Ivermectin Does Not Protect against SARS-CoV-2 Infection in the Syrian Hamster Model

Foo, Caroline S.; Abdelnabi, Rana; Vangeel, Laura; Jonghe, Steven De; Jochmans, Dirk; Weynand, Birgit; Neyts, Johan

doi:10.3390/microorganisms10030633

Cited by 7 publications

(4 citation statements)

References 29 publications

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“…67 A study (400 µg/kg of IVM per day over four days) showed an overall lack of efficacy in Syrian hamnsters. 68 Another study in hamsters showed no decrease in viral load but reported attenuation of clinical and immunological outcomes by invoking a potential immunomodulatory mechanism distinct from the original hypothesized importin target. 69 Our work suggests that IVM, and other compounds with similar modes of action, could be flagged earlier in the translation process, perhaps prior to transitioning from culture monolayers to more physiological models (e.g., which incorporate apical air and basolateral medium compartments) by testing for their (subtle) membrane-perturbing effects.…”

Section: Discussionmentioning

confidence: 99%

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

Eastman,

Rusinova,

Herold

et al. 2023

Preprint

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Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the potential for ivermectin to be repurposed as an antiviral agent, we therefore undertook a series of preclinical studies. Consistent with early reports, ivermectin decreased SARS-CoV-2 viral burden in in vitro models at low micromolar concentrations, five- to ten-fold higher than the reported toxic clinical concentration. At similar concentrations, ivermectin also decreased cell viability and increased biomarkers of cytotoxicity and apoptosis. Further mechanistic and profiling studies revealed that ivermectin nonspecifically perturbs membrane bilayers at the same concentrations where it decreases the SARS-CoV-2 viral burden, resulting in nonspecific modulation of membrane-based targets such as G-protein coupled receptors and ion channels. These results suggest that a primary molecular mechanism for the in vitro antiviral activity of ivermectin may be nonspecific membrane perturbation, indicating that ivermectin is unlikely to be translatable into a safe and effective antiviral agent. These results and experimental workflow provide a useful paradigm for performing preclinical studies on (pandemic-related) drug repurposing candidates.

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Section: Discussionmentioning

confidence: 99%

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

Eastman,

Rusinova,

Herold

et al. 2023

Preprint

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“…Studies of the efficacy of molnupiravir in Syrian hamsters inoculated with SARS-CoV-2 were carried out with doses ranging from 50 to 500 mg/kg twice daily [41][42][43][44][45][46][47][48][49][50]. Specifically, a dose-response study suggested that a 150 mg/kg dose of molnupiravir twice daily was suboptimal, and that a dose of at least 200 mg/kg twice daily was necessary to reduce pulmonary viral titers to levels near the detection limit [43].…”

Section: Dose Levels Of Molnupiravirmentioning

confidence: 99%

“…Several of the animal studies aimed to assess the effect of combining molnupiravir with another agent including an antiviral. These studies used a suboptimal dose of molnupiravir to compare its effect in monotherapy with that observed in combination therapies, thereby facilitating the detection of potential synergistic effects [10,39,41,43,44,46]. For example, a suboptimal molnupiravir dose of 150 mg/kg twice daily was used in Syrian hamsters [43,44,46].…”

Section: Dose Levels Of Molnupiravirmentioning

confidence: 99%

“…These studies used a suboptimal dose of molnupiravir to compare its effect in monotherapy with that observed in combination therapies, thereby facilitating the detection of potential synergistic effects [10,39,41,43,44,46]. For example, a suboptimal molnupiravir dose of 150 mg/kg twice daily was used in Syrian hamsters [43,44,46]. Importantly, the combination of this dose of molnupiravir with favipiravir or GS-441524 (the nucleobase of remdesivir), exhibited potent antiviral activity in Syrian hamsters [43,44].…”

Section: Dose Levels Of Molnupiravirmentioning

confidence: 99%

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Molnupiravir Revisited—Critical Assessment of Studies in Animal Models of COVID-19

Rasmussen,

Hansen

2023

Viruses

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Molnupiravir, a prodrug known for its broad antiviral activity, has demonstrated efficacy in animal models of COVID-19, prompting clinical trials, in which initial results indicated a significant effect against the disease. However, subsequent clinical studies did not confirm these findings, leading to the refusal of molnupiravir for permanent market authorization in many countries. This report critically assessed 22 studies published in 18 reports that investigated the efficacy of molnupiravir in animal models of COVID-19, with the purpose of determining how well the design of these models informed human studies. We found that the administered doses of molnupiravir in most studies involving animal COVID-19 models were disproportionately higher than the dose recommended for human use. Specifically, when adjusted for body surface area, over half of the doses of molnupiravir used in the animal studies exceeded twice the human dose. Direct comparison of reported drug exposure across species after oral administration of molnupiravir indicated that the antiviral efficacy of the dose recommended for human use was underestimated in some animal models and overestimated in others. Frequently, molnupiravir was given prophylactically or shortly after SARS-CoV-2 inoculation in these models, in contrast to clinical trials where such timing is not consistently achieved. Furthermore, the recommended five-day treatment duration for humans was exceeded in several animal studies. Collectively, we suggest that design elements in the animal studies under examination contributed to a preference favoring molnupiravir, and thus inflated expectations for its efficacy against COVID-19. Addressing these elements may offer strategies to enhance the clinical efficacy of molnupiravir for the treatment of COVID-19. Such strategies include dose increment, early treatment initiation, administration by inhalation, and use of the drug in antiviral combination therapy.

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New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

Siniavin,

Gushchin,

Shastina

et al. 2024

Antiviral Research

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Ivermectin Does Not Protect against SARS-CoV-2 Infection in the Syrian Hamster Model

Cited by 7 publications

References 29 publications

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity

Molnupiravir Revisited—Critical Assessment of Studies in Animal Models of COVID-19

New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses

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