Putative Therapeutic Impact of Inflammasome Inhibitors against COVID-19-Induced ARDS
Abstract and Figures
Given the importance of COVID-19-induced ARDS, recently, researchers have strived to determine underlying mechanisms involved in the inflammatory responses. In this regard, inflammasomes possess a distinct priority for cytokine storm occurrence and subsequently ARDS progression in ill patients with SARS-CoV-2 infection. In this mini-review, the characteristics of known inflammasome inhibitors and designed research in this field were concretely deciphered.
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The pandemic of COVID-19 caused worldwide concern. Because of the lack of appropriate medications and the inefficiency of commercially available vaccines, lots of efforts are being made to develop de novo therapeutic modalities. Besides, the possibility of several genetic mutations in the viral genome has led to the generation of resistant strains such as Omicron against neutralizing antibodies and vaccines, leading to worsening public health status. Exosomes (Exo), nano-sized vesicles, possess several therapeutic properties that participate in intercellular communication. The discovery and application of Exo in regenerative medicine have paved the way for the alleviation of several pathologies. These nano-sized particles act as natural bio-shuttles and transfer several biomolecules and anti-inflammatory cytokines. To date, several approaches are available for the administration of exosomes into the targeted site inside the body, although the establishment of standard administration routes remains unclear. Because SARS-CoV-2 primarily affects the respiratory system, we here tried to highlight the transplantation of Exo in the alleviation of COVID-19 pathologies.
Corona virus is quickly spreading around the world. The goal of viral management is to disrupt the virus’s life cycle, minimize lung damage, and alleviate severe symptoms. Numerous strategies have been used, including repurposing existing antivirals or drugs used in previous viral outbreaks. One such strategy is to repurpose FDA-approved kinase inhibitors that are potential chemotherapeutic agents and have demonstrated antiviral activity against a variety of viruses, including MERS, SARS-CoV-1, and others, by inhibiting the viral life cycle and the inflammatory response associated with COVID-19. The purpose of this article is to identify licensed kinase inhibitors that have the ability to reduce the virus’s life cycle, from entrance through viral propagation from cell to cell. Several of these inhibitors, including imatinib, ruxolitinib, silmitasertib, and tofacitinib (alone and in conjunction with hydroxychloroquine), are now undergoing clinical studies to determine their efficacy as a possible treatment drug. The FDA approved baricitinib (a Janus kinase inhibitor) in combination with remdesivir for the treatment of COVID-19 patients receiving hospital care in November 2020. While in vitro trials with gilteritinib, fedratinib, and osimertinib are encouraging, further research is necessary before these inhibitors may be used to treat COVID-19 patients.
Chronic Obstructive Pulmonary Disease (COPD) is known as the third leading cause of human death globally. Enhanced chronic inflammation and pathological remodeling are the main consequences of COPD, leading to decreased life span. Histological and molecular investigations revealed that prominent immune cell infiltration and release of several cytokines contribute to progressive chronic remodeling. Recent investigations have revealed that exosomes belonging to extracellular vesicles are involved in the pathogenesis of COPD. It has been elucidated that exosomes (Exo) secreted from immune cells are eligible to carry numerous pro-inflammatory factors exacerbating the pathological conditions. Here, in this review article, we have summarized various and reliable information about the negative role of immune cellderived exosomes in the remodeling of pulmonary tissue and airways destruction in COPD patients.
Colchicine has shown clinical benefits in the management of COVID-19 via its anti-inflammatory effect. However, the exact role of colchicine in COVID-19 patients is unknown. The current clinical trial was performed on 202 patients with moderate to severe COVID-19. Patients were randomly assigned in a 1:1 ratio to receive up to a 3-day course of 0.5 mg colchicine followed by a 12-day course of 1 mg colchicine in combination with standard care or a 15-day course of standard care. Among 202 ran-domized patients, 153 completed the study and received colchicine/standard care or List of Abbreviations: SARS-CoV-2 or COVID
Introduction
Colchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage.
Methods
The literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design (RCT vs observational) and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately.
Results
Eight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality—HR of 0.25 (95% CI: 0.09, 0.66) and OR of 0.22 (95% CI: 0.09, 0.57). There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not–OR of 0.26 (95% CI: 0.06, 1.09).
Conclusion
Colchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long‐term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin‐1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence‐based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF.
Objective
To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.
Design
We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.
Results
Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).
Conclusion
Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.
Trial registration number
RBR-8jyhxh.
Melatonin possesses multi-organ and pleiotropic effects with potency to control angiogenesis at both molecular and cellular levels. To date, many efforts have been made to control and regulate the dynamic of angiogenesis modulators in a different milieu. The term angiogenesis or neovascularization refers to the development of de novo vascular buds from the pre-existing blood vessels. This phenomenon is tightly dependent on the balance between the pro- and antiangiogenesis factors which alters the functional behavior of vascular cells. The promotion of angiogenesis is thought to be an effective strategy to accelerate the healing process of ischemic changes such as infarcted myocardium. Of note, most of the previous studies have focused on the anti-angiogenesis capacity of melatonin in the tumor niche. To the best of our knowledge, few experiments highlighted the melatonin angiogenesis potential and specific regulatory mechanisms in the cardiovascular system. Here, we aimed to summarize some previous experiments
related to the application of melatonin in cardiovascular diseases such as ischemic
injury and hypertension by focusing on the regulatory mechanisms.
The COVID-19 pandemic has profoundly influenced public health and contributed to global economic divergences of unprecedented dimensions. Due to the high prevalence and mortality rates, it is then expected that the consequence and public health challenges will last for long periods. The rapid global spread of COVID-19 and lack of enough data regarding the virus pathogenicity multiplies the complexity and forced governments to react quickly against this pandemic. Stem cells represent a small fraction of cells located in different tissues. These cells play a critical role in the regeneration and restoration of injured sites. Because of their specific niche and a limited number of stem cells, the key question is whether there are different anti-viral mechanisms against viral infection notably COVID-19. Here, we aimed to highlight the intrinsic antiviral resistance in different stem cells against viral infection. These data could help us to understand the possible viral infections in different stem cells and the activation of specific molecular mechanisms upon viral entrance.
Graphical Abstract
Objectives
We will evaluate the efficacy and safety of Melatonin, compared to the standard therapeutic regimen on clinical symptoms and serum inflammatory parameters in patients with confirmed COVID-19, who are moderately ill.
Trial design
This is a single-center, randomized, double-blind, placebo-controlled clinical trial with a parallel-group design conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran.
Participants
All patients admitted to Severe Acute Respiratory Syndrome Departments of Shahid Mohammadi Hospital, Bandar Abbas, Iran will be screened for the following criteria.
Inclusion criteria :
1. Age ≥20 years
2. Confirmed SARS-CoV-2 diagnosis (positive polymerase chain reaction).
3. Moderate COVID-19 pneumonia (via computed tomography and or X-ray imaging), requiring hospitalization.
4. Hospitalized ≤48 hours.
5. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm.
Exclusion criteria :
1. Underlying diseases, including chronic hypertension, diabetes mellitus, seizure, depression, chronic hepatitis, cirrhosis, and cholestatic liver diseases.
2. Severe and critical COVID-19 pneumonia.
3. Use of warfarin, corticosteroids, hormonal drugs, alcohol, other antiviral and investigational medicines, and illegal drugs (during the last 30 days).
4. History of known allergy to Melatonin.
5. Pregnancy and breastfeeding.
Intervention and comparator
Intervention group : The standard treatment regimen for COVID-19, according to the Iranian Ministry of Health and Medical Education's protocol, along with Melatonin capsules at a dose of 50 mg daily for a period of seven days.
Control group : The standard therapeutic regimen for COVID-19 along with Melatonin-like placebo capsules at a dose of one capsule daily for a period of seven days.
Both Melatonin and placebo capsules were prepared at the Faculty of Pharmacy and Pharmaceutical Sciences, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
Main outcomes
The primary outcomes are the recovery rate of clinical symptoms and oxygen saturation as well as improvement of serum inflammatory parameters, including C-reactive protein, tumor necrosis factor-alpha (TNF-ɑ), interleukin-1β (IL-1β), and IL-6 within seven days of randomization.
The secondary outcomes are the time to improve clinical and paraclinical features along with the incidence of serious adverse drug reactions within seven days of randomization.
Randomization
Included patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). This randomization method ensures a balanced allocation between the arms during the study. A web-based system will generate random numbers for the allocation sequence and concealment of participants. Each number relates to one of the study arms.
Blinding (masking)
All study participants, clinicians, nurses, research coordinators, and those analyzing the data are blinded to the group assignment.
Numbers to be randomized (sample size)
A total of 60 patients randomized into two groups (30 in each group).
Trial Status
The trial protocol is Version 1.0, August 14, 2020. Recruitment began August 22, 2020, and is anticipated to be completed by November 30, 2020.
Trial registration
The trial protocol has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is “ IRCT20200506047323N5 ”. The registration date was 14 August 2020.
Full protocol
The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in 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.