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PubMed1987

Detection and estimation of antimalarial drugs in body fluids--I. Field test for amodiaquine in urine and saliva.

Simple and specific tests for the detection of antimalarial drugs are required during clinical studies on the sensitivity of Plasmodium falciparum to these drugs. A specific colour test has been developed for amodiaquine which is sensitive enough to permit the visual detection of the drug, following the oral administration of a single 600 mg dose, for up to 10 days in saliva and up to seven weeks in urine. The test is based on the oxidation of amodiaquine to a yellow-coloured derivative using an aqueous solution of potassium persulphate and disodium hydrogen orthophosphate as oxidant. The colour has also been determined spectrophotometrically at 560 nm to achieve a lower detection limit of 0.5 microg amodiaquine in 10 ml biological fluid.

Journal Article↗
PubMed1985

Charge transfer and oxy radicals in antimalarial action. Quinones, dapsone metabolites, metal complexes, iminium ions, and peroxides.

A mechanism of action is proposed that encompasses almost all of the main categories of antimalarial agents: quinones and precursors, dapsone metabolites, metal complexes of thiosemicarbazones and biguanides, iminium-type ions from acridines and quinolines, and peroxides. The toxic effect of the drugs is believed to result from the generation of reactive oxygen radicals that usually arise via charge transfer. Electrochemical studies (reduction potential and reversibility) were performed on a number of these agents. Reduction potentials range from -0.23 to -1.52 V. It is likely that the in vivo values are appreciably more positive in certain cases.

Aminacrine↗
PubMed2005

Ecotoxicological evaluation of the antimalarial drug chloroquine.

There is limited information available about the potential environmental effects of chloroquine (CQ), a widely used antimalarial agent and a promising inexpensive drug in the management of HIV disease. The acute effects of CQ were studied using four ecotoxicological model systems. The most sensitive bioindicator was the immobilization of the cladoceran Daphnia magna, with an EC50 of 12 microM CQ at 72 h and a non-observed adverse effect level of 2.5 microM CQ, followed very closely by the decrease of the uptake of neutral red and the reduction of the lysosomal function in the fish cell line PLHC-1 derived from the top minnow Poeciliopsis lucida, probably due to the selective accumulation of the drug into the lysosomes. There was significant cellular stress as indicated by the increases on metallothionein and glucose-6P dehydrogenase levels after 24 h of exposure and succinate dehydrogenase activity mainly after 48 h. No changes were observed for ethoxyresorufin-O-deethylase (EROD) activity. The least sensitive model was the inhibition of bioluminescence in the bacterium Vibrio fischeri. An increase of more than five-fold in the toxicity from 24 to 72 h of exposure was observed for the inhibition of the growth in the alga Chlorella vulgaris and the content of total protein and MTS tetrazolium salt metabolization in PLHC-1 cells. At the morphological level, the most evident alterations in PLHC-1 cultures were hydropic degeneration from 25 microM CQ after 24h of exposure and the presence of many cells with pyknotic nuclei, condensed cytoplasm and apoptosis with concentrations higher than 50 microM CQ after 48 h of exposure. In conclusion, CQ should be classified as harmful to aquatic organisms.

Analysis of Variance↗
PubMedDate not supplied

Marine pharmacology in 2001--2002: marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action.

During 2001--2002, research on the pharmacology of marine chemicals continued to be global in nature involving investigators from Argentina, Australia, Brazil, Canada, China, Denmark, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Pakistan, the Philippines, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, and the United States. This current article, a sequel to the authors' 1998, 1999 and 2000 marine pharmacology reviews, classifies 106 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria, on the basis of peer-reviewed preclinical pharmacology. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 56 marine chemicals. An additional 19 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as to possess anti-inflammatory and antidiabetic effects. Finally, 31 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2001--2002 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads for the ongoing global search for therapeutic agents for the treatment of multiple disease categories.

Animals↗
PubMed2005

The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs.

Plasmodium falciparum is the main causative agent of tropical malaria, the most severe parasitic disease in the world. Growing resistance of Plasmodia towards available drugs is an increasing problem in countries where malaria is endemic. As Plasmodia are sensitive to oxidative stress, augmenting this in the parasite represents a promising principle for the development of novel antimalarial drugs. The NADP-dependent glutamate dehydrogenase (GDH) of P.falciparum is largely responsible for the production of NADPH in the parasite, which in turn serves as electron source for the antioxidative enzymes glutathione reductase and thioredoxin reductase. As GDH does not occur in the host erythrocyte, GDH is a particularly attractive target for drug therapy. The three-dimensional structure of P.falciparum GDH in the unligated state has been determined by X-ray crystallography to a resolution of 2.7A. Compared to the mammalian enzymes, two amino acid residues are exchanged in the putative active site of the parasite GDH. The most obvious differences between parasite and human GDH are the subunit interfaces of the hexameric proteins. In the parasite protein, several salt-bridges mediate contacts between the subunits whereas in the human enzyme these interactions are mainly of hydrophobic nature. Furthermore, P.falciparum GDH possesses a unique N-terminal extension that does not occur in any other GDH sequence so far studied. These findings might be exploited for the design of peptidomimetics capable of disrupting the oligomeric organisation of the parasite enzyme.

Amino Acid Sequence↗
PubMed1998

5'-O-demethyldioncophylline A, a new antimalarial alkaloid from triphyophyllum peltatum.

From the root bark of Triphyophyllum peltatum, the new naphthylisoquinoline alkaloid 5'-O-demethyldioncophylline A has been isolated. Its otherwise difficult separation from the largely dominating main alkaloid, dioncophylline A, was greatly facilitated by a bromination-benzylation procedure. From the resulting derivative, a crystal structure analysis with an anomalous X-ray diffraction was achieved, allowing confirmation of the full absolute stereostructure of the new alkaloid. The structure was further corroborated by a partial synthesis from dioncopeltine A. The natural product was shown to exhibit antimalarial activity against erythrocytic forms of Plasmodium falciparum.

Journal Article↗
PubMed1998

Microtubule inhibitors as potential antimalarial agents.

The Steering Committee on Drugs for Malaria (CHEMAL) of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) has identified tubulin as a potential drug target, but one that is not yet ;validated'. Several inhibitors of tubulins, the principal proteins of microtubules, are potent inhibitors of the development and multiplication of malarial parasites in culture and in vivo. However, most of these compounds are also inhibitors of mammalian cell proliferation. Here, Angus Bell reviews the structure and properties of microtubules, their roles in Plasmodium cells, and the effects of various microtubule inhibitors on the parasite. He argues that microtubule inhibitors are not equally toxic to all proliferating cells but, by virtue of differential tubulin binding, show selective toxicity that might allow their use as antimalarial drugs.

Journal Article↗
PubMed1998

Costs and benefits of resistance against antimalarial drugs.

Recent experiments have suggested that resistance to antimalarial drugs, in particular chloroquine, is associated with increased transmission. However, epidemiological patterns suggest the opposite: ie. that resistance should be associated with a transmission cost. Here, Jacob Koella reviews the evidence for either a cost or a benefit of chloroquine resistance and proposes ideas from population and evolutionary biology that might explain the apparent contradiction between experimental and epidemiological evidence.

Journal Article↗
PubMed1998

The use of PCR genotyping in the assessment of recrudescence or reinfection after antimalarial drug treatment.

In the past, assessment of drug efficacy against Plasmodium falciparum malaria has been performed by microscopy, screening for parasites in blood smears. However, in areas of high endemicity, reappearing parasites might be derived from new inoculations and could be classified falsely as treatment failures. Recently, a number of studies have used polymerase chain reaction (PCR) analysis of detectable parasites after drug administration to discriminate new infections from true recrudescence. The feasibility, high sensitivity and high resolution of this technique proves that it will be practical and highly valuable in studies on both drug resistance and vaccine efficacy as well as the testing of novel antimalarial drugs. In this article, Georges Snounou and Hans-Peter Beck discuss the uncertainties in the interpretation of data inherent to the technical limitations of the PCR technique, and the constraints imposed by the biology of the parasite. They suggest that although genotyping can provide strong evidence for differentiating between true recrudescence and reinfection, it must be interpreted with caution. They also propose strategies that might help minimize these uncertainties.

Journal Article↗
PubMed1985

Toxic psychosis: a complication of antimalarial therapy.

A case is reported of toxic psychosis in a patient with a diagnosis of discoid lupus erythematosus treated with hydroxychloroquine. The dose slightly exceeded the maximum recommended dose for 10 days because of a pharmacy error. Since more antimalarials are being used for various diseases, attention is called to this possible complication with a subtle onset.

Adult↗
PubMed1983

Analysis of the antimalarial, mefloquine, in blood and plasma using high-performance liquid chromatography.

An analytical method is described for the quantitation of mefloquine, a new antimalarial agent, in plasma and blood. A structurally similar quinolinemethanol compound, WR 184,806, is used as the internal standard. The method employs a three-step extraction procedure followed by reversed-phase high-performance liquid chromatography, and octanesulfonate is used as an ion-pairing reagent. Detection is achieved at 222 nm. The entire procedure is relatively simple and requires only 1 ml of sample. Good accuracy and precision are obtained over the wide concentration range tested.

Chromatography, High Pressure Liquid↗
PubMed1985

Sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine as potential antimalarial agents.

Two isomeric sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2) were prepared and tested for antimalarial activity. The compounds were evaluated for blood schizonticidal activity against Plasmodium berghei in mice and radical curative activity against Plasmodium cynomolgi in rhesus monkeys. In addition, they were evaluated for causal prophylactic activity against Plasmodium berghei yoelii in mice. Both compounds were more active and less toxic than primaquine in the P. berghei screen. One of the compounds showed radical curative activity similar to primaquine but was less active than 2. One of the compounds was active at 160 mg/kg in the P. berghei yoelii screen; the other was not active.

Aminoquinolines↗
PubMed1986

Biologically active derivatives of gossypol: synthesis and antimalarial activities of peri-acylated gossylic nitriles.

A series of peri-acylated gossylic nitriles were synthesized from gossypol dioxime by treatment of the dioxime with the appropriate acid anhydride and its salt. The reaction pathway was elucidated by isolation and characterization of intermediates. Peri-acylated gossylic nitriles (acyl = acetyl, propionyl, butyryl, and valeryl) were compared with gossypol for activity against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The gossylic nitriles all retain activity, with activity increasing with the length of the peri-acyl group. Gossylic nitrile 1,1'-divalerate shows antimalarial activity comparable to gossypol itself. The peri-acylated gossylic nitriles are strong inhibitors of parasite lactate dehydrogenase.

Acylation↗
PubMed1979

Synthesis of 4-alkyl and 4-(beta-alkylvinyl) derivatives of primaquine as potential antimalarials.

4(beta-Alkylvinyl)-6-methoxy-8-nitroquinolines (6) were prepared from 6-methoxy-8-nitroquinoline-4-carboxaldehyde (5) via a Wittig reaction. Stannous chloride reduction of 6 gave 4-(beta-alkylvinyl)-8-amino-6-methoxyquinolines (8), whereas catalytic reduction of 6 using Raney nickel catalyst gave 4-alkyl-8-amino-6-methoxyquinolines (7). Alkylation of 7 and 8 with 4-iodo-1-phthalimidopentane, followed by removal of the phthaloyl-protecting group with hydrazine, gave 4-alkyl and 4-(beta-alkylvinyl) derivatives of primiquine, respectively. These compounds were evaluated for antimalarial activity against P. berghei and P. berghei yoelii in mice and against P. cynomolgi in rhesus monkeys. Several of the compounds were active in the P. bergheii yoelii screen. None of the compounds showed significant activity in the other two screens.

Animals↗
PubMed1977

Synthetic models of DNA complexes with antimalarial compounds. 2. The problem of guanine specificity in chloroquine binding.

Stacking interactions between the aminoquinoline ring of the antimalarial chloroquine and the purine bases have been studied by preparing and examining models in which the quinoline is linked to the base by a trimethylene chain. The degree of stacking of the models which reflects the strength of the interaction was quantitatively determined in water at different temperatures by hypochromism measurement in the uv. Adenine and guanine exhibit equal affinity for the quinoline nucleus as reflected by very close hypochromism values observed for the two models at all temperatures studied.

Adenine↗
PubMed1984

Synthesis of certain hydroxy analogues of the antimalarial drug primaquine and their in vitro methemoglobin-producing and glutathione-depleting activity in human erythrocytes.

A number of hydroxy analogues of the antimalarial drug primaquine [8-[(4-amino-1-methylbutyl)amino]-6-methoxyquinoline] were synthesized and characterized by 1H NMR and mass spectra. Several of the compounds were found to be active in forming methemoglobin in human erythrocytes, particularly in those from glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. Decreased levels of glutathione (GSH) in G6PD-deficient erythrocytes were also found with compounds that were active methemoglobin formers.

Erythrocytes↗
PubMed1987

Synthesis and antimalarial effects of 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl] -6-alkylphenols and their N omega-oxides.

A series of 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl]-6-alkylphenols and their N omega-oxides were synthesized by the condensation of 4,7-dichloroquinoline and 4,7-dichloroquinoline N omega-oxide with appropriately substituted 4-amino-2-[(diethylamino)methyl]-6-alkylphenol dihydrochlorides. The latter precursors were prepared in a six-step synthesis starting from available 2-alkylphenols. Several of the title compounds display potent antimalarial activity in mice.

Aminoquinolines↗
PubMed1997

A bioassay for evaluating antimalarial activity and for measuring concentration in plasma.

Our objective was to develop a bioassay method based on the isotopic microtest of Desjardins and to validate it by comparing the results with high performance liquid chromatograph (HPLC). The bioassay was developed using a continuous culture of P. falciparum, and the test material consisted of 32 human serum samples from 22 Filipino patients treated only with chloroquine (CQ) for noncomplicated malaria. A blind assay of the serum was done using the Desjardins method and HPLC. A good correlation (r2 = 0.90, n = 32) was observed between the CQ plus monodesethylchloroquine (DCQ) concentrations obtained by HPLC and the equivalent CQ by bioassay. It was also shown that the antimalarial activity of CQ is practically identical to that of its main metabolite DCQ, the activity of DCQ being 0.9 times the activity of CQ. The bioassay is reliable, semi-automated, and reproducible. This method may be used as a complementary technique to HPLC for determining biological activity in serum and for measuring the kinetics of this activity, as well as to indicate the existence of new metabolites. The bioassay can be applied to other protozoans for which an in vitro model is available.

Adolescent↗