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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Artemisinin derivatives are an important new class of antimalarial agents. These compounds contain endoperoxide bridges which are essential for antimalarial activity. Artemisinin is believed to act via a two-step mechanism. Artemisinin is first activated by intraparasitic heme-iron which catalyzes the cleavage of this endoperoxide. A resulting free radical intermediate may then kill the parasite by alkylating and poisoning one or more essential malarial protein(s). No clinically relevant artemisinin-resistant human malaria has yet been reported. However, an artemisinin-resistant strain of murine malaria has been developed and may offer clues to the kinds of resistance that may someday develop in human malarias.
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PMID:Artemisinin antimalarials: mechanisms of action and resistance. 1021 91

Artemisinin and its derivatives are the most rapidly acting antimalarials known to-date and are well-tolerated. All derivatives in use today are produced by semi-synthesis from artemisinin: dihydroartemisinin is the product of the first step; more synthetic steps give rise to artesunate, artemether and arteether which are metabolised back to dihydroartemisinin in the body. Although their residence in the body after oral administration is very short (with half-lives of < 2 hours), they can be administered once daily. By acting on ring stages, they clear peripheral parasitaemia more quickly than other antimalarial drugs and prevent the development into mature sequestering blood stages. They are effective against all human malaria parasites, notably multidrug-resistant Plasmodium falciparum. They have anti-transmission properties, too. So far, resistance to this class of compounds has not been reported. However, when used alone, they require long treatment courses (7 days). So, combination with long-half life drugs such as mefloquine appears to be the best approach to mutually protect both drugs against resistance. While reported in experimental animals, there is no evidence neurotoxicity in human beings. Whether such event could occur after continuous or discontinuous use is not clear.
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PMID:Artemisinin and derivatives in the treatment of uncomplicated malaria. 1021 99

This systematic review of randomised or pseudorandomised trials was aimed at summarising the effectiveness and safety of artemisinin drugs for treating uncomplicated falciparum malaria. Ninety-three potentially eligible studies were identified and 38 met the inclusion criteria. Most data are from Southeast Asian areas of mefloquine-resistant falciparum malaria, Thailand in particular. Artemisinin drugs achieve high cure rates at follow-up in all endemic areas represented by the studies included provided that the duration of treatment is adequate. Combination with mefloquine improves sustained parasite clearance and is effective in multidrug resistant areas. Provided the dose of both drugs is adequate, the combination can shorten the duration of treatment. There is no evidence from randomised trials that any artemisinin derivative is better than the others. Data from just over 4,300 patients are included for analysis in this review. Despite the large amount of clinical research that has been done, variation in study design, quality and comparisons make synthesis of the data problematic. It is extremely difficult to draw clear conclusions from the existing database.
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PMID:Treatment of uncomplicated malaria with artemisinin derivatives. A systematic review of randomised controlled trials. 1021

This systematic review of randomised or pseudorandomised trials aimed at summarising the effectiveness and safety of artemisinin drugs for treating severe falciparum malaria in adults and children. Survival was better with artemisinin drugs in 1.265 patients compared with 1.183 treated with quinine (OR: 0.68; 95% CI: 0.55-0.84). However, the difference is barely significant when only studies with adequate concealment of allocation at enrolment are included in the analysis (OR: 0.77; 95% CI: 0.61-0.98). In 1784 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (OR: 0.70; 95% CI: 0.55-0.90), but not significantly better than quinine in studies reporting adequate concealment of allocation. No difference in neurological sequelae has been demonstrated. Artemisinin drugs clear parasites from the blood faster than quinine. Adverse effects are similarly common with artemisinin drugs and quinine, although reporting varies between trials. There is no evidence from this review that any one artemisinin derivative is better than the others, but comparative studies are few, small and heterogeneous.
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PMID:Treatment of severe malaria with artemisinin derivatives. A systematic review of randomised controlled trials. 1021 2

Registration in Europe of several artemisinin drugs for the treatment of malaria can soon be expected. Artemisinin is isolated from the herb Artemisia annua, in use in China more than 2000 years as a herbal tea against fever. Artemisinin drugs are being used extensively in South-East Asia and increasingly in Africa. Active derivatives have been synthesized - artemether, arteether and artesunate - which are used for oral, intramuscular, rectal and intravenous administration. The origin, mechanism of action, efficacy and safety in patients, the pharmacokinetics and the position of this group of compounds among existing antimalarials are discussed in this review.
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PMID:Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. 1035 15

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.
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PMID:Antimalarial drug resistance and combination chemotherapy. 1036 99

Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.
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PMID:Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. 1038 51

Artemisinin or Qinghaosu (QHS) and its derivatives (mainly artemether and artesunate) are novel and the most rapidly acting antimalarial drugs, effective in adults and children against all the Plasmodium of humans, including multi-drug resistant Plasmodium falciparum. Resistance to these drugs has not been identified so far. QHS derivatives are very well tolerated and there is no evidence of serious clinical toxicity in man. The neurotoxicity seen in animals after high doses of certain compounds has not been reported in humans. In the treatment of severe malaria, QHS administered by either the intramuscular (artemether and artesunate) or intravenous (artesunate) route, are at least as effective as quinine, and are simpler to use. Intramuscular artemether appears to be an excellent alternative to intravenous quinine, which is specially important since quinine resistance is common in Asia and a decrease of sensitivity to quinine has been reported in Africa. For the treatment of uncomplicated malaria, the use of QHS must be highly selective. Treatment by QHS is only totally justifiable in areas where multi-drug resistant strains are prevalent and always concurrently with an other effective, longer-acting, antimalarial drug (mefloquine, preferably). This combination approach is associated with an accelerated antimalarial response. It avoids or limits the risk of recrudescences, and protects both drugs from the development of resistance. Artemether and artesunate have also been administered by the rectal route with highly promising results for treatment of severe malaria. This route eliminates several disadvantages or risks associated with injections. The best indication for rectal administration will be probably a rescue treatment of severe malaria in rural and poorly equipped dispensaries before transfer to hospital for treatment using conventional modalities. All QHS derivatives should not be used for chemophophylaxis.
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PMID:[Current data on major novel antiamalaria drugs: Artemisinin (qinghaosu) derivatives]. 1043 2

Artemisinin and its analogues are a class of compounds of current interest in the treatment of drug-resistant malaria. These antimalarials are preferentially taken up into malaria infected erythrocytes as compared to uninfected erythrocytes, a fact that may represent an important parameter in drug potency. Numerous methods for the analysis of specific artemisinin analogues have been developed, but most are not widely adaptable to a large range of analogues. In this paper we describe a high-performance liquid chromatographic method developed and validated for artemisinin and several analogues of artemisinin using a readily available evaporative light scattering detector. This quantitation method was found to be straight forward, rapid, inexpensive and reproducible. Standard calibration curves constructed for six artemisinin compounds were linear with the detection limit determined between 6 and 60 ng. The intra- and inter-day accuracy were found to be 2.75% and 4.15%, respectively with less than 3% variation in precision. The validated assay was applied to a mixture of artemisinin derivatives, where they were easily separated and quantitated.
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PMID:Rapid determination of artemisinin and related analogues using high-performance liquid chromatography and an evaporative light scattering detector. 1043 74

An assay was developed measuring the disruption of rosettes between Plasmodium falciparuminfected (trophozoites) and uninfected erythrocytes by the antimalarial drugs quinine, artemisinin mefloquine, primaquine, pyrimethamine, chloroquine and proguanil. At 4 hr incubation rosettes were disrupted by all the drugs in a dose dependent manner. Artemisinin and quinine were the most effective anti-malarials at disrupting rosettes at their therapeutic concentrations with South African RSA 14, 15, 17 and The Gambian FCR-3 P. falciparum strains. The least effective drugs were proguanil and chloroquine. A combination of artemisinin and mefloquine was more effective than each drug alone. The combinations of pyrimethamine or primaquine, with quinine disrupted more rosettes than quinine alone. Quinine may be an effective drug in the treatment of severe malaria because the drug efficiently reduces the number of rosettes.
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PMID:Plasmodium falciparum malaria: rosettes are disrupted by quinine, artemisinin, mefloquine, primaquine, pyrimethamine, chloroquine and proguanil. 1046 15


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