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.
This study reports the first isolation and partial genetic characterization of Chikungunya virus (CHIKV) from patients during a 2006-2007 dengue-like syndrome outbreak in Gabon. The isolated viruses were phylogenetically close to strains isolated in the Democratic Republic of the Congo 7 years ago and to strains isolated more recently in Cameroon. These results indicate a continuing circulation of a genetically stable CHIKV population during 7 years in Central Africa.
The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.
FR160, a catechol iron chelator, and tetracyclines or norfloxacin exert in vitro additive or synergistic activity against a chloroquine-resistant Plasmodium falciparum clone. FR160 shows antagonistic effects in association with macrolides, ofloxacin, and rifampin.The emergence and spread of parasite resistance to currently used antimalarial drugs indicates that novel compounds need to be discovered and developed by identification of novel chemotherapeutic targets (18). Iron chelation therapy was considered a suitable treatment for various infectious diseases, including malaria (10). Iron is needed for catalysis of DNA synthesis and for a variety of enzymes involved in electron transport and energy metabolism. Recent experimental observations obtained in vitro (9,25), in rodent (6) and primate (19) models, and in clinical studies (8,15) showed antimalarial activity of desferrioxamine. However, the time window of action of desferrioxamine is relatively limited, and the antimalarial activity is slow to develop, even after continuous in vitro or in vivo exposure to desferrioxamine (4). Various iron chelators were assessed to improve the drug lipophilicity, leading to increased access of drug to intracellular parasites and to faster action (13,14). In addition, several studies explored the possibility of improving the antimalarial efficacy of iron chelators by using them in various combinations of iron chelators with different speeds of action, stage dependences, and degrees of reversibility of effects (7,27,28). The in vitro activity of FR160, a catecholate siderophore derived from spermidine, was shown previously (21). Use of combinations of antimalarials that do not have the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per-parasite mutation rates for the individual drugs multiplied by the number of parasites in an infection that are exposed to the drugs (29).In this study, we assessed the combined action of FR160 with antibiotics against Plasmodium falciparum.Parasites. When required for drug assays, the chloroquineresistant clone W2 (Indochina) was synchronized by sorbitol lysis (12). Susceptibilities to FR160 and antibiotics were determined after suspension in RPMI 1640 medium (Life Technologies, Paisley, United Kingdom) supplemented with 10% human serum (pooled from different A ϩ or AB sera from nonimmune donors) and buffered with 25 mM HEPES and 25 mM NaHCO 3 (hematocrit of 1.5% and parasitemia of 0.5%).Drugs. The synthesis of FR160 was previously described (21). All antibiotics were obtained from Sigma Chemical (St. Louis, Mo.). Stock solutions were prepared in methanol for FR160, tetracycline, doxycycline, minocycline, oxytetracycline, erythromycin, spiramycin, roxithromycin, and rifampin and in dimethyl sulfoxide for ofloxacin, norfloxacin, and rolitetracycline. Twofold serial dilutions were prepared in sterile distilled water or RPMI for all these drugs. Final concentrations were distributed in triplicate into Falcon...
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 9.5-13.4 M). The activity of doxycycline did not differ significantly (P 0.0858) between the chloroquine-susceptible isolates and the chloroquine-resistant isolates. There was no in vitro correlation between the responses to doxy-cycline 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 Plasmo-dium falciparum resistant to chloroquine and other antima-larial drugs poses a serious problem for control of malaria.
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