Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Glutaryl Melatonin Niosome Gel for Topical Oral Mucositis: Anti- Inflammatory and Anticandidiasis

Author(s): Teerasak Damrongrungruang*, Panjaree Panpitakkul, Jirachaya Somudorn, Pimpitchaya Sangchart, Pramote Mahakunakorn, Prangtip Uthaiwat, Jureerut Daduang, Panyada Panyatip, Ploenthip Puthongking and Aroonsri Priprem

Volume 17, Issue 3, 2020

Page: [195 - 206] Pages: 12

DOI: 10.2174/1567201817666200122162545

Price: $65

Abstract

Background: Glutaryl melatonin, which is synthesized from melatonin and is a pineal glandderived neurohormone with anti-inflammatory and anti-oxidant properties, was comparatively investigated for its potential use as a topical anti-inflammatory agent.

Objective: Glutaryl melatonin, synthesized and screened for in vitro anti-candidiasis and in vitro and in vivo anti-inflammatory activities, was formulated as a niosome gel for topical oral evaluation in 5- fluorouracil-induced oral mucositis in mice.

Methods: In vitro anti-fungal activity in Candida albicans, in vitro anti-inflammatory activity in Escherichia coli liposaccharide-induced RAW cells and in vivo anti-inflammatory activity using a croton oilinduced ear edema model in ICR mice were investigated. Mucositis in mice (n= 6/group, 10-week-old mice) was induced by intraperitoneal injections of 5-fluorouracil, and the mice were subjected to a topical oral application of niosome gel containing melatonin (2% w/w) or glutaryl melatonin (2% w/w) and were compared with mice subjected to blank, fluocinolone acetonide (0.5% w/w) and control conditions.

Results: Glutaryl melatonin, at a 14.2 mM concentration, showed the highest fungicidal effect on C. albicans using the broth dilution method, indicating a nonsignificant difference from 1 μM of nystatin (p = 0.05). Nitric oxide, interleukin-6 and tumor necrosis factors were analyzed by ELISA. Liposaccharide-induced RAW cells were significantly reduced by glutaryl melatonin (p < 0.01). Ear edema inhibition of glutaryl melatonin was significant 1 h after application compared with that of melatonin (p = 0.03). Food consumption and body weight of the 5-fluorouracil-treated mice were significantly lower than those of the normal mice before all treatments (p < 0.05). Differences in the amount of licking behavior, which were observed in the control group for 5 min, were noticeable in the 5- fluorouracil-treated mice but not in the mice treated with the glutaryl melatonin niosome gel.

Conclusion: Glutaryl melatonin exhibited mild anti-candidiasis and anti-inflammatory properties. The incorporation of glutaryl melatonin in a niosome gel formulation, demonstrated the potential for topical oral applications to reduce oral discomfort caused by 5-fluorouracil treatment in mice.

Keywords: Glutaryl melatonin, anti-candidiasis, anti-inflammation, niosome gel, 5-fluorouracil, injections.

« Previous Next »
Graphical Abstract

[1]
Lalla, R.V.; Latortue, M.C.; Hong, C.H.; Ariyawardana, A.; D’Amato-Palumbo, S.; Fischer, D.J. Fungal infections section, oral care study group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systemic review of oral fungal infections in patients receiving cancer therapy. Support. Care Cancer, 2010, 18, 985-992.
[http://dx.doi.org/10.1007/s00520-010-0892-z] [PMID: 20449755]
[2]
Lalla, R.V.; Patton, L.L.; Dongari-Bagtzoglou, A. Oral candidiasis: pathogenesis, clinical presentation, diagnosis and treatment strategies. J. Calif. Dent. Assoc., 2013, 41(4), 263-268.
[PMID: 23705242]
[3]
Reiter, R.J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr. Rev., 1991, 12(2), 151-180.
[http://dx.doi.org/10.1210/edrv-12-2-151] [PMID: 1649044]
[4]
Maestroni, G.J. The immunoneuroendocrine role of melatonin. J. Pineal Res., 1993, 14(1), 1-10.
[http://dx.doi.org/10.1111/j.1600-079X.1993.tb00478.x] [PMID: 8483103]
[5]
Tahan, G.; Gramignoli, R.; Marongiu, F.; Aktolga, S.; Cetinkaya, A.; Tahan, V.; Dorko, K. Melatonin expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic-acid-induced colitis in rats. Dig. Dis. Sci., 2011, 56(3), 715-720.
[http://dx.doi.org/10.1007/s10620-010-1364-5] [PMID: 20676767]
[6]
Mauriz, J.L.; Collado, P.S.; Veneroso, C.; Reiter, R.J.; González-Gallego, J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J. Pineal Res., 2013, 54(1), 1-14.
[http://dx.doi.org/10.1111/j.1600-079X.2012.01014.x] [PMID: 22725668]
[7]
Reiter, R.J.; Calvo, J.R.; Karbownik, M.; Qi, W.; Tan, D.X. Melatonin and its relation to the immune system and inflammation. Ann. N. Y. Acad. Sci., 2000, 917, 376-386.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb05402.x] [PMID: 11268363]
[8]
Terrón, M.P.; Cubero, J.; Barriga, C.; Ortega, E.; Rodríguez, A.B. Phagocytosis of Candida albicans and superoxide anion Levels in ring dove (Streptopelia risoria) heterophils: effect of melatonin. J. Neuroendocrinol., 2003, 15(12), 1111-1115.
[http://dx.doi.org/10.1111/j.1365-2826.2003.01103.x] [PMID: 14636172]
[9]
Terrón, M.P.; Cubero, J.; Marchena, J.M.; Barriga, C.; Rodriguez, A.B. Melatonin and aging: in vitro effect of young and mature ring dove physiological concentrations of melatonin on the phagocytic function of heterophils from old ring dove. Exp. Gerontol., 2002, 37(2-3), 421-426.
[http://dx.doi.org/10.1016/S0531-5565(01)00209-1] [PMID: 11772529]
[10]
Terrón, M.P.; Paredes, S.D.; Barriga, C.; Ortega, E.; Rodríguez, A.B. Comparative study of the heterophil phagocytic function in young and old ring doves (Streptopelia risoria) and its relationship with melatonin levels. J. Comp. Physiol. B, 2004, 174(5), 421-427.
[http://dx.doi.org/10.1007/s00360-004-0429-1] [PMID: 15148621]
[11]
Reiter, R.J.; Rosales-Corral, S.A.; Liu, X.Y.; Acuna-Castroviejo, D.; Escames, G.; Tan, D.X. Melatonin in the oral cavity: physiological and pathological implications. J. Periodontal Res., 2015, 50(1), 9-17.
[http://dx.doi.org/10.1111/jre.12176] [PMID: 24665831]
[12]
Caballero, G.A.; Ausman, R.K.; Quebbeman, E.J. Long-term, ambulatory, continuous IV infusion of 5-FU for the treatment of advanced adenocarcinomas. Cancer Treat. Rep., 1985, 69(1), 13-15.
[PMID: 3155649]
[13]
Sonis, S.T.; Elting, L.S.; Keefe, D.; Peterson, D.E.; Schubert, M.; Hauer-Jensen, M.; Bekele, B.N.; Raber-Durlacher, J.; Donnelly, J.P.; Rubenstein, E.B. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer, 2004, 100(9)(Suppl.), 1995-2025.
[http://dx.doi.org/10.1002/cncr.20162] [PMID: 15108222]
[14]
Maria, O.M.; Eliopoulos, N.; Muanza, T. Radiation-induced oral mucositis. Frontiers. Front. Oncol., 2017, 7, 89.
[http://dx.doi.org/10.3389/fonc.2017.00089] [PMID: 28589080]
[15]
Sugerman, P.B.; Savage, N.W.; Walsh, L.J.; Zhao, Z.Z.; Zhou, X.J.; Khan, A.; Seymour, G.J.; Bigby, M. The pathogenesis of oral lichen planus. Crit. Rev. Oral Biol. Med., 2002, 13(4), 350-365.
[http://dx.doi.org/10.1177/154411130201300405] [PMID: 12191961]
[16]
De Rossi, S.S.; Ciarrocca, K. Oral lichen planus and lichenoid mucositis. Dent. Clin. North Am., 2014, 58(2), 299-313.
[http://dx.doi.org/10.1016/j.cden.2014.01.001] [PMID: 24655524]
[17]
Thongprasom, K.; Dhanuthai, K. Steriods in the treatment of lichen planus: a review. J. Oral Sci., 2008, 50(4), 377-385.
[http://dx.doi.org/10.2334/josnusd.50.377] [PMID: 19106464]
[18]
Jainkittivong, A.; Kuvatanasuchati, J.; Pipattanagovit, P.; Sinheng, W. Candida in oral lichen planus patients undergoing topical steroid therapy. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 2007, 104(1), 61-66.
[http://dx.doi.org/10.1016/j.tripleo.2006.10.024] [PMID: 17261374]
[19]
Yap, T.; McCullough, M. Oral medicine and the ageing population. Aust. Dent. J., 2015, 60(Suppl. 1), 44-53.
[http://dx.doi.org/10.1111/adj.12283] [PMID: 25762041]
[20]
Tekbas, O.F.; Ogur, R.; Korkmaz, A.; Kilic, A.; Reiter, R.J. Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J. Pineal Res., 2008, 44(2), 222-226.
[http://dx.doi.org/10.1111/j.1600-079X.2007.00516.x] [PMID: 18289175]
[21]
Najeeb, S.; Khurshid, Z.; Zohaib, S.; Zafar, M.S. Therapeutic potential of melatonin in oral medicine and periodontology. Kaohsiung J. Med. Sci., 2016, 32(8), 391-396.
[http://dx.doi.org/10.1016/j.kjms.2016.06.005] [PMID: 27523451]
[22]
Merten, H.L.; Bachman, G.L. Glutaric acid: A potential food acidulant. J. Food Sci., 1976, 41, 463-464.
[http://dx.doi.org/10.1111/j.1365-2621.1976.tb00646.x]
[23]
McNamara, D.P.; Childs, S.L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M.S.; Mannion, R.; O’Donnell, E.; Park, A. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm. Res., 2006, 23(8), 1888-1897.
[http://dx.doi.org/10.1007/s11095-006-9032-3] [PMID: 16832611]
[24]
Thoai, P.V.; Nam, N.H. Design and synthesis of sustain-acting melatonin prodrugs. J. Chem., 2013, 2013, 6.
[25]
Phiphatwatcharaded, C.; Puthongking, P.; Chaiyarit, P.; Johns, N.P.; Sakolchai, S.; Mahakunakorn, P. The anti-oxidant effects of melatonin derivatives on human gingival fibroblasts. Arch. Oral Biol., 2017, 79, 55-61.
[http://dx.doi.org/10.1016/j.archoralbio.2017.02.022] [PMID: 28292674]
[26]
Phiphatwatcharaded, C.; Topark-Ngarm, A.; Puthongking, P.; Mahakunakorn, P. Anti-inflammatory activities of melatonin derivatives in lipopolysaccharide-stimulated RAW 264.7 cells and antinociceptive effects in mice. Drug Dev. Res., 2014, 75(4), 235-245.
[http://dx.doi.org/10.1002/ddr.21177] [PMID: 24826922]
[27]
Kaneko, Y.; Fukazawa, H.; Ohno, H.; Miyazaki, Y. Combinatory effect of fluconazole and FDA-approved drugs against Candida albicans. J. Infect. Chemother., 2013, 19(6), 1141-1145.
[http://dx.doi.org/10.1007/s10156-013-0639-0] [PMID: 23807392]
[28]
Nukulkit, C.; Priprem, A.; Damrongrungruang, T.; Benjavongkulchai, E.; Johns, N.P. Effect of polycaprolactone on in vitro release of melatonin encapsulated niosomes in artificial and whole saliva. J. Drug Deliv. Sci. Technol., 2014, 24, 153-158.
[http://dx.doi.org/10.1016/S1773-2247(14)50025-1]
[29]
Priprem, A.; Nukulkit, C.; Johns, N.P.; Laohasiriwong, S.; Yimtae, K.; Soontornpas, C. Transmucosal delivery of melatonin-encapsulated niosomes in a mucoadhesive gel. Ther. Deliv., 2018, 9(5), 343-357.
[http://dx.doi.org/10.4155/tde-2018-0001] [PMID: 29681235]
[30]
Reference method for broth dilution susceptibility testing of yeasts. Clinical and laboratory standards institute / National committee for clinical laboratory standards. Approved standard, 2nd Ed.; Document M27-A2, Wayne, PA 2002, 28(14), 1-25.
[31]
Strazielle, C.; Lalonde, R. Grooming in Lurcher mutant mice. Physiol. Behav., 1998, 64(1), 57-61.
[http://dx.doi.org/10.1016/S0031-9384(98)00014-6] [PMID: 9661982]
[32]
Li, Y.; Lindemann, C.; Goddard, M.J.; Hyland, B.I. Complex multiplexing of reward-cue- and licking-movement-related activity in single midline thalamus neurons. J. Neurosci., 2016, 36(12), 3567-3578.
[http://dx.doi.org/10.1523/JNEUROSCI.1107-15.2016] [PMID: 27013685]
[33]
Van Abeelen, J.H.; Van der Kroon, P.H.; Bekkers, M.F. Mice selected for rearing behavior: some physiological variables. Behav. Genet., 1973, 3(1), 85-90.
[http://dx.doi.org/10.1007/BF01067692] [PMID: 4715987]
[34]
Yoo, Y.M.; Jang, S.K.; Kim, G.H.; Park, J.Y.; Joo, S.S. Pharmacological advantages of melatonin in immunosenescence by improving activity of T lymphocytes. J. Biomed. Res., 2016, 30(4), 314-321.
[PMID: 27533940]
[35]
Skorik, Y.A.; Kritchenkov, A.S.; Moskalenko, Y.E.; Golyshev, A.A.; Raik, S.V.; Whaley, A.K.; Vasina, L.V.; Sonin, D.L. Synthesis of N-succinyl- and N-glutaryl-chitosan derivatives and their antioxidant, antiplatelet, and anticoagulant activity. Carbohydr. Polym., 2017, 166, 166-172.
[http://dx.doi.org/10.1016/j.carbpol.2017.02.097] [PMID: 28385220]
[36]
Badawy, M.E.I.; Rabea, E.I. Characterization and antimicrobial activity of water-soluble N-(4-carboxybutyroyl) chitosans against some plant pathogenic bacteria and fungi. Carbohydr. Polym., 2012, 87, 250-256.
[http://dx.doi.org/10.1016/j.carbpol.2011.07.054]
[37]
Iqbal, M.; Baloch, I.B.; Baloch, M.K. Evaluation of antifungal and antibacterial activities of monoesters of succinic anhydride. Bull. Chem. Soc. Ethiop., 2014, 28, 131-136.
[http://dx.doi.org/10.4314/bcse.v28i1.15]
[38]
Dortch-Carnes, J.; Tosini, G. Melatonin receptor agonist-induced reduction of SNP-released nitric oxide and cGMP production in isolated human non-pigmented ciliary epithelial cells. Exp. Eye Res., 2013, 107, 1-10.
[http://dx.doi.org/10.1016/j.exer.2012.11.007] [PMID: 23201027]
[39]
Shim, D.W.; Shin, H.J.; Han, J.W.; Ji, Y.E.; Jang, C.H.; Koppula, S.; Kang, T.B.; Lee, K.H. A novel synthetic derivative of melatonin, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation. Toxicol. Appl. Pharmacol., 2015, 284(2), 227-235.
[http://dx.doi.org/10.1016/j.taap.2015.02.006] [PMID: 25689174]
[40]
Scotland, P.E.; Coderre, T.J. Enhanced 3,5-dihydroxyphenylglycine-induced sustained nociceptive behaviors in rats with neuropathy or chronic inflammation. Behav. Brain Res., 2007, 184(2), 150-156.
[http://dx.doi.org/10.1016/j.bbr.2007.07.003] [PMID: 17681386]
[41]
Focaccetti, C.; Bruno, A.; Magnani, E.; Bartolini, D.; Principi, E.; Dallaglio, K.; Bucci, E.O.; Finzi, G.; Sessa, F.; Noonan, D.M.; Albini, A. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One, 2015, 10(2)e0115686
[http://dx.doi.org/10.1371/journal.pone.0115686] [PMID: 25671635]
[42]
Priprem, A.; Damrongrungruang, T.; Limsitthichaikoon, S.; Khampaenjiraroch, B.; Nukulkit, C.; Thapphasaraphong, S.; Limphirat, W. Topical niosome gel containing an anthocyanin complex: A potential oral wound healing in rats. AAPS PharmSciTech, 2018, 19(4), 1681-1692.
[http://dx.doi.org/10.1208/s12249-018-0966-7] [PMID: 29532424]

Rights & Permissions Print Cite
Article Metrics
25
2
© 2024 Bentham Science Publishers | Privacy Policy