Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of the Efficacy of Amphotericin B and Terbinafine Microemulsions and Their Combination on Cutaneous Leishmaniasis and Comparison with the Conventional Drug Form in BALB/c Mice

  • Research Article
  • Applications of Machine Learning and A.I. in Pharmaceutical Development and Technology
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Intracellular parasitic protozoa of Leishmania sp. causes leishmaniasis. The restricted access of the drugs to affected cells in the treatment of intracellular infections such as leishmaniasis is frequently hampered. Furthermore, most of today’s drugs have limited uses due to some containing toxic compounds, and drug resistance is on the rise. In the present investigation, Amphotericin B (AmB) and Terbinafine (Tbf) were loaded in microemulsion (ME) in combination and alone, and the in vivo efficacy was considered in BALB/c mice infected with Leishmania major (L. major). The wound size at the base of the mouse tail was measured, and real-time PCR was performed to quantify the parasite load after the infection challenge. The study demonstrated that the ME-AmB and ME-Tbf formulations are safe and effective compounds for the treatment of cutaneous leishmaniasis by enhancing the effectiveness of AmB and Tbf in reducing the parasite burden.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Roberts C, McLeod R, Rice D, Ginger M, Chance M, Goad L. Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa. Mol Biochem Parasitol. 2003;126(2):129–42. https://doi.org/10.1016/S0166-6851(02)00280-3.

    Article  CAS  PubMed  Google Scholar 

  2. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE. 2012;7(5): e35671. https://doi.org/10.1371/journal.pone.0035671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Asadi A, Kareshk AT, Sharifi I, Firouzeh N. Murine cathelicidin: as a host defensive response against Leishmania major infection. J Parasit Dis. 2020;44(3):633–8. https://doi.org/10.1007/s12639-020-01238-0.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Shalev M, Rozenberg H, Smolkin B, Nasereddin A, Kopelyanskiy D, Belakhov V, et al. Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics. Nucleic Acids Res. 2015;43(17):8601–13. https://doi.org/10.1093/nar/gkv821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Copeland NK, Aronson NE. Leishmaniasis: treatment updates and clinical practice guidelines review. Curr Opin Infect Dis. 2015;28(5):426–37. https://doi.org/10.1097/QCO.0000000000000194.

    Article  CAS  PubMed  Google Scholar 

  6. Sundar S, Mehta H, Suresh A, Singh SP, Madhukar R, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis. 2004;38(3):377–83. https://doi.org/10.1086/380971.

    Article  CAS  PubMed  Google Scholar 

  7. Soto J, Arana B, Toledo J, Rizzo N, Vega J, Diaz A, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004;38(9):1266–72. https://doi.org/10.1086/383321.

    Article  CAS  PubMed  Google Scholar 

  8. Rodrigues M, Costa R, Souza C, Foss N, Roselino A. Nephrotoxicity attributed to meglumine antimoniate (Glucantime) in the treatment of generalized cutaneous leishmaniasis. Rev Inst Med Trop Sao Paulo. 1999;41:33–7. https://doi.org/10.1590/S0036-46651999000100007.

    Article  CAS  PubMed  Google Scholar 

  9. Zulfiqar B, Shelper TB, Avery VM. Leishmaniasis drug discovery: recent progress and challenges in assay development. Drug Discov Today. 2017;22(10):1516–31. https://doi.org/10.1016/j.drudis.2017.06.004.

    Article  CAS  PubMed  Google Scholar 

  10. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006;19(1):111–26. https://doi.org/10.1128/CMR.19.1.111-126.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mostafavi M, Farajzadeh S, Sharifi I, Khazaeli P, Sharifi H. Leishmanicidal effects of amphotericin B in combination with selenium loaded on niosome against Leishmania tropica. J Parasit Dis. 2019;43(2):176–85. https://doi.org/10.1007/s12639-018-1071-2.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Awasthi BP, Mitra K. In vitro leishmanicidal effects of the anti-fungal drug natamycin are mediated through disruption of calcium homeostasis and mitochondrial dysfunction. Apoptosis. 2018;23(7):420–35. https://doi.org/10.1007/s10495-018-1468-5.

    Article  CAS  PubMed  Google Scholar 

  13. Farajzadeh S, Heshmatkhah A, Vares B, Mohebbi E, Mohebbi A, Aflatoonian M, et al. Topical terbinafine in the treatment of cutaneous leishmaniasis: triple blind randomized clinical trial. J Parasit Dis. 2016;40(4):1159–64.

    Article  PubMed  Google Scholar 

  14. Ebrahimian S, Asilian A, Faghihi G. Comparetaive study on glucantime and oral terbinafine along with systemic glucantime on cutaneous leishmaniasis. Journal of Isfahan Medical School. 2011;28(118).

  15. Zakai HA, Zimmo SK. Effects of itraconazole and terbinafine on Leishmania major lesions in BALB/c mice. Ann Trop Med Parasitol. 2000;94(8):787–91. https://doi.org/10.1080/00034983.2000.11813603.

    Article  CAS  PubMed  Google Scholar 

  16. Tripathi P, Jaiswal AK, Dube A, Mishra PR. Hexadecylphosphocholine (Miltefosine) stabilized chitosan modified Ampholipospheres as prototype co-delivery vehicle for enhanced killing of L. donovani. Int J Biol Macromol. 2017;105(1):625–37. https://doi.org/10.1016/j.ijbiomac.2017.07.076.

  17. Singh N, Kumar M, Singh RK. Leishmaniasis: current status of available drugs and new potential drug targets. Asian Pac J Trop Med. 2012;5(6):485–97.

    Article  CAS  PubMed  Google Scholar 

  18. Sahoo S, Parveen S, Panda J. The present and future of nanotechnology in human health care. Nanomedicine. 2007;3(1):20–31. https://doi.org/10.1016/j.nano.2006.11.008.

    Article  CAS  PubMed  Google Scholar 

  19. Sahu T, Ratre YK, Chauhan S, Bhaskar L, Nair MP, Verma HK. Nanotechnology based drug delivery system: current strategies and emerging therapeutic potential for medical science. J Drug Deliv Sci Technol. 2021;63: 102487. https://doi.org/10.1016/j.jddst.2021.102487.

    Article  CAS  Google Scholar 

  20. Herrero-Vanrell R, De La Torre MV, Andrés-Guerrero V, Barbosa-Alfaro D, Molina-Martínez IT, Bravo-Osuna I. Nano and microtechnologies for ophthalmic administration, an overview. J Drug Deliv Sci Technol. 2013;23(2):75–102. https://doi.org/10.1016/S1773-2247(13)50016-5.

    Article  CAS  Google Scholar 

  21. Mei L, Zhang Z, Zhao L, Huang L, Yang X-L, Tang J, et al. Pharmaceutical nanotechnology for oral delivery of anticancer drugs. Adv Drug Deliv Rev. 2013;65(6):880–90. https://doi.org/10.1016/j.addr.2012.11.005.

    Article  CAS  PubMed  Google Scholar 

  22. Lin Y-H, Tsai M-J, Fang Y-P, Fu Y-S, Huang Y-B, Wu P-C. Microemulsion formulation design and evaluation for hydrophobic compound:catechin topical application. Colloids Surf, B. 2018;161:121–8.

    Article  CAS  Google Scholar 

  23. Oliveira MB, Calixto G, Graminha M, Cerecetto H, González M, Chorilli M. Development, characterization, and in vitro biological performance of fluconazole-loaded microemulsions for the topical treatment of cutaneous leishmaniasis. Biomed Res Int. 2015;2015:1–12. https://doi.org/10.1155/2015/396894.

    CAS  Google Scholar 

  24. Chawla B, Madhubala R. Drug targets in Leishmania. J Parasit Dis. 2010;34(1):1–13.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sundar S, Singh A, Singh OP. Strategies to overcome anti-leishmanial drugs unresponsiveness. J Trop Med. 2014;2014:1–7. https://doi.org/10.1155/2014/646932.

    Article  Google Scholar 

  26. Bseiso E, Nasr M, Sammour O, Abd El Gawad N. Recent advances in topical formulation carriers of antifungal agents. Indian J Dermatol Venereol Leprol. 2015;81(5):457–63. doi: https://doi.org/10.4103/0378-6323.162328.

  27. Yazdanpanah Y, Sissoko D, Egger M, Mouton Y, Zwahlen M, Chêne G. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials. bmj. 2004;328(7434):1–7. https://doi.org/10.1136/bmj.37995.435787.A6.

  28. Farajzadeh S, Esfandiarpour I, Haghdoost AA, Mohammadi S, Mohebbi A, Mohebbi E, et al. Comparison between combination therapy of oral terbinafine and cryotherapy versus systemic meglumine antimoniate and cryotherapy in cutaneous leishmaniasis: a randomized clinical trial. Iran J Parasitol. 2015;10(1):1–8.

    PubMed  PubMed Central  Google Scholar 

  29. Seifert K, Croft SL. In vitro and in vivo interactions between miltefosine and other anti-leishmanial drugs. Antimicrob Agents Chemothe. 2006;50(1):73–9. https://doi.org/10.1128/AAC.50.1.73-79.2006.

    Article  CAS  Google Scholar 

  30. Omollo R, Alexander N, Edwards T, Khalil EA, Younis BM, Abuzaid AA, et al. Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial. Trials. 2011;12(1):1–10. https://doi.org/10.1186/1745-6215-12-166.

    Article  CAS  Google Scholar 

  31. Garnier T, Croft SL. Topical treatment for cutaneous leishmaniasis. Curr Opin Investig Drugs. 2002;3(4):538–44.

    CAS  PubMed  Google Scholar 

  32. Owais M, Gupta C. Targeted drug delivery to macrophages in parasitic infections. Curr Drug Deliv. 2005;2(4):311–8.

    Article  CAS  PubMed  Google Scholar 

  33. Minodier P, Parola P. Cutaneous leishmaniasis treatment. Travel Med Infect Dis. 2007;5(3):150–8. https://doi.org/10.1016/j.tmaid.2006.09.004.

    Article  PubMed  Google Scholar 

  34. Kale SN, Deore SL. Emulsion micro emulsion and nano emulsion: a review. Syst Rev Pharm. 2017;8(1):39–47. https://doi.org/10.5530/srp.2017.1.8.

    Article  CAS  Google Scholar 

  35. Damasceno BP, Dominici VA, Urbano IA, Silva JA, Araújo IB, Santos-Magalhães NS, et al. Amphotericin B microemulsion reduces toxicity and maintains the efficacy as an antifungal product. J Biomed Nanotechnol. 2012;8(2):290–300.

    Article  CAS  PubMed  Google Scholar 

  36. Darole PS, Hegde DD, Nair HA. Formulation and evaluation of microemulsion based delivery system for amphotericin B. AAPS PharmSciTech. 2008;9(1):122–8. https://doi.org/10.1208/s12249-007-9022-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Butani D, Yewale C, Misra A. Amphotericin B topical microemulsion: formulation, characterization and evaluation. Colloids Surf, B. 2014;116:351–8.

    Article  CAS  Google Scholar 

  38. Barot BS, Parejiya PB, Patel HK, Gohel MC, Shelat PK. Microemulsion-based gel of terbinafine for the treatment of onychomycosis: optimization of formulation using D-optimal design. AAPS PharmSciTech. 2012;13(1):184–92. https://doi.org/10.1208/s12249-011-9742-7.

    Article  CAS  PubMed  Google Scholar 

  39. Celebi N, Ermiş S, Özkan S. Development of topical hydrogels of terbinafine hydrochloride and evaluation of their antifungal activity. Drug Dev Ind Pharm. 2015;41(4):631–9. https://doi.org/10.3109/03639045.2014.891129.

    Article  CAS  PubMed  Google Scholar 

  40. do Vale Morais AR, Silva AL, Cojean S, Balaraman K, Bories C, Pomel S, et al. In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: heated Amphotericin B and Amphotericin B-loaded microemulsion. Experimental parasitology. 2018;192:85–92.

  41. Date AA, Nagarsenker M. Parenteral microemulsions: an overview. Int J Pharm X. 2008;355(1–2):19–30. https://doi.org/10.1016/j.ijpharm.2008.01.004.

    Article  CAS  Google Scholar 

  42. Louis Lima da Silveira W, PGL Damasceno B, F Ferreira L, LS Ribeiro I, S Silva K, Leandro Silva A, et al. Development and characterization of a microemulsion system containing amphotericin B with potential ocular applications. Current drug delivery. 2016;13(6):982–93.

  43. R Dabhi M, A Nagori S, R Sheth N, K Patel N, V Dudhrejiya A. Formulation optimization of topical gel formulation containing micro-emulsion of terbinafine hydrochloride with simplex lattice design. Micro and Nanosystems. 2011;3(1):1–7.

  44. Mohsin SMN, Hussein MZ, Sarijo SH, Fakurazi S, Arulselvan P, Hin T-YY. Synthesis of (cinnamate-zinc layered hydroxide) intercalation compound for sunscreen application. Chem Cent J. 2013;7(1):1–12. https://doi.org/10.1186/1752-153X-7-26.

  45. Jaafari MR, Hatamipour M, Alavizadeh SH, Abbasi A, Saberi Z, Rafati S, et al. Development of a topical liposomal formulation of Amphotericin B for the treatment of cutaneous leishmaniasis. Int J Parasitol Drugs Drug Resist. 2019;11:156–65. https://doi.org/10.1016/j.ijpddr.2019.09.004.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol. 2009;26(4):223–7.

    Article  PubMed  Google Scholar 

  47. Ajit C, Zaeri N, Munoz SJ, Suvannasankha A. Terbinafine-associated hepatotoxicity. Am J Med Sci. 2003;325(5):292–5. https://doi.org/10.1097/00000441-200305000-00008.

    Article  PubMed  Google Scholar 

  48. Tonomura Y, Yamamoto E, Kondo C, Itoh A, Tsuchiya N, Uehara T, et al. Amphotericin B-induced nephrotoxicity: characterization of blood and urinary biochemistry and renal morphology in mice. Hum Exp Toxicol. 2009;28(5):293–300.

    Article  CAS  PubMed  Google Scholar 

  49. van’t Wout JW. Herrmann WA, de Vries RA, Stricker BHC. Terbinafine-associated hepatic injury J Hepatol. 1994;21(1):115–7.

    Google Scholar 

Download references

Acknowledgements

This paper has been extracted from a Ph.D. thesis (Baharvandi Z.). We appreciate the Infectious and Tropical Diseases Research Center, Health Research Institute, Deputy of Development and Research, Ahvaz Jundishapur University of Medical Sciences. The study Protocol No. IR.AJUMS.ABHC.REC.1398.048 was approved by the Ethics Committee on Research in the School of Medicine, Ahvaz Jundishapur University of Medical Sciences.

Funding

This study was supported by the Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (No. OG-9815).

Author information

Authors and Affiliations

  1. Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Zeynab Baharvandi, Ali Jelowdar & Abdollah Rafiei

  2. Department of Parasitology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Zeynab Baharvandi, Reza Arjmand, Ali Jelowdar & Abdollah Rafiei

  3. Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Anayatollah Salimi

  4. Department of Pharmaceutics, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Anayatollah Salimi

Authors
  1. Zeynab Baharvandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anayatollah Salimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reza Arjmand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ali Jelowdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdollah Rafiei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design of the study: Z. Baharvandi, A. Salimi, A. Jelowdar, and R. Arjmand. Acquisition of data and investigation: Z. Baharvandi, A. Salimi, and A. Jelowdar. Analysis and interpretation of data: Z. Baharvandi, A. Salimi, A. Jelowdar and, A. Rafiei. Drafting the manuscript: Z. Baharvandi, A. Salimi, and A. Jelowdar. Revising the manuscript critically for important intellectual content: Z. Baharvandi, A. Salimi, A. Jelowdar, R. Arjmand, and A. Rafiei. Approval of the version of the manuscript to be published: Z. Baharvandi, A. Salimi, A. Jelowdar, R. Arjmand, and A. Rafiei.

Corresponding author

Correspondence to Ali Jelowdar.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baharvandi, Z., Salimi, A., Arjmand, R. et al. Evaluation of the Efficacy of Amphotericin B and Terbinafine Microemulsions and Their Combination on Cutaneous Leishmaniasis and Comparison with the Conventional Drug Form in BALB/c Mice. AAPS PharmSciTech 23, 280 (2022). https://doi.org/10.1208/s12249-022-02435-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02435-1

Keywords

Search

Navigation