naphthoquinones and Malaria--Falciparum

The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treating people with Plasmodium falciparum malaria. Five combinations are currently recommended, all administered over three days. Artemisinin-naphthoquine is a new combination developed in China, which is being marketed as a one-day treatment. Although shorter treatment courses may improve adherence, the WHO recommends at least three days of the short-acting artemisinin component to eliminate 90% P. falciparum parasites in the bloodstream, before leaving the longer-acting partner drug to clear the remaining parasites.. To evaluate the efficacy and safety of the artemisinin-naphthoquine combination for treating adults and children with uncomplicated P. falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; and LILACS up to January 2015. We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'arte* OR dihydroarte*' as search terms.. Randomized controlled trials comparing artemisinin-naphthoquine combinations with established WHO-recommended ACTs for the treatment of adults and children with uncomplicated malaria due to P. falciparum.. Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach.. Four trials, enrolling 740 adults and children, met the inclusion criteria. Artemisinin-naphthoquine was administered as a single dose (two trials), as two doses given eight hours apart (one trial), and once daily for three days (one trial), and compared to three-day regimens of established ACTs. Three additional small pharmaceutical company trials have been carried out. We have requested the data but have not received a response from the company. Artemisinin-naphthoquine versus artemether-lumefantrineIn three small trials from Benin, Côte d'Ivoire, and Papua New Guinea, both combinations had a very low incidence of treatment failure at Day 28, and there were no differences demonstrated in PCR-unadjusted, or PCR-adjusted treatment failure (three trials, 487 participants, low quality evidence). Only the single study from Papua New Guinea followed participants up to Day 42, and the number of treatment failures remained very low with both combinations (one trial, 186 participants, very low quality evidence). Artemisinin-naphthoquine versus dihydroartemisinin-piperaquineIn a single small trial from Indonesia, treatment failure at Day 28 and Day 42 was very low in both groups with no differences demonstrated (one trial, 144 participants, very low quality evidence).. The results of these few trials of artemisinin-naphthoquine are promising, but further trials from multiple settings are required to reliably demonstrate the relative efficacy and safety compared to established ACTs. Future trials should be adequately powered to demonstrate non-inferiority, and regimens incorporating three days of the artemisinin component are probably preferable to the one-day regimens.

Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Naphthoquinones; Quinolines; Randomized Controlled Trials as Topic

The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox-active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in developmental arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages.

Topics: Antimalarials; Catalysis; Drug Design; Glutathione Reductase; Humans; Malaria, Falciparum; Molecular Structure; NADP; Naphthoquinones; Oxidation-Reduction; Plasmodium falciparum

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.

Topics: Antimalarials; Atovaquone; Chloroquine; Contraindications; Doxycycline; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Mefloquine; Naphthoquinones; Practice Guidelines as Topic; Pregnancy; Proguanil; Risk Assessment; Travel

Many conventional treatments for uncomplicated malaria are failing because malaria parasites develop resistance to them. One way to combat this resistance is to treat people with a combination of drugs, such as atovaquone-proguanil.. To compare atovaquone-proguanil with other antimalarial drugs (alone or in combination) for treating children and adults with uncomplicated Plasmodium falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register (June 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), LILACS (1982 to June 2005), reference lists, and conference abstracts. We also contacted relevant pharmaceutical manufacturers and researchers.. Randomized controlled trials comparing atovaquone-proguanil with other antimalarial drugs for treating children and adults confirmed to have uncomplicated P. falciparum malaria.. Three authors independently assessed trial eligibility and methodological quality, and extracted data for an intention-to-treat analysis (where possible). We used relative risk (RR) and 95% confidence intervals (CI) for dichotomous data. We contacted trial authors for additional information where needed.. Ten trials, with a total of 2345 participants, met the inclusion criteria. The trials were conducted in four geographical regions and were often small, but they included comparisons across eight drugs. Nine trials were funded by a pharmaceutical company, only three carried out an intention-to-treat analysis, and allocation concealment was unclear in seven. Atovaquone-proguanil had fewer treatment failures by day 28 than chloroquine (RR 0.04, 95% CI 0.00 to 0.57; 27 participants, 1 trial), amodiaquine (RR 0.22, 95% CI 0.13 to 0.36; 342 participants, 2 trials), and mefloquine (RR 0.04, 95% CI 0.00 to 0.73; 158 participants, 1 trial). There were insufficient data to draw a conclusion for this outcome from comparisons with sulfadoxine-pyrimethamine (172 participants, 2 trials), halofantrine (205 participants, 1 trial), artesunate plus mefloquine (1063 participants, 1 trial), quinine plus tetracycline (154 participants, 1 trial), and dihydroartemisinin-piperaquine-trimethoprim-primaquine (161 participants, 1 trial). Adverse events were mainly common symptoms of malaria and did not differ in frequency between groups.. Data are limited but appear to suggest that atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine. There are insufficient data for comparisons against sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria. There are not enough data to assess safety, but a number of adverse events were identified with all drugs. Large trials comparing atovaquone-proguanil with other new combination therapies are needed.

Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Randomized Controlled Trials as Topic

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.

Topics: Animals; Atovaquone; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

Atovaquone/proguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone/proguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other antimalarial agents. In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (>/=11 kg) visiting malaria-endemic regions for /=11 kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone/proguanil based on placebo-controlled trials was 95-100%. Atovaquone/proguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone/proguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune individuals. Significantly fewer recipients of atovaquone/proguanil discontinued treatment because of adverse events than individuals receiving chloroquine plus proguanil or mefloquine (p < 0.05).. Atovaquone/proguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone/proguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone/proguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period.

Topics: Animals; Antimalarials; Atovaquone; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Travel

Malaria is a leading cause of morbidity and mortality in developing countries. Selection of mutant Plasmodium falciparum malaria strains under drug pressure has led to the development of drug resistance. There is a pressing need for effective, safe, practicable drug combinations that hve lower selection pressure. A review of the mein drug combinations, which are recently registered or are still under development, was undertaken, with special attention to the atovaquone-proguanil and artemether-lumefantrine combination.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Atovaquone; Drug Resistance, Multiple; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Naphthoquinones; Proguanil; Sesquiterpenes

Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil, and real and perceived intolerance to standard drugs such as mefloquine. A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.

Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Randomized Controlled Trials as Topic; Travel

To review the currently available information on atovaquone-proguanil for treatment and prophylaxis of malaria.. A MEDLINE search was conducted from 1966 to February 2003 using key phrases Malarone, atovaquone, proguanil, and malaria. Further articles were identified from a manual search of the references of identified articles.. English-language studies with animal and human data evaluating preclinical pharmacology, human studies on pharmacokinetics, and clinical trials were evaluated. Relevant data were extracted from identified articles.. Atovaquone-proguanil has been evaluated for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum in 8 clinical trials. In these studies, treatment with atovaquone-proguanil led to a higher (87-100% vs. 72-88%) or equally effective (94-100% vs. 90-100%) cure rate than the comparator antimalarial agents. Atovaquone-proguanil has been evaluated for prophylaxis of malaria in 6 clinical trials. In the 4 placebo-controlled trials for semi-immune residents or nonimmune migrants, the prophylaxis success rates in the atovaquone-proguanil and placebo arms ranged from 98% to 100% and 48% to 82%, respectively. The prophylaxis with success rates were similar among the 2 arms when atovaquone-proguanil was compared with other antimalarial regimens in nonimmune travelers. Atovaquone-proguanil was well tolerated in these clinical trials.. Atovaquone-proguanil is a safe and effective alternative to current recommended regimens for prophylaxis and treatment of malaria.

Topics: Antimalarials; Atovaquone; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

Topics: Antimalarials; Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Humans; Malaria, Falciparum; Metabolic Clearance Rate; Naphthoquinones; Proguanil; Risk Factors; Travel

Topics: Animals; Antimalarials; Atovaquone; Controlled Clinical Trials as Topic; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil

A widespread resistance of falciparum malaria to common antimalaria drugs is observed during the last years. Long-distance travel to high-risk destinations of falciparum malaria will contribute to increased exposition of travelers to highly resistant parasites.. Malarone (GlaxoSmithKline) is a fixed combination of atovaquone and proguanil licensed for prophylaxis and treatment of falciparum malaria. Both atovaquone and proguanil demonstrate synergistic activity against liver and blood schizonts. Malarone is well tolerated with a low rate of side effects. Malarone has an excellent efficacy profile in nonimmune subjects.. Malarone appears to be a valuable alternative malaria prophylaxis in case of intolerance of other antimalaria drugs. Atovaquone/proguanil is effective in treating acute uncomplicated malaria caused by multiresistant strains of Plasmodium falciparum.

Topics: Animals; Antimalarials; Atovaquone; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Randomized Controlled Trials as Topic

Determining the mode of action of different antimalarial drugs at the cellular level is essential to optimizing their use and to understanding the mechanisms underlying plasmodial resistance. The main targets for antimalarial drugs in Plasmodium falciparum have been the food vacuole and mitochondrial system. A new target is recently discovered organelle named the apicoplast. The apicoplast is the site of a number of metabolic pathways crucial to the survival of the parasite. It may also be involved in DNA replication and transcription. Antimalarial drugs are classified into three groups according to site of action, i.e., drugs that act on the food vacuole, drugs that block metabolic synthesis and oxidative processes, and drugs that interfere with membrane processes. Knowledge of these sites of action has enabled identification of new drugs with the most promising potential for development. Current antimalarial strategies prioritize combination therapies such as atovaquone/proguanil or artemether/lumefantrine and prolonged treatments to limit the risk of inducing drug resistant Plasmodium.

Topics: Animals; Antimalarials; Atovaquone; DNA Replication; DNA, Protozoan; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Malaria, Falciparum; Mitochondria; Naphthoquinones; Organelles; Plasmodium falciparum; Proguanil

Prophylaxis for short-term travel in malaria-endemic areas can be difficult for two reasons. The first is that currently available antimalarial drugs are becoming less effective because of the ability of the parasite to adapt to drug pressure. The second involves poor compliance with chemoprophylactic regimens due to the highly restrictive conditions of administration and adverse drug side-effects, especially in "healthy" subjects. The combination of atovaquone/proguanil (Malarone) could provide an answer to both these problems since it is not only effective on multiresistant strains of Plasmodium falciparum but also simplifies the conditions of administration and shows good tolerance in adults and children.

Topics: Adolescent; Adult; Aged; Antimalarials; Atovaquone; Child; Humans; Malaria, Falciparum; Middle Aged; Naphthoquinones; Patient Compliance; Proguanil; Travel

Malarone (atovaquone-proguanil) is a new option now available to French clinicians for prophylaxis and treatment of malaria. Administered by the oral route, malarone is almost 100% effective with few side effects. It is indicated for chemoprophylaxis in travelers entering areas with chloraquine-resistant Plasmodium falciparum. Compliance with prophylactic treatment is enhanced by the low frequency of adverse effects and the need to continue chemoprophylaxis for only 7 days after leaving the endemic area. For curative treatment of malaria, malarone is especially useful in patients with uncomplicated forms of Plasmodium falciparum malaria. This drug combination is also suitable as a stand-by treatment.

Topics: Animals; Antimalarials; Atovaquone; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Travel

As international travel becomes increasingly common and resistance to antimalarial drugs escalates, a growing number of travelers are at risk for contracting malaria. Parasite resistance to chloroquine and proguanil and real or perceived intolerance among patients to standard prophylactic agents such as mefloquine have highlighted the need for new antimalarial drugs. Promising new regimens include atovaquone and proguanil, in combination; primaquine; and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite and therefore can be discontinued shortly after the traveler leaves an area where malaria is endemic, which encourages adherence to the treatment regimen. Part 1 of this series reviews currently recommended chemoprophylactic drug regimens, and part 2 will focus on 8-aminoquinoline drugs.

Topics: Animals; Antimalarials; Atovaquone; Azithromycin; Chloroquine; Drug Resistance; Health Planning Guidelines; Humans; Malaria, Falciparum; Mefloquine; Naphthoquinones; Plasmodium falciparum; Primaquine; Proguanil

An estimated 20,000 to 30,000 cases of imported malaria are annually diagnosed in industrialised countries. Some 700 of them concern Swiss travellers and foreign guests. Exposure prophylaxis and chemoprophylaxis for high risk destinations lower the risk of malarial disease. The latter is defined as regular intake of antimalarial drugs in subtherapeutic dosage in order to suppress the development of clinical disease. Drugs are usually taken from one week before travel until four weeks after return from an endemic area. Mefloquine, doxycycline, chloroquine plus proguanil, and presumably soon also atovaquone plus proguanil are available in Switzerland for chemoprophylaxis.

Topics: Africa; Antimalarials; Asia; Atovaquone; Chloroquine; Contraindications; Doxycycline; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Malaria, Falciparum; Mefloquine; Naphthoquinones; Practice Guidelines as Topic; Proguanil; South America; Switzerland; Travel

[symbol: see text] Atovaquone + proguanil (Malarone--GlaxoSmithKline) is a fixed-dose combination of two antiparasitic drugs. In 1996, it was licensed in the UK for the treatment of acute, uncomplicated falciparum malaria. Earlier this year, the combination was licensed additionally for prophylaxis of falciparum malaria. The manufacturer claims that, when used for prophylaxis, atovaquone + proguanil "offers 97% efficacy with a side effect profile similar to placebo". Here, we assess these claims and review the place of atovaquone + proguanil as prophylaxis for non-immune people travelling from the UK.

Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Endemic Diseases; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Travel

Malarone is a combination of the two drugs atovaquone and proguanil. Malarone is useful as prophylaxis and for the treatment of falciparum malaria. Monotherapy using atovaquone or proguanil results in treatment failure in 30% and 90% respectively, whereas treatment failure is rare when a combination of the drugs is used (< 2%). This reflects the synergistic effect of this drug combination. Used as a chemoprophylaticum against falciparum malaria Malarone has an effect of > 95%. The protective mechanism is likely to act via the mitochondrial cytochrome bc complex, thus a different mechanism from other malaria drugs. For this reason, cross-resistance with other malaria drugs is not expected. The documentation of effect and safety profile of Malarone in malaria prophylaxis makes it a suitable alternative to mefloquine and doxycycline in case of contraindications. Malarone is effective for the treatment of acute uncomplicated malaria, and may be used as an alternative to mefloquine.

Topics: Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.

Topics: Adult; Aged; Antimalarials; Atovaquone; Child; Drug Combinations; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Randomized Controlled Trials as Topic

Topics: Antimalarials; Atovaquone; Chloroquine; Clinical Trials, Phase III as Topic; Drug Combinations; Drug Resistance; Drug Tolerance; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment.. For children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis.. Of 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P = 0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50-146) vs 116 (77-130) days, respectively (P = 0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P = 0.31).. The greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness.. Australian New Zealand Clinical Trials Registry ACTRN12610000913077 .

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Half-Life; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Treatment Outcome

The use of anti-malarial drug combinations with artemisinin, or with one of its derivatives, is now widely recommended to overcome drug resistance in falciparum malaria. Fixed-dose combination of artemisinin and naphthoquine is a new generation artemisinin combination therapy (ACT) offered as a single dose therapy. The aim of the study was to assess the therapeutic efficacy, safety and tolerability of three dosage schedules of fixed-dose combination of artemisinin (125 mg) and naphthoquine (50 mg) for treating uncomplicated Plasmodium falciparum malaria among adolescents and adults in Calabar, South-east Nigeria.. A total of 121 patients aged ≥15 years with uncomplicated P. falciparum malaria were enrolled and randomly assigned to three dosage schedules: (A) 700 mg (four tablets) single dose; (B) 700 mg 12-hourly x two doses; and (C) 1,400 mg (eight tablets) single dose. Patients were observed for 28 days, with clinical, parasitological, and haematological assessments.. A total of 108 patients completed the study. The overall 28-day cure rate was 88.9%. Day 28-cure rates of the three dosage schedules were 85.3%, 93.1% and 88.9% for Group A, B and C respectively. Adverse events were few and mild, the commonest being weakness and headache; there was no serious adverse event.. Concerns for emergence of parasite resistance due to the use of artemisinin-naphthoquine as single dose regimen is likely to compromise the usefulness of this potentially important combination treatment. A robust multi-centre trial is recommended to evaluate a three-day regimen with potentials to achieve high cure rates while minimizing the risk of emergence of resistant parasite strains.

Topics: Adolescent; Adult; Antimalarials; Artemisinins; Drug Administration Schedule; Drug Combinations; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Nigeria; Treatment Outcome; Young Adult

All artemisinin-based combination therapies (ACTs), recommended by the World Health Organization, are 3-day regimens. A considerable level of non-compliance on ACTs has been reported from some countries. The study aimed to assess the therapeutic efficacy of single dose treatment with new generation ACT containing artemisinin plus naphthoquine. An oral single dose of eight tablets (400 mg of naphthoquine+1000 mg artemisinin) of the combination drug was administered to adult uncomplicated falciparum malaria patients. Observations of fever, parasite clearance and reappearance, and other clinical manifestations were made on Days 0, 1, 2, 3, 7, 14, 21 and 28. Fifty-three adult falciparum positive cases, with fever or history of fever within the previous 24 h, were included in the final evaluation of the study. Mean fever clearance time, parasite clearance time were 18.2+/-8.6 h and 34.6+/-14.3 h, respectively. Adequate clinical and parasitological response was achieved in 52 cases, the rate being 98.1% (95% CI, 91.1-99.9). One patient was classified as late parasitological failure because of the reappearance of falciparum parasite on Day 14. The drug was well tolerated and no adverse reactions were detected in the patients. Since it is a single dose therapy, health workers can administer the drug as directly observed treatment.

Topics: Administration, Oral; Adolescent; Adult; Animals; Antimalarials; Artemisinins; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Parasitemia; Plasmodium falciparum; Treatment Outcome; Young Adult

The use of anti-malarial drug combinations with artemisinin or with one of its derivatives is now widely recommended to overcome drug resistance in falciparum as well as vivax malaria. The fixed oral dose artemisinin-naphthoquine combination (ANQ, ARCO) is a newer artemisinin-based combination (ACT) therapy undergoing clinical assessment. A study was undertaken to assess the safety, efficacy and tolerability of ANQ combination in areas of multi-drug resistance to generate preliminary baseline data in adult population of Papua New Guinea.. The clinical assessment was an open-labeled, two-arm, randomized study comparing ANQ combination as a single dose regimen and three days regimen (10 mg/kg/day) of chloroquine plus single dose sulphadoxine-pyrimethamine (CQ+SP) for the treatment of uncomplicated falciparum malaria with 28 days follow-up in an adult population. The primary outcome measures for efficacy were day 1, 2, 3 7, 14 and 28-day cure rates. Secondary outcomes included parasite clearance time, fever clearance time, and gametocyte carriage. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events.. Between June 2005 and July 2006, 130 patients with confirmed uncomplicated P. falciparum were randomly assigned to receive ANQ and CQ+SP, only 100 patients (51 in ANQ group and 49 in CQ+SP group) were evaluated for clinical and parasitological outcomes. All the patients treated with ANQ and CQ+SP showed adequate clinical and parasitological response with 28 days follow-up. The cure rate for ANQ on day 1, 2, 3, 7, 14, and 28 was 47%, 86%, 92%, 94%, 94% and 94%, respectively. Recrudescence account for 6%; all were cleared on day 21. For CQ+SP treated group the cure rates were 24%, 67%, 82%, 82%, 84% and 88%, respectively. Recrudescence accounted for 10%; all were cleared on day 28 except for one patient. Both regimens were well tolerated with no serious adverse events. The proportion of gametocyte carriers was higher in CQ+SP treated group than ANQ treatment (41% versus 12%; p < 0.05).. While these data are not themselves sufficient, it strongly suggests that the ANQ combination as a single dose administration is safe and effective for the treatment of uncomplicated P. falciparum malaria in the adult population of Papua New Guinea and deserves further clinical evaluation.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Blood; Chloroquine; Drug Combinations; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Papua New Guinea; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Treatment Outcome; Young Adult

Whether administration of folic acid to children with malaria anemia is helpful is controversial. Therefore, we conducted a randomised, placebo-controlled trial of 14 days of treatment with folic acid (1 mg/d) in Zambian children with malaria anemia treated with either sulfadoxine/pyrimethamine (SP) or atovaquone/proguanil (AP). Among children who received SP, the prevalence of parasitemia was higher in children treated with folic acid than among those given placebo at days 3, 7, and 14 after the start of treatment, and the difference at day 3 was statistically significant (P = 0.013). Folic acid treatment had no effect on parasitemia in children treated with AP. Administration of folic acid led to a small increase in packed cell volume over that seen in the placebo group at days 14 and 28 after the start of treatment.

Topics: Anemia; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Combinations; Folic Acid; Hematinics; Humans; Infant; Malaria, Falciparum; Naphthoquinones; Parasitemia; Population Density; Proguanil; Pyrimethamine; Sulfadoxine; Treatment Failure; Zambia

The treatment of patients with severe malaria in sub-Saharan Africa has become a challenge to clinicians due to poor compliance to quinine and the increasing multidrug resistance to antimalarials by the P. falciparum parasite. The aim of this study was to compare the efficacy and safety profile of two truncated antimalarial regimens of intravenous quinine followed by oral Malarone (Malarone arm) with intravenous quinine followed by oral quinine (quinine arm) in the treatment of severe P. falciparum malaria. The outcome measures were parasite clearance time, fever clearance time, efficacy, and adverse events profile. Consecutive patients aged 1-60 years, with a diagnosis of severe malaria with positive blood smears for P. falciparum parasites and admitted to the Moi Teaching and Referral Hospital were randomized into the two study arms. Of the 360 patients studied 167 and 193 cases were randomized into the Malarone and quinine arms, respectively. Of the five (1.4 per cent) patients who died, three came from the quinine arm. The frequency of adverse reactions was higher in the oral quinine group (31.6 per cent) than in the Malarone group (25.7 per cent). The mean parasite clearance time was 120 h and 108 h for the quinine and Malarone arms of the study, respectively, and the mean fever clearance times were 84 h and 72 h for the quinine and Malarone arms, respectively (p=0.1). Truncated therapeutic regimen using malarone after intravenous quinine is safer and as effective as conventional intravenous quinine followed by oral quinine in the treatment of severe malaria. The P. falciparum recrudescence rate was lower with the use of Malarone than for quinine.

Topics: Administration, Oral; Adolescent; Adult; Atovaquone; Child; Child, Preschool; Developing Countries; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Kenya; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Prognosis; Proguanil; Quinine; Risk Assessment; Severity of Illness Index; Single-Blind Method; Survival Analysis; Treatment Outcome

To investigate the pharmacokinetics, safety and efficacy of the recommended 3-day treatment regimen of Malarone in third-trimester pregnant women with acute uncomplicated falciparum malaria.. Twenty-six pregnant women in their third trimester (gestational age: 24-34 weeks) with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from the antenatal clinics of Mae Sot Hospital, Tak Province, Thailand, (n = 8) and the Tropical Diseases Research Centre, Ndola, Zambia (n = 18). Patients were treated with four Malarone tablets (GlaxoSmithKline: each tablet contains 250 mg atovaquone and 100 mg proguanil) once daily for 3 consecutive days. Blood samples were taken for pharmacokinetic investigations of atovaquone, proguanil, and cycloguanil up to 288 h (day 14) after the last dose. Urine samples were collected for the evaluation of proguanil and cycloguanil 0-8, 8-16, 16-24 and 24-48 h after the last dose. Efficacy assessments included the clinical and parasitological evaluation of mothers and newborns. Adverse events were evaluated at each visit to the antenatal clinics.. Malarone appeared to be effective and well tolerated when used for the treatment of falciparum malaria in pregnant women. All patients showed prompt clinical improvement and the disappearance of parasitaemia after treatment. There were no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions. The plasma concentration-time profiles of atovaquone and proguanil in most cases were best characterised by the two-compartment open model with zero-order input with/without absorption lag time and first-order elimination. There were no significant differences in any of the pharmacokinetic parameters of atovaquone, proguanil or cycloguanil between patients from Thailand and Zambia. For atovaquone, a Cmax of 1.33-8.33 microg/ml was reached at 2.0-9.3 h after the last dose on day 2. V/F, CL/F and t(1/2beta) were 6.9-39.5 l/kg, 83-384 ml/h/kg, and 57.8-130.8 h, respectively. The Cmax and t(max) values for proguanil versus cycloguanil were 383-918 versus 0-129 ng/ml and 3.3-8.6 versus 3-12 h, respectively. V/F, CL/F, and t(1/2beta) values for proguanil were 10.7-34.0 l/kg, 431-1,662 ml/h/kg and 11.2-30.3 h. The CL(R-CG), t(1/2z), (CG), proguanil/cycloguanil metabolic ratios, AUC ratios for proguanil to cycloguanil (AUC(PG/CG)) were 107.2-1,001 ml/h/kg, 5-95 ml/h/kg, 7.8-20.7 h, 5-57, and 4.7-20.2, respectively.. The pharmacokinetics of atovaquone and cycloguanil appeared to be influenced by the pregnancy status, resulting in an decrease in the Cmax and AUC of approximately twofold.

Topics: Adolescent; Adult; Antimalarials; Atovaquone; Drug Combinations; Female; Humans; Malaria, Falciparum; Naphthoquinones; Pregnancy; Proguanil; Thailand; Triazines; Zambia

There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum.. We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP).. Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year.. AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

Topics: Adolescent; Adult; Anemia; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Female; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Naphthoquinones; Parasitemia; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Proguanil; Quinine; Sesquiterpenes; Thailand

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.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Child; Drug Therapy, Combination; Electrocardiography; Female; Heart Diseases; Humans; Long QT Syndrome; Malaria, Falciparum; Male; Middle Aged; Myanmar; Myocardium; Naphthoquinones; Plasmodium falciparum; Proguanil; Sesquiterpenes; Thailand; Treatment Outcome

To study a new combination, based on dihydroartemisinin and piperaquine (CV8) and atovaquone/proguanil (Malarone) for treatment of uncomplicated falciparum malaria in Vietnam.. Vietnamese adults with falciparum malaria were allocated randomly to treatment with dihydroartemisinin/piperaquine/trimethoprim/primaquine 256/2560/720/40 mg (CV8, n = 84) or Malarone 3000/1200 mg (n = 81), both over 3 days. Patients were followed-up for 28 days.. All patients recovered rapidly. The mean (95% CI) parasite elimination half-life of CV8 was 6.8 h (6.2-7.4) and of Malarone 6.5 h (6.1-6.9) (P = 0.4). Complete parasite clearance time was 35 (31-39) and 34 h (31-38) (P = 0.9). The 28-day cure rate was 94% and 95%, respectively (odds ratio 0.84, 95% CI 0.18-3.81). No significant side-effects were found.. CV8 and Malarone are effective combinations against multi-drug resistant falciparum malaria. CV8 has the advantage of a low price.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemisinins; Atovaquone; Drug Combinations; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Parasitemia; Plasmodium falciparum; Primaquine; Proguanil; Quinolines; Sesquiterpenes; Treatment Outcome; Trimethoprim; Vietnam

To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.. Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.. The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (+/- SEM) oral clearance (Cl/F) estimates were 313+/-33 ml/h/kg and 1109+/-43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0+/-1.3 l/kg and 22.9+/-1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.. Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.

Topics: Acute Disease; Antimalarials; Artemisinins; Artesunate; Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Naphthoquinones; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Proguanil; Sesquiterpenes; Thailand

Malaria-related morbidity and mortality are greatest among young children in areas with high malaria transmission intensity. An open-label, randomized study was done to evaluate the efficacy and safety of the combination of atovaquone and proguanil formulated as pediatric-strength tablets (20 and 8 mg/kg of body weight, respectively, administered once daily for 3 days), compared with amodiaquine (10 mg/kg of body weight, once daily for 3 days), among children weighing > or =5 and <11 kg in Gabon. Two hundred patients aged 3-43 months were recruited. Use of atovaquone/proguanil resulted in a cure rate on day 28 of 95% (87 of 92 children), compared with 53% (41 of 78 children) for amodiaquine (difference, 42%; 95% CI, 30%-54%; P<.001). The incidence of adverse events was similar in both groups, and no serious adverse events were attributed to the use of atovaquone/proguanil. Atovaquone/proguanil was found to be highly effective and safe for the treatment of Plasmodium falciparum malaria in infants and young children weighing 5-10 kg in Africa.

Topics: Amodiaquine; Animals; Antimalarials; Atovaquone; Child; Drug Combinations; Drug Tolerance; Female; Humans; Infant; Malaria, Falciparum; Male; Naphthoquinones; Proguanil; Treatment Outcome

The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) < or =26 months before the study period. Subjects received prophylaxis with 1 Malarone tablet (250 mg of atovaquone and 100 mg of proguanil hydrochloride; n=148) or placebo (n=149) per day for 20 weeks. Hematologic and clinical chemistry values did not change significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI], 44%-95%) for P. vivax malaria, 96% (95% CI, 72%-99%) for P. falciparum malaria, and 93% (95% CI, 77%-98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated to Papua, Indonesia.

Topics: Adolescent; Adult; Animals; Antimalarials; Atovaquone; Chemoprevention; Child; Double-Blind Method; Female; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Naphthoquinones; Patient Compliance; Plasmodium falciparum; Plasmodium vivax; Proguanil; Transients and Migrants; Treatment Outcome

Thirty-eight of 295 subjects participating in a randomized, double-blind, placebo-controlled trial of the efficacy of daily administration of atovaquone/proguanil for malaria prevention developed malaria at some time during the 20-week prophylaxis period. These subjects (3 atovaquone/proguanil recipients and 35 placebo recipients) were treated with 4 tablets of atovaquone/proguanil per day for 3 days. Atovaquone/proguanil provided safe, well-tolerated, and effective therapy for uncomplicated malaria in nonimmune Indonesians.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Atovaquone; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Humans; Indonesia; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Naphthoquinones; Plasmodium falciparum; Plasmodium vivax; Proguanil; Treatment Outcome

In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Child; Child, Preschool; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Plasmodium falciparum; Proguanil; Sesquiterpenes; Treatment Failure

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Microbial Sensitivity Tests; Middle Aged; Naphthoquinones; Peru; Proguanil; Pyrimethamine; Sulfadoxine; Treatment Outcome

Malaria causes illness or death in unprotected travelers. Primaquine prevents malaria by attacking liver-stage parasites, a property distinguishing it from most chemoprophylactics and obviating 4-week postexposure dosing. A daily adult regimen of 30 mg primaquine prevented malaria caused by Plasmodium falciparum and P. vivax for 20 weeks in 95 of 97 glucose-6-phosphate dehydrogenase (G6PD)-normal Javanese transmigrants in Papua, Indonesia. In comparison, 37 of 149 subjects taking placebo in a parallel trial became parasitemic. The protective efficacy of primaquine against malaria was 93% (95% confidence interval [CI] 71%-98%); against P. falciparum it was 88% (95% CI 48%-97%), and >92% for P. vivax (95% CI >37%-99%). Primaquine was as well tolerated as placebo. Mild methemoglobinemia (mean of 3.4%) returned to normal within 2 weeks. Blood chemistry and hematological parameters revealed no evidence of toxicity. Good safety, tolerance, and efficacy, along with key advantages in dosing requirements, make primaquine an excellent drug for preventing malaria in nonpregnant, G6PD-normal travelers.

Topics: Adolescent; Adult; Animals; Antimalarials; Atovaquone; Chemoprevention; Child; Drug Combinations; Female; Humans; Indonesia; Malaria, Falciparum; Male; Methemoglobinemia; Middle Aged; Naphthoquinones; Patient Compliance; Plasmodium falciparum; Primaquine; Proguanil; Treatment Outcome

Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers.. In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory.. 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0.001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0.05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the atovaquone-proguanil group than in the chloroquine-proguanil group (one [0.2%] vs ten [2%], p=0.015).. Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastrointestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.

Topics: Adolescent; Adult; Aged; Antimalarials; Anxiety; Atovaquone; Chloroquine; Dizziness; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Gastrointestinal Diseases; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Proguanil; Travel; Treatment Outcome

This randomized, open-label clinical trial compared a fixed-dose combination of atovaquone and proguanil (n=55) with chloroquine (n=23) or a combination of chloroquine, sulfadoxine, and pyrimethamine (n=32) for treatment of acute falciparum malaria in the Philippines. Patients were hospitalized for 28 days to ensure medication compliance and prevent reinfection. Atovaquone-proguanil produced a significantly higher cure rate (100%) compared with that for chloroquine (30.4%; P<.0001) or chloroquine-sulfadoxine-pyrimethamine (87.5%; P<.05). Treatments did not differ significantly with respect to parasite clearance time (mean: 46.7 h for atovaquone-proguanil, 60.0 h for chloroquine, and 42.8 h for chloroquine-sulfadoxine-pyrimethamine) or fever clearance time (mean, 38.8, 46.8, and 34.5 h, respectively). Adverse events were typical of malaria symptoms; the most frequently reported events were vomiting (18% for atovaquone-proguanil, 17% for chloroquine, and 9% for chloroquine-sulfadoxine-pyrimethamine), abdominal pain (15%, 17%, and 3%, respectively), anorexia (11%, 13%, and 0%, respectively), and headache (6%, 17%, and 3%, respectively). Atovaquone-proguanil was well tolerated and more effective than chloroquine or chloroquine-sulfadoxine-pyrimethamine for treatment of multidrug-resistant falciparum malaria in the Philippines.

Topics: Antimalarials; Atovaquone; Chloroquine; Drug Therapy, Combination; Folic Acid Antagonists; Humans; Malaria, Falciparum; Naphthoquinones; Philippines; Proguanil; Pyrimethamine; Sulfadoxine

The prophylactic antimalarial activity of atovaquone was determined in a randomized, double-blind, placebo-controlled study of healthy volunteers who were challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi. Subjects were randomly assigned to one of three groups: six received seven daily doses of 750 mg of atovaquone, starting the day before challenge; six received a single dose of 250 mg of atovaquone the day before challenge; and four received placebo. Polymerase chain reaction- and culture-confirmed parasitemia developed in all four placebo recipients, but in none of the drug recipients, indicating that either of the atovaquone regimens provides effective prophylaxis (P = 0.005). However, in low-dose recipients, the drug levels by day 6.5 were profoundly subtherapeutic, indicating that parasites were eliminated prior to the establishment of erythrocytic infection. Atovaquone thus protects non-immune subjects against mosquito-transmitted falciparum malaria, and has causal prophylactic activity.

Topics: Adolescent; Adult; Animals; Anopheles; Antimalarials; Atovaquone; Double-Blind Method; Humans; Insect Bites and Stings; Malaria, Falciparum; Middle Aged; Naphthoquinones; Parasitemia; Plasmodium falciparum; Polymerase Chain Reaction

Malaria poses a major health risk to people who are exposed to infection in malaria-endemic areas. A randomized, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of Malarone (250 mg of atovaquone/100 mg of proguanil hydrochloride per tablet) for the chemoprophylaxis of Plasmodium falciparum malaria in Zambia. Adult volunteers received a three-day treatment course of Malarone to eliminate pre-existing parasitemia and were then immediately randomized to treatment with either one Malarone tablet daily (n = 136), or one placebo tablet daily (n = 138) for at least 10 weeks. Malaria blood smears were prepared on a weekly basis and a failure of chemoprophylaxis was defined as any subject who had a positive blood smear, or who withdrew from the study due to a treatment-related adverse event. The prophylaxis success rates in the Malarone and placebo groups were 98% and 63%, respectively (P < 0.001). The most commonly reported adverse events with at least a possible causal relationship to study medication were headache and abdominal pain, which occurred with a higher incidence in the placebo group. No subjects were withdrawn from the study due to a treatment-related adverse event. Thus, Malarone appears to have an excellent safety and efficacy profile for the chemoprophylaxis of P. falciparum infection.

Topics: Adolescent; Adult; Animals; Antimalarials; Atovaquone; Double-Blind Method; Drug Combinations; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Parasitemia; Plasmodium falciparum; Proguanil; Zambia

The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Atovaquone; Drug Combinations; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Naphthoquinones; Proguanil; Thailand; Treatment Outcome

Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria.. This open label, randomized trial compared atovaquone and proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment.. Both regimens were effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and proguanil hydrochloride (73).. In Kenyan children the combination of atovaquone and proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.

Topics: Acute Disease; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Therapy, Combination; Feces; Female; Humans; Malaria, Falciparum; Male; Naphthoquinones; Phenanthrenes; Plasmodium falciparum; Proguanil; Treatment Outcome

The objective of this study was to determine the safety and efficacy of atovaquone and proguanil hydrochloride combination therapy for the prophylaxis of Plasmodium falciparum malaria in at-risk nonimmune subjects in South Africa. This open-label trial was conducted at research sites in South Africa during the main malaria transmission season, February through July. The study volunteers were temporarily living in, or traveling to, a malaria-endemic area. They received I tablet of 250 mg atovaquone and 100 mg proguanil hydrochloride once daily for up to 10 weeks. Subjects were monitored using sequential clinical and laboratory assessments. Thick blood smears were stained and evaluated by a central laboratory. An immunochromatographic test for P. falciparum was also used for on-site patient management. Prophylactic success was summarized using a 95% confidence interval for the proportion of subjects who did not develop parasitemia or who withdrew due to a treatment-related adverse event. A total of 175 subjects (15% women) were enrolled in the trial. The mean duration of drug exposure was 8.9 weeks. The combination of atovaquone and proguanil hydrochloride was well tolerated. The most frequently reported adverse events considered possibly related to study treatment were headache (7%), abdominal pain (2%), increased cough (2%), and skin disorder (2%). No serious adverse events were reported, and no treatment-emergent effects were noted for any laboratory variables. One subject who was noncompliant with therapy developed parasitemia, and 3 subjects withdrew due to a treatment-related adverse event (2 subjects with headache and 1 with nausea and dizziness). The prophylaxis success rate was 97%. In this study, atovaquone and proguanil hydrochloride combination therapy had an excellent safety and efficacy profile for prophylaxis of P. falciparum malaria in nonimmune subjects.

Topics: Adult; Antimalarials; Atovaquone; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Proguanil; South Africa

Currently recommended prophylactic regimens for Plasmodium falciparum malaria are associated with a high incidence of adverse events and/or suboptimal efficacy. In a double-blind, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of atovaquone/proguanil hydrochloride (250 mg/100 mg per tablet) to eliminate preexisting infection. Immediately thereafter, subjects were randomized to one of the three prophylactic regimens to receive one atovaquone/proguanil tablet daily (n = 68), two atovaquone/proguanil tablets daily (n = 65), or placebo (n = 65) for 10 weeks. The study endpoint for any subject was the development of parasitemia, evident on blood smear, during prophylaxis. Of the evaluable subjects, all in the low-dose (54 of 54) and high-dose (54 of 54) atovaquone/proguanil groups remained malaria-free during the 10-week prophylaxis period, in contrast to only 48% (26 of 54) in the placebo group (P < .001). Both atovaquone/proguanil prophylactic regimens were as well tolerated as placebo. Thus, atovaquone/proguanil appears to be highly efficacious and safe as prophylaxis for P. falciparum malaria.

Topics: Adolescent; Adult; Aged; Antimalarials; Atovaquone; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Endemic Diseases; Female; Humans; Kenya; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Parasitemia; Proguanil; Treatment Outcome

The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CL/F) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CL/F is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (V area/F) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of V area/F is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CL/F nor V area/F were significantly affected by age, gender, and the coadministration with chloroguanide (proguanil), pyrimethamine, and tetracycline. Half-life (t1/2) showed a 0.326 power relationship with weight; thus, the population estimate of t1/2 in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CL/F and V area/F were 68% and 49%, respectively.

Topics: Adolescent; Adult; Analysis of Variance; Antimalarials; Atovaquone; Child; Child, Preschool; Computer Simulation; Databases, Factual; Dose-Response Relationship, Drug; Female; Gabon; Humans; Kenya; Malaria, Falciparum; Male; Middle Aged; Models, Biological; Naphthoquinones; Philippines; Thailand; Zambia

The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of atovaquone and proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambaréné, Gabon.. 142 adults were randomly allocated either a combination treatment of atovaquone 1000 mg daily and proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence.. In the atovaquone plus proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0.022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with atovaquone plus proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%).. Atovaquone and proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon.

Topics: Acute Disease; Adult; Amodiaquine; Antimalarials; Atovaquone; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Gabon; Humans; Malaria, Falciparum; Male; Naphthoquinones; Proguanil; Time Factors; Treatment Outcome

1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children (< or = 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Proguanil

Clinical studies have shown atovaquone (ATQ), a new blood schizontocidal drug, in combination with proguanil (PROG) to be very effective in the treatment of acute multidrug-resistant falciparum malaria. The multiple dose pharmacokinetics of PROG were determined in Thai patients with acute falciparum malaria given PROG alone (200 mg PROG twice a day for 3 days, n = 4) and concurrently PROG and ATQ (200 mg PROG and 500 mg ATQ twice a day for 3 days, n = 12). There were no statistical differences (p > 0.05) in the area under the plasma drug concentration-time curve (AUC), apparent oral clearance (CL/F) and elimination half-life (t1/2) of PROG between patients given PROG alone and PROG/ ATQ. The median (range) kinetic values of PROG in patients given PROG alone and PROG/ATQ were respectively: CL/F = 1.25 l/h/kg (0.99-1.45) and 0.95 (0.73-1.32) l/h/kg, and t1/2 = 14.2 hours (9.3-16.8) and 13.6 hours (9.1-17.6). The CL/F and t1/2 of PROG in the Thai patients treated with the 2 treatment regimens were also comparable to values reported in healthy Thai volunteers given a standard prophylactic dose (200 mg PROG). The results of this preliminary study suggest that ATQ is unlikely to affect the pharmacokinetics of PROG to a clinically important extent at an ATQ dosage of 500 mg twice a day for 3 days in malaria infected patients.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Atovaquone; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Humans; Intestinal Absorption; Malaria, Falciparum; Male; Metabolic Clearance Rate; Naphthoquinones; Proguanil

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.

Topics: Adult; Antimalarials; Atovaquone; Dose-Response Relationship, Drug; Drug Administration Schedule; Evaluation Studies as Topic; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Treatment Outcome

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC

Topics: Animals; Antimalarials; Chlorocebus aethiops; Humans; Malaria; Malaria, Falciparum; Mammals; Mice; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum; Triazoles; Vero Cells

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and ≥18 years of age) with uncomplicated malaria in Tanzania. The median weights for the three age groups were 20, 37.5, and 55 kg, respectively. Twenty-nine patients received single doses of 20 mg/kg of body weight for artemisinin and 8 mg/kg for naphthoquine, and plasma drug concentrations were assessed at 13 time points over 42 days from treatment. We used nonlinear mixed-effects modeling to interpret the data, and allometric scaling was employed to adjust for the effect of body size. The pharmacokinetics of artemisinin was best described by one-compartment model and that of naphthoquine by a two-compartment disposition model. Clearance values for a typical patient (55-kg body weight and 44.3-kg fat-free mass) were estimated as 66.7 L/h (95% confidence interval [CI], 57.3 to 78.5 L/h) for artemisinin and 44.2 L/h (95% CI, 37.9 to 50.6 L/h) for naphthoquine. Nevertheless, we show via simulation that patients weighing ≥70 kg achieve on average a 30% lower day 7 concentration compared to a 48-kg reference patient at the doses tested, suggesting dose increases may be warranted to ensure adequate exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01930331.).

Topics: 1-Naphthylamine; Adolescent; Adult; Aminoquinolines; Antimalarials; Artemisinins; Body Weight; Child; Folic Acid Antagonists; Humans; Malaria, Falciparum; Naphthoquinones; Tanzania

Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against

Topics: Antiprotozoal Agents; Cyclohexenes; Humans; Hydroquinones; Indicators and Reagents; Iodine; Malaria, Falciparum; Naphthols; Naphthoquinones; Oxidative Stress; Parasitic Sensitivity Tests; Phenols; Plasmodium falciparum; Trypanosoma brucei rhodesiense

Atovaquone-proguanil remains effective against multidrug-resistant

Topics: Antimalarials; Atovaquone; Cambodia; Cytochromes b; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil

Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.. These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

Topics: Aniline Compounds; Antimalarials; Malaria, Falciparum; Metabolic Networks and Pathways; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium falciparum; Terpenes

Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of

Topics: Animals; Anopheles; Antimalarials; Atovaquone; Cytochromes b; DNA, Protozoan; Drug Resistance; Female; Malaria, Falciparum; Mice; Mice, Inbred BALB C; Mutation; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum

A recent randomized trial showed that artemisinin-naphthoquine (AN) was non-inferior to artemether-lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens.. An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen's incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved.. In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5-5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL.. Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Cost-Benefit Analysis; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Randomized Controlled Trials as Topic; Treatment Outcome

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an antiprotozoan and anticancer drug target. We have previously identified 2-phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism, and we demonstrated antitrypanosomal, antiplasmodial, and cytotoxic activities in cell cultures. The overall results lent support to the hypothesis that 2-phenoxy-1,4-naphthoquinone binds the GAPDH catalytic cysteine covalently through a phenolate displacement mechanism. By investigating the reactivity of 2-phenoxy-1,4-naphthoquinone and its analogs with four GAPDH homologs, we showed that the covalent inhibition is not preceded by the formation of a strong non-covalent complex. However, an up to fivefold difference in inactivation rates among homologs hinted at structural or electrostatic differences of their active sites that could be exploited to further design kinetically selective inhibitors. Moreover, we preliminarily showed that 2-phenoxy-1,4-naphthoquinone displays selectivity for GAPDHs over two other cysteine-dependent enzymes, supporting its suitability as a warhead starting fragment for the design of novel inhibitors.

Topics: Antiprotozoal Agents; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Trypanocidal Agents; Trypanosoma brucei brucei

Plasmodium falciparum (Pf) like most other organisms, has a sophisticated antioxidant system, part of which includes glutathione reductase (GR). GR works by recycling toxic glutathione disulfide to glutathione, thereby reducing reactive oxygen species and making a form of glutathione (GSH) the parasite can use. Inhibition of this enzyme in Pf impedes parasite growth. In addition, it has been confirmed that PfGR is not identical to human GR. Thus, PfGR is an excellent target for antimalarial drug development. A functional assay utilizing liquid chromatography-mass spectrometry was developed to specifically identify and evaluate inhibitors of PfGR. Using recombinant PfGR enzyme and 1,4-naphthoquinone (1) as a reference compound and 4-nitrobenzothiadiazole (2) and methylene blue (3) as additional compounds, we quantified the concentration of GSH produced compared with a control to determine the inhibitory effect of these compounds. Our results coincide with that presented in literature: compounds 1-3 inhibit PfGR with IC50 values of 2.71, 8.38, and 19.23 µm, respectively. Good precision for this assay was exhibited by low values of intraday and interday coefficient of variation (3.1 and 2.4%, respectively). Thus, this assay can be used to screen for other potential inhibitors of PfGR quickly and accurately.

Topics: Antimalarials; Chromatography, Liquid; Enzyme Assays; Enzyme Inhibitors; Glutathione; Glutathione Reductase; Humans; Malaria, Falciparum; Mass Spectrometry; Methylene Blue; Naphthoquinones; Plasmodium falciparum; Reproducibility of Results; Thiadiazoles

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia.

Topics: Antimalarials; Artemether; Artemisinins; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Half-Life; Humans; Kinetics; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Plasmodium falciparum

Plasmodial heat shock protein 70 (Hsp70) chaperones represent a promising new class of antimalarial drug targets because of the important roles they play in the survival and pathogenesis of the malaria parasite Plasmodium falciparum. This study assessed a set of small molecules (lapachol, bromo-β-lapachona and malonganenones A, B and C) as potential modulators of two biologically important plasmodial Hsp70s, the parasite-resident PfHsp70-1 and the exported PfHsp70-x. Compounds of interest were assessed for modulatory effects on the steady-state basal and heat shock protein 40 (Hsp40)-stimulated ATPase activities of PfHsp70-1, PfHsp70-x and human Hsp70, as well as on the protein aggregation suppression activity of PfHsp70-x. The antimalarial marine alkaloid malonganenone A was of particular interest, as it was found to have limited cytotoxicity to mammalian cell lines and exhibited the desired properties of an effective plasmodial Hsp70 modulator. This compound was found to inhibit plasmodial and not human Hsp70 ATPase activity (Hsp40-stimulated), and hindered the aggregation suppression activity of PfHsp70-x. Furthermore, malonganenone A was shown to disrupt the interaction between PfHsp70-x and Hsp40. This is the first report to show that PfHsp70-x has chaperone activity, is stimulated by Hsp40 and can be specifically modulated by small molecule compounds.

Topics: Alkaloids; Antimalarials; Cell Line; HSP70 Heat-Shock Proteins; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Protein Aggregates; Protozoan Proteins; Small Molecule Libraries

Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of Plasmodium falciparum in vitro. KSWI-855, the compound with the highest efficacy against the asexual stages of P. falciparum in vitro, also had in vitro activity against P. falciparum gametocytes and in vivo activity against P. berghei in a murine malaria model.

Topics: Amines; Animals; Antimalarials; Benzothiazoles; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Mice; Mice, Inbred C57BL; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Surface-Active Agents; Thiourea

A series of 36 new phenylsulfanylmethyl[1,4]naphthoquinones (7-42) were synthesized by a three-component reaction that involves lawsone, the appropriate aldehyde and thiols with variable substitution patterns. These reactions involve the in situ generation of o-quinone methides (o-QM) via Knoevenagel condensation and 1,4-nucleophilic addition under conventional heating or microwave irradiation. The new naphthoquinones obtained by this methodology were shown to have moderate to good in vitro antimalarial activity against Plasmodium falciparum (3D7).

Topics: Antimalarials; Cells, Cultured; Flow Cytometry; Humans; Indolequinones; Malaria, Falciparum; Molecular Structure; Naphthoquinones; Plasmodium falciparum; Sulfhydryl Compounds

Artemisinin-naphthoquine (ART-NQ) is a fixed-dose coformulated antimalarial therapy recommended as a single-dose treatment and marketed in Papua New Guinea among other tropical countries. We conducted a tolerability, safety, and efficacy study of ART-NQ for Papua New Guinean children aged 5 to 12 years with uncomplicated malaria, comparing single-dose ART-NQ (15 and 6 mg/kg of body weight) given with water (group 1; n = 15), single-dose ART-NQ (22 and 9 mg/kg) given with milk (group 2; n = 17), or two daily doses of 22 and 9 mg/kg given with water (group 3; n = 16). Of the 48 children (45 with Plasmodium falciparum malaria, 2 with Plasmodium vivax malaria, and 1 with mixed-species malaria), 2 in group 2 did not attend all follow-up assessments. All regimens were well tolerated, with no serious adverse events. There were no clinically significant changes in pulse, blood pressure, rate-corrected electrocardiographic QT, routine biochemistry/hematology, or hearing after treatment. Fever clearance was prompt. Mean 50% parasite clearance times were 4, 4, and 5 h for groups 1, 2, and 3, respectively. One group 1 patient had PCR-confirmed P. falciparum recrudescence at day 23; four had PCR-confirmed P. falciparum reinfections on day 28 or 42; and three had P. vivax infections detected on day 42. The only recurrent parasitemia in groups 2 and 3 occurred in a group 2 child who developed a P. vivax infection on day 42. Day 14 gametocyte positivity levels were 20%, 27%, and 9% in groups 1, 2, and 3, respectively. The lower single ART-NQ dose was associated with relatively frequent recurrence of parasitemia, but the prolonged gametocytemia in all three groups has implications for the transmission of malaria.

Topics: Antimalarials; Artemisinins; Blood Pressure; Child; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Female; Follow-Up Studies; Hearing; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Papua New Guinea; Recurrence; Treatment Outcome

Artemisinin-naphthoquine (ART-NQ) is a coformulated antimalarial therapy marketed as a single-dose treatment in Papua New Guinea and other tropical countries. To build on limited knowledge of the pharmacokinetic properties of the components, especially the tetra-aminoquinoline NQ, we studied ART-NQ disposition in Papua New Guinea children aged 5 to 12 years with uncomplicated malaria, comparing a single dose (15 and 6 mg/kg of body weight) administered with water (group 1; n = 13), a single dose (22 and 9 mg/kg) with milk (group 2) (n = 17), and two daily doses of 22 and 9 mg/kg with water (group 3; n = 16). The plasma NQ concentration was assayed by high-performance liquid chromatography, and the plasma ART concentration was assayed using liquid chromatography-mass spectrometry. Population-based multicompartment pharmacokinetic models for NQ and ART were developed. NQ disposition was best characterized by a three-compartment model with a mean absorption half-life (t(1/2)) of 1.0 h and predicted median maximum plasma concentrations that ranged as high as 57 μg/liter after the second dose in group 3. The mean NQ elimination t(1/2) was 22.8 days; clearance relative to bioavailability (CL/F) was 1.1 liters/h/kg; and volume at steady state relative to bioavailability (V(ss)/F) was 710 liters/kg. Administration of NQ with fat (8.5 g; 615 kJ) versus water was associated with 25% increased bioavailability. ART disposition was best characterized by a two-compartment model with a mean CL/F (4.1 liters/h/kg) and V/F (21 liters/kg) similar to those of previous studies. There was a 77% reduction in the bioavailability of the second ART dose (group 3). NQ has pharmacokinetic properties that confirm its potential as an artemisinin partner drug for treatment of uncomplicated pediatric malaria.

Topics: Antimalarials; Artemisinins; Biological Availability; Child; Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Administration Schedule; Female; Follow-Up Studies; Half-Life; Humans; Malaria, Falciparum; Malaria, Vivax; Male; Mass Spectrometry; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax

Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The Ag(II)-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO(3) and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin.

Topics: Animals; Antimalarials; Hemin; Humans; Malaria, Falciparum; Methemoglobin; Mice; Naphthoquinones; Plasmodium falciparum; Quinolines; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides; Solubility

Artemisinin-based combination therapies (ACTs) have been adopted as the first line of treatment against malaria in nearly all malaria-endemic countries, mainly as a result of Plasmodium falciparum infection, as this species of malaria parasite has developed resistance to most of the available non-artemisinin antimalarial drugs. Artemisinin-naphthoquine (ART-NQ, also named as ARCO™; Kunming Pharmaceuticals, Kunming, China) is one of the several currently available ACTs that show a promising approach to dealing with drug-resistant malaria rather than monotherapies. Unlike other ACTs, ART-NQ requires either a single-dose treatment or a two-dose treatment within 24 h against uncomplicated P. falciparum malaria; however, this was mainly validated in adults rather than children. Batty et al. performed the first pharmacokinetic study of ART-NQ combination therapy for uncomplicated pediatric malaria, and the authors' results are described and discussed below.

Topics: Antimalarials; Artemisinins; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Malaria, Vivax; Naphthoquinones; Papua New Guinea; Plasmodium falciparum; Plasmodium vivax; Treatment Outcome

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Mice; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum

Twenty-six novel naphthoquinone aliphatic esters were synthesized by esterification of 1,4-naphthoquinone alcohols with various aliphatic acids. The 1,4-naphthoquinone alcohols were prepared from 1-hydroxy-2-naphthoic acid in nine steps with excellent yields. Twenty-four of the novel synthetic naphthoquinone esters showed significant antimalarial activity with IC(50) values in the range of 0.03-16.63 microM. The length of the aliphatic chain and the presence of C-2' substituents on the propyl chain affected the activity. Interestingly, compounds 31 and 37 showed very good antimalarial activity and were not toxic to normal Vero cells, and the PTI values of 31 (>1990.38) and 37 (1825.94) are excellent. Both 31 and 37 showed potent inhibition against P. falciparum 3D7 cyt bc(1) and no inhibition on rat cyt bc(1). They showed IC(50) values in the nanomolar range, providing full inhibition of cyt bc(1) with one molecule inhibitor bound per cyt bc(1) monomer at the Q(o) site.

Topics: Animals; Antimalarials; Antineoplastic Agents; Cell Survival; Chlorocebus aethiops; Electron Transport Complex III; Erythrocytes; Inhibitory Concentration 50; Malaria, Falciparum; Male; Mitochondrial Membranes; Naphthoquinones; Plasmodium falciparum; Rats; Rats, Wistar; Saccharomyces cerevisiae; Structure-Activity Relationship; Vero Cells

We examined the atovaquone in vitro susceptibility and the cytochrome b (cytb) gene polymorphism of African Plasmodium falciparum isolates during the first years of atovaquone/proguanil use.. Between 1999 and 2004, we collected blood samples from French P. falciparum-infected patients returning from African countries. Atovaquone susceptibility was determined using an in vitro isotopic test and cytb genotyping was performed by restriction fragment length polymorphism analysis and sequencing. These results were analysed according to the clinical response to atovaquone/proguanil treatment.. No in vitro atovaquone resistance (IC50 > 1900 nM) and no cytb mutation leading to the Y268S substitution were detected among 477 unexposed African P. falciparum isolates. Eight cytb polymorphisms were found outside the ubiquinone reduction site by sequencing the entire gene of 270 isolates. One atovaquone/proguanil treatment failure was documented; the post-treatment isolate had an atovaquone susceptibility of 8230 nM and the Ser268 Cytb change; the pre-treatment isolate, obtained 4 weeks previously, was Cytb Tyr268 (wild-type).. No atovaquone/proguanil resistance was detected by phenotyping or genotyping among 477 unexposed African P. falciparum isolates. Atovaquone/proguanil-resistant parasite was detectable only in the post-treatment isolate from a treatment failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Cytochromes b; Drug Resistance; Drug Synergism; Female; France; Humans; Infant; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Restriction Fragment Length; Proguanil; Travel

The fixed dose combination atovaquone-proguanil is a recently introduced antimalarial for treatment and prophylaxis of Plasmodium falciparum malaria. It is highly effective with a good tolerability profile and a convenient prophylactic regimen. Nevertheless, cases of treatment failure have already been reported, which have been associated to mutations in the cytochrome b gene of the Plasmodium (pfcytb). The presence of atovaquone-proguanil in vivo resistance conferring mutations in pfcytb gene in Luanda, Angola, was investigated, in order to make recommendations on prescribing this antimalarial as prophylaxis for travellers.. Two hundred and forty nine blood samples from children hospitalized at Luanda Pediatric Hospital for malaria were studied. The PCR-RFLP methodology was used in order to identify pfcytb wild type codon 268 and two point mutations: T802A and A803C.. All samples were identified as wild type for pfcytb gene at codon 268. In the studied population, no mutations associated to atovaquone-proguanil treatment failure were found. Prevalence of the studied mutations in the region was estimated to be less than 0.77% (99% significance level).. Atovaquone-proguanil can be recommended for use by travellers to Luanda with expected high efficacy. This represents an improvement compared to other currently used prophylactic antimalarials in this region. However, it is imperative to continue surveillance.

Topics: Angola; Animals; Antimalarials; Atovaquone; Cytochromes b; DNA Mutational Analysis; Drug Resistance; Humans; Malaria, Falciparum; Mutation; Naphthoquinones; Plasmodium falciparum; Polymorphism, Genetic; Proguanil; Travel

Topics: Anti-Infective Agents; Antimalarials; Artemisinins; Atovaquone; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Health Care Costs; Humans; Lumefantrine; Malaria, Falciparum; Naphthoquinones; Proguanil; Sesquiterpenes; Survival Rate; World Health Organization

There is clear evidence that most antimalarial drugs, while acting through different mechanisms, are associated with parasite growth/development inhibition and eventual parasite death. However, the exact mode of parasite death remains unclear. In the present study, we investigated the ability of various drugs, including two antimalarial drugs (chloroquine and atovaquone), a topoisemerase II inhibitor (etoposide) and a nitric oxide donor (S-nitro-N-acetyl-D, L-penicillamine), to induce apoptosis in a laboratory strain of Plasmodium falciparum. Results obtained from flow cytometric analysis showed a significant reduction in the percent of parasitemia and parasite growth in all drug-treated parasite cultures, including those treated with etoposide and S-nitro-N-acetyl-D, L-penicillamine. For further investigation, we used various biochemical approaches including the terminal dUTP nick-end labeling assay, determination of mitochondrial membrane integrity and DNA degradation/fragmentation, to analyze the changes occurring during parasite-drug interactions and eventual death. We observed that loss of membrane potential was induced in parasite cultures treated with atovaquone, while S-nitro-N-acetyl-D, L-penicillamine induced abnormal parasite forms, "crisis forms", and minor DNA degradation. However, these features were not observed in the parasite cultures treated with chloroquine nor were other features of apoptosis-like death associated with any of the drugs used in this study. The death resulting from the various drug treatments is atypical of apotosis. More studies will be needed to define the precise mode of death exhibited by P. falciparum.

Topics: Animals; Antimalarials; Apoptosis; Atovaquone; Cells, Cultured; Chloroquine; DNA Fragmentation; DNA, Protozoan; Enzyme Inhibitors; Erythrocytes; Etoposide; Flow Cytometry; Humans; In Situ Nick-End Labeling; Malaria, Falciparum; Membrane Potentials; Mitochondrial Membranes; Naphthoquinones; Nitric Oxide Donors; Parasitemia; Penicillamine; Plasmodium falciparum

In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb) gene (Tyr268Ser and Tyr268Asn). However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa.. The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing.. 295 samples from Nigeria (111), Malawi (91) and Senegal (93) were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5%) unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site.. No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; Animals; Antimalarials; Atovaquone; Child; Codon; Cytochromes b; DNA, Protozoan; Drug Resistance; Humans; Malaria, Falciparum; Malawi; Molecular Sequence Data; Mutation, Missense; Naphthoquinones; Nigeria; Plasmodium falciparum; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Proguanil; Protozoan Proteins; Senegal; Sequence Alignment; Sequence Homology, Amino Acid; Travel

We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.

Topics: Animals; Antimalarials; Atovaquone; Culture Media; Cytochrome b Group; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium falciparum; Proguanil; Recurrence; Triazines

The importation of drug-resistant malaria is a growing public health problem in non-endemic countries. The combination of atovaquone and proguanil (Malarone) has become established as an agent of choice to prevent and treat chloroquine-resistant Plasmodium falciparum malaria in travelers. We describe the first reported case in North America of genetically confirmed atovaquone/proguanil-resistant P. falciparum malaria. Polymerase chain reaction and sequence analysis of the primary and recrudescent isolates confirmed the acquisition of a point mutation (Tyr268Ser) in the cytochrome b gene of the recrudescent isolate known to confer high-level resistance to atovaquone. Suboptimal therapy may have played a contributory role in the emergence of resistance.

Topics: Adult; Animals; Antimalarials; Atovaquone; Canada; Cytochromes b; Drug Resistance; Female; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Sierra Leone

Topics: Animals; Antimalarials; Atovaquone; Biological Assay; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Half-Life; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil

Atovaquone-proguanil has recently been introduced for the treatment and prophylaxis of malaria. However, resistance of Plasmodium falciparum is increasingly reported. We assessed P. falciparum polymorphisms associated with resistance to atovaquone (cytochrome b, cytb) and to cycloguanil, the active compound of proguanil (dihydrofolate reductase, dhfr) in 100 isolates from northern Ghana. None of these exhibited cytb codon 268 mutations. Moreover, no dhfr V16A, S108T or I164L mutations linked with cycloguanil resistance were detected. However, dhfr triple mutants (S108N-I51L-C59R) conferring resistance to proguanil and sulphadoxine-pyrimethamine were seen in 51% of the isolates. In northern Ghana, P. falciparum cytb codon 268 mutations associated with atovaquone resistance are absent. Although proguanil appears to act synergistically with atovaquone in a way different from its antifolate property, the abundance of dhfr polymorphisms will likely compromise the prevention of dissemination of atovaquone-resistant parasites once emerged.

Topics: Animals; Antimalarials; Atovaquone; Child, Preschool; Cytochromes b; Drug Combinations; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Female; Folic Acid Antagonists; Ghana; Humans; Infant; Malaria, Falciparum; Male; Mutation; Naphthoquinones; Plasmodium falciparum; Polymorphism, Restriction Fragment Length; Proguanil; Pyrimethamine; Sulfadoxine; Tetrahydrofolate Dehydrogenase; Triazines

Malarone (atovaquone-proguanil) is an effective drug for the treatment and prophylaxis of multidrug-resistant falciparum malaria. However, first cases of resistance have been reported, which are associated with mutations at codon 268 of the parasite's cytochrome b gene. We report the first case of Malarone treatment failure from Central Africa.Drug concentration was well within curative range. Pre- and post-treatment Plasmodium falciparum isolates revealed codon 268 wild-type alleles, and no other mutations of the putative atovaquone-binding domain.These findings illustrate the spread of atovaquone-proguanil-resistance in Africa and question the usefulness of codon 268 as the only target for the surveillance of its emergence.

Topics: Adult; Animals; Antimalarials; Atovaquone; Biological Availability; Cytochromes b; Drug Combinations; Drug Resistance; Female; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Point Mutation; Proguanil; Treatment Failure

A 22-year-old Japanese man noticed pyrexia and diarrhea after travel to Guinea. Notable physical findings included hepatosplenomegaly. Treatment with oral quinine and minocycline was started after definitive diagnosis of falciparum malaria by blood smear. Initially, parasitemia and body temperature decreased but by the third night of therapy his temperature increased to 40 degrees C with a slight increase of parasite count. When quinine treatment was changed to atovaquone/proguanil, his temperature dropped immediately and complete plasmodial elimination was confirmed on microscopic examination. Subsequent recrudescence of the disease was not observed. It was concluded that the antimalarial treatment with atovaquone/proguanil might become invaluable in Japan.

Topics: Adult; Atovaquone; Blood Chemical Analysis; Bone Marrow Cells; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Naphthoquinones; Proguanil; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Two single-point mutations of the Plasmodium falciparum cytochrome b gene (Tyr268Asn and Tyr268Ser) were recently reported in cases of atovaquone/proguanil (Malarone) treatment failure. However, little is known about the prevalence of codon-268 mutations and their quantitative association with treatment failure.. We set out to assess the prevalence of codon-268 mutations in P. falciparum isolates imported into Europe and to quantify their association with atovaquone/proguanil treatment failure. Isolates of P. falciparum collected by the European Network on Imported Infectious Disease Surveillance between April 2000 and August 2003 were analyzed for codon-268 mutations, by use of polymerase chain reaction-restriction fragment-length polymorphism.. We successfully screened 504 samples for the presence of either Tyr268Ser or Tyr268Asn. One case of Ser268 and no cases of Asn268 were detected. Therefore, we can be 95% confident that the prevalence of Ser268 in the European patient pool does not exceed 0.96% and that Asn268 is less frequent than 0.77%. In 58 patients treated with atovaquone/proguanil, Tyr268Ser was present in 1 of 5 patients with treatment failure but in 0 of 53 successfully treated patients.. Tyr268Ser seems to be a sufficient, but not a necessary, cause for atovaquone/proguanil treatment failure. The prevalence of both codon-268 mutations is currently unlikely to be >1% in the European patient pool.

Topics: Adolescent; Adult; Aged; Amino Acid Substitution; Animals; Antimalarials; Atovaquone; Codon; Cytochromes b; DNA, Protozoan; Drug Combinations; Drug Resistance; Europe; Female; Genes, Protozoan; Humans; Malaria, Falciparum; Male; Middle Aged; Molecular Epidemiology; Mutation, Missense; Naphthoquinones; Plasmodium falciparum; Point Mutation; Polymorphism, Restriction Fragment Length; Proguanil; Protozoan Proteins; Treatment Failure

Published pharmacokinetic data indicate that after treatment of patients with therapeutic doses of atovaquone/proguanil hydrochloride (Malarone, GlaxoSmithKline Research Triangle Park, NC), the plasma half-lives of these drugs are 70h and 15h, respectively. However, using two biologic assays (mosquito transmission and in vitro asexual stage development), we demonstrate here that sera from volunteers treated with atovaquone/proguanil retained activity against Plasmodium falciparum up to 6 weeks after such treatment. This activity was due to atovaquone, as administration of this drug alone replicated the data obtained with the combination. Most notably, asexual stage development of an atovaquone-resistant strain (NGATV01) of P. falciparum was not inhibited by sera taken after atovaquone treatment. These data indicate that for atovaquone, biologic assays, though not quantitative, are more sensitive than the usual physicochemical assays. Also, persistence of atovaquone in plasma at low concentrations for long periods may increase the risk of resistant parasites arising.

Topics: Animals; Anopheles; Antimalarials; Atovaquone; Female; Humans; Insect Vectors; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Serum Bactericidal Test

Topics: Antimalarials; Antiprotozoal Agents; Atovaquone; Child, Preschool; Chromatography, High Pressure Liquid; Drug Resistance; Drug Therapy, Combination; Female; Humans; Infant; Malaria, Falciparum; Male; Naphthoquinones; Proguanil; Tablets

Resistance of Plasmodium falciparum to atovaquone in vitro and in vivo has been associated to mutations in the parasite cytochrome b gene.. Cultures were sequentially subjected to increasing doses of atovaquone alone or in combination with cycloguanil and the cytochrome b gene was sequenced. Additionally, we investigated the parasite cytochrome b gene of a patient returning from Mali with Malarone treatment failure in vivo.. All strains that survived atovaquone concentrations in vitro of 2 x 10(-8) to 2 x 10(7) M showed the M133I mutation and one strain with the highest atovaquone concentration the additional mutation L171F. Sequencing of the in vivo treatment failure revealed a point mutation at codon 268 resulting in an amino acid change from tyrosine to serine. Based on the repeated emergence of mutations at codon 268, but no detection of alterations at codon 133 in vivo, we developed a detection method for the diagnostic of codon 268 polymorphisms as a potential atovaquone/proguanil resistance marker. A nested PCR with 3 different pairs of primers for the second round was designed. Each product was digested with restriction enzymes, capable to distinguish the wild type from the two reported mutations at codon 268.. Mutations at codon 268 of the parasite cytochrome bc1 gene are associated with atovaquone/proguanil treatment failure in vivo and can be used as potential resistance marker This method provides a novel and robust tool to investigate the relevance of codon 268 polymorphisms as resistance marker and to monitor the further emergence of atovaquone/proguanil resistance.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Atovaquone; Codon; Drug Resistance; Electron Transport Complex III; Genetic Markers; Humans; Malaria, Falciparum; Mutation; Naphthoquinones; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Proguanil; Triazines

To offer effective malaria chemoprophylaxis for travelers in a country, the physician must know the precise status of malaria there (frequency, resistance), determine the degree of exposure to mosquito bites, evaluate the precise clinical condition of the traveler, and improve the traveler's compliance with treatment by providing good information on potential side-effects. These side-effects, sometimes overemphasized in the media, lead to poor compliance, particularly after returning home, and, consequently, increase the risk of acquiring malaria. The recently approved Malarone could overcome these drawbacks. But its cost is high and its wide use could also lead to the emergence of resistant strains. Therefore, training professionals in travel medicine is important in malaria prevention and decrease the prescription of abusive or inaccurate prophylaxis (e.g., most tourists traveling in organized tours in Asia, with no stay in remote malaria endemic areas, do not need any prophylaxis). In addition, prevention of mosquito bites with repellents, impregnated bed nets, and indoor insecticide-dispensing devices is still an important tool for controlling malaria in travelers.

Topics: Animals; Antimalarials; Atovaquone; Child; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple; Endemic Diseases; Female; Humans; Immunocompromised Host; Insect Bites and Stings; Malaria, Falciparum; Mosquito Control; Naphthoquinones; Patient Compliance; Pregnancy; Proguanil; Travel

Topics: Animals; Antimalarials; Atovaquone; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Male; Naphthoquinones; Plasmodium falciparum; Proguanil

We report a case of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to Kenya. Recurrent parasitemia occurred 30 days after directly observed therapy with a combination of atovaquone and proguanil. Treatment failure was confirmed by genetic fingerprinting and sequencing. The primary isolate had wild-type sequence of cytochrome b; however, the recrudescent isolate had a single mutation at position 268 (Tyr268Ser).

Topics: Adult; Animals; Antimalarials; Atovaquone; Cytochrome b Group; Drug Resistance; Drug Therapy, Combination; Female; Humans; Kenya; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Travel; Treatment Failure

Atovaquone is a new broad-spectrum antiprotozoal drug with high in vitro activity against multidrug-resistant Plasmodium falciparum. Its specific action against protozoans is based on the inhibition of the parasite cytochrome bc1 complex of the mitochondrial electron transport system. Protozoans may develop atovaquone resistance by the selection of a mutant cytochrome b gene. With the increasing availability of atovaquone-proguanil combination for prophylaxis and treatment of malarial infections, it is necessary to establish baseline data on atovaquone sensitivity before the drug is introduced massively in an endemic region. For this purpose, the activity of atovaquone was assessed indirectly by in vitro drug sensitivity assays with several serum substitutes and DNA sequencing of the cytochrome b gene. Using the standard in vitro assay procedures with 10% human serum, the geometric mean 50% inhibitory concentration (IC50) for atovaquone was calculated to be 1.15 nM (range = 0.460-4.17 nM), while the use of 10% fetal calf serum resulted in lower IC50s (geometric mean = 0.575, range = 0.266-2.20 nM). The use of Albumax, a lipid-enriched bovine albumin, over the same concentration range (0.25-16 nM) showed poor results. None of the 37 isolates with an atovaquone IC50 < 4.17 nM displayed any mutation. Further monitoring of atovaquone-resistant P. falciparum is warranted for the rational use of this new antimalarial drug.

Topics: Adolescent; Adult; Animals; Antimalarials; Atovaquone; Cameroon; Child; Culture Media; DNA Primers; Drug Resistance; Electron Transport Complex III; Humans; Malaria, Falciparum; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymerase Chain Reaction

Malarone, a fixed combination of atovaquone with proguanil (AP), has recently been recognized as a promising treatment against multidrug-resistant Plasmodium falciparum. In Vietnam, the first-line treatment for P. falciparum malaria is currently a combination of mefloquine and an artemisinin derivative, and the use of AP has not been explored. The aim of the present study, based in Vietnam, was to assess the efficacy of AP when used to treat P. falciparum recrudescences that had occurred after primary treatment with mefloquine-artesunate. All but two of the 39 patients investigated completed follow-up. The mean parasite- and fever-clearance times [and 95% confidence intervals (CI)] after AP treatment were 36 (30-42) and 21 (18-24) h, respectively. Most (32) of the 37 infections that were followed adequately appeared to be eradicated by the AP, the other five recrudescing once more. The overall cure 'rate' and (CI) was 86% (76%-98%). All of the patients tolerated the AP well. Atovaquone-proguanil appears to be a safe and promising alternative treatment for P. falciparum infections in South-east Asia, although the combination is relatively expensive and may not clear some infections with multidrug-resistant parasites.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Child; Disease Outbreaks; Drug Combinations; Drug Resistance, Multiple; Female; Follow-Up Studies; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Naphthoquinones; Parasitemia; Plasmodium falciparum; Proguanil; Recurrence; Sesquiterpenes; Treatment Failure; Vietnam

Malaria continues to be a problem for children returning or immigrating to industrialized countries from tropical regions. Proper diagnosis begins with clinical suspicion. In nonimmune children, malaria typically presents with high fever that might be accompanied by chills and headache. Symptoms and signs may be more subtle in partially immune children, and anemia and hepatosplenomegaly may also be present. Children may present with respiratory distress and/or rapidly progressing cerebral malaria that manifests as altered sensorium and, sometimes, seizures. Thick blood smears help to determine when infection is present, but a single smear without parasites is not sufficient to rule out malaria. Thin blood smears aid in identifying the species of parasite. Treatment must include careful supportive care, and intensive care measures should be available for treating children with complicated Plasmodium falciparum malaria. Medical regimens can include mefloquine, atovaquone-proguanil, sulfadoxine-pyrimethamine, quinine or quinidine, clindamycin, doxycycline, chloroquine, and primaquine.

Topics: Animals; Antimalarials; Atovaquone; Child; Chloroquine; Drug Combinations; Humans; Malaria; Malaria, Falciparum; Mefloquine; Naphthoquinones; Plasmodium falciparum; Proguanil; Pyrimethamine; Sulfadoxine

The Atovaquone/proguanil combination has quickly been established as an effective chemoprophylaxis for travellers to areas with chloroquineresistant Plasmodium falciparum malaria. We describe the molecular cause of the first reported case of primary Atovaquone/proguanil resistance observed in our department in a Plasmodium falciparum infected traveller returning from West Africa, and link our findings to other reports of resistance.

Topics: Adult; Africa; Animals; Atovaquone; Bacterial Proteins; Cytochrome b Group; Denmark; Drug Resistance, Multiple; Drug Therapy, Combination; Ferritins; Humans; Malaria, Falciparum; Male; Microbial Sensitivity Tests; Mutation; Naphthoquinones; Pharmacogenetics; Plasmodium falciparum; Polymerase Chain Reaction; Proguanil; Risk Assessment; Travel; Treatment Failure

The purpose of this open non-comparative retrospective study was to evaluate the efficacy and tolerance of Malarone for management of uncomplicated imported Plasmodium falciparum malaria. A total of 112 non-immune adult patients were included between 1999 and 2001. Excellent responses in terms of both clinical symptoms and parasite control were achieved within 4 days after the beginning of treatment in all cases. No recurrence was observed after 28 days of individual followup. Tolerance was satisfactory with no adverse events except for occasional, minor gastrointestinal upset. Based on our experience, Malarone appears to be effective, well-tolerated, and suitable for routine management of uncomplicated imported Plasmodium falciparum malaria.

Topics: Adolescent; Adult; Aged; Antimalarials; Atovaquone; Drug Therapy, Combination; Female; Gastritis; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Proguanil; Recurrence; Retrospective Studies; Treatment Outcome

(1) Quinine, halofantrine and mefloquine are effective treatments for most cases of uncomplicated Plasmodium falciparum malaria. (2) The choice of drug for prevention of P. falciparum malaria in highly endemic regions depends on the risk of chloroquine resistance, and possibly mefloquine resistance. The reference treatments are the chloroquine + proguanil combination, and mefloquine. (3) Marketing authorisation has been granted in France for the atovaquone + proguanil combination, in curative and preventive treatment of P. falciparum malaria. (4) The efficacy of the atovaquone + proguanil combination in uncomplicated malaria is similar to that of other treatments. Some strains of malaria seem to have reduced sensitivity. (5) The atovaquone + proguanil combination is also effective as prophylaxis, but there are no clinical trials showing whether it is equivalent to or better than other preventive treatments in non immune travellers. (6) According to the French licensing terms, atovaquone + proguanil prophylaxis can be stopped 7 days after leaving an endemic area, rather than 3-4 weeks with other drugs. This recommendation is based on weak evidence: mainly on theoretical arguments and on the absence of clinical malaria in some patients with evidence of P. falciparum infection. (7) The atovaquone + proguanil combination is less effective against other Plasmodium species (P. malariae, P. ovale and P. vivax). Chloroquine remains the reference treatment for these forms of malaria, which do not carry a risk of serious complications. (8) There were few adverse events in people taking the atovaquone + proguanil combination during clinical trials. During curative treatment, this combination caused more nausea and vomiting than reference treatments, while, in the prophylactic setting, it had slightly fewer adverse effects than the chloroquine + proguanil combination or mefloquine alone. But the drop out rate was not significantly different between treatment groups. (9) Atovaquone should be taken with food, to improve absorption. (10) The atovaquone + proguanil combination is expensive and is not refunded in France. In contrast, curative treatment with quinine is cheap, and is fully refunded. (11) Mefloquine and quinine remain the treatments of choice for uncomplicated malaria where there is chloroquine resistance. The atovaquone + proguanil combination is useful if mefloquine and quinine are contraindicated; unlike halofantrine, this combination does not carry the r

Topics: Antimalarials; Clinical Trials as Topic; Developing Countries; Drug Approval; Drug Combinations; Drug Costs; Drug Interactions; Drug Resistance; Ethics, Medical; France; Humans; Malaria, Falciparum; Mefloquine; Naphthoquinones; Phenanthrenes; Proguanil; Quinine; Randomized Controlled Trials as Topic; Travel

In 1996, Glaxo Wellcome offered to donate up to a million treatment courses annually of Malarone, a new antimalarial, with a view to reducing the global burden of malaria. The Malarone Donation Programme (MDP) was established the following year. Eight pilot sites were selected in Kenya and Uganda to develop and evaluate an effective, locally sustainable donation strategy that ensured controlled and appropriate use of Malarone. The pilot programme targeted individuals who had acute uncomplicated Plasmodium falciparum malaria that had not responded to first-line treatments with chloroquine or sulfadoxine-pyrimethamine. Of the 161 079 patients clinically diagnosed at the pilot sites as having malaria, 1101 (0.68%) met all the conditions for participation and received directly observed treatment with Malarone. MDP had a positive effect at the pilot sites by improving the diagnosis and management of malaria. However, the provision of Malarone as a second-line drug at the district hospital level was not an efficient and effective use of resources. The number of deaths among children and adults ineligible for MDP at the pilot sites suggested that high priority should be given to meeting the challenges of malaria treatment at the community level.

Topics: Antimalarials; Communicable Disease Control; Cooperative Behavior; Drug Industry; Health Services Accessibility; Humans; Kenya; Malaria, Falciparum; Naphthoquinones; Pilot Projects; Private Sector; Program Evaluation; Proguanil; Public Sector; Uganda

Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

We report the first in vitro and genetic confirmation of Malarone (GlaxoSmithKline; atovaquone and proguanil hydrochloride) resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01) was shown to be resistant to atovaquone and the antifolate pyrimethamine. The cytochrome b gene of isolate NGATV01 showed a single mutation, Tyr268Asn which has not been seen previously.

Topics: Amino Acid Substitution; Animals; Antimalarials; Atovaquone; Codon; Cytochromes b; Drug Combinations; Drug Resistance; Humans; London; Malaria, Falciparum; Male; Middle Aged; Mutation, Missense; Naphthoquinones; Nigeria; Parasitemia; Plasmodium falciparum; Proguanil; Protozoan Proteins; Travel

This paper describes the introduction of the Malarone Donation Programme in KENYA: Using a policy analysis approach it illustrates the political nature of donation programmes and how they are affected by a large and varied group of national, regional and international stakeholders, with different levels of influence and experience. The paper shows that interaction between these different groups may affect the development and implementation of the donation programme. It ends by raising some more general questions about public/private partnerships and corporate donation programmes, and their potential impact on national drug policies.

Topics: Antimalarials; Atovaquone; Communicable Disease Control; Drug Combinations; Drug Industry; Financing, Organized; Humans; Interinstitutional Relations; Kenya; Malaria, Falciparum; Naphthoquinones; Policy Making; Politics; Private Sector; Program Evaluation; Proguanil; Public Sector

To bring military medical problems concerning malaria to the attention of the Defence Medical Services.. Seven military medical problems related to malaria are illustrated by cases referred for secondary assessment over the past five years. Each is discussed in relation to published data.. The cases of failure of various kinds of chemoprophylaxis, diagnosis and treatment of malaria may represent just a fraction of the magnitude of the overall problem but in the absence of reliable published military medical statistics concerning malaria cases, the situation is unclear.. Present experience suggests there are a number of persisting problems affecting the military population in relation to malaria. Only publication of reliable statistics will define their magnitude. Interim remedies are proposed whose cost-effectiveness remains to be established.

Topics: Adult; Animals; Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Global Health; Humans; Kenya; Malaria, Falciparum; Malaria, Vivax; Male; Mefloquine; Military Medicine; Military Personnel; Naphthoquinones; Patient Compliance; Plasmodium falciparum; Plasmodium vivax; Proguanil; Sierra Leone; Treatment Failure; Treatment Outcome; United Kingdom

A deterministic mathematical model which predicts the probability of developing a new drug-resistant parasite population within the human host is reported. The model incorporates the host's specific antibody response to PfEMP1, and also investigates the influence of chemotherapy on the probability of developing a viable drug-resistant parasite population within the host. Results indicate that early treatment, and a high antibody threshold coupled with a long lag time between antibody stimulation and activity, are risk factors which increase the likelihood of developing a viable drug-resistant parasite population. High parasite mutation rates and fast PfEMP1 var gene switching are also identified as risk factors. The model output allows the relative importance of the various risk factors as well as the relationships between them to be established, thereby increasing the understanding of the conditions which favour the development of a new drug-resistant parasite population.

Topics: Animals; Antibodies, Protozoan; Antimalarials; Atovaquone; Computer Simulation; Drug Resistance; Humans; Malaria, Falciparum; Models, Biological; Mutation; Naphthoquinones; Plasmodium falciparum; Protozoan Proteins; Pyrimethamine; Time Factors

Topics: Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Philippines; Proguanil; Pyrimethamine; Sulfadoxine

Topics: Abdominal Pain; Administration, Oral; Antimalarials; Atovaquone; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Fees, Pharmaceutical; Humans; Malaria, Falciparum; Naphthoquinones; Nausea; Proguanil

Topics: Antimalarials; Atovaquone; Chloroquine; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Travel; Treatment Outcome

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

Topics: Animals; Antimalarials; Artemisinins; Atovaquone; Chloroquine; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Mefloquine; Naphthoquinones; Plasmodium falciparum; Sesquiterpenes

Topics: Africa; Altruism; Antimalarials; Atovaquone; Developing Countries; Drug Combinations; Drug Resistance, Multiple; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil

Sixteen Saimiri sciureus monkeys were administered PS-15-atovaquone, PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. The in vitro antimalarial activity of serum against Plasmodium falciparum obtained from these monkeys at 3, 6, and 12 hr after the administration of drug(s) were measured by bioassay and analyzed by Duncan's and Newman-Keul's tests. PS-15-atovaquone was found to be the most effective antimalarial combination, followed by PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. These dual PS-15 combinations are effective combinations and, in-particular, PS-15-atovaquone is worthy of further evaluation.

Topics: Animals; Antimalarials; Atovaquone; Biological Assay; Dapsone; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Regression Analysis; Saimiri; Sulfamethoxazole

The combination of proguanil and atovaquone has been shown to be more effective in curing drug-resistant infections of falciparum malaria than atovaquone or proguanil alone. Our current study sought to determine whether the antimalaria activity could be increased by adding dapsone. Plasma samples, obtained from individuals 4-72 h after proguanil-atovaquone administration, were 2-3 times more active against Plasmodium falciparum in vitro when dapsone was added to them. The enhanced activity of the combination of proguanil, atovaquone and dapsone is probably due to the combined activity of two synergistic combinations: proguanil-atovaquone and cycloguanil (metabolite of proguanil)-dapsone. These findings suggest that further studies are needed to evaluate the clinical value of the triple drug combination of proguanil, atovaquone and dapsone in the treatment of multi-drug resistant malaria.

Topics: Animals; Antimalarials; Atovaquone; Dapsone; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Plasmodium falciparum; Proguanil; Thailand

Topics: Antimalarials; Atovaquone; Chloroquine; Drug Resistance; Drug Therapy, Combination; Humans; Malaria; Malaria, Falciparum; Mefloquine; Naphthoquinones; Proguanil

The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimalarials; Atovaquone; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones

A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.

Topics: Administration, Oral; Animals; Antimalarials; Aotus trivirgatus; Atovaquone; Drug Synergism; Folic Acid Antagonists; Imides; Injections, Subcutaneous; Malaria, Falciparum; Mice; Naphthoquinones; Phenyl Ethers; Plasmodium falciparum; Proguanil; Sulfamethoxazole; Triazines

566C80 is a novel hydroxynaphthoquinone with broad-spectrum anti-parasitic properties. In vitro the compound was more potent against Plasmodium falciparum than any of the established anti-malarial drugs. It had good activity against the pathogen in Aotus monkeys and was also effective in rodents infected with various drug-resistant strains of P. yoelii and P. berghei. In mice the compound showed significant activity against Toxoplasma gondii. Evaluation of the metabolic stability of 566C80 to NADPH-mediated oxidative metabolism was made using microsome preparations from a number of species including man. Unlike other quinones examined, 566C80 was shown to be inert in these assays. In Phase 1 clinical studies up to 750mg of compound were given as a single oral dose to fasted healthy male adults. This was well tolerated and the plasma drug elimination half-life was approximately 70h. In these subjects a 450mg dose gave plasma concentrations of 0.1-0.3 micrograms/ml which were achieved 1 h post-dosing and remained so for at least 7 days. Volunteers ingesting food prior to drug administration had quinone plasma levels which were significantly higher. Phase II trials are now underway to assess 566C80 for use against malaria and opportunistic infections in AIDS patients.

Topics: 4-Quinolones; Acquired Immunodeficiency Syndrome; Adult; Animals; Anti-Infective Agents; Antimalarials; Aotus trivirgatus; Atovaquone; Dogs; Humans; Malaria, Falciparum; Male; Microsomes, Liver; Middle Aged; NADP; Naphthoquinones; Opportunistic Infections; Plasmodium; Rats; Toxoplasma