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1.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Article in English | MEDLINE | ID: covidwho-810756

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Atazanavir Sulfate/pharmacology , Betacoronavirus/drug effects , Cytokines/metabolism , Ritonavir/pharmacology , Animals , Atazanavir Sulfate/chemistry , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Therapy, Combination , Humans , Inflammation/metabolism , Inflammation/virology , Lopinavir/pharmacology , Molecular Docking Simulation , Monocytes/virology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Protease Inhibitors/pharmacology , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
2.
Trials ; 21(1): 827, 2020 Oct 02.
Article in English | MEDLINE | ID: covidwho-810387

ABSTRACT

OBJECTIVES: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. PARTICIPANTS: Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. MAIN OUTCOMES: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. RANDOMIZATION: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. BLINDING (MASKING): Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). TRIAL STATUS: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/therapeutic use , Medicine, Kampo , Pneumonia, Viral/drug therapy , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Drug Therapy, Combination , Drugs, Chinese Herbal/adverse effects , Female , Host-Pathogen Interactions , Humans , Japan , Male , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Severity of Illness Index , Time Factors , Treatment Outcome
3.
Indian J Ophthalmol ; 68(10): 2291-2293, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-795111

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a form of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been declared a pandemic by the World Health Organization (WHO). Ocular manifestations related to COVID-19 are uncommon with conjunctivitis being reported in a few cases. We report a unique case of vasculitic retinal vein occlusion (RVO) secondary to COVID-19 in a 52-year-old patient who presented with the diminution of vision in the left eye 10 days after he tested positive for SARS-CoV-2. All investigations for vasculitis were negative. This case supports the mechanism of thrombo-inflammatory state secondary to the "cytokine-storm" as the pathogenesis for systemic manifestations of COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Eye Infections, Viral/virology , Pneumonia, Viral/virology , Retinal Vasculitis/virology , Retinal Vein Occlusion/virology , Administration, Oral , Angiogenesis Inhibitors/therapeutic use , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Drug Therapy, Combination , Eye Infections, Viral/diagnosis , Eye Infections, Viral/drug therapy , Fluorescein Angiography , Glucocorticoids/therapeutic use , Humans , Intravitreal Injections , Male , Methylprednisolone/therapeutic use , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Ranibizumab/therapeutic use , Retinal Vasculitis/diagnosis , Retinal Vasculitis/drug therapy , Retinal Vein Occlusion/diagnosis , Retinal Vein Occlusion/drug therapy , Tomography, Optical Coherence , Vascular Endothelial Growth Factor A/antagonists & inhibitors
4.
BMJ Open ; 10(9): e041437, 2020 09 21.
Article in English | MEDLINE | ID: covidwho-788160

ABSTRACT

INTRODUCTION: To find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19. METHODS AND ANALYSIS: DisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-ß-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included. ETHICS AND DISSEMINATION: Inserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04315948 Eudra-CT 2020-000936-23.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Interferon beta-1a/therapeutic use , Lopinavir/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , Adenosine Monophosphate/therapeutic use , Adult , Alanine/therapeutic use , Betacoronavirus , Coronavirus Infections/therapy , Drug Combinations , Drug Therapy, Combination , Early Warning Score , Extracorporeal Membrane Oxygenation , Hospital Mortality , Hospitalization , Humans , Length of Stay , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/therapy , Respiration, Artificial , Standard of Care , Treatment Outcome
5.
J Interferon Cytokine Res ; 40(9): 438-442, 2020 09.
Article in English | MEDLINE | ID: covidwho-787046

ABSTRACT

A prospective observational study was conducted for assessing the therapeutic efficacy of interferon (IFN)-α2b in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first month after the coronavirus disease 2019 (COVID-19) outbreak began in Cuba. From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba. Seven hundred sixty-one (93.4%) were treated with a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon® Alpha R, Center for Genetic Engineering and Biotechnology, Havana, Cuba), 3 times per week, for 2 weeks. Fifty-three patients received the approved COVID protocol without IFN treatment. The proportion of patients discharged from hospital (without clinical and radiological symptoms and nondetectable virus by real-time polymerase chain reaction) was higher in the IFN-treated compared with the non-IFN treated group (95.4% vs. 26.1%, P < 0.01). The case fatality rate (CFR) for all patients was 2.95%, and for those patients who received IFN-α2b the CFR was reduced to 0.92. Intensive care was required for 82 patients (10.1%), 42 (5.5%) had been treated with IFN. This report provides preliminary evidence for the therapeutic effectiveness of IFN-α2b for COVID-19 and suggests that the use of Heberon Alpha R may contribute to complete recovery of patients.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Interferon-alpha/therapeutic use , Pneumonia, Viral/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Chloroquine/therapeutic use , Coronavirus Infections/mortality , Cuba , Drug Therapy, Combination , Female , Humans , Infant , Lopinavir/therapeutic use , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Prospective Studies , Ritonavir/therapeutic use , Young Adult
7.
Front Immunol ; 11: 2086, 2020.
Article in English | MEDLINE | ID: covidwho-771524

ABSTRACT

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).


Subject(s)
Betacoronavirus/genetics , Churg-Strauss Syndrome/complications , Churg-Strauss Syndrome/drug therapy , Coronavirus Infections/complications , Cyclophosphamide/therapeutic use , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/drug therapy , Immunosuppressive Agents/therapeutic use , Pneumonia, Viral/complications , Adult , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Therapy, Combination , Glucocorticoids/therapeutic use , Humans , Immunocompromised Host , Male , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Prednisolone/therapeutic use , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Rituximab/therapeutic use , Treatment Outcome
11.
Lancet ; 396(10256): 959-967, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-748089

ABSTRACT

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Antiviral Agents/adverse effects , Azithromycin/adverse effects , Betacoronavirus , Brazil/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/adverse effects , Length of Stay , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Respiratory Therapy , Standard of Care , Treatment Outcome
12.
Medwave ; 20(7): e8008, 2020 Aug 28.
Article in Spanish | MEDLINE | ID: covidwho-740553

ABSTRACT

In December 2019, a new strain of the SARS-CoV-2 coronavirus was reported in Wuhan, China, which produced severe lung involvement and progressed to respiratory distress. To date, more than seventeen million confirmed cases and more than half a million died worldwide from COVID-19. Patients with cardiovascular disease are more susceptible to contracting this disease and presenting more complications. We did a literature search on the association of cardiovascular disease and COVID-19 in databases such as Scopus, PubMed/MEDLINE, and the Cochrane Library. The purpose of this review is to provide updated information for health professionals who care for patients with COVID-19 and cardiovascular disease, given that they have a high risk of complications and mortality. Treatment with angiotensin-converting enzyme inhibitors and receptor blockers is controversial, and there is no evidence not to use these medications in patients with COVID-19. Regarding treatment with hydroxychloroquine associated or not with azithromycin, there is evidence of a higher risk with its use than clinical benefit and decreased mortality. Likewise, patients with heart failure are an important risk group due to their condition per se. Patients with heart failure and COVID-19 are a diagnostic dilemma because the signs of acute heart failure could be masked. On the other hand, in patients with acute coronary syndrome, the initial therapeutic approach could change in the context of the pandemic, although only based on expert opinions. Nonetheless, many controversial issues will be the subject of future research.


Subject(s)
Betacoronavirus , Cardiovascular Diseases/complications , Coronavirus Infections/complications , Pneumonia, Viral/complications , Acute Coronary Syndrome/etiology , Acute Coronary Syndrome/therapy , Algorithms , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/adverse effects , Azithromycin/adverse effects , Coronavirus Infections/drug therapy , Drug Therapy, Combination , Electrocardiography/drug effects , Heart Failure/etiology , Heart Failure/therapy , Humans , Hydroxychloroquine/adverse effects , Hypertension/complications , Hypertension/drug therapy , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Prognosis , Renin-Angiotensin System/physiology
13.
Ann Ital Chir ; 91: 273-276, 2020.
Article in English | MEDLINE | ID: covidwho-739593

ABSTRACT

CASE REPORT: A 64-year-old woman presented to our emergency department during the outbreak of the covid-19 emergency in Italy with syncope, anosmia, mild dyspnoea and atypical chest and dorsal pain. A chest CT scan showed an acute type B aortic dissection (ATBAD) and bilateral lung involvement with ground-glass opacity, compatible with interstitial pneumonia. Nasopharyngeal swabs resulted positive for SARS-CoV-2. For the persistence of chest pain, despite the analgesic therapy, we decided to treat her with a TEVAR. Patient's chest and back pain resolved during the first few days after the procedure. No surgical or respiratory complications occurred and the patient was discharged 14 days after surgery. DISCUSSION: By performing the operation under local anesthesia, it was possible to limit both the staff inside the operatory room and droplet/aerosol release. Since we had to perform the operation in a hemodynamics room, thanks to the limited extension of the endoprosthesis and the good caliber of the right vertebral artery we were able to reduce the risk of spinal cord ischemia despite the lack of a revascularization of the left subclavian artery. CONCLUSIONS: A minimally invasive total endovascular approach allows, through local anesthesia and percutaneous access, to avoid surgical cut down and orotracheal intubation. This, combined with a defined management protocol for infected patients, seems to be a reasonable way to perform endovascular aortic procedures in urgent setting, even in a SARSCoV- 2 positive patient. KEY WORDS: COVID-19, Dissection, TEVAR.


Subject(s)
Aneurysm, Dissecting/surgery , Aortic Aneurysm, Thoracic/surgery , Betacoronavirus/isolation & purification , Blood Vessel Prosthesis Implantation/methods , Coronavirus Infections/prevention & control , Endovascular Procedures/methods , Infection Control/methods , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Anesthesia, Local , Aneurysm, Dissecting/complications , Antibiotic Prophylaxis , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Aortic Aneurysm, Thoracic/complications , Contraindications, Procedure , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/transmission , Darunavir/therapeutic use , Diabetes Mellitus, Type 2/complications , Drug Therapy, Combination , Enoxaparin/therapeutic use , Female , Humans , Hydroxychloroquine/therapeutic use , Intraoperative Complications/prevention & control , Intubation, Intratracheal/adverse effects , Middle Aged , Nasopharynx/virology , Operating Rooms , Patient Isolation , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/transmission , Ritonavir/therapeutic use , Spinal Cord Ischemia/prevention & control , Vertebral Artery/surgery
14.
Front Immunol ; 11: 1969, 2020.
Article in English | MEDLINE | ID: covidwho-732899

ABSTRACT

Recent small-scale clinical trials have shown promising results in the use of hydroxychloroquine, an FDA approved anti-malaria drug, for the treatment of COVID-19. However, large scale, randomized and double-blind clinical trials are needed to confirm the safety and efficacy of hydroxychloroquine in COVID-19 patients. Here, we review the progress of using hydroxychloroquine or chloroquine as anti-viral agents, failed clinical trials of chloroquine in treatment of dengue virus and influenza infection, and especially the mechanism of azithromycin in inhibiting viral replication, so as to shed light on the ongoing clinical trials and further researches of hydroxychloroquine on SARS-CoV-2 infected patients.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Coronavirus Infections/virology , Disease Models, Animal , Drug Therapy, Combination , Humans , Mice , Pandemics , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Treatment Outcome , Virus Replication/drug effects
15.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-729357

ABSTRACT

Evidence to support the use of steroids in coronavirus disease 2019 (COVID-19) pneumonia is lacking. We aim to determine the impact of steroid use for COVID-19 pneumonia on hospital mortality. We performed a single-center retrospective cohort study in a university hospital in Madrid, Spain, during March of 2020. To determine the role of steroids in in-hospital mortality, patients admitted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and treated with steroids were compared to patients not treated with steroids, and we adjusted with a propensity score for patients on steroid treatment. Survival times were compared using the log rank test. Different steroid regimens were compared and adjusted with a second propensity score. During the study period, 463 out of 848 hospitalized patients with COVID-19 pneumonia fulfilled inclusion criteria. Among them, 396 (46.7%) patients were treated with steroids and 67 patients were not. Global mortality was 15.1%. The median time to steroid treatment from symptom onset was 10 days (interquartile range [IQR], 8 to 13 days). In-hospital mortality was lower in patients treated with steroids than in controls (13.9% [55/396] versus 23.9% [16/67]; hazard ratio [HR], 0.51 [95% confidence interval, 0.27 to 0.96]; P = 0.044). Steroid treatment reduced mortality by 41.8% relative to the mortality with no steroid treatment (relative risk reduction, 0.42 [95% confidence interval, 0.048 to 0.65]). Initial treatment with 1 mg/kg of body weight/day of methylprednisolone versus steroid pulses was not associated with in-hospital mortality (13.5% [42/310] versus 15.1% [13/86]; odds ratio [OR], 0.880 [95% confidence interval, 0.449 to 1.726]; P = 0.710). Our results show that the survival of patients with SARS-CoV-2 pneumonia is higher in patients treated with glucocorticoids than in those not treated. Rates of in-hospital mortality were not different between initial regimens of 1 mg/kg/day of methylprednisolone and glucocorticoid pulses.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Interferons/therapeutic use , Lopinavir/therapeutic use , Methylprednisolone/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , Aged , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/immunology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/virology , Comorbidity , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/immunology , Diabetes Mellitus/mortality , Diabetes Mellitus/virology , Drug Administration Schedule , Drug Combinations , Drug Therapy, Combination , Dyslipidemias/drug therapy , Dyslipidemias/immunology , Dyslipidemias/mortality , Dyslipidemias/virology , Female , Hospitals, University , Humans , Intensive Care Units , Length of Stay/statistics & numerical data , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/mortality , Neoplasms/virology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Retrospective Studies , Survival Analysis
16.
PLoS One ; 15(8): e0237903, 2020.
Article in English | MEDLINE | ID: covidwho-724760

ABSTRACT

AIM: To identify investigated interventions for COVID-19 prevention or treatment via trial registry entries on planned or ongoing randomised clinical trials. To assess these registry entries for recruitment status, planned trial size, blinding and reporting of mortality. METHODS: We identified trial registry entries systematically via the WHO International Clinical Trials Registry Platform and 33 trial registries up to June 23, 2020. We included relevant trial registry entries for randomized clinical trials investigating medical preventive, adjunct or supportive therapies and therapeutics for treatment of COVID-19. Studies with non-random and single-arm design were excluded. Trial registry entries were screened by two authors independently and data were systematically extracted. RESULTS: We included 1303 trial registry entries from 71 countries investigating 381 different single interventions. Blinding was planned in 47% of trials. Sample size was >200 participants in 40% of trials and a total of 611,364 participants were planned for inclusion. Mortality was listed as an outcome in 57% of trials. Recruitment was ongoing in 54% of trials and completed in 8%. Thirty-five percent were multicenter trials. The five most frequent investigational categories were immune modulating drugs (266 trials (20%)), unconventional medicine (167 trials (13%)), antimalarial drugs (118 trials (9%)), antiviral drugs (100 trials (8%)) and respiratory adjuncts (78 trials (6%)). The five most frequently tested uni-modal interventions were: chloroquine/hydroxychloroquine (113 trials with 199,841 participants); convalescent plasma (64 trials with 11,840 participants); stem cells (51 trials with 3,370 participants); tocilizumab (19 trials with 4,139 participants) and favipiravir (19 trials with 3,210 participants). CONCLUSION: An extraordinary number of randomized clinical trials investigating COVID-19 management have been initiated with a multitude of medical preventive, adjunctive and treatment modalities. Blinding will be used in only 47% of trials, which may have influence on future reported treatment effects. Fifty-seven percent of all trials will assess mortality as an outcome facilitating future meta-analyses.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Randomized Controlled Trials as Topic , Registries , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/mortality , Coronavirus Infections/virology , Drug Therapy, Combination , Humans , Hydroxychloroquine/therapeutic use , Interleukin-6/antagonists & inhibitors , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Treatment Outcome
17.
Eur Rev Med Pharmacol Sci ; 24(15): 8219-8225, 2020 08.
Article in English | MEDLINE | ID: covidwho-724284

ABSTRACT

OBJECTIVE: At the end of 2019, the Novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), spread rapidly from China to the whole world. Circadian rhythms can play crucial role in the complex interplay between viruses and organisms, and temporized schedules (chronotherapy) have been positively tested in several medical diseases. We aimed to compare the possible effects of a morning vs. evening antiviral administration in COVID patients. PATIENTS AND METHODS: We retrospectively evaluated all patients admitted to COVID internal medicine units with confirmed SARS-CoV-2 infection, and treated with darunavir-ritonavir (single daily dose, for seven days). Age, sex, length of stay (LOS), pharmacological treatment, and timing of antiviral administration (morning or evening), were recorded. Outcome indicators were death or LOS, and laboratory parameters, e.g., variations in C-reactive protein (CRP) levels, ratio of arterial oxygen partial pressure (PaO2, mmHg) to fractional inspired oxygen (FiO2) (PaO2/FiO2), and leucocyte count. RESULTS: The total sample consisted of 151 patients, 33 (21.8%) of whom were selected for antiviral treatment. The mean age was 61.8±18.3 years, 17 (51.5%) were male, and the mean LOS was 13.4±8.6 days. Nine patients (27.3%) had their antiviral administration in the morning, and 24 (72.7%) had antiviral administration in the evening. No fatalities occurred. Despite the extremely limited sample size, morning group subjects showed a significant difference in CRP variation, compared to that in evening group subjects (-65.82±33.26 vs. 83.32±304.89, respectively, p<0.032). No significant differences were found for other parameters. CONCLUSIONS: This report is the first study evaluating temporized morning vs. evening antiviral administration in SARS-CoV-2 patients. The morning regimen was associated with a significant reduction in CRP values. Further confirmations with larger and multicenter samples of patients could reveal novel potentially useful insights.


Subject(s)
Antiviral Agents/administration & dosage , Coronavirus Infections/drug therapy , Darunavir/administration & dosage , Drug Chronotherapy , Hospital Mortality , Length of Stay/statistics & numerical data , Pneumonia, Viral/drug therapy , Ritonavir/administration & dosage , Adult , Aged , Aged, 80 and over , Betacoronavirus , Blood Gas Analysis , C-Reactive Protein , Coronavirus Infections/metabolism , Drug Therapy, Combination , Humans , Italy , Leukocyte Count , Middle Aged , Oxygen/metabolism , Pandemics , Partial Pressure , Pneumonia, Viral/metabolism , Retrospective Studies
18.
Adv Ther ; 37(10): 4107-4131, 2020 10.
Article in English | MEDLINE | ID: covidwho-718499

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a serious health concern. Repurposing of existing drugs indicated for other conditions seems to be the first choice for immediate therapeutic management. The quality of early evidence favoring the different treatment options needs to be apprised for informed decision-making. METHODS: In this systematic literature review, we apprised the quality of available evidence for different therapeutic options and also the basis for different treatment guidelines. To include all studies that are in different stages of publication, we also included studies from the preprint servers BioRxiv and MedRxiv and published studies from PubMed. RESULTS: We retrieved 5621 articles and included 22 studies for the systematic review. Based on our study, chloroquine/hydroxychloroquine, either alone or in combination with azithromycin, remdesivir, corticosteroids, convalescent sera, ritonavir/lopinavir, tocilizumab and arbidol were evaluated as therapeutic options. The data from different study designs reveal contradictory findings except for convalescent sera for which the evidence available is only from case series. Based on this early evidence, various national guidelines recommend remdesivir, convalescent sera, corticosteroids and hydroxychloroquine in different subsets of patients. CONCLUSION: Establishing consensus with respect to the end points to be assessed for respiratory viruses may enhance the quality of evidence in case of future pandemics. The systematic review highlighted the lacuna and methodologic deficiency in early clinical evidence and included an update on different therapeutic management guidelines. Further clinical evidence from the ongoing trials may lead to evolution of treatment guidelines with the addition of more therapeutic options.


Subject(s)
Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Drug Therapy, Combination , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Pandemics , Practice Guidelines as Topic
19.
PLoS One ; 15(8): e0237693, 2020.
Article in English | MEDLINE | ID: covidwho-713539

ABSTRACT

Hydroxychloroquine has been touted as a potential COVID-19 treatment. Tocilizumab, an inhibitor of IL-6, has also been proposed as a treatment of critically ill patients. In this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized COVID-19 patients. Patients were hospitalized at a 13-hospital network spanning New Jersey USA between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2. Follow up was through May 5, 2020. Among 2512 hospitalized patients with COVID-19 there have been 547 deaths (22%), 1539 (61%) discharges and 426 (17%) remain hospitalized. 1914 (76%) received at least one dose of hydroxychloroquine and 1473 (59%) received hydroxychloroquine with azithromycin. After adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was 25%, 20%, 18%, and 20%, respectively. Among 547 evaluable ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted HR, 0.76 [95% CI, 0.57-1.00]), with 30 day unadjusted mortality with and without tocilizumab of 46% versus 56%. This observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized COVID-19 patients. Tocilizumab demonstrated a trend association towards reduced mortality among ICU patients. Our findings are limited to hospitalized patients and must be interpreted with caution while awaiting results of randomized trials. Trial Registration: Clinicaltrials.gov Identifier: NCT04347993.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antimalarials/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacology , Azithromycin/therapeutic use , Child , Child, Preschool , Coronavirus Infections/mortality , Coronavirus Infections/virology , Drug Therapy, Combination , Female , Follow-Up Studies , Hospitalization , Humans , Infant , Infant, Newborn , Intensive Care Units , Interleukin-6/antagonists & inhibitors , Kaplan-Meier Estimate , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Retrospective Studies , Treatment Outcome , Young Adult
20.
Cells ; 9(8)2020 08 11.
Article in English | MEDLINE | ID: covidwho-706247

ABSTRACT

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Betacoronavirus/drug effects , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , Drug Therapy, Combination , Humans , Inflammation/immunology , Inflammation/metabolism , Mice , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Signal Transduction/drug effects , Treatment Outcome , Virus Internalization/drug effects
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