[Frontiers In Bioscience, Landmark, 23, 967-996, January 1, 2018]

Leishmaniasis treatment: update of possibilities for drug repurposing

Valter Viana Andrade-Neto1, Edezio Ferreira Cunha-Junior1, Viviane dos Santos Faioes1, Thais Pereira Martins1, Raphaela Lopes Silva1, Leonor Laura Leon1, Eduardo Caio Torres-Santos1

1Laboratorio de Bioquimica de Tripanosomatideos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil


1. Abstract
2. Introduction
3. Leishmaniases
3.1. Clinical manifestations
3.2. Treatment
4. Drug repurposing strategies
4.1. New drugs repositioning candidates
4.1.1. Antifungals
4.1.2. Antiparasitic drugs
4.1.3. Anticancer drugs
4.1.4. Antidepressant drugs
4.1.5. Antihypertensive drugs
4.1.6. Antibiotics
4.1.7. Other drugs
5. Clinical trials
6. Conclusion
7. Acknowledgement
8. References


The leishmaniases represent a public health problem in under-developed countries and are considered a neglected disease by the World Health Organization (WHO). They are cuased by Leishmania parasites with different clinical manifestations. Currently, there is no vaccine, and treatment is in-efficient and is associated with both serious side effects often leading to resistance to the parasites. Thus, it is essential to search for new treatment strategies, such as drug repurposing, i.e., the use of drugs that are already used for other diseases. The discovery of new clinical applications for approved drugs is strategic for lowering the cost of drug discovery since human toxicity assays are already conducted. Here, we review a broad analysis of the different aspects of this approach for anti-leishmanial treatment.


1. Deotarse, P. P., Jain, A. S., Baile, M. B., Kolhe, N. S. and Kulkarni, A. A. Drug Repositioning : A Review. Int. J. Pharma Res. Rev. 4, 51–58 (2015)

2. Langedijk, J., Mantel-Teeuwisse, A. K., Slijkerman, D. S. and Schutjens, M.-H. D. B. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov. Today 20, 1027–1034 (2015)
DOI: 10.1016/j.drudis.2015.05.001

3. Ashburn, T. T. and Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683 (2004)
DOI: 10.1038/nrd1468

4. Sharlow, E. R. Revisiting Repurposing. Assay Drug Dev. Technol. 14, 554–556 (2016)
DOI: 10.1089/adt.2016.766

5. Jin, G. and Wong, S. T. C. Toward better drug repositioning: Prioritizing and integrating existing methods into efficient pipelines. Drug Discov. Today 19, 637–644 (2014)
DOI: 10.1016/j.drudis.2013.11.005

6. Smith, R. B. Repositioned drugs: Integrating intellectual property and regulatory strategies. Drug Discov. Today Ther. Strateg. 8, 131–137 (2012)
DOI: 10.1016/j.ddstr.2011.06.008

7. Berenstein, A. J., Magariños, M. P., Chernomoretz, A. and Agüero, F. A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases. PLoS Negl. Trop. Dis. 10, e0004300 (2016)
DOI: 10.1371/journal.pntd.0004300

8. Akhoundi, M., Kuhls, K., Cannet, A., Votýpka, J., Marty, P., Delaunay, P. and Sereno, D. A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies. PLoS Negl. Trop. Dis. 10, e0004349 (2016)
DOI: 10.1371/journal.pntd.0004349

9. Desjeux, P. Leishmaniasis: current situation and new perspectives. Comp. Immunol. Microbiol. Infect. Dis. 27, 305–318 (2004)
DOI: 10.1016/j.cimid.2004.03.004

10. Alvar, J., V?lez, I. D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J. and Boer, M. den. Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS One 7, e35671 (2012)
DOI: 10.1371/journal.pone.0035671

11. Kevric, I., Cappel, M. A. and Keeling, J. H. New World and Old World Leishmania Infections. Dermatol. Clin. 33, 579–593 (2015)
DOI: 10.1016/j.det.2015.03.018

12. Oryan, A. and Akbari, M. Worldwide risk factors in leishmaniasis. Asian Pac. J. Trop. Med. 9, 925–932 (2016)
DOI: 10.1016/j.apjtm.2016.06.021

13. Hashiguchi, Y., Gomez, E. L., Kato, H., Martini, L. R., Velez, L. N. and Uezato, H. Diffuse and disseminated cutaneous leishmaniasis: clinical cases experienced in Ecuador and a brief review. Trop. Med. Health 44, 1–9 (2016)
DOI: 10.1186/s41182-016-0002-0

14. Vernal, S., De Paula, N. A., Gomes, C. M. and Roselino, A. M. Disseminated Leishmaniasis by Leishmania viannia Subgenus: A Series of 18 Cases in Southeastern Brazil. Open Forum Infect. Dis. 3, ofv184 (2016)
DOI: 10.1093/ofid/ofv184

15. Machado, P. R. L., Rosa, M. E. A., Guimarães, L. H., Prates, F. V. O., Queiroz, A., Schriefer, A. and Carvalho, E. M. Treatment of Disseminated Leishmaniasis With Liposomal Amphotericin B. Clin. Infect. Dis. 61, 945–949 (2015)
DOI: 10.1093/cid/civ416

16. Handler, M. Z., Patel, P. A., Kapila, R., Al-Qubati, Y. and Schwartz, R. A. Cutaneous and mucocutaneous leishmaniasis: Differential diagnosis, diagnosis, histopathology, and management. J. Am. Acad. Dermatol. 73, 911-26–8 (2015)

17. Amato, V. S., Tuon, F. F., Siqueira, A. M., Nicodemo, A. C. and Neto, V. A. Treatment of mucosal leishmaniasis in Latin America: Systematic review. Am. J. Trop. Med. Hyg. 77, 266–274 (2007)

18. Mukhopadhyay, D., Dalton, J. E., Kaye, P. M. and Chatterjee, M. Post kala-azar dermal leishmaniasis: an unresolved mystery. Trends Parasitol. 30, 65–74 (2014)
DOI: 10.1016/j.pt.2013.12.004

19. Vianna, G. Comunicação à Sessão de 24 de abril de 1912 da Sociedade Brasileira de Dermatologia. Arch. Bras. Med. 1, 36–38 (1912)

20. Frézard, F., Demicheli, C. and Ribeiro, R. R. Pentavalent antimonials: New perspectives for old drugs. Molecules 14, 2317–2336 (2009)
DOI: 10.3390/molecules14072317

21. Sundar, S. and Chakravarty, J. An update on pharmacotherapy for leishmaniasis. Expert Opin. Pharmacother. 16, 237–52 (2015)
DOI: 10.1517/14656566.2015.973850

22. DNDi. Current Treatments – DNDi. at <http://www.dndi.org/diseases-projects/leishmaniasis/leish-current-treatments/>

23. Uliana, S. R. B., Trinconi, C. T. and Coelho, A. C. Chemotherapy of leishmaniasis: present challenges. Parasitology 1–17 (2017)
DOI: 10.1017/S0031182016002523

24. Chávez-Fumagalli, M. A., Ribeiro, T. G., Castilho, R. O., Fernandes, S. O. A., Cardoso, V. N., Coelho, C. S. P., Mendonça, D. V. C., Soto, M., Tavares, C. A. P., Faraco, A. A. G., Coelho, E. A. F., Chávez-Fumagalli, M. A., Ribeiro, T. G., Castilho, R. O., Fernandes, S. O. A., Cardoso, V. N., Coelho, C. S. P., Mendonça, D. V. C., Soto, M., Tavares, C. A. P., Faraco, A. A. G. and Coelho, E. A. F. New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment. Rev. Soc. Bras. Med. Trop. 48, 235–242 (2015)
DOI: 10.1590/0037-8682-0138-2015

25. Hellier, I., Dereure, O., Tournillac, I., Pratlong, F., Guillot, B., Dedet, J. P. and Guilhou, J. J. Treatment of Old World cutaneous leishmaniasis by pentamidine isethionate. An open study of 11 patients. Dermatology 200, 120–3 (2000)
DOI: 10.1159/000018343

26. Sundar, S., Singh, A., Rai, M., Prajapati, V. K., Singh, A. K., Ostyn, B., Boelaert, M., Dujardin, J.-C. and Chakravarty, J. Efficacy of Miltefosine in the Treatment of Visceral Leishmaniasis in India After a Decade of Use. Clin. Infect. Dis. 55, 543–550 (2012)
DOI: 10.1093/cid/cis474

27. Leishmaniases and Geneva. WHO Technical Report Series control of the leishmaniases. II.World Heal. Organ. III.Series. ISBN 978, 22–26 (2010)

28. Lim, H., Poleksic, A., Yao, Y., Tong, H., He, D., Zhuang, L., Meng, P. and Xie, L. Large-Scale Off-Target Identification Using Fast and Accurate Dual Regularized One-Class Collaborative Filtering and Its Application to Drug Repurposing. PLoS Comput. Biol. 12, e1005135 (2016)
DOI: 10.1371/journal.pcbi.1005135

29. Swinney, D. C. and Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov. 10, 507–19 (2011)
DOI: 10.1038/nrd3480

30. Spangenberg, T., Burrows, J. N., Kowalczyk, P., McDonald, S., Wells, T. N. C. and Willis, P. The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases. PLoS One 8, (2013)
DOI: 10.1371/journal.pone.0062906

31. Edwards, A. M., Bountra, C., Kerr, D. J. and Willson, T. M. Open access chemical and clinical probes to support drug discovery. Nat. Chem. Biol. 5, 436–440 (2009)
DOI: 10.1038/nchembio0709-436

32. Chatelain, E. and Ioset, J.-R. Drug discovery and development for neglected diseases: the DNDi model. Drug Des. Devel. Ther. 5, 175–81 (2011)

33. Peña, I., Pilar Manzano, M., Cantizani, J., Kessler, A., Alonso-Padilla, J., Bardera, A. I., Alvarez, E., Colmenarejo, G., Cotillo, I., Roquero, I., de Dios-Anton, F., Barroso, V., Rodriguez, A., Gray, D. W., Navarro, M., Kumar, V., Sherstnev, A., Drewry, D. H., Brown, J. R., Fiandor, J. M. and Julio Martin, J. New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource. Sci. Rep. 5, 8771 (2015)
DOI: 10.1038/srep08771

34. Kaiser, M., Maes, L., Tadoori, L. P., Ioset, J.-R., Spangenberg, T. and Ioset, J.-R. Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids. J. Biomol. Screen. 20, 634–645 (2015)
DOI: 10.1177/1087057115569155

35. Kaiser, M., Mäser, P., Tadoori, L. P., Ioset, J. R., Brun, R. and Sullivan, D. J. Antiprotozoal activity profiling of approved drugs: A starting point toward drug repositioning. PLoS One 10, 1–16 (2015)
DOI: 10.1371/journal.pone.0135556

36. Ali, S. A., Iqbal, J., Nabeel, Khalil, Y., Manzoor, A., Bukhari, I., Ahmad, B. and Yasinzai, M. M. Leishmanicidal activity of Nystatin (mycostatin): a potent polyene compound. J. Pak. Med. Assoc. 47, 246–8 (1997)

37. Tewary, P., Veena, K., Pucadyil, T. J., Chattopadhyay, A. and Madhubala, R. The sterol-binding antibiotic nystatin inhibits entry of non-opsonized Leishmania donovani into macrophages. Biochem. Biophys. Res. Commun. 339, 661–6 (2006)
DOI: 10.1016/j.bbrc.2005.11.062

38. Ghosh, B. K. and Chatterjee, A. N. Leishmanicidal activity of nystatin, a polyene antifungal antibiotic. I. The probable mechanism of action of nystatin on Leishmania donovani. Antibiot. Chemother. (Northfield, Ill.) 12, 204–6 (1962)

39. de Macedo-Silva, S. T., Urbina, J. A., de Souza, W. and Rodrigues, J. C. F. In vitro Activity of the Antifungal Azoles Itraconazole and Posaconazole against Leishmania amazonensis. PLoS One 8, e83247 (2013)
DOI: 10.1371/journal.pone.0083247

40. Martínez, A., Carreon, T., Iniguez, E., Anzellotti, A., Sánchez, A., Tyan, M., Sattler, A., Herrera, L., Maldonado, R. A. and Sánchez-Delgado, R. A. Searching for new chemotherapies for tropical diseases: ruthenium-clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells. J. Med. Chem. 55, 3867–77 (2012)
DOI: 10.1021/jm300070h

41. Iniguez, E., Varela-Ramirez, A., Martínez, A., Torres, C. L., Sánchez-Delgado, R. A. and Maldonado, R. A. Ruthenium-Clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis. Acta Trop. 164, 402–410 (2016)
DOI: 10.1016/j.actatropica.2016.09.029

42. Kulkarni, M. M., Reddy, N., Gude, T. and McGwire, B. S. Voriconazole suppresses the growth of Leishmania species in vitro. Parasitol. Res. 112, 2095–9 (2013)
DOI: 10.1007/s00436-013-3274-x

43. Mesquita, J. T., da Costa-Silva, T. A., Borborema, S. E. T. and Tempone, A. G. Activity of imidazole compounds on Leishmania (L.) infantum chagasi: reactive oxygen species induced by econazole. Mol. Cell. Biochem. 389, 293–300 (2014)
DOI: 10.1007/s11010-013-1954-6

44. Andrade-Neto, V. V., Cicco, N. N. T., Cunha-Junior, E. F., Canto-Cavalheiro, M. M., Atella, G. C. and Torres-Santos, E. C. The pharmacological inhibition of sterol biosynthesis in Leishmania is counteracted by enhancement of LDL endocytosis. Acta Trop. 119, 194–8 (2011)
DOI: 10.1016/j.actatropica.2011.05.001

45. Bezerra-Souza, A., Yamamoto, E. S., Laurenti, M. D., Ribeiro, S. P. and Passero, L. F. D. The antifungal compound butenafine eliminates promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis. Parasitol. Int. 65, 702–707 (2016)
DOI: 10.1016/j.parint.2016.08.003

46. Vannier-Santos, M. A., Urbina, J. A., Martiny, A., Neves, A. and de Souza, W. Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania. J. Eukaryot. Microbiol. 42, 337–46 (1995)
DOI: 10.1111/j.1550-7408.1995.tb01591.x

47. Zakai, H. A., Zimmo, S. K. and Fouad, M. A. H. Effect of itraconazole and terbinafine on Leishmania promastigotes. J. Egypt. Soc. Parasitol. 33, 97–107 (2003)

48. Sampaio, R. N. R., Takano, G. H. S., Malacarne, A. C. B., Pereira, T. R. and de Magalhães, A. V. (In vivo Terbinafine inefficacy on cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis in C57BL/6 mice). Rev. Soc. Bras. Med. Trop. 36, 531–3 (2003)
DOI: 10.1590/S0037-86822003000400018

49. Zakai, H. A. and Zimmo, S. K. Effects of itraconazole and terbinafine on Leishmania major lesions in BALB/c mice. Ann. Trop. Med. Parasitol. 94, 787–91 (2000)
DOI: 10.1080/00034983.2000.11813603

50. Gangneux, J. P., Dullin, M., Sulahian, A., Garin, Y. J. F. and Derouin, F. Experimental evaluation of second-line oral treatments of visceral leishmaniasis caused by Leishmania infantum. Antimicrob. Agents Chemother. 43, 172–174 (1999)

51. Simões-Mattos, L., Teixeira, M. J., Costa, D. C., Prata, J. R. C., Bevilaqua, C. M. L., Sidrim, J. J. C. and Rocha, M. F. G. Evaluation of terbinafine treatment in Leishmania chagasi-infected hamsters (Mesocricetus auratus). Vet. Parasitol. 103, 207–216 (2002)
DOI: 10.1016/S0304-4017(01)00595-7

52. Limoncu, M. E., Eraç, B., Gürpınar, T., Özbilgin, A., Balcıoğlu, I. C. and Hoşgör-Limoncu, M. Investigation of in vitro antileishmanial activity of moxifloxacin, linezolid and caspofungin on Leishmania tropica promastigotes. Turkiye parazitolojii Derg. 37, 1–3 (2013)
DOI: 10.5152/tpd.2013.01

53. Gebre-hiwot, A. and Frommel, D. The in-vitro anti-leishmanial activity of inhibitors of ergosterol biosynthesis. J. Antimicrob. Chemother. 32, 837–842 (1993)
DOI: 10.1093/jac/32.6.837

54. Want, M. Y., Islamuddin, M., Chouhan, G., Ozbak, H. A., Hemeg, H. A., Dasgupta, A. K., Chattopadhyay, A. P. and Afrin, F. Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis. Colloids Surf. B. Biointerfaces 130, 215–21 (2015)
DOI: 10.1016/j.colsurfb.2015.04.013

55. Sen, R., Bandyopadhyay, S., Dutta, A., Mandal, G., Ganguly, S., Saha, P. and Chatterjee, M. Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J. Med. Microbiol. 56, 1213–8 (2007)
DOI: 10.1099/jmm.0.47364-0

56. Sen, R., Ganguly, S., Saha, P. and Chatterjee, M. Efficacy of artemisinin in experimental visceral leishmaniasis. Int. J. Antimicrob. Agents 36, 43–49 (2010)
DOI: 10.1016/j.ijantimicag.2010.03.008

57. Ghaffarifar, F., Esavand Heydari, F., Dalimi, A., Hassan, Z. M., Delavari, M. and Mikaeiloo, H. Evaluation of Apoptotic and Antileishmanial Activities of Artemisinin on Promastigotes and BALB/C Mice Infected with Leishmania major. Iran. J. Parasitol. 10, 258–67

58. Rocha, V. P. C., Nonato, F. R., Guimarães, E. T., Rodrigues de Freitas, L. A. and Soares, M. B. P. Activity of antimalarial drugs in vitro and in a murine model of cutaneous leishmaniasis. J. Med. Microbiol. 62, 1001–10 (2013)
DOI: 10.1099/jmm.0.058115-0

59. Khan, M. O. F., Levi, M. S., Tekwani, B. L., Wilson, N. H. and Borne, R. F. Synthesis of isoquinuclidine analogs of chloroquine: antimalarial and antileishmanial activity. Bioorg. Med. Chem. 15, 3919–25 (2007)
DOI: 10.1016/j.bmc.2006.11.024

60. Correia, D., Silva, C. A. and Matthes, A. G. Mefloquine in the treatment of cutaneous leishmaniasis. Rev. Soc. Bras. Med. Trop. 32, 585 (1999)
DOI: 10.1590/S0037-86821999000500018

61. Galvão, L. O., Moreira, S., Medeiros, P., Lemos, G. J. P., Cunha, N. F., Antonino, R. M. P., Santos Filho, B. S. and Magalhães, A. V. Therapeutic trial in experimental tegumentary leishmaniasis caused by Leishmania (Leishmania) amazonensis. A comparative study between mefloquine and aminosidine. Rev. Soc. Bras. Med. Trop. 33, 377–382 (2000)
DOI: 10.1590/S0037-86822000000400008

62. Hendrickx, E. P., Agudelo, S. P., Munoz, D. L., Puerta, J. A. and Velez Bernal, I. D. Lack of efficacy of mefloquine in the treatment of New World cutaneous leishmaniasis in Colombia. Am. J. Trop. Med. Hyg. 59, 889–92 (1998)
DOI: 10.4269/ajtmh.1998.59.889

63. Laguna-Torres, V. A., Silva, C. A., Correia, D., Carvalho, E. M., Magalhaes, A. V and Macedo, V. de O. (Mefloquine in the treatment of cutaneous leishmaniasis in an endemic area of Leishmania (Viannia) braziliensis). Rev. Soc. Bras. Med. Trop. 32, 529–532 (1999)
DOI: 10.1590/S0037-86821999000500010

64. Brazil, R. P. and Gilbert, B. The action of oxamniquine on Leishmania braziliensis braziliensis in hamsters. Rev. Inst. Med. Trop. Sao Paulo 18, 87–8 (1976)

65. Noël, F., Pimenta, P. H. C., Dos Santos, A. R., Tomaz, E. C. L., Quintas, L. E. M., Kaiser, C. R., Silva, C. L. M. and Férézou, J. P. Δ2,3 -Ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases. Naunyn. Schmiedebergs. Arch. Pharmacol. 383, 101–107 (2011)
DOI: 10.1007/s00210-010-0578-6

66. Santos, A. R. dos, Falcão, C. A. B., Muzitano, M. F., Kaiser, C. R., Rossi-Bergmann, B. and Férézou, J. P. Ivermectin-derived leishmanicidal compounds. Bioorganic Med. Chem. 17, 496–502 (2009)
DOI: 10.1016/j.bmc.2008.12.003

67. Rasheid, K. A. and Morsy, T. A. Efficacy of ivermectin on the infectivity of Leishmania major promastigotes. J Egypt Soc Parasitol 28, 207–212 (1998)

68. Griffiths, W. A. Use of metronidazole in cutaneous leishmaniasis. Arch. Dermatol. 112, 1791 (1976)
DOI: 10.1001/archderm.1976.01630370071021

69. Al-Waiz, M., Sharquie, K. E. and Al-Assir, M. Treatment of cutaneous leishmaniasis by intralesional metronidazole. Saudi Med. J. 25, 1512–3 (2004)

70. Belhadjali, H., Elhani, I., Youssef, M., Babba, H. and Zili, J. Traitement de la leishmaniose cutanée par le métronidazole : étude de 30 cas. Presse Med. 38, 325–326 (2009)
DOI: 10.1016/j.lpm.2008.09.008

71. Mesquita, J. T., Pinto, E. G., Taniwaki, N. N., Galisteo, A. J. and Tempone, A. G. Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum. Acta Trop. 128, 666–673 (2013)
DOI: 10.1016/j.actatropica.2013.09.018

72. Zhang, R., Shang, L., Jin, H., Ma, C., Wu, Y., Liu, Q., Xia, Z., Wei, F., Zhu, X. Q. and Gao, H. In vitro and in vivo antileishmanial efficacy of nitazoxanide against Leishmania donovani. Parasitol. Res. 107, 475–479 (2010)
DOI: 10.1007/s00436-010-1906-y

73. Mesquita, J. T., Tempone, A. G. and Reim??o, J. Q. Combination therapy with nitazoxanide and amphotericin B, Glucantime, miltefosine and sitamaquine against Leishmania (Leishmania) infantum intracellular amastigotes. Acta Trop. 130, 112–116 (2014)
DOI: 10.1016/j.actatropica.2013.11.003

74. Rodrigues, F. H., Afonso-Cardoso, S. R., Gomes, M. A. B., Beletti, M. E., Rocha, A., Guimarães, A. H. B., Candeloro, I. and de Souza, M. A. Effect of imidocarb and levamisole on the experimental infection of BALB/c mice by Leishmania (Leishmania) amazonensis. Vet. Parasitol. 139, 37–46 (2006)
DOI: 10.1016/j.vetpar.2006.02.032

75. Martinez-Rojano, H., Mancilla-Ramirez, J., Quiñonez-Diaz, L. and Galindo-Sevilla, N. Activity of hydroxyurea against Leishmania mexicana. Antimicrob. Agents Chemother. 52, 3642–7 (2008)
DOI: 10.1128/AAC.00124-08

76. Tavares, J., Ouaissi, M., Ouaissi, A. and Cordeiro-da-Silva, A. Characterization of the anti- Leishmania effect induced by cisplatin, an anticancer drug. Acta Trop. 103, 133–141 (2007)
DOI: 10.1016/j.actatropica.2007.05.017

77. Kaur, S., Sachdeva, H., Dhuria, S., Sharma, M. and Kaur, T. Antileishmanial effect of cisplatin against murine visceral leishmaniasis. Parasitol. Int. 59, 62–9 (2010)
DOI: 10.1016/j.parint.2009.10.006

78. Sharma, M., Sehgal, R. and Kaur, S. Evaluation of nephroprotective and immunomodulatory activities of antioxidants in combination with cisplatin against murine visceral leishmaniasis. PLoS Negl. Trop. Dis. 6, e1629 (2012)
DOI: 10.1371/journal.pntd.0001629

79. Sharma, M. and Kaur, S. Protective efficacy of antioxidants on cisplatin-induced tissue damage caused in Leishmania donovani infected BALB/c mice against murine visceral leishmaniasis. J. Interdiscip. Histopathol. 1, 121 (2013)
DOI: 10.5455/jihp.20121219031901

80. Kaur, T., Makkar, P., Randhawa, K. and Kaur, S. Antineoplastic drug, carboplatin, protects mice against visceral leishmaniasis. Parasitol. Res. 112, 91–100 (2013)
DOI: 10.1007/s00436-012-3108-2

81. Shukla, A. K., Patra, S. and Dubey, V. K. Nanospheres Encapsulating Anti-Leishmanial Drugs for Their Specific Macrophage Targeting, Reduced Toxicity, and Deliberate Intracellular Release. Vector-Borne Zoonotic Dis. 12, 953–960 (2012)
DOI: 10.1089/vbz.2011.0948

82. Shukla, A. K., Patra, S. and Dubey, V. K. Evaluation of selected antitumor agents as subversive substrate and potential inhibitor of trypanothione reductase: an alternative approach for chemotherapy of Leishmaniasis. Mol. Cell. Biochem. 352, 261–270 (2011)
DOI: 10.1007/s11010-011-0762-0

83. van den Bogaart, E., Schoone, G. J., England, P., Faber, D., Orrling, K. M., Dujardin, J.-C., Sundar, S., Schallig, H. D. F. H. and Adams, E. R. Simple Colorimetric Trypanothione Reductase-Based Assay for High-Throughput Screening of Drugs against Leishmania Intracellular Amastigotes. Antimicrob. Agents Chemother. 58, 527–535 (2014)
DOI: 10.1128/AAC.00751-13

84. Kansal, S., Tandon, R., Verma, P. R. P., Dube, A. and Mishra, P. R. Development of doxorubicin loaded novel core shell structured nanocapsules for the intervention of visceral leishmaniasis. J. Microencapsul. 30, 441–50 (2013)
DOI: 10.3109/02652048.2012.752532

85. Kansal, S., Tandon, R., Verma, A., Misra, P., Choudhary, A. K., Verma, R., Verma, P. R. P., Dube, A. and Mishra, P. R. Coating doxorubicin-loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1-type immune responses. Br. J. Pharmacol. 171, 4038–50 (2014)
DOI: 10.1111/bph.12754

86. Sett, R., Basu, N., Ghosh, A. K. and Das, P. K. Potential of Doxorubicin as an Antileishmanial Agent. J. Parasitol. 78, 350 (1992)
DOI: 10.2307/3283487

87. Prada, C. F., Álvarez-Velilla, R., Balaña-Fouce, R., Prieto, C., Calvo-Álvarez, E., Escudero-Martínez, J. M., Requena, J. M., Ordóñez, C., Desideri, A., Pérez-Pertejo, Y. and Reguera, R. M. Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. Biochem. Pharmacol. 85, 1433–1440 (2013)
DOI: 10.1016/j.bcp.2013.02.024

88. Doherty, T. M., Sher, A. and Vogel, S. N. Paclitaxel (Taxol)-induced killing of Leishmania major in murine macrophages. Infect. Immun. 66, 4553–6 (1998)
DOI: 10.1006/excr.1996.0229

89. Moulay, L., Robert-Gero, M., Brown, S., Gendron, M.-C. and Tournier, F. Sinefungin and Taxol Effects on Cell Cycle and Cytoskeleton of Leishmania donovani promastigotes. Exp. Cell Res. 226, 283–291 (1996)

90. Sanderson, L., Yardley, V. and Croft, S. L. Activity of anti-cancer protein kinase inhibitors against Leishmania spp. J. Antimicrob. Chemother. 69, 1888–91 (2014)
DOI: 10.1093/jac/dku069

91. Wetzel, D. M., McMahon-Pratt, D. and Koleske, a. J. The Abl and Arg Kinases Mediate Distinct Modes of Phagocytosis and Are Required for Maximal Leishmania Infection. Mol. Cell. Biol. 32, 3176–3186 (2012)
DOI: 10.1128/MCB.00086-12

92. Diaz-Gonzalez, R., Kuhlmann, F. M., Galan-Rodriguez, C., da Silva, L. M., Saldivia, M., Karver, C. E., Rodriguez, A., Beverley, S. M., Navarro, M. and Pollastri, M. P. The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing. PLoS Negl. Trop. Dis. 5, e1297 (2011)
DOI: 10.1371/journal.pntd.0001297

93. Miguel, D. C., Yokoyama-Yasunaka, J. K. U. and Uliana, S. R. B. Tamoxifen is effective in the treatment of Leishmania amazonensis infections in mice. PLoS Negl. Trop. Dis. 2, e249 (2008)
DOI: 10.1371/journal.pntd.0000249

94. Eissa, M. M., Amer, E. I. and El Sawy, S. M. F. Leishmania major: activity of tamoxifen against experimental cutaneous leishmaniasis. Exp. Parasitol. 128, 382–90 (2011)
DOI: 10.1016/j.exppara.2011.05.009

95. Miguel, D. C., Zauli-Nascimento, R. C., Yokoyama-Yasunaka, J. K. U., Katz, S., Barbiéri, C. L. and Uliana, S. R. B. Tamoxifen as a potential antileishmanial agent: efficacy in the treatment of Leishmania braziliensis and Leishmania chagasi infections. J. Antimicrob. Chemother. 63, 365–8 (2009)
DOI: 10.1093/jac/dkn509

96. Miguel, D. C., Zauli-Nascimento, R. C., Yokoyama-Yasunaka, J. K. U., Pereira, L. I. A., Jerônimo, S. M. B., Ribeiro-Dias, F., Dorta, M. L. and Uliana, S. R. B. Clinical isolates of New World Leishmania from cutaneous and visceral leishmaniasis patients are uniformly sensitive to tamoxifen. Int. J. Antimicrob. Agents 38, 93–4 (2011)
DOI: 10.1016/j.ijantimicag.2011.03.012

97. Miguel, D. C., Yokoyama-Yasunaka, J. K. U., Andreoli, W. K., Mortara, R. A. and Uliana, S. R. B. Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes. J. Antimicrob. Chemother. 60, 526–34 (2007)
DOI: 10.1093/jac/dkm219

98. Trinconi, C. T., Reimão, J. Q., Bonano, V. I., Espada, C. R., Miguel, D. C., Yokoyama-Yasunaka, J. K. U. and Uliana, S. R. B. Topical tamoxifen in the therapy of cutaneous leishmaniasis. Parasitology 1–7 (2017)
DOI: 10.1017/S0031182017000130

99. Trinconi, C. T., Reimão, J. Q., Yokoyama-Yasunaka, J. K. U., Miguel, D. C. and Uliana, S. R. B. Combination therapy with tamoxifen and amphotericin B in experimental cutaneous leishmaniasis. Antimicrob. Agents Chemother. 58, 2608–13 (2014)
DOI: 10.1128/AAC.01315-13

100. Trinconi, C. T., Reimão, J. Q., Coelho, A. C. and Uliana, S. R. B. Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. J. Antimicrob. Chemother. 71, 1314–1322 (2016)
DOI: 10.1093/jac/dkv495

101. Reimão, J. Q., Miguel, D. C., Taniwaki, N. N., Trinconi, C. T., Yokoyama-Yasunaka, J. K. U. and Uliana, S. R. B. Antileishmanial activity of the estrogen receptor modulator raloxifene. PLoS Negl. Trop. Dis. 8, e2842 (2014)
DOI: 10.1371/journal.pntd.0002842

102. Andrade-Neto, V. V., Pereira, T. M., Canto-Cavalheiro, M. do and Torres-Santos, E. C. Imipramine alters the sterol profile in Leishmania amazonensis and increases its sensitivity to miconazole. Parasit. Vectors 9, 183 (2016)
DOI: 10.1186/s13071-016-1467-8

103. Mukherjee, S., Mukherjee, B., Mukhopadhyay, R., Naskar, K., Sundar, S., Dujardin, J. C., Das, A. K. and Roy, S. Imipramine Is an Orally Active Drug against Both Antimony Sensitive and Resistant Leishmania donovani Clinical Isolates in Experimental Infection. PLoS Negl. Trop. Dis. 6, e1987 (2012)
DOI: 10.1371/journal.pntd.0001987

104. Mukherjee, S., Mukherjee, B., Mukhopadhyay, R., Naskar, K., Sundar, S., Dujardin, J.-C. and Roy, S. Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection. J. Immunol. 193, 4083–4094 (2014)
DOI: 10.4049/jimmunol.1400710

105. Zilberstein, D., Liveanu, V. and Gepstein, A. Tricyclic drugs reduce proton motive force in Leishmania donovani promastigotes. Biochem. Pharmacol. 39, 935–940 (1990)
DOI: 10.1016/0006-2952(90)90210-C

106. Benson, T. J., McKie, J. H., Garforth, J., Borges, A., Fairlamb, A. H. and Douglas, K. T. Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures. Biochem. J. 286 ( Pt 1, 9–11 (1992)

107. Zilberstein, D. and Dwyer, D. M. Antidepressants cause lethal disruption of membrane function in the human protozoan parasite Leishmania. Science 226, 977–9 (1984)
DOI: 10.1126/science.6505677

108. Cunha-Júnior, E. F., Andrade-Neto, V. V., Lima, M. L., da Costa-Silva, T. A., Galisteo Junior, A. J., Abengózar, M. A., Barbas, C., Rivas, L., Almeida-Amaral, E. E., Tempone, A. G. and Torres-Santos, E. C. Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. PLoS Negl. Trop. Dis. 11, e0005281 (2017)
DOI: 10.1371/journal.pntd.0005281

109. Palit, P. and Ali, N. Oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against Leishmania donovani. J. Antimicrob. Chemother. 61, 1120–1124 (2008)
DOI: 10.1093/jac/dkn046

110. Dinesh, N., Kaur, P. K., Swamy, K. K. and Singh, S. Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels. Exp. Parasitol. 144, 84–90 (2014)
DOI: 10.1016/j.exppara.2014.06.004

111. Evans, A. T., Croft, S. L., Peters, W. and Neal, R. A. Hydrazide antidepressants possess novel antileishmanial activity in vitro and in vivo. Ann. Trop. Med. Parasitol. 83, 19–24 (1989)
DOI: 10.1080/00034983.1989.11812306

112. Alberca, L. N., Sbaraglini, M. L., Balcazar, D., Fraccaroli, L., Carrillo, C., Medeiros, A., Benitez, D., Comini, M. and Talevi, A. Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning. J. Comput. Aided. Mol. Des. 30, 305–321 (2016)
DOI: 10.1007/s10822-016-9903-6

113. Dagger, F., Campos, Z., Rangel, H. and Roman, H. Antiproliferative effect of diazepam on Leishmania mexicana. Mem. Inst. Oswaldo Cruz 91, (1996)

114. Tamargo, J. and Ruilope, L. M. Investigational calcium channel blockers for the treatment of hypertension. Expert Opin. Investig. Drugs 25, 1295–1309 (2016)
DOI: 10.1080/13543784.2016.1241764

115. Reimão, J. Q., Scotti, M. T. and Tempone, A. G. Anti-leishmanial and anti-trypanosomal activities of 1,4-dihydropyridines: In vitro evaluation and structure-activity relationship study. Bioorganic Med. Chem. 18, 8044–8053 (2010)
DOI: 10.1016/j.bmc.2010.09.015

116. Reimão, J. Q. and Tempone, A. G. Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs. Mem. Inst. Oswaldo Cruz 106, 1032–1038 (2011)
DOI: 10.1590/S0074-02762011000800022

117. Reimão, J. Q., Colombo, F. A., Pereira-Chioccola, V. L. and Tempone, A. G. In vitro and experimental therapeutic studies of the calcium channel blocker bepridil: Detection of viable Leishmania (L.) chagasi by real-time PCR. Exp. Parasitol. 128, 111–115 (2011)
DOI: 10.1016/j.exppara.2011.02.021

118. Shokri, A., Sharifi, I., Khamesipour, A., Nakhaee, N., Harandi, M. F., Nosratabadi, J., Parizi, M. H. and Barati, M. The effect of verapamil on in vitro susceptibility of promastigote and amastigote stages of Leishmania tropica to meglumine antimoniate. Parasitol. Res. 110, 1113–1117 (2012)
DOI: 10.1007/s00436-011-2599-6

119. Tempone, A. G., Taniwaki, N. N. and Reimão, J. Q. Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine. Parasitol. Res. 105, 499–505 (2009)
DOI: 10.1007/s00436-009-1427-8

120. Misra, S., Naskar, K., Sarkar, D. and Ghosh, D. K. Role of Ca2+ ion on Leishmania-macrophage attachment. Mol. Cell. Biochem. 102, 13–18 (1991)
DOI: 10.1007/BF00232154

121. Ganouly, N. K., Sodhi, S., Kaul, N., Kaur, S., Malla, N. and Mahajan, R. C. Effect of nifedipine on Leishmania donovani infection in-vivo and in-vitro: chemiluminescence responses of peritoneal macrophages and neutrophils. J. Pharm. Pharmacol. 43, 140–142 (1991)
DOI: 10.1111/j.2042-7158.1991.tb06652.x

122. Palit, P. and Ali, N. Oral therapy with amlodipine and lacidipine, 1,4-dihydropyridine derivatives showing activity against experimental visceral leishmaniasis. Antimicrob. Agents Chemother. 52, 374–377 (2008)
DOI: 10.1128/AAC.00522-07

123. Valiathan, R., Dubey, M. L., Mahajan, R. C. and Malla, N. Leishmania donovani: Effect of verapamil on in vitro susceptibility of promastigote and amastigote stages of Indian clinical isolates to sodium stibogluconate. Exp. Parasitol. 114, 103–108 (2006)
DOI: 10.1016/j.exppara.2006.02.015

124. Goyal, N., Duncan, R., Selvapandiyan, A., Debrabant, A., Baig, M. S. and Nakhasi, H. L. Cloning and characterization of angiotensin converting enzyme related dipeptidylcarboxypeptidase from Leishmania donovani. Mol. Biochem. Parasitol. 145, 147–157 (2006)
DOI: 10.1016/j.molbiopara.2005.09.014

125. Andrade-Neto, V. V., Cunha-Júnior, E. F., Canto-Cavalheiro, M. M. do, Atella, G. C., Fernandes, T. de A., Costa, P. R. R. and Torres-Santos, E. C. Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis. Antimicrob. Agents Chemother. 60, 6844–6852 (2016)
DOI: 10.1128/AAC.01545-16

126. García-Miss, M. D. R., Mut-Martín, M. C. and Góngora-Alfaro, J. L. β-Adrenergic blockade protects BALB/c mice against infection with a small inoculum of Leishmania mexicana mexicana (LV4). Int. Immunopharmacol. 24, 59–67 (2015)
DOI: 10.1016/j.intimp.2014.11.003

127. Karam, M. C., Merckbawi, R., Salman, S. and Mobasheri, A. Atenolol Reduces Leishmania major-Induced Hyperalgesia and TNF-α Without Affecting IL-1β or Keratinocyte Derived Chemokines (KC). Front. Pharmacol. 7, 1–10 (2016)
DOI: 10.3389/fphar.2016.00022

128. Genestra, M., Soares-Bezerra, R. J., Gomes-Silva, L., Fabrino, D. L., Bellato-Santos, T., Castro-Pinto, D. B., Canto-Cavalheiro, M. M. and Leon, L. L. In vitro sodium nitroprusside-mediated toxicity towards Leishmania amazonensis promastigotes and axenic amastigotes. Cell Biochem. Funct. 26, 709–717 (2008)
DOI: 10.1002/cbf.1496

129. Kawakami, N. Y., Tomiotto-Pellissier, F., Cataneo, A. H. D., Orsini, T. M., Thomazelli, A. P. F. D. S., Panis, C., Conchon-Costa, I. and Pavanelli, W. R. Sodium nitroprusside has leishmanicidal activity independent of iNOS. Rev. Soc. Bras. Med. Trop. 49, 68–73 (2016)
DOI: 10.1590/0037-8682-0266-2015

130. Singh, S., Dinesh, N., Kaur, P. K. and Shamiulla, B. Ketanserin, an antidepressant, exerts its antileishmanial action via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme of Leishmania donovani. Parasitol. Res. 113, 2161–2168 (2014)
DOI: 10.1007/s00436-014-3868-y

131. Sagher, F., Zuckerman, A., Rein, C. R. and Kitchen, D. K. The effect of high concentrations of penicillin on Leishmania tropica, in vivo and in vitro. Br. J. Dermatol. 66, 246–251 (1954)
DOI: 10.1111/j.1365-2133.1954.tb12628.x

132. Romero, I. C., Saravia, N. G. and Walker, J. Selective action of fluoroquinolones against intracellular amastigotes of Leishmania (Viannia) panamensis in vitro. J. Parasitol. 91, 1474–1479 (2005)
DOI: 10.1645/GE-3489.1

133. Cortázar, T. M., Coombs, G. H. and Walker, J. Leishmania panamensis: Comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine. Exp. Parasitol. 116, 475–482 (2007)
DOI: 10.1016/j.exppara.2007.02.018

134. Farca, A. M., Miniscalco, B., Badino, P., Odore, R., Monticelli, P., Trisciuoglio, A. and Ferroglio, E. Canine leishmaniosis: In vitro efficacy of miltefosine and marbofloxacin alone or in combination with allopurinol against clinical strains of Leishmania infantum. Parasitol. Res. 110, 2509–2513 (2012)
DOI: 10.1007/s00436-011-2792-7

135. Vouldoukis, I., Rougier, S., Dugas, B., Pino, P., Mazier, D. and Woehrlé, F. Canine visceral leishmaniasis: Comparison of in vitro leishmanicidal activity of marbofloxacin, meglumine antimoniate and sodium stibogluconate. Vet. Parasitol. 135, 137–146 (2006)
DOI: 10.1016/j.vetpar.2005.09.003

136. Rougier, S., Vouldoukis, I., Fournel, S., Pérès, S. and Woehrlé, F. Efficacy of different treatment regimens of marbofloxacin in canine visceral leishmaniosis: A pilot study. Vet. Parasitol. 153, 244–254 (2008)
DOI: 10.1016/j.vetpar.2008.01.041

137. Navin, T. R. and Pearson, R. D. Inhibition of Leishmania donovani growth by streptomycin and tobramycin. Ann. Trop. Med. Parasitol. 81, 731–3 (1987)
DOI: 10.1080/00034983.1987.11812178

138. de Oliveira-Silva, F., de Morais-Teixeira, E. and Rabello, A. Antileishmanial activity of azithromycin against Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, and Leishmania (Leishmania) chagasi. Am. J. Trop. Med. Hyg. 78, 745–9 (2008)

139. Krolewiecki, A., Leon, S., Scott, P. and Abraham, D. Activity of azithromycin against Leishmania major in vitro and in vivo. Am. J. Trop. Med. Hyg. 67, 273–7 (2002)
DOI: 10.4269/ajtmh.2002.67.273

140. Balcioglu, I. C., Ok, U. Z., Ozbel, Y., Girginkardesler, N. and Ozbilgin, A. The in vitro Effects of Azithromycin and Clarithromycin on Promastigotes and Amastigotes of Leishmania tropica. Kafkas Univ. Vet. Fak. Derg. 18, A115–A120 (2012)

141. Sinagra, Á., Luna, C., Abraham, D., Iannella, M. del C., Riarte, A. and Krolewiecki, A. J. The activity of azithromycin against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis in the golden hamster model. Rev. Soc. Bras. Med. Trop. 40, 627–630 (2007)
DOI: 10.1590/S0037-86822007000600005

142. Sampaio, R. N. R., Lucas, I. C. and Costa Filho, A. V. da. The use of azythromycin and N-methyl glucamine for the treatment of cutaneous Leishmaniasis caused by Leishmania (Leishmania) amazonensis in C57BL6 mice. An. Bras. Dermatol. 84, 125–8 (2009)
DOI: 10.1590/S0365-05962009000200004

143. Amer, E. I., Eissa, M. M. and Mossallam, S. F. Oral azithromycin versus its combination with miltefosine for the treatment of experimental Old World cutaneous leishmaniasis. J. Parasit. Dis. 40, 475–484 (2016)
DOI: 10.1007/s12639-014-0529-0

144. Roy, K., Das, S., Mondal, S., Roy, A. K. and Bera, T. The in vitro effect of clarithromycin on amastigote of Leishmania donovani. Int. J. Drug Dev. Res. 5, (2013)

145. Barteselli, A., Casagrande, M., Basilico, N., Parapini, S., Rusconi, C. M., Tonelli, M., Boido, V., Taramelli, D., Sparatore, F. and Sparatore, A. Clofazimine analogs with antileishmanial and antiplasmodial activity. Bioorganic Med. Chem. 23, 55–65 (2015)
DOI: 10.1016/j.bmc.2014.11.028

146. Neal, R. A. and Croft, S. L. An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. J. Antimicrob. Chemother. 14, 463–475 (1984)
DOI: 10.1093/jac/14.5.463

147. Arbiser, J. L. and Moschella, S. L. Clofazimine: A review of its medical uses and mechanisms of action. J. Am. Acad. Dermatol. 32, 241–247 (1995)
DOI: 10.1016/0190-9622(95)90134-5

148. Katiyar, S. K. and Edlind, T. D. Enhanced antiparasitic activity of lipophilic tetracyclines: role of uptake. Antimicrob. Agents Chemother. 35, 2198–2202 (1991)
DOI: 10.1128/AAC.35.11.2198

149. Bano, P. and Shahab, S. M. A combination of sulphadiazine, trimethoprim and metronidazole or tinidazole in kala-azar. J. Assoc. Physicians India 42, 535–6 (1994)

150. Berman, J. D. and Lee, L. S. Activity of oral drugs against Leishmania tropica in human macrophages in vitro. Am J Trop Med Hyg 32, 947–951 (1983)
DOI: 10.4269/ajtmh.1983.32.947

151. Livshin, R., Weinrauch, L., Even-Paz, Z. and El-On, J. Efficacy of Rifampicin and Isoniazid in Cutaneous Leishmaniasis. Int. J. Dermatol. 26, 55–59 (1987)
DOI: 10.1111/j.1365-4362.1987.tb04578.x

152. Arora, S. K., Sinha, R. and Sehgal, S. Use of in vitro method to assess different brands of anti-leishmanial drugs. Med. Microbiol. Immunol. 180, 21–27 (1991)
DOI: 10.1007/BF00191697

153. El-On, J., Pearlman, E., Schnur, L. F. and Greenblatt, C. L. Chemotherapeutic activity of rifampicin on leishmanial amastigotes and promastigotes in vitro. Isr. J. Med. Sci. 19, 240–5 (1983)

154. El-On, J., Messer, G. and Greenblatt, C. L. Growth inhibition of Leishmania tropica amastigotes in vitro by rifampicin combined with amphotericin B. Ann Trop Med Parasitol 78, 93–98 (1984)
DOI: 10.1080/00034983.1984.11811782

155. Peters, W., Shaw, J. J., Lainson, R., Robinson, B. L. and Leão, A. F. Potentiating action of rifampicin and isoniazid against Leishmania mexicana amazonensis. Lancet 317, 1122–1124 (1981)
DOI: 10.1016/S0140-6736(81)92296-0

156. Patterson, S., Wyllie, S., Norval, S., Stojanovski, L., Simeons, F. R., Auer, J. L., Osuna-Cabello, M., Read, K. D. and Fairlamb, A. H. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. Elife 5, 1–21 (2016)
DOI: 10.7554/eLife.09744

157. Peniche, A. G., Renslo, A. R., Melby, P. C. and Travi, B. L. Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in an Ex vivo Model System Is Selectively Enhanced by the Addition of Divalent Metal Ions. Antimicrob. Agents Chemother. 59, 6463–70 (2015)
DOI: 10.1128/AAC.05131-14

158. Yau, W.-L., Blisnick, T., Taly, J.-F., Helmer-Citterich, M., Schiene-Fischer, C., Leclercq, O., Li, J., Schmidt-Arras, D., Morales, M. A., Notredame, C., Romo, D., Bastin, P. and Späth, G. F. Cyclosporin A Treatment of Leishmania donovani Reveals Stage-Specific Functions of Cyclophilins in Parasite Proliferation and Viability. PLoS Negl. Trop. Dis. 4, e729 (2010)
DOI: 10.1371/journal.pntd.0000729

159. Meissner, U., Jüttner, S., Röllinghoff, M. and Gessner, A. Cyclosporin A-mediated killing of Leishmania major by macrophages is independent of reactive nitrogen and endogenous TNF-alpha and is not inhibited by IL-10 and 13. Parasitol. Res. 89, 221–7 (2003)

160. Pinto, E. G., da Costa-Silva, T. A. and Tempone, A. G. Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes. Acta Trop. 137, 206–10 (2014)
DOI: 10.1016/j.actatropica.2014.05.017

161. Jiang, S., Meadows, J., Anderson, S. A. and Mukkada, A. J. Antileishmanial Activity of the Antiulcer Agent Omeprazole. Antimicrob. Agents Chemother. 46, 2569–2574 (2002)
DOI: 10.1128/AAC.46.8.2569-2574.2002

162. Koutinas, A. F., Saridomichelakis, M. N., Mylonakis, M. E., Leontides, L., Polizopoulou, Z., Billinis, C., Argyriadis, D., Diakou, N. and Papadopoulos, O. A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis. Vet. Parasitol. 98, 247–261 (2001)
DOI: 10.1016/S0304-4017(01)00399-5

163. Velez, I., Agudelo, S., Hendrickx, E., Puerta, J., Grogl, M., Modabber, F. and Berman, J. Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. Ann. Intern. Med. 126, 232–6 (1997)
DOI: 10.7326/0003-4819-126-3-199702010-00010

164. Sabaté, D., Llinás, J., Homedes, J., Sust, M. and Ferrer, L. A single-centre, open-label, controlled, randomized clinical trial to assess the preventive efficacy of a domperidone-based treatment programme against clinical canine leishmaniasis in a high prevalence area. Prev. Vet. Med. 115, 56–63 (2014)
DOI: 10.1016/j.prevetmed.2014.03.010

165. Kochar, D. K., Saini, G., Kochar, S. K., Sirohi, P., Bumb, R. A., Mehta, R. D. and Purohit, S. K. A double blind, randomised placebo controlled trial of rifampicin with omeprazole in the treatment of human cutaneous leishmaniasis. J. Vector Borne Dis. 43, 161–7 (2006)

166. Silva-Vergara, M. L., Silva, L. D. A., Maneira, F. R. Z., Da Silva, A. G. and Prata, A. Azithromycin in the treatment of mucosal Leishmaniasis. Rev. Inst. Med. Trop. Sao Paulo 46, 175–177 (2004)
DOI: 10.1590/S0036-46652004000300011

167. Teixeira, A. C., Paes, M. G., Guerra, J. D. O., Prata, A. and Silva-Vergara, M. L. Low efficacy of azithromycin to treat cutaneous leishmaniasis in Manaus, AM, Brazil. Rev. Inst. Med. Trop. Sao Paulo 49, 235–8 (2007)
DOI: 10.1590/S0036-46652007000400008

168. Daoud, S. and Boushi, L. Azithromycin, ineffective in the treatment of old-world cutaneous leishmaniasis. Int. J. Dermatol. 45, 1126–1128 (2006)
DOI: 10.1111/j.1365-4632.2006.02885.x

169. Krolewiecki, A. J., Romero, H. D., Cajal, S. P., Abraham, D., Mimori, T., Matsumoto, T., Juarez, M. and Taranto, N. J. A randomized clinical trial comparing oral azithromycin and meglumine antimoniate for the treatment of American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. Am. J. Trop. Med. Hyg. 77, 640–6 (2007)

170. Khatami, A., Firooz, A., Gorouhi, F. and Dowlati, Y. Treatment of acute Old World cutaneous leishmaniasis: A systematic review of the randomized controlled trials. J. Am. Acad. Dermatol. 57, 335.e1-335.e29 (2007)
DOI: 10.1016/j.jaad.2007.01.016

171. Nassiri-Kashani, M., Firooz, A., Khamesipour, A., Mojtahed, F., Nilforoushzadeh, M., Hejazi, H., Bouzari, N. and Dowlati, Y. A randomized, double-blind, placebo-controlled clinical trial of itraconazole in the treatment of cutaneous leishmaniasis. J. Eur. Acad. Dermatol. Venereol. 19, 80–3 (2005)
DOI: 10.1111/j.1468-3083.2004.01133.x

172. Dogra, J., Aneja, N., Lal, B. B. and Mishra, S. N. Cutaneous Leishmaniasis In India. Int. J. Dermatol. 29, 661–662 (1990)
DOI: 10.1111/j.1365-4362.1990.tb02593.x

173. Salmanpour, R., Handjani, F. and Nouhpisheh, M. K. Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) for the treatment of cutaneous leishmaniasis. J. Dermatolog. Treat. 12, 159–162 (2001)
DOI: 10.1080/09546630152607899

174. El-Sayed, M. and Anwar, A. Intralesional sodium stibogluconate alone or its combination with either intramuscular sodium stibogluconate or oral ketoconazole in the treatment of localized cutaneous leishmaniasis: A comparative study. J. Eur. Acad. Dermatology Venereol. 24, 335–340 (2010)
DOI: 10.1111/j.1468-3083.2009.03417.x

175. Navin, T. R., Arana, B. A., Arana, F. E., Berman, J. D. and Chajon, J. F. Placebo-Controlled Clinical Trial of Sodium Stibogluconate (Pentostam) versus Ketoconazole for Treating Cutaneous Leishmaniasis in Guatemala. J. Infect. Dis. 165, 528–534 (1992)
DOI: 10.1093/infdis/165.3.528

176. Newlove, T., Guimaraes, L. H., Morgan, D. J., Alcantara, L., Glesby, M. J., Carvalho, E. M. and Machado, P. R. Antihelminthic Therapy and Antimony in Cutaneous Leishmaniasis: A Randomized, Double-Blind, Placebo-Controlled Trial in Patients Co-Infected with Helminths and Leishmania braziliensis. Am. J. Trop. Med. Hyg. 84, 551–555 (2011)
DOI: 10.4269/ajtmh.2011.10-0423

177. Prates, F. V. D. O., Dourado, M. E. F., Silva, S. C., Schriefer, A., Guimarães, L. H., Brito, M. D. G. O., Almeida, J., Carvalho, E. M. and Machado, P. R. L. Fluconazole in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis : A Randomized Controlled Trial. Clin. Infect. Dis. 64, 67–71 (2017)
DOI: 10.1093/cid/ciw662

178. Emad, M., Hayati, F., Fallahzadeh, M. K. and Namazi, M. R. Superior efficacy of oral fluconazole 400 mg daily versus oral fluconazole 200 mg daily in the treatment of cutaneous Leishmania major infection: A randomized clinical trial. J. Am. Acad. Dermatol. 64, 606–608 (2011)
DOI: 10.1016/j.jaad.2010.04.014

179. Farajzadeh, S., Heshmatkhah, A., Vares, B., Mohebbi, E., Mohebbi, A., Aflatoonian, M., Eybpoosh, S., Sharifi, I., Aflatoonian, M. R., Shamsi Meymandi, S., Fekri, A. R. and Mostafavi, M. Topical terbinafine in the treatment of cutaneous leishmaniasis: triple blind randomized clinical trial. J. Parasit. Dis. 40, 1159–1164 (2016)
DOI: 10.1007/s12639-014-0641-1

180. Firooz, A., Khamesipour, A., Ghoorchi, M. H., Nassiri-Kashani, M., Eskandari, S. E., Khatami, A., Hooshmand, B., Gorouhi, F., Rashighi-Firoozabadi, M. and Dowlati, Y. Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis. Arch. Dermatol. 142, 1575–1579 (2006)
DOI: 10.1001/archderm.142.12.1575

181. Meng, Y., Squires, H., Stevens, J. W., Simpson, E., Harnan, S., Thomas, S., Michaels, J., Stansby, G. and O’Donnell, M. E. Cost-Effectiveness of Cilostazol, Naftidrofuryl Oxalate, and Pentoxifylline for the Treatment of Intermittent Claudication in People With Peripheral Arterial Disease. Angiology 65, 190–197 (2014)
DOI: 10.1177/0003319712474335

182. Brito, G., Dourado, M., Polari, L., Celestino, D., Carvalho, L. P., Queiroz, A., Carvalho, E. M., Machado, P. R. L. and Passos, S. Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline. Am. J. Trop. Med. Hyg. 90, 617–620 (2014)
DOI: 10.4269/ajtmh.12-0729

183. Sadeghian, G. and MA, N. The effect of combination therapy with systemic meglumine antimoniate (Glucantime) and pentoxifylline the treatment of cutaneous leishmaniasis. Iran. J. dermatology 9, 2 (2006)

184. Báfica, A., Oliveira, F., Freitas, L. A. R., Nascimento, E. G. and Barral, A. American Cutaneous Leishmaniasis unresponsive to antimonial drugs: Successful treatment using combination of N-methilglucamine antimoniate plus pentoxifylline. Int. J. Dermatol. 42, 203–207 (2003)
DOI: 10.1046/j.1365-4362.2003.01868.x

185. Almeida, O. L. S. and Santos, J. B. Advances in the treatment of cutaneous leishmaniasis in the new world in the last ten years: a systematic literature review. An. Bras. Dermatol. 86, 497–506 (2011)
DOI: 10.1590/S0365-05962011000300012

186. Lessa, H. A., Machado, P., Lima, F., Cruz, Á. A., Bacellar, O., Guerreiro, J. and Carvalho, E. M. Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am. J. Trop. Med. Hyg. 65, 87–89 (2001)
DOI: 10.4269/ajtmh.2001.65.87

187. Machado, P. R. L., Lessa, H., Lessa, M., Guimaraes, L. H., Bang, H., Ho, J. L. and Carvalho, E. M. Oral Pentoxifylline Combined with Pentavalent Antimony: A Randomized Trial for Mucosal Leishmaniasis. Clin. Infect. Dis. 44, 788–793 (2007)
DOI: 10.1086/511643

188. Bahia, M. T., de Andrade, I. M., Martins, T. A. F., Nascimento, Á. F. da S. do, Diniz, L. de F., Caldas, I. S., Talvani, A., Trunz, B. B., Torreele, E. and Ribeiro, I. Fexinidazole: A Potential New Drug Candidate for Chagas Disease. PLoS Negl. Trop. Dis. 6, (2012)
DOI: 10.1371/journal.pntd.0001870

189. Burri, C. Chemotherapy against human African trypanosomiasis: Is there a road to success? Parasitology 137, 1987–1994 (2010)
DOI: 10.1017/S0031182010001137

190. Kaiser, M., Bray, M. A., Cal, M., Trunz, B. B., Torreele, E. and Brun, R. Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob. Agents Chemother. 55, 5602–5608 (2011)
DOI: 10.1128/AAC.00246-11

191. Singh Grewal, A., Pandita, D., Bhardwaj, S. and Lather, V. Recent Updates on Development of Drug Molecules for Human African Trypanosomiasis. Curr. Top. Med. Chem. 16, 2245–2265 (2016)
DOI: 10.2174/1568026616666160413125335

192. Wyllie, S., Patterson, S., Stojanovski, L., Simeons, F. R. C., Norval, S., Kime, R., Read, K. D. and Fairlamb, a. H. The Anti-Trypanosome Drug Fexinidazole Shows Potential for Treating Visceral Leishmaniasis. Sci. Transl. Med. 4, 119re1-119re1 (2012)

193. Wyllie, S., Patterson, S. and Fairlamb, A. H. Assessing the essentiality of Leishmania donovani nitroreductase and its role in nitro drug activation. Antimicrob. Agents Chemother. 57, 901–906 (2013)
DOI: 10.1128/AAC.01788-12

194. ClinicalTrials.gov. Trial to Determine Efficacy of Fexinidazole in Visceral Leihmaniasis Patients in Sudan. at https://clinicaltrials.gov/ct2/show/NCT01980199?term=%22fexinidazole%22+AND+%22leishmaniasis%22&rank=1

Key Words: Leishmaniasis, Treatment; Drug Repurposing, Review

Send correspondence to: Eduardo Caio Torres-Santos, Laboratorio de Bioquimica de Tripanosomatideos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brasil, Tel: 55-21-3865-8247, Fax: 55-21-38362141, E-mail: ects@ioc.fiocruz.br