Abstract

Plasmodium falciparum causes fatal malaria in over 2 million children a year in endemic areas. Resistance to chloroquine, the drug of choice for treatment, is widespread. We have developed a series of aminoquinolines (AQ) by modification of the diaminoalkane side chain of chloroquine, that are active in vitro against chloroquine-resistant P. falciparum. We tested one of the most promising long-chain compounds in rhesus macaques infected with P. cynomolgi, a monkey malaria parasite. Because of the excellent efficacy in vitro, we were surprised when the compound was not active against parasites in the monkey. We suspect that the drug is metabolized by the cytochrome P450 system in the liver and we are now isolating the metabolites of this drug using an in vitro system with rhesus monkey microsomes. These metabolites will be tested in vitro for activity against P. falciparum to dissect out the reason for treatment failure in the monkey. Although the evident drug failure is disappointing, it underscores the importance of screening for toxicity and efficacy in a primate model of human malaria before

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
2P51RR000164-37
Application #
6277420
Study Section
Project Start
1998-09-30
Project End
1999-04-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
37
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Tulane University
Department
Type
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118

  Publications

Mahalingam, Ravi; Kaufer, Benedikt B; Ouwendijk, Werner J D et al. (2018) Attenuation of Simian Varicella Virus Infection by Enhanced Green Fluorescent Protein in Rhesus Macaques. J Virol 92:
Kumar, Vinay; Mansfield, Joshua; Fan, Rong et al. (2018) miR-130a and miR-212 Disrupt the Intestinal Epithelial Barrier through Modulation of PPAR? and Occludin Expression in Chronic Simian Immunodeficiency Virus-Infected Rhesus Macaques. J Immunol 200:2677-2689
Parthasarathy, Geetha; Philipp, Mario T (2018) Intracellular TLR7 is activated in human oligodendrocytes in response to Borrelia burgdorferi exposure. Neurosci Lett 671:38-42
McNamara, Ryan P; Costantini, Lindsey M; Myers, T Alix et al. (2018) Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses. MBio 9:
Ramesh, Geeta; Martinez, Alejandra N; Martin, Dale S et al. (2017) Effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in glial and neuronal cells of the central nervous system. J Neuroinflammation 14:28
Parthasarathy, Geetha; Philipp, Mario T (2017) Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi. J Neuroinflammation 14:110
Calenda, Giulia; Villegas, Guillermo; Barnable, Patrick et al. (2017) MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa. J Acquir Immune Defic Syndr 74:e67-e74
Datta, Dibyadyuti; Bansal, Geetha P; Grasperge, Brooke et al. (2017) Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques. Vaccine 35:7049-7056
Yi, Fei; Guo, Jia; Dabbagh, Deemah et al. (2017) Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1. J Virol 91:
Jorgensen, Matthew J; Lambert, Kelsey R; Breaux, Sarah D et al. (2017) Pair housing of Vervets/African Green Monkeys for biomedical research. Am J Primatol 79:1-10

Showing the most recent 10 out of 352 publications