Volume 83, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Ivermectin (IVM) is exceptionally safe in humans, and is used for mass treatment of onchocerciasis and lymphatic filariasis. However, cases of encephalopathy, sometimes fatal, have been reported in a small number of individuals who harbored large numbers of microfilariae (mf). A loss-of-function mutation in the gene in some dog breeds and in mice leads to accumulation of the drug in the brain, causing coma and death. This hypothesis was tested in four individuals from Cameroon who experienced a post-IVM serious adverse event (SAE) and in nine non-SAE matched controls. No loss-of-function mutation was detected in in any subject. However, haplotypes, associated with altered drug disposition, were present as homozygotes in two of the SAE patients (50%), but absent as homozygotes in the controls (0%). An association of high mf load and a genetic predisposition to altered IVM distribution could be involved in IVM SAEs.


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  1. Dull HB, Meredith SE, , 1998. The Mectizan Donation Programme–a 10-year report. Ann Trop Med Parasitol 92: 6971.[Crossref] [Google Scholar]
  2. Boussinesq M, Gardon J, Gardon-Wendel N, Chippaux JP, , 2003. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria J 2 (Suppl 1): S4.[Crossref] [Google Scholar]
  3. Twum-Danso NA, , 2003. Loa loa encephalopathy temporally related to ivermectin administration reported from onchocerciasis mass treatment programs from 1989 to 2001: implications for the future. Filaria J 2 (Suppl 1): S7.[Crossref] [Google Scholar]
  4. Mackenzie CD, Geary TG, Gerlach JA, , 2003. Possible pathogenic pathways in the adverse clinical reactions seen following ivermectin administration to onchocerciasis patients. Filaria J 2 (Suppl 1): S5.[Crossref] [Google Scholar]
  5. Boussinesq M, Kamgno J, Pion SD, Gardon J, , 2006. What are the mechanisms associated with post-ivermectin serious adverse events? Trends Parasitol 22: 244246.[Crossref] [Google Scholar]
  6. Mackenzie CD, Geary T, Prichard R, Boussinesq M, , 2007. Where next with Loa loa encephalopathy? Data are badly needed. Trends Parasitol 23: 237238.[Crossref] [Google Scholar]
  7. Gardon J, Gardon-Wendel N, Demanga-Ngangue Kamgno J, Chippaux JP, Boussinesq M, , 1997. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet 350: 1822.[Crossref] [Google Scholar]
  8. Boussinesq M, Gardon J, Kamgno J, Pion SD, Gardon-Wendel N, Chippaux JP, , 2001. Relationships between the prevalence and intensity of Loa loa infection in the Central province of Cameroon. Ann Trop Med Parasitol 95: 495507.[Crossref] [Google Scholar]
  9. Pion SD, Filipe JA, Kamgno J, Gardon J, Basáñez MG, Boussinesq M, , 2006. Microfilarial distribution of Loa loa in the human host: population dynamics and epidemiological implications. Parasitology 133: 101109.[Crossref] [Google Scholar]
  10. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR, , 1989. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci U S A 86: 695698.[Crossref] [Google Scholar]
  11. Chung K, Yang CC, Wu ML, Deng JF, Tsai WJ, , 1999. Agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning. Ann Emerg Med 34: 5157.[Crossref] [Google Scholar]
  12. McCall JW, , 2005. The safety-net story about macrocyclic lactone heartworm preventives: a review, an update, and recommendations. Vet Parasitol 133: 197206.[Crossref] [Google Scholar]
  13. Paul AJ, Tranquilli WJ, Seward RL, Todd KS, Jr DiPietro JA, , 1987. Clinical observations in collies given ivermectin orally. Am J Vet Res 48: 684685. [Google Scholar]
  14. Mealey KL, , 2004. Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther 27: 257264.[Crossref] [Google Scholar]
  15. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM, , 2003. P-glycoprotein: from genomics to mechanism. Oncogene 22: 74687485.[Crossref] [Google Scholar]
  16. Edwards G, , 2003. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J 2 (Suppl 1): S8.[Crossref] [Google Scholar]
  17. Bennett JL, Williams JF, Dave V, , 1988. Pharmacology of ivermectin. Parasitol Today 4: 226228.[Crossref] [Google Scholar]
  18. Van Bogaert L, Dubois A, Janssens PG, Radermecker J, Tverdy G, Wanson M, , 1955. Encephalitis in Loa-loa filariasis. J Neurol Neurosurg Psychiatry 18: 103119.[Crossref] [Google Scholar]
  19. Chaudhary PM, Mechetner EB, Roninson IB, , 1992. Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood 80: 27352739. [Google Scholar]
  20. Albermann N, Schmitz-Winnenthal FH, Z'graggen K, Volk C, Hoffmann MM, Haefeli WE, Weiss J, , 2005. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with expression in intestine and liver. Biochem Pharmacol 70: 949958.[Crossref] [Google Scholar]
  21. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR, , 2007. ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 7: 154179.[Crossref] [Google Scholar]
  22. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I, , 1987. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 84: 265269.[Crossref] [Google Scholar]
  23. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC, , 1987. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84: 77357738.[Crossref] [Google Scholar]
  24. Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S, , 1988. Tissue distribution of P-glycoprotein encoded by a multidrug resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 48: 19261929. [Google Scholar]
  25. Li YH, Wang YH, Li Y, Yang L, , 2006. MDRl Gene polymorphisms and clinical relevance. Acta Genetica Sinica 33: 93104.[Crossref] [Google Scholar]
  26. Allabi AC, Horsmans Y, Issaoui B, Gala JL, , 2005. Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population. Eur J Clin Pharmacol 61: 97102.[Crossref] [Google Scholar]
  27. Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL, , 2001. MDRl pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics J 11: 217221.[Crossref] [Google Scholar]
  28. Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger UM, Schwab M, , 2001. Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 358: 383384.[Crossref] [Google Scholar]
  29. Brinkmann U, Eichelbaum M, , 2001. Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 1: 5964.[Crossref] [Google Scholar]
  30. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U, , 2000. Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo . Proc Nat1 Acad Sci U S A 97: 34733478.[Crossref] [Google Scholar]
  31. Brinkmann U, Roots I, Eichelbaum M, , 2001. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 6: 835839.[Crossref] [Google Scholar]
  32. Anglicheau D, Thervet E, Etienne I, Hurault De Ligny B, Le Meur Y, Touchard G, Büchler M, Laurent-Puig P, Tregouet D, Beaune P, Daly A, Legendre C, Marquet P, , 2004. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 75: 422433.[Crossref] [Google Scholar]
  33. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J, , 2003. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 13: 741757.[Crossref] [Google Scholar]
  34. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, , 2007. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res 67: 96099612.[Crossref] [Google Scholar]
  35. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM, , 2007. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315: 525528.[Crossref] [Google Scholar]
  36. Uhr M, Tontsch A, Namendorf C, Ripke S, Lucae S, Ising M, Dose T, Ebinger M, Rosenhagen M, Kohli M, Kloiber S, Salyakina D, Bettecken T, Specht M, Pütz B, Binder EB, Müller-Myhsok B, Holsboer F, , 2008. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57: 203209.[Crossref] [Google Scholar]
  37. Hori S, Ohtsuki S, Tachikawa M, Kimura N, Kondo T, Watanabe M, Nakashima E, Terasaki T, , 2004. Functional expression of rat ABCG2 on the luminal side of brain capillaries and its enhancement by astrocytederived soluble factor(s). J Neurochem 90: 526536.[Crossref] [Google Scholar]
  38. Nies AT, Jedlitschky G, König J, Herold-Mende C, Steiner HH, Schmitt HP, Keppler D, , 2004. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 129: 349360.[Crossref] [Google Scholar]
  39. Geyer J, Gavrilova O, Petzinger E, , 2009. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein and bcrp-deficient knockout mice. J Vet Pharmacol Ther 32: 8796.[Crossref] [Google Scholar]
  40. Merino G, Real R, Baro MF, Gonzalez-Lobato L, Prieto JG, Alvarez AI, Marques MM, , 2009. Natural allelic variants of bovine ATP-binding cassette transporter ABCG2: increased activity of the Ser581 variant and development of tools for the discovery of new ABCG2 inhibitors. Drug Metab Dispos 37: 59.[Crossref] [Google Scholar]
  41. Kis E, Lecoeur S, Menez C, Dupuy J, Kiki S, Krajcsi P, Alvinerie M, Lespine A, , 2009. The anthelmintic ivermectin: a substrate of breast-cancer resistant protein (BCRP). World Association for the Advancement of Veterinary Parasitology 22nd Conference, Calgary, Canada. Abstract CS2.4, 9. [Google Scholar]
  42. Poller B, Drewe J, Krähenbühl S, Huwyler J, Gutmann H, , 2010. Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell Mol Neurobiol 30: 6370.[Crossref] [Google Scholar]

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  • Received : 07 Dec 2009
  • Accepted : 26 Mar 2010
  • Published online : 06 Jul 2010

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