Defining the timing of action of antimalarial drugs against Plasmodium falciparum.
نویسندگان
چکیده
Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.
منابع مشابه
Clinical Pharmacology of the Antimalarial Chloroquine in Children and Their Mothers
Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are the parasites that infect humans. Plasmodium falciparum and Plasmodium vivax cause most of the malarial infections worldwide. Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are susceptible to chloroquine. Chloroquine was the world's most widely used antim...
متن کاملClinical Pharmacology of the Antimalarial Artemisinin-Based Combination and other Artemisinins in Children
In 2010, there were estimated 219 million cases of malaria resulting in 666,000 deaths and two-thirds were children. Children are more vulnerable than adults to malaria parasites. In sub-Saharan African countries, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. Malaria is caused by five Plasmodium parasites namely: Plasmodium falciparum, Plasmodium vivax, Plasm...
متن کاملAntimalarial evaluation of selected medicinal plant extracts used in Iranian traditional medicine
Objective(s): In an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on Iranian traditional medicine. Materials and Methods: Ten plant species found in Iran were selected and collected based on the available literature about the Iranian traditional medicine. The methanolic extracts of th...
متن کاملAntiplasmodial activity and cytotoxicity of ethanol extract of Zea mays root
Objective:Zea mays root decoction that has been traditionally used for the treatment of malaria by various tribes in Nigeria, was evaluated for antimalarial potential against malaria parasites using in vivo and in vitro models. Materials and Methods: The root extract of Zea mays was investigated for antimalarial activity against Plasmodium berghei in mice using rodent malaria models; suppressiv...
متن کاملDFT Studies and Topological Analyses of Electron Density on Acetophenone and Propiophenone Thiosemicarbazone Derivatives as Covalent Inhibitors of Falcipain-2, a Major Plasmodium Falciparum Cysteine Protease
Thiosemicarbazones (TSCs) possess significant antimalarial properties believed to be linked to the inhibition of major cysteine proteases, such as falcipain-2, in Plasmodium falciparum. However, the binding modes of TSCs to the active site of these enzymes are not clear. As a result of this, the nature of the bonding interactions between the active site of falcipain-2 and different derivatives ...
متن کاملPotentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro.
Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Antimicrobial agents and chemotherapy
دوره 57 3 شماره
صفحات -
تاریخ انتشار 2013