scholarly journals COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

2021 ◽  
Vol 10 ◽  
Author(s):  
Cirino Botta ◽  
Alessia Indrieri ◽  
Eugenio Garofalo ◽  
Flavia Biamonte ◽  
Andrea Bruni ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Molecular Mechanisms ◽  
Clinical Results ◽  
Point Of View ◽  
Janus Kinase ◽  
World Health ◽  
Cytokine Release ◽  
Graft Versus Host ◽  
Jak2 Inhibitor ◽  
Car T

Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.

scholarly journals Baricitinib in the Treatment of Patients with COVID-19: A Review of International Data and Analysis of Clinical Results in the Russian Population

2021 ◽  
Vol 66 (1-2) ◽  
pp. 47-56
Author(s):  
А. I. Zagrebneva ◽  
Е. А. Baryakh ◽  
Е. I. Zhelnova ◽  
N. G. Poteshkina ◽  
I. Р. Beloglazova ◽  
...  
Keyword(s):  
Clinical Results ◽  
Point Of View ◽  
Janus Kinase ◽  
Early Warning Score ◽  
Reversible Inhibitor ◽  
Clinical Use ◽  
Blood Oxygen Saturation ◽  
Mean Values ◽  
Average Value ◽  
Pathogenetic Therapy

The effects of baricitinib, a selective reversible inhibitor of Janus kinase 1 and 2, in the treatment of COVID-19 are associated with different aspects of pathogenesis — inhibition of viral endocytosis, reduction of excessive inflammatory response, and mitigation of vascular and pulmonary damage, which is a strong rationale for using baricitinib to treat patients with COVID-19. In the period from April to May 2020, City Clinical Hospital No. 52 obtained clinical experience of baricitinib clinical use in the therapy of 113 patients with COVID-19: 58 (51%) women and 55 (49%) men, whose average age was 57±12.6 years old. Analysis of the results of using baricitinib showed that therapy with baricitinib against the background of standard pathogenetic therapy was found to be effective in 95 (84%) patients and ineffective in 18 (16%). Significant positive changes were shown in comparison with the baseline level of the following indicators: body temperature (from 37.2±0.8˚C to 36, ±0.68˚C, P=0.000), blood oxygen saturation (from 95.5±3.0% to 96.5±2.2%, P=0.011), C-reactive protein (from 46.1±48.0 mg/L to 33.5±43.7 mg/L, P=0.010 ), National Early Warning Score (NEWS) (from 1.7±1.3 to 1.1±1.2, p=0.001). From the safety point of view, patients showed a slight decrease in the average value of the number of neutrophils — from (3.1±1.4)×109 to (3.0±2.0)×109 and lymphocytes — from (1.8±0,9)×109 to (1.7±0.9)×109, as well as minimal multidirectional changes in the mean values of transaminase activity — alanine aminotransferase changed from 33.9±23.6 U/L to 34.9±47.5 U/L, aspartate aminotransferase — from 40.6±49.0 U/L to 38.5±25.5 U/L. In general, the results obtained within the experience of the clinical use of baricitinib in 113 Russian patients with COVID-19 are consistent with the available data from foreign clinical studies and confirm the efficacy and safety of baricitinib.  

Flouride and Nitrate Status of Some Ground Waters in Chittor District of Rajasthan State (India)

2018 ◽  
Vol 6 (9) ◽  
pp. 119
Author(s):  
Trapti Sharma ◽  
R. P. Nagar ◽  
R. C. Gaur ◽  
Pooja Gupta ◽  
Charanjit Kaur
Keyword(s):  
Point Of View ◽  
World Health ◽  
Indian Council ◽  
Standard Methods ◽  
Ground Waters ◽  
Drinking Waters ◽  
Health Organization ◽  
Research World ◽  
Drinking Purpose

In Rajasthan state the ground waters of some areas like Ramganj-mandi, Morak, Barmer, Jaisalmer, Chittor and Udaipur etc. are susceptible from drinking point of view.To test the quality of groundwater in Chittor district 14, ground water samples were collected from various places and analyzed for pH, E.C., Fluoride and Nitrate parameters by standard methods (A.P.H. A., Washington, USA, 1995). The study revealed that none of the ground waters was found suitable completely from drinking point of view. Some are having electrical conductivity > 1.4 dS/m, some are having pH >8.5, some area having fluoride >1.5 ppm and some are having nitrate>45 ppm. These are the limits of various parameters permitted by various International authorities like Bureau of Indian Standard, Indian Council of Medical Research,world health Organization etc. for drinking waters. So, it is recommended to the residents of above areas to use water for drinking purpose only after reverse osmosis or adopting suitable method of removing excess of Fluoride and Nitrate for drinking water to avoid unwanted pathogenic diseases harmful for human health.

Natural products from the traditional Moroccan pharmacopoeia: A potential lead for the prevention and treatment of COVID-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1278-1285
Author(s):  
Mohamed Yafout ◽  
Amine Ousaid ◽  
Ibrahim Sbai El Otmani ◽  
Youssef Khayati ◽  
Amal Ait Haj Said
Keyword(s):  
Medicinal Plants ◽  
Plant Extracts ◽  
Molecular Mechanisms ◽  
Scientific Literature ◽  
Treatment Protocol ◽  
World Health ◽  
The World ◽  
Health Organization ◽  
Promising Source

The new SARS-CoV-2 belonging to the coronaviruses family has caused a pandemic affecting millions of people around the world. This pandemic has been declared by the World Health Organization as an international public health emergency. Although several clinical trials involving a large number of drugs are currently underway, no treatment protocol for COVID-19 has been officially approved so far. Here we demonstrate through a search in the scientific literature that the traditional Moroccan pharmacopoeia, which includes more than 500 medicinal plants, is a fascinating and promising source for the research of natural molecules active against SARS-CoV-2. Multiple in-silico and in-vitro studies showed that some of the medicinal plants used by Moroccans for centuries possess inhibitory activity against SARS-CoV or SARS-CoV-2. These inhibitory activities are achieved through the different molecular mechanisms of virus penetration and replication, or indirectly through stimulation of immunity. Thus, the potential of plants, plant extracts and molecules derived from plants that are traditionally used in Morocco and have activity against SARS-CoV-2, could be explored in the search for a preventive or curative treatment against COVID-19. Furthermore, safe plants or plant extracts that are proven to stimulate immunity could be officially recommended by governments as nutritional supplements.

scholarly journals Next Generation Sequencing for the Prediction of the Antibiotic Resistance in Helicobacter pylori: A Literature Review

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 437
Author(s):  
Ilaria Maria Saracino ◽  
Matteo Pavoni ◽  
Angelo Zullo ◽  
Giulia Fiorini ◽  
Tiziana Lazzarotto ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Next Generation Sequencing ◽  
Literature Review ◽  
Molecular Mechanisms ◽  
World Health ◽  
Next Generation ◽  
Culture Methods ◽  
Phenotypic Resistance ◽  
H Pylori ◽  
Generation Sequencing

Background and aims: Only a few antimicrobials are effective against H. pylori, and antibiotic resistance is an increasing problem for eradication therapies. In 2017, the World Health Organization categorized clarithromycin resistant H. pylori as a “high-priority” bacterium. Standard antimicrobial susceptibility testing can be used to prescribe appropriate therapies but is currently recommended only after the second therapeutic failure. H. pylori is, in fact, a “fastidious” microorganism; culture methods are time-consuming and technically challenging. The advent of molecular biology techniques has enabled the identification of molecular mechanisms underlying the observed phenotypic resistance to antibiotics in H. pylori. The aim of this literature review is to summarize the results of original articles published in the last ten years, regarding the use of Next Generation Sequencing, in particular of the whole genome, to predict the antibiotic resistance in H. pylori.Methods: a literature research was made on PubMed. The research was focused on II and III generation sequencing of the whole H. pylori genome. Results: Next Generation Sequencing enabled the detection of novel, rare and complex resistance mechanisms. The prediction of resistance to clarithromycin, levofloxacin and amoxicillin is accurate; for other antimicrobials, such as metronidazole, rifabutin and tetracycline, potential genetic determinants of the resistant status need further investigation.

scholarly journals Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuefei Jin ◽  
Wangquan Ji ◽  
Haiyan Yang ◽  
Shuaiyin Chen ◽  
Weiguo Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Endothelial Activation ◽  
World Health ◽  
Therapeutic Approaches ◽  
Inflammatory Reactions ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Implications ◽  
Endothelial Inflammation ◽  
The World ◽  
Health Organization

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

Nichts für Schönwetterkapitäne: CAR-T-Zellen – Immunonkologie trifft Intensivmedizin

2020 ◽  
Vol 41 (10) ◽  
pp. 673-679
Author(s):  
Jorge Garcia Borrega ◽  
Michael von Bergwelt-Baildon ◽  
Boris Böll
Keyword(s):  
Real World ◽  
Effector Cell ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Car T

Zusammenfassung CRS und ICANS als Nebenwirkung von CAR-T-Zellen Das Cytokine-Release-Syndrome (CRS) ist die häufigste Nebenwirkung einer CAR-T-Zell-Therapie und kann von leichtem Fieber bis zu einem Multiorganversagen führen. Pathophysiologisch kommt es beim CRS zu einem Zytokinsturm und trotz einer Therapie mit Tocilizumab sind refraktäre und tödliche Verläufe beschrieben. Die Symptome des Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) variieren von leichter Desorientiertheit bis zum lebensbedrohlichen Hirnödem. Die Pathophysiologie und Therapie des ICANS sind noch nicht ausreichend erforscht. Die Differenzialdiagnosen von CRS und ICANS sind komplex und umfassen neben Infektionen und Sepsis unter anderem auch eine Toxizität der vorhergehenden Therapie, ein Tumorlysesyndrom und nicht zuletzt einen Progress der Grunderkrankung. Ein klinischer oder laborchemischer Parameter zum sicheren Beweis oder Ausschluss eines CRS oder ICANS gibt es zum heutigen Zeitpunkt nicht. Intensivmedizinische Relevanz und potenzielle Entwicklungen der CAR-T-Zell-Therapie Erste Auswertungen von Real-world-Daten deuten auf eine höhere Rate an schweren Nebenwirkungen im Rahmen der CAR-T-Zell-Therapie als in den Zulassungsstudien hin. Für die Indikation r/r-DLBCL könnten schätzungsweise bis zu maximal 300 Patienten pro Jahr in Deutschland eine intensivmedizinische Betreuung im Rahmen der CAR-T-Zell-Therapie benötigen. Studien mit wesentlich häufigeren soliden Tumoren könnten die Patientenzahl drastisch erhöhen. Therapieziel bei CAR-T-Zell-Patienten und Entscheidungen bei Therapiezieländerung Aufgrund des neuen Therapiekonzepts kann ein Konflikt zwischen bislang palliativem Patientenkollektiv und nun möglicherweise langfristigen Remissionen entstehen. Eine frühzeitige Aufklärung über potenziell lebensbedrohliche Nebenwirkungen im Rahmen der Therapie und eine interdisziplinäre Besprechung der Therapieziele mit den Patienten ist entscheidend.

scholarly journals The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1346
Author(s):  
Priya Veluswamy ◽  
Max Wacker ◽  
Dimitrios Stavridis ◽  
Thomas Reichel ◽  
Hendrik Schmidt ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cardiovascular Complications ◽  
World Health ◽  
Endothelial Glycocalyx ◽  
Pathological State ◽  
Mediated Action ◽  
Cell Responses ◽  
Health Organization

The SARS-CoV-2 virus causing COVID-19 disease has emerged expeditiously in the world and has been declared pandemic since March 2020, by World Health Organization (WHO). The destructive effects of SARS-CoV-2 infection are increased among the patients with pre-existing chronic conditions and, in particular, this review focuses on patients with underlying cardiovascular complications. The expression pattern and potential functions of SARS-CoV-2 binding receptors and the attributes of SARS-CoV-2 virus tropism in a physio-pathological state of heart and blood vessel are precisely described. Of note, the atheroprotective role of ACE2 receptors is reviewed. A detailed description of the possible detrimental role of SARS-CoV-2 infection in terms of vascular leakage, including endothelial glycocalyx dysfunction and bradykinin 1 receptor stimulation is concisely stated. Furthermore, the potential molecular mechanisms underlying SARS-CoV-2 induced clot formation in association with host defense components, including activation of FXIIa, complements and platelets, endothelial dysfunction, immune cell responses with cytokine-mediated action are well elaborated. Moreover, a brief clinical update on patient with COVID-19 disease with underlying cardiovascular complications and those who had new onset of cardiovascular complications post-COVID-19 disease was also discussed. Taken together, this review provides an overview of the mechanistic aspects of SARS-CoV-2 induced devastating effects, in vital organs such as the heart and vessels.

scholarly journals Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice

2021 ◽  
Author(s):  
Giulia Bonaldo ◽  
Nicola Montanaro ◽  
AlbertoVaccheri ◽  
Domenico Motola
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Clinical Setting ◽  
Safety Profile ◽  
Antigen Receptor ◽  
The United States ◽  
Reporting Odds Ratio ◽  
Cytokine Release ◽  
Car T ◽  
Age Range

Abstract Purpose Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient’s own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting. Methods We performed a retrospective observational study, collecting all the reports in EU (EudraVigilance, EV) and US (FAERS) databases of ADRs regarding axicabtagene ciloleucel and tisagenlecleucel. Both descriptive and statistical analyses were performed, the latter by using Reporting Odds Ratio (ROR). Results A total number of 1426 reports of suspected ADRs were retrieved in EudraVigilance and FAERS. Patients’ reported age reflected the age range for which the drugs are approved (18–64 years for axicabtagene ciloleucel and patients aged under 25 years for tisagenlecleucel). The most reported event was cytokine release syndrome (CRS), 185 events for tisagenlecleucel and 462 for axicabtagene ciloleucel in FAERS and 137 and 498, respectively, in EudraVigilance. A disproportionality was found comparing axicabtagene ciloleucel with tisagenlecleucel for the above-mentioned event: EV ROR 2.47, 95% CI 2.22–2.74, FAERS 1.89, 1.70–2.10. Conclusion CRS represents the major problem with the administration of CAR-T therapies. Our analysis has not revealed new ADRs; however, it supports the safety profile of CAR-T with new data from real clinical setting.

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