Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria.
(49/1442)
To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT(50)) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives (t(1/2)) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t(1/2) (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups (P > 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT(50) range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria. (+info)
Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria.
(50/1442)
We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 and P = 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P < 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further. (+info)
Combination therapy for malaria in Africa: hype or hope?
(51/1442)
The development of resistance to drugs poses one of the greatest threats to malaria control. In Africa, the efficacy of readily affordable antimalarial drugs is declining rapidly, while highly efficacious drugs tend to be too expensive. Cost-effective strategies are needed to extend the useful life spans of antimalarial drugs. Observations in South-East Asia on combination therapy with artemisinin derivatives and mefloquine indicate that the development of resistance to both components is slowed down. This suggests the possibility of a solution to the problem of drug resistance in Africa, where, however, there are major obstacles in the way of deploying combination therapy effectively. The rates of transmission are relatively high, a large proportion of asymptomatic infection occurs in semi-immune persons, the use of drugs is frequently inappropriate and ill-informed, there is a general lack of laboratory diagnoses, and public health systems in sub-Saharan Africa are generally weak. Furthermore, the cost of combination therapy is comparatively high. We review combination therapy as used in South-East Asia and outline the problems that have to be overcome in order to adopt it successfully in sub-Saharan Africa. (+info)
A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.
(52/1442)
The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days. (+info)
Effects of sodium artesunate, a new antimalarial drug, on renal function.
(53/1442)
BACKGROUND: Sodium artesunate is currently used in malaria treatment. Adverse effects of this drug have not been described, probably because they cannot be differentiated from malaria-related effects. METHODS: The effects on renal function of an acute infusion of sodium artesunate (12 mg/kg body weight) were studied in the rat with clearance techniques. We also evaluate the effect of sodium artesunate on chloride lumen-bath flux (Cl Jlb) in the isolated thick ascending limb of the loop of Henle (TALH) microperfused in vitro. RESULTS: Acute infusion of artesunate to the rat decreased inulin clearance, despite an increase in renal blood flow. These effects were associated with an increase in urinary excretion of sodium, chloride, potassium, and nitric oxide metabolites (NO(2)/NO(3)). In water-loaded animals, artesunate increased sodium and water distal delivery and decreased free water clearance (C(H(2)O)) factored for sodium and water delivery. Following hypertonic NaCl infusion, artesunate decreased free water excretion (Tc(H(2)O)) corrected by clearance of osmolarity (C(Osm)). In vitro, artesunate 10(-6) and 10(-3) mol/L added to bath solution decreased chloride lumen-bath flux in isolated rabbit TALH in a dose-dependent manner, with the threshold effect at 10(-4) mol/L. This effect was completely blocked by N(G)-nitroL-arginine-metilester (L-NAME) 5 mmol/L. Artesunate 10(-4) mol/L added to the perfusion solution did not change Cl Jlb. CONCLUSION: These findings suggest that artesunate decreases glomerular filtration rate and increases renal blood flow and urinary excretion of Na, Cl, and K. These effects were due, at least in part, to the inhibition of Cl transport across cortical and medullary TALH, and were mediated by local production of nitric oxide, since it is associated with an increase in NO(2)/NO(3) urinary excretion and it is blocked by L-NAME in vitro. (+info)
Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria.
(54/1442)
As part of a study to assess the infectivity of gametocytes after treatment with four antimalarial regimens, the efficacy of each treatment was also determined. From September to December 1998, 598 children with uncomplicated malaria were treated; 135 received chloroquine (CQ) alone, 276 received pyrimethamine/sulfadoxine (Fansidar, PSD) alone, 113 received PSD with a single dose of artesunate (PSD + 1ART) and 74 received PSD combined with three doses of artesunate (PSD + 3ART). On day 28 19/63 (30.2%; 95% C.I. 19.2% to 43.1%) of children treated with CQ alone, 5/134 (3.7%; 95% C.I. 1.2% to 8.5%) treated with PSD alone, 1/71 (1.4%, 95% C.I. 0.0% to 7.9%) treated with PSD + 1ART and 0/45 (0.0%; 95% C.I. 0.0% to 7.9%) treated with PSD + 3ART were parasitaemic. The proportion of children with gametocytes on day 7 after treatment with CQ alone was 16/89 (18.0%; 95% C.I. 10.6% to 27.6%), 98/174 (56.3%; 95% C.I. 48.6% to 63.8%) after treatment with PSD alone, 8/70 (11.4%; 95% C.I. 5.1% to 21.3%) after treatment with PSD + 1ART and 4/46 (8.7%; 95% C.I., 2.4% to 20.8%) after treatment with PSD + 3ART. CQ thus has a lower efficacy than PSD or either of the PSD and artesunate combinations. Use of PSD alone as an alternative first line treatment results in a very high post-treatment gametocyte prevalence that is likely to enhance transmission. There would be greater and more sustainable benefits from using PSD and artesunate combinations. (+info)
Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae.
(55/1442)
Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria. (+info)
Assessment of the antimalarial potential of tetraoxane WR 148999.
(56/1442)
The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synergistic with chloroquine, quinine, mefloquine, and artemisinin against both D6 and W2 clones of Plasmodium falciparum. In consideration of the contrasting antagonism between artemisinin and chloroquine, these drug combination data imply that WR 148999 and artemisinin may not share a common mechanism of action. For Plasmodium berghei-infected mice given oral, subcutaneous, and intraperitoneal doses of WR 148999 ranging from 2 to 1024 mg/kg in the Thompson test, median survival times were 8.8, 11.8, and 27.5 days, respectively, compared to 8 days for control animals. Using subcutaneous administration, WR 148999 had a considerably longer duration of action than did artemisinin against P. berghei. WR 148999 did not significantly inhibit cytochrome P450 isozymes CYP 2C9, 2C19, 2D6, 2E1, or 3A4 (IC50 >500 microM) but did inhibit CYP 1A2 with an IC50 value of 36 microM, suggesting that WR 148999 may be metabolized by the latter CYP isozyme. These results combined with previous observations that formulation strategies and incorporation of polar functional groups in a series of WR 148999 analogs both failed to enhance tetraoxane oral antimalarial activity suggest that oral bioavailability of tetraoxane WR 148999 is more likely a function of extensive first-pass metabolism rather than solubility-limited dissolution. (+info)