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

Atovoquone is a novel hydroxynaphthoquinone that is currently showing clinical promise for the treatment of malaria and the AIDS-associated diseases Pneumocystis carinii pneumonia and toxoplosmosis. The drug is the end product of half a century of research by numerous groups who have investigated the ontiporositic properties of many related compounds. Atovaquone is the only member of the series to show therapeutic activity in humans when taken orally. In this article, Alan Hudson explores the background to the discovery of this drug and reviews its mode of action, and biological and clinical profiles.
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PMID:Atovaquone - a novel broad-spectrum anti-infective drug. 1546 12

Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc1 complex and inhibits parasite respiration. A growing number of failures of this drug in the treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To better understand the molecular basis of atovaquone resistance in malaria, we introduced five of these mutations, including the most prevalent variant found in Plasmodium falciparum (Y268S), into the cytochrome b gene of the budding yeast Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes, we obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.
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PMID:Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. 1571 26

Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome bc1 complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome b, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome b-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome b mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome b at its ef loop to more closely resemble Plasmodium cytochrome b increased the sensitivity of the cytochrome bc1 complex to atovaquone. A mutation within the ef loop that is associated with resistant malaria parasites rendered the complex resistant to atovaquone, thereby providing direct proof that the mutation causes atovaquone resistance. This mutation resulted in a 10-fold reduction in the in vitro activity of the cytochrome bc1 complex, suggesting that it may exert a cost on efficiency of the cytochrome bc1 complex.
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PMID:Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. 1591 36

Plasmodium falciparum remains one of the World's most prevalent and devastating pathogens. Mainly for economic reasons, the parasite's ability to develop resistance to drugs has not been matched by the rate at which new compounds are developed. Even so, there are new drugs (or new combinations of old drugs) currently under investigation, or in the process of development (at the moment): Pyronaridine, a well-tolerated, synthetic drug that may have utility for multi-resistant falciparum malaria in many parts of the world; however,problems remain over the formulation of this drug (which is a major determinant of its bioavailability) and its eventual cost. Chlorproguanil-dapsone (lap dap) is being studied as a possible low-cost'successor' to pyrimethamine-sulfadoxine; the utility of chlorproguanil-dapsone as 'salvage' therapy for clinical cases of pyrimethamine-sulfadoxine failure has yet to be tested in clinical trials. Atovaquone-proguanil (malarone) has utility against multi-resistant parasites; however, it is likely to be expensive (but is currently being provided free-of-charge in certain areas of Africa). Artemether-benflumetol (coartemether) combines the advantages of artemether (a rapid reduction in parasite load) with a second drug that reduces the risk of recrudescence; the cost of this combination is unclear. Rectal artesunate is being studied as an intervention to reduce the proportion of children with falciparum malaria who deteriorate to severe disease; the formulation is appropriate for use in rural health centres.
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PMID:Clinical trials of chemotherapy for falciparum malaria. 1599 58

Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-proguanil or atovaquone-proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.
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PMID:Short report: no evidence of cardiotoxicity of atovaquone-proguanil alone or in combination with artesunate. 1610 86

Malaria is a serious infection, and prevention traditionally relies on chemoprophylaxis during and after exposure. The risk of side effects from chemoprophylaxis needs to be balanced against the risk of infection, and there has been conducted only one prospective, double-blind study comparing the suspected side effects of mefloquine (Lariam), atovaquone/proguanil (Malarone), doxycycline and chloroquine/proguanil. Therefore the current recommendations are based on descriptive studies and case reports. There is a lack of data on the risk of infection in travellers, and the national statistics on the number of imported cases are not very useful as long as the total number of travellers at risk is not known. The risk to travellers is therefore estimated from data on malaria in the indigenous population, while the risk for travellers is expected to be lower. Atovaquone/proguanil has been registered in Europe for travels of up to four weeks, but in the United States there is no upper limit for the duration of use. It is not possible to prescribe efficient prophylaxis to pregnant women in the first trimester or infants below 11 kilograms of body weight travelling to tropical Africa.
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PMID:[Malaria chemoprophylaxis]. 1623 97

Increases in international travel and escalating drug resistance have resulted in a growing number of travelers at risk of contracting malaria. Drug resistance and intolerance to standard agents such as chloroquine, sulfadoxine/pyrimethamine and mefloquine has highlighted the need for new antimalarials. The recently licensed fixed combination of atovaquone and proguanil hydrochloride (Malarone) is a promising new agent to prevent and treat Plasmodium falciparum malaria. Randomized controlled trials have shown that atovaquone/proguanil is well tolerated and efficacious for the prevention and treatment of drug-resistant P. falciparum malaria. Atovaquone/proguanil is active against the liver stage of P. falciparum malaria parasites and when used as a prophylactic agent it can be discontinued shortly after leaving malaria-endemic areas, offering a clear advantage for drug adherence.
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PMID:Atovaquone/proguanil for the prophylaxis and treatment of malaria. 1630 98

The costs of mefloquine, chloroquine, doxycycline, primaquine, and atovaquone/proguanil are calculated for various durations of exposure to malaria. The cost is included for detecting glucose 6-phosphate dehydrogenase (G6PD) deficiency before administering primaquine for primary or terminal prophylaxis. For durations of exposure ranging from 3 to 730 days, if no terminal prophylaxis is given, doxycycline (generic) is the least expensive regimen. Compared with doxycycline hyclate, chloroquine costs three to four times more, and primaquine, after screening for G6PD, costs about eight times more. Atovaquone/proguanil is less expensive than mefloquine for a 3-day exposure, but more expensive for 7 or more days. When terminal chemoprophylaxis with primaquine for 14 days is used in addition to doxycycline, mefloquine, chloroquine, or atovaquone/proguanil, primaquine alone is the least expensive regimen for exposures of < 10 days. Thereafter, doxycycline plus 14 days of primaquine is most economical. For subsequent exposures when G6PD status is already known, primaquine alone is the least expensive regimen for up to 9 days of exposure, but doxycycline is less expensive thereafter. In general, generic doxycycline hyclate is the least expensive regimen. Primaquine alone is economically attractive. Mefloquine, doxycyline monohydrate, and atovaquone/proguanil, the most expensive regimens, are similar in cost for a 7-day exposure, but thereafter, atovaquone/proguanil is much more expensive.
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PMID:Cost considerations of malaria chemoprophylaxis including use of primaquine for primary or terminal chemoprophylaxis. 1696 14

The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereas chloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requires examination of alternative regimens. Not all treatment failures are drug resistant and other issues such as expired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policy after drug resistance is established suppresses infections rather than curing them, leading to increased transmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs. Antifolate drug resistance (i.e. pyrimethamine) means that new combinations are urgently needed particularly because addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance to each having been documented soon after drug introduction. Drug combinations delay further transmission of resistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currently recommended drug combinations for falciparum malaria are variants of artemisinin combination therapy where a rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisinins used include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard of care must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only to the successful treatment of individual patients but also for public health control of malaria.
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PMID:Treatment of falciparum malaria in the age of drug resistance. 1710 46

Atovaquone, a 2-hydroxy-1,4-naphthoquinone, was first introduced as a drug against opportunistic infections in immuno-compromised patients. Early clinical-parasitological experiences in the treatment of malaria were disappointing due to highly variable and poor absorption, a phenomenon typical for naphthoquinones. Proguanil was found to potentiate the activity of atovaquone and the combination of the two drugs was introduced as an antimalarial drug with blood schizontocidal and causal prophylactic activity. It is now widely used in therapy and prophylaxis. Despite the enhanced activity, the combination does not always overcome the problem of poor absorption of atovaquone, especially in the presence of gastro-intestinal disorders. Therefore, further combination with a fast-acting blood schizontocide, e.g. one of the artemisinins, could accelerate clinical improvement and normalization of absorption. The interaction between artemisinin and atovaquone and that of artemisinin and atovaquone + proguanil has been investigated in 37 fresh isolates of Plasmodium falciparum from northwestern Thailand, an area with high prevalence of multi-drug resistance. Interaction between atovaquone and artemisinin was synergistic above the EC(30), with mean SigmaFIC (Berenbaum) values of 0.9679 at the EC(50), 0.4014 at the EC(90) and 0.2214 at the EC(99). Synergism was more pronounced with the triple combination, i.e. atovaquone + proguanil and artemisinin, starting at the EC(10) level. The mean SigmaFIC values were 0.7626 at the EC(50), 0.2939 at the EC(90), and 0.1527 at the EC(99). The strong synergism at the therapeutically relevant effective concentrations suggests that the therapeutic efficacy of atovaquone-proguanil can be considerably enhanced by the additional administration of a suitable artemisinin derivative, e.g. artesunate.
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PMID:Pharmacodynamic interaction between atovaquone and other antimalarial compounds against Plasmodium falciparum in vitro. 1713 Dec 44


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