The Global Pandemic of Falsified Medicines: Laboratory and Field Innovations and Policy Implications
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



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 (H) and phosphorous (P) 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 (/ 408.33 for the protonated parent ion and / 183.99 plus / 124.8 the fragment ions) that were absent in the Miltefos™ capsules. Furthermore, testing using an in vitro intracellular amastigote—macrophage model, yielded EC 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.

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  1. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, , 2012. Leishmaniasis worldwide and global estimates of its incidence. WHO Leishmaniasis Control Team. PLoS ONE 7: e35671.[Crossref] [Google Scholar]
  2. Croft SL, Olliaro P, , 2011. Leishmaniasis chemotherapy–challenges and opportunities. Clin Microbiol Infect 17: 14781483.[Crossref] [Google Scholar]
  3. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J, , 2002. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347: 17391746.[Crossref] [Google Scholar]
  4. Bhattacharya SK, Sinha PK, Sundar S, Thakur CP, Jha TK, Pandey K, Das VR, Kumar N, Lal C, Verma N, Singh VP, Ranjan A, Verma RB, Anders G, Sindermann H, Ganguly NK, , 2007. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 196: 591598.[Crossref] [Google Scholar]
  5. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ, , 2012.Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 67: 25762597.[Crossref] [Google Scholar]
  6. Sundar S, Mondal D, Rijal S, Bhattacharya S, Ghalib H, Kroeger A, Boelaert M, Desjeux P, Richter-Airijoki H, Harms G, , 2008. Implementation research to support the initiative on the elimination of kala azar from Bangladesh, India and Nepal–the challenges for diagnosis and treatment. Trop Med Int Health 13: 25.[Crossref] [Google Scholar]
  7. Senior K, , 2008. Global health-care implications of substandard medicines. Lancet Infect Dis 8: 666.[Crossref] [Google Scholar]
  8. Dorlo TP, Eggelte TA, de Vries PJ, Beijnen JH, , 2012. Characterization and identification of suspected counterfeit miltefosine capsules. Analyst (Lond) 137: 12651274.[Crossref] [Google Scholar]
  9. Dorlo TP, Hillebrand MJ, Rosing H, Eggelte TA, de Vries PJ, Beijnen JH, , 2008. Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 865: 5562.[Crossref] [Google Scholar]
  10. Dorlo TP, Eggelte TA, Schoone GJ, de Dries PJ, Beijnen JH, , 2012. A poor-quality generic drug for the treatment of visceral leishmaniasis: a case report and appeal. PLoS Negl Trop Dis 6: e1544.[Crossref] [Google Scholar]
  11. Seifert K, Escobar P, Croft SL, , 2010. In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent. J Antimicrob Chemother 65: 508511.[Crossref] [Google Scholar]
  12. Frezard F, Demicheli C, Ribeiro RR, , 2009. Pentavalent antimonials: new perspectives for old drugs. Molecules 14: 23172336.[Crossref] [Google Scholar]
  13. Frézard F, Martins PS, Barbosa MC, Pimenta AM, Ferreira WA, de Melo JE, Mangrum JB, Demicheli C, , 2008. New insights into the chemical structure and composition of the pentavalent antimonial drugs, meglumine antimonate and sodium stibogluconate. J Inorg Biochem 102: 656665.[Crossref] [Google Scholar]
  14. Sundar S, Chakravarty J, , 2010. Antimony toxicity. Int J Environ Res Public Health 7: 42674277.[Crossref] [Google Scholar]
  15. Marsden PD, , 1985. Pentavalent antimonials: old drugs for old diseases. Rev Soc Brasil Med Trop 18: 187198.[Crossref] [Google Scholar]
  16. Sundar S, Sinha PR, Agrawal NK, Srivastava R, Rainey PM, Berman JD, Murray HW, Singh VP, , 1998. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 59: 139143. [Google Scholar]
  17. Romero GA, de Oliveira MR, Corriera D, Marsden PD, , 1996. Physico-chemical characteristics of meglumine antimoniate in different conditions. Rev Soc Bras Med Trop 29: 461465.[Crossref] [Google Scholar]
  18. Franco MA, Barbosa AC, Rath S, Dorea JG, , 1995. Antimony oxidation states in antileishmanial drugs. Am J Trop Med Hyg 52: 435437. [Google Scholar]
  19. Caudron JM, Ford N, Henkens M, Mace C, Kiddle-Monroe R, Pinel J, , 2008. Substandard medicines in resource-poor settings: a problem that can no longer be ignored. Trop Med Int Health 13: 10621072.[Crossref] [Google Scholar]
  20. World Health Organization, 2010. Control of the Leishmaniases. Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, March 22–26, 2010. WHO Technical Report Series 949. [Google Scholar]
  21. Chowdhury R, Mondal D, Chowdhury V, Faria S, Alvar J, Nabi SG, Boelaert M, Dash AP, , 2014. How far are we from visceral leishmaniasis elimination in Bangladesh? An assessment of epidemiological surveillance data. PLoS Negl Trop Dis 8: e3020.[Crossref] [Google Scholar]

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  • Received : 16 Sep 2014
  • Accepted : 23 Feb 2015
  • Published online : 03 Jun 2015

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