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

Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum. Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined. In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance. In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use. The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease. All of the artemisinin drugs have comparable efficacy; the choice of derivative should be based upon availability, cost and quality of the preparation. Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity.
 ...
PMID:Artemisinin drugs: novel antimalarial agents. 1106 Jul 79

Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.
 ...
PMID:Pharmacokinetics of artemisinin-type compounds. 1106 12

The effect of artemisinin on membrane fluidity of erythrocytes was investigated using spin labeling compounds, doxyl stearic acids. The membrane fluidity of erythrocytes from the in vitro culture and malaria patients was determined. In vitro, the erythrocytes in parasite culture showed an increase in membrane fluidity which was associated with the parasite counts and stage of parasites. Artemisinin caused reduction in membrane fluidity and the effect was more pronounced in the erythrocytes infected with schizont stage-parasites. In vivo, the elevation of plasma TBARs (thiobarbituric acid reactive substances) and reduction of membrane fluidity were evident in Plasmodium falciparum-infected patients, particularly in severe cases. The levels of plasma TBARs were related to the severity of the disease. Treatment with artemisinin alone showed no effect on plasma TBARs, and did not alter the membrane fluidity. Desferrioxamine, however, reduced oxidative damage during the infection without compromising the therapeutic effect of artemisinin. These findings suggested that the infected erythrocytes were prone to the effect of artemisinin. Addition of a chelator such as desferrioxamine is beneficial and can improve the treatment of severe malaria.
 ...
PMID:Effect of artemisinin on lipid peroxidation and fluidity of the erythrocyte membrane in malaria. 1108 51

Drug development offers potential solutions to a number of tropical health diseases, although the expense of pharmaceutical research and lack of return on investment has limited the production of new agents. The greatest successes have been through the development of single dose therapy and mass treatment control programmes for a number of diseases. We review some of the current treatment regimens for malaria, intestinal helminth infection, onchocerciasis, filariasis and schistosomiasis, and their use in clinical practice. Geographical spread and emergence of drug resistant parasites have hindered the control of malaria, the most important global parasitic infection. Artemisinin compounds have proved effective antimalarial agents producing rapid reduction of parasite load and can be used in combination treatment regimens to combat multidrug resistance. Intestinal helminth infections are widespread, giving rise to nutritional deficiencies and impaired childhood cognitive development. Pregnant women in developing countries are at increased risk of morbidity. Treatment with a single dose benzimidazole such as albendazole or mebendazole has beneficial effects on morbidity and rates of transmission. Diethylcarbamazine has been used in the treatment of onchocerciasis and human filariasis. A complicated escalating dose regimen over several weeks is associated with systemic and allergic reactions and may require corticosteroid cover. Simplified regimens for mass population treatment with ivermectin have proved useful and been used in combination with single dose albendazole and diethylcarbamazine. The African Programme for Onchocerciasis Control in West and Central Africa has been one of the most successful mass control programmes virtually eliminating new infections by a combination of chemotherapy, education and vector control. Schistosomiasis is of increasing importance as a result of the creation of new snail habitats by agricultural and economic development. Praziquantel has become the most widely available and effective chemotherapy for schistosomiasis. There have been a number of reports of persistent schistosome egg shedding after treatment posing concerns about the emergence of drug resistance. Eflornithine has been successfully used in patients with human trypanosomiasis failing melarsoprol therapy however expense and availability have limited its potential. Mass control treatment programmes have targeted schoolchildren, adolescents and pregnant women. The integration of schistosomiasis, onchocerciasis, filariasis and helminth control programmes has been considered as a cost-effective method of delivering treatment. It is likely that future control will be based on this optimisation and integration of existing regimens, rather than the development of new agents.
 ...
PMID:Drug treatment of tropical parasitic infections: recent achievements and developments. 1112 30

Severe malaria remains a major cause of mortality in the world. Malaria can mimic many diseases and there is no absolute diagnostic clinical features. High index of suspicion is clue for clinical diagnosis. Previous travel history to endemic area should be elicited in all, and in particular, febrile patients. Management of severe malaria needs potent antimalarial drug and intensive care. Artemisinin derivatives can be of altemative use to quinine. Dexamethasone and mannitol have no beneficial value in the management of cerebral malaria. In pulmonary oedema patients whose hydration assessments are difficult to monitor, central venous pressure evaluation may be useful. Acute renal failure patients may need dialysis until uraemic syndrome subsides or patients can void urine. Most severe malaria patients have thrombocytopenia; however, platelet concentrate transfusion is indicated only in patients with systemic bleeding. Morbidity and mortality will be reduced in severe malaria patients with early diagnosis and prompt treatment.
 ...
PMID:Guideline in management of severe malaria. 1125 92

Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.
 ...
PMID:Possible modes of action of the artemisinin-type compounds. 1137 30

Despite previously reported chloroquine-resistant forms of PF falciparum in Ghana, chloroquine remains the drug of choice in severe malaria. Artemisinin derivatives have been shown to be effective against chloroquine-resistant strains in other endemic areas. This open randomized study was conducted to compare the efficacy of chloroquine and artesunate in the treatment of childhood cerebral malaria. Out of 82 subjects that fulfilled the inclusion criteria, 36 were randomized to receive chloroquine and 46 to receive artemisinin. Blantyre coma scores, temperature and parasitaemia were monitored. Mortality and neurological deficits were documented. There was no difference in mortality rates (chloroquine, 16.7 per cent; artesunate, 21.7 per cent; p = 0.6), neurological deficit at day 14 (chloroquine, 0 per cent; artesunate, 4.3 per cent; p = 0.3), resolution of fever (p = 0.55), and coma recovery time (p = 0.8), between the two groups. The results suggest that syrup chloroquine and intramuscular/oral artesunate currently give comparable clinical responses in the treatment of cerebral malaria in Ghana. Possible reasons for this are discussed, and suggestions are made for future antimalarial drug policy.
 ...
PMID:Comparison of chloroquine with artesunate in the treatment of cerebral malaria in Ghanaian children. 1141 81

Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.
 ...
PMID:Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies. 1178 34

The efficacy of artemisinin monotherapy was studied in 227 patients with uncomplicated falciparum malaria. They all received artemisinin at t = 0 hr, t = 8 hr, and thereafter once daily; treatment was extended at random until they had taken either 5 days of artemisinin followed by 2 days of placebo (A5), or 7 days (A7) of artemisinin. The adult artemisinin dose was 500 mg; children aged < 15 years received 10 mg/kg per dose. The median (range) parasite clearance time was 39 (8-112) hr for A5 and 43 (38-104) hr for A7 (P = 0.085). The recrudescence rates were similar between the groups. The lowest parasite count achieved during treatment (Pterm) was associated with the occurrence of recrudescence (P = 0.046, Cox regression model); it was lower for patients with a radical cure or late recrudescence than for early recrudescence (P = 0.034, t-test). Artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. Extending the duration of monotherapy from 5 days to 7 days does not reduce recrudescence.
 ...
PMID:Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? 1179 58

Cross-resistance may be considered one of the most important factors leading to decreased drug susceptibility of Plasmodium falciparum. The study aimed to determine whether clinically relevant cross-sensitivity of P. falciparum existed between artemisinin and mefloquine. Seventy-six patients with falciparum malaria were admitted and treated with artemisinin derivatives. Treatment response parameters were assessed and in vitro drug sensitivity tests were performed with artemisinin, mefloquine, quinine, and chloroquine. Distinct in vitro cross-sensitivity between artemisinin and mefloquine was observed (p = 0.604; P < 0.001). To assess the relevance of this finding for clinical cross-resistance, we used an analytical model based on the relation of in vivo treatment response parameters (fever, parasite and symptom clearance) to a single reference drug with in vitro drug sensitivity data of several other drugs. Artemisinin (R = 0.554; P = 0.009) and mefloquine (R = 0.615; P = 0.002) in vitro drug sensitivities were equally well reflected in the in vivo treatment response to artemisinin, thereby suggesting the clinical relevance of in vitro cross-sensitivity.
 ...
PMID:In vivo-in vitro model for the assessment of clinically relevant antimalarial cross-resistance. 1179 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>