tetracycline and artemisinin

Increasing rates of failure of artemisinin-based combination therapy have highlighted the possibility of emerging artemisinin resistance along the Thai-Cambodian border. We used an integrated in vivo-in vitro approach to assess the presence of artemisinin resistance in western Cambodia. This article provides additional data from a clinical trial that has been published in The New England Journal of Medicine.. Ninety-four adult patients from Battambang Province, western Cambodia, who presented with uncomplicated falciparum malaria were randomized to receive high-dose artesunate therapy (4 mg/kg/day orally for 7 days) or quinine-tetracycline. Plasma concentrations of dihydroartemisinin, in vitro drug susceptibility, and molecular markers were analyzed. Cases meeting all the following criteria were classified as artemisinin resistant: failure to clear parasites within 7 days of treatment or reemergence of parasites within 28 days of follow-up; adequate plasma concentrations of dihydroartemisinin; prolonged parasite clearance; and increased in vitro drug susceptibility levels for dihydroartemisinin.. Two (3.3%) of 60 artesunate-treated patients were classified as artemisinin resistant. Their parasite clearance times were prolonged (133 and 95 h, compared with a median of 52.2 h in patients who were cured). These patients had 50% inhibitory concentrations of dihydroartemisinin that were almost 10 times higher than the reference clone W2. Resistance did not appear to be mediated by the pfmdr1 copy number or selected PfATPase6 polymorphisms previously proposed to confer artemisinin resistance.. Artemisinin resistance has emerged along the Thai-Cambodian border. The potentially devastating implications of spreading resistance to a drug that currently has no successor call for further studies of this emerging problem.. ClinicalTrials.gov identifier NCT00479206.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemisinins; Cambodia; Drug Resistance; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasma; Plasmodium falciparum; Quinine; Recurrence; Tetracycline; Thailand; Treatment Failure; Young Adult

A total of 141 cases of strictly defined cerebral malaria were studied in a controlled trial of three regimens: (1) intramuscular artemether plus oral mefloquine, (2) intravenous artesunate plus oral mefloquine, and (3) intravenous quinine (with or without an initial loading dose) plus oral tetracycline. The overall mortalities in each group were 14%, 8.3% and 34.3% respectively. The average parasite clearance time was 27.30 +/- 19.62 hours in regimen 1, 41.84 +/- 17.55 hours in regimen 2, and 47.30 +/- 21.95 hours in regimen 3. No recrudescence was observed in regimens 1 and 2, but 12.1% recrudesced in the third.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Artesunate; Humans; Malaria, Cerebral; Mefloquine; Middle Aged; Prospective Studies; Quinine; Sesquiterpenes; Tetracycline

The Wolrd Health Organization (WHO) encourages all countries to investigate antimalarial drug substances derived from herbal sources with the slogan "Hunt of the Next Artemisinin" due to the emergence of resistant strains of Plasmodium species to artemisinin. In the broad and simple sense, it was planned to help guide the young researchers set in-vitro and in-vivo models of malaria in order to be used in drug research and active ingredient studies.. In-vitro study, young Plasmodium berghei trophozoites were removed from the liquid nitrogen tank and resuspended in appropriate conditions, followed by incubation with chloroquine and tetracycline at concentrations of 0.1, 0.4, 0.8, 1.6, 6.4, 12.8 μg/mL for 24 hours at +37°C in a shaking incubator. In-vivo studies, Tetracycline group (TG) and Chloroquine group (KG) were administered 50 mg/kg of tetracycline and chloroquine by intragastric lavage and untreated control group (TACG) were administered the same amount of saline via the same route. The suppression of parasitemia in mice was followed for 24 days.. In our in-vitro study it was observed that 0.8 μg/mL of chloroquine and 1.6 μg/mL of tetracycline was enough to suppress parasitemia. In our in-vivo drug study, all of the mice in the TG group died at day 24, and all of the mice in the TAKG group died at day 12, with no parasitemia observed in the mice in the KG group.. Our study suggests that if tetracycline therapy is administered when the induction of chloroquine therapy is delayed, the exacerbation of the parasitemia may be prevented and when chloroquine is obtained chloroquine therapy can be commenced thus preventing the loss of the patient.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Disease Models, Animal; Drug Evaluation, Preclinical; In Vitro Techniques; Malaria; Male; Mice; Mice, Inbred BALB C; Plant Extracts; Plasmodium berghei; Tetracycline

The long history of the use of Artemisia annua L. to treat malaria (called Quinghao in China and Thanh hao in Vietnam) has led Vietnamese scientists to manufacture locally preparations of artemisinine and artesunate, to test their tolerance for human beings as well as their efficiency in treating P. falciparum and P. vivax infections. Associating these drugs with antibiotics (such as tetracycline or doxycycline) could be an interesting topic for future research. Under the auspices of the National Program against Malaria, specialists will try to prevent the occurrence of drug resistance in Plasmodium and to propose new associations of drugs.

Topics: Adult; Anti-Bacterial Agents; Antimalarials; Artemisinins; Artesunate; Child; Doxycycline; Drug Combinations; Drug Resistance; Drugs, Chinese Herbal; Humans; Malaria, Falciparum; Malaria, Vivax; Sesquiterpenes; Tetracycline; Vietnam

A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC(50) of 6 microM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by tetracycline only with an IC(50) of 47 microM. GST P1-1 was the most susceptible enzyme to inhibition by antimalarials with IC(50) values of 1, 2, 1, 4, and 13 microM for pyrimethamine, artemisinin, quinidine, quinine and tetracycline, respectively. The IC(50) values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC(50) values of 18, 27, 45 and 70 microM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents.

Topics: Antimalarials; Artemisinins; Carmustine; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Inhibitors; Escherichia coli; Ethacrynic Acid; Glutathione Transferase; Humans; Isoenzymes; Quinidine; Quinine; Recombinant Proteins; Sesquiterpenes; Tetracycline

Antimalarial activities of tetracycline (TC) and erythromycin (EM), alone or in combination with artemisinin (Qinghaosu, QHS), were studied using chloroquine (CQ)-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum in vitro. The antimalarial potency of TC (IC50 = 9862 nM for the CQ-sensitive parasite, 32414 nM for the CQ-resistant one) or EM (IC50 = 45787 nM for the CQ-sensitive parasite, 33397 nM for the CQ-resistant one) was much less than that of QHS (IC50 ranging from 25 to 40 nM). The CQ-resistant falciparum parasite displayed a cross-resistance to TC, while both the drug-sensitive and -resistant parasites exhibited similar responses to EM. However, antimalarial potency of EM appeared to be less than that of TC against the drug-sensitive parasite. When TC was combined with QHS, an additive interaction was observed against the CQ-sensitive falciparum parasite, while synergism was found with the CQ-resistant parasite. When EM was tested in combination with QHS, a potentiating interaction occurred with both the CQ-sensitive and resistant falciparum parasite. The above results indicated that the QHS combination with either TC or EM may be a promising antimalarial preparation with low recrudescence compared to artemisinin used alone in clinical practice.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Drug Synergism; Erythromycin; Plasmodium falciparum; Protein Synthesis Inhibitors; Sesquiterpenes; Tetracycline