| Achievements in fighting Malaria |
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Overview Research from MORU has directly resulted in the most important development in antimalarial chemotherapy in the past fifty years - our work has provided the biological, economic, and clinical basis for changing global antimalarial treatment recommendations to artemisinin combination therapies (ACTs). Our work on the Thai-Burma border, undertaken by Shoklo Malaria Research Unit (SMRU) treats more than 20,000 malaria patients each year and has enrolled more patients in antimalarial studies than any other research group. It has led the development and evaluation of artemisinin combination therapies (ACTs), and also defined the optimum methodologies for field-based assessment of antimalarial chemotherapy. MORU has conducted the largest clinical trial in severe malaria (SEAQUAMAT), which identified artemisinin-based drug artesunate as the superior drug to treat adult severe malaria. An overview of all 435 antimalarial drug trials published between 1966 and 2003, showed that MORU published one tenth of all such studies and enrolled 22% of all patients. Principal achievements in antimalarial chemotherapy:
Translating research into policy The translation of our findings into policy revision on the treatments of both uncomplicated and severe falciparum malaria has been achieved through the endorsement of our research findings by the World Health Organization (WHO), and also at a National level by the conduct of relevant clinical trials in close collaboration with National Malaria Control Programmes. Our studies have also led to WHO endorsing revised methods of assessing treatment responses. In Lao PDR we demonstrated the poor efficacy of both chloroquine and sulphadoxine-pyrimethamine in Malaria treatment. This stimulated a major reassessment of the Lao national malaria treatment policy. We then conducted a trial demonstrating the effectiveness of ACTs which proved clinically superior. This has paved the way for policy change to ACTs in Lao PDR. Our studies of antimalarial treatment in northern Burma (Myanmar) showed that chloroquine and sulfadoxine-pyrimethamine, the nationally recommended treatment, were completely ineffective. Subsequent studies of ACT effectiveness paved the way for policy change to ACTs in Burma. Counterfeit antimalarial drugs We have conducted and published surveys uncovering the horrendous and widespread problems of fake antimalarial drugs throughout Southeast Asia and we have provided simple methods for their detection. Mechanisms and epidemiology of antimalarial drug resistance • MORU has modeled the factors which lead to antimalarial drug resistance. Patients receiving incomplete therapies of only one antimalarial drug are a major source of resistance. • Our comprehensive mathematical-economic model of drug resistance contributed to revised global recommendations on antimalarial drug policy. • Genetic studies showed that pyrimethamine-resistant malaria found in Africa first arose in SE Asia. This extraordinary capability for spread emphasises the potential for travel of highly drug resistant parasites from SE Asia to Africa. • We have identified the stepwise mutations in the P. vivax genes responsible for resistance to sulphadoxin-pyrimethamine. Malaria in pregnancy Shoklo Malaria Research Unit is the major source of clinical and scientific information on vivax and falciparum malaria in pregnancy in a low transmission area, and the main source of information on antimalarial drug treatment in pregnancy. SMRU contributed 8 of the 12 existing studies on antimalarial drugs in pregnancy and worked with 69% of all patients studied. Achievements include: • Characterisation of the adverse impact of malaria in pregnancy on infant survival. • SMRU's work has contributed significantly to a WHO report endorsing artemisinins being used as antimalarials in the second and third trimesters of pregnancy. • Clinical evidence has demonstrated that the triple combination of artesunate-atovaquone-proguanil can be used safely to treat falciparum malaria in pregnant women that has proved clinically resistant to all other antimalarials. • SMRU's studies indicate that the low birth weight associated with falciparum malaria infection is due to the effects of the infection itself, rather than irreversible damage to the placenta. This emphasises the importance of prompt effective treatment of the infection. Diagnosis of malaria Assessments of new rapid tests for falciparum malaria have been carried out. A study in Laos showed that village health volunteers were able to use rapid dipstick tests accurately with a minimum of training. LAMP, a simple to use molecular tool for the diagnosis of falciparum malaria, still needs further optimization to be used as a reliable diagnostic test. Treatment of severe malaria We undertook the largest ever multi-country study to compare mortality in patients with severe malaria treated with intravenous artesunate or intravenous quinine. The Southeast Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) had participating centres in Bangladesh (Chittagong), Burma (4 centres), India (Rourkela), and Indonesia (West Papua). This showed that artesunate was associated with a 35% reduction in mortality compared with quinine. We are now conducting an even larger study in African children (AQUAMAT), to see whether artesunate can reduce the mortality from severe malaria in this critically important patient group. Pathophysiology of malaria We re-established that obstruction of flow in the smallest blood vessels by sticky, infected red blood cells is a central reason for severe disease in falciparum malaria, using a variety of techniques. We showed in early autopsy studies in adults dying from severe malaria that in patients with cerebral malaria (coma) the number of brain vessels blocked by sticky parasitized red blood cells was higher than in patients that had severe malaria without coma. But also in living patients we directly showed for the first time the blockage of small blood vessels using a microscopic camera. We developed a model to estimate the sequestered numbers of parasites in patients from measurements of a protein (PfHRP2), which is released in discrete amounts by these sequestered parasites. We have shown that in patients with severe falciparum malaria, both infected and uninfected red blood cells get rigid, especially when the patient is severely ill. MORU also identified that malaria parasites that cause severe disease have a greater potential to multiply because they are less selective in the red blood cell populations that they can infect. Mitochondrial DNA studies in a worldwide collection of P. falciparum isolates (in which MORU collaborated) suggested an early origin (50,000 to 100,000 years ago) and recent expansion (10,000 years ago) of the parasite P. falciparum. Vivax malaria We have demonstrated that in Thailand P. vivax frequently coexists with cryptic P. falciparum infection, and studied the complex interaction between these two species. Genotyping methods for field epidemiology and treatment studies of P. vivax have been developed. Clinical pharmacology Since 2000 MORU has published studies on the interactions between drugs and the human body (pharmacokinetic and pharmacodynamic studies), with a wide variety of drugs used to treat tropical infectious diseases, these include lumefantrine, mefloquine, quinine, artesunate, artemether, and dihydroartemisinin in the treatment of falciparum malaria and atovaquone and proguanil in the treatment of malaria in pregnant women. |
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