Artemisone and Artemiside Control Acute and Reactivated Toxoplasmosis in a Murine Model

e Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts.

Section: Antiprotozoal Agentsmentioning

confidence: 96%

Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity

Neville

Zach

Wang

et al. 2015

“…Artemisone is highly effective against P. falciparum in monkeys and has been used in phase IIa clinical trials for nonsevere malaria in humans (34). Recent work also indicates the marked superiority of artemiside over artemisone in both in vitro and in vivo studies involving the apicomplexan parasite Toxoplasma gondii (12). Artemiside has an advantage over artemisone in that its preparation from DHA requires only a one-step procedure (Fig.…”

mentioning

confidence: 99%

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

Guo

Guiguemde

Bentura-Marciano

et al. 2012

Self Cite

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.

“…One of the most promising compounds identified via a screening assay was compound 86, a semisynthetic artemisinin (120). This compound is orally bioavailable and capable of crossing the blood-brain barrier, with a survival increase of 60% in treated mice (90). The endochin-like quinolones (compounds 68 and 69), also identified via screening, additionally demonstrate promising characteristics, such as a high therapeutic index and efficacy against the acute and chronic stages in vitro (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…Artemisinin, the precursor of all of the semisynthetic artemisinin derivatives used to treat malaria, was isolated from the plant Artemisia annua (90). Compound 54 has poor aqueous solubility (91); however, due to its high lipophilicity, compound 54 is suspected to have high blood-brain barrier penetration; indeed, further studies on reactivation of latent T. gondii infections have shown that this compound has some ability to protect mice from immunosuppression-induced reactivated infections (90). Because of the potency of this compound, as well as closely related derivatives (artemisone) passing FDA phase I trials (92), compound 54 and other artemisinin derivatives are promising candidates for further study.…”

Section: Compounds Without Known or Suspected Modes Of Actionmentioning

confidence: 99%

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland

Zach

Wang

et al. 2016

Toxoplasma gondii is a ubiquitous apicomplexan parasite capable of infecting humans and other animals. Current treatment options for T. gondii infection are limited and most have drawbacks, including high toxicity and low tolerability. Additionally, no FDA-approved treatments are available for pregnant women, a high-risk population due to transplacental infection. Therefore, the development of novel treatment options is needed. To aid this effort, this review highlights experimental compounds that, at a minimum, demonstrate inhibition of in vitro growth of T. gondii. When available, host cell toxicity and in vivo data are also discussed. The purpose of this review is to facilitate additional development of anti-Toxoplasma compounds and potentially to extend our knowledge of the parasite.