The action of salinomycin-Na and lasalocid-Na on chloroquine- and mepacrine-resistant line ofPlasmodium berghei K 173-strain in Wistar rats

Raether, W.; Seidenath, H.; Mehlhorn, Heinz; Ganster, H.J.

doi:10.1007/bf00925589

Cited by 8 publications

(3 citation statements)

References 2 publications

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“…Until now, only three natural ionophore compounds (which are commercially available), i.e., salinomycin, lasalocid A, and gramicidin D, have been tested in vivo against Plasmodium berghei or Plasmodium yoelii. The first two compounds were shown to be inactive or weakly active (24), and gramicidin D was found to be active against P. yoelii when it was administered subcutaneously, with an ED 50 of 0.75 mg/kg, but the TI was not indicated (20). In addition, three synthetic monensin urethane derivatives that possess a very strong affinity for K ϩ were found to be moderately active against P. berghei after oral administration (26).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds

Gumila

Ancelin

Delort

et al. 1997

Antimicrob Agents Chemother

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Large-scale in vitro screening of different types of ionophores previously pinpointed nine compounds that were very active and selective in vitro against Plasmodium falciparum; their in vitro and in vivo antimalarial effects were further studied. Addition of the ionophores to synchronized P. falciparum suspensions revealed that all P. falciparum stages were sensitive to the drugs. However, the schizont stages were three- to ninefold more sensitive, and 12 h was required for complete parasite clearance. Pretreatment of healthy erythrocytes with toxic doses of ionophores for 24 to 48 h showed that the activity was not due to an irreversible effect on the host erythrocyte. No preferential ionophore adsorption in infected or uninfected erythrocytes occurred. On the other hand, ionophore molecules strongly bound to serum proteins since increasing the serum concentration from 2 to 50% led to almost a 25-fold parallel increase in the ionophore 50% inhibitory concentration. Mice infected with the malaria parasites Plasmodium vinckei petteri or Plasmodium chabaudi were successfully treated with eight ionophores in a 4-day suppressive test. The 50% effective dose after intraperitoneal administration ranged from 0.4 to 4.1 mg/kg of body weight, and the therapeutic indices were about 5 for all ionophores except monensin A methyl ether, 5-bromo lasalocid A, and gramicidin D, whose therapeutic indices were 12, 18, and 344, respectively. These three compounds were found to be curative, with no recrudescence. Gramicidin D, which presented impressive antimalarial activity, requires parenteral administration, while 5-bromo lasalocid A has the major advantage of being active after oral administration. Overall, the acceptable levels of toxicity and the good in vivo therapeutic indices in the rodent model highlight the interesting potential of these ionophores for the treatment of malaria in higher animals.

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Section: Discussionmentioning

confidence: 99%

Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds

Gumila

Ancelin

Delort

et al. 1997

Antimicrob Agents Chemother

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“…At the cytological level, shrinking of the pellicula, vacuolisation of the cytoplasm and destruction of the mitochondria were detected (Raether et al 1991). In additional experiments, it was demonstrated that salinomycin has deleterious effects on the blood stages of Plasmodium berghei and P. falciparum (Mehlhorn et al 1984;Raether et al 1985). These effects consist of vacuolisation of the cytoplasm and enlargement of the mitochondria.…”

Section: Discussionmentioning

confidence: 94%

Effects of orally administered chemotherapeutics (quinine, salinomycin) against Henneguya sp. Thelohán, 1892 (Myxozoa: Myxobolidae), a gill parasite in the tapir fish Gnathonemus petersii Günther, 1862 (Teleostei)

Dohle

Schmahl

Raether³

et al. 2002

Parasitology Research

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When given orally, quinine or salinomycin cause irreversible damage to the plasmodial developmental stages of Henneguya sp., a gill parasite in the tapir fish Gnathonemus petersii. Naturally infected tapir fish measured 75-169 mm in total length and their total weight ranged over 4.3-11.7 g. The fish bore 7-77 plasmodia in their gill arches. Medicinal food containing either quinine (5 g/1000 g food) or salinomycin (0.075 g/1000 g food) was given once a day to naturally infected fish in a food chain via water fleas ( Daphnia spp) for a period of 3, 6, or 9 days. From the monitored feeding of the tapir fish and weight determinations of the water fleas, it was calculated that gross uptake was 18.5 micro g/kg body weight fish daily for pure salinomycin and was 1.25 mg/kg body weight daily for quinine. After the end of the experiments, the fish were sacrificed and the plasmodia were carefully prepared from the gill arches and processed for transmission electron microscopy. As seen by ultrastructure investigations, for both substances the grade of damage in the parasites correlated positively with the period of application. When quinine was given for a 3-day period, the trophozoite ecto- and endoplasm exerted numerous vacuoles, caused by the drug, and the presporogonous and the pansporoblastic stages were malformed. Following a 6-day period, numerous abortive polar capsules were found in the trophozoite cytoplasm. To a large extent, the limiting membranes of the polaroblasts and valvogenic cells were destroyed. In addition, deep clefts between the polaroblasts, the valvogenic cells and between the two sporoblasts were observed. Following a 9-day treatment, all damage increased and, in addition, generative cells and two-cell stages were no longer detectable. As a first sign for the effects of salinomycin, following a 3-day treatment, a shrinking of the whole plasmodia occurred and the sutures in the pansporoblasts were enlarged. The polar capsules were malformed and the zonar structures of the polar filament were no longer detectable. The sporoplasmosomes were more electron-pale than those of the control samples. After a 9-day treatment, the pansporoblasts were completely destroyed. Under the experimental conditions chosen, both compounds were very well tolerated by the fishes.

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“…Our preliminary studies (see Material and Methods) showed that nigericin had similar activities regardless of the form of drug presentation (acid or Na ϩ salt) and the solvent (DMSO or ethanol) used for the stock solutions. The culture and test conditions (strains, hematocrit, initial level of parasitemia, duration of drug contact) and also the different susceptibilities of the different stages of the parasite could be partially responsible for these discrepancies (31). We thus incubated infected erythrocytes with the drug for a complete parasite cycle before measuring the viability of the parasite.…”

Section: Discussionmentioning

confidence: 99%

Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells

Gumila

Ancelin

Jeminet

et al. 1996

Antimicrob Agents Chemother

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Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

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The action of salinomycin-Na and lasalocid-Na on chloroquine- and mepacrine-resistant line ofPlasmodium berghei K 173-strain in Wistar rats

Cited by 8 publications

References 2 publications

Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds

Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds

Effects of orally administered chemotherapeutics (quinine, salinomycin) against Henneguya sp. Thelohán, 1892 (Myxozoa: Myxobolidae), a gill parasite in the tapir fish Gnathonemus petersii Günther, 1862 (Teleostei)

Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells

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