Abstract
Miltefosine, an effective oral treatment of visceral leishmaniasis (VL), was selected in May 2005, by the governments of India, Nepal, and Bangladesh for the elimination of VL. However, abnormally high treatment failure rates reported in patients in Bangladesh, given a miltefosine generic product (“Miltefos”, Popular Pharmaceuticals Ltd.) during 2008, led the World Health Organization (WHO) to procure this formulation for quality testing. Proton (1H) and phosphorous (31P) nuclear magnetic resonance (NMR) analyses of the Miltefos™ capsules did not give the peaks defined for Impavido®, the quality assured VL treatment product from Aeterna Zentaris. Contents of capsules of Impavido® yielded expected peaks for miltefosine (m/z 408.33 for the protonated parent ion and m/z 183.99 plus m/z 124.8 the fragment ions) that were absent in the Miltefos™ capsules. Furthermore, testing using an in vitro Leishmania donovani intracellular amastigote—macrophage model, yielded EC50 values of between 2.55 and 4.06 μg/mL and 3.02 to 5.92 μg/mL for extracts from the Impavido® capsules and the miltefosine standard, respectively. Lack of significant anti-leishmanial activity of Miltefos™ capsules was identified in this assay even at concentrations up to 100 μg/mL. Capsules of Miltefos™ were classified as falsified (absence of stated active pharmaceutical ingredient) by three methods—NMR and mass spectrometry analysis and bioassay.
Highlights
The leishmaniases are a group of neglected tropical diseases caused by parasites of the genus Leishmania
We describe here the results of studies performed on MiltefosTM batches received by World Health Organization (WHO) in 2008 at the same time as those sent to the group in Amsterdam
MiltefosTM capsules were received from WHO South East Asia Regional Office (SEARO) and the WHO Department of Neglected Tropical Diseases and Department of Essential Medicines and Pharmaceutical Policies, Geneva
Summary
The leishmaniases are a group of neglected tropical diseases caused by parasites of the genus Leishmania. The main disease manifestations are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). Active VL has a high fatality rate in almost all cases and requires treatment with anti-leishmanial drugs. Recent estimates for VL suggest between 200,000 and 400,000 cases and 20,000 and 40,000 deaths per year worldwide with over 90% of cases occurring in India, Bangladesh, Sudan, South Sudan, Brazil, and Ethiopia.[1] Current drugs for VL include pentavalent antimonials, amphotericin B (formulated as salt with deoxycholate in FungizoneÒ or in a liposomal form as AmBisomeÒ), miltefosine, and paromomycin. Multi-drug therapy by co-administration regimes is being pursued as an improved treatment strategy for VL.[2]
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