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At least 1,009 records · Page 56Linked to original sources
PubMed1996

Determination of a new antimalarial drug, benflumetol, in blood plasma by high-performance liquid chromatography.

A rapid and selective high-performance liquid chromatographic assay for determination of a new antimalarial drug (benflumetol, BFL) is described. After extraction with hexane-diethyl ether (70:30, v/v) from plasma, BFL was analysed using a C18 Partisil 10 ODS-3 reversed-phase stainless steel column and a mobile phase of acetonitrile-0.1 M ammonium acetate (90:10, v/v) adjusted to pH 4.9 with ultraviolet detection at 335 nm. The mean recovery of BFL over a concentration range of 50-400 ng/ml was 96.8 +/- 5.2%. The within-day and day-to-day coefficients of variation were 1.8-4.0 and 1.8-4.2%, respectively. The minimum detectable concentration in plasma for BFL was 5 ng/ml with a C.V. of less than 10%. This method was found to be suitable for clinical pharmacokinetic studies.

Adult↗
PubMed1986

Screening Azadirachta indica and Pisum sativum for possible antimalarial activities.

Solvent-free extracts obtained from the leaves of Azadirachta indica and Pisum sativum were screened for antimalarial action using Plasmodium berghei in mice. Four days of oral dosing with 500 mg/kg and 125 mg/kg of the methanol extract of A. indica showed a parasite suppression which was statistically significant although all test animals died after 5 days, just 1 day longer than the untreated control group. A 50 mg/kg oral dose of the aqueous extract of P. sativum was found to have significant prophylactic activity by producing a parasite suppression of 31.9%.

Animals↗
PubMed1989

Antimalarial effects of eight African medicinal plants.

Crude hot water extracts from eight medicinal plants collected in Togo, West Africa, were examined for antimalarial properties against Plasmodium falciparum using an in vitro test. The activity differed with the plant species with extracts of Cassia siamea, Jatropha gossypiifolia and Pavetta crassipes capable of 100% inhibition.

Animals↗
PubMed1990

Preliminary evaluation of extracts of Alstonia scholaris bark for in vivo antimalarial activity in mice.

The petroleum either extract and methanol extract of the bark of Alstonia scholaris were found to be devoid of antiamalarial activity in mice infected with Plasmodium berghei. However, a dose-dependent improvement of conditions and delayed mortality amongst animals receiving methanol extract of A. scholaris was noticed. Studies with A. constricta and alstonine shall help resolve the antimalarial status of the bark in question.

Animals↗
PubMedDate not supplied

Antimalarial activity of some plant remedies in use in Marracuene, southern Mozambique.

Two plants, Spirostachys africana and Bridelia cathartica, were selected for investigation on the basis of a clinical study of four herbal antimalarial remedies used in southern Mozambique. Petroleum ether, ethanol and aqueous extracts were tested for activity in vitro against Plasmodium falciparum. Crude ethanolic and aqueous extracts of the root and the ethanolic extract of the stem of B. cathartica caused a 50% inhibition of parasite growth at an incubation concentration of 0.05 microgram/ml.

Animals↗
PubMed1985

Drug induced alterations in some rat hepatic microsomal components: a comparative study of four structurally different antimalarials.

Alterations in microsomal drug metabolizing enzymes, microsomal lipids and some serum enzymes following pre-treatment of rats with therapeutic doses of four structurally different antimalarial compounds, chloroquine (CQ), quinine (Q), quinacrine (QK) and primaquine (PQ) have been investigated. CQ and Q significantly decreased the activities of aminopyrene N-demethylase, aniline hydroxylase and both microsomal and cytosolic glutathione S-transferases. Only aniline hydroxylase was markedly decreased by QK, while PQ did not have much effect on any of these enzymes. CQ, Q and QK significantly increased the cholesterol:phospholipid ratio while all four compounds decreased the phosphatidyl choline:sphingomyelin (PC/S) ratio. All the drugs increased the activities of the serum enzymes glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase and alkaline phosphatase. The possible relationships of these results to structural variations in the four drugs being investigated has been discussed.

Aminopyrine N-Demethylase↗
PubMed1989

Effects of some antimalarial drugs on rat inflammatory polymorphonuclear leukocyte function.

In vitro concentrations of chloroquine, amodiaquine, quinine, and mefloquine were assessed with respect to functional responses (chemotaxis, anion superoxide generation, and lysosomal enzyme release) of rat polymorphonuclear leukocytes (PMN) collected after induction of acute pleural inflammation. Chloroquine, amodiaquine, and mefloquine exhibited dose-dependent inhibition of: (1) random migration and oriented migration of PMN; and (2) opsonized zymosan- or phorbol myristate acetate-stimulated PMN O2- release. These effects were not stimulus-specific and were largely reversed by washing the cells before stimulation Mefloquine was the most effective drug. Quinine had no effect on PMN migration. Apart from quinine, the drugs induced similar dose-dependent increases in beta-glucuronidase release from unstimulated PMN. Only quinine inhibited the enzyme release from stimulated PMN. Our data show that the antimalarial derivatives affect PMN functions in various ways and suggest that their effects reflect nonspecific modifications of cellular membrane.

Animals↗
PubMed2005

Contribution of the pfmdr1 gene to antimalarial drug-resistance.

The emergence of drug-resistance poses a major obstacle to the control of malaria. A homolog of the major multidrug-transporter in mammalian cells was identified, Plasmodium falciparum multidrug resistance protein-1, pfmdr1, also known as the P-glycoprotein homolog 1, Pgh-1. Several studies have demonstrated strong, although incomplete, associations between resistance to the widely used antimalarial drug chloroquine and mutation of the pfmdr1 gene in both laboratory and field isolates. Genetic studies have confirmed a link between mutation of the pfmdr1 gene and chloroquine-resistance. Although not essential for chloroquine-resistance, pfmdr1 plays a role in modulating levels of resistance. At the same time it appears to be a significant component in resistance to the structurally related drug quinine. A strong association has been observed between possession of the wildtype form of pfmdr1, amplification of pfmdr1 and resistance to hydrophobic drugs such as the arylaminoalcohol mefloquine and the endoperoxide artemisinin derivatives in field isolates. This is supported by genetic studies. The arylaminoalcohol and endoperoxide drugs are structurally unrelated drugs and this resistance resembles true multidrug resistance. Polymorphism in pfmdr1 and gene amplification has been observed throughout the world and their usefulness in predicting resistance levels is influenced by the history of drug selection of each population.

ATP-Binding Cassette Transporters↗
PubMed2005

In vitro antimalarial activity of flavonoid derivatives dehydrosilybin and 8-(1;1)-DMA-kaempferide.

Multidrug-resistant Plasmodium falciparum strains are an increasing problem in endemic areas and are partly responsible for the worsening malaria situation around the world. New cheap and effective compounds active in combination with available drug in the field are urgently needed. The aim of this work was to explore the potential antiplasmodial effect of flavonoid derivatives on parasites growth in vitro. In vitro antiplasmodial activity of dehydrosilybin and 8-(1;1)-DMA-kaempferide has been evaluated by real time PCR for five P. falciparum strains. Both revealed significative antimalarial activity against the different strains. Since this drug family has been largely used and well-tolerated in humans, flavonoid derivatives could be in the near future associated with already available drugs in order to delay the spread of P. falciparum resistance.

Animals↗
PubMed2006

Activity of azithromycin or erythromycin in combination with antimalarial drugs against multidrug-resistant Plasmodium falciparum in vitro.

Azithromycin, an azalide analog of erythromycin was assayed for its in vitro activity against multidrug-resistant Plasmodium falciparum K1 strain by measuring the 3H-hypoxanthine incorporation. Azithromycin caused inhibitory effects on the parasite growth with IC50 and IC90 values of 8.4+/-1.2 microM and 26.0+/-0.9 microM, respectively. Erythromycin inhibited growth of P. falciparum with IC50 and IC90 values of 58.2+/-7.7 microM and 104.0+/-10.8 microM, respectively. The activity of antimalarial drugs in combination with azithromycin or erythromycin against P. falciparum K1 were compared. Combinations of chloroquine with azithromycin or erythromycin showed synergistic effects against parasite growth in vitro. Combinations of quinine-azithromycin and quinine-erythromycin showed potentiation. Additive effects were observed in mefloquine-azithromycin and mefloquine-erythromycin combinations. Similar results were also produced by pyronaridine in combination with azithromycin or erythromycin. However, artesunate-azithromycin and artesunate-erythromycin combinations had antagonistic effects. The in vitro data suggest that azithromycin and erythromycin will have clinical utility in combination with chloroquine and quinine. The worldwide spread of chloroquine-resistant P. falciparum might inhibit the ability to treat malaria patients with chloroquine-azithromycin and chloroquine-erythromycin in areas of drug-resistant. The best drug combinations against multidrug-resistant P. falciparum are quinine-azithromycin and quinine-erythromycin.

Animals↗
PubMed2006

Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin.

We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC(50)) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78+/-21 microM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 microM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin.

Antimalarials↗
PubMed2006

Antimalarial properties of green tea.

We show here that a crude extract of green tea as well as two of its main constituents, epigallocatechin-3-gallate (EGCG) and epicatechin gallate (ECG), strongly inhibit Plasmodium falciparum growth in vitro. Both these catechins are found to potentiate the antimalarial effects of artemisinin without interfering with the folate pathway. The importance of these findings and their mechanistic implications are discussed in view of future therapeutic strategies.

Animals↗
PubMed2003

Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery.

During intraerythrocytic infection, Plasmodium falciparum parasites crystallize toxic heme released during hemoglobin catabolism. The proposed mechanism of quinoline inhibition of crystal growth is either by a surface binding or a substrate sequestration mechanism. The kinetics of heme crystal growth was examined in this work using a new high-throughput crystal growth determination assay based on the differential solubility of free vs. crystalline FP in basic solutions. Chloroquine (IC(50)=4.3 microM) and quinidine (IC(50)=1.5 microM) showed a previously not recognized reversible inhibition of FP crystal growth. This inhibition decreased by increasing amounts of heme crystal seed, but not by greater amounts of FP substrate. Crystal growth decreases as pH rises from 4.0 to 6.0, except for a partial local maxima reversal from pH 5.0 to 5.5 that coincides with increased FP solubility. The new crystal growth determination assay enabled a partial screen of existing clinical drugs. Nitrogen heterocycle cytochrome P450 inhibitors also reversibly blocked FP crystal growth, including the azole antifungal drugs clotrimazole (IC(50)=12.9 microM), econazole (IC(50)=19.7 microM), ketoconazole (IC(50)=6.5 microM), and miconazole (IC(50)=21.4 microM). Fluconazole did not inhibit. Both subcellular fractionation of parasites treated with subinhibitory concentrations of ketoconazole and in vitro hemozoin growth assays demonstrated copurification of hemozoin and ketoconazole. The chemical diversity of existing CYP inhibitor libraries that bind FP presents new opportunities for the discovery of antimalarial drugs that block FP crystal growth by a surface binding mechanism and possibly interfere with other FP-sensitive Plasmodium pathways.

Animals↗
PubMed2003

8-quinolinamines and their pro prodrug conjugates as potent blood-schizontocidal antimalarial agents.

Synthesis and antimalarial activities of N8-(4-amino-1-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamines (5) and their pro prodrug analogues (6-7) prepared by covalently linking 5 to the redox-sensitive (8) and esterase-sensitive (9) linkers through the amide linkage are reported. The most effective 8-quinolinamines [5c (R=C5H11) and 5f (R=C8H17)] have exhibited in vitro and in vivo biological efficacy superior to that of the standard drug chloroquine against both drug-sensitive and drug-resistant malaria strains. Analogues 6-7 were evaluated for in vivo blood-schizontocidal activity as potential pro prodrug models for the primary amino group containing 8-quinolinamines (5). The most effective pro prodrug analogue (6c) has displayed promising activities against drug-sensitive and drug-resistant strains of Plasmodia in vivo.

Amides↗
PubMed2004

Quantitative structure-activity relationship in aziridinyl-1,4-naphthoquinone antimalarials: study of theoretical correlations by the PM3 method.

Several molecular parameters for 2,3,5-substituted 1,4-naphthoquinones including 2-aziridinyl and 2,3-aziridinyl-1,4-naphthoquinones with antimalarial activities were obtained with the semi-empirical PM3 method. The descriptor related to the Gibbs free energy of an isodesmic equation defining the reduction of the naphthoquinones was found to have high correlation with activity. The quantitative models reported clearly show a dependence of activity on the redox potential for reduction of the naphthoquinones. Compounds with lower values of DeltaG for reduction are more active than those with higher values of DeltaG.

Antimalarials↗
PubMed2004

Synthesis and antimalarial activity of a new series of trioxaquines.

Trioxanes 8a-b, easily accessible in two steps from allylic alcohol 6a-b, on reductive amination with 4-aminoquinolines 4a-c furnish a new series of trioxaquines 9a-b, 10a-b, 11a-b in 32-77% yields. Dicitrate salts of these trioxaquines have been evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii in mice model.

Aminoquinolines↗
PubMed2005

Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives.

The reported synthetic procedure of WR182393, a 2-guanidinoimidazolidinedione derivative with high prophylactic antimalarial activity, was found to be a mixture of three closely related products. Poor solubility of WR182393 in both water and organic solvents and its impractical synthetic method have made the purification and structure identification of the reaction mixture a highly challenging task. The problems were circumvented by prodrug approach involving carbamate formation of the mixture, which enhances the solubility of the mixture in common organic solvents and facilitates the separation and structure determination of the two products. The structures of the two components were determined by X-ray crystallography and NMR of their corresponding carbamates 3a and 4a. Additional alkyl carbamates were prepared according to the same approach and two new carbamates 3b and 4d were found to possess higher intramuscular (im) efficacy than the parent compound WR182393 against Plasmodium cynomolgi in Rhesus monkey.

Animals↗