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PubMed1995

Composition and antimalarial activity in vitro of volatile components of Lippia multiflora.

The essential oil of Lippia multiflora was prepared by hydrodistillation of leaves and stalks and characterized by GC and mass spectroscopy. The oil was tested for antimalarial activity on in vitro cultures of Plasmodium falciparum (FcB1-Columbia chloroquine-resistant strain and F32-Tanzania chloroquine-sensitive strain). The dilutions inhibiting the in vitro growth of the parasite by 50% 24 and 72 hr after administration of the essential oil to the parasite culture were 1/12,000 and 1/21,000, respectively. When tested on a highly synchronized culture, the essential oil inhibited growth mostly at the trophozoite-schizont step, indicating a potential effect on the first nuclear division of the parasite.

Animals↗
PubMed1987

The antimalarial action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress.

The antimalarial activity of qinghaosu (artemisinine) against Plasmodium falciparum in culture was enhanced by increased oxygen tension. Artesunate, a qinghaosu derivative, showed synergistic effects with miconazole, and with doxorubicin, both of which have been suggested to exert their chemotherapeutic effect through increasing the oxidant stress. In contrast, catalase, dithiothreitol and alpha-tocopherol reduced the effectiveness of qinghaosu in vitro. These results suggest that the action of qinghaosu and artesunate might involve increase in oxidant stress on the infected red cells.

Animals↗
PubMed1987

Activity of quinoline-containing antimalarials against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro.

9 quinoline-containing antimalarials and the phenanthrene methanol halofantrine were tested in vitro against 6 strains of Plasmodium falciparum with known sensitivity to chloroquine. Sensitivity to chloroquine was not uniformly associated with sensitivity to mepacrine (quinacrine), halofantrine, SN-12108 or SN-6911 (3-methylchloroquine, sontochin). Amodiaquine was slightly less potent with chloroquine-resistant strains, whereas SN-12309 closely resembled chloroquine in the pattern of sensitivity. (Bis)desethylchloroquine was nearly as potent as chloroquine against chloroquine-sensitive strains but was about 10-fold less potent than the parent drug against chloroquine-resistant strains. 2 8-aminoquinolines, primaquine and pamaquine, were more potent against chloroquine-resistant than chloroquine-sensitive strains. The mutation(s) responsible for chloroquine resistance in P. falciparum greatly reduce(s) the sensitivity to a major metabolite of the drug but also generate(s) parasites which are more susceptible to a different class of drugs, the 8-aminoquinolines.

Animals↗
PubMedDate not supplied

Studies on a new antimalarial compound: pyronaridine.

Pyronaridine, a hydroxyanilino-benzonaphthyridine derivative synthesized in 1970, is a new antimalarial compound which has been in use in China for more than 10 years. The drug is highly effective against Plasmodium falciparum and P. vivax. Furthermore, it is efficacious in combatting chloroquine-resistant strains of falciparum malaria both in vitro and in vivo, in human patients. Extensive field studies involving several thousand cases have shown that pyronaridine has promising therapeutic value in the treatment of malarial infection, including chloroquine-resistant infections. Pyronaridine given orally, intramuscularly or by intravenous drip is not only effective against malaria but also has low toxicity.

Animals↗
PubMedDate not supplied

In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections.

The interactions of amantadine with classical antimalarial drugs were evaluated against a chloriquine-resistant and a chloroquine-sensitive strain of Plasmodium falciparum in vitro. Amantadine potentiated the effect of chloroquine and quinine in both strains; it also potentiated the effect of mefloquine, halofantrine and primaquine in the chloroquine-resistant strain but had no effect in the chloroquine-sensitive strain. Amantadine had no effect on the response to pyrimethamine of either strain. Amantadine does not interfere with the activity of these compounds and may possibly enhance it.

Amantadine↗
PubMed1996

The iron environment in heme and heme-antimalarial complexes of pharmacological interest.

Mössbauer spectroscopy has been utilized to probe the electronic environment of iron in a number of Ferriprotoporphyrin IX complexes of relevance to malaria. The markedly different iron environments found for the complexes of hemin with quinine, chloroquine, and the Chinese herbal antimalarial artesunate suggest that these compounds act by protecting the heme from polymerization to insoluble hemozoin, and by facilitating the transport of the protected heme to the food vacuole membrane where it is able to exercise its cytotoxic redox catalytic activity. Mössbauer parameters determined here for purified malaria pigment and synthetic beta-hematin confirm the chemical identical-ness of these species. The Mössbauer spectra of the complexes are discussed in light of the proposed structures of the complexes.

Animals↗
PubMed1990

The prevention of antimalarial drug resistance.

The deployment of antiprotozoal drugs on a large scale for prophylaxis or monotherapy inevitably results in the selection of drug-resistance. The use of appropriately selected drug combinations may impede this process. Point mutations underlie resistance to dihydrofolate reductase inhibitors such as pyrimethamine. Potentiating combinations of such compounds with sulfonamides or sulfones have effectively delayed resistance to them. The use of triple combinations may be of value in protecting such compounds as chloroquine and mefloquine, resistance to which is associated in some cases with gene amplification. It is essential to seek partner compounds for any new antimalarials, e.g. artemisinin. Past experience with existing compounds is discussed and the need to make use of all available means of interrupting malaria transmission is stressed, rather than depending entirely on drugs.

Animals↗
PubMed1979

Mutagenicity evaluation of the two antimalarial agents chloroquine and mefloquine, using a bacterial fluctuation test.

The two antimalarial agents chloroquine and mefloquine have been tested for mutagenicity in Salmonella typhimurium strains TA1535, TA1537 and TA1538. Chloroquine was found to revert strain TA1537 at concentrations of 100 and 250 micrograms/ml, most likely due to intercalation. No mutagenicity was found with mefloquine at concentrations up to 2.5 micrograms/ml, neither without nor with metabolic activation by Ca2+-precipitated rat liver microsomes. Higher concentrations of mefloquine and chloroquine inactivated the bacteria.

Antimalarials↗
PubMed1989

A nuclear magnetic resonance study of the interactions of the antimalarials chloroquine, quinacrine, quinine and mefloquine with dipalmitoylphosphatidylcholine bilayers.

The interaction of four cationic amphiphilic antimalarials (chloroquine, quinacrine, mefloquine and quinine) with model dipalmitoylphosphatidylcholine (DPPC) bilayer membranes was studied using 2H- and 31P-nuclear magnetic resonance (NMR). The results showed no significant perturbation of lipid bilayer structure by the presence of chloroquine up to a molar ratio of 1:2 of drug to lipid. Addition of quinacrine to DPPC at the same molar ratio resulted in a 2.5 degrees C decrease in the gel to liquid crystalline phase transition temperature (Tc) of the lipids, with only a small perturbation of the order parameters of the lipid side chains. 31P-NMR spectra of quinacrine-DPPC mixtures indicated a quinacrine-induced change of head group conformation of DPPC above the Tc. These findings are consistent with quinacrine interacting only with the surface of DPPC bilayers. In contrast, both mefloquine and quinine exhibited stronger interactions with DPPC, decreasing the Tc of the lipids by 10 degrees C and 9 degrees C, respectively, and causing significant disordering of the lipid side chains. The basic bilayer structure of DPPC was, however, maintained, even at the highest molar ratio 1:2 of drug to lipid. Such behavior is consistent with penetration of both mefloquine and quinine into the interior of the bilayers. This ability of mefloquine and quinine, but not chloroquine and quinacrine, to intercalate into lipid bilayers correlates with their lower pKa values, which ensures that at physiological pH significant amounts of mefloquine or quinine remain in their uncharged lipophilic form.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

A nuclear magnetic resonance study of the interactions of the antimalarials chloroquine, quinacrine, quinine and mefloquine with lipids extracted from normal human erythrocytes.

The interaction of four antimalarials (chloroquine, quinacrine, mefloquine and quinine) with lipid membranes re-formed from lipid extracts of normal human erythrocytes was studied using 2H- and lipid extracts of normal human erythrocytes was studied using 2H- and 31P-nuclear magnetic resonance (NMR). Inclusion of small amounts of chain-perdeuterated dipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylethanolamine (DPPE) as an 2H-NMR probe allowed us to study separately the effects of drugs on PC or PE components of the membranes. Only a very small decrease in the order parameters of the DPPE, but not the DPPC probe, was observed in the presence of chloroquine at a molar ratio of 1:5 of drug to lipid. Addition of quinacrine at the same molar ratio resulted in a small but significant decrease in the order parameters of the lipid side chains; identical effects were obtained with DPPC or DPPE perdeuterated probes. The presence of quinacrine did not induce non-bilayer lipid phases. In contrast, mefloquine and quinine produced a significant disordering of the lipid side chains; the effect was considerably larger with the DPPE probe. In addition, both mefloquine and quinine induced non-bilayer phases of the lipids; mefloquine induced formation of hexagonal and micellar lipid conformation, whereas addition of quinine resulted in the formation of lipid micelles only. The lipid polymorphism induced by either of these drugs was more pronounced when the DPPE component was observed, indicating that the non-bilayer phases were enriched in PE. The results suggest the presence of strong interactions between mefloquine and quinine with lipid bilayers, especially with the PE component.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action.

Artemisinin (qinghaosu), is a promising new antimalarial drug derived from an ancient Chinese herbal remedy. When [13-14C]artemisinin is added to cultures of Plasmodium falciparum, it is converted into a product with different solubility and chromatographic properties than the parent drug. Artemisinin reacts with hemin in aqueous solution to form an adduct with an apparent molecular weight of 914 which has identical chromatographic, solubility, and electrophoretic behavior to the parasite-derived product. The reaction between artemisinin and hemin, when carried out in the presence of red cell membranes, leads to the oxidation of protein thiols. Malarial parasites are rich in hemin; artemisinin's reactivity toward hemin may explain its selective toxicity to malarial parasites.

Animals↗
PubMed1996

Amodiaquine accumulation in Plasmodium falciparum as a possible explanation for its superior antimalarial activity over chloroquine.

Amodiaquine is a 4-aminoquinoline antimalarial whose structure is similar to chloroquine. In contrast to the wealth of information available about chloroquine accumulation and its relationship to activity, little is known about the uptake characteristics of amodiaquine, a drug that is inherently more active against malaria parasites. In this study we have investigated the accumulation of amodiaquine in Plasmodium falciparum in vitro, in order to gain an insight into the mechanisms responsible for its superior activity over chloroquine. The driving force for parasite accumulation of the 4-aminoquinolines is proposed to be a transmembrane proton gradient maintained by a vacuolar ATPase. In the present study, amodiaquine accumulation was greatly reduced, at steady state, in the absence of glucose and at 0 degrees C indicating a clear energy dependence of uptake. Amodiaquine accumulation in Plasmodium falciparum was shown to be 2- to 3-fold greater than chloroquine accumulation. This observation probably accounts for amodiaquine's greater inherent activity but is surprising given that amodiaquine is a weaker base than chloroquine. With this in mind we present evidence for an intraparasitic binding component in the accumulation of the 4-aminoquinolines. Differences in binding affinity of this 'receptor' for amodiaquine and chloroquine may partially explain the greater accumulation and in vitro potency of amodiaquine compared to chloroquine.

Adenosine Triphosphate↗
PubMed1984

On the mechanism for the red-cell accumulation of mefloquine, an antimalarial drug.

The accumulation of the antimalarial drug mefloquine by human red blood cells has been studied by 19F-NMR spectroscopy. The uptake process was nonlinearly dependent on the external drug concentration. Concentrations inside cells as high as 60-times greater than those in the extracellular phosphate-buffered-saline were observed. Red-cell ghosts were also found to accumulate mefloquine with high-affinity binding sites for the drug. Hemoglobin was found to bind mefloquine with low affinity, but due to the high concentration of this protein it is a significant drug compartment in the red cell. Analysis of the 19F-NMR chemical shifts and linewidths of mefloquine in the presence of red cells, red-cells ghosts and hemoglobin indicates restricted mobility of the drug in the membrane-bound state and slow exchange with the extracellular medium. This is a significant characteristic of the reaction in connection with the prophylactic activity of the drug. Exchange of the drug between hemoglobin and the red-cell membrane, however, is fast and may play an important role in the bioavailability of the drug to the parasite.

Antimalarials↗
PubMed1996

The antimalarials quinacrine and chloroquine induce weak lysosomal storage of sulphated glycosaminoglycans in cell culture and in vivo.

The antimalarial agents quinacrine and chloroquine are well known as potent inducers of lysosomal storage of polar lipids (lipidosis) in cell culture and in vivo. In previous experiments on cultured fibroblasts, chloroquine was shown to additionally cause weak lysosomal storage of sulphated glycosaminoglycans (GAGs) thus inducing mucopolysaccharidosis (MPS). In the present study, quinacrine was investigated for this ability, because we wished to know whether or not the acridine ring system in quinacrine would enhance the MPS-inducing potency as compared to chloroquine carrying an isoquinoline ring system. Tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one) known as a potent inducer of MPS served as reference compound. The compounds were compared at a concentration (3 microM) which did not enhance the secretion of the lysosomal enzyme beta-hexosaminidase (E.C. 3.2.1.52), since this would be an indication of unspecific drug effects upon the endosomal/lysosomal compartments of the cell. Additionally the liver of quinacrine- and chloroquine-treated rats was examined with the question whether the lysosomal GAG storage induced by either drug in cell culture had an equivalent in intact organisms. Both, in cell culture and in vivo, quinacrine was found to be a more potent inducer of lysosomal GAG storage than was chloroquine. The results suggest that the acridine ring system favours this drug side effect as compared with the bicyclic isoquinoline ring system. On the other hand, quinacrine was significantly less potent than tilorone and the Symmetrically substituted acridine derivative 3,6-bis[2-(diethylamino)ethoxy]acridine investigated previously. This suggests that the asymmetric structure of the quinacrine molecule reduces the potency as compared to the symmetrically substituted bisbasic compounds with planary tricyclic ring systems such as tilorone and congeners.

Animals↗
PubMed1996

The mode of action of the antimalarial artemisinin and its derivatives.

1. Atremisinin (qinghaosu) is a sesquiterpene endoperoxide derived from a plant which was used in Chinese herbal medicine for thousands of years. 2. Artemisinin and its derivatives have potent antimalarial activity, and are now being used clinically in much of the world. 3. The artemisinin derivatives have an unusual mode of action involving the iron-catalyzed generation of a carbon-centered free radical followed by the alkylation of malaria-specific proteins.

Animals↗
PubMed1985

The side effects of antimalarial drugs indicates a polyamine involvement in both schizophrenia and depression.

The nature of the side effects produced by the antimalarials and a common moiety present in these drugs (spermidine) links the polyamines to both schizophrenia and depression. The raised incidence of psychosis in systemic lupus erythematosus and during pregnancy both associated with raised blood polyamine levels, makes the involvement of the polyamines in psychosis more likely.

Antimalarials↗
PubMed1992

High-performance liquid chromatographic determination of dihydroorotate dehydrogenase of Plasmodium falciparum and effects of antimalarials on enzyme activity.

A reversed-phase high-performance liquid chromatographic technique for the determination of dihydroorotate dehydrogenase in Plasmodium falciparum was developed. The assay was applied to the evaluation of the effects of several antimalarial drugs on the enzyme. Treatment of both the asexual and gametocyte stages of P. falciparum in culture with menoctone, primaquine or the primaquine derivative WR 238605 led to depression of the enzyme activity, although the drugs did not appear to inhibit the enzyme directly.

Aminoquinolines↗
PubMed1993

Simultaneous determination of a new antimalarial agent, CDRI compound 80/53, and its metabolite primaquine in serum by high-performance liquid chromatography.

Compound 80/53 (I) is a new substance being developed as an antimalarial agent. It is unstable in acidic conditions where it is converted into primaquine. A high-performance liquid chromatographic assay for simultaneous determination in serum of I and primaquine has been developed. Conditions were optimized to minimize the conversion of I into primaquine. The method includes extraction of the unchanged compound and primaquine from serum samples with hexane-2-propanol (pH > 8). Separation was accomplished by reversed-phase chromatography on a C18 column with acetonitrile-tetrahydrofuran-phosphate buffer. The recoveries of I and primaquine were always greater than 70%. No interference was observed in extracts obtained from drug-free serum. The detector response was linear with concentrations of I and the metabolite in the ranges 25-400 and 10-180 ng/ml, respectively, and the within-day precision (coefficient of variation) remained less than 13.7% for I and 12.5% for primaquine. The method is suitable for the determination of concentration-time profiles of I and primaquine in human serum.

Antimalarials↗