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. 1993 Nov;37(11):2337–2343. doi: 10.1128/aac.37.11.2337

Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum.

M Nateghpour 1, S A Ward 1, R E Howells 1
PMCID: PMC192389  PMID: 8285616

Abstract

Intermittent exposure to halofantrine (HF) of both chloroquine-susceptible (T9.96) and chloroquine-resistant (K1) isolates of Plasmodium falciparum in vitro resulted in a rapid reduction in susceptibility to HF. After 6 months, the 50% inhibitory concentration (IC50) of HF, determined with [G-3H]hypoxanthine incorporation as a marker, increased ninefold for the chloroquine-resistant (K1) isolate and threefold for the cloned chloroquine-susceptible (T9.96) isolate, the derived isolates being termed the K1HF3 and T9.96HF4 isolates, respectively. By microscopic examination of cultured erythrocytes, we determined that there was a fivefold increase in the IC50 for isolate T9.96HF4. The responses of the parental isolates and the HF-resistant isolates to chloroquine, mefloquine, quinine, amodiaquine, qinghaosu, and pyrimethamine were determined. In comparison with the parental K1 isolate, HF-resistant isolate K1HF3 was significantly more susceptible to the action of chloroquine and exhibited a significantly reduced susceptibility to quinine and mefloquine. The other HF-resistant isolate, T9.96HF4, showed no alteration in susceptibility to amodiaquine or chloroquine but a significantly decreased susceptibility to mefloquine. Resistance was stable in the two isolates, both in the absence of drug pressure or when kept frozen in liquid nitrogen. In contrast, continuous exposure to HF had no effect on the susceptibility of the parasites to this drug above HF concentrations of 3.2 x 10(-9) M.

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Selected References

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  1. Banyal H. S., Inselburg J. Plasmodium falciparum: induction, selection, and characterization of pyrimethamine-resistant mutants. Exp Parasitol. 1986 Aug;62(1):61–70. doi: 10.1016/0014-4894(86)90008-1. [DOI] [PubMed] [Google Scholar]
  2. Barnes D. A., Foote S. J., Galatis D., Kemp D. J., Cowman A. F. Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. EMBO J. 1992 Aug;11(8):3067–3075. doi: 10.1002/j.1460-2075.1992.tb05378.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boudreau E. F., Webster H. K., Pavanand K., Thosingha L. Type II mefloquine resistance in Thailand. Lancet. 1982 Dec 11;2(8311):1335–1335. doi: 10.1016/s0140-6736(82)91532-x. [DOI] [PubMed] [Google Scholar]
  4. Brockelman C. R., Monkolkeha S., Tanariya P. Decrease in susceptibility of Plasmodium falciparum to mefloquine in continuous culture. Bull World Health Organ. 1981;59(2):249–252. [PMC free article] [PubMed] [Google Scholar]
  5. Bygbjerg I. C., Schapira A., Flachs H., Gomme G., Jepsen S. Mefloquine resistance of falciparum malaria from Tanzania enhanced by treatment. Lancet. 1983 Apr 2;1(8327):774–775. doi: 10.1016/s0140-6736(83)92070-6. [DOI] [PubMed] [Google Scholar]
  6. Campbell C. C., Payne D., Schwartz I. K., Khatib O. J. Evaluation of amodiaquine treatment of chloroquine-resistant Plasmodium falciparum malaria on Zanzibar, 1982. Am J Trop Med Hyg. 1983 Nov;32(6):1216–1220. doi: 10.4269/ajtmh.1983.32.1216. [DOI] [PubMed] [Google Scholar]
  7. Childs G. E., Boudreau E. F., Milhous W. K., Wimonwattratee T., Pooyindee N., Pang L., Davidson D. E., Jr A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum. Am J Trop Med Hyg. 1989 Jan;40(1):7–11. doi: 10.4269/ajtmh.1989.40.7. [DOI] [PubMed] [Google Scholar]
  8. Childs G. E., Bourdeau E. F., Wimonwattratee T., Pang L., Milhous W. K. In vitro and clinical correlates of mefloquine resistance of Plasmodium falciparum in eastern Thailand. Am J Trop Med Hyg. 1991 May;44(5):553–559. doi: 10.4269/ajtmh.1991.44.553. [DOI] [PubMed] [Google Scholar]
  9. Childs G. E., Lambros C., Notsch J. D., Pamplin C. L., Davidson D. E., Jr, Ager A. Comparison of in vitro and in vivo antimalarial activities of 9-phenanthrenecarbinols. Ann Trop Med Parasitol. 1984 Feb;78(1):13–20. doi: 10.1080/00034983.1984.11811767. [DOI] [PubMed] [Google Scholar]
  10. Cosgriff T. M., Boudreau E. F., Pamplin C. L., Doberstyn E. B., Desjardins R. E., Canfield C. J. Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669). Am J Trop Med Hyg. 1982 Nov;31(6):1075–1079. doi: 10.4269/ajtmh.1982.31.1075. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Gay F., Bustos D. G., Diquet B., Rojas Rivero L., Litaudon M., Pichet C., Danis M., Gentilini M. Cross-resistance between mefloquine and halofantrine. Lancet. 1990 Nov 17;336(8725):1262–1262. doi: 10.1016/0140-6736(90)92884-k. [DOI] [PubMed] [Google Scholar]
  13. Golenser J., Casuto D., Pollack Y. Plasmodium falciparum: in vitro induction of resistance to aminopterin. Exp Parasitol. 1981 Dec;52(3):371–377. doi: 10.1016/0014-4894(81)90095-3. [DOI] [PubMed] [Google Scholar]
  14. Inselburg J. Induction and selection of drug resistant mutants of Plasmodium falciparum. Mol Biochem Parasitol. 1984 Jan;10(1):89–98. doi: 10.1016/0166-6851(84)90021-5. [DOI] [PubMed] [Google Scholar]
  15. Inselburg J. Isolation of temperature-sensitive mutants of Plasmodium falciparum. Mol Biochem Parasitol. 1985 Jun;16(1):75–83. doi: 10.1016/0166-6851(85)90050-7. [DOI] [PubMed] [Google Scholar]
  16. Jaroonvesama N., Harinasuta T., Munangmanee L. Recrudescence, poor response or resistance to quinine of falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health. 1974 Dec;5(4):504–509. [PubMed] [Google Scholar]
  17. Lambros C., Notsch J. D. Plasmodium falciparum: mefloquine resistance produced in vitro. Bull World Health Organ. 1984;62(3):433–438. [PMC free article] [PubMed] [Google Scholar]
  18. MOORE D. V., LANIER J. E. Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine. Am J Trop Med Hyg. 1961 Jan;10:5–9. doi: 10.4269/ajtmh.1961.10.5. [DOI] [PubMed] [Google Scholar]
  19. Nguyen-Dinh P., Trager W. Chloroquine resistance produced in vitro in an African strain of human malaria. Science. 1978 Jun 23;200(4348):1397–1398. doi: 10.1126/science.351801. [DOI] [PubMed] [Google Scholar]
  20. Oduola A. M., Milhous W. K., Weatherly N. F., Bowdre J. H., Desjardins R. E. Plasmodium falciparum: induction of resistance to mefloquine in cloned strains by continuous drug exposure in vitro. Exp Parasitol. 1988 Dec;67(2):354–360. doi: 10.1016/0014-4894(88)90082-3. [DOI] [PubMed] [Google Scholar]
  21. Rosario V. Cloning of naturally occurring mixed infections of malaria parasites. Science. 1981 May 29;212(4498):1037–1038. doi: 10.1126/science.7015505. [DOI] [PubMed] [Google Scholar]
  22. Schmidt L. H., Crosby R., Rasco J., Vaughan D. Antimalarial activities of various 9-phenanthrenemethanols with special attention to WR-122,455 and WR-171,669. Antimicrob Agents Chemother. 1978 Sep;14(3):292–314. doi: 10.1128/aac.14.3.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shanks G. D., Watt G., Edstein M. D., Webster H. K., Suriyamongkol V., Watanasook C., Panpunnung S., Kowinwiphat W. Halofantrine for the treatment of mefloquine chemoprophylaxis failures in Plasmodium falciparum infections. Am J Trop Med Hyg. 1991 Oct;45(4):488–491. doi: 10.4269/ajtmh.1991.45.488. [DOI] [PubMed] [Google Scholar]
  24. Thaithong S., Beale G. H., Fenton B., McBride J., Rosario V., Walker A., Walliker D. Clonal diversity in a single isolate of the malaria parasite Plasmodium falciparum. Trans R Soc Trop Med Hyg. 1984;78(2):242–245. doi: 10.1016/0035-9203(84)90287-6. [DOI] [PubMed] [Google Scholar]
  25. Thaithong S., Beale G. H. Resistance of ten Thai isolates of Plasmodium falciparum to chloroquine and pyrimethamine by in vitro tests. Trans R Soc Trop Med Hyg. 1981;75(2):271–273. doi: 10.1016/0035-9203(81)90333-3. [DOI] [PubMed] [Google Scholar]
  26. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  27. Webster H. K., Boudreau E. F., Pavanand K., Yongvanitchit K., Pang L. W. Antimalarial drug susceptibility testing of Plasmodium falciparum in Thailand using a microdilution radioisotope method. Am J Trop Med Hyg. 1985 Mar;34(2):228–235. doi: 10.4269/ajtmh.1985.34.228. [DOI] [PubMed] [Google Scholar]
  28. Webster H. K., Thaithong S., Pavanand K., Yongvanitchit K., Pinswasdi C., Boudreau E. F. Cloning and characterization of mefloquine-resistant Plasmodium falciparum from Thailand. Am J Trop Med Hyg. 1985 Nov;34(6):1022–1027. doi: 10.4269/ajtmh.1985.34.1022. [DOI] [PubMed] [Google Scholar]

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