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1.
Int Immunopharmacol ; 109: 108805, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1814595

ABSTRACT

Pulmonary vascular endothelial dysfunction is a key pathogenic mechanism in acute respiratory distress syndrome (ARDS), resulting in fibrosis in lung tissues, including in the context of COVID-19. Pirfenidone (PFD) has become a novel therapeutic agent for treating idiopathic pulmonary fibrosis (IPF) and can improve lung function, inhibit fibrosis and inhibit inflammation. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play a crucial role in various respiratory diseases. However, the role of PFD in the course of EndMT in LPS-induced ARDS remains poorly understood. The purpose of this study was to explore the anti-EndMT effects of PFD on pulmonary fibrosis after LPS-induced ARDS. First, we determined that PFD significantly reduced LPS-induced ARDS, as shown by significant pathological alterations, and alleviated the oxidative stress and inflammatory response in vitro and in vivo. Furthermore, PFD decreased pulmonary fibrosis in LPS-induced ARDS by inhibiting EndMT and reduced the expression levels of Hedgehog (HH) pathway target genes, such as Gli1 and α-SMA, after LPS induction. In summary, this study confirmed that inhibiting the HH pathway by PFD could decrease pulmonary fibrosis by downregulating EndMT in LPS-induced ARDS. In conclusion, we demonstrate that PFD is a promising agent to attenuate pulmonary fibrosis following ARDS in the future.


Subject(s)
Hedgehog Proteins , Pulmonary Fibrosis , Pyridones , Respiratory Distress Syndrome , Animals , Hedgehog Proteins/metabolism , Lipopolysaccharides , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pyridones/pharmacology , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Signal Transduction
2.
Molecules ; 27(9)2022 Apr 24.
Article in English | MEDLINE | ID: covidwho-1810048

ABSTRACT

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Animals , Benzylisoquinolines , Biological Availability , Bleomycin/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chromatography, Liquid , Humans , Lung , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Rats , Tandem Mass Spectrometry , Transforming Growth Factor beta1/metabolism
3.
Nutrients ; 14(5)2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1732145

ABSTRACT

BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive, and, ultimately, terminal interstitial disease caused by a variety of factors, ranging from genetics, bacterial, and viral infections, to drugs and other influences. Varying degrees of PF and its rapid progress have been widely reported in post-COVID-19 patients and there is consequently an urgent need to develop an appropriate, cost-effective approach for the prevention and management of PF. AIM: The potential "therapeutic" effect of the tocotrienol-rich fraction (TRF) and carotene against bleomycin (BLM)-induced lung fibrosis was investigated in rats via the modulation of TGF-ß/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. DESIGN/METHODS: Lung fibrosis was induced in Sprague-Dawley rats by a single intratracheal BLM (5 mg/kg) injection. These rats were subsequently treated with TRF (50, 100, and 200 mg/kg body wt/day), carotene (10 mg/kg body wt/day), or a combination of TRF (200 mg/kg body wt/day) and carotene (10 mg/kg body wt/day) for 28 days by gavage administration. A group of normal rats was provided with saline as a substitute for BLM as the control. Lung function and biochemical, histopathological, and molecular alterations were studied in the lung tissues. RESULTS: Both the TRF and carotene treatments were found to significantly restore the BLM-induced alterations in anti-inflammatory and antioxidant functions. The treatments appeared to show pneumoprotective effects through the upregulation of antioxidant status, downregulation of MMP-7 and inflammatory cytokine expressions, and reduction in collagen accumulation (hydroxyproline). We demonstrated that TRF and carotene ameliorate BLM-induced lung injuries through the inhibition of apoptosis, the induction of TGF-ß1/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. Furthermore, the increased expression levels were shown to be significantly and dose-dependently downregulated by TRF (50, 100, and 200 mg/kg body wt/day) treatment in high probability. The histopathological findings further confirmed that the TRF and carotene treatments had significantly attenuated the BLM-induced lung injury in rats. CONCLUSION: The results of this study clearly indicate the ability of TRF and carotene to restore the antioxidant system and to inhibit proinflammatory cytokines. These findings, thus, revealed the potential of TRF and carotene as preventive candidates for the treatment of PF in the future.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Tocotrienols , Animals , Bleomycin/toxicity , Carotenoids/adverse effects , Humans , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/prevention & control , Rats , Rats, Sprague-Dawley , SARS-CoV-2 , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Tocotrienols/adverse effects , Transforming Growth Factor beta/metabolism
4.
Carbohydr Polym ; 273: 118567, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1363900

ABSTRACT

Diffuse alveolar injury and pulmonary fibrosis (PF) are the main causes of death of Covid-19 cases. In this study a low molecular weight fucoidan (LMWF) with unique structural was obtained from Laminaria japonica, and its anti- PF and anti-epithelial-mesenchymal transition (EMT) bioactivity were investigated both in vivo and in vitro. After LWMF treatment the fibrosis and inflammatory factors stimulated by Bleomycin (BLM) were in lung tissue. Immunohistochemical and Western-blot results found the expression of COL2A1, ß-catenin, TGF-ß, TNF-α and IL-6 were declined in mice lung tissue. Besides, the phosphorylation of PI3K and Akt were inhibited by LMWF. In addition, the progression of EMT induced by TGF-ß1 was inhibited by LMWF through down-regulated both TGF-ß/Smad and PI3K/AKT signaling pathways. These data indicate that unique LMWF can protect the lung from fibrosis by weakening the process of inflammation and EMT, and it is a promising therapeutic option for the treatment of PF.


Subject(s)
COVID-19/complications , Epithelial-Mesenchymal Transition/drug effects , Polysaccharides/administration & dosage , Polysaccharides/chemistry , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , SARS-CoV-2 , A549 Cells , Animals , Bleomycin/adverse effects , COVID-19/virology , Cell Survival/drug effects , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Cytokines/pharmacology , Disease Models, Animal , Humans , Inflammation/drug therapy , Lung/immunology , Male , Mice , Mice, Inbred C57BL , Molecular Weight , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/mortality , Signal Transduction/drug effects
5.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Article in English | MEDLINE | ID: covidwho-1283899

ABSTRACT

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors , Furin/metabolism , Lung/drug effects , Pulmonary Fibrosis/drug therapy , Animals , Bleomycin , Cells, Cultured , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Lung/metabolism , Lung/pathology , Male , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Treatment Outcome
6.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Article in English | MEDLINE | ID: covidwho-1242859

ABSTRACT

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors , Furin/metabolism , Lung/drug effects , Pulmonary Fibrosis/drug therapy , Animals , Bleomycin , Cells, Cultured , Disease Models, Animal , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Lung/metabolism , Lung/pathology , Male , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Treatment Outcome
7.
Stem Cell Res Ther ; 12(1): 230, 2021 04 12.
Article in English | MEDLINE | ID: covidwho-1192728

ABSTRACT

BACKGROUND: Pulmonary fibrosis (PF), the end point of interstitial lung diseases, is characterized by myofibroblast over differentiation and excessive extracellular matrix accumulation, leading to progressive organ dysfunction and usually a terminal outcome. Studies have shown that umbilical cord-derived mesenchymal stromal cells (uMSCs) could alleviate PF; however, the underlying mechanism remains to be elucidated. METHODS: The therapeutic effects of uMSC-derived extracellular vesicles (uMSC-EVs) on PF were evaluated using bleomycin (BLM)-induced mouse models. Then, the role and mechanism of uMSC-EVs in inhibiting myofibroblast differentiation were investigated in vivo and in vitro. RESULTS: Treatment with uMSC-EVs alleviated the PF and enhanced the proliferation of alveolar epithelial cells in BLM-induced mice, thus improved the life quality, including the survival rate, body weight, fibrosis degree, and myofibroblast over differentiation of lung tissue. Moreover, these effects of uMSC-EVs on PF are likely achieved by inhibiting the transforming growth factor-ß (TGF-ß) signaling pathway, evidenced by decreased expression levels of TGF-ß2 and TGF-ßR2. Using mimics of uMSC-EV-specific miRNAs, we found that miR-21 and miR-23, which are highly enriched in uMSC-EVs, played a critical role in inhibiting TGF-ß2 and TGF-ßR2, respectively. CONCLUSION: The effects of uMSCs on PF alleviation are likely achieved via EVs, which reveals a new role of uMSC-EV-derived miRNAs, opening a novel strategy for PF treatment in the clinical setting.


Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Pulmonary Fibrosis , Animals , Bleomycin/toxicity , Mice , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/therapy , Signal Transduction , Transforming Growth Factor beta/genetics , Transforming Growth Factors , Umbilical Cord
8.
Respir Res ; 22(1): 99, 2021 Apr 06.
Article in English | MEDLINE | ID: covidwho-1169963

ABSTRACT

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Hypoxia/drug therapy , Justicia , Lung/drug effects , Plant Extracts/pharmacology , Pneumonia/prevention & control , Pulmonary Fibrosis/drug therapy , Sepsis/drug therapy , Animals , Anti-Inflammatory Agents/isolation & purification , Bleomycin , COVID-19/metabolism , COVID-19/virology , Cecum/microbiology , Cecum/surgery , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Inflammation Mediators/metabolism , Justicia/chemistry , Ligation , Lung/metabolism , Lung/microbiology , Lung/pathology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Plant Extracts/isolation & purification , Pneumonia/genetics , Pneumonia/metabolism , Pneumonia/microbiology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA Interference , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Sepsis/genetics , Sepsis/metabolism , Sepsis/microbiology , Transcriptome
9.
Med Sci Monit ; 26: e927240, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-985826

ABSTRACT

BACKGROUND Infants and young children with acute respiratory distress syndrome (ARDS) have acute progressive hypoxic respiratory failure caused by a variety of extrapulmonary pathogenic factors and cardiogenic factors. Diffuse alveolar injury and pulmonary fibrosis both are pathological features of ARDS. This study investigated the effect of Rehmannia Radix extract (RRE) on pulmonary fibrosis of infants with ARDS. MATERIAL AND METHODS The human lung fibroblasts cell line HFL1 was treated with various concentrations of Rehmannia Radix extract in different groups for different times. Flow cytometry and TUNEL assay were performed to detect cell apoptosis, and CCK8 assay was utilized to analyze cell proliferation. TGF-ß1 expression was detected by real-time quantitative PCR, and protein-level expressions of Caspase3, TGF-ß1, Bcl-2, and Smad3 were measured by western blot and immunohistochemical staining in cells or tissues. TGF-ß1 was overexpressed by recombinant human TGF-ß1 (2 ng/mL) and the treated cells and culture supernatant were harvested for analysis in each step. Bleomycin was used to induce a mouse model of pulmonary fibrosis and was confirmed by HE pathological sections. RESULTS Flow cytometry and TUNEL results showed that RRE promoted the apoptosis of HFL1 cells in a concentration-dependent manner, and it inhibited the proliferation of HFL1 cells. Upregulation of TGF-ß1 reversed the effects of RRE in HFL1 cells. RRE alleviated pulmonary fibrosis in mice through downregulating Bcl-2, TGF-ß1, and Smad3 expression. CONCLUSIONS RRE promoted apoptosis and inhibited proliferation of HFL1, and then arrested the progression of pulmonary fibrosis. RRE had a significant inhibitory effect on TGF-ß1 and Smad3. These results suggest that RRE directly prevents the development of pulmonary fibrosis by affecting the expression of TGF-ß1 and Smad3.


Subject(s)
Plant Extracts/therapeutic use , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Rehmannia/chemistry , Transforming Growth Factor beta1/metabolism , Animals , Apoptosis/drug effects , Bleomycin , Cell Line , Cell Proliferation/drug effects , Disease Progression , Humans , Mice , Plant Extracts/pharmacology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology
10.
Phytother Res ; 35(2): 974-986, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-804475

ABSTRACT

Pulmonary fibrosis is a key feature of COVID-19, Chinese herbal medicine Arenaria kansuensis has been used for curing pulmonary disease and antivirus for a long time and it has the potential against COVID-19. In this work, protective effect of A. kansuensis ethanol extract (AE) on pulmonary fibrosis was evaluated through paraquat (PQ)-induced pulmonary fibrosis animal model. Results showed that AE could significantly improve the survival rate, increase the body weight and reduce the lung index of mice at the raw drug doses of 700 and 350 mg/kg. Histopathological observation results showed that the destruction degree of lung tissue structure in mice was significantly improved with the increase of AE dosage. Collagen deposition in lung interstitium was significantly reduced. The marker protein alpha-SMA involved in PF were significantly inhibited through repressing TGF-beta1/Smads pathway. The degree of inflammatory infiltration was significantly reduced and inflammatory cytokines were significantly inhibited in mice through inhibiting the NF-kB-p65. Besides, oxidant stress level including upregulated ROS and down-regulated SOD and GSH was efficiently improved by AE through upregulation of Nrf2 and downregulation of NOX4. In summary, this study firstly showed that the protective effect of AE on pulmonary fibrosis was partly due to activation of Nrf2 pathway and the inhibition of NF-kB/TGF-beta1/Smad2/3 pathway.


Subject(s)
Arenaria Plant/chemistry , Drugs, Chinese Herbal/pharmacology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Acute Lung Injury , Animals , Arenaria Plant/physiology , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Ethanol/chemistry , Female , Male , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Paraquat , Phytotherapy , Pulmonary Edema/drug therapy , Pulmonary Edema/pathology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Survival Rate , Transforming Growth Factor beta1/metabolism
11.
Carbohydr Polym ; 247: 116740, 2020 Nov 01.
Article in English | MEDLINE | ID: covidwho-635683

ABSTRACT

Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.


Subject(s)
Betacoronavirus , Biological Products/therapeutic use , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Polysaccharides/therapeutic use , Pulmonary Fibrosis/drug therapy , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Bleomycin/toxicity , COVID-19 , Disease Models, Animal , Drug Evaluation, Preclinical , Forkhead Box Protein O3/physiology , Fungi/chemistry , Heterogeneous Nuclear Ribonucleoprotein D0/physiology , Humans , Macrophages/drug effects , Medicine, Chinese Traditional , Mice , Neutrophils/drug effects , Phytotherapy , Plants, Medicinal/chemistry , Polysaccharides/pharmacology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/prevention & control , RNA, Long Noncoding/antagonists & inhibitors , Rats , SARS-CoV-2 , Seaweed/chemistry , Signal Transduction/drug effects , Smad2 Protein/physiology , Smad3 Protein/physiology , Transforming Growth Factor beta1/antagonists & inhibitors
12.
Br J Clin Pharmacol ; 87(3): 1533-1540, 2021 03.
Article in English | MEDLINE | ID: covidwho-635720

ABSTRACT

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/drug therapy , Adult , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Chemical and Drug Induced Liver Injury/epidemiology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Databases, Factual , Female , Humans , Male , Middle Aged , Monitoring, Physiologic , Odds Ratio , Pancreatitis/chemically induced , Pancreatitis/epidemiology , Pharmacovigilance , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/epidemiology , Retrospective Studies , United States , United States Food and Drug Administration , Young Adult
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