The dormancy effect of artemisinin and derivatives
L'artemisinine source de recrudescences paludiques
But treatment failures and first signs of resistance to artemisinin soon become evident like in China with arteannuin B and artemisin monotherapy. It was due to a novel effect: a small fraction of the parasites, as a result of chemotherapeutic pressure, become ‘dormant’. Indeed, it was common to administer very high doses up to 1 200 mg/person/day. At this stage, the parasite cycle is halted, making the parasites unsusceptible to further dosing until wakening. This slows down the antimalarial activity of the drug, entailing either many frequent doses or an extended period of treatment and surveillance. Resistance can also be affected by the dormancy effect. Andrea Codd, Franka Teuscher, Dennis E Kyle, Qin Cheng and Michelle L Gatton. Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure. Malaria Journal 2011 10:56 DOI: 10.1186/1475-2875-10-56 One of the side effects of the higher doses of artemisinin is this effect induced in plasmodium. The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. The same effect is called quiescence by a French research team. Witkowski B, Lelièvre J, Barragán MJ, Laurent V, Su XZ, Berry A, Benoit-Vical F. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother. 2010 May;54(5):1872-7. doi: 10.1128/AAC.01636-09. Under a very high dose of artesunate, a Plasmodium falciparum ring-stage sub-population persists in culture and continues its cycle of development normally after drug removal. This may be one of the causes of resistance. The dormancy effect is also evident for artemisone, a new artemisin derivative L Grobler, M Chavchich, R Haynes, Assessment of the induction of dormant ring stages in Plasmodium falciparum parasites by artemisone. Antimicrob Ag and Chemotherapy, 2014, 58, 7579-82 Another possible explanation for these failures is the fact that artemisinin is a strong inducer of CYP 3A4, leading to its own fast metabolism. Kyle DE, Webster HK: Postantibiotic effect of quinine and dihydroartemisin on Plasmodium falciparum in vitro: implications for a mechanism of recrudescence. XIVth International Congress for Tropical Medicine and Malaria: abstract 0-22-6. 1996, Nagasaki Hoshen MB, Na-Bangchang K, Stein WD, Ginsburg H: Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of 'dormancy', a partial cytostatic effect of the drug, and its implication for treatment regimens. Parasitology. 2000, 121: 237-246. 10.1017/S0031182099006332. Chen N, LaCrue AN, Teuscher F, Waters NC, Gatton ML, Kyle DE, Cheng Q. Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum. Antimicrob Agents Chemother. 2014 Aug;58(8):4773-81. doi: 10.1128/AAC.02647-14 A Swiss company, Novartis, finally broke the logjam. It bought a new Chinese patent on a mix of artemether, an artemisinin derivative, and lumefantrine, another Chinese drug, and took out Western patents, planning to sell it under the name Riamet at high prices to tourists and militaries; in 2001, it agreed to sell it nearly at cost to the W.H.O. under the name Coartem. But this was only of temporary relief as since 2006 resistance has developed in South East Asia and more recently in 12 African countries, not only for Coartem, but also for other brands like Coarsucam and Artequick. In the Chinese paper Liu AR, Yu ZY, Lu LL, Sui The synergistic action of guanghuoxiang volatile oil and sodium artesunate against Plasmodium berghei and reversal of SA-resistant Plasmodium berghei. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2000;18(2):76-8. it was documented that essential oil from a plant (also called patchouli oil) had extraordinary synergistic properties with artesunate. This essential oil even reverses the resistance against Plasmodium berghei in mice. Why were ACTs based on chemical and not on natural molecules? A paper from Vietnam claims that there is no significant difference between artemisinin, artemether, artesunate treatment! Why than produce ACT pills with artemisinin derivatives? Ha V, Nguyen NH, Tran TB, Bui MC, Nguyen HP, Tran TH, Phan TQ, Arnold K, Tran TH. Severe and complicated malaria treated with artemisinin, artesunate or artemether in Viet Nam. Trans R Soc Trop Med Hyg. 1997 Jul-Aug;91(4):465-7.