Skip to main content
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1992 Dec;36(12):2761–2765. doi: 10.1128/aac.36.12.2761

Fluoxetine hydrochloride enhances in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

L Gerena 1, G T Bass Sr 1, D E Kyle 1, A M Oduola 1, W K Milhous 1, R K Martin 1
PMCID: PMC245541  PMID: 1482144

Abstract

The emergence of chloroquine resistance in Plasmodium falciparum has necessitated the development of alternate strategies for chemotherapy and chemoprophylaxis. One approach has been the identification of drugs that do not possess any intrinsic antimalarial activity when used alone but that potentiate the effect of currently available antimalarial drugs, such as chloroquine. We identified fluoxetine hydrochloride (Prozac), a commonly prescribed antidepressant, as another resistance modulator for drug-resistant P. falciparum. Studies with chloroquine-resistant clones and isolates from various geographical locations confirmed our initial observations with a chloroquine-resistant P. falciparum clone, W2. Fluoxetine concentrations of 500 nM were found to effectively modulate chloroquine resistance by 66% in clone W2. In comparison, verapamil at similar concentrations was observed to modulate chloroquine resistance in clone W2 by 61%. Neither fluoxetine nor verapamil was observed to possess any innate antimalarial activity. These data augment the current description of the chloroquine resistance phenotype and may provide additional insights into lead-directed synthesis of new antimalarial drugs.

Full text

PDF
2761

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Basco L. K., Ringwald P., Le Bras J. Chloroquine-potentiating action of antihistaminics in Plasmodium falciparum in vitro. Ann Trop Med Parasitol. 1991 Apr;85(2):223–228. doi: 10.1080/00034983.1991.11812549. [DOI] [PubMed] [Google Scholar]
  2. Beck W. T. Multidrug resistance and its circumvention. Eur J Cancer. 1990 Apr;26(4):513–515. doi: 10.1016/0277-5379(90)90028-r. [DOI] [PubMed] [Google Scholar]
  3. Bitonti A. J., Sjoerdsma A., McCann P. P., Kyle D. E., Oduola A. M., Rossan R. N., Milhous W. K., Davidson D. E., Jr Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine. Science. 1988 Dec 2;242(4883):1301–1303. doi: 10.1126/science.3057629. [DOI] [PubMed] [Google Scholar]
  4. Cornwell M. M., Safa A. R., Felsted R. L., Gottesman M. M., Pastan I. Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170-kDa protein detected by photoaffinity labeling. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3847–3850. doi: 10.1073/pnas.83.11.3847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cowman A. F., Karcz S., Galatis D., Culvenor J. G. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J Cell Biol. 1991 Jun;113(5):1033–1042. doi: 10.1083/jcb.113.5.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Desjardins R. E., Canfield C. J., Haynes J. D., Chulay J. D. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother. 1979 Dec;16(6):710–718. doi: 10.1128/aac.16.6.710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gottesman M. M., Pastan I. The multidrug transporter, a double-edged sword. J Biol Chem. 1988 Sep 5;263(25):12163–12166. [PubMed] [Google Scholar]
  8. Kelly M. W., Perry P. J., Holstad S. G., Garvey M. J. Serum fluoxetine and norfluoxetine concentrations and antidepressant response. Ther Drug Monit. 1989;11(2):165–170. doi: 10.1097/00007691-198903000-00008. [DOI] [PubMed] [Google Scholar]
  9. Kyle D. E., Oduola A. M., Martin S. K., Milhous W. K. Plasmodium falciparum: modulation by calcium antagonists of resistance to chloroquine, desethylchloroquine, quinine, and quinidine in vitro. Trans R Soc Trop Med Hyg. 1990 Jul-Aug;84(4):474–478. doi: 10.1016/0035-9203(90)90004-x. [DOI] [PubMed] [Google Scholar]
  10. Martin S. K., Oduola A. M., Milhous W. K. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science. 1987 Feb 20;235(4791):899–901. doi: 10.1126/science.3544220. [DOI] [PubMed] [Google Scholar]
  11. Oduola A. M., Weatherly N. F., Bowdre J. H., Desjardins R. E. Plasmodium falciparum: cloning by single-erythrocyte micromanipulation and heterogeneity in vitro. Exp Parasitol. 1988 Jun;66(1):86–95. doi: 10.1016/0014-4894(88)90053-7. [DOI] [PubMed] [Google Scholar]
  12. Peters W., Ekong R., Robinson B. L., Warhurst D. C., Pan X. Q. Antihistaminic drugs that reverse chloroquine resistance in Plasmodium falciparum. Lancet. 1989 Aug 5;2(8658):334–335. doi: 10.1016/s0140-6736(89)90522-9. [DOI] [PubMed] [Google Scholar]
  13. Peters W., Robinson B. L. The chemotherapy of rodent malaria. XLVI. Reversal of mefloquine resistance in rodent Plasmodium. Ann Trop Med Parasitol. 1991 Feb;85(1):5–10. doi: 10.1080/00034983.1991.11812525. [DOI] [PubMed] [Google Scholar]
  14. Wilson C. M., Serrano A. E., Wasley A., Bogenschutz M. P., Shankar A. H., Wirth D. F. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science. 1989 Jun 9;244(4909):1184–1186. doi: 10.1126/science.2658061. [DOI] [PubMed] [Google Scholar]
  15. Ye Z. G., Van Dyke K., Castranova V. The potentiating action of tetrandrine in combination with chloroquine or qinghaosu against chloroquine-sensitive and resistant falciparum malaria. Biochem Biophys Res Commun. 1989 Dec 15;165(2):758–765. doi: 10.1016/s0006-291x(89)80031-2. [DOI] [PubMed] [Google Scholar]
  16. Ye Z. G., Van Dyke K. Selective antimalarial activity of tetrandrine against chloroquine resistant Plasmodium falciparum. Biochem Biophys Res Commun. 1989 Feb 28;159(1):242–248. doi: 10.1016/0006-291x(89)92429-7. [DOI] [PubMed] [Google Scholar]
  17. Zamora J. M., Pearce H. L., Beck W. T. Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol Pharmacol. 1988 Apr;33(4):454–462. [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES