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PubMed2001

The antimalarials quinacrine and chloroquine potentiate the transplacental carcinogenic effect of ethylnitrosourea on ependymal cells.

Quinacrine and chloroquine, two widely used antimalarials, bind strongly to deoxyribonucleic acid, thus preventing mutagenesis. We studied a possible chemoprotective effect of these substances on carcinogenesis of the nervous system induced in Wistar rats by transplacental administration of ethylnitrosourea. One experimental group consisted of rats born from mothers treated with quinacrine prior to prenatal exposure to ethylnitrosourea; a second group consisted of rats chronically treated with chloroquine after prenatal exposure to ethylnitrosourea. When compared with controls, no significant differences were observed in tumor incidence. However, early tumor growth was observed in both rats treated with quinacrine (P < 0.0004) and rats treated with chloroquine (P < 0.02). These differences were due mostly to rapid development of ependymomas of the spinal cord. Our results suggest that quinacrine and chloroquine do not prevent the structural alterations induced in DNA by ethylnitrosourea, which lead, in the long term, to a high incidence of neoplasms in the nervous system. Moreover, the antimalarials studied seem to promote the carcinogenic effects of ethylnitrosourea on ependymal cells.

Animals↗
PubMed2000

Antimalarial activity of new gossypol derivatives.

Gossypol, a disesquiterpene extracted from cotton seeds, is known to inhibit strongly the Plasmodium falciparum lactate dehydrogenase, but its high toxicity has stopped any antimalarial drug development. A series of Schiffs bases was synthesized from gossypol by modification of the aldehyde groups responsible for its toxicity. A total of 13 compounds showing low cytotoxicity were then selected and were compared with gossypol for activity against 2 chloroquine-resistant strains of P. falciparum (PFB, FCB1). These in vitro activities were evaluated using an isotope-based drug-susceptibility semiautomated microdilution test followed by determination of IC50 values (50% inhibitory concentration). In all, 12 of the 13 compounds tested were active; 3 of them displayed antimalarial activity comparable with that of gossypol itself.

Animals↗
PubMed2001

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites.

Previous studies have shown that ferrochloroquine (FQ) exhibited an antimalarial activity against Plasmodium spp. The present work confirmed this activity, described the curative effect on P. vinckei and investigated the FQ toxicity in vitro and in vivo. The in vitro and in vivo growth inhibition of P. falciparum and P. berghei N, respectively, showed that FQ antimalarial activity was 1.5-10 times more potent than chloroquine. FQ completely inhibited the in vivo development of both chloroquine-susceptible and resistant P. vinckei strains and protected mice from lethal infection at a dose of 8.4 mg kg(-1) day(-1) given for 4 days subcutaneously or orally. This curative effect was 5-20 times more potent than chloroquine, according to the strains' resistance to chloroquine. At this curative dose, no clinical changes were observed in mice up to 14 days after the last administration. Nevertheless, the acute toxicity and lethality of ferrochloroquine seemed to be dependent on gastric surfeit. The FQ security index determined in vitro confirmed that it might be a promising compound.

Administration, Oral↗
PubMed1999

Antimalarial antisense activity of hexitol nucleic acids.

Antisense oligonucleotides and ribozymes have shown promise both as antimalarial agents and as tools for identifying genes vital for parasite survival. This task is urgent due to the ineffectiveness of current drug regimes on the most virulent human malarial parasite, Plasmodium falciparum. The development of new ways to modify and/or protect conventional phosphodiester oligonucleotides to improve nuclease resistance is also important. We assessed the effect of antisense oligonucleotides containing phosphorylated anhydrohexitols in suppressing the growth of P. falciparum in culture. The modified oligonucleotides were able to inhibit parasite growth in a sequence-specific manner, but not as well as the phosphorothioated antisense oligonucleotides, which are effective antimalarials at submicromolar concentrations. Two reasons are suggested: the absence of RNase H activation and differences in membrane transport.

Animals↗
PubMed2004

Genotoxic evaluation of the antimalarial drug, fansidar, in cultured human lymphocytes.

Fansidar (pyrimethamine-sulfadoxine) has been used extensively worldwide for the treatment of chloroquine resistant Plasmodium falciparum malaria, toxoplasmosis and Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Because of the wide usage of pyrimethamine-sulfadoxine in developing countries and the lake of information from open literature and reports from manufacturers about the genotoxicity of such antimalarial drug, the present work was suggested. The possible genetic toxicity of fansidar has been evaluated in human peripheral blood lymphocyte cultures. The frequencies of sister-chromatid exchanges (SCE) and micronuclei (MN) were scored as genetic endpoints. Both tests covering a wide range of induced genetic damage as primary DNA damage, clastogenicity and aneugenicity. Cultures were set up by using blood samples from two healthy donors and the treatment was done using different fansidar concentrations ranging from 1:20 to 10:200 microg/ml. From our results, it appears that this drug is able to induce moderate genotoxic effects, as revealed by the increases found in SCE and MN frequencies in cultures from the two donors at the two highest concentrations tested (5:100 and 10:200 microg/ml). In addition, cyotoxic/cytostatic effects of fansidar were revealed by a decrease in the proliferative rate index (PRI) and in the cytokinesis block proliferation index (CBPI). Our findings suggest that the use of this drug should be restricted to situations where other antimalarial drugs cannot be used. The drug should never be given to pregnant women.

Animals↗
PubMed1994

Screening Tanzanian medicinal plants for antimalarial activity.

Forty-three different plant species commonly used in traditional medicine for the treatment of malaria were selected and screened for their antimalarial activity against Plasmodium falciparum in vitro. Thirteen of the 43 species were obtained directly from traditional healers who use these plants for the treatment of malaria. The other plant species were collected on the basis of ethnomedicinal information in the literature. The plant material was collected from Morogoro, Dar es Salaam and Kagera regions in Tanzania. Fifty-eight plant samples from these 43 plant species, including leaves, roots and stem bark, were investigated. Apart from the crude EtOH extracts, petroleum ether (PE), ethyl acetate (EtAc) and H2O fractions of these extracts were also tested. The in vitro testing revealed that 37% of the investigated plants showed strong antimalarial activity with IC50 values below 10 micrograms/ml. The four most active plants included Cissampelos mucronata, Maytenus senegalensis, Salacia madagascariensis and Zanthoxylum chalybeum.

Animals↗
PubMed1994

The mode of action and the mechanism of resistance to antimalarial drugs.

The mechanism of action of the antifolate and quinoline antimalarials has been investigated over the last few decades, and recent advances should aid the development of new drugs to combat the increasingly refractile parasite. The molecular description of resistance to the antifolates has been well characterised and is due to structural changes in the target enzymes, but the factors involved in the parasite's ability to circumvent the action of the quinoline antimalarials have yet to be fully elucidated. This review discusses the mode of action of these drugs and the means used by the parasite to defeat our therapeutic ingenuity.

Animals↗
PubMed1989

Selective antimalarial activity of tetrandrine against chloroquine resistant Plasmodium falciparum.

Antimalarial activity of tetrandrine was studied using a continuous in vitro culture of Plasmodium falciparum. Experimental results showed that tetrandrine has potent antimalarial effect on both chloroquine sensitive and resistant strains of Plasmodium falciparum. Interestingly, tetrandrine is about three times more potent against the chloroquine resistant strain than it is against the sensitive strain based on their IC50 values, which were 5.09 x 10(-7) M for the sensitive strain and 1.51 x 10(-7) M for the resistant strain. In addition, reversal experiments revealed that tetrandrine cannot reverse chloroquine-resistance, although it has verapamil-like, calcium-channel-blocker activity.

Alkaloids↗
PubMed1986

Digestion of the host erythrocyte by malaria parasites is the primary target for quinoline-containing antimalarials.

Intraerythrocytic malaria parasites feed on their host cell cytosol. We show that human red blood cells infected with the malaria parasite Plasmodium falciparum, produce free amino acids the composition of which resembles that of globin, the most abundant red blood cell protein. The rate of amino acid production is almost equal to the rate of efflux of these acids from the infected cell. Production of amino acids increases with parasite age: the rates of production at the young ring and the mature trophozoite stages were 3.3 and 13.5 nmol/10(8) infected cells per min at 37 degrees, respectively, compared with 0.04 nmol/10(8) cells per min in uninfected cells. The quinoline-containing antimalarial drugs, chloroquine, quinine and mefloquine, inhibit amino acid production at the same concentrations at which they inhibit parasite growth, but have no effect on the endogenous parasite protein degradation. We suggest that parasite feeding on host cell cytosol is the primary target for the antimalarial action of these drugs. Chloroquine accumulation, the rate of amino acid production by infected cells and the inhibitory effect of the drug, were determined simultaneously at the different stages of parasite development. At all stages the rate of amino acid production and chloroquine accumulation were directly related and both were inversely related to the inhibitory efficiency of the drug. The lysosomotropic agents methylamine and NH4Cl at millimolar concentrations also inhibit amino acid production, suggesting that the process is pH dependent and localized in the vacuole. Host cytosol degradation and drug accumulation both take place in the parasite food vacuole. Our observations imply that the metabolically dependent acidification of this parasite organelle is involved in both processes.

Amino Acids↗
PubMed1988

Glutathione reductase inhibitors as potential antimalarial drugs. Effects of nitrosoureas on Plasmodium falciparum in vitro.

Malarial parasites are believed to be more susceptible to oxidative stress than their hosts. BCNU(1,3-bis(2-chloroethyl)-1-nitrosourea) and HeCNU(1-(2-chloroethyl)-3-(2-hydroxythyl)-1-nitrosourea), inhibitors of the antioxidant enzyme glutathione reductase, were found to prevent the growth of Plasmodium falciparum in all intraerythrocytic stages. When exposing infected red blood cells to 38 microM BCNU or 62 microM HeCNU for one life cycle of synchronously growing parasites, the parasitemia decreased by 90%. During the formation of new ring forms, the parasites are even more susceptible to these drugs. The treatment with BCNU or HeCNU produced a rapid depletion of GSH in the parasites and their host cells; in addition, protection against lipid peroxidation was impaired in these cells. Possible mechanisms for the antimalarial action of the inhibitors are discussed. Our results suggest that erythrocyte glutathione reductase, an enzyme of known structure, might be considered as a target for the design of antimalarial drugs.

Animals↗
PubMed1990

Antimalarial action of flavin analogues seems not be due to inhibition of glutathione reductase of host erythrocytes.

A series of 10-(4'-chlorophenyl)-3-substituted flavins (1a-f) were examined with respect to their antimalarial properties. They were tested against Plasmodium falciparum in vitro and Plasmodium vinckei vinckei in vivo. The proposition that they might act through glutathione reductase (GR) (EC 1.6.4.2) inhibition has been studied. Inhibition of P. falciparum in vitro by these compounds shows only slight variation between analogues; in contrast, inhibition of human erythrocyte GR by members of the same series is highly variable, indicating that this is probably not their primary mode of antimalarial action. Results of the P. vinckei vinckei screen showed that 10-(4'-chlorophenyl)-3-methyl,3-ethyl and 3-propyl substituted flavins are active in vivo over the dose range screened (10-70 mg/kg).

Animals↗
PubMed1990

Flavin analogs with antimalarial activity as glutathione reductase inhibitors.

10-(4'-Chlorophenyl)-3-methylflavin has antimalarial activity in vitro and in vivo (Cowden et al., J Med Chem 31: 799, 1988). This flavin analog and two of its derivatives were found to inhibit the antioxidant flavoenzyme glutathione reductase from human erythrocytes in its isolated form as well as in hemolysates. The mixed-type inhibition was completely reversible, the Ki-values being of the order of 1 microM. Surprisingly, the drugs were not competitive with FAD, but with GSSG, one of the enzyme's substrates. Malaria parasite glutathione reductase, extracted from Plasmodium falciparum, could also be inhibited by the compounds. Studies on the effects of the substances on P. falciparum in vitro, which were demonstrated morphologically and by growth inhibition, confirmed previous observations with 10-(4'-chlorophenyl)-3-methylflavin and showed similar parasiticidal characteristics for the two new derivatives. The activities of five other erythrocytic enzymes tested were not impaired by the drugs, nor was the nucleotide metabolism of erythrocytes and/or parasites significantly changed. Permeation into red blood cells was demonstrated for one compound by 19F-NMR-spectroscopy. Inhibition of glutathione reductase might contribute to, or account for, the antimalarial activity of this group of flavin analogs.

Animals↗
PubMed1992

Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs.

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by co-chromatography with the authentic standard. Ketoconazole, a known inhibitor of cytochrome P450 isozymes, caused marked inhibition of carboxyprimaquine formation with IC50 and K(i) values of 15 and 6.7 microM, respectively. This finding and the dependency of metabolite formation on NADPH indicates that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with primaquine to malaria patients, only mefloquine produced any inhibition (K(i) = 52.5 microM). Quinine, artemether, artesunate, halofantrine and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarials, with primaquine will lead to appreciably altered disposition.

Antimalarials↗
PubMed1996

The role of drug accumulation in 4-aminoquinoline antimalarial potency. The influence of structural substitution and physicochemical properties.

We have investigated a series of novel 4-aminoquinoline analogues related to amodiaquine, that possess side chain modifications designed to influence both drug pKa and lipophilicity. These compounds have been used to determine the influence of physicochemical properties on antimalarial activity against, and accumulation by, both chloroquine-susceptible and chloroquine-resistant isolates of Plasmodium falciparum. The compounds tested exhibited a 500-fold range of absolute antimalarial potency. Absolute drug potency and drug accumulation were found to be significantly correlated in each of the four isolates of Plasmodium falciparum studied. The level of accumulation was unrelated to lipophilicity and was significantly greater than the predicted levels of accumulation based on drug pKa, compartmental pH, and Henderson-Hasselbach considerations. Further analysis of the relationship between 4-aminoquinoline accumulation and activity implicated the involvement of additional forces in the accumulation process.

Aminoquinolines↗
PubMed1986

Antimalarial drugs and human neutrophil oxidative metabolism.

The effect of several commonly used antimalarial drugs on human peripheral blood neutrophil oxidative metabolism was studied. The following drugs were tested: chloroquine diphosphate, quinine HCl, mefloquine, proguanil HCl, cycloguanil, pyrimethamine, sulphadoxine, and tetracycline HCl. It was found that none of the antimalarial drugs examined, at clinically obtainable concentrations, had any inhibitory effect on neutrophil oxygen consumption, glucose oxidation, superoxide production, NBT reduction, and chemiluminescence. However, at higher concentrations chloroquine, quinine, mefloquine, and proguanil inhibited neutrophil oxidative burst. There was a slight enhancing effect on neutrophil oxidative metabolism by pyrimethamine, combination of pyrimethamine-sulphadoxine, cycloguanil and tetracycline at concentrations lower than the clinical levels.

Antimalarials↗
PubMed1986

Phagocytosis and bactericidal activity of human leucocytes under influence of antimalarial drugs.

The phagocytic and bactericidal activity of human peripheral blood leucocytes under the influence of commonly used antimalarial drugs was studied. The following drugs were used: chloroquine diphosphate, quinine HCl, mefloquine HCl, proguanil HCl, cycloguanil, pyrimethamine and tetracycline HCl. It was found that leucocytes treated with mefloquine, proguanil and cycloguanil at concentrations higher than 0.5 mg/litre showed reduced phagocytic activity against Staphylococcus aureus. None of the other drugs tested had any inhibitory effect on phagocytosis. The bactericidal ability of the leucocytes was not affected by any of the drugs. It is concluded that none of the commonly used antimalarial drugs, at concentrations obtainable in malaria prophylaxis and therapy, have any undesirable effect on the bactericidal activity of human leucocytes.

Antimalarials↗
PubMed1987

Potentiation of the antimalarial activity of qinghaosu by methoxylated flavones.

Interaction between the flavones casticin and artemetin and the antimalarial activity of chloroquine and qinghaosu (QHS) was examined using an in vitro growth assay based on [3H]hypoxanthine incorporation in synchronized cultures of a cloned line of Plasmodium falciparum. Casticin, and to a lesser extent artemetin, selectively enhanced the inhibition of growth by QHS, but had little effect on the activity of chloroquine. The findings suggest that flavones indigenous to Artemisia annua, from which QHS is isolated, might significantly alter the clinical potential of this novel antimalarial drug in the treatment of chloroquine-resistant malaria.

Animals↗
PubMed1987

The effect of combinations of qinghaosu (artemisinin) with standard antimalarial drugs in the suppressive treatment of malaria in mice.

Artemisinin is a novel antimalarial drug isolated in China from the wormwood plant Artemisia annua L. Studies with rodent malaria were carried out to detect antagonism and synergism with a variety of antimalarial drugs. Isobolograms of drug interaction were plotted at the ED90 level. With a normally susceptible strain of Plasmodium berghei, marked potentiative synergism was found with mefloquine, tetracycline and spiramycin. There was some synergism also with primaquine. Combinations of artemisinin with dapsone, sulfadiazine, sulfadoxine, pyrimethamine, pyrimethamine/sulfadoxine and cycloguanil showed antagonism. A high degree of potentiation was shown between artemisinin and primaquine with a primaquine-resistant strain, whilst the combination with mefloquine showed enhanced potentiation with a mefloquine-resistant strain. Combinations of artemisinin with mefloquine, primaquine, tetracycline or clindamycin showed marked potentiation with an artemisinin-resistant strain. The mechanisms underlying the drug interactions observed are discussed.

Animals↗