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International Journal of Molecular... Oct 2023Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is...
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Topics: Rats; Animals; Epilepsy, Temporal Lobe; Pilocarpine; Lamotrigine; Lithium; Interleukin 1 Receptor Antagonist Protein; Anticonvulsants; Seizures; Hippocampus; Disease Models, Animal
PubMed: 37895080
DOI: 10.3390/ijms242015400 -
Functional & Integrative Genomics May 2023Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the...
Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis.
Topics: Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Interleukin 1 Receptor Antagonist Protein; Lymphangiogenesis; Lymphatic Metastasis; Matrix Metalloproteinase 9; NF-kappa B; Vascular Endothelial Growth Factor C
PubMed: 37198330
DOI: 10.1007/s10142-023-01049-5 -
Annual Review of Medicine 2014Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by... (Review)
Review
Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)-regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular "molecular sensor" that forms a multimolecular platform, the NLRP3 inflammasome, which links "danger recognition" to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Carrier Proteins; Hereditary Autoinflammatory Diseases; Humans; Inflammasomes; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; NLR Family, Pyrin Domain-Containing 3 Protein; Recombinant Fusion Proteins; Signal Transduction
PubMed: 24422572
DOI: 10.1146/annurev-med-061512-150641 -
Nature Medicine Oct 2021Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019... (Randomized Controlled Trial)
Randomized Controlled Trial
Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.
Topics: Aged; COVID-19; Double-Blind Method; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Placebos; Receptors, Urokinase Plasminogen Activator; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34480127
DOI: 10.1038/s41591-021-01499-z -
Current Rheumatology Reports Jun 2016SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often... (Review)
Review
SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often misdiagnosed and unrecognized. Its main features are prominent inflammatory cutaneous and articular manifestations. Treatments with immunosuppressive drugs have been used for the management of SAPHO with variable results. To date, the use of anti-TNF-α agents has proved to be an effective alternative to conventional treatment for unresponsive or refractory SAPHO cases. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β, IL-6, and IL-8, involved in inflammation, acute-phase response induction, and chemotaxis. IL-1 inhibition strategies with anakinra have shown efficacy as first and second lines of treatment. In this review, we will describe the main characteristics of biological drugs currently used for SAPHO syndrome. We also describe some of the promising therapeutic effects of ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and anakinra. We discuss the use and impact of the new anti-IL-1 antagonists involved in the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.
Topics: Acquired Hyperostosis Syndrome; Adalimumab; Biological Products; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Tumor Necrosis Factor-alpha; Ustekinumab
PubMed: 27108452
DOI: 10.1007/s11926-016-0583-y -
Hepatology (Baltimore, Md.) Oct 2022Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival.
APPROACH AND RESULTS
Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB.
CONCLUSIONS
A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.
Topics: Adrenal Cortex Hormones; Adult; End Stage Liver Disease; Female; Hepatitis, Alcoholic; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Methylprednisolone; Middle Aged; Pentoxifylline; Receptors, Interleukin-1; Severity of Illness Index; Zinc
PubMed: 35340032
DOI: 10.1002/hep.32478 -
Annals of Clinical and Translational... Jan 2022Refractory cerebral autoinflammatory-autoimmune diseases are often associated with dysregulated innate immunity and are targeted by anakinra, an interleukin-1 receptor...
Refractory cerebral autoinflammatory-autoimmune diseases are often associated with dysregulated innate immunity and are targeted by anakinra, an interleukin-1 receptor antagonist. We analyzed the therapeutic effect of anakinra in refractory cerebral autoinflammatory response (CAIR) at a single institution from January 2017 to May 2021. In total, 12 patients with various etiologies were sympathetically treated with anakinra (100 mg/day subcutaneously). Four patients showed good responses, and among these patients, three patients had pathologically demonstrated CAIR. The other eight patients were nonresponsive. No patient had a serious adverse effect. Thus, anakinra may be a therapeutic option for refractory cerebral autoinflammatory diseases.
Topics: Adult; Anti-Inflammatory Agents; Autoimmune Diseases of the Nervous System; Brain Diseases; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Neuroinflammatory Diseases; Recurrence; Treatment Outcome; Young Adult
PubMed: 35040583
DOI: 10.1002/acn3.51500 -
European Stroke Journal Sep 2023Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers.
METHODS
We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6).
FINDINGS
25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra.
CONCLUSION
We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.
Topics: Humans; Male; Aged; Female; Interleukin 1 Receptor Antagonist Protein; Cytokines; Interleukin-6; Cerebral Hemorrhage; Interleukin Inhibitors; Receptors, Interleukin-1; Interleukin-1
PubMed: 37452707
DOI: 10.1177/23969873231185208 -
Inflammopharmacology Apr 2023In COVID-19, severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm. In this study, we aimed... (Observational Study)
Observational Study
BACKGROUND
In COVID-19, severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm. In this study, we aimed to evaluate the high-dose intravenous anakinra treatment response and outcome in patients with severe and critically ill COVID-19 compared to standard of care.
METHODS
This retrospective observational study was carried out at a tertiary referral center. The study population consisted of two groups as follows: the patients receiving high-dose intravenous anakinra (anakinra group) between 01.09.2021 and 01.02.2022 and the patients treated with standard of care (SoC, control group) as historical control group who were hospitalized between 01.07.2021 and 01.09.2021.
RESULTS
After the propensity score 1:1 matching, 79 patients in anakinra and 79 patients in SoC matched and were included into the analysis. Mean ± SD patient age was 67.4 ± 16.7 and 67.1 ± 16.3 years in anakinra and SoC groups, respectively (p = 0.9). Male gender was 38 (48.7%) in anakinra and 36 (46.2%) in SoC (p = 0.8). Overall, ICU admission was in 14.1% (n = 11) and 30.8% (n = 24) (p = 0.013; OR 6.2), intubation in 12.8% (n = 10) and 16.7% (n = 13) patients (p = 0.5), and 14.1% (n = 11) and 32.1% (n = 25) patients died in anakinra and control groups, respectively (p = 0.008; OR 7.1).
CONCLUSION
In our study, mortality was lower in patients receiving anakinra compared to SoC. Intravenous high-dose anakinra is safe and effective treatment in patients with severe and critical COVID-19.
Topics: Humans; Male; Middle Aged; Aged; Aged, 80 and over; COVID-19; Interleukin 1 Receptor Antagonist Protein; SARS-CoV-2; Propensity Score; Retrospective Studies
PubMed: 36707494
DOI: 10.1007/s10787-023-01138-8 -
International Journal of Molecular... Apr 2022Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA)... (Review)
Review
Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.
Topics: Amyloidosis; Child; Colchicine; Familial Mediterranean Fever; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Serum Amyloid A Protein
PubMed: 35409316
DOI: 10.3390/ijms23073956