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1.
Chin Chem Lett ; 32(10): 3019-3022, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1520747

ABSTRACT

The wide-spreading SARS-CoV-2 virus has put the world into boiling water for more than a year, however pharmacological therapies to act effectively against coronavirus disease 2019 (COVID-19) remain elusive. Chloroquine (CQ), an antimalarial drug, was found to exhibit promising antiviral activity in vitro and in vivo at a high dosage, thus CQ was approved by the FDA for the emergency use authorization (EUA) in the fight against COVID-19 in the US, but later was revoked the EUA status due to the severe clinical toxicity. Herein, we show that supramolecular formulation of CQ by a macrocyclic host, curcurbit[7]uril (CB[7]), reduced its non-specific toxicity and improved its antiviral activity against coronavirus, working in synergy with CB[7]. CB[7] was found to form 1:1 host-guest complexes with CQ, with a binding constant of ∼104 L/mol. The CQ-CB[7] formulation decreased the cytotoxicity of CQ against Vero E6 and L-02 cell lines. In particular, the cytotoxicity of CQ (60 µmol/L) against both Vero E6 cell line and L-02 cell lines was completely inhibited in the presence of 300 µmol/L and 600 µmol/L CB[7], respectively. Furthermore, the CB[7] alone showed astonishing antiviral activity in SARS-CoV-2 infected Vero E6 cells and mouse hepatitis virus strain A59 (MHV-A59) infected N2A cells, and synergistically improved the antiviral activity of CQ-CB[7], suggesting that CB[7]-based CQ formulation has a great potential as a safe and effective antiviral agent against SARS-CoV-2 and other coronavirus.

2.
Clin Case Rep ; 9(5): e04115, 2021 May.
Article in English | MEDLINE | ID: covidwho-1335986

ABSTRACT

Arsenic trioxide (ATO) is generally well tolerated for treatment of APL. We present a patient with severe watery diarrhea and pancreatitis thought to be due to ATO toxicity in the setting of obesity and acute kidney injury. Future studies evaluating ATO levels in patients experiencing toxicities may help guide dose modifications.

3.
Mod Rheumatol ; 31(4): 924-925, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1281812
4.
Front Pharmacol ; 12: 619588, 2021.
Article in English | MEDLINE | ID: covidwho-1256397

ABSTRACT

Downregulation of drug metabolizing enzymes and transporters by proinflammatory mediators in hepatocytes, enterocytes and renal tubular epithelium is an established mechanism affecting pharmacokinetics. Emerging evidences indicate that vascular endothelial cell expression of drug metabolizing enzymes and transporters may regulate pharmacokinetic pathways in heart to modulate local drug bioavailability and toxicity. However, whether inflammation regulates pharmacokinetic pathways in human cardiac vascular endothelial cells remains largely unknown. The lipid modified protein Wnt5A is emerging as a critical mediator of proinflammatory responses and disease severity in sepsis, hypertension and COVID-19. In the present study, we employed transcriptome profiling and gene ontology analyses to investigate the regulation of expression of drug metabolizing enzymes and transporters by Wnt5A in human coronary artery endothelial cells. Our study shows for the first time that Wnt5A induces the gene expression of CYP1A1 and CYP1B1 enzymes involved in phase I metabolism of a broad spectrum of drugs including chloroquine (the controversial drug for COVID-19) that is known to cause toxicity in myocardium. Further, the upregulation of CYP1A1 and CYP1B1 expression is preserved even during inflammatory crosstalk between Wnt5A and the prototypic proinflammatory IL-1ß in human coronary artery endothelial cells. These findings stimulate further studies to test the critical roles of vascular endothelial cell CYP1A1 and CYP1B1, and the potential of vascular-targeted therapy with CYP1A1/CYP1B1 inhibitors in modulating myocardial pharmacokinetics in Wnt5A-associated inflammatory and cardiovascular diseases.

5.
BMC Infect Dis ; 21(1): 411, 2021 May 04.
Article in English | MEDLINE | ID: covidwho-1216885

ABSTRACT

BACKGROUND AND OBJECTIVES: An effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation. MATERIALS AND METHODS: Patients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated. RESULTS: A total of 66 patients, 36 in the study group and 30 in the control group were included in the study. Mutations affecting ivermectin metabolism was detected in genetic tests of six (16.7%) patients in the study group and they were excluded from the study. At the end of the 5-day follow-up period, the rate of clinical improvement was 73.3% (22/30) in the study group and was 53.3% (16/30) in the control group (p = 0.10). At the end of the study, mortality developed in 6 patients (20%) in the study group and in 9 (30%) patients in the control group (p = 0.37). At the end of the follow-up period, the average peripheral capillary oxygen saturation (SpO2) values of the study and control groups were found to be 93.5 and 93.0%, respectively. Partial pressure of oxygen (PaO2)/FiO2 ratios were determined as 236.3 ± 85.7 and 220.8 ± 127.3 in the study and control groups, respectively. While the blood lymphocyte count was higher in the study group compared to the control group (1698 ± 1438 and 1256 ± 710, respectively) at the end of the follow-up period (p = 0.24); reduction in serum C-reactive protein (CRP), ferritin and D-dimer levels was more pronounced in the study group (p = 0.02, p = 0.005 and p = 0.03, respectively). CONCLUSIONS: According to the findings obtained, ivermectin can provide an increase in clinical recovery, improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Ivermectin/therapeutic use , Pneumonia, Viral/drug therapy , ATP Binding Cassette Transporter, Subfamily B/genetics , Aged , Amides/therapeutic use , Antiviral Agents/pharmacokinetics , Azithromycin/therapeutic use , COVID-19/blood , COVID-19/mortality , Cytochrome P-450 CYP3A/genetics , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/therapeutic use , Ivermectin/pharmacokinetics , Male , Middle Aged , Pneumonia, Viral/blood , Pneumonia, Viral/virology , Prospective Studies , Pyrazines/therapeutic use , Single-Blind Method , Treatment Outcome
6.
Front Physiol ; 12: 663869, 2021.
Article in English | MEDLINE | ID: covidwho-1191700

ABSTRACT

Polyunsaturated fatty acids are metabolized into regulatory lipids important for initiating inflammatory responses in the event of disease or injury and for signaling the resolution of inflammation and return to homeostasis. The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis. It was later reported that blocking metabolism of leukotoxins into the vicinal diols ameliorated the deleterious effects of leukotoxins, suggesting that the leukotoxin diols are contributing to the toxicity. During quantitative profiling of fatty acid chemical mediators (eicosanoids) in COVID-19 patients, we found increases in the regioisomeric leukotoxin diols in plasma samples of hospitalized patients suffering from severe pulmonary involvement. In rodents these leukotoxin diols cause dramatic vascular permeability and are associated with acute adult respiratory like symptoms. Thus, pathways involved in the biosynthesis and degradation of these regulatory lipids should be investigated in larger biomarker studies to determine their significance in COVID-19 disease. In addition, incorporating diols in plasma multi-omics of patients could illuminate the COVID-19 pathological signature along with other lipid mediators and blood chemistry.

7.
Curr Treat Options Oncol ; 22(6): 47, 2021 04 17.
Article in English | MEDLINE | ID: covidwho-1188176

ABSTRACT

OPINION STATEMENT: Prostate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.


Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Cardiovascular Diseases/epidemiology , Prostatic Neoplasms/drug therapy , Androstenes/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , COVID-19/epidemiology , COVID-19/pathology , Cardiotoxicity , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/ethnology , Disease Susceptibility , Gonadotropin-Releasing Hormone/agonists , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Health Status Disparities , Humans , Male , Prostatic Neoplasms/ethnology , SARS-CoV-2
8.
Int J Pept Res Ther ; 27(3): 1729-1740, 2021.
Article in English | MEDLINE | ID: covidwho-1188142

ABSTRACT

COVID-19 is an infectious disease caused by a newly discovered corona virus SARS-COV-2. It is the most dangerous epidemic existing currently all over the world. To date, there is no licensed vaccine and not any particular efficient therapeutic agent available to prevent or cure the disease. So development of an effective vaccine is the urgent need of the time. The proposed study aims to identify potential vaccine candidates by screening the complete proteome of SARS-COV-2 using the computational approach. From 14 protein entries in UniProtKB, 4 proteins were screened for epitope prediction based on consensus antigenicity predictions and various physico-chemical criteria like transmembrane domain, allergenicity, GRAVY value, toxicity, stability index. Comprehensive analysis of these 4 antigens revealed that spike protein (P0DTC2) and nucleoprotein (P0DTC9) show the greatest potential for experimental immunogenicity analysis. These 2 proteins have several potential CD4+ and CD8+ T-cell epitopes, as well as high probability of B-cell epitope regions as compared to well-characterized antigen the matrix protein 1 [Influenza A virus (H5N1)]. In addition, the epitope SIIAYTMSL predicted from spike protein (P0DTC2) and epitope SPRWYFYYL predicted from nucleoprotein (P0DTC9) exhibited more than 60% population coverage in the target populations Europe, North America, South Asia, Northeast Asia taken in this study. These epitopes have also been found to exhibit highly significant TCR-pMHC interactions having a joint Z value of 4.51 and 4.37 respectively. Therefore, this analysis suggests that the predicted epitopes might be suitable vaccine candidates and should be subjected to further in-vivo and in-vitro studies.

9.
Cell Biosci ; 11(1): 58, 2021 Mar 25.
Article in English | MEDLINE | ID: covidwho-1154039

ABSTRACT

BACKGROUND: SARS-CoV-2 causes COVID-19 which has a widely diverse disease profile. The mechanisms underlying its pathogenicity remain unclear. We set out to identify the SARS-CoV-2 pathogenic proteins that through host interactions cause the cellular damages underlying COVID-19 symptomatology. METHODS: We examined each of the individual SARS-CoV-2 proteins for their cytotoxicity in HEK 293 T cells and their subcellular localization in COS-7 cells. We also used Mass-Spec Affinity purification to identify the host proteins interacting with SARS-CoV-2 Orf6 protein and tested a drug that could inhibit a specific Orf6 and host protein interaction. RESULTS: We found that Orf6, Nsp6 and Orf7a induced the highest toxicity when over-expressed in human 293 T cells. All three proteins showed membrane localization in COS-7 cells. We focused on Orf6, which was most cytotoxic and localized to the endoplasmic reticulum, autophagosome and lysosomal membranes. Proteomics revealed Orf6 interacts with nucleopore proteins (RAE1, XPO1, RANBP2 and nucleoporins). Treatment with Selinexor, an FDA-approved inhibitor for XPO1, attenuated Orf6-induced cellular toxicity in human 293 T cells. CONCLUSIONS: Our study revealed Orf6 as a highly pathogenic protein from the SARS-CoV-2 genome, identified its key host interacting proteins, and Selinexor as a drug candidate for directly targeting Orf6 host protein interaction that leads to cytotoxicity.

10.
Microb Drug Resist ; 27(3): 281-290, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1137930

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, has recently emerged worldwide. In this context, there is an urgent need to identify safe and effective therapeutic strategies for treatment of such highly contagious disease. We recently reported promising results of combining hydroxychloroquine and azithromycin as an early treatment option. Although ongoing clinical trials are challenging the efficacy of this combination, many clinicians claim the authorization to or have already begun to use it to treat COVID-19 patients worldwide. The aim of this article is to share pharmacology considerations contributing to the rationale of this combination, and to provide safety information to prevent toxicity and drug-drug interactions, based on available evidence.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacology , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Azithromycin/administration & dosage , Azithromycin/adverse effects , Azithromycin/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Drug Therapy, Combination , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology , SARS-CoV-2
11.
Front Cardiovasc Med ; 8: 614562, 2021.
Article in English | MEDLINE | ID: covidwho-1127976

ABSTRACT

Background: Takotsubo cardiomyopathy is triggered by emotional or physical stress. It is defined as a reversible myocardial dysfunction, usually with apical ballooning aspect due to apical akinesia associated with hyperkinetic basal left ventricular contraction. Described in cases of viral infections such as influenza, only few have been reported associated with novel coronavirus disease 2019 (COVID-19) in the recent pandemic. Case summary: A 79-years-old man, with cardiovascular risk factors (type 2 diabetes and hypertension) and chronic kidney disease, presented to the emergency room for severe dyspnea after 8 days of presenting respiratory symptoms and fever. Baseline electrocardiogram (ECG) was normal, but he presented marked inflammatory syndrome. He was transferred to an intensive care unit to receive mechanical ventilation within 6 h, due to acute respiratory distress syndrome. He presented circulatory failure 2 days after, requiring norepinephrine support (up to up to 1.04 µg/kg/min). Troponin T was elevated (637 ng/l). ECG showed diffuse T wave inversion. Echocardiography showed reduced left ventricular ejection fraction (LVEF 40%), with visual signs of Takotsubo cardiomyopathy. Cardiac failure resolved after 24 h with troponin T decrease (433 ng/l) and restoration of cardiac function (LVEF 60% with regression of Takotsubo features). Patient died after 15 days of ICU admission, due to septic shock from ventilator-acquired pneumonia. Cardiac function was then normal. Conclusion: Mechanisms of Takotsubo cardiomyopathy in viral infections include catecholamine-induced myocardial toxicity and inflammation related to sepsis. Differential diagnoses include myocarditis and myocardial infarction. Evidence of the benefit of immunomodulatory drugs and dexamethasone are growing to support this hypothesis in COVID-19.

12.
Horm Mol Biol Clin Investig ; 42(1): 63-68, 2021 Feb 19.
Article in English | MEDLINE | ID: covidwho-1088785

ABSTRACT

After the global outbreak of coronaviruses caused diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), an outbreak due to these viruses occurred in December, 2019 in Wuhan, Hubei Province, China and led to a worldwide spread. Coronavirus 2019 disease (COVID-19) has emerged as a serious global health emergency and spread from a person to another who has the virus. But the scope of an intermediate host is not known. Population at higher risk includes individuals in higher age group (>60 years) or with comorbidities such as diabetes, hypertension, cardiovascular disease and weaker immune system. Many unknown and underestimate risk factors could be responsible for adverse outcomes in COVID-19. These risk factors should be appropriately identified, addressed and necessary actions should be taken to mitigate the effect of COVID-19 pandemic. Bhopal gas tragedy was one of the world's worst industrial chemical leak disaster. The survivors of this incident still suffer from the various complications such as increased rate of cancers, chronic illness like tuberculosis, respiratory diseases, birth defects, nerve injury, growth retardations, gynecological illness and many more. The survivors of Bhopal gas tragedy are at higher risk of developing COVID-19 related adverse outcome. One of the possible explanations can be long term effect of methyl isocyanate (MIC). MIC exposure can lead to possible toxic effect on genetic, epigenetic and non-genetic factors. In this review, we aim to establish the scientific basis for adverse outcome in COVID-19 patients who are also victims of Bhopal gas tragedy.


Subject(s)
Bhopal Accidental Release , COVID-19 , Disaster Victims , SARS-CoV-2/physiology , Survivors , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/etiology , COVID-19/virology , China/epidemiology , Comorbidity , Disaster Victims/rehabilitation , Disaster Victims/statistics & numerical data , Disasters , Humans , India/epidemiology , Middle Aged , Pandemics , SARS-CoV-2/isolation & purification , Survivors/statistics & numerical data
13.
Trials ; 22(1): 116, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1067266

ABSTRACT

OBJECTIVES: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. TRIAL DESIGN: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm. PARTICIPANTS: The study will be performed at the Institut Català d'Oncologia, a tertiary level oncological referral center in the Catalonia region (Spain). The eligibility criteria are: patients > 18 years affected by oncological diseases; ECOG performance status < 2 (Karnofsky score > 60%); a laboratory confirmed infection with SARS-CoV-2 by means of real -time PCR; radiological signs of low respiratory tract disease; absence of organ dysfunction (a total bilirubin within normal institutional limits, AST/ALT≤2.5 X institutional upper limit of normal, alkaline phosphatase ≤2.5 X institutional upper limit of normal, coagulation within normal institutional limits, creatinine clearance >30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal); absence of HIV infection; no active or latent HBV or HCV infection. The exclusion criteria are: patients with oncological diseases who are not candidates to receive any active oncological treatment; hemodynamic instability at time of study enrollment; impossibility to receive oral medication; medical history of recent or active pulmonary embolism or deep venous thrombosis or patients at high-risk of suffering them (surgical intervention, immobilization); multi organ failure, rapid worsening of respiratory function with requirement of fraction of inspired oxygen (FiO2) > 50% or high-flow nasal cannula before initiation of study treatment; uncontrolled intercurrent illness (ongoing or severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements); allergy to one or more of study treatments; pregnant or breastfeeding women; positive pregnancy test in a pre-dose examination. Patients should have the ability to understand, and the willingness to sign, a written informed consent document; the willingness to accept randomization to any assigned treatment arm; and must agree not to enroll in another study of an investigational agent prior to completion of Day +28 of study. An electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform will be used to collect the data of the trial. Removal from the study will apply in case of unacceptable adverse event(s), development of an intercurrent illness, condition or procedural complication, which could interfere with the patient's continued participation and voluntary patient withdrawal from study treatment (all patients are free to withdraw from participation in this study at any time, for any reasons, specified or unspecified, and without prejudice). INTERVENTION AND COMPARATOR: Treatment will be administered on an inpatient basis. We will compare the experimental treatment with baricitinib plus the institutional standard of care compared with the standard of care alone. During the phase I, we will define the dose-limiting toxicity of baricitinib and the dose to be used in the phase 2 part of the study. The starting baricitinib dose will be an oral tablet 4 mg-once daily which can be reduced to 2 mg depending on the observed toxicity. The minimum duration of therapy will be 5 days and it can be extended to 7 days. The standard of care will include the following therapies. Antibiotics will be individualized based on clinical suspicion, including the management of febrile neutropenia. Prophylaxis of thromboembolic disease will be administered to all participants. Remdesivir administration will be considered only in patients with severe pneumonia (SatO2 <94%) with less than 7 days of onset of symptoms and with supplemental oxygen requirements but not using high-flow nasal cannula, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the randomized phase, tocilizumab or interferon will not be allowed in the experimental arm. Tocilizumab can be used in patients in the standard of care arm at the discretion of the investigator. If it is prescribed it will be used according to the following criteria: patients who, according to his baseline clinical condition, would be an ICU tributary, interstitial pneumonia with severe respiratory failure, patients who are not on mechanical ventilation or ECMO and who are still progressing with corticoid treatment or if they are not candidates for corticosteroids. Mild ARDS (PAFI <300 mmHg) with radiological or blood gases deterioration that meets at least one of the following criteria: CRP >100mg/L D-Dimer >1,000µg/L LDH >400U/L Ferritin >700ng/ml Interleukin 6 ≥40ng/L. The use of tocilizumab is not recommended if there are AST/ALT values greater than 10 times the upper limit of normal, neutrophils <500 cells/mm3, sepsis due to other pathogens other than SARS-CoV-2, presence of comorbidity that can lead to a poor prognosis, complicated diverticulitis or intestinal perforation, ongoing skin infection. The dose will be that recommended by the Spanish Medicine Agency in patients ≥75Kg: 600mg dose whereas in patients <75kg: 400mg dose. Exceptionally, a second infusion can be assessed 12 hours after the first in those patients who experience a worsening of laboratory parameters after a first favourable response. The use of corticosteroids will be recommended in patients who have had symptoms for more than 7 days and who meet all the following criteria: need for oxygen support, non-invasive or invasive mechanical ventilation, acute respiratory failure or rapid deterioration of gas exchange, appearance or worsening of bilateral alveolar-interstitial infiltrates at the radiological level. In case of indication, it is recommended: dexamethasone 6mg/d p.o. or iv for 10 days or methylprednisolone 32mg/d orally or 30mg iv for 10 days or prednisone 40mg day p.o. for 10 days. MAIN OUTCOMES: Phase 1 part: to describe the toxicity profile of baricitinib in COVID19 oncological patients during the 5-7 day treatment period and until day +14 or discharge (whichever it comes first). Phase 2 part: to describe the number of patients in the experimental arm that will not require mechanical oxygen support compared to the standard of care arm until day +14 or discharge (whichever it comes first). RANDOMISATION: For the phase 2 of the study, the allocation ratio will be 1:1. Randomization process will be carried out electronically through the REDcap platform ( https://www.project-redcap.org/ ) BLINDING (MASKING): This is an open label study. No blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first part of the study (safety run-in cohort) will consist in the enrollment of 6 to 12 patients. In this population, we will test the toxicity of the experimental treatment. An incidence of severe adverse events grade 3-4 (graded by Common Terminology Criteria for Adverse Events v.5.0) inferior than 33% will be considered sufficient to follow with the next part of the study. The second part of the study we will perform an interim analysis of efficacy at first 64 assessed patients and a definitive one will analyze 128 assessed patients. Interim and definitive tests will be performed considering in both cases an alpha error of 0.05. We consider for the control arm this rate is expected to be 0.60 and for the experimental arm of 0.80. Considering this data, a superiority test to prove a difference of 0.20 with an overall alpha error of 0.10 and a beta error of 0.2 will be performed. Considering a 5% of dropout rate, it is expected that a total of 136 patients, 68 for each study arm, will be required to complete study accrual. TRIAL STATUS: Version 5.0. 14th October 2020 Recruitment started on the 16th of December 2020. Expected end of recruitment is June 2021. TRIAL REGISTRATION: AEMPs: 20-0356 EudraCT: 2020-001789-12, https://www.clinicaltrialsregister.eu/ctr-search/search (Not publically available as Phase I trial) Clinical trials: BARCOVID19, https://www.clinicaltrials.gov/ (In progress) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol."


Subject(s)
Antiviral Agents/adverse effects , Azetidines/adverse effects , COVID-19/drug therapy , Hematologic Neoplasms/complications , Purines/adverse effects , Pyrazoles/adverse effects , Respiratory Insufficiency/prevention & control , SARS-CoV-2/genetics , Sulfonamides/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/epidemiology , COVID-19/mortality , COVID-19/virology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Cohort Studies , Female , Hematologic Neoplasms/epidemiology , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Oxygen Inhalation Therapy , Randomized Controlled Trials as Topic , Real-Time Polymerase Chain Reaction , Respiratory Insufficiency/epidemiology , Spain/epidemiology , Treatment Outcome , Young Adult
14.
eNeurologicalSci ; 22: 100327, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1065074

ABSTRACT

Patients infected with COVID-19 virus, show a highly variable symptomatology which can include central nervous system (CNS) dysfunction. One of the most disabling CNS manifestations is persistent severe encephalopathy seen for weeks after the resolution of the acute viral pneumonia and associated acute systemic illnesses. The precise pathophysiology of this persistent Post COVID Encephalopathy is unknown but may involve direct viral invasion of microvascular endothelium, microvascular thrombosis, toxic neuronal effects of inflammatory products, vasoactive pathology at arteriolar level or leptomeningeal inflammation. Currently, there are no established specific treatments for Post COVID -19 encephalopathy. We present a case series of three patients that underwent Therapeutic Plasma Exchange (TPE) with salinized albumin that suggests a positive therapeutic effect. We believe that the results warrant further evaluation for the role of TPE with a prospective randomized trial in persistent Post COVID -19 encephalopathy syndrome.

15.
Int J Nanomedicine ; 16: 539-560, 2021.
Article in English | MEDLINE | ID: covidwho-1058334

ABSTRACT

The newly emerged ribonucleic acid (RNA) enveloped human beta-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection caused the COVID-19 pandemic, severely affects the respiratory system, and may lead to death. Lacking effective diagnostics and therapies made this pandemic challenging to manage since the SARS-CoV-2 transmits via human-to-human, enters via ACE2 and TMPSSR2 receptors, and damages organs rich in host cells, spreads via symptomatic carriers and is prominent in an immune-compromised population. New SARS-CoV-2 informatics (structure, strains, like-cycles, functional sites) motivated bio-pharma experts to investigate novel therapeutic agents that act to recognize, inhibit, and knockdown combinations of drugs, vaccines, and antibodies, have been optimized to manage COVID-19. However, successful targeted delivery of these agents to avoid off-targeting and unnecessary drug ingestion is very challenging. To overcome these obstacles, this mini-review projects nanomedicine technology, a pharmacologically relevant cargo of size within 10 to 200 nm, for site-specific delivery of a therapeutic agent to recognize and eradicate the SARS-CoV-2, and improving the human immune system. Such combinational therapy based on compartmentalization controls the delivery and releases of a drug optimized based on patient genomic profile and medical history. Nanotechnology could help combat COVID-19 via various methods such as avoiding viral contamination and spraying by developing personal protective equipment (PPE) to increase the protection of healthcare workers and produce effective antiviral disinfectants surface coatings capable of inactivating and preventing the virus from spreading. To quickly recognize the infection or immunological response, design highly accurate and sensitive nano-based sensors. Development of new drugs with improved activity, reduced toxicity, and sustained release to the lungs, as well as tissue targets; and development of nano-based immunizations to improve humoral and cellular immune responses. The desired and controlled features of suggested personalized therapeutics, nanomedicine, is a potential therapy to manage COVID-19 successfully. The state-of-the-art nanomedicine, challenges, and prospects of nanomedicine are carefully and critically discussed in this report, which may serve as a key platform for scholars to investigate the role of nanomedicine for higher efficacy to manage the COVID-19 pandemic.


Subject(s)
COVID-19/therapy , COVID-19/virology , Nanomedicine/trends , SARS-CoV-2/physiology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , Humans , Nanotechnology , Pandemics/prevention & control , SARS-CoV-2/drug effects
16.
Eur J Med Chem ; 214: 113233, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1056562

ABSTRACT

With Remdesivir being approved by FDA as a drug for the treatment of Corona Virus Disease 2019 (COVID-19), nucleoside drugs have once again received widespread attention in the medical community. Herein, we summarized modification of traditional nucleoside framework (sugar + base), traizole nucleosides, nucleoside analogues assembled by other drugs, macromolecule-modified nucleosides, and their bioactivity rules. 2'-"Ara"-substituted by -F or -CN group, and 3'-"ara" substituted by acetylenyl group can greatly influence their anti-tumor activities. Dideoxy dehydrogenation of 2',3'-sites can enhance antiviral efficiencies. Acyclic nucleosides and L-type nucleosides mainly represented antiviral capabilities. 5-F Substituted uracil analogues exihibit anti-tumor effects, and the substrates substituted by -I, -CF3, bromovinyl group usually show antiviral activities. The sugar coupled with 1-N of triazolid usually displays anti-tumor efficiencies, while the sugar coupled with 2-N of triazolid mainly represents antiviral activities. The nucleoside analogues assembled by cholesterol, polyethylene glycol, fatty acid and phospholipid would improve their bioavailabilities and bioactivities, or reduce their toxicities.


Subject(s)
Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Nucleosides/chemistry
17.
Viruses ; 13(1)2020 12 23.
Article in English | MEDLINE | ID: covidwho-1044046

ABSTRACT

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 µM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 µM enoxacin and 600 µM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 µM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Fluoroquinolones/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , SARS-CoV-2/drug effects , A549 Cells , Angiotensin-Converting Enzyme 2 , Animals , Cell Line , Chlorocebus aethiops , Ciprofloxacin/pharmacology , Enoxacin/pharmacology , Humans , Levofloxacin/pharmacology , Moxifloxacin/pharmacology , Vero Cells
18.
J Tradit Complement Med ; 11(2): 158-172, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1009709

ABSTRACT

BACKGROUND AND AIM: Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become the world pandemic. There is a race to develop suitable drugs and vaccines for the disease. The anti-HIV protease drugs are currently repurposed for the potential treatment of COVID-19. The drugs were primarily screened against the SARS-CoV-2 main protease. With an urgent need for safe and effective drugs to treat the virus, we have explored natural products isolated from edible and medicinal mushrooms that have been reported to possess anti-HIV protease. EXPERIMENTAL PROCEDURES: We have examined 36 compounds for their potential to be SARS-CoV-2 main protease inhibitors using molecular docking study. Moreover, drug-likeness properties including absorption, distribution, metabolism, excretion and toxicity were evaluated by in silico ADMET analysis. RESULTS: Our AutoDock study showed that 25 of 36 candidate compounds have the potential to inhibit the main viral protease based on their binding affinity against the enzyme's active site when compared to the standard drugs. Interestingly, ADMET analysis and toxicity prediction revealed that 6 out of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F and velutin. CONCLUSION: Our study highlights the potential of existing mushroom-derived natural compounds for further investigation and possibly can be used to fight against SARS-CoV-2 infection. TAXONOMY CLASSIFICATION BY EVISE: Disease, Infectious Disease, Respiratory System Disease, Covid-19, Traditional Medicine, Traditional Herbal Medicine, Phamaceutical Analysis.

19.
Best Pract Res Clin Rheumatol ; 35(1): 101658, 2021 03.
Article in English | MEDLINE | ID: covidwho-1002351

ABSTRACT

A variety of treatment modalities have been investigated since the beginning of the Coronavirus Disease-19 (COVID-19) pandemic. The use of antimalarials (hydroxychloroquine and chloroquine) for COVID-19 treatment and prevention has proven to be a cautionary tale for widespread, off-label use of a medication during a crisis. The investigation of antimalarials for COVID-19 has also been a driver for a deluge of scientific output in a short amount of time. In this narrative review, we detail the evidence for and against antimalarial use in COVID-19, starting with the early small observational studies that influenced strategies worldwide. We then contrast these findings to later published larger observational studies and randomized controlled trials. We detail the emerging possible cardiovascular risks associated with antimalarial use in COVID-19 and whether COVID-19-related outcomes and cardiovascular risks may differ for antimalarials used in rheumatic diseases.


Subject(s)
Antiviral Agents , COVID-19 , Cardiotoxicity , Coronavirus Infections , Hydroxychloroquine , Antiviral Agents/adverse effects , COVID-19/drug therapy , Humans , Hydroxychloroquine/adverse effects , SARS-CoV-2
20.
J Microsc Ultrastruct ; 8(4): 136-140, 2020.
Article in English | MEDLINE | ID: covidwho-1000433

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) has been widely investigated for the treatment of COVID-19. Although it is rare, several case reports of acute toxicity of HCQ due to overdose have been reported during the last two decades. The aim of this review is to summarize the management options of acute HCQ toxicity. METHODS: A literature review that was conducted using an electronic search in the Google Scholar search engine. The inclusion criteria include any patient over 12 years old presenting with HCQ intoxication symptoms from January 1999 to January 2020. RESULTS: Sixteen cases were found that have the inclusion criteria of this study. Most patients presented with altered mental status, electrocardiogram abnormalities, visual disturbance, and decrease cardiac output. Activated charcoal was the first line of management in nearly two-thirds of patients whereas 93.8% received fluid resuscitation and 81.3% of the patients need at least one type of vasopressor agent. Furthermore, potassium is given for 93.8% of the patient while 75% of the patients need sodium bicarbonate and intubation, lipid emulsion was used in three patients only and 13 patients survived. CONCLUSION: The acute HCQ toxicity may result during the treatment period of COVID-19. The most common options can use in this situation include included gastric lavage and decontamination, IV fluid resuscitation, potassium replacement, sodium bicarbonate, intravenous lipid emulsion, and extracorporeal circulation membrane oxygenation. The role of diazepam is not clear but can be used in the significant toxicity while hyperkalemia associated with severe ingestions.

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