Artesunate

The herb of Artemisia annua L.

Artesunate is a part of the artemisinin group of agents with an IC50 of < 5 μM for small cell lung carcinoma cell line H69.

The antimalarial agent artesunate causes sperm DNA damage and hepatic antioxidant defense in mice.[Pubmed:25726169]

Mutat Res Genet Toxicol Environ Mutagen. 2015 Jan 1;777:1-6.

Artesunate is an artemisinin derivative effective against multidrug resistant malaria. We analyzed the effects of Artesunate 40 mg/kg b.w. as a single dose (ART1) or 13.3mg/kg b.w. for 3 days at 24h intervals (ART2) on mice spermatozoa at morphological and molecular level, and hepatic antioxidant status following 24h and 35 days following exposures in vivo. Artesunate significantly reduced epididymal sperm count and increased the frequency of sperms with abnormal head morphology following 24h of exposure. Comet assay analysis revealed significant increase in DNA strand breaks in spermatozoa evidenced by about 3-fold increase in comet tail DNA and up to 10-fold increase in Olive tail moment following 35 days of Artesunate treatment. The damage index was significantly higher in the treated groups (40.27 +/- 6.62 and 37.07 +/- 5.35 for ART1 and ART2 respectively) as compared to the control group (16.13 +/- 3.21) indicating the genotoxic effect of Artesunate. The significant reduction in GSH, SOD and increase in lipid peroxidation indicate involvement of oxidative mechanisms in Artesunate induced toxicity in mice. The present study suggests that Artesunate has the potential to breach the testis-blood barrier and cause toxicity to male germ cells which may have implications in male reproductive toxicity.

A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNgamma-activated BV2 microglia.[Pubmed:25074847]

Bioorg Med Chem. 2014 Sep 1;22(17):4726-34.

Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of Artesunate on PGE2 production/COX-2 protein expression in LPS+IFNgamma-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-kappaB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IkappaB, p38 and MAPKAPK2 were evaluated using western blot. An NF-kappaB-bearing luciferase reporter gene assay was used to test the effect of Artesunate on NF-kappaB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFalpha (1ng/ml). Artesunate (2 and 4muM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNgamma-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFalpha and IL-6 production in activated BV2 microglia. Further investigations showed that Artesunate (0.5-4muM) significantly (p <0.001) reduced NF-kappaB-driven luciferase expression, and inhibited IkappaB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNgamma. Taken together, we have shown that Artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-kappaB and p38 MAPK signalling.

Opposite malaria and pregnancy effect on oral bioavailability of artesunate - a population pharmacokinetic evaluation.[Pubmed:25877779]

Br J Clin Pharmacol. 2015 Oct;80(4):642-53.

AIM: The aim was to compare the pharmacokinetic properties of Artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7. METHODS: Non-linear mixed-effects modelling was used to compare plasma concentration-time profiles of Artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous Artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously. RESULTS: Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of Artesunate or dihydroartemisinin after intravenous Artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered Artesunate. Malaria increased the absolute oral bioavailability of Artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%. CONCLUSIONS: The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered Artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for Artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.

Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor beta1 and interleukin-10.[Pubmed:25978851]

Int Immunopharmacol. 2015 Jul;27(1):110-21.

Immunosuppression is the main source of ineffective treatment on tumor, and the study aimed to investigate the effect of Artesunate on tumor immunosuppression. Supernatants of re-cultivated murine colorectal cancer cell Colon26 and human colorectal cancer cell RKO after pre-treatment with or without Artesunate were enrolled, and their effects on five immune parameters were assessed, including killing activity of natural killer (NK) and lymphocyte proliferation, as measured by MTT, and expressions of interleukin 2 receptor (IL-2R)alpha, CD3epsilon(+)zeta(+) and CD3epsilon(-)zeta(+) on lymphocytes, as analyzed by flow cytometry. Six immunosuppressive factors were measured by ELISA, including transforming growth factor (TGF) beta1, vascular endothelial growth factor (VEGF), IL-4, IL-6, IL-10, and prostaglandin E2 (PGE2). Then, multiple linear regression analysis was applied to reveal the correlation between immunosuppression and immunosuppressive factors, and was used to confirm the findings. It was shown that Colon26 and RKO cells secreted immunosuppressive factors and inhibited these five immune parameters steadily. After pretreatment with Artesunate, immunosuppression from the two cells was down-regulated significantly (all P<0.05), and the concentrations of TGF-beta1 and IL-10 decreased greatly (all P<0.001). There were positive correlations between the down-regulation of immunosuppression and the decrease in TGF-beta1 or IL-10. Their combined potency attributed to decreased TGF-beta1 and IL-10 with respect to the down-regulating effect of Artesunate on immunosuppression of NK killing, lymphocyte proliferation and expressions of IL-2Ralpha and CD3epsilon(+)zeta(+), was about 60%-90%. The present analysis provides clues that Artesunate reverses the immunosuppression from Colon26 and RKO colorectal cancer cells by decreasing TGF-beta1 and IL-10. This is probably one of the anti-tumor mechanisms of Artesunate.

Artesunate is a part of the artemisinin group of agents with an IC50 of < 5 μM for small cell lung carcinoma cell line H69. It is a potential inhibitor of STAT-3 and exhibits selective cytotoxicity of cancer cells over normal cells in vitro; A potent inhibitor of EXP1.

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