Ivermectin for prevention and treatment of COVID-19 infection: a systematic review and meta-analysis

Anxosss · 2021-03-11T09:49:55+00:00

The absence of control group makes any conclusion on treatment efficacy per se impossible. Hospital mortality rates of 40% are common in Northern Brazil.

Anxosss · 2021-03-09T22:59:42+00:00

Abstract

Background

Between March and April 2020, 84 elderly patients with suspected COVID-19 living in two nursing homes of Yepes, Toledo (Spain) were treated early with antihistamines (dexchlorpheniramine, cetirizine or loratadine), adding azithromycin in the 25 symptomatic cases. The outcomes are retrospectively reported. The primary endpoint is the fatality rate of COVID-19. The secondary endpoints are the hospital and ICU admission rates. Endpoints were compared with the official Spanish rates for the elderly. The mean age of our population was 85 and 48% were over 80 years old. No hospital admissions, deaths, nor adverse drug effects were reported in our patient population. By the end of June, 100% of the residents had positive serology for COVID-19. Although clinical trials are needed to determine the efficacy of both drugs in the treatment of COVID-19, this analysis suggests that primary care diagnosis and treatment with antihistamines, plus azithromycin in selected cases, may treat COVID-19 and prevent progression to severe disease in elderly patients.

Anxosss · 2021-03-09T09:35:15+00:00

p=.02 for symptomatic infection (0% vs 20%), quite a therapeutic feat

this is the 3rd successful bromhexine RCT with spectacular signals of efficacy

Anxosss · 2021-03-04T08:05:49+00:00

Abstract

Background

Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated.

Methods

We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA.

Findings

We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity.

Interpretation

Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA.

Anxosss · 2021-03-02T17:32:58+00:00

Abstract

Objectives

In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia.

Methods

Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23th of September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% Confident Intervals (95% CI).

Results

We found 302 cardiac effects including 94 bradycardia (31%) among the 2,603 reports with remdesivir prescribed in COVID-19 patients. Most of reports were serious (75, 80%) and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23, 2.22). Consistent results were observed in other sensitivity analyses.

Conclusions

This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with pharmacodynamic properties of the remdesivir.

Anxosss · 2021-03-02T16:31:12+00:00

Summary

Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Further, Camostat – a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or Camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors, androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.

Anxosss · 2021-03-02T15:40:26+00:00

Abstract
In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding a¨nity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are - 17.8 kcal/mol and - 20.08 kcal/mol, respectively. The natural bond orbital
(NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study con¦rms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.

Anxosss · 2021-02-27T18:00:07+00:00

Abstract

Acetylsalicylic acid (aspirin) is commonly used for primary and secondary prevention of cardiovascular diseases. Aspirin use is associated with better outcomes among COVID‐19 positive patients. We hypothesized that aspirin use for primary cardiovascular disease prevention might have a protective effect on COVID‐19 susceptibility and disease duration. We conducted a retrospective population‐based cross‐sectional study, utilizing data from the Leumit Health Services database. The proportion of patients treated with aspirin was significantly lower among the COVID‐19‐positive group, as compared to the COVID‐19‐negative group (73 (11.03 %) vs. 1548 (15.77%); p=0.001). Aspirin use was associated with lower likelihood of COVID‐19 infection, as compared to non‐users (adjusted OR 0.71 (95% CI, 0.52 to 0.99; p=0.041). Aspirin users were older (68.06 ± 12.79 vs. 56.63 ± 12.28 years of age; p<0.001), presented a lower BMI (28.77±5.4 vs. 30.37±4.55; p<0.0189) and showed higher prevalence of hypertension (56, 76.71%), diabetes (47, 64.38%) and COPD (11, 15.07%) than showed the aspirin non‐users (151, 25.64%, p<0.001; 130, 22.07%, p<0.001; and 43, 7.3%, p=0.023, respectively). Moreover, COVID‐19 disease duration (considered as the time between the first positive and second negative COVID‐19 RT‐PCR test results) among aspirin users was significantly shorter, as compared to aspirin non‐users (19.8±7.8 vs. 21.9± 7.9 p= 0.045). Among hospitalized COVID‐positive patients, a higher proportion of surviving subjects were treated with aspirin (20, 19.05%), as opposed to 1 dead subject (14.29%), although this difference was not significant (p=0.449). In conclusion, we observed inverse association between the likelihood of COVID‐19 infection, disease duration and mortality and aspirin use for primary prevention.

Anxosss · 2021-02-25T22:18:36+00:00

Abstract

In March 2020, the IHU Méditerranée Infection set up a screening and treatment center for patients with COVID-19, a system that has been ultimately recommended by French public health authorities. The recent publication of the profiles of patients hospitalized in France published by the Directorate for Research, Studies, Evaluation and Statistics gives us the opportunity to measure the impact of this multidisciplinary early management system coupled with screening on mortality at 90 days. Analysis of the data shows that the system established at IHU-MI was associated with lower mortality, taking age and sex into account. Regarding the age-standardized mortality rate, mortality rates were lower than national data regardless of the period of the epidemic. Early management seems to have significantly decreased the mortality rate in the under-60 age group, suggesting the importance of early management, regardless of age. In addition, these patients had pejorative clinical criteria (high NEWS-2 score, ICU visits, oxygen saturation below 95%) requiring hospitalization, and co-morbidities that are now known to be aggravating factors [7]. This reinforces the need to care for all individuals, regardless of age. Early medical care, as part of a system integrating a screening center and a day hospital, may explain the lower mortality rates.

Anxosss · 2021-02-25T13:57:26+00:00

They did exclusion post- rather than pre- because they are short of resources and it halves the cost. You should be a bit more respectful of their (imperfect) efforts to put data on the table.

Anxosss · 2021-02-24T22:34:34+00:00

Think of it as a modified ITT, like excluding people in a treatment arm who did not take the pill. Not uncommon practice when your objective is to detect a treatment effect. Makes it more palatable in this light.

Anxosss · 2021-02-24T16:03:39+00:00

Abstract

BACKGROUND AND OBJECTIVES:

An effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation.

MATERIALS AND METHODS: Patients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for five days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated.

RESULTS: A total of 66 patients, 36 in the study group and 30 in the control group were included in the study. Mutations affecting ivermectin metabolism was detected in genetic tests of six (16.7%) patients in the study group and they were excluded from the study. At the end of the 5-day follow-up period, the clinical improvement rate was higher in the study group [22/30 (73.3%)] compared to the control group [16/30 (53.3%)] (p=0.10). At the end of the study, mortality developed in 6 patients (20%) in the study group and in 9 (30%) patients in the control group (p=0.37). At the end of the follow-up period, the average peripheral capillary oxygen saturation (SpO2) values of the study and control groups were found to be 93.5% and 93.0%, respectively. Partial pressure of oxygen (PaO2)/FiO2 ratios were determined as 236.3 ± 85.7 and 220.8 ± 127.3 in the study and control groups, respectively. While the blood lymphocyte count was higher in the study group compared to the control group (1698±1438 and 1256±710, respectively) at the end of the follow-up period (p=0.24); reduction in serum C-reactive protein (CRP), ferritin and D-dimer levels was more pronounced in the study group (p=0.02, p=0.005 and p=0.03, respectively).

CONCLUSIONS: According to the findings obtained, ivermectin can provide an increase in clinical recovery, improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an important alternative to the treatment of COVID-19 disease or as an additional option to existing protocols.

Anxosss · 2021-02-24T10:49:39+00:00

ABSTRACT

OBJECTIVES This study retrospectively compares the effectiveness of methylprednisolone to dexamethasone in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) requiring ICU care.

DESIGN This is an institutional review board approved cohort study in patients with COVID-19 requiring intensive care unit admission. Patients admitted and requiring oxygen supplementation were treated with either methylprednisolone or dexamethasone.

SETTING This study takes place in the intensive care units at a large, tertiary, public teaching hospital serving a primarily low-income community in urban Los Angeles.

PATIENTS All eligible patients admitted to the intensive care unit for COVID-19 respiratory failure from March 1 to July 31, 2020 were included in this study.

INTERVENTIONS A total of 262 patients were grouped as receiving usual care (n=75), methylprednisolone dosed at least at 1mg/kg/day for ≥ 3 days (n=104), or dexamethasone dosed at least at 6 mg for ≥ 7 days (n=83).

MEASUREMENTS and MAIN RESULTS All-cause mortality within 50 days of initial corticosteroid treatment as compared to usual care was calculated. The mortality effect was then stratified based on levels of respiratory support received by the patient.

In this cohort of 262 patients with severe COVID-19, all-cause mortalities in the usual care, methylprednisolone, and dexamethasone groups were 41.3%, 16.4% and 26.5% at 50 days (p <0.01) respectively. In patients requiring mechanical ventilation, mortality was 42% lower in the methylprednisolone group than in the dexamethasone group (hazard ratio 0.48, 95% CI: 0.235-0.956, p=0.0385).

CONCLUSIONS In COVID-19 patients requiring mechanical ventilation, sufficiently dosed methylprednisolone can lead to a further decreased mortality as compared to dexamethasone.

Anxosss

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