naphthoquinones and artemisinin

Plant secondary metabolism evolved in the context of highly organized and differentiated cells and tissues, featuring massive chemical complexity operating under tight environmental, developmental and genetic control. Biotechnological demand for natural products has been continuously increasing because of their significant value and new applications, mainly as pharmaceuticals. Aseptic production systems of plant secondary metabolites have improved considerably, constituting an attractive tool for increased, stable and large-scale supply of valuable molecules. Surprisingly, to date, only a few examples including taxol, shikonin, berberine and artemisinin have emerged as success cases of commercial production using this strategy. The present review focuses on the main characteristics of plant specialized metabolism and their implications for current strategies used to produce secondary compounds in axenic cultivation systems. The search for consonance between plant secondary metabolism unique features and various in vitro culture systems, including cell, tissue, organ, and engineered cultures, as well as heterologous expression in microbial platforms, is discussed. Data to date strongly suggest that attaining full potential of these biotechnology production strategies requires being able to take advantage of plant specialized metabolism singularities for improved target molecule yields and for bypassing inherent difficulties in its rational manipulation.

Topics: Artemisinins; Axenic Culture; Berberine; Biological Products; Biotechnology; Cell Culture Techniques; Metabolic Engineering; Naphthoquinones; Paclitaxel; Phytochemicals; Plant Cells; Plants; Secondary Metabolism; Tissue Culture Techniques

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

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 therapeutic efficacy of imidocarb, artesunate, arteether, buparvaquone and arteether+buparvaquone combination was evaluated against Babesia equi of Indian origin in splenectomised donkeys with experimentally induced acute infection. Efficacies of these drugs were tested by administering each drug or drug combination to groups of donkeys (having three donkeys each group). One group of donkey was kept as untreated control for comparing the results. Parasitaemia, haematology (WBC, RBC, PCV, granulocytes and haemoglobin), biochemical parameters (SAST, SALT, alkaline phosphatase, albumin/globulin ratio) were monitored at regular intervals. Individually, arteether and buparvaquone were found to have no parasite clearing efficacy and the treated animals died within 5-6 days after showing high parasitaemia and clinical symptoms of the disease. However, artesunate treated animals were able to restrict the parasite multiplication but only during the treatment period. Animals treated with imidocarb and arteether+buparvaquone combination were able to clear the parasite from the blood circulation after 2-5 days post-treatment (PT). After 55-58 days PT, recrudescence of B. equi parasite was observed in both these groups and a mean survival period of 66 days and 69 days, respectively, was recorded in these groups. Results of haemato-biochemical parameters had shown that imidocarb had deleterious effect on the liver function while on the other hand arteether+buparvaquone combination was found to be safe. This limited study indicates that arteether+buparvaquone combination could be a better choice than imidocarb for treating B. equi infection, but further trials are required in detail.

Topics: Animals; Antiprotozoal Agents; Artemisinins; Babesiosis; Blood Cell Count; Drug Therapy, Combination; Equidae; Imidocarb; India; Naphthoquinones; Sesquiterpenes; Splenectomy

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

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

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

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

The antimalarial in vitro activities of amodiaquine and desethylamodiaquine in combination with atovaquone, quinine and artemisinin against Plasmodium falciparum were investigated in strains F-32, FCR-3 and K-1. These parasitic strains have different sensitivity profiles to the standard antimalarial chloroquine, but all can be considered sensitive to the test drugs, representing the recommended situation for introduction of two partner drugs in combination therapy. Amodiaquine showed marked synergism when combined with each of the three partner compounds at concentration ratios between 90 and 9x10(-7), including the therapeutically relevant range. The interaction profiles of desethylamodiaquine with quinine and artemisinin also showed predominantly synergism over a wide range of concentration ratios between 70 and 9x10(-7). The responses to all combinations exhibited signs of strain-specificity, but such phenomena were usually observed outside the therapeutic range of the concentration ratios. Synergism was generally more marked with increasing EC values, i.e. at concentrations expected to be therapeutically effective and thus clinically relevant. Even trace quantities of amodiaquine were able to potentiate the activity of structurally unrelated antimalarial drugs.

Topics: Amodiaquine; Animals; Antimalarials; Artemisinins; Atovaquone; Cells, Cultured; Drug Synergism; Naphthoquinones; Plasmodium falciparum; Quinine; Sesquiterpenes; Species Specificity

The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (sigmaFICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC50], EC90, and EC99). Within therapeutically relevant molar ratios (19 to 200), the combination of quinine and artemisinin showed mean sigmaFICs of 1.71 at the EC50, 0.36 at the EC90, and 0.13 at the EC99, indicating increasing synergism. Within the range of molar ratios of 4.3 to 50, the combination of mefloquine and artemisinin yielded mean sigmaFCIs of 0.93, 0.44, and 0.31 at the EC50, EC90, and EC99, respectively, indicating synergism. The atovaquone combination showed additive activity to synergism at atovaquone/artemisinin proportions considered relevant to the in vivo situation, i.e., between 4.3 and 200, with the mean sigmaFICs decreasing from 1.34 at the EC50 to 0.85 and 0.23 at the EC90 and EC99, respectively. Interstrain differences in the degree of drug interaction were seen with the three strains for all combinations. Synergism was most consistent with quinine.

Topics: Animals; Antimalarials; Artemisinins; Atovaquone; Drug Synergism; Humans; Mefloquine; Naphthoquinones; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinine; Sesquiterpenes

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

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

Antimalarial screening was performed for microbial metabolites that simulate artemisinin in their mode of action, a potent antimalarial component of an herbal remedy with a characteristic peroxide structure. Nanaomycin A was identified in this screen as an antimalarial compound, together with radicicol and several other compounds already reported (J. Antibiotics 51: 153 approximately 160, 1998). Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM. It was as potent as radicicol and about 1/10 as potent as artemisinin. Studies on the mode of action suggested that the antimalarial action of the two non-peroxides, nanaomycin A and radicicol, involved heme-dependent radical generation, as is for the peroxide artemisinin. Namely, the inhibition of in vitro growth of malaria parasite by nanaomycin A or radicicol was reversed by tocopherol, a radical scavenger added to the assay mixture. Secondly, in a reaction system established for radical detection, in which a test radical donor and beta-alanylhistidine as a radical recipient were incubated with and without hemin, the two compounds caused heme-dependent decreases of beta-alanylhistidine, as did artemisinin. Among the 14 microbial metabolites identified during this screening, a correlation was observed between antimalarial activity and heme-dependent radical generating activity.

Topics: Animals; Antimalarials; Artemisinins; Carnosine; Drug Evaluation, Preclinical; Hemin; Humans; Lactones; Macrolides; Molecular Structure; Naphthoquinones; Plasmodium falciparum; Sesquiterpenes; Structure-Activity Relationship

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

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