naphthoquinones and artenimol

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

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

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.

Topics: Antimalarials; Artemisinins; Atovaquone; Drug Interactions; Drug Resistance; Erythrocytes; Gametogenesis; Humans; Inhibitory Concentration 50; Life Cycle Stages; Methylene Blue; Naphthoquinones; Plasmodium falciparum

A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquone-sensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.

Topics: Animals; Antimalarials; Artemisinins; Atovaquone; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Resistance; Drug Synergism; Naphthoquinones; Plasmodium falciparum; Proguanil; Reproducibility of Results; Sesquiterpenes