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Authors: Xiaoyan Liu et al. 2020

Link to paper: https://doi.org/10.1016/j.apsb.2020.04.008

Journal/ Pre-Print: Acta Pharmaceutica Sinica B

Tags: Cell Biology, Clinical, Drug discovery/Drug repurpose

Research Highlights 

1. Dipyridamole (an already FDA approved drug) inhibits Mpro enzyme activity (IC50 530 nM) and SARS-CoV-2 replication in vitro (Vero 6 cells, 100 nM IC50)

2. D-dimer levels are increased in severe and critical COVID-19 patients

3. Dipyridamole treatment may improve patient outcome compared to control, but odds ratio was non-significant. An improved study is needed to show clinical efficacy.

Summary  

· This paper attempts to identify, validate and repurpose an FDA approved antiplatelet agent Dipyridamole (DIP).

· In vitro, Dipyridamole inhibits SARS-CoV-2 protease Mpro enzymatic activity (530 nM IC50) and supresses viral replication (100 nM IC50) at usable doses, albeit not more than chloroquine.

· Retrospective analysis of 124 patient’s data shows elevated levels of coagulation indices including D-dimer, CRP, IL-6 and decreased lymphocytes.

· 31 patient open label trial with DIP suggests treatment reduces D-dimer levels. Treatment may improve patient outcome, but a larger study is needed before significance can be drawn for COVID-19 treatment, which should include DIP effect on patient viral replication/load.

Impact for SARS-CoV2/COVID19 research efforts

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

The retrospective analysis of coagulation indices (looking at 124 patients) demonstrated differences in these variables across non-severe to critically ill patients (i.e. elevated D-dimer, CRP, IL-6 and decreased lymphocytes. 

Treatment of SARS-CoV2/COVID19 positive individuals

In vitro results show dipyridamole supresses viral replication (not confirmed or looked at in patient cohort). Furthermore, their preliminary drug trial shows this drug is able to reduce D-dimer levels in patients and may promote faster recovery, but a further study is needed.

Study Type

· In vitro study

· Clinical Cohort study (e.g. drug trials)

Strengths and limitations of the paper

Novelty: This paper suggests viability of repurposing an FDA approved drug as a SARS-CoV-2 antiviral and anticoagulant therapy to improve patient outcome.

Standing in the field: Reviews have highlighted potential use of DIP for COVID-19 patients.

Literature has linked high coagulation indices (high D-dimer levels) with disease severity and mortality.

Same group has published another paper in mouse pneumonia model and COVID-19 patients with coagulation dysfunction.

Appropriate statistics: Appropriate, but some results are not significant.

Low n for clinical patient trial (31 patients = 14 treatment, 17 control).

This study could be used as a pilot to calculate effect size for a future study.

Viral model used: SARS-CoV-2 (no details) in Vero E6 for in vitro portion

Patients with SARS-CoV-2 for clinical cohort

Translatability: Clinical cohort is directly translatable, using SARS-CoV-2 patients.

This drug is already FDA approved, therefore with the addition of a larger drug trial, with more stringent controls and study parameters, this drug is ready if proven effective.

Main limitations: No quantitative data on effect on viral replication in patients ± DIP treatment (therefore cannot attribute in vitro viral replication to antiviral effect patients).

Odds ratio of DIP treatment was large but non-significant (0.06).

Open label study (unblinded).

Low n for patient cohort trial.

Writing of this paper could be improved also the structure and narrative.

No discussion on combination and comparison to other drugs e.g. chloroquine that was used in vitro in this study.