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

Over 700 causal prophylactic and radical curative antimalarial drugs have been discovered during the screening of approximately 4000 chemical compounds in rodent and simian malaria models. Causal prophylactic activity in the Plasmodium berghei-rodent model was demonstrated by 10 distinct groups of chemicals: 1) tetrahydrofolate dehydrogenase inhibitors, 2) naphthoquinones, 3) dihydroacridinediones, 4) tetrahydrofurans, 5) guanylhydrazones, 6) analogues of clopidol, 7) quinoline esters, 8) dibenzyltetrahydro-pyrimidines, 9) 6-aminoquinolines, 10) 8-aminoquinolines.Of the causal prophylactic compounds, only the 6- and 8-aminoquinolines were capable of curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys. The 6-aminoquinolines were substantially less active than primaquine.This report describes a series of 4-methyl-5-phenoxy-6-methoxy-8-aminoquinolines, which are potent blood schizontocides and radical curative drugs. The most active member of this series, 4-methyl-5-(3-trifluoromethylphenoxy)-6-methoxy-8-[(4-amino-1-methylbutyl)| amino]quinoline succinate (WR 225448), was 5 times more active than primaquine in curing persistent exoerythrocytic infections of P. cynomolgi in rhesus monkeys.As a blood schizontocide, WR 225448 was effective in animal models against P. berghei, P. cynomolgi, P. vivax, and both drug-sensitive and drug-resistant strains of P. falciparum. WR 225448 was also more toxic than primaquine in rats on subacute (28-day) administration.
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PMID:New tissue schizontocidal antimalarial drugs. 697 54

Malaria chemotherapy has been well reviewed. Malarial parasites gaining resistance is the major problem in the treatment of the disease. Some strains are resistant not only to chloroquine but also to amodiaquine. Few new drugs are available or foreseen for the near future. The principal metabolite of cinchona alkaloids appears to be oxidized at C-2. This may result in a loss of activity. Pinder and Burger suggested that a trifluoromethyl group will prevent this oxidation. So 2-tribromomethyl-6-methoxy-4-(4-hydroxy-3-pyrrolidinomethylanil ino)quinoline (1) was synthesized as a potential biocide (Scheme 1).
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PMID:Synthesis and biological evaluation of some potential antimalarials. 782 2

Intraerythrocytic malaria parasites ingest the cytosol of their host cell and digest it inside their acid food vacuoles. Acidified (pH 4-5.5, 37 degrees C) human red blood cell lysates were used to simulate this process, measuring the denaturation of haemoglobin (Hb) and the release of iron, in the absence or presence of exogenous protease. Spontaneous Hb denaturation and appearance of non-heme iron were observed upon lysate acidification, their rates decreasing with increasing pH, and increasing in the presence of protease. Both processes were inhibited by the quinoline-containing anti-malarial drugs (QCDs) chloroquine, quinine, mefloquine and amodiaquine at concentrations well below those expected in the acidic food vacuole of the parasite. Spectrophotometric analysis indicated that chloroquine complexes with heme in acid-denatured haemoglobin. Other weak bases as well as verapamil and diltiazem, known to reverse the resistance of malarial parasites to chloroquine, were without effect indicating that the action of QCDs is specific. Based on our previous results and the present report, we suggest that iron release in acidified lysates is mediated through the formation of ferryl (Fe(IV)) radicals. QCDs possibly complex with this radical, as they do with heme, and prevent its contact with an adjacent heme molecule which is required for ring opening and iron release. These results may suggest that one of the anti-malarial effects of QCDs is to deprive the parasite of an adequate iron supply. Addition of iron to cultures of Plasmodium falciparum was expected to circumvent the deprivation of iron and reduce the anti-malarial effect of QCDs. However, adding iron as penetrating fructose or nitrilotriacetate complexes did not alter the parasite's susceptibility to chloroquine. Ascorbate markedly increased the release of iron in acidified lysates, and this effect was not reduced by chloroquine. Ascorbate was found to decrease parasite susceptibility to chloroquine, suggesting that iron deprivation may be an important factor in the anti-malarial action of QCDs.
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PMID:Inhibition by anti-malarial drugs of haemoglobin denaturation and iron release in acidified red blood cell lysates--a possible mechanism of their anti-malarial effect? 800 50

Resistance to quinoline containing drugs, particularly chloroquine (CQ), is a major impediment to the successful chemotherapy and prophylaxis of malaria. CQ-resistant parasites fail to accumulate as much drug as their sensitive counterparts and two major hypotheses have been proposed to account for this phenomenon. CQ-resistant parasites are thought to maintain lower intracellular drug levels by means of an active efflux system, similar to that found in multi-drug resistant cancer cells, despite major differences in both the genetic and biochemical manifestations of drug resistance in the two cell types. Alternatively, CQ-resistance could be linked to a defective CQ uptake mechanism, possibly an impaired acidification process in the food vacuole of the resistant parasite. These two theories are discussed in detail in the following review. The potential of pharmacological intervention to override these resistance mechanisms is also discussed.
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PMID:Malaria chemotherapy: resistance to quinoline containing drugs in Plasmodium falciparum. 824 75

A review of the literature on Alstonia species indicates that evidence in support of their effectiveness in the treatment of malaria is controversial. The antiprotozoal activity of the major alkaloid present in Alstonia species, echitamine, was assessed in vitro against Plasmodium falciparum and Giardia intestinalis. Echitamine displayed little antiplasmodial activity, but two quinoline alkaloids from A. coriacea (corialstonine and corialstonidine) were found to have some activity against P. falciparum although this was approximately 10 times less than that of quinine. None of the three Alstonia alkaloids was active against G. intestinalis. These results are discussed in the context of previously published data.
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PMID:Alstonia species: are they effective in malaria treatment? 824 29

The anti-malarial action of quinoline-containing compounds depends on various membrane-related processes, and drug resistance could depend, among other factors, on the membrane lipid composition. To verify this hypothesis, the constitution of phospholipid classes and the content of cholesterol of various strains of Plasmodium falciparum-infected human erythrocytes grown in in vitro cultures have been assessed in conjunction with drug susceptibility. It was found that uninfected erythrocytes in the culture serve as a major source for the increased lipid content of malaria-infected cells. Alterations of the phospholipid composition of infected cells that result from parasite lipid metabolism are also reflected in the constitution of uninfected red cells, implying lipid exchange between infected and uninfected cells. An inverse relationship between the content of acidic phospholipids and cholesterol has been observed. Some strains resistant to chloroquine and quinine were sensitive to mefloquine, and vice versa. Resistance to chloroquine or quinine was found to be directly related to the content of acidic phospholipids, while that of mafloquine displayed an inverse correlation. Concomitantly, the resistance to chloroquine was inversely related to the content of cholesterol, while the sensitivity to mefloquine decreased with cholesterol concentration. The possible mechanisms that could account for these observations are briefly discussed.
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PMID:The susceptibility of the malarial parasite Plasmodium falciparum to quinoline-containing drugs is correlated to the lipid composition of the infected erythrocyte membranes. 834 62

We have studied blood pressure and heart rate responses to standing in 29 previously ambulant adult Thai patients with acute uncomplicated falciparum malaria before and after treatment with quinine or mefloquine. There was significant, symptomatic, and usually profound orthostatic hypotension in 12 patients (41%) before antimalarial treatment. The median maximum fall in systolic pressure was 24 mm Hg, significantly greater than the maximum fall in diastolic pressure 16 mm Hg. Blood pressure fell in two phases: an initial transient and usually asymptomatic fall immediately on standing, and a progressive, usually symptomatic fall, worsening over several minutes without a rise in pulse rate. Orthostatic hypotension was associated with core temperature (r = 0.37, P = 0.05). Antimalarial treatment accentuated the delayed orthostatic hypotension during malaria, despite (in the case of quinine) a significant reduction in fever. Both antimalarial drugs attenuated the cardioacceleratory response to symptomatic postural hypotension; the mean reduction in heart rate at the time of lowest blood pressure was 22 beats.min-1. The electrocardiograph ratio of RR intervals at the 30th and 15th beats was reduced significantly in acute malaria, but was not affected further by the drugs. When restudied in convalescence all the patients had normal postural cardiovascular responses. Acute falciparum malaria is associated with impaired circulatory control and the tendency to postural hypotension is worsened significantly by antimalarial treatment with the quinoline antimalarials quinine and mefloquine.
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PMID:Abnormal circulatory control in falciparum malaria: the effects of antimalarial drugs. 851 43

CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too toxic for humans, has been the antimalarial of choice for 40 years. While a range of serious CNS effects have been documented during chloroquine therapy, the incidence is unclear (extrapyramidal symptoms occur with an incidence of 1 in 5000). Amodiaquine has a higher incidence of mild CNS effects than chloroquine. Mefloquine therapy causes dose-related transient dizziness. Serious CNS events during mefloquine therapy occur in 1:1200 Asians and 1:200 Caucasians/Africans. Risk factors include dosage, concomitant drug use/interactions, previous history of a CNS event and disease severity. Retreatment (within a month) increases the risk in Asians 7-fold. Studies indicate that the frequency of serious CNS events with mefloquine prophylaxis (1:10,000) is similar to that with chloroquine (1:13,600). Quinine causes cinchonism at standard therapeutic doses. High-tone hearing loss occurs, but irreversible auditory or ocular effects are very rare. The artemisinin derivatives are associated with dose-dependent brain lesions in rodent, canine and nonhuman primates. At low doses, histological injury has been demonstrated, without clinical neurological signs. No significant toxicity has been reported in humans. Other antimalarial drugs are seldom associated with CNS adverse events. Data do not suggest a need to diminish the correct use of the quinoline derivatives. Irreversible effects are extremely rare and usually associated with overdosing or prior history of a serious CNS event. Concomitant therapeutic use of 2 drugs from the same family, or retreatment with the same drug, should be avoided. Onset of drug-associated serious CNS events requires drug discontinuation and future avoidance of the drug.
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PMID:CNS adverse events associated with antimalarial agents. Fact or fiction? 852 12

Clinical resistance to many therapies for malaria is a rapidly evolving problem in most endemic areas, particularly, Southeast Asia. Recent studies have suggested linkages between the mdr-like genes of Plasmodium falciparum and resistance to quinoline containing compounds. Other studies have found an association between allelic polymorphisms in the DHFR gene and antifol resistance in these parasites. The purpose of this study was to further examine these associations in recent isolates from Cambodia. DNA sequences and gene copy number of the pfmdrl and the DHFR-TS gene in 10 Cambodian isolates were analyzed and correlated with the drug sensitivity pattern. No new intragenic alleles were detected in the pfmdrl gene by a full-length DNA sequence analysis of the L-14/Cambodia clone. The allelic variations seen in pfmdrl in these isolates did not correlate with chloroquine resistance as previously reported. The full-length sequence of the DHFR latter findings may be correlated with high-level resistance to the antifolate drugs as has been previously described. None of the Cambodian isolates presented gene amplification in either pfmdrl or DHFR-TS genes.
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PMID:Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates. 861 53

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


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