Reversal of Plasmodium falciparum resistance to chloroquine in Panamanian Aotus monkeys

Autor: Wilbur K. Milhous, Richard N. Rossan, Dennis E. Kyle
Rok vydání: 1993
Předmět:
Zdroj: The American journal of tropical medicine and hygiene. 48(1)
ISSN: 0002-9637
Popis: An Aotus-Plasmodium falciparum model was used to determine if chloro- quine resistance could be reversed in vivo. The putative resistance modulators tested all reverse chloroquine resistance in vitro and included verapamil, chlorpromazine, proch- lorperazine, cyproheptadine, ketotifen, a tiapamil analog (Ro 11-2933), and a chlorprom- azine analog (SKF 2133-A). Combinations of chloroquine plus chlorpromazine or proch- lorperazine confirmed reversal of chloroquine resistance as exhibited by cures obtained in six Aotus monkeys infected with chloroquine-resistant P. falciparum (Vietnam Smith/RE strain) and rapid clearance of parasitemia, followed by recrudescence in six additional monkeys. The results indicate the following order of in vivo efficacy for reversing chlo- roquine resistance in Aotus: chlorpromazine > prochlorperazine ;: desipramine >> Ro 11-2933 (tiapamil analog) > ketotifen. Cyproheptadine and verapamil were not effective in reversing chloroquine resistance and probable drug toxicity was observed with these drugs in combination with chloroquine. Despite the widespread prevalence of drug- MATERIALS AND METHODS resistant Plasmodium falciparum, chloroquine remains an important drug in the treatment of Malaria-naive Panamanian owl monkeys malaria in many parts of the world.' The dis- (Aotus lemurinus lemurinus) were used as hosts covery that chloroquine resistance could be re- for chloroquine-resistant P. falciparum, and pre- versed in vitro by using verapamil suggested a viously described procedures and husbandry novel approach to combination therapy and practices were followed." The chloroquine-re- raised hopes that the clinical response to chlo- sistant Vietnam Smith strain was used in the roquine could be restored.? Numerous com- initial experiments with chloroquine combined pounds besides verapamil have now been shown with verapamil or SKF 2133-A (a chlorproma- to reverse chloroquine resistance in vitro, 3 -6 but zine analog). In subsequent studies, a recrudes- experience with resistance modulators plus chlo- cent isolate from a Vietnam Smith strain-in- roquine in vivo is limited. In various mouse ma- fected Aotus monkey treated with chloroquine laria models, verapamil, cyproheptadine, keto- was used. This strain, designated Vietnam Smitlh/ tifen, and amlodipine have been shown to reverse RE, was more resistant to chloroquine as evi- S. chloroquine resistance,'- ` but primate in vivo denced by limited effects on parasitemia in Aotus Sdata versus chloroquine-resistant P. falciparum monkeys receiving 20 mg/kg/day of chloroquine are limited to a single observation."' In that study, for seven days. desipramine given in combination with chloro- Each monkey was inoculated intravenously Squine cleared parasitemia in Aotus monkeys in- with 5 x 106 trophozoites of the chloroquine- fected with chloroquine-resistant P. falciparum, resistant Vietnam Smith or Vietnam Smith/RE but in each case the infection eventually recru- strain of P. falciparum. The inoculum size pro- desced. In this study, we report our results with duced a parasitemia of at least 5 x IO1/mm' by a series of resistance modulators in a Panaman- the fifth day postinoculation, at which time treat- "ian Aolus-P. falciparum model. The results con- ment was begun. Stock solutions of water-soluble firm the reversal of P. falciparum chloroquine drug were prepared at appropriate concentra- resistance in Aotus and allow for comparison of tions and maintained at 4*C during the course relative abilities of different compounds to re- of treatment. A suspension of water-insoluble verse chloroquine resistance, drugs was prepared in 0.3% methylcellulose just
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