Chotivanich, K., R. Udomsangpetch, R. McGready, S. Proux, P. Newton, S. Pukrittayakamee, S. Looareesuwan, and N.J. White, Central role of the spleen in malaria parasite clearance. Journal of Infectious Diseases, 2002. 185(10): p. 1538-41. [PubMed Link]
In acute malaria, red blood cells (RBCs) that have been parasitized, but no longer contain a malaria parasite, are found in the circulation (ring-infected erythrocyte surface antigen [RESA]-RBCs). These are thought to arise by splenic removal of dead or damaged intraerythrocytic parasites and return of the intact RBCs to the circulation. In a study of 5 patients with acute falciparum malaria who had previously undergone splenectomy, it was found that none of these 5 patients had any circulating RESA-RBCs, in contrast to the uniform finding of RESA-RBCs in all patients with acute malaria and intact spleens. Parasite clearance after artesunate treatment was markedly prolonged, although the parasites appeared to be dead and could not be cultured ex vivo. These observations confirm the central role of the spleen in the clearance of parasitized RBCs after antimalarial treatment with an artemisinin derivative. Current criteria for high- grade antimalarial drug resistance that are based on changes in parasitemia are not appropriate for asplenic patients.

Guerin, P., P. Olliaro, F. Nosten, P. Druilhe, R. Laxminarayan, F. Binka, W. Kilama, N. Ford, and N. White, Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infectious diseases, 2002. 2(9): p. 564. [PubMed Link]
Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the cost-benefit information that would justify much-needed increases in global support for appropriate and effective malaria control.

Guthmann, J.P., S. Kasparian, R. Phetsouvanh, N. Nathan, M. Garcia, S. Phompida, A. Brockman, M. Gastellu, and D. Legros, The efficacy of chloroquine for the treatment of acute, uncomplicated, Plasmodium falciparum malaria in Laos. Ann Trop Med Parasitol, 2002. 96(6): p. 553-7. [PubMed Link]
To assess the local efficacy of chloroquine for the treatment of acute, uncomplicated, Plasmodium falciparum malaria, children and adults from Sekong province (an area of Laos with a low intensity of transmission) were tested in a 28-day, in-vivo study. Complete data were collected from 88 of the 102 subjects enrolled between October 1999 and September 2000. After genotypic analysis to distinguish recrudescing infections from re-infections, 35 (39.7%, with a 95% confidence interval of 29.5%-50.7%) of these 88 patients were considered treatment failures. These results seriously question the use of chloroquine as the first-line treatment for P. falciparum malaria in the study area.

Haataja, L., R. McGready, R. Arunjerdja, J.A. Simpson, E. Mercuri, F. Nosten, and L. Dubowitz, A new approach for neurological evaluation of infants in resource-poor settings. Annals of Tropical Paediatrics, 2002. 22(4): p. 355-68. [PubMed Link]
Research assessing the neurological development of infants in developing countries is scanty as no suitable standardised tests are available for field-use in constrained circumstances. We describe the development and application of two simple assessments. Firstly, we aimed to develop a test suitable for assessing acute neurological disturbances caused by such diverse effects as infections, drugs or toxins. This test (Shoklo Neurological Test) is aimed at infants between 9 and 36 months. The second test (Shoklo Developmental Test) is aimed not only to follow the evolution of the signs tested initially in the acute phase but also to evaluate later neurodevelopmental sequelae which might be caused by the same events. The latter test is suitable for infants aged from 3 to 12 months. Both tests can be performed easily in non-optimal conditions. The examinations were tested in a cohort of infants from a Karen refugee camp and administered in a rural setting by health workers, after appropriate training. In order to validate the tests we also applied them to a cohort of London infants. The Griffiths Developmental Scales were applied in the same infants and both the Shoklo Neurological and the Shoklo Developmental Tests showed good correlation with this standardised neurodevelopmental assessment.

McGready, R., K.L. Thwai, T. Cho, Samuel, S. Looareesuwan, N.J. White, and F. Nosten, The effects of quinine and chloroquine antimalarial treatments in the first trimester of pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2002. 96(2): p. 180-4. [PubMed Link]
Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand, 1995-2000). Parasites were still present on day 6 or 7 in 4.7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance rate following quinine was 28.7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted in a high rate of gametocyte carriage: person-gametocyte-weeks = 42.5 (95% CI 27.8-62.1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4.5% (5/111). Significantly more women complained of tinnitus following quinine treatment compared to on admission: 64.5% (78/121) vs 31.6% (59/187), P < 0.001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy, 17.8% (16.5- 19.0), did not differ significantly from rates in women treated with quinine: 22.9% (95% CI 15.5-30.3), or chloroquine: 18.3% (95% CI 9.3- 27.3), P = 0.42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality, stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in the first trimester of pregnancy.

McGready, R., A. Brockman, T. Cho, M.A. Levesque, A.N. Tkachuk, S.R. Meshnick, and F. Nosten, Haemozoin as a marker of placental parasitization. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2002. 96(6): p. 644-6.[PubMed Link]
Both Plasmodium vivax and P. falciparum malaria can cause the delivery of low birthweight babies. In this report, we have quantitated haemozoin levels in placentas from women living on the Thai-Burmese border in a region of low transmission for both P. falciparum and P. vivax malaria from June 1995 to January 2000. P. falciparum malaria infections during pregnancy lead to the accumulation of haemozoin (malaria pigment) in the placenta, especially in infections near term and in primigravid pregnancies. Haemozoin concentration was not associated with adverse birth outcomes. Women with P. vivax infections during pregnancy do not have measurable levels of placental haemozoin suggesting that P. vivax-infected erythrocytes do not accumulate in the placenta as much as P. falciparum-infected ones.

Nair, S., A. Brockman, L. Paiphun, F. Nosten, and T.J. Anderson, Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension. International Journal of Parasitology, 2002. 32(7): p. 852-8. [PubMed Link]
Current methods used to genotype point mutations in Plasmodium falciparum genes involved in resistance to antifolate drugs include restriction digestion of PCR products, allele-specific amplification or sequencing. Here we demonstrate that known point mutations in dihydrofolate reductase and dihydropteroate synthase can be scored quickly and accurately by single-nucleotide primer extension and detection of florescent products on a capillary sequencer. We use this method to genotype parasites in natural infections from the Thai- Myanmar border. This approach could greatly simplify large-scale screening of resistance mutations of the type required for evaluating and updating antimalarial drug treatment policies. The method can be easily adapted to other P. falciparum genes and will greatly simplify scoring of point mutations in this and other parasitic organisms.

Newton, P.N., M. van Vugt, P. Teja-Isavadharm, D. Siriyanonda, M. Rasameesoroj, P. Teerapong, R. Ruangveerayuth, T. Slight, F. Nosten, Y. Suputtamongkol, S. Looareesuwan, and N.J. White, Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 2002. 46(4): p. 1125-7. [PubMed Link]
Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ significantly from 1, suggesting that DHA can be formulated to be an acceptable oral alternative to artesunate.

Nosten, F. and P. Brasseur, Combination therapy for malaria: the way forward? Drugs, 2002. 62(9): p. 1315-29. [PubMed Link]
Unless new strategies are deployed to combat malaria, the already enormous health and economic burden related to the disease in tropical countries is bound to worsen. The main obstacle to malaria control is the emergence of drug resistant strains of Plasmodium falciparum. As for HIV/AIDS and tuberculosis, the use of combinations of antimalarial drugs reduces the risk of selecting for resistant mutants of the plasmodial parasites. In large field trials, the combination of an artemisinin derivative and a partner drug with an unrelated mode of action (in this case mefloquine), has shown a remarkable double effect: preventing the emergence and spread of drug resistance, and interrupting the transmission of P. falciparum. This has opened the way for a new approach to the deployment of antimalarial drugs. Coupled with early detection and confirmed diagnosis, this strategy represents the only way forward in the chemotherapy of malaria. Massive economic assistance will be needed to detect and treat adequately the estimated 500 million cases of malaria per year, but without radical action there is no prospect of 'Rolling Back' malaria.

van Vugt, M., E. Leonardi, L. Phaipun, T. Slight, K.L. Thway, R. McGready, A. Brockman, L. Villegas, S. Looareesuwan, N.J. White, and F. Nosten, Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil. Clinical Infectious Diseases, 2002. 35(12): p. 1498-504. [PubMed Link]
In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone- proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone- proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.