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 ::  Mechanism of action
 ::  Pharmacokinetics
 ::  Therapeutic indi...
 ::  Dosage and contr...
 ::  Adverse effects
 ::  Clinical studies
 ::  Conclusions
 ::  References
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DRUG REVIEW
Year : 2003  |  Volume : 49  |  Issue : 1  |  Page : 101-3

Miltefosine: great expectations against visceral leishmaniasis.


Department of Clinical Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai, India., India

Correspondence Address:
B More
Department of Clinical Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai, India.
India
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DOI: 10.4103/0022-3859.911

PMID: 12865588

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Keywords: Antiprotozoal Agents, pharmacology,therapeutic use,Human, Leishmaniasis, Visceral, drug therapy,Phosphorylcholine, analogs &derivatives,pharmacology,therapeutic use,


How to cite this article:
More B, Bhatt H, Kukreja V, Ainapure S S. Miltefosine: great expectations against visceral leishmaniasis. J Postgrad Med 2003;49:101

How to cite this URL:
More B, Bhatt H, Kukreja V, Ainapure S S. Miltefosine: great expectations against visceral leishmaniasis. J Postgrad Med [serial online] 2003 [cited 2014 Jul 29];49:101. Available from: http://www.jpgmonline.com/text.asp?2003/49/1/101/911


Visceral leishmaniasis is a disease endemic in 47 countries and continues to be a difficult therapeutic challenge.[1] There are an estimated 500 000 cases per year in Asia (primarily India), South America and South Africa. Up to half of the world’s cases of visceral leishmaniasis (Kala azar) occur in India, and about 90% of patients live in the Indian state of Bihar.[2]

Hexadecylphosphocholine (Miltefosine) is a phosphorylcholine ester of hexadecanol, a membrane-active, alkylphospholipid. It is the first effective oral agent for visceral leishmaniasis, an intracellular protozoal infection of tissue macrophages.[3],[4] The emergence of leishmaniasis strains resistant to pentavalent antimonials and the growing incidence of visceral leishmaniasis among AIDS patients have made the availability of an oral agent extremely important for management of this disease.[1]


  ::   Mechanism of action Top


a) Anti-leishmaniasis Action

Leishmania have high levels of ether-lipids and these are mainly found in the glycosylphosphophatidylinositol anchored glycoprotein and glycolipids present on the surface of the parasites. Miltefosine acts on key enzymes involved in the metabolism of ether lipids. These enzymes include diethylacetonephosphate acetyltransferase, sn-l-acyl-2-lyso-glycero-phosphocholine and sn-l-alkyl-2-lyso-glycero-3-phosphocholine acyltransferase. The initating steps in the ether –lipid metabolism occur in glycosomes. Miltefosine does not act on the enzymes involved in the initial steps in ether lipid metabolism in leishmania. However, the metabolism of the latter phosphatidylcholine base intermediates, which are involved in the synthesis of acyl- and alkyl-glycerophospholipids are associated with glycosomes. Miltefosine inhibits this glycosomal alkyl specific alkyl-specific-acyl CoA acyltransferase in a dose dependent manner.[5]

In vitro studies demonstrate that miltefosine stimulates T cells and macrophages to secrete activating cytokines, including interferon (IFN)- gamma and enhances macrophage production of microcidal reactive nitrogen and oxygen intermediates. To determine these effects in vivo genetically deficient mice were infected with Leishmania donovani. Intracellular killing was retained in T cell deficient mice suggesting that miltefosine induced visceral leishmanicidal effect does not require host T cell-dependent or activated macrophage- mediated mechanisms.[6]

b) Anticancer Action

Miltefosine was originally discovered and synthesized as an anti cancer agent. Its action is exerted at the plasma membrane level, where it interferes with mitogenic signal transduction pathways. Malignant cells are highly sensitive to the lethal action of miltefosine; while normal cells remain relatively unaffected, illustrating the potential anti-tumour properties of the drug. Moreover, miltefosine induce apoptosis in various tumour cell lines and in combination with other anticancer regimens cause additive cytotoxic effects.[7] Miltefosine also interacts with its molecular targets in myeloid cells to induce molecular and cellular effects associated with introduction of differentiation, distinct from its cytotoxic activity.[8] The mode of action is mediated via the cell membrane by inducing apoptosis. There is an increase in intracellular free calcium via calcium channels in the cell membrane.[9]


  ::   Pharmacokinetics Top


Miltefosine is well absorbed after oral administration and is widely distributed. It has a long half-life of about 8 days.[10] However little pharmacokinetic data is available in human beings. In rat, miltefosine is rapidly taken up and accumulates in several internal organs, such as kidney, liver, lung, spleen and adrenal glands. On oral administration of miltefosine 30 mg/kg of body weight twice per day, concentrations of 155 to 189 nmol/g of tissue are achieved.[11] Miltefosine is degraded slowly in vivo, with half-life of 96 hours in mice.[12] It is slowly metabolized by phospholipase to form products such as choline and long chain alcohols that are physiological metabolites and can be recycled into phospholipids.[12],[13]


  ::   Therapeutic indications Top


1. Visceral Leishmaniasis

Orally administered miltefosine is an effective modality of treatment of Indian visceral leishmaniasis including antimony resistant cases.[11],[14],[15] A case has been reported of visceral leishmaniasis with HIV co-infection, which responded to treatment with miltefosine.[16] Topical treatment with miltefosine has been shown to efficiently reduce parasite load in experimental cutaneous leishmaniasis. The clinical application of miltefosine for the treatment cutaneous leishmaniasis represent a potential future use for the drug.[17]

Intracellular visceral infection is suppressed by once or twice weekly orally administered miltefosine in T cell- deficient nude mice infected with Leishmania donovani. This supports the usefulness of miltefosine as oral maintenance therapy for T cell deficient patients with visceral leishmaniasis.[10]

2. As an Anticancer Agent

Skin metastasis of breast cancer has been treated with 6% miltefosine applied locally once daily in the first week and twice daily following week, with significant reductions in the lesions.[18]

3. Other Potential Uses

Miltefosine has significant amoebicidal activity in vitro. Entameoba histolytica, could be a possible new target for it.[12] Miltefosine is also effective against Trypanosoma cruzi and Trypanosoma brucei, however further studies are needed.[5]

Miltefosine is potent inducer of apoptosis and displays increased antileukemic efficacy against BCR-ABL-positive blasts.[19] Human urinary bladder carcinoma cells line responds to treatment with miltefosine, which could prove to be of benefit for patients with urinary bladder neoplasia.[20] Its use has been evaluated in squamous cell head and neck cancer[21] and number of metastatic solid tumors.[22] However, more studies are required to prove its efficacy. Limited activity is demonstrated against in advanced colorectal carcinoma[23] Oral miltefosine in a dose 50mg thrice daily has no activity in soft tissue sarcoma.[24]


  ::   Dosage and contraindications Top


The recommended dose of miltefosine for the treatment of visceral leishmaniasis is 100mg/day (approximately 2.5 mg/kg per day) for 28 days. The dose should be adjusted based on patients weight so that a dose of 4mg/kg per day is not exceeded. Miltefosine is available as 50mg oral tablet (Asta Medica, Frankfrut, Germany). The drug is registered and expected to be soon available in India. It is contraindicated in women with child bearing potential because of its teratogenic effects in animal studies.[11],[16]


  ::   Adverse effects Top


Miltefosine is well tolerated with considerably fewer adverse effects as compared to antimonials and amphotericin. The most commonly seen adverse effects are nausea and vomiting.[25] There is an increase in aspartate aminotransferase and creatinine and/or blood urea nitrogen level, which is mild. Grade III hepatotoxicity and renal damage, has also been reported in some cases. However, these changes are reversible in the face of continued treatment or after discontinuation of treatment.[4],[8],[25] Diarrhoea and hepatotoxicity[4] is reported and is common during first 2 weeks treatment. Miltefosine though used as an antineoplastic agent is devoid of hematological toxicity.


  ::   Clinical studies Top


Visceral Leishmaniasis

Sunder et al demonstrated that 100mg/day miltefosine for 28 days is a promising oral treatment regimen for visceral leishmaniasis cases, including those with antimony unresponsive infection.[4],[11],[15] The results of various studies that have evaluated the efficacy of miltefosine by different researchers are summarised in [Table - 1].

Skin Metastasized Breast Cancer

In a phase, II trial, 6 % miltefosine solution was topically applied in patients with skin metastasized breast cancer. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and further facilitate tissue penetration of miltefosine. It is found to be an effective treatment modality, and to reduce the skin lesion.[5],[18]

In another trial, miltefosine was applied to the skin at a dose of 2 drops/10cm2 skin area. Twenty-five patients were treated; most of them had been heavily pre-treated with chemotherapy for a median period of 14 weeks. In 7 patients grade I skin toxicity was seen and in 4 patients grade III local toxicities necessitated dose adjustment. The responses were seen in 9 patients (1 complete response, 2 partial responses, 6 minor responses) giving a total response rate of 36%, with stable disease in 11 patients 44%) and progressive disease in 5 (20%). Those lesions which were superficial or < 2cm in diameter were most likely to respond.[26]


  ::   Conclusions Top


It is evident from studies in Indian visceral leishmaniasis that oral miltefosine is a highly effective and a well tolerated drug. In immunocompromised patients with conventional treatment with anti-leishmanial drugs, cured visceral leishmaniasis or cutaneous lesion may relapse. By rapid reduction of parasite load the duration of treatment can be reduced[17] and subsequent relapses prevented. Nevertheless, larger controlled phase III studies miltefosine are required to support these findings. It is hoped that miltefosine becomes an approved antileishmanial drug available at reasonable cost for the majority of patients. In view of the fact that the only known reservoir of the leishmania parasite is man, it can be expected that miltefosine will play a key role in eradication of visceral leishmaniasis.

 
 :: References Top

1.Gangneux JP. Treatment of visceral leishmaniasis: recent modalities. Presse Med 1999;28:2057-66.  Back to cited text no. 1    
2.Sundar S, Agarwal G, Ria M, Murray HW. Treatment of Indian visceral leishmaniasis with single dose or daily infusion of low dose liposomal amphotericin B, a randomized trial. BMJ 2002:25;323:419-22.  Back to cited text no. 2    
3.Hansjorg E. Miltefosine for visceral leishmaniasis. New Engl J Med 2000;342:894-5.  Back to cited text no. 3    
4.Sundar S, Gupta B, Makharia MK, Singh MK, Voss A, Rosenkiamer F, Engel J, Murray HW. Oral treatment of visceral leishmaniasis with miltefosine. Ann Trop Med Parasitol 1999:93;589-97  Back to cited text no. 4    
5.Lux H, Heise N, Klenner T, Hart D, Opperdoes FR. Ether –lipid ((alkyl- phospholipid) matabolism and the mechanism of action of ether –lipid analogues in visceral leishmania. Mol Biochem Parasitol 2000;111:1-14.  Back to cited text no. 5    
6.Murray HW, Delph- Etienne S. Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in Tcells and activated macrophage microcidal mechanisms. J Inf Dis 2000;181:795-9.  Back to cited text no. 6    
7.Ruiter GA,Verheij M, Zerp SF, van Blitterswijk WJ. Alkyl-lysophospholipids as anticancer agents and enhancers of radiation-induced apoptosis. Int J Radiat Oncol Biol Phy 2001;49:415-9.  Back to cited text no. 7    
8.Beckers T, Voegeli R, Hilgard P. Molecular and cellular effects of hexadecylphosphocholine (miltefosine) in human myeloid leukemic cell lines. Eur J Cancer 1994;30D:2143-50.  Back to cited text no. 8    
9.Henke J, Engekman J, Kutsher B, Nssner G, Engel J, Voegeli R, Leitofritz D. Changes of intracellular calcium, fatty acids and phospholipids during miltefosine-induced apoptosis monitored by fluorescence- and 13C NMR – spectroscopy. Anticancer Res 1999;19:4027-32  Back to cited text no. 9    
10.Murray HW. Suppression of post treatment recurrence of experimental visceral leishmaniasis in t- cell- deficient mice by oral miltefosine. Antimicrob Agents Chemother 2000;44:3235-6.  Back to cited text no. 10    
11.Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fisher C, Voss A, Berman J. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 1999;341:1795-800.  Back to cited text no. 11    
12.Bresiser A, Kim DJ, Fleer EA, Damenz W, Drube A, Berger M, Nagel AG, Eibl H, Unger C. Distribution and metabolism of hexadecylphosphocholine in mice. Lipids 1987;22:925-6.  Back to cited text no. 12    
13.Seifert K, Duchaene M, Werndorfer WH, Kollaritsch H, Scheiner, Wiedermann G, Hottkowitz, Eibi H. Effects of miltefosine and other alkylphosphocholines on human ingtestinal parasite entamoeba histolytica. Antimicrob Agents Chemother 2001;45:1505-10.  Back to cited text no. 13    
14.Mohan A, Seth S. Oral miltefosine in treatment of kala azar. Nat Med J Ind 2000;13:202-3.  Back to cited text no. 14    
15.Sundar S, Rosenkiamer F, Makharia MK, Mandal AK, Voss A, Hilgard P, Murray HW. Trial of miltefosine for visceral leishmaniasis. Lancet 1998;352:1821-3.  Back to cited text no. 15    
16.Thakur CP, Sinha PK, Singh KR, Hassan SM, Narain S. Miltefosine in a case of visceral leishmaniasis: and rising incidence of this disease in India. Trans R Soc Trop Med Hyg 2000;94:696-7.  Back to cited text no. 16    
17.Schmidt-Ott R, Klenner T, Overath P, Aebischer. Topical treatment with heaxdecylphosphocholine (miltex) efficiently reduces parasite in experimental cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 1999;93:85-90.  Back to cited text no. 17    
18.Terwogt JM, Mandjes IA, Sindermann H, Beijnen JH, Hunink WWW. Phase II trial of topically applied miltefosine solution in patients with skin metastasized breast cancer. Br J Cancer 1999;79:1158-61  Back to cited text no. 18    
19.Konstantinov SM, Eibl H, Berger MR. BCR-ABL influences the antileukaemic efficacy of alkylphosphocholine. Br J Haematol 1999;107:365-80.  Back to cited text no. 19    
20.Konstantinov SM, Berger MR. Human urinary bladder carcinoma cell line respond to treatment with alkylphosphocholine. Cancer Lett 1999;144:153-60.  Back to cited text no. 20    
21.Verweij J, Gandia D, Planting AS, Stoter G, Armand JP. Phase II study of oral miltefosine in patients with squamous cell head and neck cancer. Eur J Cancer 1993;29A:778-9.  Back to cited text no. 21    
22.Verweij J, Planting AS, van der Burg M, Stoter G. A dose finding study of miltefosine (hexadecylphosphocholine) in patients with solid tumors. J Cancer Res Clin Oncol 1992;188:606-8.  Back to cited text no. 22    
23.Planting AS, Stoter G, Verweij J. Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer. Eur J Cancer 1993;29A:518-9.  Back to cited text no. 23    
24.Verweij J, Krzemieniecki K, Kok T, Poveda A, Pottelsberghe C, Mouridsen H. Phase II study of oral Miltefosine (hexadecylphosphocholine) advanced sarcomas of adults-an EORTC soft tissue and bone sarcoma group study. Eur J Cancer 1993;29A:208-9.  Back to cited text no. 24    
25.Smorenburg CH, Seynaevec, Bontenbal M, Planting AS, Sindermann H, Verweij J. Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs 2000;11:825-8.  Back to cited text no. 25    
26.Clive S, Gardiner J, Leonard RC. Miltefosine as topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother Pharmacol 1999;44:S29-30.  Back to cited text no. 26    
27.Sundar S, Makharia A, More DK, Agarwal G, Voss A, Bachmann P, Murray HW. Oral treatment of visceral leishmaniasis with miltefosine. Clin Inf Dis 2000:93:589-97.  Back to cited text no. 27    


    Tables

[Table - 1]

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