Three human monocyte subsets are recognized with different functions in the immune system: CD14++/CD16- classical monocytes (CM), CD14++/CD16+ intermediate monocytes (IM) and CD14+/CD16++ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX3CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap.
Background: The assessment of renal function in clinical practice remains challenging. Using creatinine to assess the glomerular filtration rate (GFR) is notoriously inaccurate, and determination of the true GFR, e.g., using inulin or iohexol, is laborious and not feasible in daily practice. Proenkephalin (PENK) is a novel candidate biomarker for kidney function that is filtrated in the glomerulus, has shown to represent steady-state GFR in patients with different severities of renal insufficiency. In this pilot study in non-steady-state critically ill patients, we compared plasma PENK concentrations with creatinine-based GFR assessments and validated both against the “true GFR” measured using a gold standard method: iohexol plasma clearance. Methods: Twenty-three critically ill patients with septic shock were included. Kidney function was determined using the Modification of Diet in Renal Disease formula (eGFR MDRD ), Endogenous Creatinine Clearance (GFR ECC ), and iohexol plasma clearance (GFR iohexol ) during a 6-h window. Plasma PENK concentrations were measured using the penKid immunoassay. Results: The eGFR MDRD and GFR ECC correlated with the GFR iohexol ( R 2 = 0.82, P < 0.0001 and R 2 = 0.82, P < 0.0001 respectively); however, bias and variability were considerable: the eGFR MDRD overestimated the true GFR with 31 ± 35% (95% limits of agreement: −37% to 100%) and the GFR ECC with 37 ± 49% (95% limits of agreement: −59% to 133%). Plasma PENK concentrations showed a very strong inverse correlation with the GFR iohexol ( R 2 = 0.90, P < 0.0001) which tended to be better compared with the correlation of eGFR MDRD ( P = 0.06) and GFR ECC ( P = 0.08) with the GFR iohexol . Conclusions: In this pilot study in non-steady-state critically ill sepsis patients, GFR appears to be more accurately reflected by plasma PENK concentrations compared to conventional creatinine-based methods. Therefore, PENK holds promise as an accurate and feasible biomarker to determine kidney function during non-steady-state conditions in the critically ill.
Aims EA‐230 is a human chorionic gonadotropin hormone‐derived linear tetrapeptide, developed for the treatment of systemic inflammation‐related disorders. EA‐230 has shown promising immunomodulatory and tissue‐protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows‐up on these results by investigating the safety, efficacy and pharmacokinetics of EA‐230 under systemic inflammatory conditions induced by experimental human endotoxaemia. Methods In this randomized, double blind, placebo‐controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli‐derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2‐hour continuous infusion of EA‐230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12). Results EA‐230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA‐230 resulted in a significant attenuation of the LPS‐induced increase in plasma levels of inflammatory mediators interleukin (IL)‐6, IL‐8, IL‐1 receptor antagonist, monocyte chemoattractant protein‐1, macrophage inflammatory proteins‐1α and ‐1β, and vascular cell adhesion protein‐1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 ± 0.1°C to 1.3 ± 0.2°C, P < .05) and symptom scores (peak decrease from 7.4 ± 1.0 to 4.0 ± 1.2 points, P < .05). EA‐230 exhibited a very short elimination half‐life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12–0.24] hours and 2.2 [1.3–3.8] L/kg, respectively). Conclusion Administration of EA‐230 is safe and results in attenuation of the systemic inflammatory response in humans.
Aims EA‐230 is a newly developed synthetic linear tetrapeptide (AQGV) derived from the chorionic gonadotropin hormone (β‐hCG). We investigated the pharmacokinetics, safety and tolerability of EA‐230 in healthy subjects using different administration strategies. Methods Double‐blind, randomized, placebo‐controlled, dose‐escalating phase I studies in healthy subjects using intravenous administration were conducted. In the single dosage study, 32 subjects were assigned to four single dosage groups (1, 3, 10 or 30 mg/kg). In the multiple dosage study, 24 subjects were assigned to three dosage groups (10, 20 or 30 mg/kg, thrice daily for 3 days). In the continuous dosage study, 24 subjects were assigned to three dosage groups (15, 30, or 90 mg/kg/hour for 2 hours). Pharmacokinetics, safety and tolerability assessments were performed up to 14 days. Results The highest dosage of EA‐230 (continuous infusion of 90 mg/kg/hour for 2 hours) showed more than proportional increases in exposure (Cmax136%; AUC0‐last137%), a large volume of distribution (geometric mean and 95% CI: 13 [3–58] L/kg), a high clearance rate (26 [15–43] L/h/kg), and a short half‐life (0.35 [0.13–1.0] minutes). EA‐230 was well tolerated and no safety concerns were observed. Conclusion These dose‐escalating phase I studies with different administration strategies reveal a pharmacokinetic profile of EA‐230 with a large volume of distribution and a short half‐life. Furthermore, EA‐230 was well tolerated and no safety issues emerged. These results have enabled further clinical development in a phase IIa trial assessing the pharmacodynamics of this compound during systemic inflammation described elsewhere in this issue.
was observed for TNF-α (R 2 = 0.33, p = 0.0509) and IL-1RA (R 2 = 0.28, p = 0.08). None of the kidney injury markers or changes in blood pressure were associated with GFR iohexol. In multiple linear regression analysis, both peak IL-6 (p = 0.002) and IL-8 (p = 0.01) concentrations remained significantly correlated with GFR iohexol , without collinearity. Discussion: Concentrations of pro-inflammatory cytokines, but not blood pressure, are correlated with the endotoxemia-induced increase in GFR in healthy volunteers. These findings may indicate that inflammatory mediators orchestrate the augmented GFR observed in a subgroup of sepsis patients.
The extent of the systemic inflammatory response following infectious or noninfectious insults is related to impaired patient outcome. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230 is a newly developed synthetic linear tetrapeptide derived from the "pregnancy hormone" human chorionic gonadotropin. In this review, we describe the immunomodulatory and renoprotective properties of EA-230 in preclinical animal models, phase 1 studies in humans and phase 2a studies performed during human experimental endotoxemia. In addition, details pertaining to the design of a recently completed phase 2b study in 180 patients who underwent cardiac surgery to investigate the safety and immunomodulatory and renoprotective properties of EA-230 are discussed.
Background The cardiac surgery–induced systemic inflammatory response may induce postoperative hemodynamic instability and impairment of renal function. EA-230, a linear tetrapeptide (A-Q-G-V), is derived from the beta chain of the human chorionic gonadotropin pregnancy hormone. It has shown immunomodulatory and renoprotective effects in several animal models of systemic inflammation. In phase 1 and phase 2a studies, these immunomodulatory effects were confirmed during human experimental endotoxemia, and EA-230 was found to have an excellent safety profile. Objective The objective of this first in-patient study is to test the safety and tolerability as well as the immunomodulatory and renoprotective effects of EA-230 in a proof-of-principle design in patients with systemic inflammation following on-pump cardiac surgery. Methods We describe a prospective, randomized, double-blind, placebo-controlled study in which 180 elective patients undergoing on-pump coronary artery bypass grafting, with or without concomitant valve surgery, are enrolled. Patients will be randomized in a 1:1 ratio and will receive either EA-230 (90 mg/kg/hour) or a placebo. These will be infused at the start of the surgical procedure until the end of the use of the cardiopulmonary bypass. The primary focus of this first-in-patient study will be on safety and tolerability of EA-230. The primary efficacy end point is the modulation of the inflammatory response by EA-230 quantified as the change in interleukin-6 plasma concentrations after surgery. The key secondary end point is the effect of EA-230 on renal function. The study will be conducted in 2 parts to enable an interim safety analysis by an independent data monitoring committee at a sample size of 60. An adaptive design is used to reassess statistical power halfway through the study. Results This study has been approved by the independent competent authority and ethics committee and will be conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, and European Directive 2001/20/CE regarding the conduct of clinical trials. Results of this study will be submitted for publication in a peer-reviewed scientific journal. Enrollment of this study commenced in July 2016, and results are expected at the end of 2018. Conclusions This adaptive phase 2 clinical study is designed to test the safety and tolerability of EA-230 in patients undergoing cardiac surgery. In addition, efficacy end points focused on the effect of the systemic inflammatory response and renal function are investigated. Trial Registration ClinicalTrials.gov NCT03145220; https://clinicaltrials.gov/ct2/show/NCT03145220 (Archived by WebCite at http://www.webcitation.org/74JPh8GNN) International Registered Report Identifier (IRRID) DERR1-10.2196/11441
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.