Reference Type: Journal Article
Author: Ashley, E.; McGready, R.; Proux, S.; Nosten, F.
Year: 2006
Title: Malaria
Journal: Travel Med Infect Dis
Volume: 4
Issue: 3-4
Pages: 159-173
Date: May - July
Abstract: Malaria is increasing worldwide due to the emergence and spread of drug resistant strains. This poses major health and economic problems for the population living in endemic areas and increases the risk of infections in travelers. The diagnosis of malaria relies on a biological proof of infection by microscopy or with a rapid test. The treatment must be initiated without delay preferably with an artemisinin containing regimen. Uncomplicated malaria can be treated with oral drugs while severe infections will be hospitalized and treated with injectables. Special attention will be given to the most susceptible groups: children and pregnant women.
Notes: 1477-8939 (Print)
Journal article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16887738
Author Address: Shoklo Malaria Research Unit, 68/30 Ban Toong Road, Mae Sot, Tak, 63110 Thailand; Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand; Centre for Clinical Vaccinology and Tropical Medicine Churchill Hospital, Old Road, Headington, Oxford, UK.

Reference Type: Journal Article
Author: Ashley, E.; McGready, R.; Singhasivanon, P.; Nosten, F.; Carrara, V.; Price, R.
Year: 2006
Title: In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003
Journal: Trop Med Int Health
Volume: 11
Issue: 12
Pages: 1898-9; author reply 1899
Date: Dec
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17176355

Reference Type: Journal Article
Author: Ashley, E. A.; Lwin, K. M.; McGready, R.; Simon, W. H.; Phaiphun, L.; Proux, S.; Wangseang, N.; Taylor, W.; Stepniewska, K.; Nawamaneerat, W.; Thwai, K. L.; Barends, M.; Leowattana, W.; Olliaro, P.; Singhasivanon, P.; White, N. J.; Nosten, F.
Year: 2006
Title: An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand
Journal: Trop Med Int Health
Volume: 11
Issue: 11
Pages: 1653-60
Date: Nov
Abstract: Background Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. Methods On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. Results The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P = 0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. Conclusion This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.
Notes: Journal Article
England
Tm & ih.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17054744
Author Address: Shoklo Malaria Research Unit, Tak, Thailand.

Reference Type: Journal Article
Record Number: 274
Author: Ashley, E. A.; Stepniewska, K.; Lindegardh, N.; McGready, R.; Hutagalung, R.; Hae, R.; Singhasivanon, P.; White, N. J.; Nosten, F.
Year: 2006
Title: Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria
Journal: Antimicrob Agents Chemother
Volume: 50
Issue: 7
Pages: 2281-5
Date: Jul
Abstract: A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.
Notes: 0066-4804 (Print)
Journal Article
Randomized Controlled Trial
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16801402
Author Address: Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot, Tak 63110, Thailand. SMRU@tropmedres.ac

Reference Type: Journal Article
Author: Carrara, V. I.; Sirilak, S.; Thonglairuam, J.; Rojanawatsirivet, C.; Proux, S.; Gilbos, V.; Brockman, A.; Ashley, E. A.; McGready, R.; Krudsood, S.; Leemingsawat, S.; Looareesuwan, S.; Singhasivanon, P.; White, N.; Nosten, F.
Year: 2006
Title: Deployment of Early Diagnosis and Mefloquine- Artesunate Treatment of Falciparum Malaria in Thailand: The Tak Malaria Initiative
Journal: PLoS Med
Volume: 3
Issue: 6
Pages: e183
Date: Jun 6
Abstract: BACKGROUND: Early diagnosis and treatment with artesunate-mefloquine combination therapy (MAS) have reduced the transmission of falciparum malaria dramatically and halted the progression of mefloquine resistance in camps for displaced persons along the Thai-Burmese border, an area of low and seasonal transmission of multidrug-resistant Plasmodium falciparum. We extended the same combination drug strategy to all other communities (estimated population 450,000) living in five border districts of Tak province in northwestern Thailand. METHODS AND FINDINGS: Existing health structures were reinforced. Village volunteers were trained to use rapid diagnostic tests and to treat positive cases with MAS. Cases of malaria, hospitalizations, and malaria-related deaths were recorded in the 6 y before, during, and after the Tak Malaria Initiative (TMI) intervention. Cross-sectional surveys were conducted before and during the TMI period. P. falciparum malaria cases fell by 34% (95% confidence interval [CI], 33.5-34.4) and hospitalisations for falciparum malaria fell by 39% (95% CI, 37.0-39.9) during the TMI period, while hospitalisations for P. vivax malaria remained constant. There were 32 deaths attributed to malaria during, and 22 after the TMI, a 51.5% (95% CI, 39.0-63.9) reduction compared to the average of the previous 3 y. Cross-sectional surveys indicated that P. vivax had become the predominant species in Thai villages, but not in populations living on the Myanmar side of the border. In the displaced persons population, where the original deployment took place 7 y before the TMI, the transmission of P. falciparum continued to be suppressed, the incidence of falciparum malaria remained low, and the in vivo efficacy of the 3-d MAS remained high. CONCLUSIONS: In the remote malarious north western border area of Thailand, the early detection of malaria by trained village volunteers, using rapid diagnostic tests and treatment with mefloquine-artesunate was feasible and reduced the morbidity and mortality of multidrug-resistant P. falciparum.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16719547
Author Address: Shoklo Malaria Research Unit, Tak, Thailand.

Reference Type: Journal Article
Author: Hutagalung, R.; Htoo, Hsar; Nwee, P.; Arunkamomkiri, J.; Zwang, J.; Carrara, I.V.; Ashley, E.; Singhasivanon, P.; White, N J.; Nosten, F.
Year: 2006
Title: A case control auditory evaluation of patients treated with artemether-lumefantrine
Journal: American Journal of Tropical Medicine and Hygiene
Volume: 74
Issue: 2
Pages: 211-214
Date: February 1, 2006
Alternate Journal: Am J Trop Med Hyg
Abstract: Artemether-lumefantrine is the first registered, fixed, artemisinin-based combination treatment. Artemisinin derivatives are highly effective antimalarials with a favorable safety profile. Concerns remain over their potential neurotoxicity, although there has been no clinical evidence of this in humans. In animals (rats, dogs, and monkeys) artemether, a derivative of artemisinin is associated with an unusual toxicity pattern in specific brain nuclei involving the auditory and vestibular pathways. A recent report from Mozambique described a small but significant and irreversible hearing loss in patients exposed to artemether-lumefantrine. To explore this issue, we conducted a case-control study using tympanometry, audiometry and auditory brain-stem responses. We assessed 68 subjects who had been treated with artemether-lumefantrine within the previous five years and 68 age- and sex-matched controls living in the malarious region along the Thailand-Myanmar border. There were no differences in the test results between cases and controls. There was no neurophysiologic evidence of auditory brainstem toxicity that could be attributed to artemether-lumefantrine in this study population.
URL: http://www.ajtmh.org/cgi/content/abstract/74/2/211

Reference Type: Journal Article
Author: Kosaisavee, V.; Suwanarusk, R.; Nosten, F.; Kyle, D. E.; Barrends, M.; Jones, J.; Price, R.; Russell, B.; Lek-Uthai, U.
Year: 2006
Title: Plasmodium vivax: isotopic, PicoGreen, and microscopic assays for measuring chloroquine sensitivity in fresh and cryopreserved isolates
Journal: Exp Parasitol
Volume: 114
Issue: 1
Pages: 34-9
Date: Sep
Abstract: In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study.
Notes: 0014-4894 (Print)
Journal Article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16545375
Author Address: Faculty of Public Health, Mahidol University, Bangkok, Thailand.

Reference Type: Journal Article
Author: McGready, R.; Ashley, E. A.; Tan, S. O.; Brabin, B.; Nosten, F.
Year: 2006
Title: Re: Malaria in pregnancy
Journal: Bjog
Volume: 113
Issue: 2
Pages: 246
Date: Feb
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412009

Reference Type: Journal Article
Record Number: 281
Author: McGready, R.; Stepniewska, K.; Lindegardh, N.; Ashley, E. A.; La, Y.; Singhasivanon, P.; White, N. J.; Nosten, F.
Year: 2006
Title: The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria
Journal: Eur J Clin Pharmacol
Date: Oct 20
Abstract: OBJECTIVE: To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. METHODS: Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. RESULTS: The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. CONCLUSION: Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17053895
Author Address: Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot, Tak, Thailand.

Reference Type: Journal Article
Author: McGready, R.; Stepniewska, K.; Ward, S. A.; Cho, T.; Gilveray, G.; Looareesuwan, S.; White, N. J.; Nosten, F.
Year: 2006
Title: Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria
Journal: Eur J Clin Pharmacol
Volume: 62
Issue: 5
Pages: 367-71
Date: May
Abstract: OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. METHODS: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. RESULTS: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. CONCLUSION: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.
Notes: 0031-6970 (Print)
Journal Article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16552504
Author Address: Shoklo Malaria Research Unit, P.O. Box 46, Mae Sot, Thailand.

Reference Type: Journal Article
Author: Mueller, E. A.; van Vugt, M.; Kirch, W.; Andriano, K.; Hunt, P.; de Palacios, P. I.
Year: 2006
Title: Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: A pooled analysis of individual patient data from randomized clinical trials
Journal: Acta Trop
Date: Oct 11
Abstract: To demonstrate the superiority of the six-dose over the four-dose regimen of artemether-lumefantrine (co-artemether, Coartem((R))) in patients >12 years, data from 11 randomized clinical trials were pooled and analyzed. A total of 1368 patients with uncomplicated Plasmodium falciparum malaria (six-dose: 598; four-dose: 770) were included in the analysis, together with 717 patients treated with comparators. Analysis of the 28-day cure rate based on the ITT and evaluable populations yielded corrected cure rates for the six-dose regimen of 87% and 97% compared with 74% and 87%, respectively, with the four-dose regimen (P<0.0001, for both comparisons). For mefloquine/artesunate, the most frequently used comparator, cure rates were 87% and 99%, respectively. The six-dose regimen was well tolerated and not markedly different to the four-dose regimen. The main finding of our analysis is that the six-dose regimen of co-artemether is more effective than the four-dose regimen in adolescents and adults without compromising safety.
Notes: Journal article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17045558

Reference Type: Journal Article
Author: Nair, S.; Nash, D.; Sudimack, D.; Jaidee, A.; Barends, M.; Uhlemann, A. C.; Krishna, S.; Nosten, F.; Anderson, T. J.
Year: 2006
Title: Recurrent Gene Amplification and Soft Selective Sweeps During Evolution of Multidrug Resistance in Malaria Parasites
Journal: Mol Biol Evol
Date: Nov 23
Abstract: When selection is strong and beneficial alleles have a single origin local reductions in genetic diversity are expected. However, when beneficial alleles have multiple origins or were segregating in the population prior to a change in selection regime, the impact on genetic diversity may be less clear. We describe an example of such a "soft" selective sweep in the malaria parasite Plasmodium falciparum that involves adaptive genome rearrangements. Amplification in copy number of genome regions containing the pfmdr1 gene on chromosome 5 confer resistance to mefloquine and spread rapidly in the 1990s. Using flanking microsatellite data and real-time PCR determination of copy number we show that 5-15 independent amplification events have occurred in parasites on the Thailand/Burma border. The amplified genome regions (amplicons) range in size from 14.7-49 kb and contain 2 to 11 genes, with 2 to 4 copies arranged in tandem. To examine the impact of drug selection on flanking variation we genotyped 48 microsatellites on chromosome 5 in 326 parasites from a single Thai location. Diversity was reduced in a 170 to 250 kb (10-15 cM) region of chromosomes containing multiple copies of pfmdr1, consistent with hitchhiking resulting from the rapid recent spread of selected chromosomes. However, diversity immediately flanking pfmdr1 is reduced by only 42% on chromosomes bearing multiple amplicons relative to chromosomes carrying a single copy. We highlight two features of these results: (1) All amplicon breakpoints occur in monomeric A/T tracts (9-45bp). Given the abundance of these tracts in P. falciparum, we expect that duplications will occur frequently at multiple genomic locations and have been underestimated as drivers of phenotypic evolution in this pathogen. (2) The signature left by the spread of amplified genome segments is broad, but results in only limited reduction in diversity. If such "soft" sweeps are common in nature statistical methods based on diversity reduction may be inefficient at detecting evidence for selection in genome-wide marker screens. This may be particularly likely when mutation rate is high, as appears to be the case for gene duplications, and in pathogen populations where effective population sizes are typically very large.
Notes: Journal article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17124182
Author Address: Southwest Foundation for Biomedical Research (SFBR), San Antonio, Texas, USA.

Reference Type: Journal Article
Author: Newton, P. N.; McGready, R.; Fernandez, F.; Green, M. D.; Sunjio, M.; Bruneton, C.; Phanouvong, S.; Millet, P.; Whitty, C. J.; Talisuna, A. O.; Proux, S.; Christophel, E. M.; Malenga, G.; Singhasivanon, P.; Bojang, K.; Kaur, H.; Palmer, K.; Day, N. P.; Greenwood, B. M.; Nosten, F.; White, N. J.
Year: 2006
Title: Manslaughter by Fake Artesunate in Asia-Will Africa Be Next?
Journal: PLoS Med
Volume: 3
Issue: 6
Pages: e197
Date: Jun 13
Accession Number: 16752952
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16752952

Reference Type: Journal Article
Author: Nosten, F.; Ashley, E.; McGready, R.; Price, R.
Year: 2006
Title: We still need artesunate monotherapy
Journal: Bmj
Volume: 333
Issue: 7557
Pages: 45
Date: Jul 1
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16809721

Reference Type: Journal Article
Author: Nosten, F.; McGready, R.; D'Alessandro, U. ; Bonell, A.; Verhoeff, F. H.; Menendez, C.; Mutabingwa, T.K.; Brabin, B. J.
Year: 2006
Title: Antimalarial drugs in pregnancy: a review
Journal: Current Drug Safety
Volume: 1
Issue: 1
Pages: 1-16

Reference Type: Journal Article
Author: Price, R. N.; Uhlemann, A. C.; van Vugt, M.; Brockman, A.; Hutagalung, R.; Nair, S.; Nash, D.; Singhasivanon, P.; Anderson, T. J.; Krishna, S.; White, N. J.; Nosten, F.
Year: 2006
Title: Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria
Journal: Clin Infect Dis
Volume: 42
Issue: 11
Pages: 1570-7
Date: Jun 1
Abstract: BACKGROUND: Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). METHODS: On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. RESULTS: All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. CONCLUSIONS: The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.
Notes: 1537-6591 (Electronic)
Journal Article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16652314
Author Address: Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom. ricprice@doctors.org.uk

Reference Type: Journal Article
Author: Simpson, J. A.; Agbenyega, T.; Barnes, K. I.; Di Perri, G.; Folb, P.; Gomes, M.; Krishna, S.; Krudsood, S.; Looareesuwan, S.; Mansor, S.; McIlleron, H.; Miller, R.; Molyneux, M.; Mwenechanya, J.; Navaratnam, V.; Nosten, F.; Olliaro, P.; Pang, L.; Ribeiro, I.; Tembo, M.; van Vugt, M.; Ward, S.; Weerasuriya, K.; Win, K.; White, N. J.
Year: 2006
Title: Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
Journal: PLoS Med
Volume: 3
Issue: 11
Pages: e444
Date: Nov
Alternate Journal: PLoS medicine
Abstract: BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.
Notes: Wellcome Trust
Journal Article
Research Support, Non-U.S. Gov't
United States
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17132053
Author Address: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia. julieas@unimelb.edu.au

Reference Type: Journal Article
Author: White, N.; Dondorp, A.; Nosten, F.; Day, N.
Year: 2006
Title: Artesunate versus quinine for severe falciparum malaria - Authors' reply
Journal: Lancet
Volume: 367
Issue: 9505
Pages: 111-112
Date: Jan 14
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16413872
Author Address: Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.

Reference Type: Journal Article
Record Number: 278
Author: White, N. J.; Ashley, E. A.; Nosten, F.
Year: 2006
Title: Toxic brainstem encephalopathy after artemisinin treatment for breast cancer
Journal: Ann Neurol
Volume: 59
Issue: 4
Pages: 725-6
Date: Apr
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16566014