title: In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil.
abstract: We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.
authors.affiliation: Department of Medicine, Infectious Diseases Unit, Malaria Research Laboratory, M9/02, Karolinska University Hospital, Karolinska Institute, SE 171-76 Stockholm, Sweden. mita.maini-thapar@medks.ki.se
authors.forename: Mita M
authors.initials: MM
authors.lastname: Thapar
authors.forename: Jose P
authors.initials: JP
authors.lastname: Gil
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D003470:Culture Media; D003573:Cytochrome b Group / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000517:prevention & control; D009285:Naphthoquinones / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D002727:Proguanil / Q000494:pharmacology*; D012008:Recurrence; D014227:Triazines / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D003470:Culture Media; D003573:Cytochrome b Group; D009285:Naphthoquinones; D014227:Triazines; C026009:cycloguanil; D002727:Proguanil; D053626:Atovaquone