Drug repurposing for the treatment of COVID-19

Kato, Yuri; Nishiyama, Kazuhiro; Nishimura, Akiyoshi; Noda, Takamasa; Okabe, Kaori; Kusakabe, Takahiro; Kanda, Yasunari; Nishida, Motohiro

doi:10.1016/j.jphs.2022.04.007

Cited by 21 publications

(13 citation statements)

References 74 publications

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“…Dyn plays a critical role in clathrin-dependent endocytosis, and SARS-CoV-2 enter into host cells via clathrin-dependent endocytosis (Yang et al 2022). Kato et al mentioned that the tricyclic antidepressant clomipramine suppressed ACE2-mediated SARS-CoV-2 entry (Kato et al 2021;Kato et al 2022). In this study, we found that clomipramine inhibited the PS-liposome-stimulated GTPase activity of Dyn 2, which was ubiquitously expressed, and Dyn 3, which was expressed in the lung (Reis et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…mentioned that the tricyclic antidepressant clomipramine suppressed ACE2-mediated SARS-CoV-2 entry (Kato et al . 2021; Kato et al . 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Kato et al . mentioned that the tricyclic antidepressant clomipramine suppressed ACE2-mediated SARS-CoV-2 entry ( 13, 23 ). In this study, we found that clomipramine inhibited the PS-liposome-stimulated GTPase activity of Dyn 2, which was ubiquitously expressed, and Dyn 3, which was expressed in the lung ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

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Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation

Mizumoto

Otomo

Takahashi

2022

Preprint

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Three dynamin isoforms play critical roles in clathrin-dependent endocytosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via clathrin-dependent endocytosis. We previously reported that clomipramine inhibits the GTPase activity of dynamin 1, which is in mainly neuron. Therefore, we investigated whether clomipramine inhibits the activity of other dynamin isoforms in this study. We found that, similar to its inhibitory effect on dynamin 1, clomipramine inhibited the L-α-phosphatidyl-L-serine-stimulated GTPase activity of dynamin 2, which is expressed ubiquitously, and dynamin 3, which is expressed in the lung. Inhibition of GTPase activity raises the possibility that clomipramine can suppress SARS-CoV-2 entry into host cells.

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Section: Discussionmentioning

confidence: 99%

“…mentioned that the tricyclic antidepressant clomipramine suppressed ACE2-mediated SARS-CoV-2 entry (Kato et al . 2021; Kato et al . 2022).…”

Section: Discussionmentioning

confidence: 99%

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Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation

Mizumoto

Otomo

Takahashi

2022

Preprint

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“…All of this sheds light on an emerging concern, stressing the urgent need to develop safe and effective therapeutic agents for COVID-19 treatment. In this scenario, researchers and physicians from all over the world have been joining their resources to slow down the virus’s spread, developing new antiviral drugs for SARS-CoV-2 and/or testing the anti-COVID efficacy of old drugs by a drug repurposing approach [ 6 , 7 , 8 ]. The pharmacological treatment targets virus and host proteins to counter viral entry and replication and immune system factors involved in the inflammatory reaction [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

et al. 2022

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The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulnerable to COVID-19 exhibiting severe symptoms, thus characterizing valid therapeutic strategies for better management of the disease is still a challenge.

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“…1 Various new and repurposed antiviral drugs have been considered as treatment for COVID-19 and evaluated in clinical trials, including remdesivir, favipiravir, azithromycin, hydroxychloroquine, and ritonavir. 2,3 To date, only the antivirals remdesivir (Veklury) and a combination of nirmatrelvir with ritonavir (Paxlovid) have received emergency use approval (EUA) for COVID-19 treatment by the FDA and EMA and few repurposed drugs have shown clinical efficacy in reducing mortality, the need for mechanical ventilation or improving the clinical status of COVID-19 patients admitted to hospital. [4][5][6] Early in the COVID-19 pandemic, the World Health Organization (WHO) identified enisamium (4-(benzylcarbamoyl)-1-methylpyridinium, trade name Amizon ® MAX) as a candidate drug for the treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

RNA polymerase inhibitor enisamium for treatment of moderate COVID-19 patients: a randomized, placebo-controlled, multicenter, double-blind phase 3 clinical trial

Holubovska

Babich²,

Mironenko

et al. 2022

Preprint

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Background Enisamium (trade name Amizon MAX) is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication and improves influenza patient recovery. We aimed to evaluate the clinical efficacy of enisamium treatment combined with standard care compared to standard care plus treatment with a placebo control in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. This trial was registered with ClinicalTrials.gov under NCT04682873. Methods The study was a phase three, multi-center, double-blind, randomized, placebo-controlled trial conducted in 14 clinical centers. Hospitalized patients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection were eligible. Patients were randomly assigned to receive either enisamium (500 mg per dose, 4 times a day) or a placebo. The treatment lasted ≤7 days in case of early discharge from the hospital, or loss of the patient's ability to swallow due to the need for ventilation. All patients received standard of care as deemed necessary by the investigator and the health status of each patient. All patients received standard of care as deemed necessary by the investigator and each patient's health status. The primary outcome was an improvement of at least two points on an 8-point, modified WHO severity rating (SR) scale within 29 days of randomization. The primary and safety outcomes were analyzed in accordance to the intention-to-treat (ITT) principle. Findings A total of 592 patients were enrolled and randomized between May 2020 and March 2021. Only patients with a baseline SR of 4 (285 subjects or 48.1%) were included in the ITT analysis. Patients with a baseline SR of 5 were excluded as the interim analysis did not show relevant differences between the enisamium group and placebo in this sub-group. The patients with a baseline SR of 4 were divided into two groups: 142 (49.8%) were assigned to the enisamium group and 143 (50.2%) to the placebo group. No differences were observed between the safety or patient tolerability profiles of the enisamium and placebo treatment. Analysis of the ITT population showed that if patients were treated within 4 days of the onset of COVID-19 symptoms, the median time to improvement was 8 for the enisamium group and 13 days for the placebo group (p = 0.0051). For patients treated within 7 days of the onset of COVID-19 symptoms, the median time to improvement was 10 days for the enisamium group and 11 days for the placebo group (p = 0.0035). Comparison of groups using a stratified one-sided Logrank criterion (adjustment using stratification by age categories: "<40 years", "40-<65 years" and "≥65 years") showed statistically significant differences between the groups (p = 0.00945, one-sided). Interpretation Enisamium is safe to use in COVID-19 patients. In COVID-19 patients that did not require supplementary oxygen (SR = 5), standard treatment was sufficient to aid recovery and enisamium did not offer significant clinical benefits. However, we found that standard care combined with enisamium offers a significant clinical benefit when given to patients with moderate COVID-19 requiring supplementary oxygen (SR = 4), if enisamium is given within 7 days of the onset of symptoms. These data suggest that enisamium therapy can be used as therapy against SARS-CoV-2 infection in these patients. Funding Farmak JSC, Wellcome Trust, and Royal Society.

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Drug repurposing for the treatment of COVID-19

Cited by 21 publications

References 74 publications

Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation

Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation

Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

RNA polymerase inhibitor enisamium for treatment of moderate COVID-19 patients: a randomized, placebo-controlled, multicenter, double-blind phase 3 clinical trial

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