. (2009) revealed that Aloe vera did not delay the onset of severe mucositis compared with the placebo [15]. But it was also confirmed that receiving Aloe vera patients had less mucositis than the placebo group. However, Su, et al. (2004) showed that oral Aloe vera was not a beneficial adjunct to head and neck radiotherapy compared with placebo [18]. Some author (2012) combined these differences with more time of exposure to the cavity and due to its dosage form, its preparation Puataweepong, et al. used fresh Aloe vera gel prepared under well-controlled technique of enzyme deactivation [1].
Misoprostol is a synthetic prostaglandin E1 analogue, it has anti-inflammatory and mucosa-protecting properties. There are limited data presented by Hanson, et al., 1995, to suggest that its topical administration may benefit patients receiving head and neck radiotherapy [7]. In a Radiation Therapy Oncology Group (RTOG) (1996-2007) phase II trial of misoprostol in 33 patients receiving radical dose radiotherapy, the incidence of mucositis was compared with that in historical controls and misoprostol was not only ineffective but might have also resulted in worse toxicity. Veness et al. (2006) provided with the negative results of topical misoprostol in reducing the severity of radiation-induced mucositis when given before daily radiotherapy [20]. Results of study presented by Lalla et al. (2011) receiving high-dose chemotherapy, misoprostol rinse was safe, but we did not find a beneficial effect on severity of oral mucositis, mouth pain severity, duration of hospital stay, and need for total parenteral nutrition [10]. But authors marked some limitation because accrual was terminated before the planned sample size was achieved.
Presented data allows to predict a possibility of development new formulas for topical treatment of mucositis using conception of foreign pharmacy, for example, adding water-soluble topical anesthetics, antihistamines, antacids if viscous liquid dosage forms.
Conclusions. Treatment of mucositis is an actual problem for modern oncology. Compounded topical drugs give the opportunity to combine different components for meeting the needs of individuals. Taking into account the experience of other countries, development of new compositions, study of efficacy and stability mouthwashes have significant perspective for scientific researches.
REFERENCES
1. Ahmadi, A. (2012), Potential prevention: Aloe vera mouthwash may reduce radiation-induced oral mucositis in head and neck cancer patients, Chinese Journal of Integrative Medicine, 18 (8), 635-640. doi:10.1007/s11655-012-1183-y.
2. Atlantic Provinces Pediatric Hematology/Oncology Network. Guidelines for the Prevention and Management of Mucositis in Children Receiving Cancer Therapy, 2017. http://www.apphon-rohppa.com/en/guidelines/mucositis-guidelines.
3. Chan A., Ignoffo R. (2005), Survey of topical oral solutions for the treatment of chemo-induced oral mucositis, Journal of Oncology Pharmacy Practice, 11 (4), 139-143.
4. Chaveli-López B, Bagán-Sebastián JV. (2016), Treatment of oral mucositis due to chemotherapy, J Clin Exp Dent., 8 (2), 201-210.
5. Derzhavhyj reestr likarskich zasobiv Ukrainy [State Register of Medicines of Ukraine]. http://www.drlz.com.ua. [in Ukrainian]
6. Elad S., Cheng KKF., Lalla RV., Yarom N., Hong C., Logan RM., Bowen. J, Gibson R., Saunders DP., Zadik Y., Ariyawardana A., Correa ME, Ranna V., Bossi P. (2020), Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy, Cancer, 126 (19). 4423. DOI: 10.1002/cncr.33100.
7. Hanson WR, Marks JE, Reddy SP, Simon S, Mihalo WE, Tova Y. (1995), Protection from radiation-induced oral mucositis by misoprostol, a prostaglandin E1 analog: a placebo-controlled, double-blind clinical trial, Am J Ther., 2, 1-8.
8. Heley N. I., Kostenko YE. YA., Heley V. M., Fedorov D. YU. (2020), Suchasni pohlyady na problemu vtorynnykh urazhen' slyzovoyi obolonky rotovoyi porozhnyny yak pobichnoho efektu kompleksnoho protypukhlynnoho likuvannya (ohlyad literatury) [Modern views on the problem of secondary lesions of the oral mucosa as a side effect of complex antitumor treatment (literature review)], Klinichna stomatolohiya - clinical stomatology, 2, 4-13 [in Ukrainian].
9. Kompendium. Likarski preparaty [Compendium. Medical preparations] https://compendium.com.ua. [in Ukrainian]
10. Lalla, R. V., Gordon, G. B., Schubert, M., Silverman, S., Hutten, M., Sonis, S. T. Peterson, D. E. (2011), A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy, Supportive Care in Cancer, 20 (8), 1797-1804. doi:10.1007/s00520-011-1277-7.
11. Liu S, Zhao Q, Zheng Z, Liu Z, Meng L, Dong L and Jiang X. (2021), Status of Treatment and Prophylaxis for Radiation-Induced Oral Mucositis in Patients with Head and Neck Cancer, Front. Oncol., 11, 642575. doi: 10.3389/fonc.2021.642575.
12. Loyd V. (2011) Allen Oral Mucositis and Compounded Mouthwashes. US Pharm., 36 (7) (Oncology suppl), 12-15.
13. Pharmacist's Letter / Prescriber's Letter. November. (2014), Magic Mouthwash Recipes.
14. Popelo YU. V., Bilokon S. O., Lochmatova N. M. (2013), Projavy pobichnogo vplyvu himioterapevtychnogo likuvannja zi zlojakisnymy puhlynamy na stan organiv porozhnyny rota [Manifestations of side effects of chemotherapeutic treatment with malignant tumors on the condition of the oral cavity], Materialy III zyizdu ukrayinskoyi asotsiatsiyi cherepno-shchelepno-lytsevykh khirurhiv [Proceedings of the III Congress of the Ukrainian Association of Craniofacial Surgeons] Kyiv, 134-136 [in Ukrainian].
15. Puataweepong P, Dhanachai M, Dangprasert S, Sithatani C, Sawangsilp T, Narkwong L, et al. (2009), The efficacy of oral Aloe vera juice for radiation induced mucositis in head and neck cancer patients: a doubleblind placebo-controlled study, Asian Biomed., 3, 375-382.
16. Pulito C., Cristaudo A., La Porta C., Zapperi S., Blandino G., Morrone A., Strano S. (2020), Oral mucositis: the hidden side of cancer therapy, Journal of Experimental & Clinical Cancer Research, 39, 210. https://doi.org/10.1186/s13046-020-01715-7
17. Shulga Y. O., Dankevich O. S. Analiz assortimenta ekstemporal'nyh preparatov i gotovyh lekarstennyh sredstv dlya primeneniya v stomatologii [Analysis of assortment of extemporaneous and commercial preparations using in stomatology] Studencheskaya medicinskaya nauka XXI veka. IV Forum molodezhnyh nauchnyh obshchestv: materialy XIX mezhdunarodnoj nauchno-prakticheskoy konferentsii studentov i molodyh uchenyh i IV Foruma molodezhnyh nauchnyh obshchestv (Vitebsk, 23-24 okt. 2019 g.) / pod red. A. T. Shchastnogo. [Student's medical science of XXI century, IV Forum of youth scientific societies: proceedings of the XIX International scientific and practical conference of the students and young scientists and IV Forum of youth scientific societies (Vitebsk, 23-24 October 2019) / edited by A. T. Shchastniy] Vitebsk: VSMU, 2019, 942-946 [in Russian].
18. Su CK., Mehta V., Ravikumar L., Shah R., Pinto H., Halpern J., et al. (2004), Phase II double-blind randomized study comparing oral Aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms, Int JRadiat Oncol Biol Phys., 60, 171-177.
19. Sukhina I. S. (2017), Profilaktika i lechenie himio-indukovanogo oralnogo mukozitu [Prevention and treatment of chemo-induced oral mucositis], Aktualni problemy suchasnoji meditsyny - Actual problems of modern medicine, 17, 1 (57), 325-329 [in Ukrainian].
20. Veness M., Foroudi F., Gebski V., Timms, I., Sathiyaseelan, Y., Cakir B., Tiver K. (2006), Use of topical misoprostol to reduce radiation-induced mucositis: Results of a randomized, double-blind, placebo-controlled trial. Australasian Radiology, 50 (5), 468-474. doi:10.1111/j.1440-1673.2006.01628.x
