Artemisinins Inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense In Vitro Growth

Abstract

Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.Diseases caused by insect-borne trypanosomatid parasites are a significant and neglected public health problem worldwide. Chagas' disease, caused by infection with Trypanosoma cruzi, is a major agent of disease in Latin America, with 16 to 18 million infected individuals and an annual death toll of 50,000. It is also an emerging problem in the United States, where an estimated 100,000 infected individuals reside (16). Trypanosoma brucei subspp., the causative agents of human African trypanosomiasis or "sleeping sickness," infect 50,000 annually. Approximately 300,000 to 500,000 people have trypanosomiasis and will die if not treated (18). Current therapeutic options for Trypanosoma infections, benznidazole and nifurtimox for Chagas' disease treatment and suramin, pentamidine, melarsoprol, and eflornithine for treatment of sleeping sickness, are far from ideal (8,17). These drugs all suffer from one or more disadvantages-high cost, parenteral administration, long treatment courses (months), high clinical failure rates, or parasite drug resistance-and they elicit multiple, serious, and potentially fatal toxic side effects. New therapeutic alternatives are obviously desirable for treatment of these lifethreatening infections.Artemisinin is a sesquiterpene lactone isolated from Artemisia annua, an annual herb that has been used in traditional Chinese medicine for over 2,000 years (21). Artemisinin is hydrophobic, passes biological membranes easily, and is a potent antimalarial with effective 50% inhibitory concentrations (IC 50 values) ranging from 4.2 to 16.2 nM for different derivatives. Oral, parenteral, or rectal dosages achieve micromolar plasma concentrations (22). Artemisinin derivatives have been used to treat malaria cases around the world, and their extensive usage has not been associated with any significant toxicity (19). Artemisinin generates bioreactive radicals capable of intracellular damage, depolarizes mitochondrial membrane potential in yeast, and inhibits the Plasmodium falciparum endoplasmic reticulum calcium pump (SERCA), and artemisininresistant P. falciparum contains SERCA mutations (9,13,14,(20)(21)(22).Artemisinin compounds also show efficacy against Leishmania spp. of trypanosomatid parasites, achieving 50% killing at 750 nM for Leishmania major promastigotes, at 3 to 30 M for intracellular amastigote stages in macrophages, and at 1.4 to 382.9 M against Leishmania infantum promastigotes (1, 23). Artemether treatment (50 mg/kg of body weight/day) of footpad lesions in mice, by oral, intralesional, intramuscular, or intravenous administration, significantly reduces lesion size and L. major parasite numbers (23). Oral dih...

Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin

“…These include repellency against beetles (16), larvicidal activity against Anopheles stephensi (17), insecticidal activity against elm leaf beetle (18), and use as an acaricide (19). Moreover, AN and its derivatives have effects on a number of viruses (20), a variety of human cancer cell lines (20,21), and several neglected tropical parasitic diseases including schistosomiasis (22), leishmaniasis (23,24), New-and Old-World trypanosomiases (25), and some livestock diseases (26).…”

Controlling bruchid pests of stored cowpea seeds with dried leaves of Artemisia annua and two other common botanicals

“…Together with its semi-synthetically prepared derivatives such as dihydroartemisinin, artesunate and artemether, artemisinin has also displayed unique pharmacological activities against a wide range of parasitic organisms including bacteria (Bone and Morgan, Brisibe et al 9587 1992) such as Enterobacter species, Klebsiella pneumoniae, Streptococcus faecalis, Staphylococcus aureus, Shigella dysenteriae, Escherichia coli and Pneumocystis carinii (Chen et al, 1994), an opportunistic pathogen which causes pneumonia in HIV/AIDS and other immune-compromised patients. Recent studies have demonstrated that artemisinin derivatives are equally potent and efficacious against several other common infectious parasites of man including Toxoplasma gondii (Jones-Brando et al, 2006) which causes toxoplasmosis that is responsible for behavioral abnormalities in patients, Trypanosoma and Schistosoma species (Mishina et al, 2007;Utzinger et al, 2001) that are responsible for human trypanosomiasis or 'sleeping sickness' and schistosomiasis, respectively. Artemisinin derivatives are also effective against some other pathogens including those responsible for cryptosporidiosis, amoebiasis, giardiasis, clonorchiasis and leishmaniasis (Ma et al, 2004;Yang and Liew, 1993).…”

Water deficit effect on the accumulation of biomass and artemisinin in annual wormwood(Artemisia annua L., Asteraceae)

“…Besides its antimalarial activity, artemisinin has proved effective against cancer (Posner et al, 1999;Singh and Lai, 2004;Efferth, 2005), Eimeria spp., Babesia spp., Leishmania spp., Neospora caninum, Trypanosoma brucei rhodesiense (Mishina et al, 2007), and Schistosoma spp. (Utzinger et al, 2001;Xiao et al, 2004), the latter living in the circulatory system of the host.…”