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Clin Appl Thromb Hemost ; 27: 10760296211066945, 2021.
Article in English | MEDLINE | ID: covidwho-1574469


INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.

Arginine/analogs & derivatives , COVID-19/drug therapy , Partial Thromboplastin Time/methods , Pipecolic Acids/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Thrombocytopenia/drug therapy , Thrombosis/drug therapy , Aged , Arginine/pharmacology , Arginine/therapeutic use , COVID-19/complications , Female , Humans , Male , Middle Aged , Pipecolic Acids/pharmacology , Platelet Aggregation Inhibitors/pharmacology , SARS-CoV-2 , Sulfonamides/pharmacology , Thrombocytopenia/chemically induced , Thrombosis/chemically induced
Molecules ; 26(19)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1463770


The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

Antiviral Agents/pharmacology , Arginine/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Rutin/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Coronavirus 3C Proteases/metabolism , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , Solubility
Cardiovasc Drugs Ther ; 35(2): 195-203, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-737530


Thrombin is a trypsin-like serine protease with multiple physiological functions. Its role in coagulation and thrombosis is well-established. Nevertheless, thrombin also plays a major role in inflammation by activating protease-activated receptors. In addition, thrombin is also involved in angiogenesis, fibrosis, and viral infections. Considering the pathogenesis of COVID-19 pandemic, thrombin inhibitors may exert multiple potential therapeutic benefits including antithrombotic, anti-inflammatory, and antiviral activities. In this review, we describe the clinical features of COVID-19, the thrombin's roles in various pathologies, and the potential of argatroban in COVID-19 patients. Argatroban is a synthetic, small molecule, direct, competitive, and selective inhibitor of thrombin. It is approved to parenterally prevent and/or treat heparin-induced thrombocytopenia in addition to other thrombotic conditions. Argatroban also possesses anti-inflammatory and antiviral activities and has a well-established pharmacokinetics profile. It also appears to lack a significant risk of drug-drug interactions with therapeutics currently being evaluated for COVID-19. Thus, argatroban presents a substantial promise in treating severe cases of COVID-19; however, this promise is yet to be established in randomized, controlled clinical trials.

Arginine/analogs & derivatives , COVID-19 , Pipecolic Acids/pharmacology , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Antithrombins/pharmacology , Arginine/pharmacology , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/drug therapy , COVID-19/immunology , Drug Development , Humans , Inflammation/drug therapy