Inhibition of SARS‐CoV‐2 replication using calcineurin inhibitors: are concentrations required clinically achievable?

Solanich, Xavier; Padullés, N; Niubó, Jordi; Videla, Sebastián; Antolí, Arnau; Rocamora-Blanch, Gemma; Corbella, Emili

doi:10.1111/joim.13264

Cited by 3 publications

(3 citation statements)

References 6 publications

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“…In this context, our findings showing that CsA dampens the production of several epithelial cytokines would support its repurposing. Furthermore, our observation of a reduction of viral titer as well as of cytokine production at concentrations compatible with CsA administration to patients would support its usage in vivo (as recently questioned by Solanich et al [ 77 ]).…”

Section: Discussionsupporting

confidence: 69%

Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants

et al. 2022

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SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a “quick and dirty” approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more “aggressive”/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines.

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Section: Discussionsupporting

confidence: 69%

Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants

et al. 2022

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“…Based on this finding, it has been suggested that CNIs could be used as an antiviral agent to treat COVID-19. However, we would like to highlight that the concentrations used in cell culture are not clinically achievable, as they correspond to highly toxic blood levels in humans (24). Accordingly, the proposed use of tacrolimus should be restricted to the inflammatory stages of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial

et al. 2021

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Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients.Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization.Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC.Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19.Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

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“…We believed that by considering a high dose of ciclosporin, the plasma concentrations needed for the prevention of virus replication would be achievable by the medication. Solanich, X., et al claimed that the antiviral (and not anti-inflammatory) effects of ciclosporin will not be achieved by previously suggested doses [15] . We wanted to see if a high dose of ciclosporin, given over a short duration, would benefit severe COVID-19 cases.…”

Section: Discussionmentioning

confidence: 99%

Combined Therapy of Ciclosporin Plus Favipiravir in the Management of Patients with Severe COVID-19, not Responding to Dexamethasone: A non-Controlled Prospective Trial

Barati

Hashemian

Tabarsi

et al. 2021

International Immunopharmacology

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Background Regarding the COVID-19 pandemic, potential therapeutic agents are being evaluated almost every day. Ciclosporin, a calcineurin inhibitor, is characterized by beneficial antiviral and immunomodulatory effects. The present study aimed to evaluate the efficacy of ciclosporin in managing COVID-19. Methods This study was a prospective non-controlled clinical trial carried out on 20 patients. Confirmed COVID-19 patients received two doses of ciclosporin (10 mg/kg and 5 mg/kg injections) 24 hours apart. Mortality rate and the lengths of intensive care unit (ICU) and hospital stays were assessed for all 20 patients. Results The mortality rate and the need for mechanical ventilation were calculated as 50%. The percentage of ICU admission was 70%. The lengths of ICU and hospital stays were 8.13 ± 6.81 and 14.25 ± 8.55 days, respectively. The levels of ferritin and white blood cells were significantly higher after injecting the second dose of ciclosporin. Seven patients (35%) had radiologically improved lungs after ciclosporin therapy. Conclusion It seems that the protocol of two doses of ciclosporin in combination with favipiravir does not have favorable effects among COVID-19 patients that do not respond to dexamethasone. Controlled trials are needed to confirm the results.

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Inhibition of SARS‐CoV‐2 replication using calcineurin inhibitors: are concentrations required clinically achievable?

Cited by 3 publications

References 6 publications

Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants

Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial

Combined Therapy of Ciclosporin Plus Favipiravir in the Management of Patients with Severe COVID-19, not Responding to Dexamethasone: A non-Controlled Prospective Trial

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