Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

Abstract

This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.

Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses

“…injection of 5 ϫ 10 4 PE from peripheral blood of infected donor mice, an inoculum that caused fatal experimental cerebral malaria (ECM) in at least 80% of infected C57BL/6 mice. The link between early death and ECM in mouse models has been discussed previously (2,4): mice that died at a parasitemia of 20% or below, with accompanying neurological symptoms and drastic reductions in body weight and temperature, were considered to have died of ECM, which where possible was confirmed by the presence in the central nervous system (CNS) of hemorrhages, edema, and intravascular leukocyte accumulation upon histopathological analysis. Untreated mice that did not die from ECM went on to succumb to severe anemia and hyperparasitemia, as has been reported in all other cases where mice are resistant to ECM induced by P. berghei ANKA (21,22).…”

“…Mefloquine (Sigma) was dissolved in DMSO and used in the same way as the artemisinin derivatives. Drug structures have been shown elsewhere (2). Artemisone and chloroquine were injected 6 times, twice on days 6, 7, and 8.…”

“…Most drugs that recently have been approved for human use are artemisinin derivatives (1). However, some artemisinin derivatives that have been introduced have already encountered various degrees of resistance and consequently have been used in drug combinations (2,3,4).…”

“…However, a thorough study is needed to establish the efficacy of additional combinations of artemisone with commercially available antimalarial drugs. For this purpose, we used high-throughput in vitro screening against P. falciparum and a reliable CM model (P. berghei ANKA in C57Bl mice) for in vivo validation (2).…”

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

“…The most promising molecules, artemisone (BAY 44-9585) and artemiside (Fig. 4), are semisynthetic 10 alkylaminoartemisinins that can be synthesized from dihydroartemisinin [61]. Both molecules showed very promising activity in the treatment of cerebral malaria in a murine model [62].…”