artemisone and artemisinin

The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite

Topics: Antimalarials; Artemisinins; Drug Synergism; Oxidation-Reduction; Oxidative Stress; Plasmodium falciparum; Reactive Oxygen Species

The in vitro activity of the new artemisinin derivative artemisone as well as other molecules of the same class against Helicobacter pylori and their effects when combined with standard antibiotics were evaluated. Since H. pylori can be internalised into gastric epithelial cells, the effects of artemisinin, dihydroartemisinin and artemisone against intracellular H. pylori were also investigated. Bacteriostatic [minimum inhibitory concentration (MIC)] and bactericidal [minimum bactericidal concentration (MBC)] activities were assessed against 24 clinical strains of H. pylori with different antibiotics susceptibilities. Artemisone showed MIC50 and MIC90 values of 0.25 mg/L and 0.5 mg/L, respectively, and an MBC50 value of 0.5 mg/L. Artemisone was synergistic with amoxicillin in 60% of strains, with clarithromycin in 40% and with metronidazole in 20%. There was no interaction between artemisone and omeprazole or bismuth citrate. Against intracellular H. pylori, only dihydroartemisinin at 2× MIC caused a 1 log10 CFU decrease after 18 h and 24 h of incubation. This is the first demonstration in vitro of the activity of artemisinin derivatives against intracellular H. pylori and indicates that artemisone has the potential to be efficacious for the treatment of H. pylori infection, especially in combination with antibiotics.

Topics: Anti-Infective Agents; Artemisinins; Drug Synergism; Helicobacter Infections; Helicobacter pylori; Humans; Microbial Sensitivity Tests; Microbial Viability

Malaria remains one of the world's most common infectious diseases, being responsible for more deaths than any other communicable disease except tuberculosis. There is strong evidence that tumour necrosis factor α and interleukin-1β are important contributors to the systemic disease caused by the infection with Plasmodium falciparum. Circulating levels of TNFα are increased after infection, as a consequence of stimulation of monocyte-macrophages by infected red blood cells or parasite products, as shown in vitro for the malaria pigment haemozoin. TNFα in turn enhances the synthesis of metalloproteinase-9 in monocytes and macrophages. Metalloproteinase-9 acts on the extracellular matrix but also on non-traditional substrates, including precursors of inflammatory cytokines, which are proteolytically activated and contribute to the amplification of the inflammatory response. The aim of the present work was to establish whether artemisinin and its derivatives artemisone, artesunate and dihydroartemisinin possess immuno-modulatory properties. In particular, it is necessary to evaluate their effects on mRNA levels and secretion of MMP-9 by the human monocytic cell line (THP-1 cells) stimulated by hemozoin or TNFα. 5μM of each derivative, although not artemisinin itself, induced significantly inhibited TNFα production. Artesunate, artemisone and DHA antagonized haemozoin-induced MMP-9 secretion by 25%, 24% and 50%, respectively. mRNA levels were also depressed by 14%, 20% and 27%, respectively, thus reflecting in part the effect observed on protein production. The derivatives significantly inhibited both TNFα-induced MMP-9 secretion and mRNA levels to a greater extent than haemozoin itself. Both haemozoin and TNFα increased NF-κB driven transcription by 11 and 7.7 fold, respectively. Artesunate, artemisone and DHA inhibited haemozoin-induced NF-κB driven transcription by 28%, 34%, and 49%, respectively. Similarly the derivatives, but not artemisinin, prevented TNFα-induced NF-κB driven transcription by 47-51%. The study indicates that artemisinins may attenuate the inflammatory potential of monocytes in vivo. Thus, in addition to direct anti-parasitic activities, the beneficial clinical effects of artemisinins for the treatment of malaria include the apparent ability to attenuate the inflammatory response, thus limiting the risk of progression to the more severe form of the disease, including the onset of cerebral malaria.

Topics: Artemisinins; Artesunate; Cytokines; Gene Expression Regulation; Humans; Inflammation Mediators; Malaria, Cerebral; Malaria, Falciparum; Matrix Metalloproteinase 9; Monocytes; Plasmodium falciparum; Polymerase Chain Reaction; RNA, Messenger

Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting both alone and in combination with established chemotherapeutic agents.. The anti-proliferative effects of ART and ATM were tested on a panel of human cancer cells in vitro using the methylthiazoletetrazolium assay, and the effect on cell cycling established by flow cytometry. Immunoblot analyses were performed to determine effects at the molecular level. Finally, ART and ATM were combined with the common anti-cancer agents oxaliplatin, gemcitabine and thalidomide.. ART and ATM caused dose dependent decreases in cell number. ATM was consistently superior to ART, with IC50 s significantly lower in the former. Neither drug caused significant changes to the cell viability (%viable cells >95%), but arrested cell cycling. Blockade was either exclusively at the level of G1, or at all phases of the cell cycle, and associated with reductions in cyclin D1, CDK4 and pRb. Combination studies showed the anti-proliferative effect of ATM was often enhanced by addition of the other drugs, whilst ART exhibited antagonistic properties.. ART and ATM are active in cancer cell lines, with ATM displaying the greater anti-proliferative effect when used alone. ATM also enhances the effects of the above drugs, with ART being less likely to improve activities. Taken together, ATM should be thought of as the ART-derived compound next in line for further study.

Topics: Antineoplastic Agents; Artemisinins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Flow Cytometry; Gemcitabine; Humans; Immunoblotting; Inhibitory Concentration 50; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Thalidomide

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.

Topics: Animals; Anti-Infective Agents; Artemisinins; Calcium-Transporting ATPases; Parasitic Sensitivity Tests; Sesquiterpenes; Trypanosoma brucei rhodesiense; Trypanosoma cruzi

Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca(2+) ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of Toxoplasma gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin-resistant (ART(r)) mutant clones that differed in their sensitivities in vitro by three- to fivefold compared with that of the wild-type parasites were obtained. ART(r) mutants were cross-resistant to other derivatives of artemisinin, the most potent of which was artemisone. Resistance was not due to molecular alterations or differences in the expression of SERCA or other putative targets, such as proteins that code for multidrug resistance or translationally controlled tumor protein. ART(r) mutants were resistant to the induction of protein secretion from micronemes, a calcium-dependent process that is triggered by artemisinin. ART(r) mutants were not cross-resistant to secretion induced by thapsigargin but were more sensitive and were unable to regulate cytoslic calcium following treatment with this compound. These studies implicate calcium homeostasis in the mechanism of action of artemisinins against apicomplexan parasites.

Topics: Animals; Antiprotozoal Agents; Artemisinins; Blotting, Western; Calcium; Calcium-Transporting ATPases; Drug Resistance; Homeostasis; Mutagenesis; Mutation; Sarcoplasmic Reticulum; Toxoplasma