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1.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1733276

ABSTRACT

Background In the absence of antiviral alternatives, interventions under research for COVID-19 might be offered following guidelines from WHO for monitored emergency use of unregistered and experimental interventions (MEURI). Ivermectin is among several drugs explored for its role against SARS-CoV-2, with a well-known safety profile but conflicting data regarding clinical utility for COVID-19. The aim of this report is to inform on the results of a MEURI Program of high-dose ivermectin in COVID-19 carried out by the Ministry of Health of the Province of La Pampa, Argentina. Methods COVID-19 subjects, within 5 days of symptoms onset were invited to participate in the program, which consisted in the administration of ivermectin 0.6 mg/kg/day for 5 days plus standard of care. Active pharmacosurveillance was performed for 21 days, and hepatic laboratory assessments were performed in a subset of patients. Frequency of Intensive Care Unit (ICU) admission and COVID-19-related mortality of subjects in the ivermectin intention to treat group were compared with that observed in inhabitants of the same province during the same period not participating in the program. Results From 21,232 subjects with COVID-19, 3,266 were offered and agreed to participate in the ivermectin program and 17,966 did not and were considered as controls. A total of 567 participants reported 819 adverse events (AEs);3.13% discontinued ivermectin due to adverse events. ICU admission was significantly lower in the ivermectin group compared to controls among participants ≥40 year-old (1.2 vs. 2.0%, odds ratio 0.608;p = 0.024). Similarly, mortality was lower in the ivermectin group in the full group analysis (1.5 vs. 2.1%, odds ratio 0.720;p = 0.029), as well as in subjects ≥ 40 year- old (2.7 vs. 4.1%, odds ratio 0.655;p = 0.005). Conclusions This report highlights the safety and possible efficacy of high dose ivermectin as a potentially useful intervention deserving public health-based consideration for COVID-19 patients.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314556

ABSTRACT

Background: There are limited antiviral options for the treatment of patients with coronavirus disease 2019 (COVID-19) that have demonstrated clinical efficacy and none of them is an oral drug. Ivermectin (IVM), a macrocytic lactone with a wide anti-parasitary spectrum, has shown potent in vitro activity against SARS-CoV-2 in cell cultures. Methods: We completed a pilot, randomized, controlled, outcome-assessor blinded clinical trial with the goal of evaluating the antiviral activity of high dose IVM in COVID-19 patients. Eligible patients were adults (aged 18 to 69 years) with mild or moderate RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. 45 patients were randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care. The primary endpoint was viral load reduction in respiratory secretions at day-5. Viral load in respiratory secretions was measured through quantitative RT-PCR. Concentrations of IVM in plasma were measured on multiple treatment days.Findings: The trial run between May 18 and September 29, 2020 with 45 randomized patients (30 in the IVM group and 15 controls). There was no difference in viral load reduction between groups but a significant difference in reduction was found in patients with higher median plasma IVM levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004). The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02). Adverse events were reported in 5 (33%) patients in the controls and 13 (43%) in the IVM treated group, without a relationship between IVM plasma levels and adverse events.Interpretation: A concentration dependent antiviral activity of oral high dose IVM was identified in this pilot trial at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.Trial Registration: This trial is registered with ClinicalTrials.gov, NCT004381884.Funding Statement: This work was supported by grant IP-COVID-19-625 from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.Declaration of Interests: AK reports grants from Laboratorio Elea/Phoenix. MAT, MDG and ES are employees of Laboratorios Elea/Phoenix. SG is a moember of the Board of Directors of Laboratorio Elea/Phoenix. All other authors declare no competing interests.Ethics Approval Statement: Ethical approval was obtained from the Institutional Independent Ethics Committees and from district and national regulatory agencies. All participating individuals provided written informed consent. The trial was done in accordance with the principles of the Declaration of Helsinki.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-312363

ABSTRACT

Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52];p=0.0002);14/650 (2.1%) deaths on ivermectin;57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

4.
Viruses ; 13(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470998

ABSTRACT

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.


Subject(s)
Active Transport, Cell Nucleus/drug effects , Atorvastatin/pharmacology , COVID-19/drug therapy , Ivermectin/pharmacology , SARS-CoV-2/drug effects , alpha Karyopherins/metabolism , A549 Cells , Actin Cytoskeleton/drug effects , Animals , Antiviral Agents/pharmacology , Cell Line, Tumor , Chlorocebus aethiops , Drug Repositioning , HeLa Cells , Humans , NF-kappa B/metabolism , Vero Cells , rho GTP-Binding Proteins/metabolism
6.
Germs ; 11(2):221-237, 2021.
Article in English | ProQuest Central | ID: covidwho-1380261

ABSTRACT

Introduction The objective of this cross-sectional study was to describe the main symptoms associated with COVID-19, and their diagnostic characteristics, to aid in the clinical diagnosis. Methods An analysis of all patients diagnosed by RT-PCR for SARS-CoV-2 between April and May 2020 in Argentina was conducted. The data includes clinical and demographic information from all subjects at the time of presentation (n=67318, where 12% were positive for SARS-CoV-2). The study population was divided into four age groups: pediatric (0-17 years), young adults (18-44 years), adults (4564 years), and elderly (65-103 years). Multivariate logistic regression was used to measure the association of all symptoms and to create a diagnostic model based on symptoms. Results Symptoms associated with COVID-19 were anosmia, dysgeusia, headache, low-grade fever, odynophagia, and malaise. However, the presentation of these symptoms was different between the different age groups. In turn, at the time of presentation, the symptoms associated with respiratory problems (chest pain, abdominal pain, and dyspnea) had a negative association with COVID-19 or did not present statistical relevance. On the other hand, the model based on 16 symptoms, age and sex, presented a sensitivity of 80% and a specificity of 46%. Conclusions There were significant differences between the different age groups. Additionally, there were interactions between different symptoms that were highly associated with COVID-19. Finally, our findings showed that a regression model based on multiple factors (age, sex, interaction between symptoms) can be used as an accessory diagnostic method or a rapid screening of suspected COVID-19 cases.

7.
Germs ; 11(2): 221-237, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1323495

ABSTRACT

INTRODUCTION: The objective of this cross-sectional study was to describe the main symptoms associated with COVID-19, and their diagnostic characteristics, to aid in the clinical diagnosis. METHODS: An analysis of all patients diagnosed by RT-PCR for SARS-CoV-2 between April and May 2020 in Argentina was conducted. The data includes clinical and demographic information from all subjects at the time of presentation (n=67318, where 12% were positive for SARS-CoV-2). The study population was divided into four age groups: pediatric (0-17 years), young adults (18-44 years), adults (45-64 years), and elderly (65-103 years). Multivariate logistic regression was used to measure the association of all symptoms and to create a diagnostic model based on symptoms. RESULTS: Symptoms associated with COVID-19 were anosmia, dysgeusia, headache, low-grade fever, odynophagia, and malaise. However, the presentation of these symptoms was different between the different age groups. In turn, at the time of presentation, the symptoms associated with respiratory problems (chest pain, abdominal pain, and dyspnea) had a negative association with COVID-19 or did not present statistical relevance. On the other hand, the model based on 16 symptoms, age and sex, presented a sensitivity of 80% and a specificity of 46%. CONCLUSIONS: There were significant differences between the different age groups. Additionally, there were interactions between different symptoms that were highly associated with COVID-19. Finally, our findings showed that a regression model based on multiple factors (age, sex, interaction between symptoms) can be used as an accessory diagnostic method or a rapid screening of suspected COVID-19 cases.

8.
EClinicalMedicine ; 37: 100959, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1275282

ABSTRACT

BACKGROUND: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. METHODS: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. FINDINGS: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. INTERPRETATION: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. FUNDING: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

9.
J Pharm Sci ; 110(6): 2501-2507, 2021 06.
Article in English | MEDLINE | ID: covidwho-1046101

ABSTRACT

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.


Subject(s)
COVID-19 , Ivermectin , Administration, Oral , Animals , Humans , Ivermectin/toxicity , Nasal Sprays , SARS-CoV-2 , Swine
10.
PLoS One ; 15(11): e0242184, 2020.
Article in English | MEDLINE | ID: covidwho-919023

ABSTRACT

Ivermectin has recently shown efficacy against SARS-CoV-2 in-vitro. We retrospectively reviewed severe COVID-19 patients receiving standard doses of ivermectin and we compared clinical and microbiological outcomes with a similar group of patients not receiving ivermectin. No differences were found between groups. We recommend the evaluation of high-doses of ivermectin in randomized trials against SARS-CoV-2.


Subject(s)
Coronavirus Infections/drug therapy , Immunosuppressive Agents/therapeutic use , Ivermectin/therapeutic use , Pneumonia, Viral/drug therapy , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Nasopharynx/virology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
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