 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Journal of Postgraduate Medicine, Vol. 49, No. 1, Jan-March, 2003, pp. 101-104 Miltefosine: Great Expectations Against Visceral Leishmaniasis More B, Bhatt H, Kukreja V,* Ainapure SS* Department of Clinical Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel and *Department of Pharmacology, LTM Medical College, Sion, Mumbai, India. Code Number: jb03027 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 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 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 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 cancer21 and number of metastatic solid tumors.22 However, more studies are required to prove its efficacy. Limited activity is demonstrated against in advanced colorectal carcinoma23 Oral miltefosine in a dose 50mg thrice daily has no activity in soft tissue sarcoma.24 Dosage and Contraindications 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 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 hepatotoxicity4 is reported and is common during first 2 weeks treatment. Miltefosine though used as an antineoplastic agent is devoid of hematological toxicity. Clinical studies 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 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 reduced17 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. More B, Bhatt H, Kukreja V,* Ainapure SS* Department of Clinical Pharmacology, Seth G. S. Medical College and K. E. M. Hospital, Parel and *Department of Pharmacology, LTM Medical College, Sion, Mumbai, India. References
Copyright 2003 - Journal of Postgraduate Medicine. Online full-text also available at http://www.jpgmonline.com/ The following images related to this document are available:Photo images[jp03027t1.jpg] |
| |||||||||
