Skip to main content

Advertisement

SpringerLink
Log in

Miltefosine (Impavido): the first oral treatment against leishmaniasis

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Miltefosine is a novel antileishmanial drug that has significant selectivity in both in vitro and in vivo models. Clinical efficacy was demonstrated for the treatment of visceral leishmaniasis with the advantage of oral administration over the currently recommended antileishmanial drugs that require parenteral administration. Miltefosine produces high cure rates also in patients resistant to the standard antimonial therapy.

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

Similar content being viewed by others

References

  1. Achterberg V, Gercken G (1987) Cytotoxicity of ester and ether lysophospholipids on Leishmania donovani promastogotes. Mol Biochem Parasitol 23:117–122

    Article  CAS  PubMed  Google Scholar 

  2. Achterberg V, Gercken G (1987) Metabolism of ether lyophospholipids in Leishmania donovani promastigotes. Mol Biochem Parasitol 26:277–287

    Article  CAS  PubMed  Google Scholar 

  3. Berman JD (1991) Biological mechanisms of clinical antileishmanial agents: a review. J Cell Pharmacol 2:85–82

    Google Scholar 

  4. Berman JD (1997) Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 24:684–703

    CAS  PubMed  Google Scholar 

  5. Bryceson ADM, Chulay JD, Ho M, Mugambii M, Were JB (1985) Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies. Trans R Soc Trop Med Hyg 79:700–704

    CAS  PubMed  Google Scholar 

  6. Bryceson ADM (1987) Therapy in man. In: Peters W, Killick-Kendrick R (eds) The leishmaniasis in biology and medicine, Vol 2. Academic Press, New York, pp 848–907

  7. Burdzy K, Munder PG, Fischer H, Westphal O (1964) Steigerung der Phagozytose von Perionialmagrophagen durch Lysolecithin. Z Naturforsch 19B:1118

    CAS  Google Scholar 

  8. Croft SL, Neal RA, Pendergast W, Chan JH (1987) The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem Pharmacol 36:2633–2636

    Article  CAS  PubMed  Google Scholar 

  9. Croft SL, Neal RA, Thornton E, Herrmann DBJ (1993) Antileishmanial activity of the ether phospholipid ilmofosine. Trans R Soc Trop Med Hyg 87:217–219

    Google Scholar 

  10. Croft SL, Snowdon D, Yardley V (1996) The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. J Antimicrob Chemother 38:1041–1047

    CAS  PubMed  Google Scholar 

  11. Davidson RN, Di Martino L, Gradoni L, Giacchino R (1994) Liposomal amphotericin B (Am Bisome) in Mediteranian visceral leishmaniasis: a multicenter trial. Q J Med 87:75–81

    CAS  PubMed  Google Scholar 

  12. Davidson RN (1998) Practical guide for the treatment of leishmaniasis. Drug 56:1009–1018

    CAS  Google Scholar 

  13. Desjeux P (1996) Leishmaniasis: public health aspects and control. Clin Dermatol 14:417–423

    Article  CAS  PubMed  Google Scholar 

  14. Dietze R, Milan EP, Berman JD, Grogl M (1993) Treatment of Brazilian Kala-Azar with a short course of Amphocil (Amphotericin B-chlolesterol dispersion). Clin Infect Dis 17:981–986

    CAS  PubMed  Google Scholar 

  15. Dogra J (1991) A double-blind study on the efficacy of oral Dapsone in cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 85:212–213

    CAS  PubMed  Google Scholar 

  16. Escobar P, Yardley V, Croft SL (2001) Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice. Antimicrob Agents Chemother 45:1872–1875

    Article  CAS  PubMed  Google Scholar 

  17. Escobar P, Matu S, Marques C, Croft SL (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B. Acta Trop 81:151–157

    Article  CAS  PubMed  Google Scholar 

  18. Gokhale PC, Kshirsagar NA, Khan MU, Pandya SK (1994) Successful treatment of resistant visceral Leishmaniasis with liposomal Amphotericin B. Trans R Soc Trop Med Hyg 88:228

    CAS  PubMed  Google Scholar 

  19. Grevelink SA, Lerner EA (1996) Leishmaniasis. J Am Acad Dermatol 34:257–272

    CAS  PubMed  Google Scholar 

  20. Grogl M, Oduola AMJ, Cordero LDC, Kyle DE (1989) Leishmania spp: development of Pentostam resistant clones in vitro by discontinuous drug exposure. Exp Parasitol 69:78–90

    CAS  PubMed  Google Scholar 

  21. Harms G, Zwingenberger K, Sandkamp B, Omena S, Pedrosa C, Richter J, Rosenkaimer F (1993) Immunochemotherapy of visceral leishmaniasis. A pilot trial of sequential treatment with recombinant interferon-gamma and pentavalent antimony. J Interferon Res 13:39–41

    CAS  PubMed  Google Scholar 

  22. Hepburn NC, Nolan J, Fenn L, Herd RM, Neilson JMM (1994) Cardiac effects of sodium stibogluconate. Q J Med 87:465–472

    Google Scholar 

  23. Herwaldt BL (1999) Miltefosine—the long-awaited therapy for visceral leishmaniasis? N Engl J Med 341:1840–1842

    Article  CAS  PubMed  Google Scholar 

  24. Hilgard P, Stekar J, Voegeli R, Engel J, Schumacher W, Eibl HJ, Unger C, Berger MR (1988) Characterization of the antitumor activity of hexadecylphosphocholine (D-18506). Eur J Cancer Clin Oncol 24:1457–1461

    CAS  PubMed  Google Scholar 

  25. Hilgard P, Kampherm E, Nolan L, Pohl J, Reissmann T (1991) Investigation into the immunological effects of miltefosine, a new anticancer agent under development. J Cancer Res Clin Oncol 117:403–408

    CAS  PubMed  Google Scholar 

  26. Hochhuth CH, Vehmeyer K, Eibl HJ, Unger C (1992) Hexadecylphosphocholine induces interferone-γ secretion and expression of GM-CSF mRNA in human mononuclear cells. Cell Immunol 141:161–168

    CAS  PubMed  Google Scholar 

  27. Jha TK, Giri YN, Singh TK, Jha S (1995) Use of amphotericin B in drug resistant cases of visceral leishmaniasis in north Bihar, India. Am J Trop Med Hyg 52:536–538

    CAS  PubMed  Google Scholar 

  28. Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fischer C, Voss A, Berman J (1999) Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 341:1795–1800

    Article  CAS  PubMed  Google Scholar 

  29. Klenner T, Beckers T, Nooter K, Holtmann H (1996) Influence of hexadecylphosphocholine (Miltefosine) on cytokine synthesis and biological responses. Adv Exp Med Biol 416:181–187

    CAS  PubMed  Google Scholar 

  30. Kuhlencord A, Maniera T, Eibl H, Unger C (1992) Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicrob Agents Chemother 36:1630–1634

    CAS  PubMed  Google Scholar 

  31. Le Fichoux Y, Rousseau D, Ferrua B, Ruette S, Lelievre A, Grousson D, Kubar J (1998) Short- and long-term efficacy of hexadecylphosphocholine against established Leishmania infantum infection in BALB/c mice. Antimicrob Agents Chemother 42:654–658

    PubMed  Google Scholar 

  32. Lira R, Sundar S, Makharia A, et al (1999) Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony resistantstrains of Leishmania donovani. J Infect Dis 180:564

    Article  CAS  PubMed  Google Scholar 

  33. Lira R, Contreras LM, Santa-Rita RM, Urbina JA (2001) Mechanism of action of anti-proliferative lysophospholipid analogues against the protozoan parasite Trypanosoma cruzi: potentiation of the in-vitro activity by the sterol biosynthesis inhibitor ketoconazole. J Antimicrob Chemother 47:537–546

    Article  CAS  PubMed  Google Scholar 

  34. Lux H, Hart DT, Parker PJ, Klenner T (1996) Ether lipid metabolism, GPI anchor biosynthesis, and signal transduction are putative targets for antileishmanial alkyl phospholipid analogues. Adv Exp Med Biol 416:201–211

    CAS  PubMed  Google Scholar 

  35. Lux H, Heise N, Klenner T, Hart D, Opperdoes FR (2000) Ether-lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether-lipid analogues in Leishmania. Mol Biochem Parasitol 111:1–14

    Article  CAS  PubMed  Google Scholar 

  36. McBride M, Linney M, Claydon EJ, Weber J (1994) Visceral leishmaniasis following treatment with liposomal amphotericin B. Clin Infect Dis 19:362

    CAS  PubMed  Google Scholar 

  37. Murray HW, Squires KE, Harms G, Rosenkaimer F (1992) Clinical trials of interferon-gamma for leishmaniasis. In: Sonnenfeld G, Czarniecki C, Nacy C, et al (eds) Cytokines and resistance to nonviral infections. Biomedical Press, Augusta, pp 199–206

  38. Murray HW (2000) Suppression of posttreatment recurrence of experimental visceral leishmaniasis in T-cell-deficient mice by oral miltefosine. Antimicrob Agents Chemother 44:3235–3236

    Article  CAS  PubMed  Google Scholar 

  39. Murray HW, Delph-Etienne S (2000) Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microbicidal mechanisms. J Infect Dis 181:795–799

    Article  CAS  PubMed  Google Scholar 

  40. Safa O, Parkin SM, Matthew AM, Bibby MC (1997) Morphological and immunological observations on the effects of hexadecylphosphocholine (HPC) in nude mice bearing MT-1 breast cancer xenografts. Anticancer Res 17:37–44

    CAS  PubMed  Google Scholar 

  41. Santa-Rita RM, Barbosa HS, Meirelles MNSL, Castro SL de (2000) Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi. Acta Trop 75:219–228

    Article  CAS  PubMed  Google Scholar 

  42. Schmidt-Ott R, Klenner T, Overath P, Aebischer T (1999) Topical treatment with hexadecylphosphocholine (Miltex®) efficiently reduces parasite burden in experimental cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 93:85–90

    CAS  PubMed  Google Scholar 

  43. Soto J, Toledo J, Gutierrez P, Nicholis RS, Padilla J, Engel J, Fischer C, Voss A, Berman J (2001) Treatment of American cutaneous leishmaniasis with Miltefosine, an oral agent. Clin Infect Dis 33:E57–E61

    Article  CAS  PubMed  Google Scholar 

  44. Squires KE, Rosenkaimer F, Sherwood JA, Were JBO, Murray HW (1993) Immunochemotherapy for visceral Leishmaniasis. A controlled pilot trial of antimony versus antimony plus interferon-gamma. Am J Trop Med Hyg 48:666–669

    CAS  PubMed  Google Scholar 

  45. Sundar S, Rosenkaimer F, Murray HW (1994) Successful treatment of refractory visceral leishmaniasis in India using antimony plus interferon-gamma. J Infect Dis 170:659–662

    CAS  PubMed  Google Scholar 

  46. Sundar S, Rosenkaimer F, Lesser ML, Murray HW (1995) Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis J Infect Dis 171:992–996

  47. Sundar S, Rosenkaimer F, Makharia MK, Goyal AK, Mandal AK, Voss A, Hilgard P, Murray HW (1998) Trial of miltefosine for visceral leishmaniasis. Lancet 352:1821–1823

    Article  CAS  PubMed  Google Scholar 

  48. Sundar S, Gupta LB, Makharia MK, Singh MK, Voss A, Rosenkaimer F, Engel J, Murray HW (1999) Oral treatment of visceral leishmaniasis with miltefosine. Ann Trop Med Parasitol 93:589–597

    Article  CAS  PubMed  Google Scholar 

  49. Sundar S, Makharia A, More DK, Agraval G, Voss A, Fischer C, Bachmann P, Murray HW (2001) Short course of oral miltefosine for treatment of visceral leishmaniasis. Clin Infect Dis 31:1110–1113

    Article  Google Scholar 

  50. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J (2002) Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347:1739–1746

    Google Scholar 

  51. Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J (2003) Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 22:434–438

    Article  PubMed  Google Scholar 

  52. Teklemariam S, Hiwot AG, Frommel D, Miko TL (1994) Aminosidine and its combination with sodium stibogluconate in the treatment of diffuse cutaneous leishmaniasis caused by Leishmania aethiopica. Trans R Soc Trop Med Hyg 88:334–339

    CAS  PubMed  Google Scholar 

  53. Thakur CP, Kumar M, Pandey AK (1991) Evaluation of efficacy of longer durations of therapy for fresh cases of kala-azar with sodium stibogluconate. Indian J Med Res 92:103–120

    Google Scholar 

  54. Thakur CP, Olliaro P, Gothoskar S, Bhowmick S (1992) Treatment of visceral leishmaniasis (kala-azar) with aminosidine (paromomycine)-antimonial combinations, a pilot study in Bihar, India. Trans R Soc Trop Med Hyg 86:615–616

    CAS  PubMed  Google Scholar 

  55. Tsushima S, Yoshioka Y, Tanida S, Nomura H, Nojima S, Hozumi M (1982) Syntheses and antimicrobial activities of alkyl lysophospholipids. Chem Pharm Bull (Tokyo) 30:3260–3270

    Google Scholar 

  56. Unger C, Maniera T, Kaufmann-Kolle P, Eibl H (1998) In vivo antileishmanial activity of hexadecylphosphocholine and other alkylphosphocholines. Drugs Today 34 (Suppl F):133–140

    CAS  Google Scholar 

  57. Verweij J, Plating A, Berg M van der, Stoter G (1992) A dose finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumors. J Cancer Res Clin Oncol 118:606–608

    CAS  PubMed  Google Scholar 

  58. Wilcocks C, Manson-Bahr PEC (1972) Manon's tropical diseases. Baillière Tindall, London, pp 119–133

Download references

Author information

Authors and Affiliations

  1. Zentaris AG, Weismüllerstrasse 45, 60314, Frankfurt am Main, Germany

    H. Sindermann & J. Engel

  2. London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    S. L. Croft

  3. Georg-August-University of Göttingen, Institute of Hygiene, Windausweg 2, 37073, Göttingen, Germany

    K. R. Engel & W. Bommer

  4. Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg, 37077, Göttingen, Germany

    H. J. Eibl

  5. Klinik für Tumorbiologie, Breisacher Strasse 117, 79106, Freiburg, Germany

    C. Unger

Authors
  1. H. Sindermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. L. Croft
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. R. Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Bommer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. J. Eibl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Unger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Engel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sindermann, H., Croft, S.L., Engel, K.R. et al. Miltefosine (Impavido): the first oral treatment against leishmaniasis. Med Microbiol Immunol 193, 173–180 (2004). https://doi.org/10.1007/s00430-003-0201-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-003-0201-2

Keywords

Search

Navigation