naphthoquinones and Malaria

This study aimed to synthesize the existing evidence on the efficacy and safety of a single dose artemisinin-naphthoquine (ASNQ) for treatment of uncomplicated malaria in endemic countries.. A meta-analysis of randomized, controlled trials (RCT), assessing efficacy and safety of single dose ASNQ was carried out. Comparator drugs included artemether-lumefentrine (AL), chloroquine plus sulfadoxine-pyrimethamine (CQSP) and dihydroartemisinin-piperaquine (DHP). The efficacy and safety profile of non-comparator, single-arm studies on the single dose ASNQ was also assessed. The primary endpoint was efficacy defined as an absence of PCR-confirmed parasitaemia. The methodological quality of the included studies was assessed using the six domains for the risk of bias.. Five RCTs and three single-arm studies were included in this review. As RCT studies did not compare the same anti-malarial drugs, it was difficult to do a pooled analysis. At day 28, a pooled analysis of two RCTs (n = 271) showed a comparable efficacy on PCR-confirmed parasitaemia between ASNQ and AL. Another RCT, which compared ASNQ and CQSP or ASNQ and DHP, also showed comparable efficacy. At day 42, one RCT comparing ASNQ and DHP and another RCT comparing ASNQ and AL reported comparable levels of efficacy. The proportion of parasite clearance was faster in the ASNQ groups than the comparators at day 1, and almost all parasites were cleared by day 3 in the ASNQ groups.. The present review provides some evidence to support that there is similar efficacy and safety of the single dose ASNQ compared to other anti-malarial drugs in treating uncomplicated malaria. Larger, adequately powered, well-designed studies are recommended to substantiate the efficacy and safety in different populations and in different epidemiological settings. As the potential evolution of drug resistance is a great concern and this cannot be addressed in a short-term study, the use of single dose ASNQ needs further evaluation.

Topics: Antimalarials; Artemisinins; Humans; Malaria; Naphthoquinones; Randomized Controlled Trials as Topic; Treatment Outcome

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Topics: Animals; Cell Membrane; Chagas Disease; Humans; Hydrophobic and Hydrophilic Interactions; Leishmania; Leishmaniasis; Malaria; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Trypanosoma cruzi; Tuberculosis

Topics: Adult; Antimalarials; Atovaquone; Child; Clothing; Doxycycline; Female; Humans; Insect Repellents; Insecticides; Malaria; Mefloquine; Mosquito Control; Naphthoquinones; Pregnancy; Proguanil; Travel

Topics: Adult; Antimalarials; Artemether; Artemisinins; Atovaquone; Chloroquine; Climate; Doxycycline; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Mefloquine; Naphthoquinones; Pregnancy; Proguanil; Risk Factors; Self Medication; Sesquiterpenes; Time Factors; Travel

Topics: Adult; Antimalarials; Atovaquone; Child; Chloroquine; Clothing; Doxycycline; Female; Humans; Insect Repellents; Insecticides; Malaria; Mefloquine; Mosquito Control; Naphthoquinones; Pregnancy; Proguanil; Travel

Topics: Adult; Antimalarials; Atovaquone; Child; Chloroquine; Clothing; Doxycycline; Female; Humans; Insect Repellents; Insecticides; Malaria; Mefloquine; Mosquito Control; Naphthoquinones; Pregnancy; Travel

Three new antimalarial drugs have recently been registered in the Netherlands: atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are effective against parasites with multiple resistance. Atovaquone-proguanil and artemether-lumefantrine seem in practice to be equivalent for the treatment of non-severe Plasmodium falciparum infections for respectively persons of more than 11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular injection) is registered for the treatment of severe malaria in children up to 17 years of age. Atovaquone-proguanil is also registered for prophylactic use in adults. The intravenous administration of quinine is preferable in the case of seriously ill patients. In patients with non-severe malaria for whom parenteral treatment is indicated, artemotil is a good alternative for quinine.

Topics: Antimalarials; Artemether; Artemisinins; Atovaquone; Drug Approval; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Naphthoquinones; Netherlands; Proguanil; Sesquiterpenes; Treatment Outcome

The morbidity and mortality associated with malaria have spurred efforts to find novel antimalarial agents with improved potency and selectivity. Leads for agents continue to be obtained from natural sources (plants and microorganisms) and chemical syntheses. Screening of commercial or specialized databases have also yielded promising leads. The structural diversity of compounds with good (micromolar and lower) activity point to the considerable tolerance for different structural elements in the "antimalarial pharmacophore." It may also be a reflection of the varied targets present in the plasmodia. The challenge in malaria chemotherapy is to find safe and selective agents whose potencies will not be compromised by plasmodial resistance. Modification of potential leads should also aim at improving "drug-like" character, viz. to ensure acceptable oral bioavailability. A review of the literature shows that there is a growing trend towards the development of target-specific antimalarial agents (for example, agents inhibiting plasmodial farnesyl transferase, cyclin dependent kinases, proteases, choline transport). An increasing number of reports focus on the development of chemosensitizers, agents that are capable of reversing plasmodial resistance.

Topics: Alkaloids; Alkyl and Aryl Transferases; Animals; Antimalarials; Chalcone; Databases as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Inhibitory Concentration 50; Malaria; Models, Chemical; Naphthoquinones; Peptides; Phenothiazines; Plasmodium; Protease Inhibitors; Quaternary Ammonium Compounds; Terpenes; Xanthones

An increasing number of families, including children and the elderly, are seeking more adventurous travel in exotic parts of the world. Holiday destinations now include once-remote regions such as subSaharan Africa and New Guinea. This increase in visits to tropical and subtropical regions, combined with widespread chloroquine-resistant malaria, now places millions of Western travelers at risk of infection annually. At least 30,000 travelers from industrialized countries are reported to contract malaria each year and approximately 1 in 100 travelers who acquire Plasmodium falciparum malaria will die.

Topics: Adult; Africa South of the Sahara; Aged; Antimalarials; Atovaquone; Child; Drug Combinations; Drug Resistance; Family; Humans; Malaria; Naphthoquinones; New Guinea; Proguanil; Randomized Controlled Trials as Topic; Travel; United States

Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

Topics: Aminoquinolines; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Clinical Trials as Topic; Dapsone; Drug Combinations; Drug Design; Drug Resistance; Ethanolamines; Flavonoids; Fluorenes; Fosfomycin; Global Health; Humans; Lumefantrine; Malaria; Naphthoquinones; Naphthyridines; Plasmodium falciparum; Proguanil; Sesquiterpenes

U.S. military aviators are currently restricted to the use of chloroquine or doxycycline for malaria prophylaxis. Ground forces are allowed the additional option of taking mefloquine. These medications are begun before deployment, must be taken for 4 weeks after leaving the malarious area, and primaquine must be added to the regimen the last 2 of those 4 weeks. Compliance with this regimen is often poor, especially in populations who travel abroad frequently for short periods of time. Causal malaria prophylaxis offers potential benefits of decreased length of postdeployment regimens and obviates the need for a second medication for terminal prophylaxis. Potential obstacles include adverse drug reactions, cost, and rapid development of resistance to new medications by Plasmodium species, which should be weighed against the risks to health and mission success in each deployment.

Topics: Aminoquinolines; Antimalarials; Atovaquone; Aviation; Chloroquine; Doxycycline; Drug Combinations; Humans; Malaria; Mefloquine; Military Personnel; Naphthoquinones; Primaquine; Proguanil; United States

Topics: Adult; Antimalarials; Atovaquone; Child; Chloroquine; Doxycycline; Female; Humans; Insect Repellents; Insecticides; Malaria; Mefloquine; Mosquito Control; Naphthoquinones; Pregnancy; Proguanil; Travel

Topics: Antimalarials; Atovaquone; Chloroquine; Doxycycline; Humans; Malaria; Mefloquine; Naphthoquinones; 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

Topics: Aminoquinolines; Antimalarials; Artemisinins; Atovaquone; Chemical Phenomena; Chemistry; Drug Design; Drug Evaluation, Preclinical; Drug Resistance; Humans; Malaria; Naphthoquinones; Research; Sesquiterpenes

Topics: Aminoquinolines; Animals; Antimalarials; Artemisinins; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Mice; Naphthoquinones; Plasmodium falciparum; Pyrimethamine; Quinolines; Sesquiterpenes; Sulfadoxine

Topics: Animals; Antimalarials; Antimetabolites; Chickens; Electron Transport; Malaria; Naphthoquinones; Plasmodium; Plasmodium malariae; Ubiquinone

Topics: Animals; Antimalarials; Birds; Chloroquine; Dapsone; Humans; India; Malaria; Malaria, Avian; Mammals; Naphthoquinones; Oxytetracycline; Plasmodium; Plasmodium falciparum; Quinacrine; Rats; Reptiles

Topics: Acridines; Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Cinchona; Culture Media; Humans; Malaria; Microbial Sensitivity Tests; Naphthoquinones; Phytotherapy; Plants, Medicinal; Plasmodium; Plasmodium falciparum; Plasmodium malariae; Plasmodium vivax; Proguanil; Pyrimethamine; Quinacrine; Quinolines; Sulfonamides; Sulfones

The Ministry of Health recommended in Benin, since 2004, artemisinin-based combination, artemether-lumtefantrine (Coartem®), therapy for the treatment of uncomplicated malaria. To resolve the difficulties related to observance, we are interested in a new combination, artemisinin-naphthoquine (Arco®). A study was conducted to assess and compare the efficacy and tolerability of the fixed combination artemisinin (125 mg)-naphthoquine (50 mg), a single-dose drug, administered one day versus artemether (20 mg)-lumefantrine (120 mg).The clinical assessment was a single-blinded, two-arm, randomized trial comparing Arco® combination as a single-dose regimen and three-day regimen of Coartem® for the treatment of uncomplicated falciparum malaria, from july to october 2008 and may to september 2009, with 28 days of follow-up in children. PCR genotyping was used to classify re-infection or recrudescence. The primary outcome measures for efficacy were cure rates on days 3, 7, 14, 21 and 28. Secondary outcomes included parasite clearance time and fever clearance time. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events. A total of 174 patients (84 in Arco® group and 90 in Coartem® group) were evaluated for clinical and parasitological outcomes. The cure rate was 98.8% for Arco® and 100% for Coartem® on day 28, with no statistically significant difference. Fever clearance was obtained within 24 hours in both groups. The parasite clearance is obtained at 48 hours in Arco® group and at 60 hours in Coartem® group. Both treatments were well tolerated without major side effects. This study therefore concluded that the combination of artemisinin-naphthoquine is as effective and well tolerated as the combination artemether-lumefantrine in the treatment of uncomplicated malaria in Benin children. This medication administered in single dose is therapy of choice to reduce compliance problems during malaria treatment and also to facilitate community-based care of malaria.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Benin; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Malaria; Male; Naphthoquinones; Single-Blind Method; Treatment Outcome

A practical and simple regimen for all malaria species is needed towards malaria elimination in Indonesia. It is worth to compare the efficacy and safety of a single dose of artemisinin-naphthoquine (AN) with a three-day regimen of dihydroartemisinin-piperaquine (DHP), the existing programme drug, in adults with uncomplicated symptomatic malaria.. This is a phase III, randomized, open label using sealed envelopes, multi-centre, comparative study between a single dose of AN and a three-day dose of DHP in Jayapura and Maumere. The modified WHO inclusion and exclusion criteria for efficacy study were used in this trial. A total of 401 eligible adult malaria subjects were hospitalized for three days and randomly treated with AN four tablets single dose on day 0 or DHP three to four tablets single daily dose for three days, and followed for 42 days for physical examination, thick and thin smears microscopy, and other necessary tests. The efficacy of drug was assessed by polymerase chain reaction (PCR) uncorrected and corrected.. There were 153 Plasmodium falciparum, 158 Plasmodium vivax and 90 P. falciparum/P. vivax malaria. Mean of fever clearance times were similar, 13.0 ± 10.3 hours in AN and 11.3 ± 7.3 hours in DHP groups. The mean of parasite clearance times were longer in AN compared with DHP (28.0 ± 11.7 hours vs 25.5 ± 12.2 hours, p = 0.04). There were only 12 PCR-corrected P. falciparum late treatment failures: seven in AN and five in DHP groups. The PCR uncorrected and corrected on day -42 of adequate clinical and parasitological responses for treatment of any malaria were 93.7% (95% Cl: 90.3-97.2) and 96.3% (95% Cl: 93.6-99.0) in AN, 96.3% (95% Cl: 93.5-99.0) and 97.3% (95% Cl: 95.0-99.6) in DHP groups. Few and mild adverse events were reported. All the abnormal haematology and blood chemistry values had no clinical abnormality.. AN and DHP are confirmed very effective, safe and tolerate for treatment of any malaria. Both drugs are promising for multiple first-line therapy policies in Indonesia.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemisinins; DNA, Protozoan; Female; Humans; Indonesia; Malaria; Male; Middle Aged; Naphthoquinones; Parasitemia; Polymerase Chain Reaction; Quinolines; Treatment Outcome; Young Adult

Malarone was compared with placebo in a double-blind, randomized, placebo-controlled trial of prophylaxis of malaria in predominately Plasmodium vivax areas of Colombia. The study population consisted of 180 completely non-immune Colombian soldiers, male, average age 19 years, and average weight 63 kg. Twenty-four subjects were considered unevaluable because of compliance issues, including one Malarone subject (with no detectable drug levels) who became infected with P. vivax. Of the 97 evaluable subjects who received Malarone (250 mg atovaquone plus 100 mg proguanil hydrochloride) daily from 1 day before entering the endemic area to 7 days after leaving the endemic area, none became parasitemic. Of the 46 evaluable placebo subjects, 11 became infected with P. vivax and 2 became infected with Plasmodium falciparum. The protective efficacy of Malarone for all malaria and for P. vivax malaria was 100% (LL 95% CI = 63%) and 100% (LL 95% CI = 58%), respectively, and was 96% if the one case with undetectable blood levels was included. Malarone has high protective efficacy for P. vivax in Colombia.

Topics: Adolescent; Adult; Antimalarials; Atovaquone; Colombia; Double-Blind Method; Drug Combinations; Humans; Malaria; Male; Military Personnel; Naphthoquinones; Placebos; Proguanil

Atovaquone-proguanil has been shown to be effective and well tolerated for malaria prophylaxis in residents of countries of endemicity and in nonimmune adult travelers, but data about traveling children are limited. In a randomized, open-label, multicenter prophylaxis trial, 221 nonimmune pediatric travelers (age, 2-17 years) received either atovaquone-proguanil or chloroquine-proguanil. Safety and clinical outcome were evaluated 7, 28, and 60 days after travel. By posttravel day 7, a total of 39 (35%) of 110 atovaquone-proguanil and 41 (37%) of 111 chloroquine-proguanil recipients reported > or =1 adverse event. The data indicate that, over the course of treatment, fewer atovaquone-proguanil recipients had treatment-related adverse events (8% vs. 14%), including gastrointestinal complaints (5% vs. 10%). Two subjects discontinued prophylaxis because of drug-related adverse events; both had received chloroquine-proguanil. Observed compliance with prophylaxis was similar before and during travel, but it was higher for atovaquone-proguanil in the posttravel period. No study participant developed malaria. Atovaquone-proguanil was well tolerated and is an important addition to the limited arsenal of prophylactic agents available to children.

Topics: Adolescent; Antimalarials; Atovaquone; Child; Child, Preschool; Chloroquine; Drug Therapy, Combination; Humans; Infant; Malaria; Naphthoquinones; Patient Compliance; Proguanil; Travel

We performed a prospective, double-blind, randomized study to compare the occurrence of neuropsychiatric adverse events and concentration impairment during prophylactic use of either mefloquine or atovaquone plus chloroguanide (INN, proguanil).. Our potential study population consisted of all persons who were included in the MAL30010 trial at the Travel Clinic, Rotterdam, The Netherlands. All subjects were randomized to receive either active atovaquone (250 mg) plus chloroguanide (100 mg) daily plus a placebo for mefloquine weekly or active mefloquine (250 mg) weekly plus a placebo for atovaquone plus chloroguanide daily. Each subject was followed up from a baseline screening visit up to the index date, 7 days after he or she left the malaria-endemic area. We measured the interindividual and intraindividual changes in mood disturbance by means of the Dutch shortened Profile of Mood States and 3 domains of the Neurobehavioral Evaluation System, which included sustained attention, coding speed, and visuomotor accuracy between baseline and follow-up visit.. The cohort consisted of 119 subjects with a mean age of 35 years. A significant deterioration in depression, anger, fatigue, vigor, and total mood disturbance domains occurred during use of mefloquine but not during use of atovaquone plus chloroguanide. Stratification for sex showed between-treatment differences in female patients but not in male patients. In both treatment groups, sustained attention deteriorated after travel, especially with increased duration of stay.. Prophylactic use of mefloquine was associated with significantly higher scores on scales for depression, anger, and fatigue and lower scores for vigor than prophylactic use of atovaquone plus chloroguanide.

Topics: Adolescent; Adult; Affect; Antimalarials; Atovaquone; Chi-Square Distribution; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Malaria; Male; Mefloquine; Naphthoquinones; Proguanil; Prospective Studies; Sex Factors

A double-blind, placebo-controlled study was conducted to measure the impact of malaria prophylaxis with atovaquone/proguanil (A-P) on the immunogenicity of vaccines against typhoid fever and cholera, Salmonella serotype Typhi Ty21a and Vibrio cholerae CVD103-HgR, respectively. A total of 330 Gabonese schoolchildren were assigned to receive either A-P or placebo for 12 weeks. Vaccination occurred 3 weeks after the start of prophylaxis, and immunogenicity was assessed 4 weeks after vaccination. The protective efficacy of A-P against Plasmodium falciparum malaria was of 97% (95% confidence interval, 79%-100%). The 2 treatment groups did not differ significantly with regard to changes in antibody titers after vaccination (P=.96 for anti-S. Typhi IgG antibodies, P=.07 for anti-S. Typhi IgA antibodies, and P=.64 for vibriocidal antibodies). The A-P combination was highly effective for malaria prophylaxis, without interfering with the in vivo immunogenicity of CVD103-HgR and Ty21a vaccines, and it could therefore be simultaneously administered with these vaccines.

Topics: Administration, Oral; Adolescent; Antimalarials; Atovaquone; Chemoprevention; Child; Child, Preschool; Cholera Vaccines; Double-Blind Method; Female; Humans; Immunity; Malaria; Male; Naphthoquinones; Proguanil; Treatment Outcome; Typhoid-Paratyphoid Vaccines

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Atovaquone; Child; Child, Preschool; Double-Blind Method; Drug Combinations; Female; Humans; Malaria; Male; Mefloquine; Middle Aged; Naphthoquinones; Proguanil; Travel; Treatment Outcome

The combination of atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis.. 320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear.. 25 of 140 children in the placebo group and none of the 125 children in the atovaquone plus proguanil group had positive smears during chemosuppression (p<0.001). Adverse events during the chemosuppression phase did not differ between the groups.. The combination of atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.. The efficacy and safety of combined atovaquone and proquanil as a chemosuppressive antimalarial were investigated in a randomized placebo-control study of 315 schoolchildren 4-16 years of age from Lambarene, Gabon--an area where Plasmodium falciparum malaria is endemic and parasites are highly resistant to chloroquine. The children were categorized on the basis of weight (11-20, 21-30, 31-40, and 41 kg and over). At baseline, 115 children (37%) had a positive blood smear for malaria. In the initial phase of the study, all 315 children received the combined treatment. After 3 days of curative treatment, P. falciparum and P. malariae were still detected in 5 and 11 children, respectively. After 1 week of curative treatment, all children with these parasites had negative blood smears. Of the 265 children who completed the initial curative phase, 125 were assigned the combined treatment (dose adjusted for weight) and 140 received a placebo. During a total of 28 person-years of observation in the atovaquone and proquanil group, protective efficacy was 100%. In the 28 person-years of observation accumulated among untreated controls, positive blood smears were detected in 25 children; parasites began to emerge 4 weeks after the initial curative phase. During the 4-week follow-up period, during which time neither group received treatment, positive blood smears were found in 12 controls and 3 cases (emerging only in the last 4 observation days). Although gastrointestinal symptoms were reported, the rate did not differ significantly between cases and controls. These findings suggest that the combination of atovaquone and proquanil could replace current antimalarial regimens if donated supplies were available.

Topics: Adolescent; Antimalarials; Atovaquone; Child; Child, Preschool; Cohort Studies; Double-Blind Method; Drug Therapy, Combination; Humans; Malaria; Naphthoquinones; Proguanil

The purpose of this study was to compare an experimental regimen of atovaquone plus proguanil with the standard regimen of quinine plus tetracycline for the treatment of uncomplicated falciparum malaria. The study was designed as an open, randomized study of men presenting with symptoms of uncomplicated malaria and thick-smear slide confirmation of parasitemia (1000-100,000 ring forms/microL). Subjects were hospitalized for 28 days to insure medication compliance and to rule out the possibility of reinfections. With 77 patients in each group, the cure rates were 98.7% and 100% for atovaquone plus proguanil and quinine plus tetracycline, respectively. The parasite clearance times (mean, 56 h) and fever clearance times (mean, 19 h) were significantly shorter in the atovaquone plus proguanil group, and there were significantly fewer side effects in the atovaquone plus proguanil group. Atovaquone plus proguanil is an efficacious, easily administered, safe regimen for the treatment of uncomplicated, multidrug-resistant falciparum malaria in Brazil.

Topics: Adolescent; Adult; Aged; Antimalarials; Atovaquone; Brazil; Drug Therapy, Combination; Humans; Malaria; Male; Middle Aged; Naphthoquinones; Proguanil; Quinine; Tetracycline

More than 200 000 chemical compounds have been screened for antimalarial activity over the past 10 years by the US Army Antimalarial Drug Development Program. By means of extensive animal testing, 26 of these compounds were selected for clinical study in human subjects volunteering for such trials. Of these, 7 have received complete clinical trials and are in various stages of field evaluation, 4 are currently undergoing clinical trial, and 2 are still awaiting testing in volunteer subjects. Thus far, 2 compounds (WR 33 063 and WR 30 090) have demonstrated greater activity against drug-resistant Plasmodium falciparum than any other known drug. Several other compounds presently being tested in human subjects are even more potent.

Topics: Amino Acids; Antimalarials; Clinical Trials as Topic; Drug Evaluation; Drug Resistance; Guanidines; Humans; Malaria; Naphthoquinones; Phenanthrenes; Plasmodium falciparum; Pteridines; Pyridines; Pyrimidines; Quinazolines; Quinolines; Sulfones; Triazines; Xylenes

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

Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antimalarials; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Malaria; Male; Mice; Naphthoquinones; Oxidative Stress; Plasmodium berghei; Plumbaginaceae

Plumbagin is a derivative of napthoquinone which is isolated from the roots of plants in several families. These compound exhibits a wide range of biological and pharmacological activities including antimalarial, antibacterial, antifungal, and anticancer activities. The aim of the study was to investigate blood kinetics and tissue distribution of plumbagin in healthy and Plasmodium berghei-infected mice using Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and radiochemical analysis by gamma counter. Plumbagin was labeled with (99m)technetium and the reducing agent stannous chloride dihydrate (50 μg/ml) at pH 6.5. Blood kinetics and tissue distribution of the radiolabeled plumbagin were investigated in healthy and P. berghei-infected mice (2 males and 2 females for each experimental group). In vitro and in vivo stability of plumbagin complex suggested satisfactory stability profiles of (99m)Tc-plumbagin complex in plasma and normal saline (92.21-95.47%) within 24 h. Significant difference in blood kinetics parameters (Cmax, AUC, t1/2, MRT, Vd, and CL) were observed between P. berghei-infected and healthy mice. The labeled complex distributed to all organs of both healthy and infected mice but with high intensity in liver, followed by lung, stomach, large intestine and kidney. Accumulation in spleen was markedly noticeable in the infected mice. Plumbagin-labeled complex was rapidly cleared from blood and major routes of excretion were hepatobiliary and pulmonary routes. In P. berghei-infected mice, t1/2 was significantly decreased, while Vd and CL were increased compared with healthy mice. Result suggests that malaria disease state influenced the pharmacokinetics and disposition of plumbagin. SPECT/CT imaging with radiolabeled (99m)Tc is a viable non-invasive technique that can be applied for investigation of kinetics and biodistribution of plumbagin in animal models.

Topics: Animals; Brain; Female; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Intestinal Mucosa; Kidney; Lung; Malaria; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Models, Animal; Myocardium; Naphthoquinones; Plasmodium berghei; Spleen; Technetium; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Plumbagin was isolated and characterized from the roots of Plumbago zeylanica using chromatography: TLC, Column chromatogram, HPLC, FTIR and

Topics: Acetylcholinesterase; Animals; Anopheles; Cytochrome P-450 Enzyme System; Esterases; Female; Gastrointestinal Tract; Glutathione Transferase; Insect Proteins; Insect Repellents; Larva; Malaria; Mosquito Vectors; Muscles; Naphthoquinones; Superoxide Dismutase

Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice.. In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test).. Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time.. Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.

Topics: Animals; Antimalarials; Biological Availability; Body Weight; Chloroquine; Disease Models, Animal; Female; In Vitro Techniques; Malaria; Male; Mice; Mice, Inbred ICR; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum; Toxicity Tests

Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study.

Topics: Animals; Antimalarials; Cell Line; Disease Models, Animal; Humans; Inhibitory Concentration 50; Malaria; Mice; Naphthoquinones; Parasitemia; Parasitic Sensitivity Tests; Phenazines; Plasmodium berghei; Plasmodium falciparum

Gametocytes are the transmission stages of Plasmodium parasites, the causative agents of malaria. As their density in the human host is typically low, they are often undetected by conventional light microscopy. Furthermore, application of RNA-based molecular detection methods for gametocyte detection remains challenging in remote field settings. In the present study, a detailed comparison of three methods, namely light microscopy, magnetic fractionation and reverse transcriptase polymerase chain reaction for detection of Plasmodium falciparum and Plasmodium vivax gametocytes was conducted.. Peripheral blood samples from 70 children aged 0.5 to five years with uncomplicated malaria who were treated with either artemether-lumefantrine or artemisinin-naphthoquine were collected from two health facilities on the north coast of Papua New Guinea. The samples were taken prior to treatment (day 0) and at pre-specified intervals during follow-up. Gametocytes were measured in each sample by three methods: i) light microscopy (LM), ii) quantitative magnetic fractionation (MF) and, iii) reverse transcriptase PCR (RTPCR). Data were analysed using censored linear regression and Bland and Altman techniques.. MF and RTPCR were similarly sensitive and specific, and both were superior to LM. Overall, there were approximately 20% gametocyte-positive samples by LM, whereas gametocyte positivity by MF and RTPCR were both more than two-fold this level. In the subset of samples collected prior to treatment, 29% of children were positive by LM, and 85% were gametocyte positive by MF and RTPCR, respectively.. The present study represents the first direct comparison of standard LM, MF and RTPCR for gametocyte detection in field isolates. It provides strong evidence that MF is superior to LM and can be used to detect gametocytaemic patients under field conditions with similar sensitivity and specificity as RTPCR.

Topics: Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Clinical Laboratory Techniques; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Immunomagnetic Separation; Infant; Malaria; Male; Microscopy; Naphthoquinones; Papua New Guinea; Parasitology; Plasmodium falciparum; Plasmodium vivax; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity

1,4-Naphthoquinone derivatives are known to have relevant activities against several parasites. Among the treatment options for malaria, atovaquone, a 1,4-naphthoquinone derivative, is widely applied in the treatment and prophylaxis of such disease. Based on the structure simplification of atovaquone, we designed and synthesized four novel naphthoquinoidal derivatives. The compounds were obtained by the underexplored epoxide-opening reaction of 1,4-naphthoquinone using aniline derivatives as nucleophiles. The antiplasmodial activity of the synthesized compounds was performed in vivo using Peter's 4days suppression test. Significant parasitemia reduction and increased survival were observed for some of the compounds.

Topics: Animals; Antimalarials; Epoxy Compounds; Malaria; Mice; Molecular Structure; Naphthoquinones; Plasmodium falciparum; Survival Analysis

Malaria has been known as one of the major causes of morbidity and mortality on a large scale in tropical countries until now. In the past decades, many scientific groups have focused their attention on looking for ideal drugs to this disease. So far, this research area is still a hot topic. In the present study, the antimalarial activity of 1, 4- naphthoquinonyl derivatives was modeled by linear and nonlinear statistical methods, that is to say, by forward stepwise multilinear regression (MLR) and radial basis function neural networks (RBFNN). The derived QSAR models have been statistically validated both internally - by means of the Leave One Out (LOO) and Leave Many Out (LMO) crossvalidation, and Y-scrambling techniques, as well as externally (by means of an external test set). The statistical parameters provided by the MLR model were R(2) =0.7876, LOOq(2) =0.7068, RMS =0.3377, R0 2 =0.7876, k =1.0000 for the training set,and R(2) =0.7648, q(2) ext =0.7597, RMS=0.2556, R0 2=0.7598, k=1.0417 for the external test set. The RBFNN model gave the following statistical results, namely: R(2)=0.8338, LOOq(2)=0.5869, RMS=0.2781, R0 2 = 0.8335, k=1.0000 for the training set, and R(2) =0.7586, q(2) ext =0.7189, RMS=0.2788, R0 2=0.7129, k=1.0284 for the external test set. Overall, these results suggest that the QSAR MLR-based model is a simple, reliable, credible and fast tool for the prediction and virtual screening of 1, 4-naphoquinone derivatives with high antimalarial activity. In addition, the energies of the highest occupied molecular orbital were found to have high correlation with the activity.

Topics: Antimalarials; Humans; Malaria; Models, Biological; Naphthoquinones; Neural Networks, Computer; Plasmodium; Quantitative Structure-Activity Relationship

Naphthoquine (NQ), as a component of ARCO® which composed of NQ and artemisinin, is a new 4-aminoquinoline antimalarial synthesized by our institute. Here, a naphthoquine-resistant line of rodent malaria parasite was selected through exposing Plasmodium berghei Keyberg 173 strain to progressively increased drug pressure. The selected strain showed a more than 200-fold decreased susceptibility to NQ with a stable resistance phenotype after 10 serial passages without drug pressure or when cryopreserved over a period of 12 months. In a cross-resistance assay, the susceptibility of NQ-resistant parasites to chloroquine was decreased by 14.5-fold. These findings imply NQ-resistant parasites might be selected by long-term usage of NQ in epidemic areas and the efficacy of NQ or ARCO® in chloroquine-resistant Plasmodium falciparum epidemic areas should be monitored closely.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Dose-Response Relationship, Drug; Drug Resistance; Ethanolamines; Fluorenes; Lumefantrine; Malaria; Male; Mice; Naphthoquinones; Plasmodium berghei; Pyrimethamine; Random Allocation

Atovaquone is a hydroxy-naphthoquinone that is used to treat parasitic and fungal infections including Plasmodium falciparum (malaria), Pneumocystis jivorecii (pneumonia) and Toxoplasma gondii (toxoplasmosis). It blocks mitochondrial oxidation of ubiquinol in these organisms by binding to the ubiquinol oxidation site of the cytochrome bc(1) complex. Failure of atovaquone treatment has been linked to the appearance of mutations in the mitochondrially encoded gene for cytochrome b. In order to determine the optimal parameters required for inhibition of respiration in parasites and pathogenic fungi and overcome drug resistance, we have synthesized and tested the inhibitory activity of novel hydroxy-naphthoquinones against blood stage P. falciparum and liver stage P. berghei and against cytochrome bc(1) complexes isolated from yeast strains bearing mutations in cytochrome b associated with resistance in Plasmodium, Pneumocystis, and Toxoplasma. One of the new inhibitors is highly effective against an atovaquone resistant Plasmodium and illustrates the type of modification to the hydroxy-naphthoquinone ring of atovaquone that might mitigate drug resistance.

Topics: Antifungal Agents; Antiprotozoal Agents; Cell Line; Drug Design; Drug Resistance; Humans; Malaria; Molecular Structure; Naphthoquinones; Plasmodium; Structure-Activity Relationship; Yeasts

Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc(1) complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc(1) complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc(1) complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic.

Topics: Animals; Antimalarials; Atovaquone; Cattle; Cytochromes b; Electron Transport Complex III; Humans; Kinetics; Malaria; Naphthoquinones; Plasmodium falciparum; Pneumocystis

To study the antimalarial activity of naphthoquine phosphate combined with artemisinine against Plasmodium knowlesi in rhesus monkey.. Monkeys were randomly divided into 9 groups (3/group). The monkeys in groups A and B were treated i.g. once daily for 3 days with 6 or 10 mg/kg of naphthoquine phosphate respectively. Those in groups C and D were treated i.g. twice for the 1st day and once for the 2nd and 3rd day with 31.6 or 100 mg/kg of artemisinine respectively. In groups E, F and G, they were treated i.g. only once with the combination of naphthoquine phosphate 10 mg/kg and artemisinine 10, 20 or 25 mg/kg respectively. Groups H and I served as controls which were treated i.g. only once with 10 mg/kg of naphthoquine phosphate and 30 mg/kg of artemisinine respectively. Parasitemia was examined beginning 24 h after drug administration. The observation lasted 105 days when no more parasite was found.. At 24 h after drug administration, the parasite reduction rate in all groups was higher than 90%. The parasite clearance time for groups E, F and G was (56.0 +/- 16.0), (53.3 +/- 4.6), and (56.0 +/- 8.0) h respectively, more rapid than that of Group H [(69.3 +/- 4.6) h]. There were 1, 3, 3, 2, 2, and 3 monkeys in groups A, B, D, E, F, and G respectively which were cured. No monkeys were cured in groups C, H and I.. The combination of naphthoquine phosphate and artemisinine is superior to the single component and the optimum proportion in the combination is 1 : 2.5 in treating P. knowlesi infection in monkeys.

Topics: Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Macaca mulatta; Malaria; Male; Naphthoquinones; Plasmodium knowlesi

Topics: Antimalarials; Atovaquone; Chemoprevention; Disease Outbreaks; Doxycycline; Drug Combinations; Humans; Malaria; Male; Mefloquine; Military Personnel; Naphthoquinones; Proguanil; Sierra Leone; United Kingdom

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

Topics: Amino Acid Sequence; Animals; Antimalarials; Atovaquone; Cytochromes b; Dose-Response Relationship, Drug; Electron Transport Complex III; Inhibitory Concentration 50; Kinetics; Malaria; Models, Molecular; Molecular Sequence Data; Mutation; Naphthoquinones; Oxygen Consumption; Plasmodium falciparum; Point Mutation; Protein Binding; Saccharomyces cerevisiae; Sequence Homology, Amino Acid; Time Factors; Ubiquinone

Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria; Mefloquine; Naphthoquinones; Proguanil

Long-term travellers and expatriates are often non-compliant with malaria chemoprophylaxis due to a gradual neglect of the malaria risk combined with an unwillingness to take drugs for prolonged periods. The available regimes either have limited efficacy or are hampered by side effects, fears, cost and lack of data on long-term use. In order to prevent the dire consequences of malaria, we suggest tailoring the antimalarial strategy to the individual traveller. This requires balancing the risk of getting malaria, based on local transmission patterns, mosquito control and other factors, with the traveller's access to medical care and the options for chemoprophylaxis, the use of which in some cases may be limited to the rainy season or periods of travel to high-risk areas.

Topics: Antimalarials; Atovaquone; Chloroquine; Counseling; Doxycycline; Drug Combinations; Humans; Insect Bites and Stings; Malaria; Mefloquine; Mosquito Control; Naphthoquinones; Proguanil; Risk Assessment; Risk Factors; Travel

Sixteen travellers to West Africa used four kinds of antimalaria chemoprophylaxis. Suspected malaria in three persons and vaginal candidiasis in one caused all seven doxycycline users to change their medication. One of these was persuaded to use Artemisia vulgaris extract. In the course of the three-month journey, there were seven suspected cases of malaria, only two of which could be confirmed by antibody and antigen detection or expert microscopy; both were in travellers who had used A. vulgaris. A. vulgaris had no effect on parasite growth in vitro. The use of natural products for malaria prophylaxis should be discouraged.

Topics: Africa, Western; Antimalarials; Atovaquone; Doxycycline; Drug Combinations; Female; Humans; Malaria; Male; Mefloquine; Naphthoquinones; Plant Preparations; Proguanil; Surveys and Questionnaires; Travel

Topics: Antimalarials; Atovaquone; Disease Outbreaks; Doxycycline; Drug Combinations; Humans; Malaria; Male; Mefloquine; Military Personnel; Naphthoquinones; Proguanil; Sierra Leone

The antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against Plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. Among seven benzophenazines tested, four had significant in vitro activities; important, the parasites resistant to chloroquine were more susceptible to the active phenazines in vitro. The doses of phenazines causing 50% inhibition of parasite growth varied from 1.67 to 9.44 microM. The two most active ones were also tested in vivo against Plasmodium berghei in mice, in parallel with lapachol and beta-lapachone. The 3-sulfonic acid-beta-lapachone-derived phenazine was the most active causing up to 98% inhibition of parasitaemia in long term treatment (7 doses) subcutaneously, whereas the phenazine from 3-bromo-beta-lapachone was inactive. Thus, these simple phenazines, containing polar (-Br,-I) and ionizable (-SO(3)H, -OH) groups, easily synthesized from cheap, natural or synthetic precursors (lapachol and beta-lapachone), at rather low cost, provide prototypes for development of new antimalarials aiming the chloroquine resistant parasites.

Topics: Animals; Antimalarials; Dose-Response Relationship, Drug; Malaria; Mice; Naphthoquinones; Phenazines; Plasmodium berghei; Plasmodium falciparum

Data on the long-term safety of atovaquone/proguanil in nonimmune travelers are limited.. An open-label study, involving 300 Danish soldiers stationed in Eritrea for 6 months was initiated. The subjects self-reported their symptoms on a post-travel questionnaire. The study compared the symptoms of compliers and noncompliers.. No serious adverse events occurred. Diarrhea, stomach pain, headache, cough, and loss of appetite were the most common symptoms reported. No case of Plasmodium falciparum malaria occurred.. Atovaquone/proguanil was safe and well tolerated in this group of long-term nonimmune travelers.

Topics: Adult; Antimalarials; Atovaquone; Denmark; Drug Administration Schedule; Drug Combinations; Eritrea; Humans; Malaria; Male; Military Personnel; Naphthoquinones; Proguanil; Surveys and Questionnaires; Travel

Atovaquone/proguanil in Europe is only licensed for 4 weeks of travel. Data on its long-term tolerability in nonimmune travelers are scarce.. We prospectively studied adverse reactions reported by long-term travelers using atovaquone/proguanil among a population intolerant to mefloquine. The average length of atovaquone/proguanil use was 9 weeks (4.5 to 34 weeks). Adverse events were recorded on a regular questionnaire. Travelers rated complaints as: (1) mild, not interfering with their daily activities; (2) moderate, causing interference, such as canceling a trip or being confined to the hotel; or (3) severe, causing a visit to a doctor or clinic. Hospital admission was classified as category 3 and specified. We then compared our data with those on adverse reactions from 2 large multicenter studies of atovaquone/proguanil in nonimmune travelers.. One hundred and fifty-four subjects used atovaquone/proguanil for a total of 1538 weeks. Diarrhea was the most common ailment (18%). Further complaints were abdominal pain (mild 4%, moderate 5%, severe 2%), headache (mild 4%, moderate 4%, severe 1%), dizziness (mild 3%, moderate 1%, severe 1%), and insomnia (mild 6%, moderate 0%, severe 0%). Two subjects of 154 (1%) discontinued prophylaxis, both due to diarrhea. Nobody was admitted to hospital. No case of malaria was reported. Comparison with data from previous, larger atovaquone/proguanil studies shows that the adverse events reported by the long-term atovaquone/proguanil users are no different in type and frequency of occurrence to those travel-related health problems normally encountered in the Tropics.. Atovaquone/proguanil was well tolerated by these long-term travelers. Long-term users of atovaquone/ proguanil antimalarial prophylaxis suffer no more ailments than normally occur to travelers in tropical regions.

Topics: Antimalarials; Atovaquone; Drug Combinations; Endemic Diseases; Europe; Female; Humans; Longitudinal Studies; Malaria; Male; Naphthoquinones; Product Surveillance, Postmarketing; Proguanil; Prospective Studies; Surveys and Questionnaires; Travel

Malaria is a life-threatening illness which can be particularly risk in children. This paper guides nurses who offer travel advice on the best approaches to take with parents. It is best to avoid travelling to areas affected by the disease at all. However, if people do travel, they should take prophylactic medication as well as other precautions to avoid being bitten by mosquitoes.

Topics: Animals; Antimalarials; Atovaquone; Chemoprevention; Child; Culicidae; Doxycycline; Drug Combinations; Humans; Insect Bites and Stings; Malaria; Mefloquine; Naphthoquinones; Proguanil; Travel

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

Topics: Adult; Aged; Animals; Antimalarials; Atovaquone; Child; Dogs; Drug Combinations; Germany; Humans; Malaria; Naphthoquinones; Proguanil; Travel; Tropical Medicine; Vaccination

Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Enzyme Inhibitors; Glutathione; Glutathione Reductase; Humans; Malaria; Naphthoquinones; Parasitic Sensitivity Tests; Prodrugs

The most-prescribed malaria drug could produce psychiatric side effects in more than one-quarter of all travelers who take it.

Topics: Antimalarials; Consumer Product Safety; Doxycycline; Drug Costs; Humans; Malaria; Mefloquine; Mental Disorders; Naphthoquinones; Proguanil; United States; United States Food and Drug Administration

A lipophilic extract of the root bark of Stereospermum kunthianum revealed antiplasmodial activity in vitro. Bioassay-guided fractionation led to the isolation of four novel naphthoquinones (sterekunthals A and B, pyranokunthones A and B) and one novel anthraquinone (anthrakunthone) together with the known naphthoquinone pinnatal. The structures of the novel compounds were determined by comprehensive analyses of their 1D and 2D NMR data. The antiplasmodial activities and toxicity against the endothelial cell line ECV-304 of the isolated compounds have been assessed.

Topics: Animals; Antiprotozoal Agents; Bignoniaceae; Cell Line; Endothelium; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Malaria; Molecular Structure; Naphthoquinones; Plant Bark; Plant Roots; Plasmodium falciparum

Malaria is a major tropical disease, which kills two million people annually. The population at risk from this disease has increased because of the difficulties in eradicating the mosquito vector in the endemic regions and the emergence and spread of parasite resistance to all the commonly used antimalarials. Since antimalarials are the major arsenal for treatment of the disease, there is an urgent need for newer drugs with novel mechanisms of action, which will be effective against all strains of the parasite. As a part of our anti-infective drug discovery program, we have investigated 18 compounds including several synthetic and natural naphthoquinones as potential antimalarial agents. We have identified aminonaphthoquinones, as a class of antimalarial compounds with antimalarial activity against Plasmodium falciparum. Among these compounds, 2-amino-3-chloro-1,4-naphthoquinone is the most potent. It had an IC(50)of 0.18 micro M (37.3 ng ml(-1)) against the W2 clone, and is more potent than chloroquine, which had an IC(50)of 0.23 micro M (72 ng ml(-1)). It was also active against the D6 clone. In general, 2-amino-1,4-naphthoquinone analogs and the 4-amino-1,2-napthoquinone analog showed promising antimalarial activity in the bioassay. In contrast, a number of 2-hydroxy-1,4-naphthoquinones and dimeric quinones were less active.

Topics: Animals; Antimalarials; Chloroquine; Drug Evaluation, Preclinical; Inhibitory Concentration 50; Malaria; Naphthoquinones; Plasmodium falciparum; Structure-Activity Relationship

Topics: Antimalarials; Atovaquone; Doxycycline; Drug Combinations; Humans; Malaria; Naphthoquinones; Proguanil; Travel

Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Humans; Malaria; Mefloquine; Naphthoquinones; Proguanil; Treatment Outcome

Malaria is still continuing to be one of the most dreadful diseases of the tropical countries particularly due to the development of resistance to the existing antimalarials. From observed, antimalarial activity of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives acting through redox cycling mechanism, molecular modeling and three dimensional-quantitative structure activity relationship (3D-QSAR) studies have been carried out on a set of 63 compounds to identify important pharmacophors. Among several 3D-QSAR models generated, three models with correlation coefficient r > 0.82, match > 0.60 and chance = 0.00 have shown two common biophoric sites: one being the oxygen atom at position 1 of the naphthoquinone ring in terms of pi-population, charge and electron donating ability while the second being the center of the phenyl ring in terms of its 6pi-electrons. In addition to these sites, the models also share two common secondary sites: one positively contributing H-acceptor site while the second site contributing negatively in terms of steric refractivity. All these models showed good agreement between the experimental, calculated and predicted antimalarial activities.

Topics: Antimalarials; Malaria; Models, Molecular; Naphthoquinones; Oxygen; Protons; Structure-Activity Relationship; Sulfhydryl Compounds

Sera from patients treated with atovaquone-proguanil (Malarone) have previously been shown to inhibit the mosquito transmission of Plasmodium falciparum, though the inhibition was not complete and the effect declined 2 weeks after treatment. In marked contrast, the inhibition of transmission of P. berghei by human sera (fed to mosquitoes, with P. berghei gametocytes, via membrane feeders) from volunteers treated with atovaquone-proguanil was total up to day 28 post-treatment and still very significant at day 56. In view of the short half-lives of atovaquone and proguanil, this was unexpected, and further experiments, reported here, were undertaken. In contrast to the incomplete blockade of infectivity of P. falciparum by serum taken 4 days post-treatment, such serum was totally inhibitory against P. berghei at a 1:10,000 dilution, indicating a remarkable sensitivity of P. berghei and demonstrating an unusual difference between the two Plasmodium species in response to a drug. The inhibitory effect on P. berghei after day 4 was caused by atovaquone and mainly through blockade of development from ookinete to oocyst. Despite previous information on the rapid elimination of atovaquone by patients, the present data indicate that low concentrations of this drug may persist in the plasma for some weeks after treatment.

Topics: Animals; Antimalarials; Atovaquone; Chromatography, High Pressure Liquid; Culicidae; Disease Vectors; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Mice; Naphthoquinones; Plasmodium berghei; Proguanil; Rats; Rats, Wistar

Topics: Adolescent; Adult; Aged; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Combinations; Drug Interactions; Humans; Malaria; Naphthoquinones; Proguanil

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Atovaquone; Azithromycin; Chloroquine; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Naphthoquinones; Plasmodium falciparum; Plasmodium vivax; Primaquine; Proguanil; Pyrimethamine; Risk Assessment

Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.

Topics: Africa; Altruism; Antimalarials; Atovaquone; Developing Countries; Drug Combinations; Drug Industry; Humans; Malaria; Naphthoquinones; Proguanil

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

The malarial parasite Plasmodium falciparum can only synthesize pyrimidine nucleotides via the de novo pathway which is therefore a suitable target for development of antimalarial drugs. New assay procedures have been developed using high-pressure liquid chromatography (HPLC) which enable concurrent measurement of pyrimidine intermediates in malaria. Synchronized parasites growing in erythrocytes were pulse-labeled with [14C]bicarbonate at 6-h intervals around the 48-h asexual life cycle. Analysis of malarial extracts by HPLC showed tht incorporation of [14C]bicarbonate into pyrimidine nucleotides was maximal during the transition from trophozoites to schizonts. The reaction, N-carbamyl-L-aspartate-->L-dihydroorotate (CA-asp-->DHO) catalyzed by malarial dihydroorotase is inhibited by L-6-thiodihydroorotate (TDHO) in vitro (Ki = 6.5 microM), and TDHO, as the free acid or methyl ester, induces a major accumulation of CA-asp in malaria. Atovaquone, a naphthoquinone, is a moderate inhibitor of dihydroorotate dehydrogenase in vitro (Ki = 27 microM) but induces major accumulations of CA-asp and DHO. Pyrazofurin induces accumulation of orotate and orotidine in malaria, consistent with inhibition of orotidine 5'-monophosphate (OMP) decarboxylase with subsequent dephosphorylation of the OMP accumulated. Although TDHO, atovaquone, and pyrazofurin arrest the growth of P. falciparum, only moderate decreases in UTP, CTP, and dTTP were observed. 5-Fluoroorotate also arrests the growth of P. falciparum with major accumulations of 5-fluorouridine mono-, di-, and triphosphates and the most significant inhibition of de novo biosynthesis of pyrimidine nucleotides.

Topics: Amides; Animals; Antimalarials; Atovaquone; Bicarbonates; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Dihydroorotase; Dihydroorotate Dehydrogenase; Erythrocytes; Humans; Kinetics; Malaria; Naphthoquinones; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Plasmodium falciparum; Pyrazoles; Pyrimidines; Ribonucleosides; Ribose

The activity of atovaquone against Plasmodium berghei ANKA during sporogonic development has been examined. Anopheles stephensi mosquitoes were fed on gametocyte infected mice which had been treated 8 h previously with atovaquone or diluent alone. Mosquito midguts were examined for oocysts, and salivary gland infections were estimated using an ELISA for the circumsporozoite protein (CSP). The number of oocysts per midgut fell by at least 97% when mosquitoes were fed on mice dosed with 0.1-10 mg atovaquone/kg body weight. This was paralleled by a decrease in the prevalence of oocyst-infected mosquitoes from 70-90% in controls to 40% or 10% respectively. No oocysts were observed at a dose of 100 mg/kg. CSP ELISA results indicated that mosquitoes fed on atovaquone failed to produce sporozoites. Mosquitoes which fed on gametocytaemic, atovaquone-treated mice (0.1-100 mg/kg) did not transmit malaria to naive mice. These results demonstrate that atovaquone has a highly potent inhibitory activity against the mosquito stages of P. berghei.

Topics: Animals; Anopheles; Antimalarials; Atovaquone; Enzyme-Linked Immunosorbent Assay; Female; Insect Vectors; Malaria; Mice; Naphthoquinones; Plasmodium berghei; Protozoan Proteins

Topics: Aminoquinolines; Amodiaquine; Antimalarials; Artemisinins; Calcium Channel Blockers; Chloroquine; Humans; Malaria; Mefloquine; Naphthoquinones; Phenanthrenes; Primaquine; Quinine; Sesquiterpenes; Sulfadoxine

The influence of the novel hydroxynaphthoquinone 566C80 on exoerythrocytic development of Plasmodium berghei was examined in Brown Norway rats. The procedure employed was designed to identify residual activity of the drug against tissue merozoites emerging into the bloodstream and to distinguish this from any observed causal prophylactic activity against the liver stages. Single oral doses of 10 and 1 mg/kg of 566C80 administered 3 hours after sporozoite-inoculation were effective in preventing the appearance of a patent parasitaemia, while a dose of 0.1 mg/kg significantly reduced the severity of the ensuing blood infection. There was a pronounced residual effect of 566C80 against the blood forms at a dose of 10 mg/kg, a slight residual effect at a dose of 1 mg/kg, but no apparent residual effect at 0.1 mg/kg. At the time when EE merozoites would normally emerge into the bloodstream, an aliquot of blood was sub-inoculated into mice from sporozoite-infected, 566C80-treated rats. This procedure confirmed that 566C80 is active against the exoerythrocytic stages of Plasmodium berghei.

Topics: Animals; Antimalarials; Atovaquone; Drug Evaluation, Preclinical; Erythrocytes; Female; Malaria; Naphthoquinones; Plasmodium berghei; Rats; Rats, Inbred BN

Novel hydroxynaphthoquinones are reported with outstanding efficacy against Plasmodium, Eimeria and Theileria species. Biochemical evidence is presented for the selective toxicity of these compounds being due to inhibition of parasite respiratory systems.

Topics: Animals; Antiprotozoal Agents; Apicomplexa; Cattle; Chickens; Coccidiosis; Eimeria; Malaria; Mice; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum; Protozoan Infections; Theileriasis; Toxoplasma; Toxoplasmosis, Animal

Topics: Animals; Antimalarials; Chloroquine; Dimethylpolysiloxanes; Drug Implants; Malaria; Male; Mefloquine; Mice; Mice, Inbred Strains; Naphthoquinones; Piperidines; Plasmodium berghei; Primaquine; Proguanil; Pyrimethamine; Quinolines; Silicone Elastomers; Sulfadiazine; Triazines

Data are presented on the causal prophylactic action of about 100 compounds of various types against Plasmodium yoelii nigeriensis N67 in mice. Examples are given to show how action against pre-erythrocytic schizonts may be differentiated from action on emerging erythrocytic stages. In a series of 35 8-aminoquinolines, all but 10 showed definite causal prophylactic activity at tolerated doses. The data permit the compounds to be ranked in order of activity, and many are shown to be more active in this test system than primaquine. Marked causal prophylactic activity is displayed by a variety of quinone structures, several of which show a significant residual action on blood stages. A high level of activity is found in dihydrofolate reductase inhibitors within several chemical classes. Rorguanil is more effective as a causal prophylactic than a blood schizontocide in the mouse as in man. Sulphonamides and sulphones are also effective in this system. The active levels are influenced by the content of PABA in the diet of the hosts. Causal prophylactic action has been detected in a number of experimental compounds including some antibiotics (such as tetracycline and clindamycin). The pyrocatechol RC 12 shows only slight activity at the maximum tolerated dose. Chloroquine, mepacrine, quinine, quinolinemethanols and phenanthrenemethanols are inactive as causal prophylactics. It is concluded that a rodent malaria-mouse model does provide a relatively simple model for the screening of drugs for causal prophylaxis, and the data so obtained are of relevance to the detection of causal prophylactics against human malaria.

Topics: Amidines; Aminoquinolines; Animals; Anti-Bacterial Agents; Antimalarials; Drug Evaluation, Preclinical; Folic Acid Antagonists; Malaria; Mice; Naphthoquinones; Plasmodium berghei; Pyrimidines; Quinones; Sulfonamides; Sulfones; Tetrahydrofolate Dehydrogenase; Urea

Topics: Animals; Antimalarials; Malaria; Mice; Microbial Sensitivity Tests; Mitochondria; Naphthoquinones; Plasmodium; Ubiquinone

Topics: Animals; Antimalarials; Malaria; Mice; Naphthoquinones

Topics: Animals; Body Weight; Carbon Dioxide; Chemical Phenomena; Chemistry; Epinephrine; Hypoxia; Malaria; Methods; Mice; Morphine; Naphthoquinones; Organ Size; Oxygen Consumption; Plasmodium; Pulmonary Edema; Time Factors

Topics: Animals; Anopheles; Antimalarials; Chloroquine; Malaria; Naphthoquinones; Oxytetracycline; Penicillin G; Plasmodium vivax; Primaquine; Proguanil; Pyridines; Pyrimethamine; Quinacrine; Quinine; Quinolines; Sulfadiazine; Thiosemicarbazones

Topics: Animals; Antimalarials; Chloroquine; Malaria; Mice; Naphthoquinones; Plasmodium

Topics: Animals; Antimalarials; Chloroquine; Cricetinae; Malaria; Mice; Naphthoquinones; Plasmodium; Primaquine; Quinine

Topics: Animals; Antimalarials; Chemistry, Organic; Chloroquine; Malaria; Mice; Naphthoquinones; Organic Chemistry Phenomena

Topics: Animals; Birds; Malaria; Naphthoquinones

Topics: Humans; Malaria; Malaria, Vivax; Male; Naphthoquinones

Topics: Animals; Humans; Malaria; Malaria, Avian; Naphthoquinones; Plasmodium; Quinones

Topics: Antimalarials; Humans; Malaria; Naphthoquinones; Respiration; Respiratory System

Topics: Animals; Carbohydrate Metabolism; Humans; Malaria; Naphthoquinones; Parasites; Plasmodium