Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study

Miller, R. Scott; Li, Qigui; Cantilena, Louis R.; Leary, Kevin J.; Saviolakis, George A.; Meléndez, Víctor; Smith, Bryan; Weina, Peter J.

doi:10.1186/1475-2875-11-255

Cited by 37 publications

(31 citation statements)

References 26 publications

(41 reference statements)

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“…We have shown that artesunate inhibits the replication of JCPyV in COS-7 cells with an EC 50 of 2.9 M, a concentration that can be achieved in plasma (60)(61)(62). However, to be eligible for therapeutic treatment for PML, artesunate also needs to cross the blood-brain barrier and enter the CNS.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC 50 ) of 2.9 M. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 M, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC 50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

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Section: Discussionmentioning

confidence: 99%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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“…However, to inhibit the replication of BKV in RPTECs by 50% (i.e., the EC 50 ), a concentration of 4.2 M (1.6 g/ml) artesunate was needed, and it is still unclear if this concentration can be attained in kidney epithelial cells in vivo. Following intravenous administration of artesunate in healthy volunteers, plasma concentrations up to 217 M (83.34 g/ml) have been described (29,53,54), indicating that the EC 50 could at least be achieved in the plasma.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Sharma

Marschall

Henriksen

et al. 2014

Antimicrob Agents Chemother

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dPolyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 M. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentrationdependent manner. Artesunate at 10 M reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 M reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2=-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G 0 or G 2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 M were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions.

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“…ART was able to inhibit viability in clinically achievable concentrations [10] and in a time-dependent manner in IL-6-independent and -dependent MM cell lines (Suppl. Table S1A; Fig.…”

Section: Resultsmentioning

confidence: 99%

Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis

et al. 2014

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Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naïve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment.

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Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study

Cited by 37 publications

References 26 publications

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis

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