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Overcoming the Challenge; In Vivo Efficacy of Miltefosine for Chronic Cutaneous Leishmaniasis

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Abstract

Background

Cutaneous Leishmaniasis (CL) is the most common form of leishmaniasis. CL can be divided into two major groups: acute CL (ACL) and chronic CL (CCL). The aim of this study is to compare the efficacy of miltefosin and pentavalent antimony compounds in vivo with the CCL patient samples.

Materials

Three study groups were formed, each consisting of five male Mus musculus (Balb/C) mice. In this model, promastigotes from the culture of a CCL patient were utilized. 100 μL L. tropica promastigote suspension with a density of 108 promastigotes/ml were injected into the hint-right footpad of each experimental animal intradermally. Footpads of the mice were measured every two weeks until 24th week. From the 13th week, miltefosin 50 mg/kg/day was administered orally using gavage for 21 days, Meglumin antimoniate (MA) was administered by intramuscular (IM) injection daily for 21 days at 50 mg/kg/day and saline was administered IM for 21 days for the miltefosine, MA and control group, respectively.

Results

The footpad measurements of the miltefosine group were lower than the control group statistically. Between the MA group and the miltefosine group and MA group and the control group, there was no statistically significant difference. Giemsa stained slides revealed amastigotes in one, two and all of the slides for the miltefosine, MA and control group, respectively. Molecular tests were performed with the Rotor-Gene device and L. tropica consistent peaks were obtained in one of the miltefosine group, four in the MA group and all mice in the control group.

Conclusions

Demonstration of both clinical and laboratory improvement in four of the five experimental animals provides strong evidence that miltefosine is an effective drug in the treatment of CCL. In the literature, no clinical or laboratory studies using miltefosine have been performed with CCL patients only.

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References

  1. Karimkhani C, Wanga V, Coffeng LE, Naghavi P, Dellavalle RP, Naghavi M (2016) Global burden of cutaneous leishmaniasis: a cross-sectional analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis 16:584–591. https://doi.org/10.1016/S1473-3099(16)00003-7

    Article  PubMed  Google Scholar 

  2. Du R, Hotez PJ, Al-Salem WS, Acosta-Serrano A (2016) Old world cutaneous leishmaniasis and refugee crises in the Middle East and North Africa. PLoSNegl Trop Dis 10:e0004545. https://doi.org/10.1371/journal.pntd.0004545

    Article  CAS  Google Scholar 

  3. Abuzaid AA, Abdoon AM, Aldahan MA, Alzahrani AG, Alhakeem RF, Asiri AM et al (2017) Cutaneous leishmaniasis in Saudi Arabia: a comprehensive overview. Vector Borne Zoonotic Dis 17:673–684. https://doi.org/10.1089/vbz.2017.2119

    Article  PubMed  PubMed Central  Google Scholar 

  4. Reithinger R, Dujardin J-C, Louzir H, Pirmez C, Alexander B, Brooker S (2007) Cutaneous leishmaniasis. Lancet Infect Dis 7:581–596. https://doi.org/10.1016/S1473-3099(07)70209-8

    Article  PubMed  Google Scholar 

  5. Hotez PJ, Velasquez RM, Wolf JE (2014) Neglected tropical skin diseases: their global elimination through integrated mass drug administration? JAMA Dermatology 150:481–482. https://doi.org/10.1001/jamadermatol.2013.8759

    Article  PubMed  Google Scholar 

  6. Ponte-Sucre A, Gamarro F, Dujardin J-C, Barrett MP, López-Vélez R, García-Hernández R et al (2017) Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoSNegl Trop Dis 11:e0006052. https://doi.org/10.1371/journal.pntd.0006052

    Article  CAS  Google Scholar 

  7. Mathers CD, Ezzati M, Lopez AD (2007) Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoSNegl Trop Dis 1:e114. https://doi.org/10.1371/journal.pntd.0000114

    Article  Google Scholar 

  8. World Health Organization. Leishmaniasisn.d.https://www.who.int/leishmaniasi/en/.

  9. García Bustos MF, Barrio A, Prieto GG, de Raspi EM, Cimino RO, Cardozo RM et al (2014) In vivo antileishmanial efficacy of miltefosine against Leishmania (Leishmania) amazonensis. J Parasitol 100:840–847. https://doi.org/10.1645/13-376.1

    Article  PubMed  Google Scholar 

  10. Coelho AC, Trinconi CT, Costa CHN, Uliana SRB (2014) In vitro and in vivo miltefosine susceptibility of a Leishmaniaamazonensis isolate from a patient with diffuse cutaneous leishmaniasis. PLoSNegl Trop Dis 8:e2999. https://doi.org/10.1371/journal.pntd.0002999

    Article  CAS  Google Scholar 

  11. Özbilgin A, Çulha G, Uzun S, Harman M, Topal SG, Okudan F et al (2016) Leishmaniasis in Turkey: first clinical isolation of Leishmania major from 18 autochthonous cases of cutaneous leishmaniasis in four geographical regions. Trop Med Int Heal. https://doi.org/10.1111/tmi.12698

    Article  Google Scholar 

  12. Toz SO, Culha G, Zeyrek FY, Ertabaklar H, Alkan MZ, Vardarlı AT et al (2013) A real-time ITS1-PCR based method in the diagnosis and species identification of leishmania parasite from human and dog clinical samples in Turkey. PLoSNegl Trop Dis 7:e2205. https://doi.org/10.1371/journal.pntd.0002205

    Article  CAS  Google Scholar 

  13. Wakelin D (1989) Nature and nurture: overcoming constraints on immunity. Parasitology 99(Suppl):S21–35

    Article  Google Scholar 

  14. Morrone A, Pitidis A, Pajno MC, Dassoni F, Latini O, Barnabas GA et al (2011) Epidemiological and geographical aspects of leishmaniasis in Tigray, northern Ethiopia: a retrospective analysis of medical records, 2005–2008. Trans R Soc Trop Med Hyg 105:273–280. https://doi.org/10.1016/j.trstmh.2011.02.003

    Article  PubMed  Google Scholar 

  15. Coelho AC, Trinconi CT, Costa CHN, Uliana SRB (2014) In vitro and in vivo miltefosine susceptibility of a leishmaniaamazonensis isolate from a patient with diffuse cutaneous leishmaniasis. PLoSNegl Trop Dis 8:1–11. https://doi.org/10.1371/journal.pntd.0002999

    Article  CAS  Google Scholar 

  16. Soto J, Arana BA, Tolado J, Rizzo N, Vega JC, Diaz A et al (2004) Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 38:1266–1272. https://doi.org/10.1086/383321

    Article  CAS  PubMed  Google Scholar 

  17. Monge-Maillo B, López-Vélez R, Saravolatz LD (2015) Miltefosine for visceral and cutaneous leishmaniasis: drug characteristics and evidence-based treatment recommendations. Clin Infect Dis 60:1398–1404. https://doi.org/10.1093/cid/civ004

    Article  PubMed  Google Scholar 

  18. Soto J, Rea J, Balderrama M, Toledo J, Soto P, Valda L et al (2008) Efficacy of miltefosine for Bolivian cutaneous leishmaniasis. Am J Trop Med Hyg 78:210–211

    Article  Google Scholar 

  19. Dorlo TPC, van Thiel PPAM, Schoone GJ, Stienstra Y, van Vugt M, Beijnen JH et al (2011) Dynamics of parasite clearance in cutaneous leishmaniasis patients treated with miltefosine. PLoSNegl Trop Dis 5:e1436. https://doi.org/10.1371/journal.pntd.0001436

    Article  CAS  Google Scholar 

  20. Mohebali M, Fotouhi A, Hooshmand B, Zarei Z, Akhoundi B, Rahnema A et al (2007) Comparison of miltefosine and meglumineantimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop 103:33–40. https://doi.org/10.1016/j.actatropica.2007.05.005

    Article  CAS  PubMed  Google Scholar 

  21. Escobar P, Matu S, Marques C, Croft SL (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop 81:151–157

    Article  CAS  Google Scholar 

  22. RezaeiRiabi T, Sharifi I, MiraminMohammadi A, Khamesipour A, Hakimi PM (2013) Evaluation of a possible synergistic effect of meglumineantimoniate with paromomycin, miltefosine or allopurinol on in vitro susceptibility of leishmaniatropica resistant isolate. Iran J Parasitol 8:396–401

    Google Scholar 

  23. Özbilgin A, Çavuş İ, Kaya T, Yıldırım A, Harman M (2020) Comparison of in vitro resistance of wild leishmania isolates, which are resistant to pentavalent antimonial compounds, against drugs used in the treatment of leishmaniasis. TurkiyeParazitolojiiDerg 44:12–16. https://doi.org/10.4274/tpd.galenos.2019.6661

    Article  Google Scholar 

  24. Keynan Y, Larios OE, Wiseman MC, Plourde M, Ouellette M, Rubinstein E (2008) Use of oral miltefosine for cutaneous leishmaniasis in Canadian soldiers returning from Afghanistan. Can J Infect Dis Med Microbiol 19:394–396

    Article  Google Scholar 

  25. Killingley B, Lamb LEM, Davidson RN (2009) Miltefosine to treat cutaneous leishmaniasis caused by Leishmania tropica. Ann Trop Med Parasitol 103:171–175. https://doi.org/10.1179/136485909X398177

    Article  CAS  PubMed  Google Scholar 

  26. Prevention C-C for DC and CDC—Leishmaniasis—Resources for health Professionals 2017

  27. Tuntland T, Ethell B, Kosaka T, Blasco F, Zang R, Jain M et al (2014) Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research. Front Pharmacol. https://doi.org/10.3389/fphar.2014.00174

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Ege University Research Funds for funding this research, and ‘Parasite Bank’ in Celal Bayar University Faculty of Medicine for keeping and supplying the isolates.

Funding

This project was supported by Research Funds of Ege University with the Project no: 17-TIP-017.

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Correspondence to Varol Tunalı.

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Ethical Approval

This study was approved by the Celal Bayar University Local Ethical Committee for Laboratory Animals (No: 77.637.435‐55‐27.09.2016).

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Tunalı, V., Harman, M., Çavuş, İ. et al. Overcoming the Challenge; In Vivo Efficacy of Miltefosine for Chronic Cutaneous Leishmaniasis. Acta Parasit. 66, 354–360 (2021). https://doi.org/10.1007/s11686-020-00285-0

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