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PubMed1984

Combination of the antibiotics erythromycin and tetracycline with three standard antimalarials against Plasmodium falciparum in vitro.

Combinations of antibiotics and standard antimalarials have been assayed against P. falciparum in vitro, using incorporation of 14C isoleucine as an indicator of drug action. Chloroquine and erythromycin have been shown to act synergistically against a chloroquine-resistant strain and additively towards a chloroquine-sensitive strain, confirming their action against sensitive and resistant P. berghei in vivo, described elsewhere. Combinations of erythromycin with mefloquine or quinine acted anergically in 24 hour assays in which unphysiologically high concentrations of quinolinemethanol were necessary for demonstrable drug effect. In 48 hour assays, an additive effect was obtained with these combinations. Tetracycline is additive in combination with each of the standard antimalarials used in this study. The relevance of results obtained in vitro to parasite drug sensitivities in vivo is discussed.

Animals↗
PubMed1986

Affinity of antimalarial drugs for stacked haematin linked on sepharose.

The affinity to haematin of antimalarial drugs and of some closely related compounds has been measured by the use of a polymeric haematin linked to an agarose gel. Haematin-drug interaction shows a low specificity and does not exhibit the sharp structure-activity relationship observed in the biological activities of the compounds. It is suggested that a chloroquine-haematin interaction does not explain the biological properties of this antimalarial, although it constitutes a necessary step in the concentration of the drug in the parasitized erythrocyte.

Antimalarials↗
PubMed1991

The mode of action of chloroquine. Non-weak base properties of 4-aminoquinolines and antimalarial effects on strains of Plasmodium.

The mode of action of chloroquine was investigated by studying the properties of its 7-H derivatives, which retain the weak base properties of the quinolines but exhibit low antimalarial activity. Using a specific probe [4-(1-amino-butylamino)quinoline] it has been shown that weak base properties are sufficient to induce concentration of the drug in the parasite's food vacuole. However, the chloroquine uptake we measured for the 7-H derivatives revealed a significantly low concentration of drug within the parasitized red blood cell--about 1/20 of that of chloroquine. Thus, the substitution of the chlorine atom of chloroquine by a proton produces a compound which can always be targeted to the parasite's food vacuole, but which is less easily taken up by the parasite than is chloroquine. Antimalarial activities of 4-aminoquinoline drugs seem to be due not only to their weak base properties but also to other characters of these molecules. The mechanism of uptake of chloroquine by the parasites is apparently linked to structural characters of the quinoline ring, such as the presence of the chlorine atom. The importance of the lysosomotropic properties of chloroquine has to be reconsidered in the light of this new information.

Aminoquinolines↗
PubMed2000

Comparative clinical characteristics and response to oral antimalarial therapy of children with and without Plasmodium falciparum hyperparasitaemia in an endemic area.

The clinical characteristics and the responses to oral antimalarial therapy of 104 children presenting consecutively with or without Plasmodium falciparum hyperparasitaemia (HP) were investigated in an endemic area. At presentation, although the 52 children with HP were significantly younger and had significantly higher heart rates than the 52 without, there were no significant differences between the two groups in their symptoms or in any other clinical feature of their malaria. Responses to oral antimalarial drugs were similar in both groups. Analysis of the disposition kinetics of parasitaemia, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t1/2pd), volumes of blood completely cleared of parasites per unit time (CLBpd), and parasite-clearance-time:t1/2pd ratios. Three children in the HP group, all aged < 3 years, progressed to cerebral malaria within 8 h of presentation, and another HP child presented with isolated trunkal ataxia, indicative of cerebellar involvement. No child in the non-HP group had any of the features of severe malaria. Although the clinical characteristics and responses to oral therapy of children with and without HP are therefore very similar, young children with HP appear to have an increased risk of developing other features of severe malaria.

Adolescent↗
PubMed1997

Haematin (haem) polymerization and its inhibition by quinoline antimalarials.

Haematin (ferriprotoporphyrin IX) is released from haemoglobin during its degradation in the malarial parasites' food vacuole and is detoxified by its polymerization into a form of beta-haematin called haemozoin, or malarial pigment. This process is protein independent in vitro. Quinoline antimalarial blood schizonticides accumulate in the food vacuole and may inhibit haematin polymerization by binding to haematin and preventing its incorporation into the growing haemozoin chain. Drug resistance to quinolines is thought to be due to reduced accumulation of the drug in the food vacuole. As some quinolines overcome this resistance, quinolines, as a class, remain a potential source of future antimalarial drugs.

Animals↗
PubMed1998

Why is it that antimalarial drug treatments do not always work?

The objective of antimalarial drug treatment in severe malaria is to save the patient's life. In uncomplicated malaria it is to reduce the parasite biomass to zero, or down to a level where host defences can deal with the remainder. Treatment regimens with rapidly eliminated drugs must generally cover four asexual life-cycles (i.e. > 6 days for Plasmodium falciparum and P. vivax) to eradicate all the parasites in the blood. For slowly eliminated drugs, blood concentrations must exceed the parasites' minimum inhibitory concentration (and preferably the minimum parasiticidal concentration) until all parasites have been eradicated. Resistance means that there is a right shift in the concentration-effect relationship. This may be large and abrupt, as with the point mutations that confer pyrimethamine, sulphonamide or atovaquone resistance, or slow and gradual, as with the processes that determine resistance to chloroquine, quinine or mefloquine. Although treatment failure in malaria usually results from poor compliance, inadequate dosing, pharmacokinetic factors or resistance, some infections will recrudesce when none of these factors operates. How parasites persist despite apparently adequate antimalarial treatment remains unresolved.

Animals↗
PubMed2004

Progress in the research of artemisinin and its analogues as antimalarials: an update.

Malaria is the number one infectious disease in the world today. Worldwide, over two million people die each year from malaria. This shocking reality is largely due to the emergence of drug resistant strains of Plasmodium falciparum. Artemisinin, a sesquiterpene lactone endoperoxide isolated from Artemesia annua has been shown to be a fast acting, safe and effective drug against multidrug-resistant and sensitive strains of P. falciparum. This article reports a survey of the literature dealing with artemisinin related antimalarial issues that have appeared from 1980s to the beginning of 2003. A broad range of medical and pharmaceutical disciplines is covered, including a brief introduction about discovery, phytochemical aspects, antimalarial mechanism of action, pharmacokinetics, and major drawbacks and various structural modifications made to overcome them.

Animals↗
PubMed2001

Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum.

The emergence and spread of multidrug-resistant Plasmodium falciparum compromises the treatment of malaria, especially during pregnancy, where the choice of antimalarials is already limited. Artesunate (n=528) or artemether (n=11) was used to treat 539 episodes of acute P. falciparum malaria in 461 pregnant women, including 44 first-trimester episodes. Most patients (310 [57.5%]) received re-treatments after earlier treatment with quinine or mefloquine. By use of survival analysis, the cumulative artemisinin failure rate for primary infections was 6.6% (95% confidence interval, 1.0-12.3), compared with the re-treatment failure rate of 21.7% (95% confidence interval, 15.4-28.0; P=.004). The artemisinins were well tolerated with no evidence of adverse effects. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality, and mean gestation at delivery. These results are reassuring, but further information about the safety of these valuable antimalarials in pregnancy is needed.

Animals↗
PubMed2003

Chloroquine versus sulfadoxine-pyrimethamine for treatment of Plasmodium falciparum malaria in Savannakhet Province, Lao People's Democratic Republic: an assessment of national antimalarial drug recommendations.

The in vivo efficacies of the Lao People's Democratic Republic (Laos) nationally recommended antimalarial agents--chloroquine and sulfadoxine-pyrimethamine-were assessed in a randomized, comparative trial that involved 100 patients with uncomplicated Plasmodium falciparum malaria who were followed for 42 days after starting treatment. Despite a shorter mean time to fever clearance associated with administration of chloroquine (mean time to clearance, 35.6 h; 95% confidence interval [CI], 26.3-45.0 h), compared with that associated with sulfadoxine-pyrimethamine (61.1 h; 95% CI, 50.9-71.3 h; P<.001), treatment failures were twice as frequent among patients receiving chloroquine therapy than among those receiving sulfadoxine-pyrimethamine therapy (36% vs. 18%; P=.02). Of 23 treatment failures, 10 (43%) were high grade. Treatment failure rates among children (age range, 5-15 years) were 4.9 times higher (95% CI, 2-12) than those among adults (P<.0001). Gametocytemia after antimalarial treatment was associated with receipt of sulfadoxine-pyrimethamine therapy and with treatment failure (P=.009). The efficacy of both chloroquine and sulfadoxine-pyrimethamine in Laos is unsatisfactory.

Adolescent↗
PubMed2006

Role of US military research programs in the development of US Food and Drug Administration--approved antimalarial drugs.

US military physicians and researchers helped identify the optimum treatment dose of the naturally occurring compound quinine and collaborated with the pharmaceutical industry in the development and eventual US Food and Drug Administration approval of the synthetic antimalarial drugs chloroquine, primaquine, chloroquine-primaquine, sulfadoxine-pyrimethamine, mefloquine, doxycycline, halofantrine, and atovaquone-proguanil. Because malaria parasites develop drug resistance, the US military must continue to support the creation and testing of new drugs to prevent and treat malaria until an effective malaria vaccine is developed. New antimalarial drugs also benefit civilians residing in and traveling to malarious areas.

Antimalarials↗
PubMed2006

HIV immunosuppression and antimalarial efficacy: sulfadoxine-pyrimethamine for the treatment of uncomplicated malaria in HIV-infected adults in Siaya, Kenya.

BACKGROUND: The altered immune response of persons with human immunodeficiency virus (HIV) infection could result in increased rates of antimalarial treatment failure. We investigated the influence of HIV infection on the response to sulfadoxine-pyrimethamine treatment. METHODS: Febrile adults with Plasmodium falciparum parasitemia were treated with sulfadoxine-pyrimethamine and were monitored for 28 days. HIV status and CD4 cell count were determined at study enrollment. RESULTS: Of the adults enrolled in the study, 508 attended all follow-up visits, including 130 HIV-uninfected adults, 256 HIV-infected adults with a high CD4 cell count (> or =200 cells/ micro L), and 122 HIV-infected adults with a low CD4 cell count (<200 cells/ micro L). The hazard of treatment failure at day 28 of follow-up was significantly higher for HIV-infected adults with a low CD4 cell count (20.5%) than for HIV-uninfected adults (7.7%). Anemia (hemoglobin level, <110 g/L) modified the effect of HIV status on treatment failure. When we controlled for fever and parasite density, the hazard of treatment failure for HIV-infected adults with a low CD4 cell count and anemia was 3.4 times higher than that for HIV-uninfected adults (adjusted hazard ratio, 3.38; 95% confidence interval, 1.56-7.34). CONCLUSIONS: HIV-infected persons with a low CD4 cell count and anemia have an increased risk of antimalarial treatment failure. The response to malaria treatment in HIV-infected persons must be carefully monitored. Proven measures for the control and prevention of malaria must be incorporated into the basic package of services provided by HIV/acquired immunodeficiency syndrome care and treatment programs in malarious areas.

Adult↗
PubMed1996

Antimalarial activity of novel arylene bis(methylketone) compounds.

Because of the spread of drug-resistant Plasmodium species, there is an urgent need for novel effective antimalarial agents. A series of arylene bis(methylketone) compounds were screened in vitro against a number of Plasmodium falciparum clones and in vivo against Plasmodium berghei. 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium chloride (Cytokine Network Inc. [CNI]-H0294) was the most effective of the compounds in vitro, with an IC50 of 1.5-4.0 microM against parasite clones with a wide range of sensitivities to chloroquine and pyrimethamine. Other compounds in the series had in vitro IC50 values of 20-25 microM. In a 4-day test for suppression of P. berghei parasitemia in vivo, 50 mg/kg/day CNI-H0294 significantly decreased parasitemia by >90%. The compound was found to have low toxicity in mice, with an LD50 of 590 +/- 66 mg/kg intraperitoneally, and rapid plasma kinetics. These results show that CNI-H0294 has considerable antimalarial activity and merits further study.

Animals↗
PubMed1995

Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war.

Malaria has had an enormous impact on human history, not least in times of war. The disease has been treatable by a natural remedy, quinine, since the 17th century, but the production of synthetic antimalarial agents was first achieved in Germany in the wake of the Great War of 1914-1918, in which malaria had caused immense problems. In the 1920s research workers in the Bayer laboratories of the IG Farbenindustrie consortium developed the 8-aminoquinoline plasmoquine (the forerunner of primaquine). They went on to develop the acridine dye, atebrin (mepacrine) and the 4-aminoquinolines, Resochin (developed at the end of the Second World War in America as chloroquine) and Sontochin. British attempts to match the advances achieved by the Germans were at first unproductive, partly because collaboration between academic and industrial organizations in the UK was beset by concerns over patent rights. However, with the outbreak of World War II, when supplies of antimalarials were scarce, ICI succeeded in the large-scale production of mepacrine (essential to prosecution of the war, particularly in the Far East) and also initiated a programme of collaborative research that eventually led to the discovery of proguanil (Paludrine); this, in its turn led to the diaminopyrimidine, pyrimethamine. A massive cooperative screening programme in the USA during World War II eventually bore fruit in the realization of the therapeutic potential of chloroquine, and in the later development of amodiaquine and primaquine. Some of this work also influenced the subsequent discovery of mefloquine and halofantrine at the Walter Reed Army Institute of Research.

Animals↗
PubMed2006

Identification of new antimalarial drugs by linear discriminant analysis and topological virtual screening.

OBJECTIVES: A quantitative structure-activity relationship study using a database of 395 compounds previously tested against chloroquine-susceptible strains of the blood stages of Plasmodium falciparum to predict new in vitro antimalarial drugs has been developed. METHODS: Topological indices were used as structural descriptors and were related to antimalarial activity by using linear discriminant analysis (LDA) and multilinear regression (MLR). Two discriminant equations were obtained (FD1 and FD2), which allowed us to carry out successful classification of 90% and 80% of compounds, respectively. The IC50 values of the compounds were introduced to get an MLR equation model suitable to predict their in vitro activities. RESULTS: Using this model, a set of 27 drugs against a chloroquine-susceptible clone (3D7) of P. falciparum have been selected and evaluated in vitro. Among these drugs are monensin, nigericin, vincristine, vindesine, ethylhydrocupreine and salinomycin with in vitro IC50s at nanomolar concentrations (0.3, 0.4, 2, 6, 26 and 188 nM, respectively). Other compounds such as hycanthone, amsacrine, aphidicolin, bepridil, amiodarone, ranolazine and triclocarban showed in vitro IC50 values below 5 microM in the mathematical model. CONCLUSIONS: These results demonstrate the usefulness of the approach for the selection and design of new lead drugs active against P. falciparum.

Animals↗
PubMed1998

Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine.

Comparative mutagenic and genotoxic effects of three antimalarial drugs, chloroquine, primaquine and amodiaquine, were assessed in the Ames mutagenicity assay (in strains TA97a, TA100, TA102 and TA104) and in vivo sister chromatid exchange (SCE) and chromosome aberration (CA) assays in bone marrow cells of mice. These are the most commonly used antimalarial drugs available at present throughout the world. The results of the bacterial mutagenicity assays showed a very weak mutagenic effect of all three drugs in Salmonella strains TA97a and TA100 both with and without S9 mix and in TA104 only with S9 mix. The results of the in vivo SCE and CA assays indicate that these three drugs are genotoxic in bone marrow cells of mice.

Amodiaquine↗
PubMed2007

Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases.

OBJECTIVE: The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases (CTDs). A high incidence of heart conduction disorders, including bundle-branch block and incomplete or complete atrioventricular block, has been observed among patients treated with CQ. Since no data were available for HCQ, we studied electrocardiograms (ECGs) in 85 unselected patients with CTD treated with HCQ as the sole antimalarial. METHODS: Eighty-five unselected out-patients treated with HCQ for a minimum of 1 yr, and without established cardiac diseases had standard 12-lead ECGs. RESULTS: Two incomplete right bundle-branch blocks and one left bundle-branch block were observed. No atrioventricular block was observed. The mean PR interval was 137 +/- 20 ms (range 99-188). The mean QTc interval was 410 ms (range 349-464). The mean heart rate was 73 beats/min (range 53-102). CONCLUSION: PR interval, QTc interval and heart rate were not different from normal values. The rate of heart conduction disorders was similar to what is expected in the general population, and contrasted with prior results in CQ-treated patients. Our results add further evidence on the safety of HCQ compared with CQ.

Adolescent↗
PubMed2002

The popular herbal antimalarial, extract of Cryptolepis sanguinolenta, is potently cytotoxic.

The aqueous root extract of Cryptolepis sanguinolenta (CSE) is a popular antimalarial in West African ethnomedicine. Cryptolepine (CLP), the major alkaloid of the plant, is a cytotoxic DNA intercalator that has promise as an anticancer agent. To date the aqueous root extract, the traditional antimalarial formulation, has not been evaluated for toxicity. In this study, we have examined the in vitro toxicity of CSE and CLP using V79 cells, a Chinese hamster lung fibroblast frequently used to assess genetic toxicity, and a number of organ-specific human cancer cell lines. CSE and CLP caused a dose- and time-dependent reduction in viability of the V79 cell line. Flow cytometric analysis of CSE- and CLP-treated (24 h) asynchronously growing V79 cells using propidium iodide (PI) staining revealed an accumulation of cells (up to 55%) in the sub-G1 phase of the cell cycle, indicative of cell death. The V79 cells and almost all the organ-specific human cancer cell lines exposed to CSE and CLP were profoundly growth inhibited, as measured in a clonogenicity assay. In a V79 cell mutation assay (hprt gene), CSE (5-50 microg/ml) only induced mutation at the highest dose employed (mutation frequency approximately 4 and 38 mutant clones per 10(6) cells for control and CSE, respectively), but CLP (0.5-5.0 microM) was not mutagenic. These results indicate that CSE and CLP are very cytotoxic and may be weak mammalian mutagens and/or clastogens. The poor genotoxicity of CSE and CLP coupled with their potent cytotoxic action support their anticancer potential.

Animals↗
PubMed1993

Molecular modelling of malaria calmodulin suggests that it is not a suitable target for novel antimalarials.

The recent cloning and sequencing of many calmodulin genes permits alignment of DNA and protein sequences, as well as structural comparison based on homology modelling. The crystal structure of calmodulin places the four Ca(2+)-binding domains in a dumbbell-like configuration, with a large hydrophobic cleft in each half of the molecule. Calmodulin from Plasmodium falciparum has a high level of sequence identity (89%) with its mammalian counterpart. However, a lower degree of sequence conservation is observed among calmodulins from other lower eukaryotes. Potentially important differences in calmodulin sequences involve amino acids with side-chains forming the hydrophobic clefts as well as in the central helix; these differences could alter interactions with small hydrophobic molecules such as chloroquine and with enzymes modulated by calmodulin. Our modelling studies suggest that neither of the antimalarials examined (chloroquine and quinine) bind tightly to calmodulin. We conclude that the differences between host and parasite calmodulins are insufficient to merit this protein being chosen as a realistic target for antimalarial drug design. By contrast, our sequence comparisons reveal that the fungal calmodulins are significantly divergent from those of higher eukaryotes suggesting that at least in these species, calmodulin might be a target for novel antimycotic drugs.

Amino Acid Sequence↗