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Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus

Efficacy of NB-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula. Animals were untreated (n = 3), treated IV TID (8 hourly) with 1850 mg/kg/day NB-DNJ (n = 6) or placebo (n = 3) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for each group +/- standard deviation is plotted. Note: Temperatures in panel C show means of only 5 out of the 6 animals treated with NB-DNJ due to the temperature chip failing in one of the animals in this group.
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pone.0167018.g005: Efficacy of NB-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula. Animals were untreated (n = 3), treated IV TID (8 hourly) with 1850 mg/kg/day NB-DNJ (n = 6) or placebo (n = 3) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for each group +/- standard deviation is plotted. Note: Temperatures in panel C show means of only 5 out of the 6 animals treated with NB-DNJ due to the temperature chip failing in one of the animals in this group.

Mentions: One animal survived until day 14, in the placebo treatment group (Fig 5A), despite complete lethality of placebo or untreated animals in previous studies. This animal had lost 17% of its starting body weight by day 12 and had an elevated temperature consistent with EBOV infection, which was confirmed by qRT-PCR at necropsy (data not shown). While all 6 animals treated with NB-DNJ reached humane end points and were euthanized, this group demonstrated reduced clinical signs in comparison with untreated animals (Fig 5B) (though no difference to animals treated with placebo), delayed onset of fever (Fig 5C) and, as seen in the initial safety study, reduced weight gain (Fig 5D).


Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model
Efficacy of NB-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula. Animals were untreated (n = 3), treated IV TID (8 hourly) with 1850 mg/kg/day NB-DNJ (n = 6) or placebo (n = 3) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for each group +/- standard deviation is plotted. Note: Temperatures in panel C show means of only 5 out of the 6 animals treated with NB-DNJ due to the temperature chip failing in one of the animals in this group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120828&req=5

pone.0167018.g005: Efficacy of NB-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula. Animals were untreated (n = 3), treated IV TID (8 hourly) with 1850 mg/kg/day NB-DNJ (n = 6) or placebo (n = 3) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for each group +/- standard deviation is plotted. Note: Temperatures in panel C show means of only 5 out of the 6 animals treated with NB-DNJ due to the temperature chip failing in one of the animals in this group.
Mentions: One animal survived until day 14, in the placebo treatment group (Fig 5A), despite complete lethality of placebo or untreated animals in previous studies. This animal had lost 17% of its starting body weight by day 12 and had an elevated temperature consistent with EBOV infection, which was confirmed by qRT-PCR at necropsy (data not shown). While all 6 animals treated with NB-DNJ reached humane end points and were euthanized, this group demonstrated reduced clinical signs in comparison with untreated animals (Fig 5B) (though no difference to animals treated with placebo), delayed onset of fever (Fig 5C) and, as seen in the initial safety study, reduced weight gain (Fig 5D).

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus