Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

William Harvey wrote about malaria, snake bite and rabies, three diseases now having their greatest impact in tropical developing countries. Global malarial mortality has not declined for 50 years. The most effective control measure would be a vaccine. Temporary immunity in humans, through hundreds of bites by irradiated infected mosquitoes, was achieved in the 1970s. A promising current strategy is effector T-cell vaccination directed at infected hepatocytes. RTS,S/(SB)ASO2, an adjuvanted fusion protein, produced transient protection in 70% of vaccines. Prime (DNA vaccine) boost (poxvirus recombinant) is particularly immunogenic. Pyrethroid-treated bed nets reduce childhood mortality and deplete the mosquito population, interrupting transmission. Chlorproguanil-dapsone is more effective than pyrimethamine-sulfadoxine in treating uncomplicated chloroquine-resistant malaria. Artemisinin derivatives are as effective as quinine in severe disease. Snake bite is an underestimated and neglected cause of morbidity and mortality in rural communities in tropical countries. Sutherland's pressure-immobilisation technique is recommended first-aid for victims of neurotoxic elapid snakes. Rabies post-exposure prophylaxis, using new generation cell culture vaccines, is now feasible in developing countries, employing an economical 8-site intradermal regimen. This Harveian Oration, the first in 350 years to be devoted to tropical medicine, emphasises the importance of this speciality in the twenty-first century.
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PMID:'To search and studdy out the secrett of tropical diseases by way of experiment'. 1179 90

Malaria is a major health problem in many countries and according to an estimate of the WHO, more than 500 million infections occur per year. Artemisinin, a sesquiterpene from Artemisia annua L., has received considerable attention as a promising and potent antimalarial drug for its stage speciticity, its rather low toxicity, effectiveness against drug-resistant Plasmodium species and activity against cerebral malaria. From recent studies it seems that hemin is primarily involved in the antimalarial activity of the constituents of Artemisia annua L. Thus, the interaction of a compound with hemin may represent a crucial screening test to define its efficacy. In this study the interaction between artemisinin and hemin was investigated by UltraViolet/Visible (UV/Vis) spectrophotometry and High Performance Liquid Chromatography/Diode Array Detector/Mass Spectrometry (HPLC/DAD/MS). In addition, some flavonols isolated from Artemisia annua L. were also tested to investigate their possible role in the interaction between artemisinin and hemin. These two simple physico-chemical methods can be useful as rapid and widespread screening methods for the search of other alkylating antimalarial constituents from natural sources or for the evaluation of the activity of semisynthetic analogues of artemisinin.
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PMID:Simple and rapid physico-chemical methods to examine action of antimalarial drugs with hemin: its application to Artemisia annua constituents. 1183 40

Multiple drug resistance is a significant problem in small-cell lung cancer (SCLC). Artemisinin (ART) is a natural product used to treat drug-resistant malaria. The drug is effective because the Fe2+ present in infected erythrocytes acts non-enzymatically to convert ART to toxic products. We tested the effects of ART on drug-sensitive (H69) and multi-drug-resistant (H69VP) SCLC cells, pretreated with transferrin (TF) to increase the intracellular Fe2+ level. Antibody staining followed by flow cytometry analysis showed twice the level of TF receptors on the H69VP as compared to the H69 cells. Low doses of ART were cytotoxic to SCLC cells. The cytotoxicity of ART for H69VP cells (IC50=24 nM) was ten-fold lower than for H69 cells (IC50=2.3 nM), indicating that ART is part of the drug resistance phenotype. Pretreatment of H69 cells with 220-880 nM TF did not alter the IC50 for ART. However, in the ART-resistant H69VP cells, pretreatment with TF lowered the ART IC50 to near drug-sensitive levels (IC50=5.4 nM after 4 h pretreatment with 880 nM TF). Desferrioxamine (5 microM) inhibited the effect of TF on the IC50 for ART in drug-resistant cells but did not have an effect on ART cytotoxicity in drug-sensitive cells. DNA fragmentation as measured by ELISA occurred within ART-treated cells, with kinetics indicating apoptosis rather than necrosis. This was confirmed by TUNEL staining. These data indicate the potential use of ART and TF in drug-resistant SCLC.
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PMID:Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells. 1188 69

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means +/- standard deviations, 50 +/- 23 and 34 +/- 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P = 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose- and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.
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PMID:Artemisinin pharmacokinetics and efficacy in uncomplicated-malaria patients treated with two different dosage regimens. 1189 85

Praziquantel is the current mainstay for morbidity control of schistosomiasis. Artemisinin and its derivatives, widely used for the treatment of malaria, also display antischistosomal properties. The present study is an effort to assess the therapeutic efficacy of artesunate, an artemisinin derivative, in Schistosoma haematobium infections in a human population. The efficacy of artesunate and praziquantel were comparatively studied in primary schoolchildren from two villages, Lampsar (n=180) and Makhana (n=108), located along the Lampsar river in the delta of the Senegal River Basin in Northern Senegal (West Africa). In each village, half of the infected children were treated with a single oral dose of 40 mg/kg praziquantel and half with artesunate following the recommended malaria monotherapy regimen. For both drugs, cure and egg count reduction rates were, without apparent explanation, higher in Makhana than in Lampsar. In both villages, high and nearly comparable egg count reduction rates were obtained with both drugs at each follow-up after treatment (5, 12 and 24 weeks) in the heavy infected group of children (>50 eggs/10 ml of urine). No major adverse effects were observed. The results demonstrate that artesunate is effective against S. haematobium, but the results obtained with praziquantel were consistently better.
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PMID:Efficacy of artesunate and praziquantel in Schistosoma haematobium infected schoolchildren. 1190 4

In the scenario of drug-resistant Plasmodium falciparum malaria combination therapy represents an effective approach. Artemisinin and its derivatives are of special interest because they represent the most effective group of compounds against multidrug-resistant malaria with a rapid onset of action and a short half-life. Interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine were therefore investigated against three strains of P. falciparum using a 48-h in vitro culture assay. Two of the strains were chloroquine sensitive and one was partially chloroquine resistant. Observed effective concentrations (O) of the combined compounds at different concentration ratios were calculated for different degrees of inhibition (EC50, EC90, EC99) and compared to expected calculated effective concentrations (E) using a probit method. Synergism with mean O/E EC90 values of 0.25 and 0.8 were found with the combination of artemisinin and the two Mannich bases, amodiaquine and pyronaridine, respectively, whereas chloroquine showed addition with a mean value of 1.2. Although both amodiaquine and chloroquine are 4-aminoquinolines, their interaction with artemisinin appears to be different. The combination of artemisinin with amodiaquine represents an important option for the treatment of falciparum malaria.
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PMID:Plasmodium falciparum: in vitro interactions of artemisinin with amodiaquine, pyronaridine, and chloroquine. 1197 51

Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the antimalarial activities of artemisinin analogues, we performed molecular docking simulations to probe the interactions of these analogues with hemin, and then performed three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies on the basis of the docking models employing comparative molecular force fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular docking simulations generated probable 'bioactive' conformations of artemisinin analogues and provided a new insight into the antimalarial mechanism. The subsequent partial least squares (PLS) analysis indicates that the calculate binding energies correlate well with the experimental activity values. The CoMFA and CoMSIA models based on the bioactive conformations proved to have good predictive ability and in turn match well with the docking result, which further testified the reliability of the docking model. Combining these results, that is molecular docking and 3-D-QSAR, together, the binding model and activity of new synthesized artemisinin derivatives were well explained.
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PMID:Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues. 1211 Mar 8

With the emergence of multidrug-resistant falciparum malaria, new drugs and drugs in combination are urgently needed. New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand in recent years for treatment of uncomplicated and severe falciparum malaria are as follows: atovaquone, and artemisinin derivatives (artesunate, artemether, arteether, and dihydroartemisinin) combined with other antimalarials.Malarone, artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline have been evaluated with improvement of the cure rate in uncomplicated malaria. Artemisinin derivatives intravenously or intrarectally combined with mefloquine may be alternatives to intravenous quinine for treatment of severe malaria. In Thailand, drug treatment for uncomplicated malaria consists of the combinations or artesunate plus mefloquine or artemether plus lumefantrine or quinine plus tetracycline. In treatment of severe malaria, antimalarial drugs of choice are intravenous quinine or artemisinin derivatives.
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PMID:The future outlook of antimalarial drugs and recent work on the treatment of malaria. 1223 33

Artemisinin and its derivatives are widely used throughout the world. The mechanism of action of these compounds appears to involve the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centred free radicals. The involvement of heme explains why the drugs are selectively toxic to malaria parasites. The resulting carbon-centred free radicals are alkylate heme and proteins, one of which is the translationally controlled tumour protein. Clinically relevant artemisinin resistance has not been demonstrated, but it is likely to occur since artemisinin resistance has been obtained in laboratory models. At high doses, artemisinin can be neurotoxic but toxicity has not been found in clinical studies. The mechanism of neurotoxicity may be similar to the mechanism of action.
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PMID:Artemisinin: mechanisms of action, resistance and toxicity. 1243 50

Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T-->M mutation at residue 61 linked to an S-->T (but not an S-->N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.
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PMID:Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations. 1243


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