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1.
Lancet Respir Med ; 9(5): 522-532, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537199

ABSTRACT

BACKGROUND: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. METHODS: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. FINDINGS: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1·7 [-9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [-6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI -7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. INTERPRETATION: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FUNDING: Sanofi and Regeneron Pharmaceuticals.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , International Cooperation , Male , Middle Aged , Mortality , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
2.
Lancet Respir Med ; 9(5): 511-521, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537197

ABSTRACT

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , India , Male , Middle Aged , Mortality , Respiration, Artificial/methods , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
3.
Open Heart ; 8(2)2021 11.
Article in English | MEDLINE | ID: covidwho-1523054

ABSTRACT

BACKGROUND: Early in the COVID-19 pandemic, the National Health Service (NHS) recommended that appropriate patients anticoagulated with warfarin should be switched to direct-acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately coprescribed two anticoagulants following a medication change and associated monitoring. OBJECTIVE: To describe which people were switched from warfarin to DOACs; identify potentially unsafe coprescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. METHODS: With the approval of NHS England, we conducted a cohort study using routine clinical data from 24 million NHS patients in England. RESULTS: 20 000 of 164 000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in coprescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. International normalised ratio (INR) testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). CONCLUSIONS: Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people coprescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.


Subject(s)
Anticoagulants/administration & dosage , Blood Coagulation/drug effects , COVID-19 , Drug Substitution/standards , Factor Xa Inhibitors/administration & dosage , Practice Guidelines as Topic/standards , Practice Patterns, Physicians'/standards , State Medicine/standards , Warfarin/administration & dosage , Aged , Anticoagulants/adverse effects , Blood Coagulation Tests , Drug Monitoring , Drug Prescriptions , Drug Substitution/adverse effects , Drug Utilization/standards , England , Factor Xa Inhibitors/adverse effects , Female , Humans , Male , Middle Aged , Patient Safety , Primary Health Care/standards , Retrospective Studies , Risk Assessment , Risk Factors , Warfarin/adverse effects
4.
Mayo Clin Proc ; 95(6): 1213-1221, 2020 06.
Article in English | MEDLINE | ID: covidwho-1450185

ABSTRACT

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.


Subject(s)
Death, Sudden, Cardiac , Hydroxychloroquine , Long QT Syndrome , Lopinavir , Risk Adjustment/methods , Ritonavir , Torsades de Pointes , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/adverse effects , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Drug Combinations , Drug Monitoring/methods , Drug Repositioning/ethics , Drug Repositioning/methods , Electrocardiography/methods , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/mortality , Long QT Syndrome/therapy , Lopinavir/administration & dosage , Lopinavir/adverse effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Torsades de Pointes/chemically induced , Torsades de Pointes/mortality , Torsades de Pointes/therapy
5.
Lancet Respir Med ; 9(8): 924-932, 2021 08.
Article in English | MEDLINE | ID: covidwho-1413874

ABSTRACT

BACKGROUND: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.


Subject(s)
COVID-19 , Colchicine , Administration, Oral , Ambulatory Care/methods , Ambulatory Care/statistics & numerical data , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , Colchicine/administration & dosage , Colchicine/adverse effects , Double-Blind Method , Drug Monitoring/methods , Female , Hospitalization/statistics & numerical data , Humans , Intention to Treat Analysis , Male , Middle Aged , Outcome Assessment, Health Care , Risk Assessment , SARS-CoV-2/isolation & purification
7.
Int Immunopharmacol ; 99: 108043, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1370550

ABSTRACT

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 h 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.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cyclosporine/therapeutic use , Pyrazines/therapeutic use , Adult , Aged , Aged, 80 and over , Dexamethasone/therapeutic use , Drug Monitoring , Drug Therapy, Combination , Female , Humans , Intensive Care Units , Male , Middle Aged , Pandemics , Prospective Studies , Respiration, Artificial , SARS-CoV-2 , Treatment Outcome , Young Adult
8.
J Am Geriatr Soc ; 69(11): 3023-3033, 2021 11.
Article in English | MEDLINE | ID: covidwho-1367342

ABSTRACT

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.


Subject(s)
COVID-19/drug therapy , Cellular Senescence/drug effects , Flavonols/therapeutic use , Skilled Nursing Facilities , Aged , COVID-19/prevention & control , Clinical Trials as Topic , Drug Monitoring , Humans
9.
BMC Pulm Med ; 21(1): 268, 2021 Aug 17.
Article in English | MEDLINE | ID: covidwho-1362052

ABSTRACT

BACKGROUND: Curcumin, a derivative of the spice turmeric, has been adopted by Eastern medicine for centuries as an adjunct to treat several medical conditions (e.g., anorexia and arthritis) because of its well-established anti-inflammatory properties. Studies have shown that the use of curcumin in mice models has led to reduction in several inflammatory markers as well as key inflammatory pathway enzymes. As a result, studies in Western medicine have developed to determine if this recognized benefit can be utilized for patients with inflammatory lung diseases, such as asthma. This study will seek to better understand if curcumin can be used as an adjunctive therapy for improving asthma control of patients with moderate to severe asthma; a finding we hope will allow for a more affordable treatment. METHODS: This study will utilize a randomized, placebo controlled, double blinded pilot superiority phase 2 trial at an outpatient pulmonary clinic in Southern California, USA. Subjects will be receiving Curcumin 1500 mg or matching placebo by mouth twice daily for the study period of 12 weeks. Subjects will be randomized to either a placebo or intervention Curcumin. Subjects will have 6 clinic visits: screening visit, a baseline visit, monthly clinic visits (weeks 4, 8, and 12), at weeks 4, 8, and a follow-up clinic visit or phone-call (week 16). Changes in asthma control test scores, number of days missed from school/work, FEV1 (% predicted), FEV1/FVC ratio, FVC (% predicted), blood eosinophil count, blood total IgE, and FeNO levels will be compared by group over time. DISCUSSION: The therapeutic effects of curcumin have been studied on a limited basis in asthmatics and has shown mixed results thus far. Our study hopes to further establish the benefits of curcumin, however, there are potential issues that may arise from our study design that we will address within this paper. Moreover, the onset of the COVID-19 pandemic has resulted in safety concerns that have delayed initiation of our study. This study will contribute to existing literature on curcumin's role in reducing lung inflammation as it presents in asthmatics as well as patients suffering from COVID-19. TRIAL REGISTRATION: This study protocol has been approved by the Institutional Review Board at Loma Linda University Health, (NCT04353310). IND# 145101 Registered April 20th, 2020. https://clinicaltrials.gov/ct2/show/NCT04353310 .


Subject(s)
Asthma , COVID-19 , Curcumin , Eosinophils , Immunoglobulin E/blood , Administration, Oral , Adult , Ambulatory Care/methods , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Antioxidants/administration & dosage , Antioxidants/adverse effects , Asthma/blood , Asthma/diagnosis , Asthma/drug therapy , Asthma/physiopathology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/physiopathology , Clinical Trials, Phase II as Topic , Curcumin/administration & dosage , Curcumin/adverse effects , Double-Blind Method , Drug Monitoring/methods , Female , Humans , Leukocyte Count/methods , Male , Randomized Controlled Trials as Topic , SARS-CoV-2/isolation & purification , Severity of Illness Index
10.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1305444

ABSTRACT

ABSTRACT: In this article, we present a case of apixaban elimination prolonged by 450% in a patient with coronavirus disease 2019 because of multiple conditions, including drug-drug interaction, severe inflammation, and acute kidney injury. Therapeutic drug monitoring was used to explain unusual routine coagulation assays. This grand round highlights the importance of dialog between the clinician and a therapeutic drug monitoring consultant for optimal patient care.


Subject(s)
Acute Kidney Injury/metabolism , COVID-19/metabolism , Drug Monitoring/methods , Pyrazoles/metabolism , Pyridones/metabolism , Renal Elimination/drug effects , Teaching Rounds/methods , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Aged, 80 and over , Antiviral Agents/adverse effects , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Interactions/physiology , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/metabolism , Factor Xa Inhibitors/therapeutic use , Humans , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/prevention & control , Male , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridones/adverse effects , Pyridones/therapeutic use , Renal Elimination/physiology , Severity of Illness Index , Time Factors
11.
Ther Drug Monit ; 43(4): 570-576, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1305442

ABSTRACT

ABSTRACT: Therapeutic drug monitoring of hydroxychloroquine (HCQ) has been recommended to optimize the treatment of patients with COVID-19. The authors describe an ultrahigh-performance liquid chromatography tandem spectrometry method developed in a context of emergency, to analyze HCQ in both human plasma and blood samples. After adding the labeled internal standard and simple protein precipitation, plasma samples were analyzed using a C18 column. Blood samples required evaporation before analysis. The total chromatographic run time was 4 minutes (including 1.5 minutes of column equilibration). The assay was linear over the calibration range (r2 > 0.99) and up to 1.50 mcg/mL for the plasma samples (5.00 mcg/mL for the blood matrix). The limit of quantification was 0.0150 mcg/mL for plasma samples (0.05 mcg/mL blood matrix) with accuracy and precision ranging from 91.1% to 112% and from 0.750% to 11.1%, respectively. Intraday and interday precision and accuracy values were within 15.0%. No significant matrix effect was observed in the plasma or blood samples. This method was successfully applied to patients treated for COVID-19 infection. A simple and rapid ultrahigh-performance liquid chromatography tandem spectrometry method adapted to HCQ therapeutic drug monitoring in the context of SARS-CoV-2 infection was successfully developed and validated.


Subject(s)
COVID-19/drug therapy , Drug Monitoring/standards , Emergency Medical Services/standards , Hydroxychloroquine/blood , Tandem Mass Spectrometry/standards , Antirheumatic Agents/blood , Antirheumatic Agents/therapeutic use , COVID-19/blood , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Drug Monitoring/methods , Emergency Medical Services/methods , Humans , Hydroxychloroquine/therapeutic use , Pandemics , Tandem Mass Spectrometry/methods
12.
Molecules ; 26(8)2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1302417

ABSTRACT

Two new ultra-high performance liquid chromatography (UHPLC) methods for analyzing 21 selected antivirals and their metabolites were optimized, including sample preparation step, LC separation conditions, and tandem mass spectrometry detection. Micro-solid phase extraction in pipette tips was used to extract antivirals from the biological material of Hanks balanced salt medium of pH 7.4 and 6.5. These media were used in experiments to evaluate the membrane transport of antiviral drugs. Challenging diversity of physicochemical properties was overcome using combined sorbent composed of C18 and ion exchange moiety, which finally allowed to cover the whole range of tested antivirals. For separation, reversed-phase (RP) chromatography and hydrophilic interaction liquid chromatography (HILIC), were optimized using extensive screening of stationary and mobile phase combinations. Optimized RP-UHPLC separation was carried out using BEH Shield RP18 stationary phase and gradient elution with 25 mmol/L formic acid in acetonitrile and in water. HILIC separation was accomplished with a Cortecs HILIC column and gradient elution with 25 mmol/L ammonium formate pH 3 and acetonitrile. Tandem mass spectrometry (MS/MS) conditions were optimized in both chromatographic modes, but obtained results revealed only a little difference in parameters of capillary voltage and cone voltage. While RP-UHPLC-MS/MS exhibited superior separation selectivity, HILIC-UHPLC-MS/MS has shown substantially higher sensitivity of two orders of magnitude for many compounds. Method validation results indicated that HILIC mode was more suitable for multianalyte methods. Despite better separation selectivity achieved in RP-UHPLC-MS/MS, the matrix effects were noticed while using both chromatographic modes leading to signal enhancement in RP and signal suppression in HILIC.


Subject(s)
Antiviral Agents/pharmacokinetics , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Solid Phase Microextraction , Tandem Mass Spectrometry , Antiviral Agents/chemistry , Drug Monitoring , Humans , Reproducibility of Results
13.
Lancet Respir Med ; 9(5): 498-510, 2021 05.
Article in English | MEDLINE | ID: covidwho-1301092

ABSTRACT

BACKGROUND: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. METHODS: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. FINDINGS: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. INTERPRETATION: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. FUNDING: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.


Subject(s)
Ambulatory Care/methods , COVID-19 , Interleukins , Polyethylene Glycols , SARS-CoV-2 , Viral Load/drug effects , Virus Shedding/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/immunology , Double-Blind Method , Drug Monitoring/methods , Female , Humans , Intention to Treat Analysis , Interleukins/administration & dosage , Interleukins/adverse effects , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , RNA, Viral/isolation & purification , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Treatment Outcome
15.
J Ethnopharmacol ; 279: 114367, 2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1281457

ABSTRACT

BACKGROUND: Although the rapid emergence of coronavirus disease 2019 (COVID-19) poses a considerable threat to global public health, no specific treatment is available for COVID-19. ReDuNing injection (RDN) is a traditional Chinese medicine known to exert antibacterial, antiviral, antipyretic, and anti-inflammatory effects. In addition, RDN has been recommended in the diagnosis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia by the National Health Council and the National Administration of Chinese Medicine. However, there is no information regarding its efficacy against COVID-19. AIM OF STUDY: This study was designed to determine the clinical efficacy of RDN in patients with COVID-19 and characterize its antiviral activity against SARS-CoV-2 in vitro. MATERIALS AND METHODS: A total of 50 adults with COVID-19 were included in this study, and the primary endpoint was recovery from clinical symptoms following 14 days of treatment. General improvements were defined as the disappearance of the major symptoms of infection including fever, fatigue, and cough. The secondary endpoints included the proportion of patients who achieved clinical symptom amelioration on days 7 and 10, time to clinical recovery, time to a negative nucleic acid test result, duration of hospitalization, and time to defervescence. Plaque reduction and cytopathic effect assays were also performed in vitro, and reverse-transcription quantitative PCR was performed to evaluate the expression of inflammatory cytokines (TNF-α, IP-10, MCP-1, IL-6, IFN-α, IFN-γ, IL-2 and CCL-5) during SARS-CoV-2 infection. RESULTS: The RDN group exhibited a shorter median time for the resolution of clinical symptoms (120 vs. 220 h, P < 0.0001), less time to a negative PCR test result (215 vs. 310 h, P = 0.0017), shorter hospitalization (14.8 vs. 18.5 days, P = 0.0002), and lower timeframe for defervescence (24.5 vs. 75 h, P = 0.0001) than the control group. In addition, time to improved imaging was also shorter in the RDN group than in the control group (6 vs.8.9 days, P = 0.0273); symptom resolution rates were higher in the RDN group than in the control group at 7 (96.30% vs. 39.13%, P < 0.0001) and 10 days (96.30% vs. 56.52%, P = 0.0008). No allergic reactions or anaphylactic responses were reported in this trial. RDN markedly inhibited SARS-CoV-2 proliferation and viral plaque formation in vitro. In addition, RDN significantly reduced inflammatory cytokine production in infected cells. CONCLUSIONS: RDN relieves clinical symptoms in patients with COVID-19 and reduces SARS-CoV-2 infection by regulating inflammatory cytokine-related disorders, suggestion that this medication might be a safe and effective treatment for COVID-19.


Subject(s)
COVID-19 , Cytokines/analysis , Drugs, Chinese Herbal , SARS-CoV-2 , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Nucleic Acid Testing/methods , Cell Line , China/epidemiology , Cytotoxicity Tests, Immunologic/methods , Drug Monitoring/methods , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/adverse effects , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Symptom Assessment/methods , Treatment Outcome
16.
Medicine (Baltimore) ; 100(22): e26253, 2021 Jun 04.
Article in English | MEDLINE | ID: covidwho-1258821

ABSTRACT

ABSTRACT: Pathophysiological changes are important risk factors for critically ill patients with pneumonia manifesting sub-therapeutic antibiotic exposures during empirical treatment. The effect of coronavirus disease 2019 (COVID-19) on antibiotic dosing requirements is uncertain. We aimed to determine the effect of COVID-19 on ß-lactam pharmacokinetics (PK) and PK target attainment in critically ill patients with a personalized dosing strategy.Retrospective, single-center analysis of COVID-19 ± critically ill patients with pneumonia (community-acquired pneumonia or hospital-acquired pneumonia) who received continuous infusion of a ß-lactam antibiotic with dosing personalized through dosing software and therapeutic drug monitoring. A therapeutic exposure was defined as serum concentration between (css) 4 to 8 times the EUCAST non-species related breakpoint).Data from 58 patients with pneumonia was analyzed. Nineteen patients were tested COVID-19-positive before the start of the antibiotic therapy for community-acquired pneumonia or hospital-acquired pneumonia. Therapeutic exposure was achieved in 71% of COVID-19 patients (68% considering all patients). All patients demonstrated css above the non-species-related breakpoint. Twenty percent exceeded css above the target range (24% of all patients). The median ß-lactam clearance was 49% compared to ß-lactam clearance in a standard patient without a significant difference regarding antibiotic, time of sampling or present COVID-19 infection. Median daily doses were 50% lower compared to standard bolus dosing.COVID-19 did not significantly affect ß-lactam pharmacokinetics in critically ill patients. Personalized ß-lactam dosing strategies were safe in critically ill patients and lead to high PK target attainment with less resources.


Subject(s)
COVID-19/drug therapy , beta-Lactams/administration & dosage , beta-Lactams/pharmacokinetics , Aged , Aged, 80 and over , Body Mass Index , Critical Illness , Dose-Response Relationship, Drug , Drug Monitoring , Female , Humans , Infusions, Intravenous , Male , Metabolic Clearance Rate , Middle Aged , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , beta-Lactams/economics , beta-Lactams/therapeutic use
17.
Chest ; 160(1): 74-84, 2021 07.
Article in English | MEDLINE | ID: covidwho-1258346

ABSTRACT

BACKGROUND: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. RESEARCH QUESTION: Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19? STUDY DESIGN AND METHODS: We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes. RESULTS: Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects. INTERPRETATION: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.


Subject(s)
COVID-19 , Progesterone/administration & dosage , SARS-CoV-2/isolation & purification , COVID-19/physiopathology , COVID-19/therapy , Clinical Protocols/standards , Drug Monitoring , Humans , Hypoxia/diagnosis , Hypoxia/etiology , Injections, Subcutaneous , Male , Middle Aged , Oxygen Inhalation Therapy/methods , Pilot Projects , Progestins/administration & dosage , Severity of Illness Index , Treatment Outcome
18.
Drug Test Anal ; 13(7): 1238-1248, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1258052

ABSTRACT

The outbreak of the new coronavirus disease changed the world upside down. Every day, millions of people were subjected to diagnostic testing for Covid-19, all over the world. Molecular tests helped in the diagnosis of current infection by detecting the presence of viral genome whereas serological tests helped in detecting the presence of antibody in blood as well as contributed to vaccine development. This testing helped in understanding the immunogenicity, community prevalence, geographical spread and conditions post-infection. However, with the contagious nature of the virus, biological specimen sampling involved the risk of transmission and spread of infection. Clinic or pathology visit was the most concerning part. Trained personnel and resources was another barrier. In this scenario, microsampling played an important role due to its most important advantage of remote, contactless, small volume and self-sampling. Minimum requirements for sample storage and ease of shipment added value in this situation. The highly sensitive instruments and validated assay formats assured the accuracy of results and stability of samples. Microsampling techniques are contributing effectively to the Covid-19 pandemic by reducing the demand for clinical staff in population-level testing. The validated and established applications supported the use of microsampling in diagnosis, therapeutic drug monitoring, development of treatment or vaccines and clinical trials for Covid-19.


Subject(s)
COVID-19 Testing , COVID-19/diagnosis , Specimen Handling , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19 Vaccines/therapeutic use , Clinical Trials as Topic , Drug Monitoring , Humans , Population Surveillance , Predictive Value of Tests
19.
J Clin Pharmacol ; 61(11): 1406-1414, 2021 11.
Article in English | MEDLINE | ID: covidwho-1241509

ABSTRACT

Glucocorticoids are frequently prescribed in inflammatory diseases and have recently experienced a boom in the treatment of COVID-19. Small studies have shown an effect of glucocorticoids on inflammatory marker levels, but definitive proof is lacking. We investigated the influence of prednisone on inflammatory biomarkers in a previous multicenter, randomized, placebo-controlled trial that compared a 7-day treatment course of 50-mg prednisone to placebo in patients hospitalized with community-acquired pneumonia. We compared levels of C-reactive protein (CRP), procalcitonin (PCT), leukocyte and neutrophil count between patients with and without glucocorticoid treatment at baseline and on days 3, 5, and 7 and at discharge by Wilcoxon tests and analysis of variance. A total of 356 patient data sets in the prednisone group and 355 in the placebo group were available for analysis. Compared to placebo, use of prednisone was associated with reductions in levels of CRP on days 3, 5, and 7 (mean difference of 46%, P < .001 for each time point). For PCT, no such difference was observed. Leukocyte and neutrophil count were higher in the prednisone group at all time points (mean difference of 27% for leukocytes and 33% for neutrophils, P <.001 for all time points). We conclude that after administration of glucocorticoids in community-acquired pneumonia, patients had lower CRP levels and increased leukocyte and neutrophil count as compared to the placebo group. PCT levels were not different between treatment groups. PCT levels thus may more appropriately mirror the resolution of infection compared to more traditional inflammatory markers.


Subject(s)
C-Reactive Protein/analysis , COVID-19 , Community-Acquired Infections , Leukocyte Count/methods , Pneumonia , Prednisone/administration & dosage , Procalcitonin/blood , Aged, 80 and over , Analysis of Variance , Biomarkers, Pharmacological/blood , COVID-19/drug therapy , COVID-19/epidemiology , Community-Acquired Infections/drug therapy , Community-Acquired Infections/epidemiology , Drug Monitoring/methods , Female , Glucocorticoids/administration & dosage , Humans , Male , Pneumonia/blood , Pneumonia/drug therapy , Pneumonia/epidemiology , Pneumonia/etiology , SARS-CoV-2 , Statistics, Nonparametric
20.
Lupus Sci Med ; 8(1)2021 05.
Article in English | MEDLINE | ID: covidwho-1219866

ABSTRACT

INTRODUCTION: Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE. METHODS: Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study. DISCUSSION AND DISSEMINATION: Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04358302).


Subject(s)
Clinical Trials as Topic , COVID-19 , Child , Drug Monitoring , Humans , Hydroxychloroquine/therapeutic use , Lupus Erythematosus, Systemic , SARS-CoV-2 , Treatment Outcome
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