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)

It has been suggested that the host antimalarial response depends in part on phagocyte-derived oxidants and that the parasite itself exerts an oxidative stress on its erythrocytic environment. Intraerythrocytic malaria parasites are particularly susceptible to being damaged by oxidative drugs, several of which are under development as chemotherapeutic agents. Thus the antioxidant status and associated regulatory mechanisms of the blood during malaria infection are of great interest. The important antioxidant ascorbate (AH-) and isoascorbate (IAH-), an isomer that does not occur naturally in animals, were found to have similar redox properties. We therefore assessed the usefulness of IAH- as a marker for studies of AH- handling in vivo and in vitro under normal conditions and in murine malaria infection. DHIA added to whole blood from normal or Plasmodium vinckei-infected mice in vitro was rapidly taken up into blood cells and reduced to IAH-. Intracellular IAH- derived from the exogenous DHIA was released into the plasma by blood cells from malaria-infected mice but not those from normal mice. Uptake and reduction of DHIA had no effect on plasma or cellular levels of AH- under these conditions. IAH- injected i.v. into either normal or P. vinckei-infected mice was rapidly cleared in both cases and led to an increase in plasma levels of AH-; this suggested displacement of the latter from some intracellular site, presumably not associated with blood cells. DHIA administered as an intravascular bolus into either normal or malaria-infected mice was rapidly reduced. However, in contrast to the in vitro situation, the concentration of plasma IAH- derived from the injected DHIA was approximately the same in both the infected and control animals. The IAH- so formed disappeared quickly from the plasma. Intravenous injection of DHIA into malaria-infected mice caused a rapid, prolonged increase in the proportion of plasma vitamin C in the form of DHA, whereas in uninfected mice there was a transient decrease in plasma DHA followed by normalisation. The changes in plasma AH- and DHA following IV injection of a single dose of DHA closely paralleled those seen after DHIA administration. These observations indicate that: (i) blood cells from normal and malaria-infected mice take up and reduce DHIA in a similar fashion, but they have different ways of handling the resulting IAH-; (ii) cells other than blood cells are important in the reduction of plasma DHIA and DHA in vivo; (iii) malaria-infected mice are less capable of handling oxidative challenge than normal ones; (iv) in some circumstances IAH- and DHIA may be useful nonisotopic markers for studies of vitamin C handling in vitro and in vivo.
 ...
PMID:Vitamin C redox reactions in blood of normal and malaria-infected mice studied with isoascorbate as a nonisotopic marker. 910 Dec 45

Artesunate (ARS) is a water-soluble artemisinin derivative that is a potential alternative to quinine for the treatment of severe childhood malaria. We studied the pharmacokinetics and bioavailability of ARS given by the intramuscular (i.m.) route in an open crossover study design. Fourteen children were randomized to receive intravenous (i.v.) ARS in a loading dose (2.4 mg/kg of body weight) followed 12 h later by an i.m. dose (1.2 mg/kg) (group I), and 14 children were randomized to receive i.m. ARS (2.4 mg/kg) followed by an i.v. dose of ARS (1.2 mg/kg) (group II). We carried out a two-compartment analysis of ARS and dihydroartemisinin (DHA; the principal antimalarial metabolite) levels in 21 children (groups I and II combined). Absorption of i.m. ARS was rapid, with the maximum concentration of DHA in serum being achieved in less than 1 h in most children (median time to the maximum concentration of drug in serum, 35.1 min; range, 10.8 to 71.9 min). The absolute bioavailability of DHA was a median of 86.4% (range, 11.4 to 462.1%), the median steady-state volume of distribution was 1.3 liters/kg (range, 0.5 to 7.9 liters/kg), and the median clearance was 0.028 liters/kg/min (range, 0.001 to 1.58 liters/kg/min). There were no major adverse events attributable to ARS. Parasite clearance kinetics were comparable between the two treatment groups. These results support the use of i.m. ARS in children with severe malaria.
 ...
PMID:Intramuscular bioavailability and clinical efficacy of artesunate in gabonese children with severe malaria. 1243 98

Penetration of cerebrospinal fluid (CSF) by artesunate and DHA was assessed in six adults with cerebral or severe malaria. Lumbar punctures were performed on admission and during convalescence, at 15 min (patient 1), 30 min (patient 2), 45 min (patient 3), 60 min (patient 4), 90 min (patient 5), and 120 min (patient 6) after intravenous administration of 120 mg of artesunate. No artesunate was detectable in CSF. In both studies, DHA levels in CSF increased with time while dihydroartemisinin levels in plasma fell. Dihydroartemisinin might accumulate in CSF during frequent artesunate dosing.
 ...
PMID:Penetration of dihydroartemisinin into cerebrospinal fluid after administration of intravenous artesunate in severe falciparum malaria. 1249 15

The antimalarial activity of artemether following oral or intramuscular administration in the plasma of 15 adults with acute uncomplicated Plasmodium falciparum malaria was measured by bioassay. The peak concentrations in plasma following oral administration were higher in patients with acute illness (median, 1,905 mmol of dihydroartemisinin [DHA] equivalents per liter; range, 955 to 3,358 mmol of DHA equivalents per liter) than in patients in the convalescent phase (median, 955 mmol of DHA equivalents per liter; range, 576 to 1,363 mmol of DHA equivalents per liter), and clearance (CL/F) was lower in patients in the acute phase (1.11 liters/kg/h; range, 0.21 to 3.08 liters/kg/h) than in patients in the convalescent phase (median, 2.76 liters/kg/h; range, 1.56 to 5.74 liters/kg/h) (P< or =0.008). Antimalarial activity in terms of the peak concentration in plasma (Cmax) after oral administration was a median of 16 times higher than that after intramuscular administration. The ratio of the area under the plasma concentration-time curve during the first 24 h (AUC(0-24)) after oral administration of artemether to the AUC(0-24) after intramuscular administration was a median of 3.3 (range, 1 to 11) (P=0.0001). In the acute phase, the time to Cmax was significantly shorter after oral administration (median, 1 h; range, 0.5 to 3.0 h) than after intramuscular administration (median, 8 h; range, 4 to 24 h) (P=0.001). Intramuscular artemether is absorbed very slowly in patients with acute malaria.
 ...
PMID:Artemether bioavailability after oral or intramuscular administration in uncomplicated falciparum malaria. 1463 85

Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria, but no pharmacokinetic characterisation was undertaken. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4 (CV4): dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate), which was followed by CV8 (the same components as CV4 but in increased quantities), Artecom (in which primaquine was omitted) and Artekin or Duo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates >95%), and have demonstrated that currently recommended regimens are not associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state/bioavailability, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of an ACT.
 ...
PMID:Piperaquine: a resurgent antimalarial drug. 1561 51

Traditional antimalarial medicinal preparations are widely used concurrently with antimalarial drugs in malaria endemic areas. The plant Aspilia africana (Pers.) C.D. Adams is commonly used for traditional treatment of malaria symptoms in East and Central Africa. An in vitro study of interactions between an extract from this plant with artemisinin against two strains of Plasmodium falciparum showed an antagonist relationship against both the chloroquine-sensitive D10 and the chloroquine- and sulphonamide-resistant K1 strains of Plasmodium falciparum. The extract reduced accumulation of radiolabelled dihydroartemisinin ((3)H-DHA) by erythrocytes infected with the chloroquine- and sulphonamide-resistant K1 strain of Plasmodium falciparum while it increased its accumulation by erythrocytes infected with the chloroquine-sensitive D10 strain. These results suggest complex interactions between the antimalarial medicinal plant and artemisinin. This study also proposes an in vitro approach to investigating interactions between antimalarial drugs and traditional medicines.
 ...
PMID:In vitro interactions of Aspilia africana (Pers.) C.D. Adams, a traditional antimalarial medicinal plant, with artemisinin against Plasmodium falciparum. 1610 29

In Rwanda, amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) is the current first-line treatment for malaria, introduced in 2001 as an interim strategy before the future deployment of an artemisinin-based combination treatment (ACT). Dihydroartemisinin/piperaquine (DHA-PQP) is a new co-formulated and well tolerated ACT increasingly used in Southeast Asia where it has proved to be highly effective against Plasmodium falciparum malaria. We tested the efficacy, safety and tolerability of DHA-PQP in children with uncomplicated P. falciparum malaria. A randomised, open trial was carried out in 2003-2004. Seven hundred and sixty-two children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to one of the following treatments: amodiaquine+artesunate; AQ+SP; or DHA-PQP. Patients were followed-up until Day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Children treated with DHA-PQP or AQ+AS had a significantly higher cure rate compared with those treated with amodiaquine+sulfadoxine/pyrimethamine (95.2% and 92.0% vs. 84.7%, respectively). Parasite clearance was significantly faster in children treated with DHA-PQP and AQ+AS compared with those treated with amodiaquine+sulfadoxine/pyrimethamine. The frequency of adverse events was significantly lower in patients treated with DHA-PQP than in those treated with combinations containing amodiaquine. A 3-day treatment with DHA-PQP proved to be efficacious with a good safety and tolerability profile and could be a good candidate for the next first-line treatment.
 ...
PMID:Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. 1676 6

The clinical efficacy of the monotherapy involving the administration of a high dose of dihydroartemisinin (DHA 900 mg) for 5 days was compared with that of the combination regimen (DHA 600 mg + mefloquine [MQ] 750 mg) in an open randomized study in 90 patients with uncomplicated falciparum malaria in the southern part of Viet Nam. Patients were randomly treated with the DHA-5 day monotherapy regimen (300, 300, 100, 100, and 100 mg given at 0, 24, 48, 72, and 96 h) or the DHA-MQ combination regimen (300 mg DHA at 0 h, then 300 mg DHA plus 750 mg MQ at 24 h). The end points for comparison were the parasite and fever clearance times (PCT and FCT) and recrudescence rates (by day 28 for DHA-5 days and day 42 for DHA-MQ). Eighty-nine patients completed the trial per protocol, including 45 cases receiving DHA-5 day and 44 receiving DHA-MQ. There was no difference in clinical manifestations, parasitemia density or other laboratory tests between the two patient groups. The PCTs were 35.3 +/- 17.4 h (mean +/- SD; range, 12-96) and 37.8 +/- 19.2 h (range, 12-96), respectively for the DHA-5 day and DHA-MQ regimens (P > 0.05). Twelve patients receiving the DHA-5 day regimen relapsed with falciparum malaria by day 28 (26.7%) and 5 patients receiving the DHA-MQ regimen relapsed by day 42 (11.4%) (P=0.07). Survival analysis showed that the DHA-5 day regimen had a radical cure rate significantly lower than that of the DHA-MQ regimen (P=0.003). The high dose of DHA in the monotherapy regimen did not increase the efficacy of the treatment of patients with uncomplicated Plasmodium falciparum malaria. The DHA combination regimens are suggested to be the better regimens for DHA.
 ...
PMID:Clinical efficacy of high dose monotherapy of oral dihydroartemisinin in uncomplicated falciparum malaria in viet nam. 1764 23

The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.
 ...
PMID:The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates. 1776 32

The disposition of chloroquine (CQ) and the related 4-aminoquinoline, piperaquine (PQ), were compared in Papua New Guinean children with uncomplicated malaria. Twenty-two children were randomized to 3 days of PQ phosphate at 20 mg/kg/day (12 mg of PQ base/kg/day) coformulated with dihydroartemisinin (DHA-PQ), and twenty children were randomized to 3 days of CQ at 10 mg base/kg/day with a single dose of sulfadoxine-pyrimethamine (CQ-SP). After a 42-day intensive sampling protocol, PQ, CQ, and its active metabolite monodesethyl-chloroquine (DECQ) were assayed in plasma by using high-performance liquid chromatography. A two-compartment model with first-order absorption was fitted to the PQ and CQ data. There were no significant differences in age, gender, body weight, or admission parasitemia between the two groups. The PCR-corrected 42-day adequate clinical and parasitological responses were 100% for DHA-PQ and 94% for CQ-SP, but P. falciparum reinfections during follow-up were common (33 and 18%, respectively). For PQ, the median volume of distribution at steady state, allowing for bioavailability (Vss/F), was 431 liters/kg (interquartile range [IQR], 283 to 588 liters/kg), the median clearance (CL/F) was 0.85 liters/h/kg (IQR, 0.67 to 1.06 liters/h/kg), the median distribution half-life (t 1/2 alpha) was 0.12 h (IQR, 0.05 to 0.66 h), and the median elimination half-life (t 1/2 beta) was 413 h (IQR, 318 to 516 h). For CQ, the median Vss/F was 154 liters/kg (IQR, 101 to 210 liters/kg), the median CL/F was 0.80 liters/h/kg (IQR, 0.52 to 0.96 liters/h/kg), the median t 1/2 alpha was 0.43 h (IQR, 0.05 to 1.82 h), and the median t 1/2 beta was 233 h (IQR, 206 to 298 h). The noncompartmentally derived median DECQ t 1/2 beta was 290 h (IQR, 236 to 368 h). Combined molar concentrations of DECQ and CQ were higher than those of PQ during the elimination phase. Although PQ has a longer t 1/2 beta than CQ, its prompt distribution and lack of active metabolite may limit its posttreatment malaria-suppressive properties.
 ...
PMID:Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. 1796 17


1 2 3 4 5 Next >>