• 1.

    Dull HB, Meredith SE, 1998. The Mectizan Donation Programme–a 10-year report. Ann Trop Med Parasitol 92: 6971.

  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 6.

    Mackenzie CD, Geary T, Prichard R, Boussinesq M, 2007. Where next with Loa loa encephalopathy? Data are badly needed. Trends Parasitol 23: 237238.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 12.

    McCall JW, 2005. The safety-net story about macrocyclic lactone heartworm preventives: a review, an update, and recommendations. Vet Parasitol 133: 197206.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 14.

    Mealey KL, 2004. Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther 27: 257264.

  • 15.

    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM, 2003. P-glycoprotein: from genomics to mechanism. Oncogene 22: 74687485.

  • 16.

    Edwards G, 2003. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J 2 (Suppl 1): S8.

  • 17.

    Bennett JL, Williams JF, Dave V, 1988. Pharmacology of ivermectin. Parasitol Today 4: 226228.

  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 25.

    Li YH, Wang YH, Li Y, Yang L, 2006. MDRl Gene polymorphisms and clinical relevance. Acta Genetica Sinica 33: 93104.

  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 29.

    Brinkmann U, Eichelbaum M, 2001. Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 1: 5964.

  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
  • 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.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 284 117 7
PDF Downloads 94 41 5
 
 
 
 
 
 
 
 
 
 
 

Analysis of the mdr-1 Gene in Patients Co-Infected with Onchocerca volvulus and Loa loa Who Experienced a Post-Ivermectin Serious Adverse Event

Catherine BourguinatInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Catherine Bourguinat in
Current site
Google Scholar
PubMed
Close
,
Joseph KamgnoInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Joseph Kamgno in
Current site
Google Scholar
PubMed
Close
,
Michel BoussinesqInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Michel Boussinesq in
Current site
Google Scholar
PubMed
Close
,
Charles D. MackenzieInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Charles D. Mackenzie in
Current site
Google Scholar
PubMed
Close
,
Roger K. PrichardInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Roger K. Prichard in
Current site
Google Scholar
PubMed
Close
, and
Timothy G. GearyInstitute of Parasitology, McGill University, Sainte Anne de Bellevue, Quebec, Canada; Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon; Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier, France; Filarial Diseases Unit, Michigan State University, East Lansing, Michigan

Search for other papers by Timothy G. Geary in
Current site
Google Scholar
PubMed
Close
View More View Less
Restricted access

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 Loa loa microfilariae (mf). A loss-of-function mutation in the mdr-1 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 mdr-1 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 Loa mf load and a genetic predisposition to altered IVM distribution could be involved in IVM SAEs.

Author Notes

*Address correspondence to Roger K. Prichard, Institute of Parasitology, McGill University, 21 111 Lakeshore Road, Sainte Anne-de-Bellevue, Quebec, H9X 3V9, Canada. E-mail: roger.prichard@mcgill.ca

Financial support: This study was supported by a Canadian Institutes of Health grant to RKP and by Mectizan Donation Program as part of their support to the Filariasis Research Center in Yaoundé (JK).

Authors' addresses: Catherine Bourguinat, Roger K. Prichard, and Timothy G. Geary, Institute of Parasitology, McGill University, Quebec, Canada, E-mail: roger.prichard@mcgill.ca. Joseph Kamgno, Filariasis Research Centre and Faculty of Medicine and Biomedical Sciences University of Yaoundé I, Yaoundé, Cameroon. Michel Boussinesq, Unité Mixte de Recherche 145, Institut de Recherche pour le Développement and Université Montpellier 1, Montpellier Cedex 5, France. Charles D. Mackenzie, Filarial Diseases Unit, Michigan State University, East Lansing, MI.

Save