naphthoquinones and Parasitemia

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

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

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

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

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

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

Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro.. In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated.. in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses.. Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters.. N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Chagas Disease; Disease Models, Animal; Electrocardiography; Male; Mice; Naphthoquinones; Nitroimidazoles; Parasitemia; Time Factors; Trypanocidal Agents

Piroplasmosis caused by the Babesia microti-like piroplasm (Bml) is increasingly being detected in dogs in Europe. Sick dogs show acute disease with severe anaemia associated with thrombocytopenia with a poor response to current available drugs. This study assesses the safety and tolerance of three treatments and compares their efficacy over a full year of follow up in dogs naturally infected with Bml.. Fifty-nine dogs naturally infected with Bml were randomly assigned to a treatment group: imidocarb dipropionate (5 mg/kg SC, 2 doses 14 d apart) (IMI); atovaquone (13.3 mg/kg PO q 8 h, 10 d)/azithromycin (10 mg/kg PO q 24 h, 10 d) (ATO); or buparvaquone (5 mg/kg IM, 2 d apart)/azithromycin (same dosage) (BUP). Before and after treatment (days 15, 45, 90 and 360), all dogs underwent a physical exam, blood tests and parasite detection (blood cytology and PCR). Clinical efficacy was assessed by grading 24 clinical and 8 clinicopathological signs from low to high severity.. Before treatment, most dogs had severe regenerative anaemia (88.13%) and thrombocytopenia (71.4%). On treatment Day 45, clinical signs were mostly reduced in all dogs, and by Day 90, practically all dogs under the ATO or BUP regimen were clinically healthy (76.4 and 88%, respectively). Highest percentage reductions in laboratory abnormalities (82.04%) were detected in animals treated with ATO. Over the year, clinical relapse of Bml was observed in 8 dogs (8/17) treated with IMI. However, on Day 360, these animals had recovered clinically, though clinicopathological abnormalities were still present in some of them. Parasitaemia was PCR-confirmed on Days 90 and 360 in 47.05 and 50% of dogs treated with ATO, 68 and 60.08% with BUP, and 94.1 and 73.3% with IMI, respectively. Even after 360 days, 13.3% of the dogs treated with IMI returned a positive blood cytology result.. IMI showed the worse clinical and parasitological, efficacy such that its use to treat Bml infection in dogs is not recommended. The treatments ATO and BUP showed better efficacy, though they were still incapable to completely eliminate PCR-proven infection at the recommended dose. All three treatments showed good tolerance and safety with scarce adverse events observed.

Topics: Animals; Antiprotozoal Agents; Atovaquone; Azithromycin; Babesia microti; Babesiosis; Dog Diseases; Dogs; Drug Therapy, Combination; Europe; Female; Imidocarb; Male; Naphthoquinones; Parasitemia; Polymerase Chain Reaction

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.

Topics: Animals; Antiprotozoal Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Gastric Absorption; Hepatomegaly; Humans; Inhibitory Concentration 50; Intubation, Gastrointestinal; Leishmania infantum; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Naphthoquinones; Organ Specificity; Parasitemia; Pterocarpans; Splenomegaly; Toxicity Tests, Subacute

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

The present study describes an outbreak of tropical theileriosis cases refractory to buparvaquone treatment, which occurred in a small-size dairy farm in Tunisia. Out of seven treated cows, four died in spite of repeated buparvaquone injections (2.5 and 5 mg kg(-1)) and the monitoring of the affected cows showed no improvement of the course of the disease with a consistent decrease in the haematocrit, the persistence of fever and an increased parasitaemia after treatment. Ticks were fed on a calf experimentally infected with one isolate established in culture from one of the cases and the resultant infected ticks ground up to generate a supernatant infected with the potentially resistant stock. This was used to experimentally infect three calves, and the clinical observations, post-buparvaquone treatment, showed an absence of the usual effect of buparvaquone treatment on the parasite Theileria annulata, such as the rapid decline of schizont index and parasitaemia and a rapid recovery from the disease. These results confirmed for the first time the occurrence of resistance to buparvaquone in the protozoan T. annulata.

Topics: Animals; Antiprotozoal Agents; Cattle; Dairying; Disease Outbreaks; Drug Resistance; Hematocrit; Naphthoquinones; Parasitemia; Schizonts; Theileria annulata; Theileriasis; Treatment Failure; Tunisia

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

We synthesized new naphthoimidazoles from beta-lapachone with an aromatic moiety linked to the imidazole ring, using phenylic and heterocyclic aldehydes. The most active compound against Trypanosoma cruzi had a p-methyl group linked to the phenyl ring, presenting an EC(50) value of 15.5 +/- 2.9 microM. No reliable correlation could be established with the biological activity and the structure of in the phenylic series. For the heterocyclic series, activity was associated with a three bond-distance from nitrogen to the imidazole ring, in accordance with our previous work.

Topics: Animals; Anti-Infective Agents; Imidazoles; Mice; Models, Molecular; Molecular Conformation; Naphthoquinones; Parasitemia; Pyrans; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

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

Comparative studies of the efficacy of parvaquone (Parvexon) and parvaquone-plus-frusemide (Fruvexon) Bimeda Chemicals, Ireland, were done on 60 naturally infected cases of East Coast fever (ECF; Theileria parva infection in cattle). Small-scale dairy farmers in the peri-urban of Dar Es Salaam city reported ECF-suspected cases from March to mid-October 2001 and were treated with the two drugs alternately, as were diagnosed positive for ECF. Four sub-groups of 15 cattle each (early stage, 15; advanced stage, 15) were treated with parvaquone and parvaquone-plus-frusemide. Twenty-eight out of 30 (93.3%) cattle treated with parvaquone-plus-frusemide were cured, so do 24 out of 30 (80.0%) cattle treated with parvaquone without frusemide. Early diagnosis and prompt management of pulmonary signs, which accounted for 30.0% of total ECF cases is advised in order to improve cure rates. Unlike parvaquone without frusemide (Parvexon), parvaquone-plus-frusemide (Fruvexon) proved useful in the management of pulmonary signs, hence, a drug of choice in the treatment of ECF cases that are accompanied by or are likely to manifest pulmonary signs.

Topics: Age Factors; Animals; Antiprotozoal Agents; Body Temperature; Cattle; Cattle Diseases; Diuretics; Drug Combinations; Female; Furosemide; Male; Naphthoquinones; Parasitemia; Sex Factors; Suburban Population; Tanzania; Theileria parva; Theileriasis

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

The efficacy of 5 drugs was tested against experimental Babesia felis infection in domestic cats. Two of the drugs, rifampicin and a sulphadiazine-trimethoprim combination, appeared to have an anti-parasitic effect, but were inferior to primaquine. The other 3 drugs, buparvaquone, enrofloxacin and danofloxacin, had no significant anti-babesial effect.

Topics: Animals; Anti-Infective Agents; Antiprotozoal Agents; Babesiosis; Cat Diseases; Cats; Drug Combinations; Enrofloxacin; Fluoroquinolones; Hematocrit; Naphthoquinones; Parasitemia; Primaquine; Quinolones; Rifampin; Sulfadiazine; Trimethoprim

Two trials were conducted to compare the efficacy of parvaquone and buparvaquone for the treatment of naturally acquired East Coast fever (ECF, Theileria parva infection) which, if untreated, is almost invariably fatal in European breeds of cattle. In the first trial 28 naive cattle were exposed in a paddock infested with ticks carrying a virulent form of the disease. Twelve were treated with each drug when they developed clinical ECF. All 24 cattle were cured. In the second study, 100 cases of ECF occurring naturally on farms in Kenya were treated, 50 with each drug. Parvaquone cured 44 (88%) buparvaquone cured 45 (90%). Intercurrent infections, predominantly anaplasmosis and bacterial pneumonia or scour, were treated specifically. It is concluded that parvaquone and buparvaquone are similarly effective in curing ECF and cure rates are maximised by accurate diagnosis and prompt treatment of both ECF and intercurrent infections.

Topics: Administration, Topical; Animals; Antimalarials; Biopsy; Cattle; Female; Fever; Injections, Intramuscular; Insecticides; Kenya; Male; Naphthoquinones; Nitriles; Parasitemia; Pyrethrins; Random Allocation; Theileriasis; Tick Infestations

A clinical trial testing the prophylactic effect of a 5 mg kg-1 dose of buparvaquone on either Theileria annulata or Theileria parva experimental infections of calves demonstrated its efficacy for periods of at least seven days. The drug given 1 h or seven days before 50% lethal T. annulata sporozoite infection protected all eight calves, but prophylaxis was insufficient after 14 days to protect two out of four calves from severe reaction. When immunity was challenged by a lethal second parasite dose a month after the first, all these calves were immune. In the T. parva trial, calves given drug 1 h or seven days before a 25% lethal infection underwent minimal reaction, but some were over-protected and were susceptible to a similar challenge sporozoite dose. Although drug levels remaining 14 days after prophylaxis protected these calves from the mild challenge, some parameters measured were within the range of the 'no drug' control group. These results indicated the effectiveness of a single 5 mg kg-1 dose of buparvaquone for more than seven days but also the potential risk of its use in the infection and treatment method of immunisation. It is suggested that there may be circumstances where simple field prophylactic treatment with buparvaquone may be beneficial.

Topics: Animals; Antibodies, Protozoan; Antiprotozoal Agents; Cattle; Fluorescent Antibody Technique, Indirect; Naphthoquinones; Parasitemia; Theileria annulata; Theileria parva; Theileriasis

The aim of this work was to develop a new pharmaceutical form of atovaquone and to study its activity against Toxoplasma gondii in vitro and in vivo. Nanocapsules were chosen as the oral dosage form of administration. An analytical method was developed to determine the drug content in nanocapsules. The stability of these nanocapsules were assessed by following drug content, size, pH and osmolarity for a period of six months. The in vitro activity of atovaquone-loaded nanocapsules against tachyzoites of T. gondii (RH stain) was comparable to its suspension form. In vivo studies were carried out in murine models of acute and chronic toxoplasmosis. Mice acutely infected with the virulent RH strain were orally treated with a dose regimen of 15 mg/kg/day for 10 days, starting from day 1 post-infection. 75% of the mice receiving atovaquone-loaded nanocapsules survived 30 days post-infection, compared to none of untreated controls and none of mice treated with the suspension with the same dose regimen. In mice chronically infected by the COUL or the ME49 strain (Type II strains), then treated for six weeks, treatment with atovaquone (15 mg/kg/d, nanoparticles or suspension) resulted in a decrease of brain parasitic burden, which was significantly more pronounced in ME49-infected mice and in those treated with drug-loaded nanocapsules. These results show that the sensibility of T. gondii to atovaquone is different according to the strains and that the activity of atovaquone in the treatment of toxoplasmosis is enhanced when administered in nanoparticular form.

Topics: Acute Disease; Administration, Oral; Animals; Antiprotozoal Agents; Atovaquone; Brain; Capsules; Chronic Disease; Colloids; Disease Models, Animal; Drug Carriers; Drug Stability; Female; Lung; Mice; Naphthoquinones; Parasitemia; Solubility; Survival Rate; Suspensions; Temperature; Toxoplasma; Toxoplasmosis, Animal

This study demonstrates the activity of the hydroxynaphthoquinone (HNQ), atovaquone, against Babesia divergens, the cause of a rare but lethal form of human babesiosis. In vitro studies showed that unlike other anti-malarial drugs, the HNQs studied have a high level of anti-babesial activity and atovaquone was more active than imidocarb, the most effective compound used so far for human B. divergens babesiosis and also used routinely for the treatment of bovine babesiosis. Atovaquone also proved to be extremely active against B. divergens in gerbils (Meriones unguiculatus). Acute fulminating infections were effectively treated with as little as 1.0 mg/kg with increasing effectiveness up to 10 mg/kg, which compares well with the activity of imidocarb. Although immunosuppression with dexamethasone slowed the decline of parasitemias after treatment with atovaquone, gerbil survival was unaffected. Pretreatment of gerbils with 4 daily low doses of atovaquone did not have any effect on the development of subsequent infections. However, if treatment was continued after infection, daily doses as low as 0.5 mg/kg effectively suppressed the parasites.

Topics: Acute Disease; Animals; Antiprotozoal Agents; Atovaquone; Babesia; Babesiosis; Cattle; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Erythrocytes; Gerbillinae; Hemoglobinuria; Humans; Naphthoquinones; Parasitemia; Regression Analysis

The traditional therapy for the treatment of human Babesia microti infections has been the combination of clindamycin and quinine. However, in recent years, it has become apparent that some patients have not responded to this regimen. We became involved in the treatment of several cases of babesiosis in which atovaquone was used to treat this infection. Therefore, using the hamster model, we determined the efficacy of atovaquone alone as well as atovaquone plus azithromycin for the treatment of experimental babesiosis. Atovaquone (100 mg/kg/day) and atovaquone (100 mg/kg/day) with azithromycin (150 mg/kg/day) were effective agents for the treatment of experimental babesiosis in hamsters. When atovaquone was used as monotherapy recrudescences occurred. Organisms obtained from recrudescent animals, when inoculated into uninfected animals, proved to be unresponsive to atovaquone therapy, suggesting the emergence of drug resistance. Resistant organisms did not emerge in hamsters treated with the combination of atovaquone and azithromycin. Atovaquone should be considered in the therapeutic regimen of patients with babesiosis who have either failed standard therapy or have become intolerant to such therapy.

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Antiprotozoal Agents; Artemisinins; Atovaquone; Azithromycin; Babesiosis; Cricetinae; Disease Models, Animal; Drug Therapy, Combination; Naphthoquinones; Parasitemia; Recurrence; Sesquiterpenes

Atovaquone was evaluated for the prevention and treatment of babesiosis in hamsters. When atovaquone was administered before inoculation of 10(6) Babesia microti and continued for 8 days thereafter, 9 of 10 hamsters survived beyond 54 days, but all untreated controls died within 12 days after inoculation. Quantitation of parasitemia showed a mean of 75% erythrocytes parasitized by day 5 in controls, but atovaquone recipients never exceeded 0.7% of parasitized erythrocytes over 54 days of observation. Clindamycin plus quinine was also effective but less so than atovaquone. When treatment was not started until parasitemia became established, atovaquone in doses of 300, 150, and 80 mg/kg/day was effective in the recovery of all animals compared with 50% of those receiving 10 mg/kg/day and 10% of untreated controls. With its remarkable safety record, atovaquone offers promise for clinical trials in babesiosis of both humans and lower animals.

Topics: Animals; Antiprotozoal Agents; Atovaquone; Babesiosis; Chemoprevention; Cricetinae; Dexamethasone; Evaluation Studies as Topic; Glucocorticoids; Immunosuppression Therapy; Male; Naphthoquinones; Parasitemia; Survival Analysis