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1.
World Neurosurg ; 157: e357-e363, 2022 01.
Article in English | MEDLINE | ID: covidwho-1757929

ABSTRACT

BACKGROUND: Prior studies demonstrated reduced risk for venous thromboembolism (VTE) in neurosurgical patients secondary to prophylaxis with both heparin and low-molecular-weight heparin. The ability to monitor low-molecular-weight heparin by obtaining anti-factor Xa (anti-Xa) serum levels provides an opportunity to evaluate safety and efficacy. The aim of this study was to describe characteristics of patients who have anti-Xa levels outside of the goal range (0.2-0.4/0.5 IU/mL) and investigate incidence of major bleeding and VTE. METHODS: A single-center, retrospective, observational study was conducted on neurosurgical patients receiving enoxaparin for VTE prophylaxis between August 2019 and December 2020. Significance testing was conducted via Fisher exact test and independent samples t test. RESULTS: The study included 85 patients. Patients were less likely to have an anti-Xa level in the goal range if they were male, had a higher weight, or were morbidly obese. Three neuroendovascular patients (3.5%) experienced a major bleed. Serum anti-Xa levels were significantly higher in patients who experienced major bleeds compared with patients who did not (0.45 ± 0.16 IU/mL vs. 0.28 ± 0.09 IU/mL, P = 0.003). Patients with a supraprophylactic anti-Xa level (>0.5 IU/mL) were more likely to experience a major bleed (P = 0.005). One VTE event occurred: the patient experienced a pulmonary embolism with anti-Xa level at goal. CONCLUSIONS: Anti-Xa-guided enoxaparin dosing for VTE prophylaxis in neurosurgical patients may help prevent major bleeding. These data suggest that a higher anti-Xa level may predispose patients to major bleeding. Further evaluation is needed to identify the goal anti-Xa level for VTE prophylaxis in this population.


Subject(s)
Enoxaparin/blood , Factor Xa Inhibitors/blood , Hemorrhage/blood , Neurosurgical Procedures/trends , Pre-Exposure Prophylaxis/trends , Adult , Aged , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/blood , Drug Monitoring/methods , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/prevention & control , Humans , Male , Middle Aged , Obesity, Morbid/blood , Obesity, Morbid/surgery , Pre-Exposure Prophylaxis/methods , Retrospective Studies , Sex Factors , Venous Thromboembolism/blood , Venous Thromboembolism/prevention & control
2.
Eur J Pharmacol ; 914: 174615, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1549762

ABSTRACT

In this study, the therapeutic efficacy of quercetin in combination with remdesivir and favipiravir, were evaluated in severe hospitalized COVID-19 patients. Our main objective was to assess the ability of quercetin for preventing the progression of the disease into critical phase, and reducing the levels of inflammatory markers related to SARS-Cov-2 pathogenesis. Through an open-label clinical trial, 60 severe cases were randomly divided into control and intervention groups. During a 7-day period, patients in the control group received antivirals, i.e., remdesivir or favipiravir, while the intervention group was treated with 1000 mg of quercetin daily in addition to the antiviral drugs. According to the results, taking quercetin was significantly associated with partial earlier discharge and reduced serum levels of ALP, q-CRP, and LDH in the intervention group. Furthermore, although the values were in normal range, the statistical outputs showed significant increase in hemoglobin level and respiratory rate in patients who were taking quercetin. Based on our observations, quercetin is safe and effective in lowering the serum levels of ALP, q-CRP, and LDH as critical markers involved in COVID-19 severity. However, according to the non-significant borderline results in comparing the mortality, the ICU-admission rate, and the duration of ICU-admission, further studies can be helpful to compensate the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides , COVID-19 , Pyrazines , Quercetin , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Alanine/administration & dosage , Alanine/adverse effects , Amides/administration & dosage , Amides/adverse effects , Antioxidants/administration & dosage , Antioxidants/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Biomarkers/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , Drug Monitoring/methods , Drug Monitoring/statistics & numerical data , Female , Hemoglobins/analysis , Humans , Male , Middle Aged , Outcome and Process Assessment, Health Care , Patient Discharge/statistics & numerical data , Pyrazines/administration & dosage , Pyrazines/adverse effects , Quercetin/administration & dosage , Quercetin/adverse effects , Respiratory Rate/drug effects
3.
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
4.
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
5.
PLoS One ; 16(11): e0260656, 2021.
Article in English | MEDLINE | ID: covidwho-1533423

ABSTRACT

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.


Subject(s)
Antifungal Agents/administration & dosage , Critical Illness/therapy , Drug Monitoring/methods , Drug-Related Side Effects and Adverse Reactions/epidemiology , Intensive Care Units/statistics & numerical data , Voriconazole/administration & dosage , Antifungal Agents/adverse effects , Female , France/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors , Voriconazole/adverse effects
6.
Int J Lab Hematol ; 44(2): 399-406, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1511317

ABSTRACT

INTRODUCTION: The Summary of Product Characteristics for the direct thrombin inhibitor argatroban states monitoring should be by activated partial thromboplastin time (APTT), with a target range of 1.5-3.0 times the patients' baseline APTT. APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Previous studies have shown sensitivity differences of APTT reagents to argatroban. Some recent publications have favoured the use of anti-IIa methods to determine the plasma drug concentration of argatroban. This study aims to compare the anti-IIa assays: Hemoclot thrombin inhibitor assay (HTI) and Ecarin chromogenic assay (ECA) alongside the APTT. METHODS: Residual plasma of 25 samples from 8 patients (3 with COVID-19 and HIT: n = 18, 5 with HIT: n = 7) was tested at two sites: site A: Sysmex CS5100 by HTI and APTT (Actin FS and SynthASil), and also on Stago STA Compact Max: ECA and APTT (CK Prest); and site B: Stago STA R Max 2 by ECA and APTT (Cephascreen). RESULTS: Mean APTT ratio was 1.96 (Actin FS), 1.84 (SynthASil), 1.59 (CK Prest) and 2.48 (Cephascreen). Mean argatroban concentration by HTI was 0.60 µg/mL and by ECA was 0.65 µg/mL (site A) and 0.70 µg/mL (site B). There was a poor correlation to HTI in APTT ratios (range r2  = .0235-0.4181) with stronger correlations between ECA methods to HTI (r2  = .8998 site A, r2  = .8734 site B). CONCLUSION: This study confirms previous publications on the unsuitability of APTT and expands this by being multisited and included APTT reagents that use mechanical clot detection. Both anti-IIa methods are more suitable.


Subject(s)
COVID-19 , Thrombocytopenia , Anticoagulants/adverse effects , Arginine/analogs & derivatives , Drug Monitoring/methods , Heparin/adverse effects , Humans , Partial Thromboplastin Time , Pipecolic Acids/pharmacology , Sulfonamides , Thrombocytopenia/chemically induced
7.
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
8.
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
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.
J Crohns Colitis ; 16(2): 190-198, 2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1319160

ABSTRACT

BACKGROUND AND AIMS: Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling [fingerPRICKS] compared to conventional venepuncture. METHODS: We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire. RESULTS: Therapeutic drug monitoring requests for adalimumab (96.5 [70.5-106] per week to 52 [33.5-57.0], p < 0.001) but not infliximab (184.5 [161.2-214.2] to 161 [135-197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding 6 months. Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab and ustekinumab drug, and anti-adalimumab and anti-infliximab antibody levels. The median [interquartile range] volume of serum obtained using intracapillary sampling was 195 µL [130-210]. More than 87% [90/103] of patients agreed that intracapillary testing was easy and 69% [71/103] preferred it to conventional venepuncture. In routine care, 75.3% [58/77] of patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring. CONCLUSIONS: Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.


Subject(s)
Drug Monitoring , Inflammatory Bowel Diseases , Self-Testing , Adalimumab/therapeutic use , COVID-19 , Cross-Sectional Studies , Drug Monitoring/methods , Humans , Inflammatory Bowel Diseases/drug therapy , Infliximab/therapeutic use , Pandemics , SARS-CoV-2 , United Kingdom
11.
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
12.
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
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
14.
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
15.
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
16.
Clin Pharmacol Ther ; 110(1): 108-122, 2021 07.
Article in English | MEDLINE | ID: covidwho-1212738

ABSTRACT

Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID-19); however, well-established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID-19 to cause clinically relevant drug-drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real-world data from electronic health records, including a database representing nearly 120,000 patients with COVID-19, were consistent with several of the drugs causing transporter-mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID-19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.


Subject(s)
Antiviral Agents , COVID-19 , Drug Interactions , Drug-Related Side Effects and Adverse Reactions , Membrane Transport Proteins/metabolism , Virus Internalization/drug effects , Virus Replication/drug effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , COVID-19/virology , Clinical Trials as Topic , Drug Monitoring/methods , Drug Monitoring/standards , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/metabolism , Drug-Related Side Effects and Adverse Reactions/prevention & control , Electronic Health Records/statistics & numerical data , HEK293 Cells , Humans , Hydroxychloroquine/pharmacokinetics , Risk Assessment/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
17.
AIDS Res Hum Retroviruses ; 37(4): 297-303, 2021 04.
Article in English | MEDLINE | ID: covidwho-1207217

ABSTRACT

In the era of COVID-19, providers are delaying laboratory testing in people with HIV (PWH). The purpose of this study was to examine the clinical significance of renal, liver, and lipid testing. We reviewed the charts of 261 PWH who initiated care at an academic HIV clinic between January 1, 2016 and December 21, 2018. Analysis included one-sided binomial exact tests and multiple linear, Poisson, and Beta regression models. The most common abnormality was a glomerular filtration rate (GFR) <60 mL/min (10%). Age <40 years [estimated relative rate (rr) 0.017, 95% confidence interval (CI) 0.207 to 0.494], cobicistat (rr 0.284, 95% CI 0.128 to 0.63), and tenofovir alafenamide (rr 0.295 95% CI 0.151 to 0.573) were associated with a decreased risk of GFR <60 mL/min. An increased AST and ALT ≥2 × upper limit of normal (ULN) was found in 5% and 3%, respectively. Hepatitis C and use of darunavir and lopinavir were associated with increased AST or ALT. When a GFR was <60 mL/min or an AST or ALT was ≥2 × ULN, no action was taken in 53% of cases. In 18% of cases the only intervention was repeat testing. The most common interventions after lipid results were calculation of a 10-year cardiovascular risk score (31%) and addition of a statin (18%). Taking action after lipid results was strongly associated with age ≥40 (rr 7.37, 95% CI 3.0 to 18.3). Young PWH without hepatitis C rarely have renal, liver, or lipid test results that alter clinical care. Decreased testing should be considered.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/epidemiology , Drug Monitoring/methods , HIV Infections/drug therapy , Adult , Aged , Female , Glomerular Filtration Rate , HIV Infections/physiopathology , Humans , Lipids/blood , Liver Function Tests , Male , Middle Aged , Young Adult
18.
Ther Drug Monit ; 43(4): 455-458, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1205884

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
19.
JAMA Netw Open ; 4(4): e216468, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1196363

ABSTRACT

Importance: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. Objective: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. Design, Setting, and Participants: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Interventions: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. Main Outcomes and Measures: The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Results: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. Conclusions and Relevance: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19-associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04403100.


Subject(s)
COVID-19 , Early Medical Intervention , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Ritonavir/administration & dosage , Antiviral Agents/administration & dosage , Brazil/epidemiology , COVID-19/epidemiology , COVID-19/therapy , Drug Monitoring/methods , Drug Monitoring/statistics & numerical data , Drug Therapy, Combination/methods , Early Medical Intervention/methods , Early Medical Intervention/statistics & numerical data , Female , Hospitalization/statistics & numerical data , Humans , Male , Medical Futility , Middle Aged , Risk Adjustment/methods , Symptom Assessment/methods , Treatment Outcome
20.
Int J Lab Hematol ; 43(6): 1284-1290, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1186165

ABSTRACT

INTRODUCTION: Patients with COVID-19 frequently exhibit a hypercoagulable state with high thrombotic risk, particularly those admitted to intensive care units (ICU). Thromboprophylaxis is mandatory in these patients; nevertheless, thrombosis still occurs in many cases. Thus, the problem of assessing an adequate level of anticoagulation in ICU patients becomes evident during the COVID-19 pandemic. The aim of this study was to evaluate the heparin resistance and the efficacy of heparin monitoring using an anti-Xa activity assay. METHODS: Thirty-seven heparin-treated patients admitted to ICU for SARS-CoV-2 pneumonia were retrospectively studied for antifactor Xa activity (anti-Xa), activated partial thromboplastin time (APTT), Antithrombin, Fibrinogen, D-Dimer, Factor VIII, von Willebrand Factor, and the total daily amount of heparin administered. The correlation between APTT and anti-Xa was evaluated for unfractionated heparins (UFH). The correlations between the daily dose of UFH or the dosage expressed as IU/kg b.w. for low molecular weight heparin (LMWH) and anti-Xa were also evaluated. RESULTS: Twenty-one patients received calcium heparin, 8 sodium heparin, and 8 LMWH. A moderate correlation was found between APTT and anti-Xa for UFH. APTT did not correlate with coagulation parameters. 62% of UFH and 75% of LMWH treated patients were under the therapeutic range. About 75% of patients could be considered resistant to heparin. CONCLUSIONS: SARS-COV2 pneumonia patients in ICU have frequently heparin resistance. Anti-Xa seems a more reliable method to monitor heparin treatment than APTT in acute patients, also because the assay is insensitive to the increased levels of fibrinogen, FVIII, and LAC that are common during the COVID-19 inflammatory state.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/blood , Drug Monitoring/methods , Heparin/therapeutic use , Intensive Care Units , Pandemics , SARS-CoV-2 , Thrombophilia/drug therapy , Aged , Anticoagulants/administration & dosage , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Comorbidity , Diabetes Mellitus/epidemiology , Drug Resistance , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/therapeutic use , Female , Heparin/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Male , Middle Aged , Partial Thromboplastin Time , Respiratory Tract Diseases/epidemiology , Retrospective Studies , Thrombophilia/blood , Thrombophilia/etiology , Thrombosis/epidemiology , Thrombosis/etiology , Thrombosis/prevention & control
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