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154 The Journal of the Royal Institute of Thailand Volume III - 2011 154 Quinine and Quin-Ghao, Natureûs Two Most Important Anti-malarial Drugs Quinine or Artesunate for the treatment of severe malaria. In the last decade of the last century it was recognized that the Quin-Ghao derived antimalarial drugs had very potent antimalarial action and a broad stage speficity, that is killing young parasites in the red blood cells. Malaria parasites in the red blood cells mature during a 48 hour life cycle. During maturation, parasite derived proteins are transported to the red cell membrane, making the red blood cell sticky and adherent to the endothelial vessel wall of the microcirculation. This blocks the normal blood flow to vital organs, and is thought to be the pivotal mechanism in severe malaria pathophysiology. Quinine has a slower antimalarial action, and does not kill the ring form parasites. As a consequence, clinical trials were designed to compare quinine with the Qinghaosu derivatives for the treatment of severe malaria. The initial trial, though, were conducted with the fat-soluble derivative artemether, produced outside of China. Several large trials in both Africa and Southeast Asia were conducted, but a meta-analysis in 1919 patients could not show a significant life-saving effect of artemether over quinine. It took many years before it was shown that the erratic absorption of artemether from its intramuscular injection site was the likely explanation for this lack of superiority. Especially in very sick patients, with a high chance to die, plasma concentrations of artemether were found to remain dangerously low in individual cases. Water-soluble artesunate does not have these pharmacokinetic disadvantages, and provides very reliable blood concentrations after both intravenous and intramuscular administration. After a promising pilot trial in adults patients with severe falciparum malaria in Northwestern Thailand, two large trials comparing artesunate with quinine were conducted (Figure 5). The first trial with the acronym ùSEAQUAMATû, included 1461 mainly adult patients with severe malaria in 4 Asian countries in India, Bangladesh, Myanmar and Papua Indonesia (Dondorp et al, 2005). The study was stopped prematurely by the ùdata safety monitoring boardû because of the superiority ùbeyond doubtû of artesunate over quinine in saving lives from severe malaria. Mortality was 35% lower in patients treated with artesunate, and this was not at the expense of an increase in neurological sequelae in the survivors. Side-effects like hypoglycaemia, were higher in patients treated with quinine. This important finding resulted in an adaptation of the WHO-treatment guidelines for severe malaria in adults. However, it did not lead to a change in policy for the treatment of paediatric severe malaria in Africa, where the majority of cases occur. For this reason a large trial was organized in 150-159_mac9 4/26/12, 9:20 PM 154