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1.
Int J Pharm ; 608: 121122, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1433361

ABSTRACT

Herein, we demonstrated the development and characterization of a dry powder inhaler (DPI) formulation of edoxaban (EDX); and investigated the in-vitro anticoagulation effect for the management of pulmonary or cerebral coagulopathy associated with COVID-19 infection. The formulations were prepared by mixing the inhalable micronized drug with a large carrier lactose and dispersibility enhancers, leucine, and magnesium stearate. The drug-excipient interaction was studied using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) methods. The drug and excipients showed no physical inter particulate interaction. The in-vitro drug aerosolization from the developed formulation was determined by a Twin Stage Impinger (TSI) at a flow rate of 60 ± 5 L /min. The amount of drug deposition was quantified by an established HPLC-UV method. The fine particle fraction (FPF) of EDX API from drug alone formulation was 7%, whereas the formulations with excipients increased dramatically to almost 7-folds up to 47%. The developed DPI formulation of EDX showed a promising in-vitro anticoagulation effect at a very low concentration. This novel DPI formulation of EDX could be a potential and effective inhalation therapy for managing pulmonary venous thromboembolism (VTE) associated with COVID-19 infection. Further studies are warranted to investigate the toxicity and clinical application of the inhaled EDX DPI formulation.


Subject(s)
Blood Coagulation Disorders/drug therapy , COVID-19 , Dry Powder Inhalers , Pyridines/administration & dosage , Thiazoles/administration & dosage , Administration, Inhalation , Aerosols , Blood Coagulation Disorders/virology , COVID-19/complications , Humans , Particle Size , Powders
2.
Eur Rev Med Pharmacol Sci ; 25(16): 5310-5317, 2021 08.
Article in English | MEDLINE | ID: covidwho-1395678

ABSTRACT

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.


Subject(s)
Antiemetics/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Palonosetron/therapeutic use , Pyridines/therapeutic use , Aged , Antiemetics/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , COVID-19 , Female , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Humans , Irinotecan/administration & dosage , Irinotecan/therapeutic use , Leucovorin/administration & dosage , Leucovorin/therapeutic use , Male , Middle Aged , Nausea/prevention & control , Oxaliplatin/administration & dosage , Oxaliplatin/therapeutic use , Palonosetron/administration & dosage , Pandemics , Prospective Studies , Pyridines/administration & dosage , Vomiting/prevention & control
3.
Naunyn Schmiedebergs Arch Pharmacol ; 394(3): 561-567, 2021 03.
Article in English | MEDLINE | ID: covidwho-1235720

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been characterized by lymphopenia as well as a proinflammatory cytokine storm, which are responsible for the poor prognosis and multiorgan defects. The transcription factor nuclear factor-κB (NF-κB) modulates the functions of the immune cells and alters the gene expression profile of different cytokines in response to various pathogenic stimuli, while many proinflammatory factors have been known to induce NF-κB signalling cascade. Besides, NF-κB has been known to potentiate the production of reactive oxygen species (ROS) leading to apoptosis in various tissues in many diseases and viral infections. Though the reports on the involvement of the NF-κB signalling pathway in COVID-19 are limited, the therapeutic benefits of NF-κB inhibitors including dexamethasone, a synthetic form of glucocorticoid, have increasingly been realized. Considering the fact, the abnormal activation of the NF-κB resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might be associated with the pathogenic profile of immune cells, cytokine storm and multiorgan defects. Thus, the pharmacological inactivation of the NF-κB signalling pathway can strongly represent a potential therapeutic target to treat the symptomatology of COVID-19. This article signifies pharmacological blockade of the phosphorylation of inhibitor of nuclear factor kappa B kinase subunit beta (IKKß), a key downstream effector of NF-κB signalling, for a therapeutic consideration to attenuate COVID-19.


Subject(s)
COVID-19/drug therapy , Drug Delivery Systems/trends , I-kappa B Kinase/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Signal Transduction/physiology , Animals , COVID-19/epidemiology , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/metabolism , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , I-kappa B Kinase/metabolism , Lymphopenia/drug therapy , Lymphopenia/epidemiology , Lymphopenia/metabolism , NF-kappa B/metabolism , Nitriles/administration & dosage , Pyridines/administration & dosage , Signal Transduction/drug effects , Sulfones/administration & dosage
4.
Br J Pharmacol ; 177(21): 4971-4974, 2020 11.
Article in English | MEDLINE | ID: covidwho-998832

ABSTRACT

In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signalling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endotheliitis. Activation of proteinase-activated receptor 1 (PAR1), in particular by the serine protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. We discuss evidence for a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and other as-yet non-approved antagonists of PAR1 and proteinase-activated receptor 4 (PAR4). LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Coronavirus Infections/drug therapy , Lactones/administration & dosage , Pneumonia, Viral/drug therapy , Pyridines/administration & dosage , Receptor, PAR-1/antagonists & inhibitors , Animals , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Drug Repositioning , Humans , Lactones/pharmacology , Pandemics , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacology , Pneumonia, Viral/virology , Pyridines/pharmacology , Receptor, PAR-1/metabolism , Receptors, Thrombin/antagonists & inhibitors , Receptors, Thrombin/metabolism , SARS-CoV-2
5.
J Thromb Haemost ; 18(6): 1320-1323, 2020 06.
Article in English | MEDLINE | ID: covidwho-116313

ABSTRACT

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Subject(s)
Antithrombins/blood , Antiviral Agents/adverse effects , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Dabigatran/blood , Factor Xa Inhibitors/blood , Pneumonia, Viral/drug therapy , Pyrazoles/blood , Pyridines/blood , Pyridones/blood , Thiazoles/blood , Administration, Oral , Aged , Aged, 80 and over , Antithrombins/administration & dosage , Antithrombins/adverse effects , Antiviral Agents/administration & dosage , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Dabigatran/administration & dosage , Dabigatran/adverse effects , Darunavir/adverse effects , Drug Interactions , Drug Monitoring , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Humans , Italy , Lopinavir/adverse effects , Male , Pandemics , Patient Safety , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Risk Assessment , Risk Factors , Ritonavir/adverse effects , SARS-CoV-2 , Severity of Illness Index , Thiazoles/administration & dosage , Thiazoles/adverse effects
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