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 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For more than three centuries we have relied on the extracts of the bark of Cinchona species to treat malaria. Now, it seems we may be changing to the leaves of a Chinese weed, Artemisia annua, and its active compound artemisinin. Artemisinin-derived drugs have been proved particularly effective treatments for severe malaria, even for multidrug-resistant malaria. However, this promising antimalarial compound remains expensive and is hardly available on a global scale. Therefore, many research groups have directed their investigations toward the enhancement of artemisinin production in A. annua cell cultures or whole plants in order to overproduce artemisinin or one of its precursors. This article provides a brief review of the state of art of the different aspects in A. annua research.
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PMID:State of the art of the production of the antimalarial compound artemisinin in plants. 903 39

A 30-h in vitro susceptibility test of Plasmodium falciparum wild isolates to artemisinin, chloroquine, sulfadoxine/pyrimethamine and mefloquine was performed in Kibaha, Tanzania. A sigmoid Emax model was fitted to all data for each isolate and drug combination. Artemisinin and mefloquine exhibited 100% growth inhibition against all isolates tested (n = 69-74). The EC30 values for artemisinin and mefloquine were 44 and 146 nM respectively. Chloroquine and sulfadoxine/ pyrimethamine resistance was 30% and 13% respectively. Susceptibility parameters (EC50,90,95 and 92 values and s) varied between compounds and isolates indicating the different sensitivity of P. falciparum isolates. No correlation between susceptibility parameters of artemisinin and the other compounds was found. The high in vitro activities of artemisinin and mefloquine indicate their potential role for the treatment of multidrug-resistant malaria in Africa.
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PMID:In vitro susceptibility of Tanzanian wild isolates of Plasmodium falciparum to artemisinin, chloroquine, sulfadoxine/pyrimethamine and mefloquine. 917 20

The pharmacokinetics of artemisinin was studied in 11 Vietnamese patients with uncomplicated falciparum malaria after a single 500 mg oral dose. Curative treatment with mefloquine (15 mg/kg) was provided 24 hr after the artemisinin dose. Artemisinin concentrations were measured by high-performance liquid chromatography with electrochemical detection. The following pharmacokinetic results were found (all mean +/- SD); calculated volume of distribution/bioavailability = 22.8 +/- 16.6 L.kg-1, mean absorption time = 1.16 +/- 0.92 hr, calculated maximum concentration = 364 +/- 250 micrograms.L-1 occurring at 2.88 +/- 1.71 hr after drug intake, and an elimination half-life of 2.72 +/- 1.76 hr. Bioavailability was low. These results do not differ from results in healthy subjects. Parasites disappeared rapidly, with a mean parasite clearance time of 36 hr. No relationship was found between pharmacokinetics and the parasite elimination rate. Tolerance to the single dose of artemisinin was good. No adverse effects were detected. In conclusion, pharmacokinetics of a single dose of artemisinin for uncomplicated falciparum malaria is not different from findings in healthy subjects. A single dose of 500 mg of artemisinin is effective in reducing parasitemia in nonsevere lalciparum malaria and is well-tolerated.
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PMID:The pharmacokinetics of a single dose of artemisinin in patients with uncomplicated falciparum malaria. 918 May 98

Severe malaria remains a major cause of mortality and morbidity for children living in many tropical regions. With the emergence of strains of Plasmodium falciparum resistant to both chloroquine and quinine, alternative antimalarial agents are required. The artemisinin group of compounds are rapidly effective in severe disease when given by intramuscular or intravenous injection. However, these routes of administration are not always available in rural areas. In an open, randomized comparison 109 Vietnamese children, aged between 3 months and 14 years, with severe P.falciparum malaria, were allocated at random to receive artemisinin suppositories followed by mefloquine (n = 37), intramuscular artesunate followed by mefloquine (n = 37), or intravenous quinine followed by pyrimethamine/sulfadoxine (n = 35). There were 9 deaths: 2 artemisinin, 4 artesunate and 5 quinine-treated children. There was no difference in fever clearance time, coma recovery, or length of hospital stay among the 3 groups. However, parasite clearance times were significantly faster in artemisinin and artesunate-treated patients than in those who received quinine (P < 0.0001). Both artemisinin and artesunate were very well tolerated, but children receiving these drugs had lower peripheral reticulocyte counts by day 5 of treatment than those in the quinine group (P = 0.011). No other adverse effect or toxicity was found. There was no treatment failure in these 2 groups, but 4 patients in the quinine group failed to clear their parasites within 7 d of starting treatment and required alternative antimalarial therapy. Artemisinin suppositories are easy to administer, cheap, and very effective for treating children with severe malaria. In rural areas where medical facilities are lacking these drugs will allow antimalarial therapy to be instituted earlier in the course of the disease and may therefore save lives.
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PMID:Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. 923 Dec 12

Falciparum malaria may have infected Homo sapiens (and perhaps H erectus) in the Asia Pacific region for more than 100,000 years. This estimate is based on the gene frequency of alpha-thalassaemia, the protection it affords against falciparum malaria and assumptions of untreated mortality from the infection. Up until the end of the 19th century, there was a high mortality from malaria in the coastal parts of Malaya, but the malaria control campaign, begun in 1901 at Klang, was described by Sir Ronald Ross as the first successful antimalarial work in the (then) British Empire. This was extended to Singapore in 1911. When the Far Eastern Association of Tropical Medicine held its Fifth Biennial Congress in Singapore in 1923, malaria was still a major killing disease in parts of Malaya and Sarawak. The mechanism of life-threatening malaria involves cytoadherence of parasitised erythrocytes in microvascular beds, a process enhanced by the products of macrophage activation induced by malarial pyrogen. Improvements in the chemotherapy of life-threatening falciparum malaria with chloroquine and quinine have been countered by the emergence of resistant strains. Artemisinin derivatives may become the treatment of choice during the coming decade. Apart from traditional anti-mosquito methods, control of malaria now involves the use of insecticide-impregnated bed nets, new entomological strategies, including genetic manipulation of mosquitoes and selective chemoprophylaxis. Antigenic diversity and antigenic variation of the malaria parasite have so far defeated attempts to produce an effective vaccine.
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PMID:The 1996 Runme Shaw Memorial Lecture: malaria--past, present and future. 928 35

Despite few efforts to develop new antimalarial compounds by the major pharmaceutical companies, some promising new therapeutics have been developed and tested clinically by small groups and companies throughout the world. Really new substances are scarce but combinations of known medicarnents have been shown to be a rational and effective approach to overcome problems with single compounds. Additionally, combination regimens are more easily authorized and accepted for treatment than completely new substances. Some examples in this respect are combinations of either atovaquone, doxycycline or clindamycin with a 'classical' antimalarial. Artemisinin, benflumetol and pyronaridine were originally developed in China and disperse currently to the rest of the world. First independent and international clinical trials gave promising results and one should bear in mind those substances for future applications. Especially artemisinin and its derivatives are of great interest because they represent, besides quinine, the only other therapeutic option for the treatment of multidrug-resistant severe malaria.
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PMID:[Malaria therapy in the era of chloroquine resistance]. 962 23

Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of approximately 18 microM. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.
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PMID:The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. 963 75

Background: Since 1988, the incidence of malaria imported into the Netherlands has been stable, but the population groups have remarkably changed. Methods: The records of all patients with malaria in the Academic Medical Centre, Amsterdam, between October 1991 and December 1994 were analyzed. Results: Of the 286 patients, 149 (52%) were Dutch citizens and 114 (40%) were originally from malaria endemic areas (92 immigrants, 22 asylum-seekers), whereas between 1979 and 1988 these figures were 85 and 15%. The remaining 23 (8%) patients were 11 children born in the Netherlands to immigrants, 10 foreigners from nonmalarious areas, and 2 for whom the origin is unknown. Plasmodium falciparum was found in 197 (69%) patients, mostly acquired in subSaharan Africa; P. vivax (61 patients, 21%) was mainly acquired in Asia. Two vivax infections proved to be chloroquine-resistant. The compliance with the malaria chemoprophylaxis was poor: only 38% (30/80) of the Dutch citizens and 8% (4/52) of the settled immigrants and children were fully compliant. Severe complicated falciparum malaria developed in 18 (10%) patients, two of whom died. The majority of the falciparum cases were treated with halofantrine or sulfadoxine-pyrimethamine. Artemisinin was used in two. Conclusions: Among the patients with imported malaria, settled immigrants and their (nonimmune) children constitute a growing number. Compliance with chemoprophylaxis is decreasing in Dutch travelers and remains poor in the immigrants. Quinine was increasingly used both as initial treatment for severe falciparum malaria as well as in patients with nonsevere malaria who were nauseated or vomiting.
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PMID:The Changing Pattern of Imported Malaria in the Academic Medical Centre, Amsterdam. 981 9

Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted until none could be detected. Artemisinin concentration versus time curves of all subjects were analysed with model-independent methods. Mean Cmax was 108 micrograms/L (SD = 60, range 29-169), mean tlag was 0.3 h (SD = 0), mean tmax was 6.5 h (SD = 3.9, range 2-14). By comparing the area under the concentration-time curve with that found in a previous study on oral artemisinin, average bioavailability relative to oral administration was estimated to be approximately 30%. Median parasite clearance time was 24 h (range 24-72). We concluded that therapeutic blood concentrations of artemisinin can be reached after rectal administration. There was a large inter-individual variation in blood concentrations attained. The dose given by rectal administration should probably be twice the usual oral dose, i.e., at least 20 mg/kg of body weight twice daily.
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PMID:The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria. 985 Apr 2

The treatment of choice for severe malaria is quinine. However, a gradual progression of resistance to quinine has become a concern in parts of the world. Artemisinin-related compounds are a relatively new class of drugs. This meta-analysis assesses the evidence regarding the clinical effectiveness of artemether for severe malaria. Computerized literature searches identified all randomized clinical trials of artemether in comparison with quinine. Standardized data extraction was independently performed by both authors. Results of nine trials, entered in the meta-analysis, demonstrate the absence of a significant difference between artemether and quinine in terms of mortality rate (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.50-1.14). Statistical pooling of data from trials in Southeast Asia showed a trend toward enhanced reduction of mortality (OR, 0.38; 95% CI, 0.14-1.02). These data demonstrate the equality of artemether and quinine for severe malaria and indicate a trend toward greater effectiveness of artemether in regions where there is recognized quinine resistance.
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PMID:Artemether for severe malaria: a meta-analysis of randomized clinical trials. 1019 84


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