Author: Price, R. N.; Dorsey, G.; Ashley, E. A.; Barnes, K. I.; Baird, J. K.; d'Alessandro, U.; Guerin, P. J.; Laufer, M. K.; Naidoo, I.; Nosten, F.; Olliaro, P.; Plowe, C. V.; Ringwald, P.; Sibley, C. H.; Stepniewska, K.; White, N. J.
Year: 2007
Title: World Antimalarial Resistance Network I: clinical efficacy of antimalarial drugs
Journal: Malar J
Volume: 6
Pages: 119
Abstract: The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17822532
Author Address: International Health Program, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia. ricprice@doctors.org.uk

Author: Golfetto, I.; McGready, R.; Ghebremeskel, K.; Min, Y.; Dubowitz, L.; Nosten, F.; Drury, P.; Simpson, J. A.; Arunjerdja, R.; Crawford, M. A.
Year: 2007
Title: Fatty acid composition of milk of refugee Karen and urban Korean mothers. Is the level of DHA in breast milk of Western women compromised by high intake of saturated fat and linoleic acid?
Journal: Nutr Health
Volume: 18
Issue: 4
Pages: 319-32
Abstract: BACKGROUND: Lower proportions of docosahexaenoic acid (DHA) and total n-3 metabolites have been reported in breast milk of European, Australian and North American women compared with milk of mothers from non-Western countries. This difference is not always explained by intakes of marine products. OBJECTIVE: We investigated the possibility that the relative composition of DHA and total n-3 metabolites in breast milk of non-Western mothers with low fat intakes is higher than the levels commonly reported in their Western counterparts. Subjects: Mature milk of refugee Karen women from two different camps in Thailand (n=26 and n=53), and transition milk from urban Korean mothers (n=12) in Seoul was collected. In common with their respective community, the mothers have low fat intake, which is predominately of plant origin. RESULTS: The percentage levels of DHA and n-3 metabolites in the milk of the Karen mothers were 0.52 +/- 0.14 and 0.85 +/- 0.24 (camp 1) and 0.54 +/- 0.22 and 0.92 +/- 0.42 (camp 2). In the Korean milk, DHA was 0.96 +/- 0.21 and total n-3 metabolites 1.51 +/- 0.3. CONCLUSION: We postulate that the levels of DHA and total n-3 metabolites may be compromised in breast milk of mothers on the Western high fat diet. This calls into question the use of DHA composition of such milk as a reference for the formulation of milk designed, for infant feed or, to test the function of DHA in neuro-visual development.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18087864
Author Address: The Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, Holloway Road, London, UK.

Author: Uhlemann, A. C.; McGready, R.; Ashley, E. A.; Brockman, A.; Singhasivanon, P.; Krishna, S.; White, N. J.; Nosten, F.; Price, R. N.
Year: 2007
Title: Intrahost selection of Plasmodium falciparum pfmdr1 alleles after antimalarial treatment on the northwestern border of Thailand
Journal: J Infect Dis
Volume: 195
Issue: 1
Pages: 134-41
Abstract: BACKGROUND: Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. METHODS: In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. RESULTS: Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P<.001). CONCLUSIONS: Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17152017
Author Address: Centre for Infection, Division of Cellular and Molecular Medicine, St. George's, University of London, London, United Kingdom.

Author: Stepniewska, K.; Chotivanich, K.; Brockman, A.; Day, N. P.; White, N. J.
Year: 2007
Title: Overestimating resistance in field testing of malaria parasites: simple methods for estimating high EC50 values using a Bayesian approach
Journal: Malar J
Volume: 6
Issue: 1
Pages: 4
Date: Jan 17
Abstract: ABSTRACT: Conventional methods of assessing in-vitro antimalarial drug-concentration effect relationships in field testing of fresh isolates assess each isolate individually. This leads to systematic overestimation of EC50 values for the most resistant isolates, and thus overestimation of the degree of resistance. In antimalarial drug-susceptibility studies conducted on the north-western border of Thailand the overestimation of EC50 for the most resistant isolate ranged from 15% for artesunate to 43% for mefloquine. If isolates cannot be stored for re-testing, more accurate estimations of the degree of resistance can be obtained using a Bayesian approach to data analysis which is described here.
Notes: Journal article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17229314

Author: Nosten, F.; McGready, R.; Mutabingwa, T.
Year: 2007
Title: Case management of malaria in pregnancy
Journal: Lancet Infect Dis
Volume: 7
Issue: 2
Pages: 118-25
Abstract: In all malarious areas, infection by any of the main human plasmodial species during pregnancy is detrimental to the mother and the fetus. These potentially fatal infections must be prevented, but when they develop they require prompt diagnosis and treatment. Current tools to detect malaria parasites in pregnant women are often not used and remain too insensitive to detect a low parasitaemia. The kinetics, safety, and efficacy of available antimalarial drugs are poorly documented because pregnant women are systematically excluded from clinical trials. A considerable effort, involving clinical trials, is urgently required to improve the diagnosis and case management of malaria during pregnancy if the morbidity and mortality of maternal malaria is to be reduced.
Notes: Journal Article
United States
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17251082
Author Address: Shoklo Malaria Research Unit, Mae Sot, Thailand. smru@tropmedres.ac

Author: Nair, S.; Nash, D.; Sudimack, D.; Jaidee, A.; Barends, M.; Uhlemann, A. C.; Krishna, S.; Nosten, F.; Anderson, T. J.
Year: 2007
Title: Recurrent gene amplification and soft selective sweeps during evolution of multidrug resistance in malaria parasites
Journal: Mol Biol Evol
Volume: 24
Issue: 2
Pages: 562-73
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 polymerase chain reaction 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 to 49 kb and contain 2-11 genes, with 2-4 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 2 features of these results: 1) All amplicon break points occur in monomeric A/T tracts (9-45 bp). 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.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17124182

Author: Mytton, O. T.; Ashley, E. A.; Peto, L.; Price, R. N.; La, Y.; Hae, R.; Singhasivanon, P.; White, N. J.; Nosten, F.
Year: 2007
Title: Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria
Journal: Am J Trop Med Hyg
Volume: 77
Issue: 3
Pages: 447-50
Abstract: Dihydroartemisinin-piperaquine (DP) could become a leading fixed combination malaria treatment worldwide. Although there is accumulating evidence of efficacy and safety from clinical trials, data on cardiotoxicity are limited. In two randomized controlled trials in Thailand, 56 patients had ECGs performed before treatment, 4 hours after the first dose, and 4 hours after the last dose. The mean (95% CI) changes in QTc interval (Bazett's correction) were 2 (-6 to 9) ms and 14 (7 to 21) ms, respectively. These small changes on the third day of treatment are similar to those observed elsewhere in the convalescent phase following antimalarial treatment with drugs known to have no cardiac effects and are therefore likely to result from recovery from acute malaria and not the treatment given. At therapeutic doses, DP does not have clinically significant effects on the electrocardiogram.
Notes: Journal Article
Randomized Controlled Trial
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=17827358
Author Address: Shoklo Malaria Research Unit, Mae Sot, Thailand.

Author: Mytton, O.; McGready, R.; Lee, S.; Roberts, C.; Ashley, E.; Carrara, V.; Thwai, K.; Jay, M.; Wiangambun, T.; Singhasivanon, P.; Nosten, F.
Year: 2007
Title: Safety of benzyl benzoate lotion and permethrin in pregnancy: a retrospective matched cohort study
Journal: Bjog
Volume: 114
Issue: 5
Pages: 582-587
Abstract: Objective To assess the safety of benzyl benzoate lotion (BBL) and permethrin, topical treatments for scabies, during pregnancy. Design A retrospective controlled cohort study. Population Refugee and migrant women attending antenatal clinics (ANC) on the Thai-Burmese border between August 1993 and April 2006. Methods Women treated with either BBL (25%) or permethrin (4%) were identified from a manual search of antenatal records. Each case of scabies was matched with four scabies-free controls for gravidity, age, smoking status, malaria, period of treatment and gestational age at treatment. Conditional Poisson regression was used to estimate risk ratios for outcomes of pregnancy (proportion of abortions, congenital abnormalities, neonatal deaths, stillbirths and premature babies), mean birthweight and estimated median gestational age, for scabies and scabies-free women, independently for BBL and permethrin. Results There were no statistically significant differences in pregnancy outcomes between women who were treated with either BBL (n= 444) compared with their matched controls (n= 1,776) or permethrin (n= 196) treated women and their matched controls (n= 784). Overall, only 10.9% (n= 66) of treatments were in the first trimester. Retreatment rates were higher with BBL 16.4%, than permethrin 9.7%, P= 0.038. Scabies was more common during cooler periods. Conclusion We found no evidence of adverse effects on pregnancy outcome due to topical 25% BBL or 4% permethrin.
Notes: Journal article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17439567
Author Address: Shoklo Malaria Research Unit, PO Box 46 Mae Sot, Tak, Thailand.

Author: Ward, S. A.; Sevene, E. J.; Hastings, I. M.; Nosten, F.; McGready, R.
Year: 2007
Title: Antimalarial drugs and pregnancy: safety, pharmacokinetics, and pharmacovigilance
Journal: Lancet Infect Dis
Volume: 7
Issue: 2
Pages: 136-44
Alternate Journal: The Lancet infectious diseases
Abstract: Before a recommendation for antimalarial drug use in pregnancy is made, it is essential that we understand the potential risks involved and have mechanisms in place to monitor risk during treatment. This requires data on drug disposition during pregnancy and potential toxicological liabilities to the developing fetus and mother. In most cases this information is not available. We review the reproductive toxicology of the main antimalarial drug classes in use or under development. Preclinical data are presented if appropriate, but as human experience overrides such data, in instances in which preclinical studies do not correlate with the human experience the data are reviewed only briefly. Additionally, we highlight the lack of appropriate drug disposition data in pregnancy and suggest mechanisms that can be used to capture data on risk after drug treatment in pregnancy.
Notes: Journal Article
United States
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17251084

Author: Villegas, L.; McGready, R.; Htway, M.; Paw, M. K.; Pimanpanarak, M.; Arunjerdja, R.; Viladpai-Nguen, S. J.; Greenwood, B.; White, N. J.; Nosten, F.
Year: 2007
Title: Chloroquine prophylaxis against vivax malaria in pregnancy: a randomized, double-blind, placebo-controlled trial
Journal: Trop Med Int Health
Volume: 12
Issue: 2
Pages: 209-18
Abstract: Objective To assess the safety of chloroquine (CQ) as prophylaxis against Plasmodium vivax infection during pregnancy. Method One thousand pregnant Karen women were enrolled in a randomized, double-blind, placebo-controlled trial of chemoprophylaxis with chloroquine (500 mg phosphate (or 300 mg base) weekly). Women received a median (range) chloroquine phosphate total dose of 9500 (1500-17 500) mg. The mothers were actively followed from inclusion to delivery and their infants until 12 months of age. Results Chloroquine prophylaxis completely prevented P. vivax episodes; 10.1% (95%CI: 7.3-14.5) of women in the placebo group experienced at least one episode of vivax malaria but no episode occurred in women in the CQ group. By contrast, the numbers of P. falciparum episodes were similar in each group: 7.4% (95%CI: 3.7-11.1) and 5.6% (95%CI: 3.3-7.9) in the placebo and CQ groups respectively (P = 0.56). Chloroquine prophylaxis was well tolerated and there was no difference in the proportions of reported side effects between CQ treated and placebo groups except for the duration of palpitations and sleeping disorders which were more frequent in those who had received CQ. Chloroquine prophylaxis had no impact on maternal anaemia, birth weight, gestational age, development of newborns or on growth, neurological development or visual acuity in infants at 1 year of age. Conclusion Chloroquine is safe and effective as prophylaxis against P. vivax during pregnancy in this population.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17300627
Author Address: Shoklo Malaria Research Unit, Mae SotThailand.

Author: Myint, H. Y.; Ashley, E. A.; Day, N. P.; Nosten, F.; White, N. J.
Year: 2007
Title: Efficacy and safety of dihydroartemisinin-piperaquine
Journal: Trans R Soc Trop Med Hyg
Volume: 101
Issue: 9
Pages: 858-66
Abstract: Dihydroartemisinin-piperaquine, a fixed-dose combination antimalarial, is an inexpensive, safe and highly effective treatment for uncomplicated falciparum or vivax malaria. Efficacy assessed over 28-63 days has consistently exceeded 95% in the treatment of multidrug-resistant falciparum malaria. More than 2600 patients have been treated with this combination in prospective studies, mainly in Southeast Asia. Tolerability was uniformly good, and no serious adverse effects have been identified. The dosing regimen has been simplified from four doses to once daily over 3 days. More information on efficacy in Africa, and more pharmacokinetic and efficacy data in children are needed.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17659311
Author Address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.

Author: McGready, R.; Kaveri, S. V.; Lacroix-Desmazes, S.; Krudsood, S.; Newton, P. N.
Year: 2007
Title: Acquired haemophilia A in early pregnancy associated with Plasmodium vivax malaria and hyperthyroidism
Journal: Aust N Z J Obstet Gynaecol
Volume: 47
Issue: 1
Pages: 76-7
Date: Feb
Notes: Journal Article
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17261106
Author Address: Shoklo Malaria Research Unit, Tak, Thailand 63110.

Author: Mayxay, M.; Barends, M.; Brockman, A.; Jaidee, A.; Nair, S.; Sudimack, D.; Pongvongsa, T.; Phompida, S.; Phetsouvanh, R.; Anderson, T.; White, N. J.; Newton, P. N.
Year: 2007
Title: In Vitro Antimalarial Drug Susceptibility and Pfcrt Mutation among Fresh Plasmodium Falciparum Isolates from the Lao Pdr (Laos)
Journal: Am J Trop Med Hyg
Volume: 76
Issue: 2
Pages: 245-250
Date: Feb
Abstract: Recent drug trials in Laos have shown high levels of Plasmodium falciparum resistance to chloroquine, but there are no published data on in vitro antimalarial drug susceptibility. We used the double-site enzyme-linked pLDH immunodetection (DELI) assay to estimate the in vitro antimalarial drug susceptibility of 108 fresh P. falciparum isolates from southern Laos. The geometric mean (95% confidence interval) 50% inhibitory concentration values (nmol/L) were 152.4 (123.8-187.6) for chloroquine, 679.8 (533.8-863.0) for quinine, 45.9 (37.9-55.7) for mefloquine, 5.0 (4.4-6.4) for artesunate, 6.3 (4.5-8.9) for dihydroartemisinin, and 59.1 (46.4-75.3) for lumefantrine. The proportion of isolates defined as resistant were 65%, 40%, and 8% for chloroquine, quinine, and mefloquine, respectively. Of 53 isolates genotyped for the pfcrt T76K chloroquine-resistance mutation, 48 (91%) were mutants. P. falciparum in Laos is multi-drug resistant; antimalarial immunity resulting from the use of ineffective chloroquine before 2005 probably contributes significantly to the therapeutic responses in clinical trials.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17297031

Author: Kamya, M. R.; Yeka, A.; Bukirwa, H.; Lugemwa, M.; Rwakimari, J. B.; Staedke, S. G.; Talisuna, A. O.; Greenhouse, B.; Nosten, F.; Rosenthal, P. J.; Wabwire-Mangen, F.; Dorsey, G.
Year: 2007
Title: Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial
Journal: PLoS Clin Trials
Volume: 2
Issue: 5
Pages: e20
Abstract: OBJECTIVES: To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blinded clinical trial. SETTING: Apac, Uganda, an area of very high malaria transmission intensity. PARTICIPANTS: Children aged 6 mo to 10 y with uncomplicated falciparum malaria. INTERVENTION: Treatment of malaria with AL or DP, each following standard 3-d dosing regimens. OUTCOME MEASURES: Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs. CONCLUSION: DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17525792
Author Address: Department of Medicine, Makerere University, Kampala, Uganda.

Author: Janssens, B.; van Herp, M.; Goubert, L.; Chan, S.; Uong, S.; Nong, S.; Socheat, D.; Brockman, A.; Ashley, E. A.; Van Damme, W.
Year: 2007
Title: A randomized open study to assess the efficacy and tolerability of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia
Journal: Trop Med Int Health
Volume: 12
Issue: 2
Pages: 251-9
Abstract: OBJECTIVES: To compare the efficacy and tolerability of dihydroartemisinin-piperaquine (DHA-PQP) with that of a 3-day regimen of mefloquine and artesunate (MAS3) for the treatment of uncomplicated falciparum malaria in Cambodia. METHOD: Randomized open-label non-inferiority study over 64 days. RESULTS: Four hundred and sixty-four patients were included in the study. The polymerase chain reaction genotyping-adjusted cure rates on day 63 were 97.5% (95% confidence interval, CI, 93.8-99.3) for DHA-PQP and 97.5% (95% CI, 93.8-99.3) for MAS3, P = 1. There were no serious adverse events, but significantly more episodes of vomiting (P = 0.03), dizziness (P = 0.002), palpitations (P = 0.04), and sleep disorders (P = 0.03) reported in the MAS3 treatment group, consistent with the side-effect profile of mefloquine. CONCLUSIONS: DHA-PQP was as efficacious as MAS3, but much better tolerated, making it more appropriate for use in a routine programme setting. This highly efficacious, safe and more affordable fixed-dose combination could become the treatment of choice for Plasmodium falciparum malaria in Cambodia.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17300633
Author Address: Medecins Sans Frontieres, Phnom Penh, Cambodia. b.janssens@bigfoot.com

Author: Imwong, M.; Snounou, G.; Pukrittayakamee, S.; Tanomsing, N.; Kim, J. R.; Nandy, A.; Guthmann, J. P.; Nosten, F.; Carlton, J.; Looareesuwan, S.; Nair, S.; Sudimack, D.; Day, N. P.; Anderson, T. J.; White, N. J.
Year: 2007
Title: Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites
Journal: J Infect Dis
Volume: 195
Issue: 7
Pages: 927-33
Abstract: BACKGROUND: Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites that caused the primary infection. METHODS: Paired samples were collected before initiation of antimalarial treatment and at recurrence of parasitemia from 149 patients with vivax malaria in Thailand (n=36), where reinfection could be excluded, and during field studies in Myanmar (n=75) and India (n=38). RESULTS: Combined genetic data from 2 genotyping approaches showed that novel P. vivax populations were present in the majority of patients with recurrent infection (107 [72%] of 149 patients overall [78% of patients in Thailand, 75% of patients in Myanmar {Burma}, and 63% of patients in India]). In 61% of the Thai and Burmese patients and in 55% of the Indian patients, the recurrent infections contained none of the parasite genotypes that caused the acute infection. CONCLUSIONS: The P. vivax populations emerging from hypnozoites commonly differ from the populations that caused the acute episode. Activation of heterologous hypnozoite populations is the most common cause of first relapse in patients with vivax malaria.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17330781
Author Address: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Author: Golfetto, I.; McGready, R.; Ghebremeskel, K.; Min, Y.; Dubowitz, L.; Nosten, F.; Drury, P.; Simpson, J. A.; Arunjerdja, R.; Crawford, M. A.
Year: 2007
Title: Fatty acid composition of milk of refugee Karen and urban Korean mothers. Is the level of DHA in breast milk of Western women compromised by high intake of saturated fat and linoleic acid?
Journal: Nutr Health
Volume: 18
Issue: 4
Pages: 319-32
Abstract: BACKGROUND: Lower proportions of docosahexaenoic acid (DHA) and total n-3 metabolites have been reported in breast milk of European, Australian and North American women compared with milk of mothers from non-Western countries. This difference is not always explained by intakes of marine products. OBJECTIVE: We investigated the possibility that the relative composition of DHA and total n-3 metabolites in breast milk of non-Western mothers with low fat intakes is higher than the levels commonly reported in their Western counterparts. Subjects: Mature milk of refugee Karen women from two different camps in Thailand (n=26 and n=53), and transition milk from urban Korean mothers (n=12) in Seoul was collected. In common with their respective community, the mothers have low fat intake, which is predominately of plant origin. RESULTS: The percentage levels of DHA and n-3 metabolites in the milk of the Karen mothers were 0.52 +/- 0.14 and 0.85 +/- 0.24 (camp 1) and 0.54 +/- 0.22 and 0.92 +/- 0.42 (camp 2). In the Korean milk, DHA was 0.96 +/- 0.21 and total n-3 metabolites 1.51 +/- 0.3. CONCLUSION: We postulate that the levels of DHA and total n-3 metabolites may be compromised in breast milk of mothers on the Western high fat diet. This calls into question the use of DHA composition of such milk as a reference for the formulation of milk designed, for infant feed or, to test the function of DHA in neuro-visual development.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18087864
Author Address: The Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, Holloway Road, London, UK.

Author: Barends, M.; Jaidee, A.; Khaohirun, N.; Singhasivanon, P.; Nosten, F.
Year: 2007
Title: In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border
Journal: Malar J
Volume: 6
Pages: 81
Abstract: BACKGROUND: On the borders of Thailand, Plasmodium falciparum has become resistant to nearly all available drugs, and there is an urgent need to find new antimalarial drugs or drug combinations. Ferroquine (SSR97193) is a new 4-aminoquinoline antimalarial active against chloroquine resistant and sensitive P. falciparum strains in vivo and in vitro. This antimalarial organic iron complex (a ferrocenyl group has been associated with chloroquine) is meant to use the affinity of Plasmodium for iron to increase the probability for encountering the anti-malarial molecule.The aim of the present study was to investigate the activity of ferroquine against P. falciparum isolates from an area with a known high multi-drug resistance rate. METHODS: Parasite isolates were obtained from patients with acute falciparum malaria attending the clinics of SMRU. In vitro cultures of these isolates were set-up in the SMRU-laboratory on pre-dosed drug plates, and grown in culture for 42 hours. Parasite growth was assessed by the double-site enzyme-linked pLDH immunodetection (DELI) assay. RESULTS: Sixty-five P. falciparum isolates were successfully grown in culture. The ferroquine mean IC50 (95% CI) was 9.3 nM (95% C.I.: 8.7 - 10.0). The mean IC50 value for the principal metabolite of ferroquin, SR97213A, was 37.0 nM (95% C.I.: 34.3 - 39.9), which is four times less active than ferroquine. The isolates in this study were highly multi-drug resistant but ferroquine was more active than chloroquine, quinine, mefloquine and piperaquine. Only artesunate was more active than ferroquine. Weak but significant correlations were found between ferroquine and its principal metabolite (r2 = 0.4288), chloroquine (r2 = 0.1107) and lumefantrine (r2 = 0.2364). CONCLUSION: The results presented in this study demonstrate that the new ferroquine compound SSR97193 has high anti-malarial activity in vitro against multi-drug resistant P. falciparum.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17597537
Author Address: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand.

Author: Ashley, E. A.; Stepniewska, K.; Lindegardh, N.; McGready, R.; Annerberg, A.; Hutagalung, R.; Singtoroj, T.; Hla, G.; Brockman, A.; Proux, S.; Wilahphaingern, J.; Singhasivanon, P.; White, N. J.; Nosten, F.
Year: 2007
Title: Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria
Journal: Trop Med Int Health
Volume: 12
Issue: 2
Pages: 201-8
Abstract: Background Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether-lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. Methods In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration-time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Results Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC((0-->infinity)) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114-5781) mug/ml h, compared with 432 (308-992) mug/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84-100) in the six-dose arm and 85% (70-100) in the three-dose arm (P = 0.3). Conclusion Artemether-lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17300626
Author Address: Shoklo Malaria Research Unit, Mae Sot, Thailand.