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Volume 62, Issue 7

Activity of antimalarial drugs and in a murine model of cutaneous leishmaniasis Free

Abstract

The currently used treatments for leishmaniasis, a neglected parasitic disease, are associated with several side effects, high cost and resistance of the parasites. Here we evaluated and the antileishmanial activity of five antimalarial drugs against . Mefloquine was effective against promastigotes in axenic cultures and showed an IC (concentration giving half-maximal inhibition) value of 8.4±0.7 µM. In addition, mefloquine, chloroquine and hydroxychloroquine were active against intracellular amastigotes in macrophage-infected cultures, presenting IC values of 1.56±0.19 µM, 0.78±0.08 µM and 0.67±0.12 µM, respectively. The ultrastructural analysis of chloroquine- or mefloquine-treated amastigotes showed an accumulation of multivesicular bodies in the cytoplasm of the parasite, suggesting endocytic pathway impairment, in addition to the formation of myelin-like figures and enlargement of the Golgi cisternae. CBA mice were infected with in the ear dermis, and treated by oral and/or topical routes with chloroquine and mefloquine. Treatment of -infected mice with chloroquine by the oral route reduced lesion size, which was associated with a decrease in the number of parasites in the ear, as well as the parasite burden in the draining lymph nodes. In contrast, mefloquine administration by both routes decreased the lesion size in infected mice without causing a reduction in parasite burden. Our results revealed a promising antileishmanial effect of chloroquine and suggest its use in cutaneous leishmaniasis treatment.

  • Received:
  • Accepted:
  • Published Online:
© 2013 SGM
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2013-07-01
2024-04-24
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References

  1. Ashburn T. T., Thor K. B. 2004; Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683 [View Article][PubMed]
     [Google Scholar]
  2. Awasthi A., Mathur R. K., Saha B. 2004; Immune response to Leishmania infection. Indian J Med Res 119:238–258[PubMed]
     [Google Scholar]
  3. Bermudez L. E., Kolonoski P., Wu M., Aralar P. A., Inderlied C. B., Young L. S. 1999; Mefloquine is active in vitro and in vivo against Mycobacterium avium complex. Antimicrob Agents Chemother 43:1870–1874[PubMed]
     [Google Scholar]
  4. Bézivin C., Tomasi S., Lohézic-Le Dévéhat F., Boustie J. 2003; Cytotoxic activity of some lichen extracts on murine and human cancer cell lines. Phytomedicine 10:499–503 [View Article][PubMed]
     [Google Scholar]
  5. Borges V. M., Vannier-Santos M. A., de Souza W. 1998; Subverted transferrin trafficking in Leishmania-infected macrophages. Parasitol Res 84:811–822 [View Article][PubMed]
     [Google Scholar]
  6. Byrd T. F., Horwitz M. A. 1991; Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens. J Clin Invest 88:351–357 [View Article][PubMed]
     [Google Scholar]
  7. Chaves S. P., Torres-Santos E. C., Marques C., Figliuolo V. R., Persechini P. M., Coutinho-Silva R., Rossi-Bergmann B. 2009; Modulation of P2X7 purinergic receptor in macrophages by Leishmania amazonensis and its role in parasite elimination. Microbes Infect 11:842–849 [View Article][PubMed]
     [Google Scholar]
  8. Croft S. L., Sundar S., Fairlamb A. H. 2006; Drug resistance in leishmaniasis. Clin Microbiol Rev 19:111–126 [View Article][PubMed]
     [Google Scholar]
  9. de Oliveira Cardoso F., de Souza C. S., Mendes V. G., Abreu-Silva A. L., Gonçalves da Costa S. C., Calabrese K. S. 2010; Immunopathological studies of Leishmania amazonensis infection in resistant and in susceptible mice. J Infect Dis 201:1933–1940 [View Article][PubMed]
     [Google Scholar]
  10. Desjeux P. 2001; The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 95:239–243 [View Article][PubMed]
     [Google Scholar]
  11. Faria D. R., Gollob K. J., Barbosa J. Jr, Schriefer A., Machado P. R. L., Lessa H., Carvalho L. P., Romano-Silva M. A., de Jesus A. R. et al. 2005; Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis. Infect Immun 73:7853–7859 [View Article][PubMed]
     [Google Scholar]
  12. Fortier A. H., Leiby D. A., Narayanan R. B., Asafoadjei E., Crawford R. M., Nacy C. A., Meltzer M. S. 1995; Growth of Francisella tularensis LVS in macrophages: the acidic intracellular compartment provides essential iron required for growth. Infect Immun 63:1478–1483[PubMed]
     [Google Scholar]
  13. Frézard F., Demicheli C., Ribeiro R. R. 2009; Pentavalent antimonials: new perspectives for old drugs. Molecules 14:2317–2336 [View Article][PubMed]
     [Google Scholar]
  14. Galvão L. O., Moreira Júnior S., Medeiros Júnior P., Lemos G. J., Cunha N. F., Antonino R. M., Santos Filho B. S., Magalhães A. V. 2000; 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 [View Article][PubMed]
     [Google Scholar]
  15. Ghedin E., Debrabant A., Engel J. C., Dwyer D. M. 2001; Secretory and endocytic pathways converge in a dynamic endosomal system in a primitive protozoan. Traffic 2:175–188 [View Article][PubMed]
     [Google Scholar]
  16. Gomes I. N., Calabrich A. F., Tavares R. S., Wietzerbin J., de Freitas L. A., Veras P. S. 2003; Differential properties of CBA/J mononuclear phagocytes recovered from an inflammatory site and probed with two different species of Leishmania . Microbes Infect 5:251–260 [View Article][PubMed]
     [Google Scholar]
  17. Guimarães E. T., Santos L. A., dos Santos R. R., Teixeira M. M., dos Santos W. L. C., Soares M. B. P. 2006; Role of interleukin-4 and prostaglandin E2 in Leishmania amazonensis infection of BALB/c mice. Microbes Infect 8:1219–1226 [View Article][PubMed]
     [Google Scholar]
  18. Heurtault B., Legrand P., Mosqueira V., Devissaguet J.-P., Barratt G., Bories C. 2001; The antileishmanial properties of surface-modified, primaquine-loaded nanocapsules tested against intramacrophagic Leishmania donovani amastigotes in vitro . Ann Trop Med Parasitol 95:529–533 [View Article][PubMed]
     [Google Scholar]
  19. Hrabák A., Sefrioui H., Vercruysse V., Temesi A., Bajor T., Vray B. 1998; Action of chloroquine on nitric oxide production and parasite killing by macrophages. Eur J Pharmacol 354:83–90 [View Article][PubMed]
     [Google Scholar]
  20. Huynh C., Sacks D. L., Andrews N. W. 2006; A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes. J Exp Med 203:2363–2375 [View Article][PubMed]
     [Google Scholar]
  21. Ingram K., Ellis W., Keiser J. 2012; Antischistosomal activities of mefloquine-related arylmethanols. Antimicrob Agents Chemother 56:3207–3215 [View Article][PubMed]
     [Google Scholar]
  22. Jang C.-H., Choi J.-H., Byun M.-S., Jue D.-M. 2006; Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford) 45:703–710 [View Article][PubMed]
     [Google Scholar]
  23. Kaye P., Scott P. 2011; Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9:604–615 [View Article][PubMed]
     [Google Scholar]
  24. Keiser J., Manneck T., Vargas M. 2011; Interactions of mefloquine with praziquantel in the Schistosoma mansoni mouse model and in vitro . J Antimicrob Chemother 66:1791–1797 [View Article][PubMed]
     [Google Scholar]
  25. Khan I., Yasmin R., Sidiki I. 2007; Chloroquine in cutaneous leishmaniasis. J Pak Assoc Dermatol 17:95–100
     [Google Scholar]
  26. Küster T., Stadelmann B., Hermann C., Scholl S., Keiser J., Hemphill A. 2011; In vitro and in vivo efficacies of mefloquine-based treatment against alveolar echinococcosis. Antimicrob Agents Chemother 55:713–721 [View Article][PubMed]
     [Google Scholar]
  27. Laguna-Torres V. A., Silva C. A., Correia D., Carvalho E. M., Magalhães A. V., Macêdo Vde. O. 1999; [Mefloquine in the treatment of cutaneous leishmaniasis in an endemic area of Leishmania (Viannia) braziliensis.]. Rev Soc Bras Med Trop 32:529–532 (in Portuguese) [PubMed] [CrossRef]
     [Google Scholar]
  28. Landires E. A. G., Andrial M., Hosokawa A., Nonaka S., Hashiguchi Y. 1995; Oral treatment of new world cutaneous leishmaniasis with anti-malarial drugs in Ecuador: a preliminary clinical trial. Jpn J Trop Med Hyg 23:151–157 [View Article]
     [Google Scholar]
  29. Lemos de Souza V., Ascenção Souza J., Correia Silva T. M., Sampaio Tavares Veras P., Rodrigues de-Freitas L. A. 2000; Different Leishmania species determine distinct profiles of immune and histopathological responses in CBA mice. Microbes Infect 2:1807–1815 [View Article][PubMed]
     [Google Scholar]
  30. Murray H. W., Berman J. D., Davies C. R., Saravia N. G. 2005; Advances in leishmaniasis. Lancet 366:1561–1577 [View Article][PubMed]
     [Google Scholar]
  31. Noor S. M., Khan M. M., Hussain D. 2005; Intralesional chloroquine in cutaneous leishmaniasis. J Pak Assoc Dermatol 15:18–21
     [Google Scholar]
  32. O’Neill P. M., Bray P. G., Hawley S. R., Ward S. A., Park B. K. 1998; 4-Aminoquinolines–past, present, and future: a chemical perspective. Pharmacol Ther 77:29–58 [View Article][PubMed]
     [Google Scholar]
  33. Oliveira L. F., Schubach A. O., Martins M. M., Passos S. L., Oliveira R. V., Marzochi M. C., Andrade C. A. 2011; Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Trop 118:87–96 [View Article][PubMed]
     [Google Scholar]
  34. Pereira B. A. S., Alves C. R. 2008; Immunological characteristics of experimental murine infection with Leishmania (Leishmania) amazonensis . Vet Parasitol 158:239–255 [View Article][PubMed]
     [Google Scholar]
  35. Reithinger R., Dujardin J. C., Louzir H., Pirmez C., Alexander B., Brooker S. 2007; Cutaneous leishmaniasis. Lancet Infect Dis 7:581–596 [View Article][PubMed]
     [Google Scholar]
  36. Rolain J. M., Colson P., Raoult D. 2007; Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 30:297–308 [View Article][PubMed]
     [Google Scholar]
  37. Sen R., Ganguly S., Saha P., Chatterjee M. 2010; Efficacy of artemisinin in experimental visceral leishmaniasis. Int J Antimicrob Agents 36:43–49 [View Article][PubMed]
     [Google Scholar]
  38. Smith D. F., Peacock C. S., Cruz A. K. 2007; Comparative genomics: from genotype to disease phenotype in the leishmaniases. Int J Parasitol 37:1173–1186 [View Article][PubMed]
     [Google Scholar]
  39. Taylor M. C., Kelly J. M. 2010; Iron metabolism in trypanosomatids, and its crucial role in infection. Parasitology 137:899–917 [View Article][PubMed]
     [Google Scholar]
  40. WHO (2010). Control of Leishmaniasis: Report of a Meeting of the WHO Expert Committee on the Control of Leishmaniasis, Geneva, 22–26 March 2010. WHO Technical Report Series no. 949. Geneva: World Health Organization
  41. Yang D. M., Liew F. Y. 1993; Effects of qinghaosu (artemisinin) and its derivatives on experimental cutaneous leishmaniasis. Parasitology 106:7–11 [View Article][PubMed]
     [Google Scholar]
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Activity of antimalarial drugs in vitro and in a murine model of cutaneous leishmaniasis
J. Med. Microbiol. 62, 1001 (2013); https://doi.org/10.1099/jmm.0.058115-0
/content/journal/jmm/10.1099/jmm.0.058115-0
/content/journal/jmm/10.1099/jmm.0.058115-0
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