Activity of Doxycyclineagainst Preerythrocytic Malaria

Marussig, Myriam; Motard, A.; Rénia, Laurent; Baccam, D.; Lebras, J.; Charmot, G; Mazier, Dominique

doi:10.1093/infdis/168.6.1603

Cited by 12 publications

(9 citation statements)

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“…thouarsii decoction was assessed in a standard bioassay of cultured mouse primary hepatocytes infected with P. yoelii sporozoites [14,15]. Parasite inhibition was observed in the exposed cultures (IC 50 8.5 ± 0.7 μg/ml), with hepatic forms completely eliminated at concentrations of 20 μg/ml or greater.…”

Section: Resultsmentioning

confidence: 99%

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

et al. 2006

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BackgroundThe global spread of multidrug–resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s.Methods and FindingsUsing bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 μM, TI 46, and IC50 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages.ConclusionsA readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.

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Section: Resultsmentioning

confidence: 99%

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

et al. 2006

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“…Tetracycline acts on mitochondria (22) and depresses the activity of dihydroorotate dehydrogenase, an iron-dependent enzyme of the pyrimidine pathway in P. falciparum (23,41), presumably due to the inhibition of enzyme protein synthesis. Doxycycline reduces the levels of malaria nucleoside 5Ј-triphosphates and deoxynucleoside 5Ј-triphosphates (58) and has shown inhibitory effects against preerythrocytic stages (28). Tetracyclines could also act on the dihydroorotate dehydrogenase enzyme by chelating its iron center.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activities of Antibiotics against Plasmodium falciparum Are Inhibited by Iron

Pradines

Rogier

Fusaı̈

et al. 2001

Antimicrob Agents Chemother

107

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The in vitro activities of cyclines (tetracycline, doxycycline, minocycline, oxytetracycline, and rolitetracycline), macrolides (erythromycin, spiramycin, roxithromycin, and lincomycin), quinolones (norfloxacin and ofloxacin), rifampin, thiamphenicol, tobramycin, metronidazole, vancomycin, phosphomycin, and cephalosporins (cephalexin, cefaclor, cefamandole, cefuroxime, ceftriazone, cefotaxime, and cefoxitin) were evaluated on Plasmodium falciparum clones, using an isotopic, micro-drug susceptibility test. Only tetracyclines, macrolides, quinolones, and rifampin demonstrated in vitro activity against P. falciparum, which increased after a prolonged exposure (96 or 144 h). In the presence of iron (FeCl 3 ), only the activities of tetracyclines and norfloxacin were decreased. Their in vitro activity against intraerythrocytic stages of multidrug-resistant P. falciparum and their efficacy in vivo favor the use of antibiotics as antimalarial drugs. However, due to their slow antimalarial action and to the fact that they act better after prolonged contact, they probably need to be administered in conjunction with a rapidly acting antimalarial drug, such as a short course of chloroquine or quinine.

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“…Doxyxycline reduces levels of malaria nucleoside 5Ј-triphosphates and deoxynucleoside 5Ј-triphosphates 27 and has shown inhibitory effects against pre-erythrocytic stages. 13,28 No large studies on doxycycline safety and toxicity have been reported. The severity and disability of side effects have not been well defined.…”

Section: Discussionmentioning

confidence: 99%

Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro activity of doxycycline against Senegalese isolates.

Pradines

Spiegel²,

Rogier³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activities of doxycycline, chloroquine, quinine, amodiaquine, artemether, pyrimethamine, and cycloguanil were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro, drug susceptibility test. The 71 50% inhibitory concentration (IC 50 ) values for doxycycline ranged from 0.7 to 108.0 M and the geometric mean IC 50 for the 71 isolates was 11.3 M (95% confidence interval ϭ 9.5-13.4 M). The activity of doxycycline did not differ significantly (P ϭ 0.0858) between the chloroquine-susceptible isolates and the chloroquine-resistant isolates. There was no in vitro correlation between the responses to doxycycline and those to artemether, chloroquine, quinine, amodiaquine, pyrimethamine, and cycloguanil, suggesting no in vitro cross-resistance among these drugs. Potency was increased by prolonged exposure. In 96-hr incubations, the activity of doxycycline was 4-5-fold more increased than in 48-hr incubations. The in vitro activity of doxycycline against intraerythrocytic stages of multidrug-resistant P. falciparum, its action against the preerythrocytic forms, the lack of correlation between the responses in vitro of P. falciparum to doxycycline and the other antimalarial drugs, and its original potential site of action are factors that favor its use as antimalarial drug.The current options for reducing the morbidity and mortality of malaria are chemoprophylaxis and chemotherapy. Therefore, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria.

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Activity of Doxycyclineagainst Preerythrocytic Malaria

Cited by 12 publications

References 0 publications

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

In Vitro Activities of Antibiotics against Plasmodium falciparum Are Inhibited by Iron

Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro activity of doxycycline against Senegalese isolates.

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