Annals of Tropical Medicine & Parasitology
ISSN: 0003-4983 (Print) 1364-8594 (Online) Journal homepage: http://www.tandfonline.com/loi/ypgh19
Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro H. L. Williams, Deadre J. Johnson, V. C. N. Okoye & S. K. Martin To cite this article: H. L. Williams, Deadre J. Johnson, V. C. N. Okoye & S. K. Martin (1992) Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro, Annals of Tropical Medicine & Parasitology, 86:5, 467-473, DOI: 10.1080/00034983.1992.11812695 To link to this article: https://doi.org/10.1080/00034983.1992.11812695
Published online: 15 Nov 2016.
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Annals of Tropical Medicine and Parasitology, Vol. 86, No.5, 467-473 (1992)
Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro BY H. L. WILLIAMS, DEADRE]. JOHNSON, V. C. N. OKOYE Department of Hematology, Division of Medicine, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, U.S.A. S. K. MARTIN* United States Army Medical Research Unit-Kenya, Unit 64109, Box 401, APO AE 09831-4109, U.S.A. AND
Received 19 July 1991, Revised 11 May 1992, Accepted 1 June 1992
Compounds that inhibit the P-glycoprotein-related efflux mechanism of multidrug-resistant cells reverse chloroquine resistance in vitro. Hence, the co-administration of chloroquine and an efflux-blocking drug could potentially treat chloroquine-resistant malaria infections. We administered a drug combination (chloroquine and a tiapamil analogue), that has been shown to reverse chloroquine resistance in vitro, to Aotus monkeys but failed to safely clear experimentally-induced chloroquine-resistant Plasmodiumfalciparum parasitaemias.
The report that chloroquine-resistant malaria parasites could be made sensitive to chloroquine in vitro by simultaneously exposing them to chloroquine and verapamil provided the rationale for a potentially new strategy for the treatment of chloroquine-resistant malaria infections (Martin et a/., 1987). Even though the mechanism of chloroquine resistance in P. falciparum remains unproven, one of the contending theories is that chloroquine-resistant malaria parasites, like multidrug-resistant cancer cells, prevent the drug from reaching toxic intracellular levels by an active efflux process (Krogstad et a!., 1987). The hallmark of this multidrug-resistant phenotype is the presence of increased amounts of a 170 kDa P-glycoprotein in membranes of resistant cells. P-glycoprotein is coded for by a family of mdr genes which are concomitantly amplified in the "Author to whom correspondence should be addressed. 0003-4983/92/050467 + 07 $08.00/0
resistant phenotypes (Gros et a!., 1986; Ueda et a/., 1987). Therefore any compound that compromises this efflux process would potentially enhance chloroquine toxicity selectively against chloroquine-resistant parasites. Effluxblocking drugs or reversing agents have been successfully used in vitro to reduce the IC 50 of resistant parasites to sensitive levels (Bitonti et a!., 1988; Basco et a!., 1990; Kyle et a/., 1990). Coincidentally, increased amounts of Pglycoprotein and its associated m-RNA have also been found in several normal host tissues (Fojo et a!., 1987; Thiebaut et al., 1987). Although the significance of this glycoprotein in normal host tissue remains unknown, its localization in tissues that subserve an excretory/ secretory function has led investigators to also ascribe a transport function to it (Gottesman and Pastan 1988). Consequently, attempts to treat chloroquine-resistant malaria infections with a combination of chloroquine and a reversing © 1992 Liverpool School of Tropical Medicine
WILLIAMS ET AL.
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ISSN: 0003-4983 (Print) 1364-8594 (Online) Journal homepage: http://www.tandfonline.com/loi/ypgh19
Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro H. L. Williams, Deadre J. Johnson, V. C. N. Okoye & S. K. Martin To cite this article: H. L. Williams, Deadre J. Johnson, V. C. N. Okoye & S. K. Martin (1992) Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro, Annals of Tropical Medicine & Parasitology, 86:5, 467-473, DOI: 10.1080/00034983.1992.11812695 To link to this article: https://doi.org/10.1080/00034983.1992.11812695
Published online: 15 Nov 2016.
Submit your article to this journal
Article views: 1
View related articles
Citing articles: 3 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ypgh19
Annals of Tropical Medicine and Parasitology, Vol. 86, No.5, 467-473 (1992)
Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro BY H. L. WILLIAMS, DEADRE]. JOHNSON, V. C. N. OKOYE Department of Hematology, Division of Medicine, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, U.S.A. S. K. MARTIN* United States Army Medical Research Unit-Kenya, Unit 64109, Box 401, APO AE 09831-4109, U.S.A. AND
Received 19 July 1991, Revised 11 May 1992, Accepted 1 June 1992
Compounds that inhibit the P-glycoprotein-related efflux mechanism of multidrug-resistant cells reverse chloroquine resistance in vitro. Hence, the co-administration of chloroquine and an efflux-blocking drug could potentially treat chloroquine-resistant malaria infections. We administered a drug combination (chloroquine and a tiapamil analogue), that has been shown to reverse chloroquine resistance in vitro, to Aotus monkeys but failed to safely clear experimentally-induced chloroquine-resistant Plasmodiumfalciparum parasitaemias.
The report that chloroquine-resistant malaria parasites could be made sensitive to chloroquine in vitro by simultaneously exposing them to chloroquine and verapamil provided the rationale for a potentially new strategy for the treatment of chloroquine-resistant malaria infections (Martin et a/., 1987). Even though the mechanism of chloroquine resistance in P. falciparum remains unproven, one of the contending theories is that chloroquine-resistant malaria parasites, like multidrug-resistant cancer cells, prevent the drug from reaching toxic intracellular levels by an active efflux process (Krogstad et a!., 1987). The hallmark of this multidrug-resistant phenotype is the presence of increased amounts of a 170 kDa P-glycoprotein in membranes of resistant cells. P-glycoprotein is coded for by a family of mdr genes which are concomitantly amplified in the "Author to whom correspondence should be addressed. 0003-4983/92/050467 + 07 $08.00/0
resistant phenotypes (Gros et a!., 1986; Ueda et a/., 1987). Therefore any compound that compromises this efflux process would potentially enhance chloroquine toxicity selectively against chloroquine-resistant parasites. Effluxblocking drugs or reversing agents have been successfully used in vitro to reduce the IC 50 of resistant parasites to sensitive levels (Bitonti et a!., 1988; Basco et a!., 1990; Kyle et a/., 1990). Coincidentally, increased amounts of Pglycoprotein and its associated m-RNA have also been found in several normal host tissues (Fojo et a!., 1987; Thiebaut et al., 1987). Although the significance of this glycoprotein in normal host tissue remains unknown, its localization in tissues that subserve an excretory/ secretory function has led investigators to also ascribe a transport function to it (Gottesman and Pastan 1988). Consequently, attempts to treat chloroquine-resistant malaria infections with a combination of chloroquine and a reversing © 1992 Liverpool School of Tropical Medicine
WILLIAMS ET AL.
468
V-1 Rx: Mefloquine IM
WR-95 12~------------------------~
10 •••••••••••••••••••••••••••••••••••••••••••••••
0
E
Q)
E
·u; ~
0
0.
(/!.
Mefloquine
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