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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are three areas in which Australian scientists have made outstanding contributions to the study of the chemotherapy of human parasitic infections. Naturally occurring products of plants have great potential as antiparasitic agents and although several native species have been shown to have antimalarial and anthelmintic activity, their potential as chemotherapeutic agents has not been fully realised; secondly, the demands of war ensured that the Army Malaria Unit at Cairns carried out meticulous and exceptional studies to evaluate new antimalarial compounds. Not only were they able to prove the effectiveness of atebrin, Proguanil and chloroquine as prophylactics, they also obtained much new information on the pharmacokinetics of antimalarials and about the infection itself. Full recognition of these pioneering studies involving over 1000 volunteers infected with malaria, which can never be repeated, has not been appreciated. The third significant contribution is the molecular studies on the mechanisms of drug resistance Plasmodium falciparum of both the antifolate- and quinoline-containing drugs and the identification and subsequent biochemical and molecular analysis of drug resistance in Giardia intestinalis infections.
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PMID:Dreamtime, devastation and deviation: Australia's contribution to the chemotherapy of human parasitic infections. 884 65

The presently used therapy for Babesia microti infections, a combination of quinine and clindamycin, does not always result in parasitologic cures. To identify possible alternative chemotherapeutic agents for such infections, we screened, in the hamster-B. microti system, 12 antiprotozoal drugs that have either recently been released for human use or were in experimental stages of development at the Walter Reed Army Institute of Research for the treatment of malaria and leishmaniasis. Several well-recognized antimalarial drugs, such as mefloquine, halofantrine, artesunate, and artelenic acid, exhibited little or no effect on parasitemia. Two 8-aminoquinolines, WR006026 [8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride] and WR238605 [8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5 -(3-trifluoromethylphenoxy-7) quinoline succinate], produced clearance of patent parasitemia. Furthermore, blood from infected hamsters treated with WR238605 via an intramuscular injection failed to infect naive hamsters on subpassage, thus producing a parasitologic cure. These two compounds merit further screening in other systems and may prove useful in treating human babesiosis.
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PMID:Evaluation of selected antiprotozoal drugs in the Babesia microti-hamster model. 898 Jul 61

The quinoline-containing antimalarial drugs, chloroquine, quinine and mefloquine, are a vital part of our chemotherapeutic armoury against malaria. These drugs are thought to act by interfering with the digestion of haemoglobin in the blood stages of the malaria life cycle. Chloroquine is a dibasic drug which diffuses down the pH gradient to accumulate about a 1000-fold in the acidic vacuole of the parasite. The high intravacuolar concentration of chloroquine is proposed to inhibit the polymerisation of haem. As a result, the haem which is released during haemoglobin breakdown builds up to poisonous levels, thereby killing the parasite with its own toxic waste. The more lipophilic quinolinemethanol drugs, mefloquine and quinine, are not concentrated so extensively in the food vacuole and probably have alternative sites of action. The technique of photoaffinity labelling has been used to identify a series of proteins which interact specifically with mefloquine. These studies have led us to speculate that the quinolinemethanols bind to high density lipoproteins in the serum and are delivered to the erythrocytes where they interact with an erythrocyte membrane protein, known as stomatin, and are then transferred to the intracellular parasite via a pathway used for the uptake of exogenous phospholipid. The final target(s) of quinine and mefloquine action are not yet fully characterised, but may include parasite proteins with apparent molecular weights of 22 kDa and 36 kDa. As resistance to the quinoline antimalarials rises inexorably, there is an urgent need to understand the molecular basis for decreased drug sensitivity. A parasite-encoded homologue of P-glycoprotein has been implicated in the development of drug resistance, possibly by controlling the level of accumulation of the quinoline-containing drugs. As our molecular understanding of these processes increases, it should be possible to design novel antimalarial strategies which circumvent the problem of drug resistance.
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PMID:Quinoline antimalarials: mechanisms of action and resistance. 908 93

The preparation from ferriprotoporphyrin IX (FP) in aqueous acid medium of the related pigments beta- and B-hematin [see G. Blauer and M. Akkawi, Biochem. Mol. Biol. Int. 35, 231 (1995)] is presented under different conditions. Both pigments are characterized by infrared spectra which differ in the range of 1600-1700 cm-1 in their strong bands with absorption peaks measured at 1648 +/- 2 cm-1 for B-hematin and at 1663 +/- 1 cm-1 for beta-hematin. The pH dependence of B-hematin formation at 37 degrees C and at different concentrations of acetic acid and FP exhibits a maximum yield near pH 4. The formation of beta-hematin at 70 degrees C shows high yield in 6 M acetic acid or in the presence of 0.028 M trichloroacetate at pH 4.6. The dependence of the yield of the pigments on the time and temperature of incubation, concentration of FP, and the presence of different electrolytes was investigated. Both B- and beta-hematin are either insoluble or very slightly soluble in different solvents at room temperature, and appear to dissociate into regular FP in strongly alkaline aqueous medium. In the presence of different quinoline-based drugs, the formation of both B- and beta-hematin at pH 4-5 is inhibited. Under certain conditions, the effect of added carboxylic acids on pigment formation is suggested to be due, at least in part, to the prevention of initial hydrogen bonding among FP carboxyl groups. For both B- and beta-hematin, branched and cyclic macromolecular structures are proposed involving linkages between an FP iron and a side-chain carboxylate group of another FP, in addition to hydrogen bonds between FP carboxyl groups. B- and beta-hematin are assumed to differ in molecular weight and the extent of bond formation. Possible mechanisms for beta-hematin production from B-hematin and certain relations between the synthetic pigments and the malaria pigment are suggested.
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PMID:Investigations of B- and beta-hematin. 911 63

The interaction of a variety of quinoline antimalarial drugs as well as other quinoline derivatives with strictly monomeric ferriprotoporphyrin IX [Fe(III)PPIX] has been investigated in 40% aqueous DMSO solution. At an apparent pH of 7.5 and 25 degrees C, log K values for bonding are 5.52 +/- 0.03 (chloroquine), 5.39 +/- 0.04 (amodiaquine), 4.10 +/- 0.02 (quinine), 4.04 +/- 0.03 (9-epiquinine), and 3.90 +/- 0.08 (mefloquine). Primaquine, 8-hydroxyquinoline, 5-aminoquinoline, 6-aminoquinoline, 8-aminoquinoline, and quinoline exhibit no evidence of interaction with Fe(III)PPIX. The enthalpy and entropy changes for the interaction of quinolines with Fe(III)PPIX, as determined from the temperature dependence of the log K values, exhibit a compensation phenomenon that is suggestive of hydrophobic interaction. This is supported by the finding that the interactions of chloroquine and quinine with Fe(III)PPIX are weakened by increasing concentrations of acetonitrile. Interactions of chloroquine, quinine, and 9-epiquinine with Fe(III)PPIX are shown to remain strong at pH 5.6, the approximate pH of the food vacuole of the malaria parasite which is believed to be the locus of drug activity. Implications for the design of antimalarial drugs are briefly discussed.
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PMID:Thermodynamic factors controlling the interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX. 933 73

Hemoglobin degradation in intraerythrocytic malaria parasites is a vast process that occurs in an acidic digestive vacuole. Proteases that participate in this catabolic pathway have been defined. Studies of protease biosynthesis have revealed unusual targeting and activation mechanisms. Oxygen radicals and heme are released during proteolysis and must be detoxified by dismutation and polymerization, respectively. The quinoline antimalarials appear to act by preventing sequestration of this toxic heme. Understanding the disposition of hemoglobin has allowed identification of essential processes and metabolic weakpoints that can be exploited to combat this scourge of mankind.
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PMID:Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. 934 45

Plasmodium falciparum is the causative agent of the most deadly form of human malaria. Chemotherapy traditionally has been the main line of defense against this parasite, and chloroquine, the drug of choice, has been one of the most successful drugs ever developed. Unfortunately, the evolution and spread of resistance to chloroquine and other quinoline-containing drugs means that these compounds are now virtually useless in many endemic areas. Future prospects for the use of quinoline compounds improved considerably when it was demonstrated that chloroquine resistance could be circumvented in vitro by a number of structurally and functionally unrelated compounds such as verapamil and desipramine. The phenomenon of resistance reversal by compounds such as verapamil is also a key feature of drug resistance in mammalian cells, and this has raised the possibility that the underlying mechanisms of drug resistance of the two cell types could be similar. This hypothesis has prompted a large number of studies into the genetics and biochemistry of resistance to quinoline-containing drugs in P. falciparum. Both the genetic and the biochemical studies have raised issues of controversy and stimulated much debate. These issues are discussed in this review, in the context of a comparison with the genetics and biochemistry of multidrug resistance in mammalian cells.
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PMID:A comparison of the phenomenology and genetics of multidrug resistance in cancer cells and quinoline resistance in Plasmodium falciparum. 950 Jan 57

When malaria parasites digest hemoglobin, they release FP intracellularly. FP is an oxidized form of heme which is toxic for biological membranes. The parasites are not poisoned when they digest hemoglobin, however, because they sequester FP in hemozoin. In fact, the refractile, dark brown substance in hemozoin is sequestered FP. Chloroquine binds tightly to nonhemozoin FP and, under certain circumstances, enhances its toxicity. In addition, chloroquine interferes with FP sequestration and causes toxic nonhemozoin FP to accumulate to lethal levels in erythrocytes parasitized with malaria parasites. Evidently, this is how chloroquine kills malaria parasites. It is desirable, therefore, to know more about FP sequestration and how it is affected by chloroquine. Malaria parasites possess a catalyst for FP sequestration which is modulated by treatment with quinoline antimalarial drugs such as chloroquine and quinine. Chloroquine treatment causes the activity of the catalyst to decrease by 80 to 90 percent. Quinine treatment has no obvious direct effect on the catalyst for FP sequestration. Nevertheless, quinine treatment antagonizes and reverses the chloroquine-induced loss of ability to sequester FP. The effect of chloroquine treatment also is antagonized by various metabolic inhibitors, including inhibitors of protein biosynthesis such as cycloheximide. These findings indicate that chloroquine, like quinine, does not interact directly with the catalyst for FP sequestration. Instead, they are evidence that chloroquine acts by increasing the amount, accessibility, or reactivity of a regulator of the catalyst for FP sequestration. I propose that chloroquine increases the amount of the regulator, which inactivates the catalyst for FP sequestration, which leads to accumulation of nonhemozoin FP, which binds with high-affinity to chloroquine and which ultimately kills the malaria parasite.
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PMID:Involvement of heme in the antimalarial action of chloroquine. 960 Nov 31

The malaria parasite metabolizes haemoglobin and detoxifies the resulting haem by polymerizing it to form haemozoin (malaria pigment). A polymer identical to haemozoin, beta-haematin, can be obtained in vitro from haematin at acidic pH. Quinoline-containing anti-malarials (e.g. chloroquine) inhibit the formation of either polymer. Haem polymerization is an essential and unique pharmacological target. To identify molecules with haem polymerization inhibitory activity (HPIA) and quantify their potency, we developed a simple, inexpensive, quantitative in-vitro spectrophotometric microassay of haem polymerization. The assay uses 96-well U-bottomed polystyrene microplates and requires 24 h and a microplate reader. The relative amounts of polymerized and unpolymerized haematin are determined, based on solubility in DMSO, by measuring absorbance at 405 nm in the presence of test compounds as compared with untreated controls. The final product (a solid precipitate of polymerized haematin) was validated using infrared spectroscopy and the assay proved reproducible; in this assay, activity could be partly predicted based on the compound's chemical structure. Both water-soluble and water-insoluble compounds can be quantified by this method. Although the throughput of this assay is lower than that of radiometric methods, the assay is easier to set up and cheaper, and avoids the problems related to radioactive waste disposal.
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PMID:A microtitre-based method for measuring the haem polymerization inhibitory activity (HPIA) of antimalarial drugs. 970 May 28

Quinoline-containing antimalarial drugs, such as chloroquine, quinine and mefloquine, are mainstays of chemotherapy against malaria. The molecular basis of the action of these drugs is not completely understood, but they are thought to interfere with hemoglobin digestion in the blood stages of the malaria parasite's life cycle. The parasite degrades hemoglobin, in an acidic food vacuole, producing free heme and reactive oxygen species as toxic by-products. The heme moieties are neutralized by polymerisation, while the free radical species are detoxified by a vulnerable series of antioxidant mechanisms. Chloroquine, a dibasic drug, is accumulated several thousand-fold in the food vacuole. The high intravacuolar chloroquine concentration is proposed to interfere with the polymerisation of heme and/or the detoxification of the reactive oxygen species, effectively killing the parasite with its own metabolic waste. Chloroquine resistance appears to arise as a result of a decreased level of chloroquine uptake, due to an increased vacuolar pH or to changes in a chloroquine importer or receptor. The more lipophilic quinolinemethanol drugs mefloquine and quinine do not appear to be concentrated so extensively in the food vacuole and may act on alternative targets in the parasite. Resistance to the quinolinemethanols is thought to involve a plasmodial homolog of P-glycoprotein. As the malaria parasites become increasingly resistant to the quinoline antimalarials, there is an urgent need to understand the molecular mechanisms for drug action and resistance so that novel antimalarial drugs can be designed. A number of modified quinolines and bisquinoline compounds show some promise in this regard.
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PMID:Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. 971 45


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