Abstract:Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its e… Show more
“…The difference in efficacy of iminosugars in EBOV-infected mouse and guinea pig models may be due to differences between species, EBOV-strains used or the potency of the different iminosugars, and cannot be determined without performing direct comparisons. Discrepancies in efficacy testing chloroquine against EBOV have been reported previously with efficacy observed in mice [55] but not when tested in guinea pigs [56] or hamsters [57]. The different effects on the pseudotyped virus could similarly be explained by use of GP from different EBOV-isolates and it is worth noting that, in Chang et al .…”
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.
“…The difference in efficacy of iminosugars in EBOV-infected mouse and guinea pig models may be due to differences between species, EBOV-strains used or the potency of the different iminosugars, and cannot be determined without performing direct comparisons. Discrepancies in efficacy testing chloroquine against EBOV have been reported previously with efficacy observed in mice [55] but not when tested in guinea pigs [56] or hamsters [57]. The different effects on the pseudotyped virus could similarly be explained by use of GP from different EBOV-isolates and it is worth noting that, in Chang et al .…”
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.
“…If unavailable, we reported the half maximal inhibitory concentration or EC 50 values from the World Health Organization categorization and prioritization table 60 . A total of 14 studies included experiments on animals 26, 27, 29, 39, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50. Three of these trials were carried out on monkey species,39, 44, 50 such as the rhesus macaques, whilst the remaining 11 studies where carried on small animal models, such as mice, hamsters, or guinea pigs.…”
Section: Resultsmentioning
confidence: 99%
“…This is believed to take place by inhibiting various factors such as vesicle sorting and endosome-membrane fusion, as well as increasing endosomal pH 27 . Chloroquine was shown to successfully inhibit the Ebola virus in vitro in different studies and with various cell lines 27, 36, 39, 46. Animal studies, on the other hand, revealed mixed results.…”
BackgroundThe Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD.ObjectiveWe aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy.MethodsWe conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial.ResultsWe identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence.ConclusionsSeveral established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.
“…2), a very well-known remedy in Traditional Chinese Medicine (TCM) for the treatment of a number of diseases such as tuberculosis, dysentery, malaria, cancer, and fever, 19 isolated from different species of plants from the Menispermaceae family, was shown to inhibit EBOV entry into host cells and infection of human macrophages (EC 50 ¼ 55 nM) by binding to TPC. [22][23][24] 20 Madrid et al showed that the antimalarial chloroquine (CQ) (Fig.…”
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