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The synthetic era began at IG Farben in the 1930s. The 8-aminoquinoline pamaquine was the first synthetic antimalarial, introduced in 1925 as Plasmochin. The 4-aminoquinoline [[wikipedia:Chloroquine|chloroquine]], synthesised by Hans Andersag at IG Farben in 1934 as Resochin and (after wartime disruption) re-developed by the U.S. Army research programme during the Second World War as the successor to atabrine (quinacrine), became the standard antimalarial of the post-war decades.<ref name="loeb1946">Loeb RF, Clark WM, Coatney GR, Coggeshall LT, Dieuaide FR, Dochez AR, Hakansson EG, Marshall EK Jr, Marvel CS, McCoy OR, et al. Activity of a new antimalarial agent, chloroquine (SN 7618). ''JAMA''. 1946 Apr 27;130(17):1069-1070.</ref> Primaquine, the 8-aminoquinoline that finally provided eradication of ''P. vivax'' liver-stage hypnozoites, came from the same wartime programme. Chloroquine resistance in ''P. falciparum'' was first reported in Cambodia and in Colombia in the 1950s and 1960s; it spread westward across south-east Asia, jumped to East Africa in the 1970s, and by the 1990s had reached most of sub-Saharan Africa, with substantial increases in malaria mortality in regions that lost the medicine. | The synthetic era began at IG Farben in the 1930s. The 8-aminoquinoline pamaquine was the first synthetic antimalarial, introduced in 1925 as Plasmochin. The 4-aminoquinoline [[wikipedia:Chloroquine|chloroquine]], synthesised by Hans Andersag at IG Farben in 1934 as Resochin and (after wartime disruption) re-developed by the U.S. Army research programme during the Second World War as the successor to atabrine (quinacrine), became the standard antimalarial of the post-war decades.<ref name="loeb1946">Loeb RF, Clark WM, Coatney GR, Coggeshall LT, Dieuaide FR, Dochez AR, Hakansson EG, Marshall EK Jr, Marvel CS, McCoy OR, et al. Activity of a new antimalarial agent, chloroquine (SN 7618). ''JAMA''. 1946 Apr 27;130(17):1069-1070.</ref> Primaquine, the 8-aminoquinoline that finally provided eradication of ''P. vivax'' liver-stage hypnozoites, came from the same wartime programme. Chloroquine resistance in ''P. falciparum'' was first reported in Cambodia and in Colombia in the 1950s and 1960s; it spread westward across south-east Asia, jumped to East Africa in the 1970s, and by the 1990s had reached most of sub-Saharan Africa, with substantial increases in malaria mortality in regions that lost the medicine. | ||
The antifolate combination sulfadoxine-pyrimethamine (Fansidar, Roche 1971) filled the post-chloroquine gap for a brief period before resistance emerged within five years of its widespread deployment. [[wikipedia:Mefloquine|Mefloquine]] (the U.S. Walter Reed antimalarial | The antifolate combination sulfadoxine-pyrimethamine (Fansidar, Roche 1971) filled the post-chloroquine gap for a brief period before resistance emerged within five years of its widespread deployment. [[wikipedia:Mefloquine|Mefloquine]] (the U.S. Walter Reed antimalarial discovery programme, approved 1989) gave a once-weekly prophylactic option but produced a neuropsychiatric adverse-effect profile (vivid dreams, anxiety, depression, in rare cases psychosis) that has largely retired it from current use. [[wikipedia:Atovaquone|Atovaquone]] (Wellcome) combined with the antimalarial proguanil as Malarone (1997) provided well-tolerated travel prophylaxis and is now the most commonly prescribed prophylactic regimen for short-term travel to malarial regions, alongside doxycycline. | ||
The transformative event of contemporary antimalarial pharmacology was the discovery of [[wikipedia:Artemisinin|artemisinin]] by [[wikipedia:Tu Youyou|Tu Youyou]] of the Chinese Academy of Traditional Chinese Medicine in 1972. Tu's work was conducted under Project 523, the classified Chinese antimalarial-research programme established at the request of [[wikipedia:Ho Chi Minh|Ho Chi Minh]] for the antimalarial supply of the North Vietnamese army during the Vietnam War; the project screened thousands of compounds from traditional Chinese medicine, and Tu identified artemisinin (qinghaosu) in extracts of ''[[wikipedia:Artemisia annua|Artemisia annua]]'' (sweet wormwood), used in traditional medicine for fever for over a thousand years and described in Ge Hong's fourth-century ''Zhouhou Beiji Fang''.<ref name="tu2011am">Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. ''Nature Medicine''. 2011 Oct;17(10):1217-1220. PMID 21989013.</ref> The compound's structure (a sesquiterpene lactone with an endoperoxide bridge essential for antiplasmodial activity) was unprecedented; its mechanism of action involves iron-mediated cleavage of the endoperoxide and the resulting generation of carbon-centred radicals that alkylate parasite proteins. Tu received the Nobel Prize in 2015. The semi-synthetic derivatives artesunate (water-soluble, for intravenous use in severe malaria), artemether (lipid-soluble, oral), and dihydroartemisinin are short-acting (terminal half-life one to two hours); they are combined in modern practice with a longer-acting partner agent to reduce the selection pressure for resistance. | The transformative event of contemporary antimalarial pharmacology was the discovery of [[wikipedia:Artemisinin|artemisinin]] by [[wikipedia:Tu Youyou|Tu Youyou]] of the Chinese Academy of Traditional Chinese Medicine in 1972. Tu's work was conducted under Project 523, the classified Chinese antimalarial-research programme established at the request of [[wikipedia:Ho Chi Minh|Ho Chi Minh]] for the antimalarial supply of the North Vietnamese army during the Vietnam War; the project screened thousands of compounds from traditional Chinese medicine, and Tu identified artemisinin (qinghaosu) in extracts of ''[[wikipedia:Artemisia annua|Artemisia annua]]'' (sweet wormwood), used in traditional medicine for fever for over a thousand years and described in Ge Hong's fourth-century ''Zhouhou Beiji Fang''.<ref name="tu2011am">Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. ''Nature Medicine''. 2011 Oct;17(10):1217-1220. PMID 21989013.</ref> The compound's structure (a sesquiterpene lactone with an endoperoxide bridge essential for antiplasmodial activity) was unprecedented; its mechanism of action involves iron-mediated cleavage of the endoperoxide and the resulting generation of carbon-centred radicals that alkylate parasite proteins. Tu received the Nobel Prize in 2015. The semi-synthetic derivatives artesunate (water-soluble, for intravenous use in severe malaria), artemether (lipid-soluble, oral), and dihydroartemisinin are short-acting (terminal half-life one to two hours); they are combined in modern practice with a longer-acting partner agent to reduce the selection pressure for resistance. | ||
The contemporary first-line treatment of uncomplicated ''P. falciparum'' malaria is therefore an '''artemisinin-based combination therapy''' (ACT). The WHO-recommended combinations include artemether-lumefantrine (Coartem/Riamet), artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, and the recent artesunate-pyronaridine. Each combination delivers a rapid parasite-killing pulse from the artemisinin component and a longer-lasting clearance from the partner. The intravenous formulation of artesunate is the standard treatment for severe malaria worldwide; the SEAQUAMAT and AQUAMAT trials demonstrated its superiority over intravenous quinine in adults and in African children respectively. The unfortunate counterpart of the ACT story is the emergence of artemisinin partial resistance in southeast Asia, first reported in 2008 in western Cambodia and now confirmed in the Greater Mekong subregion, in eastern India, and (most recently and most concerningly) in Eritrea, Rwanda, and Uganda;<ref name="uwimana2020">Uwimana A, Legrand E, Stokes BH, Ndikumana JM, Warsame M, Umulisa N, Ngamije D, Munyaneza T, Mazarati JB, Munguti K, et al. Emergence and clonal expansion of in vitro artemisinin-resistant ''Plasmodium falciparum'' kelch13 R561H mutant parasites in Rwanda. ''Nature Medicine''. 2020 Oct;26(10):1602-1608. PMID 32747827.</ref> the molecular marker is the K13 propeller gene, and the clinical phenotype is delayed parasite clearance rather than overt treatment failure, although partner- | The contemporary first-line treatment of uncomplicated ''P. falciparum'' malaria is therefore an '''artemisinin-based combination therapy''' (ACT). The WHO-recommended combinations include artemether-lumefantrine (Coartem/Riamet), artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, artesunate-sulfadoxine-pyrimethamine, and the recent artesunate-pyronaridine. Each combination delivers a rapid parasite-killing pulse from the artemisinin component and a longer-lasting clearance from the partner. The intravenous formulation of artesunate is the standard treatment for severe malaria worldwide; the SEAQUAMAT and AQUAMAT trials demonstrated its superiority over intravenous quinine in adults and in African children respectively. The unfortunate counterpart of the ACT story is the emergence of artemisinin partial resistance in southeast Asia, first reported in 2008 in western Cambodia and now confirmed in the Greater Mekong subregion, in eastern India, and (most recently and most concerningly) in Eritrea, Rwanda, and Uganda;<ref name="uwimana2020">Uwimana A, Legrand E, Stokes BH, Ndikumana JM, Warsame M, Umulisa N, Ngamije D, Munyaneza T, Mazarati JB, Munguti K, et al. Emergence and clonal expansion of in vitro artemisinin-resistant ''Plasmodium falciparum'' kelch13 R561H mutant parasites in Rwanda. ''Nature Medicine''. 2020 Oct;26(10):1602-1608. PMID 32747827.</ref> the molecular marker is the K13 propeller gene, and the clinical phenotype is delayed parasite clearance rather than overt treatment failure, although partner-medicine failure compounds the picture. | ||
The contemporary public-health pharmacopoeia of malaria extends beyond the treatment medicines to prevention. Insecticide-treated bed nets, indoor residual spraying, intermittent preventive therapy in pregnancy (sulfadoxine-pyrimethamine in regions of preserved sensitivity), seasonal malaria chemoprevention in children of the Sahel (sulfadoxine-pyrimethamine plus amodiaquine), and the recent licensing of the [[wikipedia:RTS,S|RTS,S]] vaccine (Mosquirix, 2021) and the more efficacious R21 vaccine (2023) have together produced substantial reductions in malaria incidence and mortality in the African continent; child mortality from malaria has approximately halved between 2000 and 2020 across the WHO African region. The post-2020 plateau in progress, attributed to the COVID-19 disruption of malaria programmes and to the accumulating resistance challenges, is a current focus of WHO and partner attention. | The contemporary public-health pharmacopoeia of malaria extends beyond the treatment medicines to prevention. Insecticide-treated bed nets, indoor residual spraying, intermittent preventive therapy in pregnancy (sulfadoxine-pyrimethamine in regions of preserved sensitivity), seasonal malaria chemoprevention in children of the Sahel (sulfadoxine-pyrimethamine plus amodiaquine), and the recent licensing of the [[wikipedia:RTS,S|RTS,S]] vaccine (Mosquirix, 2021) and the more efficacious R21 vaccine (2023) have together produced substantial reductions in malaria incidence and mortality in the African continent; child mortality from malaria has approximately halved between 2000 and 2020 across the WHO African region. The post-2020 plateau in progress, attributed to the COVID-19 disruption of malaria programmes and to the accumulating resistance challenges, is a current focus of WHO and partner attention. | ||