Efficacy and Safety of Miltefosine or Thermotherapy for Cutaneous Leishmaniasis in Colombia.

Summary

Cutaneous leishmaniasis (CL) is a worldwide disease, endemic in 88 countries, that has shown an increasing incidence the last two decades. It is estimated that in 2005, about of 20,000 new cases of CL were diagnosed in Colombia. So far, pentavalent antimony compounds have been considered the treatment of choice with a percentage of cure of about 85%. However, the high efficacy of these drugs is counteracted by their adverse events and disadvantages. Previous studies have shown that miltefosine could be a potential alternative of treatment for CL. The main objective of this study is to evaluate the efficacy and safety of miltefosine or thermotherapy for the treatment for CL. In this study the efficacy of oral treatment of miltefosine 150 mg/day for 28 days or a thermotherapy device used for one session at 50 celsius degrees during 30 seconds will be compared with the standard treatment of intramuscular injections of 20 mg/Kg/day of pentavalent antimonials (GlucantimeÒ) for 20 days in CL parasitologically proven patients. This trial will be conducted according to the International approved GCP (Good Clinical Practice) guidelines.

Timeline

Start

2006-06

Primary completion

2008-08

Completion

2009-12

Publications

• Background 1.World Health Organization. Division of Control of Tropical Diseases. Leishmaniasis control home page. [Consultado: 20 de septiembre de 2006]. Disponible en: www.who.int/health-topics/leishmaniasis.htm
• Background 2.Echeverry Gaitan MC, Gaona Narváez J, Gualtero SM. Guia de Atención de Leishmaniasis. Revisión y actualización. 2006.
• Background Bejarano EE, Uribe S, Rojas W, Dario Velez I. Phlebotomine sand flies (Diptera: Psychodidae) associated with the appearance of urban Leishmaniasis in the city of Sincelejo, Colombia. Mem Inst Oswaldo Cruz. 2002 Jul;97(5):645-7.
• Background Bejarano EE, Uribe S, Rojas W, Velez ID. Presence of Lutzomyia evansi, a vector of American visceral leishmaniasis, in an urban area of the Colombian Caribbean coast. Trans R Soc Trop Med Hyg. 2001 Jan-Feb;95(1):27-8. doi: 10.1016/s0035-9203(01)90320-7. No abstract available.
• Background Agudelo LA, Uribe J, Sierra D, Ruiz F, Velez ID. Presence of American cutaneous Leishmaniasis vectors surrounding the city of Medellin, Colombia. Mem Inst Oswaldo Cruz. 2002 Jul;97(5):641-2.
• Background Berman J. Report to 1999 Miltefosine PDT of the phase II study. 1999. WHO/TDR.
• Background Croft SL, Neal RA, Pendergast W, Chan JH. The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem Pharmacol. 1987 Aug 15;36(16):2633-6. doi: 10.1016/0006-2952(87)90543-0.
• Background Ministerio de Proteccion Social, Instituto Nacional de Salud, and SIVIGILA. informe Leishmaniasis semestre 2005. http://www.ins.gov.co/pdf/vcsp/informe_leishmanisis_1sem_2005.pdf. Fecha de acceso: 09/22/06
• Background Leandro C, Campino L. Leishmaniasis: efflux pumps and chemoresistance. Int J Antimicrob Agents. 2003 Sep;22(3):352-7. doi: 10.1016/s0924-8579(03)00211-5.
• Background Velez ID, Hendrickx E, Robledo SM, del Pilar Agudelo S. [Gender and cutaneous leishmaniasis in Colombia]. Cad Saude Publica. 2001 Jan-Feb;17(1):171-80. doi: 10.1590/s0102-311x2001000100018. Spanish.
• Background Navin TR, Arana BA, Arana FE, de Merida AM, Castillo AL, Pozuelos JL. Placebo-controlled clinical trial of meglumine antimonate (glucantime) vs. localized controlled heat in the treatment of cutaneous leishmaniasis in Guatemala. Am J Trop Med Hyg. 1990 Jan;42(1):43-50. doi: 10.4269/ajtmh.1990.42.43.
• Background Velasco-Castrejon O, Walton BC, Rivas-Sanchez B, Garcia MF, Lazaro GJ, Hobart O, Roldan S, Floriani-Verdugo J, Munguia-Saldana A, Berzaluce R. Treatment of cutaneous leishmaniasis with localized current field (radio frequency) in Tabasco, Mexico. Am J Trop Med Hyg. 1997 Sep;57(3):309-12. doi: 10.4269/ajtmh.1997.57.309.
• Background Berman JD, Neva FA. Effect of temperature on multiplication of Leishmania amastigotes within human monocyte-derived macrophages in vitro. Am J Trop Med Hyg. 1981 Mar;30(2):318-21. doi: 10.4269/ajtmh.1981.30.318.
• Background Sacks DL, Barral A, Neva FA. Thermosensitivity patterns of Old vs. New World cutaneous strains of Leishmania growing within mouse peritoneal macrophages in vitro. Am J Trop Med Hyg. 1983 Mar;32(2):300-4. doi: 10.4269/ajtmh.1983.32.300.
• Background Neva FA, Petersen EA, Corsey R, Bogaert H, Martinez D. Observations on local heat treatment for cutaneous leishmaniasis. Am J Trop Med Hyg. 1984 Sep;33(5):800-4. doi: 10.4269/ajtmh.1984.33.800.
• Background Wilcocks & Manson-Bahr. Manon's tropical diseases.London: Bailliére Tindall; 1972. p. 119-33.
• Background Herwaldt BL, Arana BA, Navin TR. The natural history of cutaneous leishmaniasis in Guatemala. J Infect Dis. 1992 Mar;165(3):518-27. doi: 10.1093/infdis/165.3.518.
• Background Herwaldt BL. Leishmaniasis. Lancet. 1999 Oct 2;354(9185):1191-9. doi: 10.1016/S0140-6736(98)10178-2.
• Background Remme JH, Blas E, Chitsulo L, Desjeux PM, Engers HD, Kanyok TP, Kengeya Kayondo JF, Kioy DW, Kumaraswami V, Lazdins JK, Nunn PP, Oduola A, Ridley RG, Toure YT, Zicker F, Morel CM. Strategic emphases for tropical diseases research: a TDR perspective. Trends Parasitol. 2002 Oct;18(10):421-6. doi: 10.1016/s1471-4922(02)02387-5.
• Background Marsden PD. Mucosal leishmaniasis ("espundia" Escomel, 1911). Trans R Soc Trop Med Hyg. 1986;80(6):859-76. doi: 10.1016/0035-9203(86)90243-9.
• Background Saravia NG, Weigle K, Segura I, Giannini SH, Pacheco R, Labrada LA, Goncalves A. Recurrent lesions in human Leishmania braziliensis infection--reactivation or reinfection? Lancet. 1990 Aug 18;336(8712):398-402. doi: 10.1016/0140-6736(90)91945-7.
• Background Kreutzer RD, Corredor A, Grimaldi G Jr, Grogl M, Rowton ED, Young DG, Morales A, McMahon-Pratt D, Guzman H, Tesh RB. Characterization of Leishmania colombiensis sp. n (Kinetoplastida: Trypanosomatidae), a new parasite infecting humans, animals, and phlebotomine sand flies in Colombia and Panama. Am J Trop Med Hyg. 1991 Jun;44(6):662-75. doi: 10.4269/ajtmh.1991.44.662.
• Background Angulo VM, Tarazona Z, Vega A, Vélez Bernal ID, Betancur Martinez J. Leismaniosis Chagas y Malaria. 27-41. 2002. Colombia, Ascofame.
• Background Vélez Bernal ID, Rodriguez Garcia E, Duarte Forero R, López Carvajal L, Castaño Arbeláez M. Enfermedades Tropicales. Guia de manejo de ETV y accidente ofídico. 17-55. 2005. Colombia, PECET
• Background Franke ED, Lucas CM, Tovar AA, Kruger JH, De Rivera MV, Wignall FS. Diffuse cutaneous leishmaniasis acquired in Peru. Am J Trop Med Hyg. 1990 Sep;43(3):260-2. doi: 10.4269/ajtmh.1990.43.260.
• Background Hepburn NC, Tidman MJ, Hunter JA. Aminosidine (paromomycin) versus sodium stibogluconate for the treatment of American cutaneous leishmaniasis. Trans R Soc Trop Med Hyg. 1994 Nov-Dec;88(6):700-3. doi: 10.1016/0035-9203(94)90237-2.
• Background Berman JD. Treatment of New World cutaneous and mucosal leishmaniases. Clin Dermatol. 1996 Sep-Oct;14(5):519-22. doi: 10.1016/0738-081x(96)00048-x.
• Background Hendrickx EP, Agudelo SP, Munoz DL, Puerta JA, Velez Bernal ID. Lack of efficacy of mefloquine in the treatment of New World cutaneous leishmaniasis in Colombia. Am J Trop Med Hyg. 1998 Dec;59(6):889-92. doi: 10.4269/ajtmh.1998.59.889.
• Background Navin TR, Arana BA, Arana FE, Berman JD, Chajon JF. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis. 1992 Mar;165(3):528-34. doi: 10.1093/infdis/165.3.528.
• Background Franke ED, Wignall FS, Cruz ME, Rosales E, Tovar AA, Lucas CM, Llanos-Cuentas A, Berman JD. Efficacy and toxicity of sodium stibogluconate for mucosal leishmaniasis. Ann Intern Med. 1990 Dec 15;113(12):934-40. doi: 10.7326/0003-4819-113-12-934.
• Background Rojas R, Valderrama L, Valderrama M, Varona MX, Ouellette M, Saravia NG. Resistance to antimony and treatment failure in human Leishmania (Viannia) infection. J Infect Dis. 2006 May 15;193(10):1375-83. doi: 10.1086/503371. Epub 2006 Apr 7.
• Background Kuhlencord A, Maniera T, Eibl H, Unger C. Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicrob Agents Chemother. 1992 Aug;36(8):1630-4. doi: 10.1128/AAC.36.8.1630.
• Background Hepburn NC, Nolan J, Fenn L, Herd RM, Neilson JM, Sutherland GR, Fox KA. Cardiac effects of sodium stibogluconate: myocardial, electrophysiological and biochemical studies. QJM. 1994 Aug;87(8):465-72.
• Background Croft SL, Coombs GH. Leishmaniasis--current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol. 2003 Nov;19(11):502-8. doi: 10.1016/j.pt.2003.09.008. No abstract available.
• Background Thakur CP, Kumar M, Pandey AK. Comparison of regimes of treatment of antimony-resistant kala-azar patients: a randomized study. Am J Trop Med Hyg. 1991 Oct;45(4):435-41. doi: 10.4269/ajtmh.1991.45.435.
• Background Singh S, Sivakumar R. Challenges and new discoveries in the treatment of leishmaniasis. J Infect Chemother. 2004 Dec;10(6):307-15. doi: 10.1007/s10156-004-0348-9.
• Background Soto-Mancipe J, Grogl M, Berman JD. Evaluation of pentamidine for the treatment of cutaneous leishmaniasis in Colombia. Clin Infect Dis. 1993 Mar;16(3):417-25. doi: 10.1093/clind/16.3.417.
• Background Soto J, Buffet P, Grogl M, Berman J. Successful treatment of Colombian cutaneous leishmaniasis with four injections of pentamidine. Am J Trop Med Hyg. 1994 Jan;50(1):107-11. doi: 10.4269/ajtmh.1994.50.107.
• Background Amato VS, de Paula JG, Imamura R, Amato Neto V, Duarte MI, Boulos MI, Boulos M, Nicodemo AC, de Mendonca JS. [Treatment of american cutaneous leishmaniasis, with lesions in the mucosa, using pentamidine isethionate]. Rev Soc Bras Med Trop. 1996 Sep-Oct;29(5):477-81. doi: 10.1590/s0037-86821996000500011. Portuguese.
• Background Correia D, Macedo VO, Carvalho EM, Barral A, Magalhaes AV, de Abreu MV, Orge ML, Marsden P. [Comparative study of meglumine antimoniate, pentamidine isethionate and aminosidine sulfate in the treatment of primary skin lesions caused by Leishmania (Viannia) braziliensis]. Rev Soc Bras Med Trop. 1996 Sep-Oct;29(5):447-53. doi: 10.1590/s0037-86821996000500007. Portuguese.
• Background Amato V, Amato J, Nicodemo A, Uip D, Amato-Neto V, Duarte M. [Treatment of mucocutaneous leishmaniasis with pentamidine isothionate]. Ann Dermatol Venereol. 1998 Aug;125(8):492-5. French.
• Background Robledo SM, Puerta JA, Munoz DL, Guardo M, Velez ID. [Efficacy and tolerance of pentamidine for treatment of cutaneous leishmaniasis caused by por L. (V) panamensis in Colombia]. Biomedica. 2006 Oct;26 Suppl 1:188-93. Spanish.
• Background de Paula CD, Sampaio JH, Cardoso DR, Sampaio RN. [A comparative study between the efficacy of pentamidine isothionate given in three doses for one week and N-methil-glucamine in a dose of 20mgSbV/day for 20 days to treat cutaneous leishmaniasis]. Rev Soc Bras Med Trop. 2003 May-Jun;36(3):365-71. Epub 2003 Jul 31. Portuguese.
• Background Andersen EM, Cruz-Saldarriaga M, Llanos-Cuentas A, Luz-Cjuno M, Echevarria J, Miranda-Verastegui C, Colina O, Berman JD. Comparison of meglumine antimoniate and pentamidine for peruvian cutaneous leishmaniasis. Am J Trop Med Hyg. 2005 Feb;72(2):133-7.
• Background Lieber-Mbomeyo A, Lipsker D, Milea M, Heid E. [Rhabdomyolysis induced by pentamidine (Pentacarinat) during treatment of cutaneous leishmaniasis: 2 cases]. Ann Dermatol Venereol. 2002 Jan;129(1 Pt 1):50-2. French.
• Background Lightburn E, Morand JJ, Meynard JB, Kraemer P, Chaudier B, Pages F, Garnotel E, Patte JH, Banzet S, Dampierre H, Lepage J, Morillon M, Boutin JP, Hovette P, Chouc C. [Management of American cutaneous leishmaniasis. Outcome apropos of 326 cases treated with high-dose pentamidine isethionate]. Med Trop (Mars). 2003;63(1):35-44. French.
• Background Delobel P, Pradinaud R. Rhabdomyolysis associated with pentamidine isethionate therapy for American cutaneous leishmaniasis. J Antimicrob Chemother. 2003 May;51(5):1319-20. doi: 10.1093/jac/dkg195. Epub 2003 Mar 28. No abstract available.
• Background Hauben M, Reich L. A case report of rhabdomyolysis with pentamidine that prompted a retrospective evaluation of a pharmacovigilance tool under investigation. Br J Clin Pharmacol. 2004 Dec;58(6):675-6. doi: 10.1111/j.1365-2125.2004.02215.x. No abstract available.
• Background Invetigator's Brochure Miltefosine. D-18506. 27-10-1999. Frankfurt, Alemania, ASTA Medica
• Background Croft SL, Snowdon D, Yardley V. The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. J Antimicrob Chemother. 1996 Dec;38(6):1041-7. doi: 10.1093/jac/38.6.1041.
• Background Sundar S, Rosenkaimer F, Makharia MK, Goyal AK, Mandal AK, Voss A, Hilgard P, Murray HW. Trial of oral miltefosine for visceral leishmaniasis. Lancet. 1998 Dec 5;352(9143):1821-3. doi: 10.1016/S0140-6736(98)04367-0.
• Background Verweij J, Planting A, van der Burg M, Stoter G. A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours. J Cancer Res Clin Oncol. 1992;118(8):606-8. doi: 10.1007/BF01211805.
• Background Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, Diaz A, Luz M, Gutierrez P, Arboleda M, Berman JD, Junge K, Engel J, Sindermann H. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004 May 1;38(9):1266-72. doi: 10.1086/383321. Epub 2004 Apr 9.
• Background Alvaro Ruíz Morales, Luis Enrique Morrillo Zárate. Epidemiología clínica. Bogotá, Editorial Médica Panamericana
• Lopez L, Cruz C, Godoy G, Robledo SM, Velez ID. Thermotherapy effective and safer than miltefosine in the treatment of cutaneous leishmaniasis in Colombia. Rev Inst Med Trop Sao Paulo. 2013;55(3):S0036-46652013000300197. doi: 10.1590/S0036-46652013000300011.
• Lopez L, Robayo M, Vargas M, Velez ID. Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. Trials. 2012 May 17;13:58. doi: 10.1186/1745-6215-13-58.

Drugs

Indications