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Miltefosine: issues to be addressed in the future
Transactions of the Royal Society of Tropical Medicine and Hygiene (2006) 100S, S41—S44
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
Miltefosine: issues to be addressed in the future J. Berman a,∗, A.D.M. Bryceson b, S. Croft c, J. Engel d, W. Gutteridge e, J. Karbwang f, H. Sindermann g, J. Soto, S. Sundar h, J.A. Urbina i a
6205 Poindexter Lane, Rockville, MD 20852, USA London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK c Drugs for Neglected Diseases Initiative (DNDi), 1 Place St Gervais, CH-1201 Geneva, Switzerland d Zentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt am Main, Germany e 10 Soleoak Drive, Sevenoaks, Kent TN13 1QD, UK f Special Programme for Research and Training in Tropical Diseases, World Health Organization, 20 Avenue Appia, CH-1211 Geneva, Switzerland g Consorcio de Investigaciones Biocl´ınicas, Calle 60 A 5-54 Suite 201, Bogot´ a, Colombia h Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India i Laboratorio de Qu´ımica Biol´ ogica, Centro de Biof´ısica y Bioqu´ımica, Instituto Venezolano de Investigaciones Cientificas, Apartado 21827, Caracas 1020A, Venezuela Available online 5 June 2006 b
KEYWORDS Visceral leishmaniasis; Cutaneous leishmaniasis; Mucosal leishmaniasis; Miltefosine; Resistance; Toxicity
Summary Future issues that need to be addressed for miltefosine are efficacy against nonIndian visceral leishmaniasis, efficacy in HIV-coinfected patients, efficacy against the many forms of cutaneous and mucosal disease, effectiveness under clinical practice conditions, generation of drug resistance and the need to provide a second antileishmanial agent to protect against this disastrous event, and the ability to maintain reproductive contraceptive practices under routine clinical conditions. © 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Miltefosine is the only oral agent with demonstrated value as a single agent treatment for both visceral (VL) and cutaneous (CL) disease at the present time. The fact that there is currently no alternative to miltefosine as a single oral
∗
Corresponding author. Tel.: +1 301 594 7105; fax: +1 301 480 3621. E-mail address: [email protected] (J. Berman).
agent does not imply that miltefosine will necessarily be superior to non-oral therapies for all forms of leishmaniasis. Rather, miltefosine needs to be evaluated to determine its usefulness in the treatment of leishmanial disease other than Indian VL and Leishmania panamensis CL. As an editorial writer asked ‘How broadly applicable will miltefosine therapy be for the diversity encompassed by human leishmaniasis, which includes several clinical syndromes, caused by about 21 Leishmania species in 88 countries?’ (Herwaldt, 1999). With this in mind, the authors of this supplement list below the future issues that need to be addressed.
0035-9203/$ — see front matter © 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2006.02.009
S42
2. Visceral leishmaniasis Will miltefosine be as effective against visceral disease in Brazil due to L. chagasi, in Mediterranean regions due to L. infantum and in Africa due to L. donovani, which may differ from Indian L. donovani? Formal studies are underway in Brazil and in Ethiopia.
J. Berman et al. Venezuela for mucosal leishmaniasis and diffuse cutaneous leishmaniasis respectively. Diffuse cutaneous leishmaniasis never heals spontaneously, so single case studies are valid if performed carefully to a protocol with adequate follow-up.
6. Effectiveness in routine use versus efficacy in clinical trials
3. HIV-coinfected patients Will miltefosine be able effectively to suppress Leishmania in HIV-coinfected persons if given for longer periods of time, and will relapsing parasites show miltefosine resistance? HIV-coinfected patients have been receiving miltefosine on a compassionate named-person basis in Europe. The combined experience was reported by Zentaris at the end of 2004 (Sindermann et al., 2004). Thirty-nine patients of mean weight 59 kg received initial treatment of 100 mg per day for a mean of 55 days. CD4 cell count (SD) was 127 (97) cells/ml (range 24—371 cells/ml; data are for 33 patients). Thirtyfour patients received antiviral combination treatment, and 33 patients received highly active antiretroviral therapy. Most of the patients had previously failed multiple courses of other antileishmanial therapies, including amphotericin B. Of the 25 patients who showed initial cure or improvement, 22 relapsed and received a second course lasting a mean of 48 days; 15 patients of these responded. These results suggest that miltefosine provided an initial response in many patients, but that most relapsed. The dose of miltefosine, chosen because it had been well investigated in 40 kg Indian patients, may be too low on a per kg basis for European patients. Further trials are needed but will be difficult to organize. In European centres antiretrovirals will obscure the impact of miltefosine, while in countries where the two infections are co-endemic and antiretrovirals are not in routine use, long-term treatment and follow-up are difficult to organize, and there are seldom facilities to evaluate drug sensitivity.
4. Cutaneous leishmaniasis Will miltefosine be valuable for the wide range of cutaneous syndromes in the New and Old World? The studies of Soto et al. (2004) have highlighted the problem of differences in species sensitivity (Escobar et al., 2002), which will be a problem in the treatment of CL in South America. Investigators in each of the several endemic regions will need to study ∼40 patients whose parasites have been speciated in order to assess efficacy, using appropriate controls and sensitive techniques to assess end points.
5. Mucosal leishmaniasis Will miltefosine be valuable for mucosal disease and for more exotic syndromes such as diffuse cutaneous disease? Few centres accumulate enough patients for formal trials and have the expertise to assess carefully the results of treatment, but studies have been started in Bolivia and
Will miltefosine be as effective and safe under routine clinical conditions as under formal study? In formal studies, large but not huge numbers of patients are examined, the patients are carefully chosen, and dosing is carefully monitored and enforced, and all patients are followed up. In routine use, these strict controls are not present, efficacy may be lower than expected and unexpected adverse events may occur. Once a drug is released into the private sector, poor patients may purchase an inadequate dosage, and thus encourage treatment failure and drug resistance. For visceral disease, a large Phase IV (postregistration) trial of miltefosine, 2.5 mg/kg/day for 4 weeks, has been completed in India and in Nepal and the data are now being analysed.
7. Resistance Is single-agent therapy the best course? How rapidly is resistance generated clinically? Resistance has been generated to Sbv and pentamidine in many regions of India by monotherapy with these agents. In the laboratory, resistance to miltefosine could be generated rapidly in culture forms (Seifert et al., 2003), but cross-resistance to other known antileishmanials was not observed. In humans miltefosine has a long half-life (100—200 h) and low therapeutic ratio. Plasma levels reach steady state after 26 days of continuous administration. A 4-week course of treatment may be expected to leave a subtherapeutic level in the blood for some weeks post-therapy, a characteristic that could encourage resistance. In immunecompromised (HIV-infected) individuals, there will undoubtedly be a greater number of viable parasites exposed to subtherapeutic drug levels. In India, where VL is an anthroponosis, widespread use of miltefosine as a single agent might lead to the rapid emergence of resistance (Bryceson, 2001). In contrast, in regions where leishmaniasis is a zoonosis and the vast majority of the parasites do not come into contact with drug, resistance should be much less likely to emerge. The use of two drugs with different modes of action and which therefore do not share the same resistance mechanisms might reduce the chance of selection of resistant mutants (White, 1999). This theory underlies the success of artemether—mefloquine combinations that have controlled and reversed drug resistance in malaria on the borders of Thailand (Simpson et al., 2000; White et al., 1999). If one of the two drugs were to be very active and had a short half-life, it might be expected to reduce the biomass of parasites to a level at which a second, more slow acting drug would be able to kill the remainder. The extent of the kill by the first drug, and the plasma concentration and area under the curve of the second drug are critical to the success
Miltefosine: Future issues of this combination. On this hypothesis, one may speculate that paromomycin or liposomal amphotericin might be suitable partners for miltefosine. However, the results of experiments in vitro and in animal models will be important in identifying drug combinations that are synergistic rather than antagonistic. Possible combinations of miltefosine with other antileishmanial drugs have been explored in both in vitro and in vivo models (Seifert and Croft, 2006). In the in vivo experiments, the highest potentiation of miltefosine activity was achieved with amphotericin B, slightly less with paromomycin. No significant interaction was observed when miltefosine was combined with sodium stibogluconate. Basic science investigations into the modes of action of lysophospholipid analogues against trypanosomatid parasites may help to elucidate resistance mechanisms and strategies. Such studies are likely to include: (i) Studies on the molecular mechanisms of resistance to lysophospholipid analogues in several trypanosomatids, which seems to involve P glycoprotein-like multidrug efflux transporters (Cortes-Selva et al., 2005a, 2005b; Munoz-Martinez et al., 2004; Perez-Victoria et al., 2001, 2002), but also a defective ATP dependent P-type phospholipid translocase (Perez-Victoria et al., 2003a, 2003b; Seifert et al., 2003) and development of possible pharmacological intervention to interfere with it. (ii) Further characterization of structure-activity relationships of lysophospholipid analogues both as antiproliferative agents (de Castro et al., 2004) and as inhibitors of putative targets, such as phosphatidyl-ethanolamine N-methyl-transferase (Lira et al., 2001).
8. Reproductive toxicity Will it be possible to maintain strict reproductive contraception in female patients, for the period of miltefosine administration and approximately eight half-lives post-drugadministration, i.e. 3 months taking into account potential between-patient variability in peak drug levels and elimination half-lives? This safety issue would normally be part of Phase IV (postmarketing) surveillance, but is here included as a separate issue because of its importance. A pregnancy register must be kept for all use of the drug. In summary, the goal at the clinical level is to deliver enough drug to kill the parasite in each of the different leishmanial diseases under the conditions in which they occur, safely and without inducing drug resistance. The cooperation and commitment of national and local health authorities will be needed to achieve this goal and to control leishmaniasis as a public health problem in the endemic areas. The problem of getting enough free drug to poor patients in rural areas will need special attention (Sundar and Murray, 2005).
References Bryceson, A., 2001. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop. Med. Int. Health 6, 928—934.
S43 de Castro, S.L., Santa-Rita, R., Urbina, J.A., Croft, S.L., 2004. Antiprotozoal lysophospholipid analogues: a comparison of their activity against Trypanosomatid parasites and tumor cells. MiniRevs Med. Chem. 4, 139—148. Cortes-Selva, F., Jimenez, I.A., Munoz-Martinez, F., Campillo, M., Bazzocchi, I.L., Pardo, L., Ravelo, A.G., Castanys, S., Gamarro, F., 2005a. Dihydro-beta-agarofuran sesquiterpenes: a new class of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in the protozoan parasite Leishmania. Curr. Pharm. Des. 11, 3125—3139. Cortes-Selva, F., Munoz-Martinez, F., Ilias, A., Jimenez, A.I., Varadi, A., Gamarro, F., Castanys, S., 2005b. Functional expression of a multidrug P-glycoprotein transporter of Leishmania. Biochem. Biophys. Res. Commun. 329, 502—507. Escobar, P., Matu, S., Marques, C., Croft, S.L., 2002. Sensitivities of Leishmania species to exadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop. 81, 151—157. Herwaldt, B.L., 1999. Miltefosine — the long-awaited therapy for visceral leishmaniasis? N. Engl. J. Med. 341, 1840—1842. Lira, R., Contreras, L.M., Santa-Rita, R., Urbina, J.A., 2001. Mechanism of action of antiproliferative alkyl-lysophospholipids against the protozoan parasite Trypanosoma cruzi. Potentiation of in vitro activity by the sterol biosynthesis inhibitor ketoconazole. J. Antimicrob. Chemother. 47, 537— 546. Munoz-Martinez, F., Lu, P., Cortes-Selva, F., Perez-Victoria, J.M., Jimenez, I.A., Ravelo, A.G., Sharom, F.J., Gamarro, F., Castanys, S., 2004. Celastraceae sesquiterpenes as a new class of modulators that bind specifically to human P-glycoprotein and reverse cellular multidrug resistance. Cancer Res. 64, 7130— 7138. Perez-Victoria, J.M., Perez-Victoria, F.J., Parodi-Talice, A., Jimenez, I.A., Ravelo, A.G., Castanys, S., Gamarro, F., 2001. Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoproteinlike transporter modulator. Antimicrob. Agents Chemother. 45, 2468—2474. Perez-Victoria, J.M., Di Pietro, A., Barron, D., Ravelo, A.G., Castanys, S., Gamarro, F., 2002. Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: a search for reversal agents. Curr. Drug Targets 3, 311— 333. Perez-Victoria, F.J., Castanys, S., Gamarro, F., 2003a. Leishmania donovani resistance to miltefosine involves a defective inward translocation of the drug. Antimicrob. Agents Chemother. 47, 2397—2403. Perez-Victoria, F.J., Gamarro, F., Ouellette, M., Castanys, S., 2003b. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J. Biol. Chem. 278, 49965—49971. Seifert, K., Croft, S.L., 2006. In vitro and in vivo interactions between miltefosine and other antileishmanial drugs. Antimicrob. Agents Chemother. 50, 73—79. Seifert, K., Matu, S., Perez-Victoria, F.J., Castanys, S., Gamarro, F., Croft, S.L., 2003. Characterization of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int. J. Antimicrob. Agents 22, 380—387. Simpson, J.A., Watkins, E.R., Price, R.N., Aarons, L., Kyle, D.E., White, N.J., 2000. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob. Agents Chemother. 44, 3414—3424. Sindermann, H., Engel, K.R., Fischer, C., Bommer, W., the Miltefosine Compassionate Use Program, 2004. Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection. Clin. Infect. Dis. 39, 1520—1523. Soto, J., Arana, B.A., Toledo, J., Rizzo, N., Vega, J.C., Diaz, A., Luz, M., Gutierrez, P., Arboleda, M., Berman, J.D., Junge, K., Engel,
S44 J., Sindermann, H., 2004. Miltefosine for new world cutaneous leishmaniasis. Clin. Infect. Dis. 38, 1266—1272. Sundar, S., Murray, H., 2005. Availability of miltefosine for the treatment of kala-azar in India. Bull. World Health Organ 83, 394—395.
J. Berman et al. White, N.J., 1999. Delaying antimalarial drug resistance with combination chemotherapy. Parassitologia 41, 301—308. White, N.J., van Vugt, M., Ezzet, F., 1999. Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether—lumefantrine. Clin. Pharmacokinet. 37, 105—125.
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
Miltefosine: issues to be addressed in the future J. Berman a,∗, A.D.M. Bryceson b, S. Croft c, J. Engel d, W. Gutteridge e, J. Karbwang f, H. Sindermann g, J. Soto, S. Sundar h, J.A. Urbina i a
6205 Poindexter Lane, Rockville, MD 20852, USA London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK c Drugs for Neglected Diseases Initiative (DNDi), 1 Place St Gervais, CH-1201 Geneva, Switzerland d Zentaris GmbH, Weismuellerstrasse 50, 60314 Frankfurt am Main, Germany e 10 Soleoak Drive, Sevenoaks, Kent TN13 1QD, UK f Special Programme for Research and Training in Tropical Diseases, World Health Organization, 20 Avenue Appia, CH-1211 Geneva, Switzerland g Consorcio de Investigaciones Biocl´ınicas, Calle 60 A 5-54 Suite 201, Bogot´ a, Colombia h Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India i Laboratorio de Qu´ımica Biol´ ogica, Centro de Biof´ısica y Bioqu´ımica, Instituto Venezolano de Investigaciones Cientificas, Apartado 21827, Caracas 1020A, Venezuela Available online 5 June 2006 b
KEYWORDS Visceral leishmaniasis; Cutaneous leishmaniasis; Mucosal leishmaniasis; Miltefosine; Resistance; Toxicity
Summary Future issues that need to be addressed for miltefosine are efficacy against nonIndian visceral leishmaniasis, efficacy in HIV-coinfected patients, efficacy against the many forms of cutaneous and mucosal disease, effectiveness under clinical practice conditions, generation of drug resistance and the need to provide a second antileishmanial agent to protect against this disastrous event, and the ability to maintain reproductive contraceptive practices under routine clinical conditions. © 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Miltefosine is the only oral agent with demonstrated value as a single agent treatment for both visceral (VL) and cutaneous (CL) disease at the present time. The fact that there is currently no alternative to miltefosine as a single oral
∗
Corresponding author. Tel.: +1 301 594 7105; fax: +1 301 480 3621. E-mail address: [email protected] (J. Berman).
agent does not imply that miltefosine will necessarily be superior to non-oral therapies for all forms of leishmaniasis. Rather, miltefosine needs to be evaluated to determine its usefulness in the treatment of leishmanial disease other than Indian VL and Leishmania panamensis CL. As an editorial writer asked ‘How broadly applicable will miltefosine therapy be for the diversity encompassed by human leishmaniasis, which includes several clinical syndromes, caused by about 21 Leishmania species in 88 countries?’ (Herwaldt, 1999). With this in mind, the authors of this supplement list below the future issues that need to be addressed.
0035-9203/$ — see front matter © 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2006.02.009
S42
2. Visceral leishmaniasis Will miltefosine be as effective against visceral disease in Brazil due to L. chagasi, in Mediterranean regions due to L. infantum and in Africa due to L. donovani, which may differ from Indian L. donovani? Formal studies are underway in Brazil and in Ethiopia.
J. Berman et al. Venezuela for mucosal leishmaniasis and diffuse cutaneous leishmaniasis respectively. Diffuse cutaneous leishmaniasis never heals spontaneously, so single case studies are valid if performed carefully to a protocol with adequate follow-up.
6. Effectiveness in routine use versus efficacy in clinical trials
3. HIV-coinfected patients Will miltefosine be able effectively to suppress Leishmania in HIV-coinfected persons if given for longer periods of time, and will relapsing parasites show miltefosine resistance? HIV-coinfected patients have been receiving miltefosine on a compassionate named-person basis in Europe. The combined experience was reported by Zentaris at the end of 2004 (Sindermann et al., 2004). Thirty-nine patients of mean weight 59 kg received initial treatment of 100 mg per day for a mean of 55 days. CD4 cell count (SD) was 127 (97) cells/ml (range 24—371 cells/ml; data are for 33 patients). Thirtyfour patients received antiviral combination treatment, and 33 patients received highly active antiretroviral therapy. Most of the patients had previously failed multiple courses of other antileishmanial therapies, including amphotericin B. Of the 25 patients who showed initial cure or improvement, 22 relapsed and received a second course lasting a mean of 48 days; 15 patients of these responded. These results suggest that miltefosine provided an initial response in many patients, but that most relapsed. The dose of miltefosine, chosen because it had been well investigated in 40 kg Indian patients, may be too low on a per kg basis for European patients. Further trials are needed but will be difficult to organize. In European centres antiretrovirals will obscure the impact of miltefosine, while in countries where the two infections are co-endemic and antiretrovirals are not in routine use, long-term treatment and follow-up are difficult to organize, and there are seldom facilities to evaluate drug sensitivity.
4. Cutaneous leishmaniasis Will miltefosine be valuable for the wide range of cutaneous syndromes in the New and Old World? The studies of Soto et al. (2004) have highlighted the problem of differences in species sensitivity (Escobar et al., 2002), which will be a problem in the treatment of CL in South America. Investigators in each of the several endemic regions will need to study ∼40 patients whose parasites have been speciated in order to assess efficacy, using appropriate controls and sensitive techniques to assess end points.
5. Mucosal leishmaniasis Will miltefosine be valuable for mucosal disease and for more exotic syndromes such as diffuse cutaneous disease? Few centres accumulate enough patients for formal trials and have the expertise to assess carefully the results of treatment, but studies have been started in Bolivia and
Will miltefosine be as effective and safe under routine clinical conditions as under formal study? In formal studies, large but not huge numbers of patients are examined, the patients are carefully chosen, and dosing is carefully monitored and enforced, and all patients are followed up. In routine use, these strict controls are not present, efficacy may be lower than expected and unexpected adverse events may occur. Once a drug is released into the private sector, poor patients may purchase an inadequate dosage, and thus encourage treatment failure and drug resistance. For visceral disease, a large Phase IV (postregistration) trial of miltefosine, 2.5 mg/kg/day for 4 weeks, has been completed in India and in Nepal and the data are now being analysed.
7. Resistance Is single-agent therapy the best course? How rapidly is resistance generated clinically? Resistance has been generated to Sbv and pentamidine in many regions of India by monotherapy with these agents. In the laboratory, resistance to miltefosine could be generated rapidly in culture forms (Seifert et al., 2003), but cross-resistance to other known antileishmanials was not observed. In humans miltefosine has a long half-life (100—200 h) and low therapeutic ratio. Plasma levels reach steady state after 26 days of continuous administration. A 4-week course of treatment may be expected to leave a subtherapeutic level in the blood for some weeks post-therapy, a characteristic that could encourage resistance. In immunecompromised (HIV-infected) individuals, there will undoubtedly be a greater number of viable parasites exposed to subtherapeutic drug levels. In India, where VL is an anthroponosis, widespread use of miltefosine as a single agent might lead to the rapid emergence of resistance (Bryceson, 2001). In contrast, in regions where leishmaniasis is a zoonosis and the vast majority of the parasites do not come into contact with drug, resistance should be much less likely to emerge. The use of two drugs with different modes of action and which therefore do not share the same resistance mechanisms might reduce the chance of selection of resistant mutants (White, 1999). This theory underlies the success of artemether—mefloquine combinations that have controlled and reversed drug resistance in malaria on the borders of Thailand (Simpson et al., 2000; White et al., 1999). If one of the two drugs were to be very active and had a short half-life, it might be expected to reduce the biomass of parasites to a level at which a second, more slow acting drug would be able to kill the remainder. The extent of the kill by the first drug, and the plasma concentration and area under the curve of the second drug are critical to the success
Miltefosine: Future issues of this combination. On this hypothesis, one may speculate that paromomycin or liposomal amphotericin might be suitable partners for miltefosine. However, the results of experiments in vitro and in animal models will be important in identifying drug combinations that are synergistic rather than antagonistic. Possible combinations of miltefosine with other antileishmanial drugs have been explored in both in vitro and in vivo models (Seifert and Croft, 2006). In the in vivo experiments, the highest potentiation of miltefosine activity was achieved with amphotericin B, slightly less with paromomycin. No significant interaction was observed when miltefosine was combined with sodium stibogluconate. Basic science investigations into the modes of action of lysophospholipid analogues against trypanosomatid parasites may help to elucidate resistance mechanisms and strategies. Such studies are likely to include: (i) Studies on the molecular mechanisms of resistance to lysophospholipid analogues in several trypanosomatids, which seems to involve P glycoprotein-like multidrug efflux transporters (Cortes-Selva et al., 2005a, 2005b; Munoz-Martinez et al., 2004; Perez-Victoria et al., 2001, 2002), but also a defective ATP dependent P-type phospholipid translocase (Perez-Victoria et al., 2003a, 2003b; Seifert et al., 2003) and development of possible pharmacological intervention to interfere with it. (ii) Further characterization of structure-activity relationships of lysophospholipid analogues both as antiproliferative agents (de Castro et al., 2004) and as inhibitors of putative targets, such as phosphatidyl-ethanolamine N-methyl-transferase (Lira et al., 2001).
8. Reproductive toxicity Will it be possible to maintain strict reproductive contraception in female patients, for the period of miltefosine administration and approximately eight half-lives post-drugadministration, i.e. 3 months taking into account potential between-patient variability in peak drug levels and elimination half-lives? This safety issue would normally be part of Phase IV (postmarketing) surveillance, but is here included as a separate issue because of its importance. A pregnancy register must be kept for all use of the drug. In summary, the goal at the clinical level is to deliver enough drug to kill the parasite in each of the different leishmanial diseases under the conditions in which they occur, safely and without inducing drug resistance. The cooperation and commitment of national and local health authorities will be needed to achieve this goal and to control leishmaniasis as a public health problem in the endemic areas. The problem of getting enough free drug to poor patients in rural areas will need special attention (Sundar and Murray, 2005).
References Bryceson, A., 2001. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop. Med. Int. Health 6, 928—934.
S43 de Castro, S.L., Santa-Rita, R., Urbina, J.A., Croft, S.L., 2004. Antiprotozoal lysophospholipid analogues: a comparison of their activity against Trypanosomatid parasites and tumor cells. MiniRevs Med. Chem. 4, 139—148. Cortes-Selva, F., Jimenez, I.A., Munoz-Martinez, F., Campillo, M., Bazzocchi, I.L., Pardo, L., Ravelo, A.G., Castanys, S., Gamarro, F., 2005a. Dihydro-beta-agarofuran sesquiterpenes: a new class of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in the protozoan parasite Leishmania. Curr. Pharm. Des. 11, 3125—3139. Cortes-Selva, F., Munoz-Martinez, F., Ilias, A., Jimenez, A.I., Varadi, A., Gamarro, F., Castanys, S., 2005b. Functional expression of a multidrug P-glycoprotein transporter of Leishmania. Biochem. Biophys. Res. Commun. 329, 502—507. Escobar, P., Matu, S., Marques, C., Croft, S.L., 2002. Sensitivities of Leishmania species to exadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop. 81, 151—157. Herwaldt, B.L., 1999. Miltefosine — the long-awaited therapy for visceral leishmaniasis? N. Engl. J. Med. 341, 1840—1842. Lira, R., Contreras, L.M., Santa-Rita, R., Urbina, J.A., 2001. Mechanism of action of antiproliferative alkyl-lysophospholipids against the protozoan parasite Trypanosoma cruzi. Potentiation of in vitro activity by the sterol biosynthesis inhibitor ketoconazole. J. Antimicrob. Chemother. 47, 537— 546. Munoz-Martinez, F., Lu, P., Cortes-Selva, F., Perez-Victoria, J.M., Jimenez, I.A., Ravelo, A.G., Sharom, F.J., Gamarro, F., Castanys, S., 2004. Celastraceae sesquiterpenes as a new class of modulators that bind specifically to human P-glycoprotein and reverse cellular multidrug resistance. Cancer Res. 64, 7130— 7138. Perez-Victoria, J.M., Perez-Victoria, F.J., Parodi-Talice, A., Jimenez, I.A., Ravelo, A.G., Castanys, S., Gamarro, F., 2001. Alkyl-lysophospholipid resistance in multidrug-resistant Leishmania tropica and chemosensitization by a novel P-glycoproteinlike transporter modulator. Antimicrob. Agents Chemother. 45, 2468—2474. Perez-Victoria, J.M., Di Pietro, A., Barron, D., Ravelo, A.G., Castanys, S., Gamarro, F., 2002. Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in Leishmania: a search for reversal agents. Curr. Drug Targets 3, 311— 333. Perez-Victoria, F.J., Castanys, S., Gamarro, F., 2003a. Leishmania donovani resistance to miltefosine involves a defective inward translocation of the drug. Antimicrob. Agents Chemother. 47, 2397—2403. Perez-Victoria, F.J., Gamarro, F., Ouellette, M., Castanys, S., 2003b. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J. Biol. Chem. 278, 49965—49971. Seifert, K., Croft, S.L., 2006. In vitro and in vivo interactions between miltefosine and other antileishmanial drugs. Antimicrob. Agents Chemother. 50, 73—79. Seifert, K., Matu, S., Perez-Victoria, F.J., Castanys, S., Gamarro, F., Croft, S.L., 2003. Characterization of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int. J. Antimicrob. Agents 22, 380—387. Simpson, J.A., Watkins, E.R., Price, R.N., Aarons, L., Kyle, D.E., White, N.J., 2000. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob. Agents Chemother. 44, 3414—3424. Sindermann, H., Engel, K.R., Fischer, C., Bommer, W., the Miltefosine Compassionate Use Program, 2004. Oral miltefosine for leishmaniasis in immunocompromised patients: compassionate use in 39 patients with HIV infection. Clin. Infect. Dis. 39, 1520—1523. Soto, J., Arana, B.A., Toledo, J., Rizzo, N., Vega, J.C., Diaz, A., Luz, M., Gutierrez, P., Arboleda, M., Berman, J.D., Junge, K., Engel,
S44 J., Sindermann, H., 2004. Miltefosine for new world cutaneous leishmaniasis. Clin. Infect. Dis. 38, 1266—1272. Sundar, S., Murray, H., 2005. Availability of miltefosine for the treatment of kala-azar in India. Bull. World Health Organ 83, 394—395.
J. Berman et al. White, N.J., 1999. Delaying antimalarial drug resistance with combination chemotherapy. Parassitologia 41, 301—308. White, N.J., van Vugt, M., Ezzet, F., 1999. Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether—lumefantrine. Clin. Pharmacokinet. 37, 105—125.