| Combating drug-resistance |
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Combination therapy, a basic concept in the treatment of HIV, has only been applied to malaria relatively recently through the development of artemisinin-based combination therapy (ACTs). Studies at SMRU have been pivotal in the development of these therapies. Whilst these drugs now form a cornerstone of malaria treatment in all malaria-endemic countries, worrying signs of parasite resistance to ACTs have emerged from Western Cambodia. In the past, resistance to other antimalarial drugs (chloroquine and sulphadoxin-pyrimethamine) have emerged in this part of the world, and have subsequently spread through the rest of Asia, Africa and South America directly contributing to the increase in malaria attributable mortality at the end of the last century. MORU, as part of the Task Force on Antimalarial Drug Resistance in Cambodia, performs research to describe the resistance problem in malaria patients in Western Cambodia. The mechanism by which these parasites have become resistant are investigated in the laboratory up to the molecular level. We also try to develop better tests (in-vitro sensitivity tests and molecular markers), to identify these resistant parasites in patients with malaria. and to develop alternative treatments that might still be effective in infections with these multiresistant parasites. Mathematical modeling by MORU’S modeling team helps to guide the efforts that have now started to contain this important problem. Mathematical modelling of various containment strategies revealed that elimination of falciparum malaria from this region seems the only way to eliminate the problem, since the most resistant parasite strains will also be the most persistent strains to remain circulating, so that a sustained effort for up to 10 years, whatever strategy is chosen, is necessary. Studies on primaquine as a transmission blocking agent, using a mosquito feeding model, helps to further establish the role of this drug in malaria control. MORU is also planning extensive studies on the prevalence and importance of G6PD deficiency in the region, and its impact on malaria control measures. The drug primaquine not only kills the sexual stages of the parasite (called gametocytes), but also the dormant stages in the liver (called hypnozoites) that cause relapse infections in vivax and ovale malaria. Since the drug is oxidative, it can cause haemolysis in patients with G6PD deficiency, but this is probably not the case in patients with a mild deficiency . This should be more extensively studied, since this is essential knowledge in the planning of large scale malaria elimination efforts, where primaquine is used both as a transmission blocking drug and in the radical treatment of vivax malaria (which causes 50% of all malaria in South East Asia). MORU also investigates the (molecular) mechanisms of resistance against other antimalarial drugs, like sulphadoxin-pyrimethamine, and not only in P. falciparum, but also in P. vivax, P. ovale and P. malariae. Clinical pharmacology is an integral part of the studies on drug resistance and the assessment of pharmacokinetic-pharmacodynamic relationships (see malaria in pregnancy). |
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