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1.
N Engl J Med ; 385(1): 11-22, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1585668

ABSTRACT

BACKGROUND: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation. RESULTS: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups. CONCLUSIONS: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).


Subject(s)
COVID-19/drug therapy , Glucocorticoids/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Systemic Inflammatory Response Syndrome/drug therapy , Adolescent , Antibodies, Viral , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Child , Child, Preschool , Cohort Studies , Confidence Intervals , Drug Therapy, Combination , Female , Hospitalization , Humans , Immunomodulation , Male , Propensity Score , Regression Analysis , Respiration, Artificial , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/mortality , Systemic Inflammatory Response Syndrome/therapy , Treatment Outcome
2.
PLoS One ; 16(12): e0261707, 2021.
Article in English | MEDLINE | ID: covidwho-1581734

ABSTRACT

The objective of this retrospective cohort study was to describe pre-treatment characteristics, treatment patterns, health resource use, and clinical outcomes among adults hospitalized with COVID-19 in the United States (US) who initiated common treatments for COVID-19. The Optum® COVID-19 electronic health records database was used to identify patients >18 years, diagnosed with COVID-19, who were admitted to an inpatient setting and received treatments of interest for COVID-19 between September 2020 and January 2021. Patients were stratified into cohorts based on index treatment use. Patient demographics, medical history, care setting, medical procedures, subsequent treatment use, patient disposition, clinical improvement, and outcomes were summarized descriptively. Among a total of 26,192 patients identified, the most prevalent treatments initiated were dexamethasone (35.4%) and dexamethasone + remdesivir (14.9%), and dexamethasone was the most common subsequent treatment. At day 14 post-index, <10% of patients received any treatments of interest. Mean (standard deviation [SD]) patient age was 65.6 (15.6) years, and the most prevalent comorbidities included hypertension (44.8%), obesity (35.4%), and diabetes (25.7%). At the end of follow-up, patients had a mean (SD) 8.1 (6.6) inpatient days and 1.4 (4.1) days with ICU care. Oxygen supplementation, non-invasive, or invasive ventilation was required by 4.5%, 3.0%, and 3.1% of patients, respectively. At the end of follow-up, 84.2% of patients had evidence of clinical improvement, 3.1% remained hospitalized, 83.8% were discharged, 4% died in hospital, and 9.1% died after discharge. Although the majority of patients were discharged alive, no treatments appeared to alleviate the inpatient morbidity and mortality associated with COVID-19. This highlights an unmet need for effective treatment options for patients hospitalized with COVID-19.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/therapeutic use , Hypertension/epidemiology , Obesity/epidemiology , Patient Discharge , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adenosine Monophosphate/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Drug Therapy, Combination/methods , Female , Follow-Up Studies , Humans , Male , Middle Aged , RNA, Viral/genetics , Retrospective Studies , Treatment Outcome , United States/epidemiology , Young Adult
3.
Pol J Vet Sci ; 23(1): 127-132, 2020 Mar.
Article in English | MEDLINE | ID: covidwho-1575092

ABSTRACT

INTRODUCTION: Effective and safe anesthesia for rodents has long been a leading concern among biomedical researchers. Intraperitoneal injection constitutes an alternative to inhalant anesthesia. PURPOSE: The aim of this study was to identify a safe, reliable, and effective anesthesia and postoperative analgesia protocol for laboratory rats exposed to painful procedures. MATERIAL AND METHODS: Twenty-seven female Wistar rats in an ongoing study that required surgery were randomized into groups for three different intraperitoneal anesthesia protocols and three different analgesia regimens. The anesthesia groups were (1) medetomidine + ketamine (MK), (2) ketamine + xylacine (KX), and (3) fentanyl + medetomidine (FM). Three analgesia groups were equally distributed among the anesthesia groups: (1) local mepivacaine + oral ibuprofen (MI), (2) oral tramadol + oral ibuprofen (TI), and (3) local tramadol + oral tramadol + + oral ibuprofen (TTI). A core was assigned to measure anesthesia (0-3) and analgesia (0-2) effectiveness; the lower the score, the more effective the treatment. RESULTS: The mean MK score was 0.44 versus 2.00 for FM and 2.33 for KX. Mean score for analgesia on the first postoperative day was TTI (4.66) TI (9.13), and MI (10.14). Mean score 48 hours after surgery was TTI (3.4), TI (6.71), and MI (9.5). These differences were statistically significant. CONCLUSION: MK was shown to be a reliable, safe, and effective method of anesthesia. The TTI analgesia regimen is strongly recommended in light of these results.


Subject(s)
Fentanyl/pharmacology , Ketamine/pharmacology , Medetomidine/pharmacology , Xylazine/pharmacology , Adjuvants, Anesthesia/administration & dosage , Adjuvants, Anesthesia/pharmacology , Anesthetics, Dissociative/administration & dosage , Anesthetics, Dissociative/pharmacology , Animals , Drug Therapy, Combination , Female , Fentanyl/administration & dosage , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacology , Ketamine/administration & dosage , Medetomidine/administration & dosage , Random Allocation , Rats , Rats, Wistar , Xylazine/administration & dosage
4.
PLoS One ; 16(3): e0248128, 2021.
Article in English | MEDLINE | ID: covidwho-1575679

ABSTRACT

BACKGROUND: The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. METHODS: Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. RESULTS: Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. CONCLUSION: Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Pandemics/prevention & control , Data Management/methods , Drug Therapy, Combination/methods , Female , Hospitalization , Humans , Male , SARS-CoV-2/drug effects
5.
J Infect Public Health ; 15(1): 56-64, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1562368

ABSTRACT

BACKGROUND: There is conflicting evidence regarding the effect of asthma and its different therapeutic options on COVID-19 severity and the clinical outcomes. AIM: This study aimed to investigate the relationship between using inhaled corticosteroids (ICS) by asthmatic patients and the severity of COVID-19. MATERIALS AND METHODS: This retrospective observational study was conducted from March 15 to October 23, 2020 and included data of all COVID-19 asthmatic patients (n = 287) at King Abdulaziz Medical City. Twelve patients were excluded due to poor medication history documentation or using ICS for non-asthma indication. Ordinal logistic regression was used to determine the clinical variables that affect COVID-19 severity. The clinical outcomes of ICS and non-ICS users were compared. RESULTS: Of the sample (n = 275), 198 (72%) were using ICS therapy. No significant difference was found between ICS and non-ICS users in disease severity (P = 0.12), mortality (P = 0.45), ICU admission (P = 0.78), and the occurrence of complications. However, the number of days on ventilation were significantly increased in ICS users (P = 0.006). Being prescribed the ICS/LABA combination (adj OR: 0.72 [0.15,1.2]; P = 0.021), being hypertensive (adj OR: 0.98 [0.28,1.6]; P = 0.006), having cancer (adj OR: 1.49 [0.12, 2.8]; P = 0.033), or having diabetes (adj OR: 0.75 [0.09, 1.4]; P = 0.024) could not increase the risk for more severe disease. CONCLUSION: Overall, ICS therapy did not alter the COVID-19 severity or mortality in asthmatic patients. The continued use of ICS during the pandemic should be encouraged to prevent asthma exacerbations.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Drug Therapy, Combination , Humans , Retrospective Studies , SARS-CoV-2 , Steroids
6.
J Med Virol ; 93(12): 6750-6759, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544329

ABSTRACT

Only a few treatments are approved for coronavirus disease-2019 (COVID-19) infections, with continuous debate about their clinical impact. Repurposing antiviral treatments might prove the fastest way to identify effective therapy. This trial aimed to evaluate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or ravidasvir (RDV) added to standard care (SOC) for patients with moderate and severe COVID-19 infection. Multicentre parallel randomized controlled open-label trial. One hundred and twenty eligible patients with moderate and severe COVID-19 infection were randomized to one of the study arms. Ten days of treatment with SOF plus DCV or RDV in addition to the standard of care compared to SOC. Follow up in 7 days. Sum of the counted symptoms at 7 and 10 days, mean change in oxygen saturation level, viral negativity, and rate of intensive care unit (ICU) admission. Compared to SOC, the SOF-DCV group experienced a significantly lower sum of the counted symptoms (fever, headache, generalized aches, or respiratory distress) combined with no evidence of deterioration (ICU admission and mechanical ventilation) on Days 7 and 10 of treatment. Oxygen saturation also significantly improved among the SOF-DCV group compared to SOC starting from Day 4. The study also showed positive trends regarding the efficacy of SOF-DCV with a lower incidence of mortality. On the other hand, adding SOF-RDV to SOC did not show significant improvements in endpoints. The results support the efficacy and safety of SOF-DCV as an add-on to SOC for the treatment of moderate to severe COVID-19 infections.


Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , COVID-19/drug therapy , Carbamates/therapeutic use , Imidazoles/therapeutic use , Pyrrolidines/therapeutic use , Sofosbuvir/therapeutic use , Valine/analogs & derivatives , Adult , Drug Therapy, Combination/methods , Female , Genotype , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , Treatment Outcome , Valine/therapeutic use
7.
J Med Virol ; 93(12): 6557-6565, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544300

ABSTRACT

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/pathology , Drug Combinations , Drug Therapy, Combination , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Oxazines/administration & dosage , Piperazines/administration & dosage , Pyridones/administration & dosage , Ritonavir/administration & dosage , Treatment Outcome
9.
Reumatol Clin (Engl Ed) ; 17(9): 491-493, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1510266

ABSTRACT

SARS-COV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Biological Factors/therapeutic use , COVID-19/drug therapy , Immunosuppressive Agents/therapeutic use , Physician's Role , Rheumatologists , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , Drug Therapy, Combination , Education, Medical, Graduate , Fellowships and Scholarships , Global Health , Humans , Immunocompromised Host , Opportunistic Infections/complications , Opportunistic Infections/drug therapy , Opportunistic Infections/immunology , Patient Care Team/organization & administration , Practice Patterns, Physicians' , Rheumatic Diseases/complications , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , Rheumatologists/education , Rheumatologists/organization & administration , Rheumatology/education , Rheumatology/methods , Rheumatology/organization & administration , Spain/epidemiology
10.
Front Immunol ; 12: 656419, 2021.
Article in English | MEDLINE | ID: covidwho-1506563

ABSTRACT

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.


Subject(s)
Antitubercular Agents/therapeutic use , Berberine/therapeutic use , Immunologic Factors/therapeutic use , Isoniazid/therapeutic use , Rifampin/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Animals , Antitubercular Agents/pharmacology , Berberine/pharmacology , Cytokines/immunology , Dendritic Cells/drug effects , Drug Therapy, Combination , Female , Humans , Immunologic Factors/pharmacology , Isoniazid/pharmacology , Lung/drug effects , Lung/immunology , Lung/microbiology , Lung/pathology , Macrophages/drug effects , Macrophages/immunology , Male , Mice, Inbred C3H , Mice, Inbred C57BL , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/growth & development , Neutrophils/drug effects , Neutrophils/immunology , Rifampin/pharmacology , Spleen/drug effects , Spleen/immunology , Spleen/microbiology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology
12.
Virol J ; 18(1): 142, 2021 07 08.
Article in English | MEDLINE | ID: covidwho-1496196

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the role of antiviral drugs in reducing the risk of developing severe illness in patients with moderate COVID-19 pneumonia. METHODS: This retrospective cohort study included 403 adult patients with moderate COVID-19 pneumonia who were admitted to Shenzhen Third People's Hospital, China. The antiviral drugs arbidol, interferon alpha-1b, lopinavir-ritonavir and ribavirin were distributed to the patients for treatment. The primary endpoint of this study was the time to develop severe illness. RESULTS: Of the 462 patients admitted, 403 had moderate COVID-19 symptoms at hospital admission and were included in this study. 90 of the 403 (22.3%) patients progressed to severe illness. The use of arbidol was associated with a lower severity rate 3.5% compared to control group 30.5%, p-value < 0.0001; the adjusted hazard ratio was 0.28 (95% CI: 0.084-0.90, p = 0.033). The use of interferon alpha-1b was associated with a lower severity rate 15.5% compared to control group 29.3%, with p-value < 0.0001; the adjusted hazard ratio was 0.30 (95% CI: 0.15-0.58, p =  0.0005). The use of lopinavir-itonavir and ribavirin did not show significant differences in adjusted regression models. Early use of arbidol within 7 days of symptom onset was significantly associated with a reduced recovery time of - 5.2 days (IQR - 3.0 to - 7.5, p = 4e-06) compared with the control group. CONCLUSION: Treatment with arbidol and interferon alpha-1b contributes to reducing the severity of illness in patients with moderate COVID-19 pneumonia. Early use of arbidol may reduce patients' recovery time.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Indoles/administration & dosage , Interferon-alpha/administration & dosage , Adult , China , Drug Therapy, Combination , Female , Hospitalization , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Treatment Outcome
13.
Medicine (Baltimore) ; 100(28): e26538, 2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1494086

ABSTRACT

ABSTRACT: Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , COVID-19/mortality , Long QT Syndrome/mortality , SARS-CoV-2 , Aged , COVID-19/virology , Chloroquine/adverse effects , Drug Therapy, Combination , Drugs, Chinese Herbal/adverse effects , Electrocardiography , Female , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Hydroxychloroquine/adverse effects , Indoles/adverse effects , Interferons/adverse effects , Long QT Syndrome/chemically induced , Lopinavir/adverse effects , Male , Middle Aged , Odds Ratio , Quinolones/adverse effects , Retrospective Studies , Ritonavir/adverse effects , Severity of Illness Index
14.
Am J Epidemiol ; 190(11): 2405-2419, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1493668

ABSTRACT

Hydroxychloroquine (HCQ) was proposed as an early therapy for coronavirus disease 2019 (COVID-19) after in vitro studies indicated possible benefit. Previous in vivo observational studies have presented conflicting results, though recent randomized clinical trials have reported no benefit from HCQ among patients hospitalized with COVID-19. We examined the effects of HCQ alone and in combination with azithromycin in a hospitalized population of US veterans with COVID-19, using a propensity score-adjusted survival analysis with imputation of missing data. According to electronic health record data from the US Department of Veterans Affairs health care system, 64,055 US Veterans were tested for the virus that causes COVID-19 between March 1, 2020 and April 30, 2020. Of the 7,193 veterans who tested positive, 2,809 were hospitalized, and 657 individuals were prescribed HCQ within the first 48-hours of hospitalization for the treatment of COVID-19. There was no apparent benefit associated with HCQ receipt, alone or in combination with azithromycin, and there was an increased risk of intubation when HCQ was used in combination with azithromycin (hazard ratio = 1.55; 95% confidence interval: 1.07, 2.24). In conclusion, we assessed the effectiveness of HCQ with or without azithromycin in treatment of patients hospitalized with COVID-19, using a national sample of the US veteran population. Using rigorous study design and analytic methods to reduce confounding and bias, we found no evidence of a survival benefit from the administration of HCQ.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hospitalization/statistics & numerical data , Hydroxychloroquine/therapeutic use , Veterans/statistics & numerical data , Aged , Aged, 80 and over , Anti-Bacterial Agents/adverse effects , Azithromycin/adverse effects , COVID-19/mortality , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/adverse effects , Intention to Treat Analysis , Machine Learning , Male , Middle Aged , Pharmacoepidemiology , Retrospective Studies , SARS-CoV-2 , Treatment Outcome , United States/epidemiology
15.
Drug Saf ; 43(7): 657-660, 2020 07.
Article in English | MEDLINE | ID: covidwho-1482335

ABSTRACT

INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.


Subject(s)
Coronavirus Infections , Drug Interactions , Drug Therapy, Combination , Hydroxychloroquine , Metformin , Pandemics , Pneumonia, Viral , Adult , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/mortality , Female , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Metformin/pharmacokinetics , Metformin/therapeutic use , Middle Aged , Pharmacovigilance , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , SARS-CoV-2
16.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1478110

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
17.
Medicine (Baltimore) ; 100(29): e26705, 2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1475905

ABSTRACT

ABSTRACT: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/therapeutic use , Methylprednisolone/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/complications , COVID-19/mortality , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Dexamethasone/administration & dosage , Drug Therapy, Combination , Female , Humans , India , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Male , Methylprednisolone/administration & dosage , Middle Aged , Retrospective Studies , Treatment Outcome
18.
Medicine (Baltimore) ; 100(30): e26641, 2021 Jul 30.
Article in English | MEDLINE | ID: covidwho-1475904

ABSTRACT

BACKGROUND: This review aims to evaluate the supportive effects of frequently used traditional Chinese medicine (TCM) for the treatment of coronavirus disease 2019 (COVID-19). METHODS: Five databases were searched through July 7, 2020. Randomized controlled trials investigating the efficacy of TCM for use in the treatment of COVID-19 were included. Newcastle-Ottawa Scale (NOS) and modified Jadad score were used for the evaluation of the methodological quality of the included studies. Weighted mean difference, odds ratio (OR), and 95% confidence interval (95% CI) were calculated for pooling out results. Data were extracted for conducting a meta-analysis using STATA version 12.0. RESULTS: Eight studies with a total of 750 patients were included in this meta-analysis. All included trial groups involved treatment with TCM and Western medicine, while the control groups were treated only with Western medicine. The intervention therapy significantly improved the overall effective rate (n = 346, OR = 2.5, 95% CIs = 1.46-4.29), fever symptom disappearance rate (n = 436; OR = 3.6; 95% CIs = 2.13-6.08), fatigue symptom disappearance rate (n = 436; OR = 3.04; 95% CIs = 1.76-5.26), cough symptom disappearance rate (n = 436; OR = 2.91; 95% CIs = 1.36-6.19), and sputum production reduction (n = 436; OR = 5.51; 95% CIs = 1.94-15.64). Based on the Newcastle-Ottawa Scale assessment, 6 studies received a score of 4, and 1 study achieved a score of 5. One study was assessed using the modified Jadad score, achieving a score of 6. CONCLUSIONS: The integration of TCM with Western medicine has significantly improved the treatment for COVID-19 patients compared to Western medicine treatment alone. Combined therapy using TCM and Western medicine revealed the potential adjunctive role of TCM in treating COVID-19. However, high-quality clinical studies are still required to further evaluate the efficacy and safety of TCM in the treatment of COVID-19.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Drug Therapy, Combination/methods , Humans , Medicine, Chinese Traditional/methods , Treatment Outcome
19.
Nat Commun ; 12(1): 6055, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1475294

ABSTRACT

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/administration & dosage , Indoles/administration & dosage , Leucine/administration & dosage , Pyrrolidinones/administration & dosage , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacokinetics , Alanine/administration & dosage , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/pharmacokinetics , Animals , COVID-19/virology , Chlorocebus aethiops , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/enzymology , Coronavirus Protease Inhibitors/adverse effects , Coronavirus Protease Inhibitors/pharmacokinetics , Disease Models, Animal , Drug Design , Drug Synergism , Drug Therapy, Combination , HeLa Cells , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Infusions, Intravenous , Leucine/adverse effects , Leucine/pharmacokinetics , Mice , Pyrrolidinones/adverse effects , Pyrrolidinones/pharmacokinetics , SARS Virus/drug effects , SARS Virus/enzymology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Vero Cells
20.
JAMA Netw Open ; 4(10): e2129639, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1473778

ABSTRACT

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.


Subject(s)
Arthritis, Rheumatoid/drug therapy , COVID-19/mortality , Inflammatory Bowel Diseases/drug therapy , Psoriasis/drug therapy , Tumor Necrosis Factor Inhibitors/therapeutic use , Adult , Arthritis, Rheumatoid/epidemiology , Comorbidity , Drug Therapy, Combination/adverse effects , Female , Hospitalization/statistics & numerical data , Humans , Inflammatory Bowel Diseases/epidemiology , Male , Middle Aged , Pandemics , Psoriasis/epidemiology , Registries , Retrospective Studies , SARS-CoV-2
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